CN107362439B

CN107362439B - Preparation method of drug-coated balloon catheter, drug-coated balloon catheter prepared by preparation method and application of drug-coated balloon catheter

Info

Publication number: CN107362439B
Application number: CN201710692366.3A
Authority: CN
Inventors: 赵丽晓; 张毅; 赵轩铖; 李京龙; 梁红梅
Original assignee: Lepu Medical Technology Beijing Co Ltd
Current assignee: Lepu Medical Technology Beijing Co Ltd
Priority date: 2017-08-14
Filing date: 2017-08-14
Publication date: 2020-09-01
Anticipated expiration: 2037-08-14
Also published as: CN107362439A

Abstract

The invention provides a preparation method of a drug-coated balloon catheter, the prepared drug-coated balloon catheter and application thereof, wherein the method comprises the following steps: preparing active drug seed crystals, and screening out seed crystals with the length of 1-3 mu m to prepare active drug seed crystal suspension; respectively adding the active drug solution and the additive solution into different channels of a spraying machine, mixing and atomizing at the nozzle tip of an ultrasonic nozzle of the spraying machine, spraying the mixture on the surface of the balloon dilatation catheter to obtain a drug coating with proper crystal size, and carrying out homogenization post-treatment to obtain the drug coating balloon catheter with more uniform crystals. The invention ensures that the drug coating and the saccule are firmly combined and the drug crystal is uniform and complete; the balloon can ensure that the drug loss is less in balloon preparation and in vivo delivery, the effective drug concentration entering the vascular wall of a diseased part is higher, the drug loading efficiency is higher, the in-situ stenosis or restenosis in the blood vessel is effectively treated, the risks of late thrombosis, restenosis and the like are reduced, and meanwhile positive reconstruction of the blood vessel can be formed.

Description

Preparation method of drug-coated balloon catheter, drug-coated balloon catheter prepared by preparation method and application of drug-coated balloon catheter

Technical Field

The invention belongs to the field of medical instruments, and particularly relates to a preparation method of a drug coating balloon catheter, the prepared drug coating balloon catheter and application thereof.

Background

The medicine balloon is a therapeutic balloon medicine release technology developed on the basis of interventional medical treatment such as balloon dilatation or balloon angioplasty, and the active medicine is coated on the surface of the balloon, and when the balloon reaches a diseased part, a blood vessel is dilated, and the active medicine is released when the balloon is contacted with the endothelial tissue of the blood vessel, so that the effects of prevention and treatment are achieved.

At present, more and more people are dedicated to the research of the drug balloon, more and more drug balloons and carrier technologies are disclosed, but not all the drug balloons can achieve good effects, and the factors influencing the effectiveness of the drug balloon mainly include the following points: 1) the firmness of the drug coating is that the drug balloon enters a human blood vessel through an interventional operation, and is subjected to blood flow scouring before reaching a lesion part, and the challenges of friction of catheters, guide wires, stenotic lesions and the like, and due to the reasons, many drug balloons cannot achieve an obvious treatment effect; 2) the carrier or the matrix, the medicines used by a plurality of medicine balloons are fat-soluble medicines, the bioavailability of the single fat-soluble medicine coating is low, the absorption is poor, the carrier or the matrix are generally substances with strong water solubility, the utilization rate of the medicines can be improved, and 3) the crystallization form of the active medicine has great influence on the absorption, retention time and the like of the active medicine in vivo, thereby influencing the treatment effect.

When preparing a drug balloon catheter, different coating techniques and preparation processes thereof may have great influence on the firmness of a drug coating, the bioavailability of a fat-soluble drug coating and the crystal morphology of an active drug, and the main preparation methods at present are a dipping method, a microinjection method and a spraying method.

CN103611212A discloses a preparation method of a drug balloon, which comprises the steps of carrying out hydrophilic treatment on a balloon, then coating paclitaxel on the balloon or directly rolling paclitaxel drug on the balloon to obtain a drug coating, wherein the size of drug crystals is 20-40 microns, so that the drug coating of the prepared drug coating balloon is not firmly bonded with the surface of the balloon, serious drug washout can be caused in the in-vivo delivery process, the drug loss is large, and the problems of large drug crystal size, uneven drug coating and the like exist.

CN104922735A discloses a preparation method of a drug balloon, which comprises the following steps: (1) preparing a particle coating on the surface of the balloon, wherein the particle coating is made of sodium chloride, calcium chloride or urea, (2) placing the balloon with the particle coating in a medicine solution, crystallizing the medicine on the surface of the particle coating to form a medicine coating, taking the balloon out of the medicine solution, and drying to obtain the medicine balloon. The inorganic salt is coated on the surface of the balloon in a dip-coating mode, so that the layer is uneven, and meanwhile, the inorganic salt is very easy to dissolve when entering human blood, so that a medicine layer on the inorganic salt is very easy to fall off; and because the inorganic salt layer is coated with a layer firstly instead of being mutually soluble with the active medicament solution, the nucleation effect of the contact surface is insufficient, so that the crystallization effect of the active medicament is limited.

CN106620887A discloses a method for producing a drug balloon, which adopts a multiple spraying technique to spray a drug solution on the surface of the balloon layer by layer, and performs solvent vapor treatment on the drug coating at 76 ℃. Multilayer spraying is beneficial to controlling the supersaturation degree of a medicine solution and the volatilization speed of a solvent thereof, thereby being helpful for the formation of crystals of an active medicine, but can reduce the overall firmness of a medicine coating; and the solvent steam treatment under heating, recrystallization is separated out after the medicine on the surface of the balloon is amorphized, and the binding force between the original medicine coating and the balloon body of the balloon can be completely destroyed, so that the firmness of the medicine coating is poorer.

Therefore, in the art, it is desirable to develop a drug balloon catheter with small and uniform active drug particle size and good coating firmness to avoid the active drug component being washed off during delivery.

