WO2020258834A1

WO2020258834A1 - Drug-eluting balloon catheter and preparation method therefor

Info

Publication number: WO2020258834A1
Application number: PCT/CN2020/071050
Authority: WO
Inventors: 张海军; 周超; 宋彩霞; 张军伟; 冯相蓺
Original assignee: 山东瑞安泰医疗技术有限公司
Priority date: 2019-06-27
Filing date: 2020-01-09
Publication date: 2020-12-30
Also published as: CN110292701B; CN110292701A

Abstract

A drug-eluting balloon catheter and a preparation method therefor. The drug is composed of drug microsphere particles of different particle sizes. The surface of the drug microsphere particles is coated with a phospholipid. The drug coating consists of two parts: a coating close to the balloon is composed of a phospholipid-coated drug and a hydrophilic excipient, and an outermost coating is composed of a hydrophobic or amphiphilic excipient. The outer coating reduces the resistance against the balloon when it passes through a blood vessel to a target lesion, and reduces drug loss during delivery. The coating close to the balloon promotes rapid release of the drug from the surface of the balloon and absorption by a target blood vessel, and the drug diffused to the adventitia can be continuously released to surrounding tissues to inhibit long-term restenosis. The drug-eluting balloon catheter has good application prospects in interventional therapy.

Description

Drug eluting balloon catheter and preparation method thereof

Technical field

The invention relates to the field of medical devices, in particular to a drug-eluting balloon catheter used for angioplasty and a preparation method thereof.

Background technique

Since Gruntzig first clinically applied percutaneous coronary intervention (PCI) in 1977, intravascular restenosis has been the main focus of treatment debate. The application of drug-eluting stents effectively solves this problem and reduces the restenosis rate of the target vessel to below 3%. However, in-stent restenosis caused by drug-eluting stents is extremely difficult to deal with. If a drug-eluting stent is placed again, the probability of secondary restenosis is as high as 43%, and patients treated with drug-eluting stents need to take longer Dual antiplatelet drugs prevent thrombosis in the stent; in addition, PCI is not ideal for the treatment of small blood vessels, bifurcated vessels, and in situ lesions. In recent years, with the increasing incidence of coronary heart disease in my country and the increasing level of medical technology, more and more patients are receiving cardiac interventional therapy. According to statistics from the Quality Control Center for Coronary Heart Disease Interventional Therapy of the National Health and Family Planning Commission and the National Cardiovascular Disease Center, the number of PCI operations in my country has increased from 454,500 in 2013 to 915,300 in 2018. In addition, compared with developed countries and regions, the number of PCI operations per capita in my country is still lagging behind, indicating that China's PCI device market has great potential in the future. As the number of PCI operations increases year by year, the number of patients with in-stent restenosis is also increasing.

At present, the methods used for restenosis include: simple balloon re-expansion, atherectomy, rotational atherectomy, intravascular radiotherapy and repeated stent implantation, etc. The existing bare balloon and drug stent There are certain limitations. The restenosis rate of naked balloons is relatively high, and the therapeutic effect of drug stents on small blood vessels and bifurcated vessels is not good, neither of which shows its ideal effectiveness or safety.

The emergence of the drug-eluting balloon (DEB for short) has brought new hope for solving restenosis. Drug-coated balloon catheters are coated with a layer of drug on the balloon surface of the balloon catheter, and can currently be used to treat in-stent restenosis and small vessel disease. After the drug coating on the surface of the balloon reaches the target lesion, it is eluted from the surface of the balloon and released to the blood vessel of the lesion.

The drug utilization of the drug-eluting balloon is mainly affected by two aspects: drug delivery and drug release. Studies have shown that more than 70% of the drug in the drug balloon is lost in the process of balloon delivery. In addition to the loss of the drug during the delivery process, the drug cannot be completely released during the short-term expansion of the balloon (within 60 seconds). After the operation, about 5%-10% of the drug will remain on the surface of the balloon.

Chinese patent application CN201610808118.6 discloses a drug balloon. A protective film with several sealing gaps is added to the drug coating to avoid the loss of the drug during delivery. The sealing gap of the protective film can be opened when the balloon is expanded. , So that the drug is exposed on the blood vessel wall, so that the drug is released from the gap to improve the utilization rate of the drug. However, since most of the drug coating area is still enclosed in the protective film when the balloon is expanded, it is isolated and cannot directly contact the blood vessel wall. A too small contact area will also adversely affect the release of the drug.