Disclosure of Invention

Aiming at the defects of the prior art, the invention aims to provide a preparation method of a drug coating balloon catheter, the prepared drug coating balloon catheter and application thereof.

In order to achieve the purpose, the invention adopts the following technical scheme:

in one aspect, the present invention provides a method of making a drug-coated balloon catheter, the method comprising the steps of:

(1) preparing seed crystals of the active drug, screening out seed crystals with the length of 1-3 mu m, and preparing active drug seed crystal suspension;

(2) respectively adding the active drug seed crystal suspension, the active drug solution and the additive solution into different channels of a spraying machine, mixing and atomizing at the nozzle tip of an ultrasonic nozzle of the spraying machine, and spraying the mixture on the surface of a balloon to obtain the balloon dilatation catheter with a drug coating on the surface;

(3) and (3) carrying out homogenization post-treatment on the balloon dilatation catheter with the drug coating on the surface obtained in the step (2) to obtain the drug coating balloon catheter.

According to the invention, the drug coating can be firmly combined on the surface of the balloon dilatation catheter by the preparation method, and the drug crystals in the obtained drug-coated balloon catheter are small and uniform.

In the invention, the atomized liquid medicine is sprayed by using compressed gas by the ultrasonic spraying process, so that liquid medicine particles can be flushed to the surface of the balloon at a certain speed, and the binding force between the medicine coating and the balloon is better, and the firmness of the medicine coating can be better ensured compared with other medicine coating modes.

In the invention, the crystal seeds of the active medicament are required to be utilized to induce the crystallization precipitation of the active medicament, so that small and uniform medicament microcrystals are obtained on the surface of the balloon dilatation catheter, and the additive is used in the preparation method disclosed by the invention, so that the crystallization of the active medicament is enhanced together with the crystal seeds of the active medicament, the crystal particles of the active medicament are more uniform, and the firmness of the combination of the medicament coating and the balloon can be enhanced.

The size (i.e., length) of the seed crystals of the active drug described in step (1) in the present invention is selected to be 1 μm to 3 μm, for example, 1 μm, 1.3 μm, 1.5 μm, 1.8 μm, 2 μm, 2.2 μm, 2.4 μm, 2.6 μm, 2.8 μm or 3 μm. The invention screens the optimum interval of the crystal seed size of the active drug through a large number of tests, and the interval is matched with the technical scheme of the invention: if the length of the seed crystal is less than 1 μm, the crystal of the active drug may be incompletely crystallized, while if the length of the seed crystal is more than 3 μm, the active drug may be preferentially grown on a part of the crystal, and the crystal size may vary.

Preferably, the preparation method of the seed crystal of the active drug in the step (1) comprises the following steps: adding an active drug into an organic solvent a, and dissolving the drug by adopting an ultrasonic or heating mode to obtain a supersaturated solution of the active drug; and (3) carrying out evaporative crystallization, cooling crystallization or a mode of adding ice water for rapid cooling and rapid stirring on the supersaturated solution to obtain the crystal seed of the active drug.

Preferably, the supersaturated solution has a concentration of from 30mg/mL to 65mg/mL, for example 30mg/mL, 33mg/mL, 35mg/mL, 38mg/mL, 40mg/mL, 45mg/mL, 48mg/mL, 50mg/mL, 53mg/mL, 55mg/mL, 58mg/mL, 60mg/mL or 65 mg/mL.

Preferably, the preparation method of the active drug seed suspension in the step (1) comprises the following steps: adding the active drug seed crystal into the solvent b for dispersion to obtain the active drug seed crystal suspension.

Preferably, the concentration of the active drug seed suspension is between 0.1mg/mL and 1mg/mL, such as 0.1mg/mL, 0.3mg/mL, 0.5mg/mL, 0.8mg/mL or 1mg/mL, preferably 0.6 mg/mL.

Preferably, the solvent b is, but not limited to, purified water and/or deionized water.

Preferably, a suspending agent is added into the seed crystal suspension;

preferably, the suspending agent is, but not limited to, any one or a combination of at least two of glycerin, syrup, sorbitol, gums, sodium alginate, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium cellulose sulfate, sodium hydroxyethylcellulose, aluminum stearate, or colloidal magnesium aluminum silicate.

Preferably, the method for screening out the seed crystal with the length of 1-3 μm in the step (1) is a screening method, a sedimentation method or an electron microscope method.

In the invention, the active drug seed crystal suspension, the active drug solution and the additive solution are respectively added into different channels of the spraying machine in the step (2), wherein the active drug and the additive solution can be prepared to obtain a mixed solution of the active drug and the additive, that is, the active drug and the additive are dissolved in an organic solvent c to obtain a mixed solution of the active drug and the additive, and then the mixed solution and the active drug seed crystal suspension are respectively added into different channels of the spraying machine, or the active drug solution is dissolved in an organic solvent d to obtain an active drug solution, the additive is dissolved in an organic solvent e to obtain an additive solution, and then the two solutions and the active drug solution are respectively added into different channels of the spraying machine.

Preferably, the active drug is paclitaxel.

Preferably, the weight ratio of the active drug to the additive in step (2) is 1: 0.1-20, such as 1:0.1, 1:0.3, 1:0.5, 1:1, 1:3, 1:5, 1:8, 1:10, 1:13, 1:15, 1:18 or 1:20, preferably 1: 0.3-1.

Preferably, the concentration of the active pharmaceutical solution of step (2) is 1mg/mL to 50mg/mL, such as 1mg/mL, 3mg/mL, 5mg/mL, 8mg/mL, 10mg/mL, 15mg/mL, 18mg/mL, 20mg/mL, 25mg/mL, 28mg/mL, 30mg/mL, 35mg/mL, 38mg/mL, 40mg/mL, 45mg/mL, 48mg/mL or 50mg/mL, preferably 15mg/mL to 35 mg/mL.

Preferably, the additive solution of step (2) has a concentration of 1mg/mL to 20mg/mL, such as 1mg/mL, 3mg/mL, 5mg/mL, 8mg/mL, 10mg/mL, 12mg/mL, 15mg/mL, 18mg/mL or 20mg/mL, preferably 5mg/mL to 15 mg/mL.

Preferably, the additive is any one or a combination of at least two of urea, iopromide, polysorbate, polyethylene glycol, ethylene glycol glucoside, alkyl glycoside, meglumine, pectin, mannitol, methyl cellulose, vinyl cellulose, hydroxypropyl cellulose, mannitol, or acetamide.

Preferably, the preparation material of the balloon dilatation catheter is any one or the combination of at least two of nylon, nylon elastomer Pebax or polyethylene.

Preferably, the organic solvent a, the organic solvent c, the organic solvent d and the organic solvent e are independently any one or a combination of at least two of methanol, ethanol, ethyl acetate, diethyl ether, acetonitrile, acetone, hexane, isopropanol, dichloromethane, tetrahydrofuran, ethyl formate or methyl acetate.

Preferably, the mixed solution is atomized into small medical liquid particles of 10 to 20 μm (e.g., 10, 12, 14, 16, 18, or 20 μm) at the nozzle of the ultrasonic nozzle in step (2). In the small liquid medicine particles, active medicine microcrystals are used as seed crystals to induce the active medicine to crystallize and separate out in the process of supersaturation crystal separation.

In the invention, the active drug seed crystal suspension, the active drug solution and the additive solution in the step (2) are respectively injected into a drug balloon ultrasonic spraying device, the active drug solution/additive solution is ultrasonically atomized into small drug solution particles of 10-20 μm at the tip of a nozzle, the drug components in the small drug solution particles are mixed with active drug microcrystals, the active drug microcrystals are used as seed crystals in the drug solution to induce the crystallization of the active drug, and finally the drug coating with small and uniform active drug crystal particle size is prepared.

Preferably, the ultrasonic nozzle in the step (2) has more than 3 nozzles, wherein one nozzle located at the middle position is a 99.99% high purity nitrogen gas channel/filtered compressed air channel.

Preferably, the pressure of the high-purity nitrogen gas or the filtered compressed air is 0.01MPa to 0.20MPa, such as 0.01MPa, 0.02MPa, 0.04MPa, 0.06MPa, 0.08MPa, 0.1MPa, 0.13MPa, 0.15MPa, 0.18MPa or 0.2 MPa.

Preferably, the ultrasonic generator power of the coating machine in the step (2) is 0.8W-5.0W, such as 0.8W, 1W, 1.3W, 1.5W, 1.8W, 2W, 2.5W, 2.8W, 3W, 3.5W, 3.8W, 4W, 4.5W, 4.8W or 5W.

Preferably, the rate of advance of the active pharmaceutical solution and the additive solution in the spray coater of step (2) is independently 0.01mL/min to 0.50mL/min, e.g., 0.01mL/min, 0.03mL/min, 0.05mL/min, 0.08mL/min, 0.1mL/min, 0.15mL/min, 0.18mL/min, 0.2mL/min, 0.25mL/min, 0.3mL/min, 0.35mL/min, 0.4mL/min, 0.45mL/min, or 0.5 mL/min.

In the present invention, when the active drug and the additive are prepared as described above to obtain the active drug solution and the additive solution, respectively, the active drug solution and the additive solution are added to different channels of the spray coater and their advancing speeds are controlled to be 0.01mL/min to 0.50mL/min, respectively, and when the active drug and the additive are prepared as described above to obtain a mixed solution of the two, they are added to different channels of the spray coater and their advancing speeds are controlled to be 0.01mL/min to 0.50 mL/min.

Preferably, the seed suspension in the spray coater of step (2) is advanced at a rate of 0.03mL/min to 0.20mL/min, such as 0.03mL/min, 0.05mL/min, 0.08mL/min, 0.1mL/min, 0.15mL/min, 0.18mL/min, or 0.2 mL/min.

Preferably, the balloon dilatation catheter is longitudinally advanced at a speed of 1-20 mm/s (e.g., 1-20 mm/s, 3-5 mm/s, 8-10 mm/s, 13-15 mm/s, 18-20 mm/s) and axially rotated at a speed of 1-20 rpm (e.g., 1-20 rpm, 3-5 rpm, 8-8 rpm, 10-13 rpm, 15-18 rpm, or 20 rpm) during the ultrasonic spraying of step (2).

Preferably, the distance between the ultrasonic spray head in the step (2) and the surface of the balloon dilatation catheter is 0.5 cm-3 cm, such as 0.5cm, 0.8cm, 1cm, 1.3cm, 1.5cm, 1.8cm, 2cm, 2.3cm, 2.5cm, 2.8cm or 3 cm.

Preferably, the homogenization post-treatment in the step (3) is to perform steam treatment on the balloon dilatation catheter with the drug coating on the surface in a post-treatment tool of a spraying machine by using an organic solvent for 0.5-2 h, such as 0.5h, 0.8h, 1h, 1.2h, 1.4h, 1.6h, 1.8h or 2 h. Then taking out, and carrying out the subsequent production processes of conduit welding, packaging box sterilization and the like.

In the invention, the homogenization post-treatment is normal-temperature treatment, and heating is not needed; during the homogenization post-treatment, the drug coating crystals continue to grow but are not allowed to recrystallize, and the aim of not recrystallizing can be achieved by controlling the conditions as described above.

Preferably, the organic solvent used in the homogenization post-treatment is any one of methanol, ethanol, ethyl acetate, diethyl ether, acetonitrile, acetone, hexane, isopropanol, dichloromethane, tetrahydrofuran, ethyl formate or methyl acetate or a combination of at least two thereof.

In another aspect, the invention provides a drug-coated balloon catheter prepared by the preparation method, which comprises a balloon dilatation catheter and a drug coating coated on the surface of the balloon dilatation catheter, wherein the drug coating comprises active drug crystals and the additive.