Chinese patent application CN201110176942.1 introduces a method for preparing drug balloons by electrostatic self-assembly, which covers balloons of different materials with drug coatings through the self-assembly method. Due to the large number of cycles of electrostatic self-assembly, the amount of drug can be controlled by layer-by-layer stacking. However, as the surface charge gradually decreases after three times, the drug amount and binding force of the outer layer assembly show a downward trend.

Chinese patent application CN201711399181.X introduces a drug balloon with nanometer and/or micrometer excipient particles and drug particles. A hydrophobic coating with a certain viscosity is used to increase the drug coating and the balloon and coating. The binding force between the layer particles reduces the loss of the drug during the delivery process. However, the adhesion between the hydrophobic coating and the surface of the balloon is relatively large, and the drug is not easily transferred to the tissue during the contact between the balloon and the target diseased tissue.

The key technical point of the drug balloon is how to achieve the bonding balance between the drug coating and the balloon surface and increase the tissue absorption of the drug in a short time. If the adhesive force between the drug coating and the balloon surface is small, the drug is likely to fall off during the balloon folding process, or it is easy to lose during the delivery process when placed in the lesion, or expand before contact with the target tissue In the process, it is easy to break off and be washed away by the high-speed flow of blood. If the adhesive force between the drug coating and the balloon surface is large, the drug will not be easily transferred to the tissue during the contact between the balloon and the target diseased tissue. Therefore, the pharmaceutical preparation must be firmly attached to the surface of the balloon catheter until it reaches the target site, and then quickly released and absorbed by the tissue.

Summary of the invention

In view of the above-mentioned shortcomings of the prior art, it is necessary to develop targeted coatings for drug balloons, which can deliver most of the active drugs to the target lesion area in the clinical process. The balloon catheter should quickly release the active drug at the target lesion site. The active drug should penetrate the target tissue quickly. The purpose of the present invention is to provide a balloon catheter with a rapid drug release coating, which is used to deliver active drugs to the target lesion site. The drug is released in a very short period of time and quickly penetrates into the tissue at the diseased site, thereby improving the drug Absorption in target diseased tissues. The absorbed drugs are distributed in different vascular wall structures according to their particle size. Large-diameter drugs are preferentially distributed in the inner membrane, and small-sized drugs are preferentially distributed in the outer membrane. The mini-drug storage is continuously released into the tissue to exert its efficacy and inhibit long-term restenosis.

In order to achieve the above objective, the present invention provides a method for preparing a drug eluting balloon catheter, which includes the following steps:

(1) Dissolve the drug or the mixture of the drug and the degradable polymer material in an organic solvent, add the resulting solution dropwise to an aqueous solution containing an emulsifier, use the pelletizing method to make the drug form microspheres, and centrifuge to remove large particles Granules, take the supernatant to obtain the drug microsphere suspension;

(2) Disperse at least one drug microsphere suspension with different particle size ranges obtained according to the method of step (1) into an aqueous solution containing phospholipids and excipient I;

(3) First use ultrasonic spraying or dip coating to apply the solution of step (2) to the surface of the balloon, then use the ultrasonic spraying method to spray the solution of excipient II on the surface of the balloon, and finally vacuum dry the balloon. Obtain drug-eluting balloon catheters containing drugs of different particle sizes.

In step (1), the drug is a fat-soluble drug, and the fat-soluble drug is a macrolide immunosuppressant, a macrolide antibiotic, rapamycin, a structural derivative of rapamycin, One or more of everolimus, structural derivatives of everolimus, paclitaxel, and structural derivatives of paclitaxel. After the drug is dissolved in the organic solvent, the concentration in the organic solvent is 1 mg/ml-500 mg/ml.

In step (1), the degradable polymer material is polylactide-glycolide (PDLGA), polylactide-caprolactone (PLACL), monomethoxypolyethylene glycol polyracemic One or more of lactic acid glycolic acid copolymer (MPEG-PDLGA), polyethylene glycol polyracemic lactic acid glycolic acid copolymer (PDLGA-PEG-PDLGA) and polytrimethylene carbonate (PTMC). The intrinsic viscosity of the degradable polymer material is in the range of 0.1-2.0 dl/g, and the concentration of the degradable polymer material in the organic solvent is 1 mg/ml-500 mg/ml.