The drug coating balloon catheter prepared by the method has small and uniform active drug crystal granularity, is not easy to wash off in the conveying process, has higher effective drug concentration entering the vascular wall of a lesion part, and has higher drug loading efficiency.

Preferably, the active drug crystals have a length of 50nm to 20 μm, such as 50nm, 60nm, 80nm, 100nm, 300nm, 500nm, 800nm, 1 μm, 3 μm, 5 μm, 8 μm, 10 μm, 13 μm, 15 μm, 18 μm or 20 μm. Preferably 500nm to 10 μm. In the invention, the crystal length of the active drug cannot be too large, otherwise the combination of the active drug on the surface of the balloon dilatation catheter is not firm enough, and the drug loss is easily caused in the preparation and in-vivo transportation processes, so that the drug amount entering a diseased part is reduced, and the bioavailability of the active drug is reduced due to the excessively large crystal, and the effectiveness of the drug balloon catheter is reduced.

Preferably, the drug coating has a thickness of 0.5 μm to 15 μm, such as 0.5 μm, 1 μm, 3 μm, 5 μm, 7 μm, 9 μm, 10 μm, 12 μm, 14 μm or 15 μm, preferably 2 to 10 μm. If the drug coating is too thin, the effective tissue drug concentration of the active drug is not achieved; if the drug coating is too thick, it is more likely to be lost by blood flow scouring, and the "effective" drug loading concentration of the catheter cannot be guaranteed.

Preferably, the drug-loading dose on the surface of the balloon dilatation catheter is 1-6 mu g/mm²E.g. 1. mu.g/mm²、1.5μg/mm²、1.8μg/mm²、2μg/mm²、2.3μg/mm²、2.5μg/mm²、2.8μg/mm²、3μg/mm²、3.5μg/mm²、3.8μg/mm²、4μg/mm²、4.5μg/mm²、4.8μg/mm²、5μg/mm²、5.3μg/mm²、5.5μg/mm²、5.8μg/mm²Or 6. mu.g/mm²。

The drug coating balloon catheter prepared by the preparation method can enhance the bonding firmness of the drug coating and the surface of the balloon catheter, the drug coating is uniform and complete, and the drug-loading dose on the surface of the balloon dilatation catheter is increased.

In another aspect, the present invention provides the use of a drug-coated balloon catheter as described above as a device for treating in situ stenosis or restenosis within a blood vessel.

Compared with the prior art, the invention has the following beneficial effects:

the preparation method can firmly combine the drug coating on the surface of the balloon dilatation catheter, and ensure that the drug crystals in the obtained drug-coated balloon catheter are small and uniform, thereby ensuring that the drug coating on the surface of the balloon catheter is not easy to wash off in the conveying process in a human body, having higher drug loading efficiency, leading the effective drug concentration entering the vascular wall of a lesion part to be larger, improving the drug utilization degree and reducing the toxic and side effects.

Drawings

FIG. 1 is a schematic view of an ultrasonic spray process of the present invention;

FIG. 2 is a scanning electron microscope image of the drug coating in the drug-coated balloon catheter prepared according to the present invention, with a scale of 20 μm;

FIG. 3 is a schematic representation of the homogenization post-treatment of the present invention;

FIG. 4 is a schematic diagram of the overall structure of a pulsating flow simulation device used in an in vitro pulsating flow simulation test for drug coating firmness; wherein 1 is a plunger pump, 2, 9 and 10 are one-way valves, 3 and 8 are liquid path buffer devices, 4 is a proportional valve, 5 is a flowmeter, 6 is a vascular stent test model, and 7 is a pressure sensor.

Detailed Description

The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.

Example 1

In this example, the drug-coated balloon catheter was prepared by the following preparation method:

(1) adding paclitaxel as active drug into ethanol as organic solvent, and dissolving with ultrasound or heating to obtain supersaturated solution of active drug, wherein the concentration of the supersaturated solution is 30 mg/mL; obtaining seed crystals of the active medicament by evaporating and crystallizing the supersaturated solution, screening out the seed crystals with the length of 1-3 mu m by adopting a screening method, adding the seed crystals of the active medicament and a suspending agent glycerol into purified water and/or physiological saline for dispersion, and preparing an active medicament seed crystal suspension, wherein the concentration of the active medicament seed crystal suspension is 0.6 mg/mL;

(2) respectively adding the active drug seed crystal suspension, an active drug solution (obtained by dissolving an active drug in ethanol) and an additive polysorbate solution (obtained by dissolving additive polysorbate in ethanol) into different channels of a spraying machine, mixing and atomizing at the nozzle tip of an ultrasonic nozzle of the spraying machine, and spraying the mixture onto the surface of a balloon dilatation catheter (the balloon dilatation catheter is made of nylon) to obtain the balloon dilatation catheter with a drug coating on the surface; wherein the weight ratio of the active medicament to the additive is 1:1, the concentration of the active medicament solution is 15mg/mL, and the concentration of the additive solution in the step (2) is 10 mg/mL;

fig. 1 is a schematic diagram of an ultrasonic spraying process, in which the mixed solution is atomized into small drug solution particles of 10 to 20 μm at the nozzle of the ultrasonic nozzle, the ultrasonic nozzle has more than 3 nozzles, wherein one nozzle located at the middle position is a 99.99% high purity nitrogen channel/filtered compressed air channel, the pressure of the high purity nitrogen or filtered compressed air is 0.01MPa, the ultrasonic generator power of the spraying machine is 1.0W, the advancing speeds of the active drug solution and the additive solution in the spraying machine are both 0.03mL/min, the advancing speed of the active drug seed crystal suspension is 0.03mL/min, the longitudinal advancing speed of the balloon dilatation catheter during the ultrasonic spraying is 5mm/s, and the axial rotation speed is 10 rpm.

(3) And (3) carrying out steam treatment on the balloon dilatation catheter with the drug coating on the surface obtained in the step (2) for 1h by using an organic solvent in a post-treatment tool of a spraying machine to obtain the drug coating balloon catheter.

The uniform post-treatment is as shown in figure 3, only the balloon body part of the balloon is treated, and the process is carried out at normal temperature, and the process is simple and easy to implement. But the organic solvent amount in the tool is ensured to be consistent, and the stability of the prepared balloon drug coating is ensured.

The drug coating balloon catheter prepared by the method comprises a balloon dilatation catheter and a drug coating coated on the surface of the balloon dilatation catheter, wherein the drug coating comprises active drug crystals and additives, the active drug crystals are 500 nm-5 mu m in length, the thickness of the drug coating is 2-10 mu m, and the drug loading dose on the surface of the balloon dilatation catheter prepared by the method is 3 mu g/mm²。

The balloon dilatation catheter prepared by the method is subjected to splitting and folding of the balloon body, then is pressed to the nominal pressure of the catheter, and the scanning electron microscope is used for carrying out appearance characterization on the drug coating on the surface of the catheter, as shown in figure 2. The medicine coating has good firmness, is complete and uniform, and has no chapping and falling off phenomena; the length range of the crystal in the drug coating is 4-9 μm, which is very uniform. The clinical safety and the effectiveness of the medicine can be fully ensured from the two points.

Example 2

(1) adding paclitaxel as active drug into ethanol as organic solvent, and dissolving with ultrasound or heating to obtain supersaturated solution of active drug, wherein the concentration of the supersaturated solution is 40 mg/mL; performing evaporative crystallization, cooling crystallization or rapid cooling by adding ice water and rapid stirring on the supersaturated solution to obtain seed crystals of the active medicament, screening out the seed crystals with the length of 1-3 mu m by adopting a screening method, and adding the seed crystals of the active medicament and sorbitol serving as a suspending agent into purified water and/or physiological saline for dispersion to prepare active medicament seed crystal suspension, wherein the concentration of the active medicament seed crystal suspension is 1 mg/mL;

(2) respectively adding the active drug seed crystal suspension, an active drug solution (obtained by dissolving an active drug in ethanol) and an additive urea solution (obtained by dissolving additive urea in ethanol) into different channels of a spraying machine, mixing and atomizing at the nozzle tip of an ultrasonic nozzle of the spraying machine, and spraying the mixture on the surface of a balloon dilatation catheter (the balloon dilatation catheter is made of nylon) to obtain the balloon dilatation catheter with a drug coating on the surface; wherein the weight ratio of the active medicament to the additive is 1:0.1, the concentration of the active medicament solution is 10mg/mL, and the concentration of the additive solution in the step (2) is 5 mg/mL;

as shown in fig. 1, the ultrasonic spraying process is a schematic diagram, wherein the mixed solution is atomized into small drug solution particles of 10 μm to 20 μm at the nozzle of the ultrasonic spray head, the ultrasonic spray head has more than 3 nozzles, wherein one nozzle at the middle position is a 99.99% high purity nitrogen channel or a filtered compressed air channel, the pressure of the high purity nitrogen or the filtered compressed air is 0.20MPa, the ultrasonic generator power of the spraying machine is 3.0W, the advancing speed of the active drug solution and the additive solution in the spraying machine is 0.5mL/min, the advancing speed of the active drug seed crystal suspension is 0.1mL/min, the longitudinal advancing speed of the balloon dilatation catheter during the ultrasonic spraying is 1mm/s, and the axial rotating speed is 20 rpm.

The drug-coated balloon catheter prepared by the preparation method comprises a balloon dilatation catheter and a drug-coated balloon dilatation catheter coated on the surface of the balloon dilatation catheterThe drug coating comprises an active drug paclitaxel crystal and the additive, the length of the active drug crystal is 5-10 mu m, the thickness of the drug coating is 0.5-5 mu m, and the drug-loading dose on the surface of the balloon dilatation catheter prepared by the method is 5 mu g/mm²。

Example 3

(1) adding an active drug into an organic solvent a, and dissolving the drug by adopting an ultrasonic or heating mode to obtain a supersaturated solution of the active drug, wherein the concentration of the supersaturated solution is 65 mg/mL; carrying out evaporative crystallization, cooling crystallization or rapid cooling by adding ice water and rapid stirring on the supersaturated solution to obtain seed crystals of the active medicament, screening out the seed crystals with the length of 1-3 mu m by adopting a screening method, adding the seed crystals of the active medicament and sodium cellulose sulfate serving as a suspending agent into purified water and/or physiological saline for dispersion, and preparing an active medicament seed crystal suspension, wherein the concentration of the active medicament seed crystal suspension is 0.1 mg/mL;

(2) respectively adding the active drug seed crystal suspension, an active drug solution (obtained by dissolving an active drug in an organic solvent) and an additive solution (obtained by dissolving an additive in an organic solvent) into different channels of a spraying machine, mixing and atomizing at the nozzle tip of an ultrasonic nozzle of the spraying machine, and spraying the mixture on the surface of a balloon dilatation catheter (the balloon dilatation catheter is prepared from a nylon elastomer Pebax) to obtain the balloon dilatation catheter with a drug coating on the surface; wherein the weight ratio of the active medicament to the additive is 1:20, the concentration of the active medicament solution is 1mg/mL, and the concentration of the additive solution in the step (2) is 1 mg/mL;

as shown in fig. 1, the ultrasonic spraying process is a schematic diagram, wherein the mixed solution is atomized into small drug solution particles of 10 μm to 20 μm at the nozzle of the ultrasonic spray head, the ultrasonic spray head has more than 3 nozzles, wherein one nozzle located at the middle position is a 99.99% high purity nitrogen channel or a filtered compressed air channel, the pressure of the high purity nitrogen or the filtered compressed air is 0.1MPa, the ultrasonic generator power of the spraying machine is 0.8W, the advancing speed of the active drug solution and the additive solution in the spraying machine is 0.01mL/min, the advancing speed of the active drug seed crystal suspension is 0.05mL/min, the longitudinal advancing speed of the balloon dilatation catheter during the ultrasonic spraying is 1mm/s, and the axial rotation speed is 1 r/s.