In step (1), the organic solvent is one or more of acetone, dichloromethane, chloroform, ethyl acetate and tetrahydrofuran.

In step (1), the emulsifier is one or more of polyvinyl alcohol, polysorbate 20, polysorbate 80, and vitamin E polyethylene glycol succinate. In the aqueous solution containing the emulsifier, the concentration of the emulsifier is 0.5%-10% (mass fraction).

In step (1), the spheroidizing methods include phacoemulsification, high-speed homogenization, membrane emulsification, micelles, etc., through these methods, the drug can be formed into microspheres of different particle sizes. In the present invention, the range of the particle size of the drug microspheres is 15nm-7μm, and the microspheres exceeding this range are removed by centrifugal filtration.

In step (2), the phospholipid is one of soybean lecithin, egg yolk lecithin, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, diphosphatidylglycerol (cardiolipin), phosphatidylinositol and sphingomyelin, or Many kinds. The concentration of phospholipid in the final solution formed in step (2) (a mixture of drug microsphere suspension and an aqueous solution containing phospholipid and excipient I) is 0.2%-3.0% (mass fraction).

In step (2), the excipient I is a hydrophilic excipient. The hydrophilic excipient is one or more of iopromide, iohexol, ioverol, urea and polyethylene glycol; the final solution formed by excipient I in step (2) (drug The concentration of the microsphere suspension and the aqueous solution containing the phospholipid and excipient I) is 0.01%-10% (mass fraction).

In step (2), the volume ratio of the suspension of drug microspheres with different particle size ranges to the aqueous solution containing phospholipids and excipient I is 1:0.1-1:1.

In step (2), the suspension of drug microspheres with different particle size ranges means that the particle sizes of the microspheres in the suspension are not completely the same. Preferably, drug microspheres smaller than 300 nm and drug microspheres larger than or equal to 300 microns are present in the suspension.

In step (3), the excipient II is a hydrophobic excipient or an amphiphilic excipient. The hydrophobic excipient is any one or two of butyryl tri-n-hexyl citrate and shellac, and the amphiphilic excipient is one of dextran, polysorbate and sorbitol. Kind or more. In the solution of excipient II, the concentration range of excipient II is 0.01%-10% (mass fraction). The solvent for dissolving the hydrophobic excipient is one or more of diethyl ether, n-hexane, petroleum ether, ethanol, propanol, ethyl acetate, dichloromethane and acetone.

In step (3), the drug concentration of the finally obtained drug eluting balloon catheter is 1 μg/mm ² -10 μg/mm ² .

Compared with the prior art, the present invention has at least the following advantages and beneficial effects:

(1) The drug particles in the drug eluting balloon catheter of the present invention exist in the form of drug microspheres of different particle sizes, and the small size nanospheres (<300nm) have strong penetrating ability and can diffuse to the adventitia of the artery wall Among them, they act as micro-drug reservoirs, which are continuously released into the tissues to exert their efficacy and inhibit long-term restenosis; large-size drug microspheres diffuse into the intima and media to inhibit intimal hyperplasia;

(2) The drug particles in the drug eluting balloon catheter of the present invention are wrapped by phospholipids, and a phospholipid bilayer similar to the cell membrane is formed on the outside of the drug. The drug is absorbed by the blood vessel wall, which overcomes the shortcomings of the drug being washed away by the high-speed blood flow before being absorbed by the blood vessel tissue;

(3) The coating in the drug-eluting balloon catheter of the present invention is divided into two layers. The part close to the balloon is composed of hydrophilic excipients and drugs of different particle sizes wrapped by phospholipids, and the outer layer is made of hydrophobic excipients. Composition or amphiphilic excipients. The excipients in the outer layer help maintain the integrity of the coating, reduce the resistance when the balloon passes through the blood vessel to the target lesion, and reduce the drug loss during the delivery process; the hydrophilic excipients close to the balloon have It helps to create a high molecular surface area between the drug and the blood vessel wall and improve the bioavailability of the drug.

Description of the drawings

Figure 1 Schematic diagram of phospholipid-encapsulated drug microsphere particles.