The drug coating balloon catheter comprises a balloon dilatation catheter and a drug coating coated on the surface of the balloon dilatation catheter, the drug coating comprises active drug microcrystals and additives, the length of active drug crystals is 50 nm-3 mu m, the thickness of the drug coating is 3 mu m-10 mu m, and the drug loading dose on the surface of the balloon dilatation catheter obtained through preparation is 6 mu g/mm²。

Example 4

(1) adding paclitaxel as active drug into acetone as organic solvent, and dissolving with ultrasound or heating to obtain supersaturated solution of active drug, wherein the concentration of the supersaturated solution is 50 mg/mL; performing evaporative crystallization, cooling crystallization or rapid cooling by adding ice water and rapid stirring on the supersaturated solution to obtain seed crystals of the active medicament, screening out the seed crystals with the length of 1-3 mu m by adopting a screening method, and adding the seed crystals of the active medicament and sodium carboxymethyl cellulose serving as a suspending agent into purified water and/or physiological saline for dispersion to prepare active medicament seed crystal suspension, wherein the concentration of the active medicament seed crystal suspension is 0.5 mg/mL;

(2) respectively adding the active drug seed crystal suspension, an active drug solution (obtained by dissolving an active drug in acetone) and an additive solution (obtained by dissolving additive polyethylene glycol in acetone) into different channels of a spraying machine, mixing and atomizing at the nozzle tip of an ultrasonic nozzle of the spraying machine, and spraying the mixture on the surface of a balloon dilatation catheter to obtain the balloon dilatation catheter with a drug coating on the surface (the balloon dilatation catheter is made of polyethylene); wherein the weight ratio of the active medicament to the additive is 1:10, the concentration of the active medicament solution is 40mg/mL, and the concentration of the additive solution in the step (2) is 20 mg/mL;

as shown in fig. 1, the ultrasonic spraying process is a schematic diagram, wherein the mixed solution is atomized into small drug solution particles of 10 μm to 20 μm at the nozzle of the ultrasonic spray head, the ultrasonic spray head has more than 3 nozzles, wherein one nozzle at the middle position is a 99.99% high purity nitrogen channel or a filtered compressed air channel, the pressure of the high purity nitrogen or the filtered compressed air is 0.20MPa, the ultrasonic generator power of the spraying machine is 5.0W, the advancing speed of the active drug solution and the additive solution in the spraying machine is 0.50mL/min, the advancing speed of the active drug seed crystal suspension is 0.2mL/min, the longitudinal advancing speed of the balloon dilatation catheter during the ultrasonic spraying is 20mm/s, and the axial rotating speed is 20 rpm.

(3) And (3) carrying out steam treatment on the balloon dilatation catheter with the drug coating on the surface obtained in the step (2) for 0.5-2 h in a post-treatment tool of a spraying machine by using an organic solvent to obtain the drug coating balloon catheter.

The drug coating balloon catheter comprises a balloon dilatation catheter and a drug coating coated on the surface of the balloon dilatation catheter, the drug coating comprises active drug microcrystals and additives, the length of the active drug microcrystals is 10-20 mu m, the thickness of the drug coating is 10-15 mu m, and the drug loading dose on the surface of the balloon dilatation catheter is obtained through preparation and is 1 mu g/mm²。

Example 5

(1) adding paclitaxel as an active drug into acetonitrile as an organic solvent, and dissolving the drug by adopting an ultrasonic or heating mode to obtain a supersaturated solution of the active drug, wherein the concentration of the supersaturated solution is 30mg/mL mg/mL; performing evaporative crystallization, cooling crystallization or rapid cooling by adding ice water and rapid stirring on the supersaturated solution to obtain seed crystals of the active medicament, screening out the seed crystals with the length of 1-3 mu m by adopting a screening method, and adding the seed crystals of the active medicament, sodium cellulose sulfate serving as a suspending agent and sodium hydroxyethyl cellulose into purified water and/or physiological saline for dispersion to prepare active medicament seed crystal suspension, wherein the concentration of the active medicament seed crystal suspension is 0.6 mg/mL;

(2) respectively adding the active drug seed crystal suspension, an active drug solution (obtained by dissolving an active drug in acetonitrile) and an additive solution (obtained by dissolving additive methyl cellulose and hydroxypropyl cellulose in acetonitrile) into different channels of a spraying machine, mixing and atomizing at the nozzle tip of an ultrasonic nozzle of the spraying machine, and spraying the mixture on the surface of a balloon dilatation catheter to obtain the balloon dilatation catheter with a drug coating on the surface (the preparation material of the balloon dilatation catheter is nylon); wherein the weight ratio of the active medicament to the additive is 1:3, the concentration of the active medicament solution is 15mg/mL, and the concentration of the additive solution in the step (2) is 8 mg/mL;

as shown in fig. 1, the ultrasonic spraying process is a schematic diagram, wherein the mixed solution is atomized into small drug solution particles of 10 μm to 20 μm at the nozzle of the ultrasonic spray head, the ultrasonic spray head has more than 3 nozzles, wherein one nozzle at the middle position is a 99.99% high purity nitrogen channel or a filtered compressed air channel, the pressure of the high purity nitrogen or the filtered compressed air is 0.08MPa, the ultrasonic generator power of the spraying machine is 1.0W, the advancing speed of the active drug solution and the additive solution in the spraying machine is 0.2mL/min, the advancing speed of the active drug seed crystal suspension is 0.15mL/min, the longitudinal advancing speed of the balloon dilatation catheter during the ultrasonic spraying is 15mm/s, and the axial rotating speed is 8 r/s.