Figure 2 is a schematic diagram of the structure of the drug eluting balloon catheter of the present invention.

Figure 3 The size and distribution of the drug microspheres prepared in Example 1.

Figure 4 The size and distribution of the drug microspheres prepared in Example 3.

Figure 5 An ultrasound image of blood vessels of the drug-eluting balloon catheter of Comparative Example 1 6 months after dilation.

Fig. 6 Ultrasound images of blood vessels of the drug-eluting balloon catheter of Example 13 6 months after dilation.

Detailed ways

The following describes the content of the present invention in more detail with reference to specific examples, and further explains the present invention, but these examples do not limit the present invention.

The methods used in the examples, unless otherwise specified, all use conventional methods in the art. The reagents used in the examples are all commercially available products.

Unless otherwise specified, the following concentrations are percentages by mass.

Example 1

Weigh 10mg of rapamycin and dissolve it in 10ml of acetone. Add this solution dropwise to 50ml of 1% PVA solution, emulsify it with ultrasonic at 4°C for 40 minutes, then stir the emulsion overnight at 1000rpm. Centrifuge the emulsion overnight at 3500 rpm and take the supernatant to obtain a suspension of rapamycin microsphere particles (also called suspension, the same below), using a nano particle size analyzer (Zetasizer Nano ZS90) The size and distribution of solid microsphere particles were tested, and the particle size range was 1.5 μm-6.0 μm. The result is shown in Figure 3.

Example 2

Weigh 1mg of rapamycin, dissolve it in 10ml of acetone, add this solution dropwise to 100ml of 2% polysorbate 20 solution, emulsify the emulsion with ultrasonic for 40 minutes at 4°C, and then stir the emulsion overnight with rotation speed Centrifuge the emulsion overnight at 3500 rpm, and take the supernatant to obtain a suspension of rapamycin microsphere particles. The size and distribution of solid microsphere particles are tested by a nanoparticle sizer. The particle size range is 0.5μm-5μm.

Example 3

Weigh 100mg of rapamycin and 150mg of PDLGA with an intrinsic viscosity of 0.8dl/g, and dissolve them in a mixed solvent of 10ml of acetone and dichloromethane (volume ratio 2:8), and add this solution dropwise to 100ml with a mass fraction of In a 2% polysorbate 80 solution, use a high-speed homogenizer at 18000rpm to emulsify for 4 minutes, then stir the emulsion overnight at 1000rpm, centrifuge the overnight emulsion at 3500rpm, and take the supernatant. That is, a suspension of rapamycin microsphere particles is obtained, and the size and distribution of the solid microsphere particles are tested with a nanoparticle sizer, and the particle size range is 15nm-120nm. The result is shown in Figure 4.

Example 4

Weigh 10mg of rapamycin and 10mg of PTMC with an intrinsic viscosity of 1.2dl/g, dissolve them in a mixed solvent of 10ml of acetone and dichloromethane (volume ratio of 8:2), and add this solution dropwise to 100ml of mass fraction In 10% polysorbate 80 solution, use a high-speed homogenizer to emulsify at 15000rpm for 2 minutes, then stir the emulsion overnight at 1000rpm, centrifuge the overnight emulsion at 3500rpm, and take the supernatant. That is, a suspension of rapamycin microsphere particles is obtained, and the size and distribution of the solid microsphere particles are tested by a nanometer particle sizer, and the particle size ranges from 15 nm to 120 nm.

Example 5

The drug used is paclitaxel, and the drug concentration is 250 mg/ml. The other processes and conditions are the same as those in Example 1, which will not be repeated here.

Example 6

The drug used is everolimus, the concentration of everolimus in acetone is 500mg/ml, the degradable polymer material is PDLGA-PEG-PDLGA, the concentration of PDLGA-PEG-PDLGA in acetone is 400mg/ml, others The process and conditions are the same as in Embodiment 3, and will not be repeated here.

Example 7

Take the rapamycin drug microsphere particle suspension (volume ratio 8:2) of Example 1 and Example 3, and add it to the aqueous solution containing soy lecithin (PC80) and iopromide. The volume ratio of the spherical particle suspension to the aqueous solution is 1:0.13, and the final concentrations of PC80 and iopromide are 0.2% and 0.01%, respectively. The drug suspension is sprayed onto the surface of the balloon by means of ultrasonic spraying. After the surface of the balloon is dried, the ethanol solution of butyryl tri-n-hexyl citrate is sprayed onto the dried surface of the balloon by ultrasonic spraying. The concentration of the butyryl tri-n-hexyl citrate solution is 1%, and the final drug-eluting balloon is The concentration of rapamycin on the catheter is 2.0 μg/mm ² .

Example 8

Take the rapamycin drug microsphere particle suspension (volume ratio 5:5) of Example 1 and Example 3, and add it to the aqueous solution containing soy lecithin (PC80) and iopromide. The volume ratio of the spherical particle suspension to the aqueous solution is 1:0.13, and the final concentrations of PC80 and iopromide are 1% and 1%, respectively. The above-mentioned drug suspension is sprayed onto the surface of the balloon by means of ultrasonic spraying. After the surface of the balloon is dried, use the ultrasonic spray method to spray the ether solution of butyryl tri-n-hexyl citrate onto the dried surface of the balloon. The concentration of the butyryl tri-n-hexyl citrate solution is 0.1%, and the final drug-eluting balloon is obtained. The concentration of rapamycin on the catheter is 4.0 μg/mm ² .

Example 9

Take the rapamycin drug microsphere particle suspension (volume ratio 2:8) of Example 1 and Example 3 and add it to the aqueous solution containing soy lecithin (PC80) and iopromide. The volume ratio of the spherical particle suspension to the aqueous solution is 1:0.13, and the final concentrations of PC80 and iopromide are 2% and 10%, respectively. The above-mentioned drug suspension is sprayed onto the surface of the balloon by means of ultrasonic spraying. After the surface of the balloon is dried, use the ultrasonic spray method to spray the aqueous solution of polysorbate onto the dried surface of the balloon. The concentration of the polysorbate solution is 0.1%, and the final drug eluates the concentration of rapamycin on the balloon catheter It is 6.1μg/mm ² .

Example 10

Take the rapamycin drug microsphere particle suspension of Example 1 and add it to the aqueous solution containing soy lecithin (PC20) and iopromide. The volume ratio of the rapamycin drug microsphere particle suspension to the aqueous solution is 1 : 0.2, the final concentrations of PC20 and iopromide are 3% and 2% respectively, and the above-mentioned drug suspension is sprayed onto the surface of the balloon by ultrasonic spraying. After the surface of the balloon is dried, use the ultrasonic spray method to spray the acetone solution of butyryl tri-n-hexyl citrate onto the dried surface of the balloon. The concentration of the tri-n-hexyl butyryl citrate solution is 3%, and the finally obtained drug-eluting balloon The concentration of rapamycin on the catheter is 10.0 μg/mm ² .

Example 11

Take the rapamycin drug microsphere particle suspension of Example 1 and Example 4 (volume ratio 1:9) and add it to the aqueous solution containing phosphatidylserine and iohexol to suspend the rapamycin drug microsphere particle The volume ratio of the liquid to the aqueous solution is 1:0.5, and the final concentrations of phosphatidylserine and iohexol are 0.5% and 1%, respectively. The drug suspension is sprayed onto the surface of the balloon by means of ultrasonic spraying. After the surface of the balloon is dried, use the ultrasonic spray method to spray the acetone solution of butyryl tri-n-hexyl citrate onto the dried surface of the balloon. The concentration of the tri-n-hexyl butyryl citrate solution is 1%, and the final drug-eluting balloon is obtained The concentration of rapamycin on the catheter is 2.5 μg/mm ² .

Example 12

Take the rapamycin drug microsphere particle suspension of Example 2 and Example 4 (volume ratio 1:9) and add it to the aqueous solution containing phosphatidylserine and iohexol. The rapamycin drug microsphere particle The volume ratio of the suspension to the aqueous solution is 1:1, and the final concentrations of phosphatidylserine and iohexol are 0.5% and 1%, respectively. The drug suspension is sprayed onto the surface of the balloon by ultrasonic spraying. After the surface of the balloon is dried, use the ultrasonic spray method to spray the acetone solution of butyryl tri-n-hexyl citrate onto the dried surface of the balloon. The concentration of the tri-n-hexyl butyryl citrate solution is 1%, and the final drug-eluting balloon is obtained The concentration of rapamycin on the catheter is 3.0 μg/mm ² .