The drug coating balloon catheter comprises a balloon dilatation catheter and a drug coating coated on the surface of the balloon dilatation catheter, the drug coating comprises active drug microcrystals and additives, and the active drug microcrystals are 50nm in length3 mu m, the thickness of the drug coating is 0.5 to 8 mu m, and the drug-loading dose on the surface of the balloon dilatation catheter prepared by the method is 2 mu g/mm²。

Comparative example 1

Different from the embodiment 1, the method is characterized in that the seed crystal of the active drug is not added, namely, the active drug solution and the additive solution are directly mixed in the preparation process, and then the obtained mixed solution is ultrasonically sprayed on the surface of the balloon dilatation catheter by adopting an ultrasonic nozzle of a spraying machine to obtain the balloon dilatation catheter with the drug coating on the surface; and carrying out homogenization post-treatment on the obtained balloon dilatation catheter with the drug coating on the surface to obtain the drug coating balloon catheter. Otherwise, the selection of the other conditions was the same as in example 1.

Comparative example 2

The difference from example 1 is that no additive solution is used and the remaining preparation methods and conditions are selected as in example 1.

Test 1: in-vitro pulsation simulation test for firmness of drug coating

The coating firmness of the drug-coated balloon catheters prepared in examples 1-5 and comparative examples 1-2 was evaluated by in vitro simulation, by: 10 pieces of the drug-coated balloon catheters prepared in the examples 1-5 and the comparative examples 1-2, which are 3.0 x 35mm in specification, are split and folded according to the same process parameters, and then sheathed with a protective sleeve for later use.

Adopting a pulsating flow simulation device to simulate the action of the drug coating saccule on the pulsating flow of the blood vessel in vitro (the device controls the systolic pressure of 130mmHg and the diastolic pressure of 80mmHg at the frequency of 75 times/minute), and then testing the residual drug content on the surface of the drug coating saccule by using a High Performance Liquid Chromatography (HPLC); and collecting the solution in the equipment, carrying out a particle test experiment, and detecting the firmness of the drug delamination on the surface of the balloon after the simulated pulsating flow effect. Fig. 4 is a schematic diagram of the overall structure of the device for simulating pulsating flow in the experiment.

Wherein, the external pulsating flow simulation is carried out on a laminar flow purification table, and the glass instrument and other required samples are clean and have no particles; the method for determining the content of the residual drug on the surface of the drug coating balloon comprises the following steps: the drug content of paclitaxel in the test sample is calculated by injecting the test sample solution and the reference solution respectively according to HPLC (appendix V D of the second part (2010 version) of the pharmacopoeia of the people's republic of China). The particle test was carried out according to the relevant regulations in appendix IX "insoluble particle inspection method" of the second part of pharmacopoeia 2005 edition of the people's republic of China.

The results obtained when tested according to the above method are shown in table 1.

TABLE 1 in vitro pulsating flow simulation test results

And (3) testing 2: testing drug balloon effectiveness in animals

10 balloon catheters with drug coatings prepared in examples 1-5 and comparative examples 1-2, each with the specification of 3.0 x 35mm, are split and folded according to the same process parameters, and then sheathed with a protective sleeve for standby. And carrying out small experimental porcine coronary vessel interventional experiments to research the in vivo safety and effectiveness of each group. The specific animal experiment method is as follows: each pig carries out the expansion of the drug balloon on the right coronary, anterior descending branch and circumflex branch of the coronary vessel by an interventional method, the expansion ratio is 1.1-1.2: 1 (balloon/artery), and the expansion time is 60 s. Drug balloon delivery procedure (HPLC), entry into coronary vascular tissue (HPLC-MS) and balloon surface drug residue after opening (HPLC) were determined.

TABLE 2 results of in vivo experiments in animals

As can be seen from table 1, the drug-coated balloon catheters of the present invention, after in vitro pulsatile flow simulation experiments, had average drug loss significantly lower for examples 1-5 (average 2.5%) than for comparative examples 1-2 (average 22.0%); fewer drug particles are shed, indicating that the drug coating of the invention has high bonding strength with the balloon. As can be seen from table 2, the average drug loss during surgery in animals is significantly lower for examples 1-5 (average 4.3%) than for comparative examples 1-2 (average 22.3%).

Through comprehensive analysis of the experimental results (table 1 and table 2), it can be seen that the in vitro pulsating flow simulation and the in vivo animal result of the drug balloon are consistent to prove that the drug balloon has less scouring loss drug amount (within 10%) compared with the comparative example, and the particle size test proves that the drug balloon has less fallen particles and no large particles, thereby proving that the drug coating has better firmness; at the same time, the tissue drug concentration C in vivo_maxThe invention also proves that more drugs enter the tissues, less drugs remain on the saccule, and more drugs can enter the vascular tissues at the pathological change position, so that the clinical safety (reducing the risks of immediate and late thrombosis) and the effectiveness (effectively inhibiting restenosis) are ensured.

The applicant states that the present invention is illustrated by the above embodiments of the drug-coated balloon catheter and the preparation method and application thereof, but the present invention is not limited to the above embodiments, i.e. it does not mean that the present invention must be implemented by the above embodiments. It will be apparent to those skilled in the art that any modification of the present invention, equivalent substitutions of selected materials and additions of auxiliary components, selection of specific modes and the like, which are within the scope and disclosure of the present invention, are contemplated by the present invention.

Claims

1. A method for preparing a drug-coated balloon catheter, the method comprising the steps of:

(2) respectively adding the active drug seed crystal suspension, the active drug solution and the additive solution into different channels of a spraying machine, mixing and atomizing the active drug seed crystal suspension, the active drug solution and the additive solution into small drug liquid particles of 10-20 microns at the nozzle tip of an ultrasonic nozzle of the spraying machine, and spraying the small drug liquid particles on the surface of the balloon in a single layer at one time to obtain the balloon dilatation catheter with the drug coating on the surface;

(3) carrying out homogenization post-treatment on surface crystals on the balloon dilatation catheter with the drug coating on the surface obtained in the step (2) to obtain the drug coating balloon catheter;

the homogenization post-treatment in the step (3) is normal-temperature treatment without heating; the drug coating crystals continue to grow during the homogenization post-treatment, but no recrystallization is allowed to occur.