Example 13

Take the rapamycin drug microsphere particle suspension of Example 2 and Example 4 (volume ratio 5:5) and add it to the aqueous solution containing PC80 and polyethylene glycol 400. The rapamycin drug microsphere particle The volume ratio of the suspension to the aqueous solution is 1:1, and the final concentrations of PC80 and polyethylene glycol 400 are 1% and 1%, respectively. The drug suspension is sprayed onto the surface of the balloon by means of ultrasonic spraying. After the surface of the balloon is dried, the dextran aqueous solution is sprayed onto the dried surface of the balloon by ultrasonic spraying. The concentration of the dextran solution is 1%, and the final drug elution balloon catheter concentration of rapamycin It is 3.0μg/mm ² .

Comparative example 1

Take the rapamycin drug microsphere particle suspension of Example 1 and add it to the aqueous solution of iopromide. The volume ratio of the rapamycin drug microsphere particle suspension to the aqueous solution is 1:1. The concentration is 2%, and the drug suspension is sprayed onto the surface of the balloon by ultrasonic spraying. The concentration of rapamycin on the finally obtained drug-eluting balloon catheter was 3.0 μg/mm ² .

Comparative example 2

Weigh 1mg of rapamycin, dissolve it in 10ml of acetone, add this solution dropwise to 100ml of 0.1% polysorbate 20 solution, emulsify the emulsion with ultrasonic for 40 minutes at 4°C, and then stir the emulsion overnight at a rotating speed Centrifuge the emulsion overnight at 3500 rpm, and take the supernatant to obtain a suspension of rapamycin microsphere particles. Use a nanoparticle sizer to test the size and distribution of solid particles. The particle size ranges from 10μm-50μm. .

In vitro simulation test

The porcine coronary vessels were used to simulate the target vessels of the coronary artery system for in vitro simulation tests.

The drug-eluting balloon catheters prepared in Examples 7-13 and Comparative Example 1 were respectively inserted into the simulated target blood vessel, and the balloon fluid was filled to about 12 atm. The transitional extension rate (that is, the ratio of the diameter of the balloon to the diameter of the blood vessel) is about 1.10 to 1.20. The drug is delivered to the target tissue within a liquid filling time of 30 to 60 seconds, and then the balloon catheter is deflated and taken out of the in vitro simulation test system to collect the target blood vessel tissue. Through tissue extraction and HPLC, analyze the drug content in the molecular target tissue and the residual drug amount retained on the balloon. The HPLC test conditions are: Shimadzu LC-20A high performance liquid chromatograph, column: Aglilent ZORBAX Eclipse XDB-C18 4.6×150, 5μm, mobile phase: methanol: acetonitrile: water=67:22:11 (volume ratio), column temperature: 40°C, ultraviolet detector, detection wavelength 265nm, flow rate: 1.0ml/min.

HPLC determination results are shown in Table 1:

Table 1 In vitro simulation test results

The results in Table 1 show that: compared with the single-layer coated drug-eluting balloon catheter, the drug-eluting balloon catheter of the present invention reduces the coating resistance when the balloon passes through the blood vessel to the pathological path, and reduces the drug in the blood vessel. Loss in the system. In addition, compared with a drug-eluting balloon catheter without a phospholipid-coated drug, the drug-eluting balloon catheter of the present invention promotes the absorption of the drug by the blood vessel wall and improves the bioavailability.

Test the lumen changes of blood vessels after the drug-eluting balloon catheter is filled.

The balloon catheter prepared in Example 13 and the balloon catheter prepared in Comparative Example 1 were used on the left anterior descending coronary artery (abbreviation: LAD) and left circumflex artery (abbreviation: LCX) of miniature pigs to perform 1:(1.1~ 1.2) The blood vessels are dilated and the catheter is withdrawn. After 6 months, intravascular ultrasound technology was used to observe the vascular stenosis rate of the target vessel. 5 is an ultrasound image of the blood vessel after expansion by the balloon catheter of Comparative Example 1, and FIG. 6 is an ultrasound image of the blood vessel after expansion by the balloon catheter of Example 13.

The balloon catheter prepared in Example 13 had an average vascular stenosis rate of 8.2% after expansion, and the balloon catheter of Comparative Example 1 had an average vascular stenosis rate of 15.6% after expansion.