2. The method of claim 1, wherein the seed crystals of the active drug of step (1) are prepared by: adding an active drug into an organic solvent a, and dissolving the drug by adopting an ultrasonic or heating mode to obtain a supersaturated solution of the active drug; and (3) carrying out evaporative crystallization, cooling crystallization or a mode of adding ice water for rapid cooling and rapid stirring on the supersaturated solution to obtain the crystal seed of the active drug.

3. The method of claim 2, wherein the active agent is paclitaxel.

4. The method of claim 2, wherein the supersaturated solution has a concentration of from 30mg/mL to 65 mg/mL.

5. The preparation method according to claim 2, wherein the organic solvent a is any one or a combination of at least two of methanol, ethanol, ethyl acetate, diethyl ether, acetonitrile, acetone, hexane, isopropanol, dichloromethane, tetrahydrofuran, ethyl formate and methyl acetate.

6. The method for preparing the active pharmaceutical ingredient suspension of claim 1, wherein the active pharmaceutical ingredient suspension of step (1) is prepared by: adding the active drug seed crystal into the solvent b for dispersion to obtain the active drug seed crystal suspension.

7. The method of claim 1, wherein the active drug seed suspension is at a concentration of 0.1mg/mL to 1 mg/mL.

8. The method of claim 1, wherein the active drug seed suspension is at a concentration of 0.6 mg/mL.

9. The method according to claim 6, wherein the solvent b is purified water and/or deionized water.

10. The method of claim 1, wherein a suspending agent is added to the seed suspension.

11. The method of claim 10, wherein the suspending agent is any one or a combination of at least two of glycerin, syrup, sorbitol, gum, sodium alginate, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, sodium cellulose sulfate, sodium hydroxyethyl cellulose, aluminum stearate, and colloidal magnesium aluminum silicate.

12. The method according to claim 1, wherein the method for screening out the seed crystal having a length of 1 μm to 3 μm in step (1) is a screening method, a sedimentation method or an electron microscopy method.

13. The method according to claim 1, wherein the concentration of the active pharmaceutical agent solution in the step (2) is 1mg/mL to 50 mg/mL.

14. The method of claim 1, wherein the concentration of the active pharmaceutical agent solution of step (2) is 15mg/mL to 35 mg/mL.

15. The method according to claim 1, wherein the concentration of the additive solution in the step (2) is 1mg/mL to 20 mg/mL.

16. The method according to claim 1, wherein the concentration of the additive solution in the step (2) is 5mg/mL to 15 mg/mL.

17. The method according to claim 1, wherein the additive is any one or a combination of at least two of urea, iopromide, polysorbate, polyethylene glycol, ethylene glycol glucoside, alkyl glycoside, meglumine, pectin, mannitol, methyl cellulose, vinyl cellulose, hydroxypropyl cellulose, mannitol, and acetamide.

18. The method according to claim 1, wherein the ultrasonic nozzle of step (2) has more than 3 nozzles, and one of the nozzles located at the center is a 99.99% high purity nitrogen gas passage or a filtered compressed air passage.

19. The method according to claim 18, wherein the pressure of the high-purity nitrogen gas or the filtered compressed air is 0.01 to 0.20 MPa.

20. The method of claim 1, wherein the ultrasonic generator of the coating machine of step (2) has a power of 0.8W to 5.0W.

21. The method of claim 1, wherein the active pharmaceutical solution and the additive solution are independently propelled at a rate of 0.01mL/min to 0.50mL/min in the spray coater of step (2).

22. The method according to claim 1, wherein the seed suspension is advanced at a speed of 0.03mL/min to 0.20mL/min in the spray coater of step (2).

23. The manufacturing method according to claim 1, wherein, in the ultrasonic spraying of the step (2), the longitudinal advancing speed of the balloon dilatation catheter is 1-20 mm/s and the axial rotating speed is 1-20 rpm.

24. The preparation method according to claim 1, wherein the distance between the ultrasonic spray head in the step (2) and the surface of the balloon dilatation catheter is 0.5 cm-3 cm.

25. The preparation method according to claim 1, wherein the homogenization post-treatment in the step (3) is to perform steam treatment on the balloon dilatation catheter with the drug coating on the surface in a post-treatment tool of a spraying machine by using an organic solvent for 0.5 to 2 hours.

26. The method according to claim 25, wherein the organic solvent is any one or a combination of at least two of methanol, ethanol, ethyl acetate, diethyl ether, acetonitrile, acetone, hexane, isopropanol, dichloromethane, tetrahydrofuran, ethyl formate, and methyl acetate.

27. The method of claim 25, wherein the organic solvent is methanol or ethanol.

28. The drug-coated balloon catheter prepared by the preparation method according to any one of claims 1 to 27, wherein the drug-coated balloon catheter comprises a balloon dilatation catheter and a drug coating coated on the surface of the balloon dilatation catheter, and the drug coating comprises active drug crystals and additives.

29. The drug-coated balloon catheter of claim 28, wherein the active drug crystals have a length of 50nm to 20 μ ι η.

30. The drug-coated balloon catheter of claim 28, wherein the active drug crystals have a length of 500nm to 10 μ ι η.

31. The drug-coated balloon catheter of claim 28, wherein the drug coating has a thickness of 0.5-15 μ ι η.

32. The drug-coated balloon catheter of claim 28, wherein the drug coating has a thickness of 2-10 μm.

33. The drug-coated balloon catheter of claim 28, wherein the drug-loaded dose on the surface of the balloon dilatation catheter is 1-6 μ g/mm²。

34. The drug-coated balloon catheter of claim 28, wherein the balloon dilation catheter is made of any one or a combination of at least two of nylon, nylon elastomer Pebax, and polyethylene.