The results show that, compared with the drug-eluting balloon catheter of Comparative Example 1, the stenosis rate of the blood vessel after the expansion of the drug-eluting balloon catheter of the present invention is significantly reduced.

The above test results show that the drug-eluting balloon catheter of the present invention reduces drug loss during the delivery process, and at the same time, the drug can be released to and absorbed by the tissue relatively faster during the expansion process.

Claims

A method for preparing a drug-eluting balloon catheter is characterized by comprising the following steps:

(1) Dissolve the drug or the mixture of the drug and the degradable polymer material in an organic solvent, add the resulting solution dropwise to an aqueous solution containing an emulsifier, use the pelletizing method to make the drug form microspheres, and centrifuge to remove large particles Granules, take the supernatant to obtain the drug microsphere suspension;

(2) Disperse at least one drug microsphere suspension with different particle size ranges obtained according to the method of step (1) into an aqueous solution containing phospholipids and excipient I;

(3) First use ultrasonic spraying or dip coating to apply the solution of step (2) to the surface of the balloon, then use the ultrasonic spraying method to spray the solution of excipient II on the surface of the balloon, and finally vacuum dry the balloon. Obtain drug-eluting balloon catheters containing drugs of different particle sizes.
The preparation method according to claim 1, wherein the drug is a fat-soluble drug, and the fat-soluble drug is a macrolide immunosuppressant, a macrolide antibiotic, rapamycin, and One or more of the structural derivatives of paclitaxel, everolimus, everolimus, paclitaxel and paclitaxel; the concentration of the drug in the organic solvent in step (1) is 1mg/ml-500mg/ml.
The preparation method according to claim 1, wherein the degradable polymer material is polylactide-glycolide, polylactide-caprolactone, monomethoxy polyethylene glycol poly One or more of racemic lactic acid glycolic acid copolymer, polyethylene glycol polyracemic lactic acid glycolic acid copolymer and polytrimethylene carbonate; the intrinsic viscosity range of the degradable polymer material is 0.1- 2.0dl/g, the concentration of the degradable polymer material in the organic solvent in step (1) is 1mg/ml-500mg/ml.
The preparation method according to claim 1, wherein the organic solvent is one or more of acetone, dichloromethane, chloroform, ethyl acetate and tetrahydrofuran; the emulsifier is polyvinyl alcohol One or more of polysorbate 20, polysorbate 80 and vitamin E polyethylene glycol succinate; the concentration of the emulsifier in the aqueous solution of step (1) is 0.5wt%-10wt%.
The preparation method according to claim 1, characterized in that: in step (1), the spheroidizing method includes phacoemulsification, high-speed homogenization, membrane emulsification or micelles, and the particle size range of the obtained drug microspheres is 15 nm. 7 μm; In step (2), the volume ratio of the suspension of drug microspheres with different particle size ranges to the aqueous solution containing phospholipids and excipient I is 1:0.1-1:1.
The preparation method according to claim 1, wherein the phospholipids are soybean lecithin, egg yolk lecithin, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylinositol and sphingomyelin. The concentration of the phospholipid in the final solution formed in step (2) is 0.2wt%-3.0wt%.
The preparation method according to claim 1, wherein the excipient I is a hydrophilic excipient, and the hydrophilic excipient is iopromide, iohexol, ioverol, urea And one or more of polyethylene glycol; the concentration of excipient I in the final solution formed in step (2) is 0.01wt%-10wt%.
The preparation method according to claim 1, wherein the excipient II is a hydrophobic excipient or an amphiphilic excipient, and the hydrophobic excipient is tri-n-hexyl butyryl citrate and Any one or two of shellac, the amphiphilic excipient is one or more of dextran, polysorbate and sorbitol; the solution concentration of the excipient II is 0.01 wt%-10wt%, the solvent for dissolving the hydrophobic excipient is one or more of ether, n-hexane, petroleum ether, ethanol, propanol, ethyl acetate, dichloromethane and acetone.
The preparation method according to claim 1, wherein the drug concentration of the obtained drug eluting balloon catheter is 1 μg/mm 2 -10 μg/mm 2 .
A drug-eluting balloon catheter prepared according to the method for preparing a drug-eluting balloon catheter according to any one of claims 1-9.