WO2023083086A1

WO2023083086A1 - Drug-coated and drug-eluting balloon catheter, and preparation method therefor

Info

Publication number: WO2023083086A1
Application number: PCT/CN2022/129463
Authority: WO
Inventors: 马勤川; 潘远航
Original assignee: 上海博脉安医疗科技有限公司
Priority date: 2021-11-09
Filing date: 2022-11-03
Publication date: 2023-05-19
Also published as: CN116099108A

Abstract

Provided in the present invention are a drug-coated and drug-eluting balloon catheter, and a preparation method therefor. The method comprises: encapsulating a drug with biological material to prepare microspheres, mixing the microspheres with an adhesion agent and a dispersant, and coating the balloon surface of a drug-eluting balloon catheter with the obtained solution by using a needle coating method. The present invention solves the problems of the drug's poor tissue absorption capability and short retention time in tissue.

Description

A drug-coated, drug-eluting balloon catheter and preparation method thereof

technical field

The invention relates to the field of drug equipment preparation, in particular to a drug coating, a drug-eluting balloon catheter and a preparation method thereof.

Background technique

The main means of treating vascular stenosis is implantation of drug-eluting stents. After implantation of stents, patients need to take antithrombotic drugs orally for a long time and affect subsequent surgical treatment, and there is a problem of late stent thrombosis. Therefore, as a new interventional medical concept, "intervention without implantation" is being accepted by more and more clinicians and patients, and drug-eluting balloon (DCB) is a new type of interventional treatment concept. product.

As a new type of intravascular drug release technology, drug-eluting balloons are coated with anti-proliferative drugs on the surface of the balloon. The drug carried on the surface of the balloon is quickly transferred to the blood vessel wall and retained for a period of time, thereby inhibiting the proliferation of the vascular intimal. Human clinical studies have confirmed that the restenosis of blood vessels at the lesion usually occurs 1 to 3 months after balloon angioplasty, and the restenosis reaches the peak at about 3 months, which requires the drugs on the balloon to penetrate into the blood vessels In the wall, and the effective drug concentration is maintained long enough to minimize restenosis.

At present, the drug balloons on the market mainly use paclitaxel as an anti-proliferative drug, among which paclitaxel-releasing balloon catheter Sequence Please from Braun, Germany is the representative. Because rapamycin is poorly fat-soluble, it cannot penetrate into the blood vessel wall quickly, and its retention time in the tissue is short, so the therapeutic effect is not good, so it is difficult to apply to drug balloons. At present, there is no rapamycin drug in China. Balloon listing. In foreign countries, the Magic Touch balloon catheter of the medical equipment company Concept Medical uses rapamycin nanocrystals as an anti-proliferative drug for the drug balloon, but the retention time of the tissue concentration is short, less than 1 month. M.A. Medical United Company uses rapamycin microspheres as an anti-proliferation drug for drug balloons, and its technical route adopts recyclable liposome technology, which has been widely used in anti-tumor drugs, but the production process Spraying with heptane has disadvantages such as poor coating uniformity and low drug stability. Therefore, the drug balloon currently on the market is mainly paclitaxel. However, paclitaxel itself can inhibit the proliferation of smooth muscle cells by acting on cells to cause apoptosis or death, that is, paclitaxel has certain cytotoxicity. Rapamycin and its derivatives achieve the purpose of anti-proliferation through a cytostatic mechanism, that is, acting on cells to stop their growth. In view of the fact that the safety of rapamycin is generally better than that of paclitaxel, the safety of rapamycin has been confirmed clinically, and it has been widely used in drug stents. Therefore, a drug coated with rapamycin was developed. The drug balloon dilatation catheter will have a wide range of application scenarios.

Contents of the invention

Aiming at the problems in the prior art, the object of the present invention is to provide a drug coating, a drug-eluting balloon catheter and a preparation method thereof, which solve the problems of poor drug tissue absorption and short retention time in tissues.

According to one aspect of the present invention, a drug coating is provided, including drug microspheres, an adhesive and a dispersant, and the drug microspheres are made by encapsulating drugs with biological materials.

In some embodiments, the biomaterial is racemic polylactic acid or poly(lactic-co-glycolic acid).

In some embodiments, the drug is a fat-soluble drug.

In some embodiments, the drug is one or more of macrolide immunosuppressants, rapamycin, eulimus, everolimus, rapamycin, zotarolimus mix.

In some embodiments, the adhesive is phospholipid and/or cholesterol.

In some embodiments, the adhesive is 1,2-dioleoyl-SN-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-SN-glycero-3-phosphocholine (DPPC), 1,2-Dierucoyl-SN-glycero-3-phosphorylcholine (DEPC), 1,2-dimyristoyl-SN-glycero-3-phosphorylcholine (DMPC), 1 , A mixture of one or more of 2-distearoyl-SN-glycero-3-phosphocholine (DSPC) and cholesterol.

In some embodiments, the dispersant is PEGylated liposomes and/or polyethylene oxide.

In some embodiments, the dispersant is 1,2-distearoyl-SN-glycerol-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-2000 (DSPE-mPEG2000), 1 ,2-Distearoyl-SN-glycerol-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-1000 (DSPE-mPEG1000), 1,2-dimyristoyl-rac-glycerol- A mixture of one or more of 3-methoxy polyethylene glycol 2000 (DMG-PEG2000) and polyethylene oxide.

In some embodiments, the mass ratio of the adhesive to the dispersant is 1:1˜10:1.

In some embodiments, the mass ratio of the drug microspheres to the adhesive is 1:0.5˜1:5.

According to another aspect of the present invention, a drug-eluting balloon catheter is provided, including a balloon: the above-mentioned drug coating is provided on the balloon.

According to another aspect of the present invention, there is also provided a method for preparing the above-mentioned drug-eluting balloon catheter: comprising the following steps:

Step 1, making the drug microspheres by encapsulating the drug with the biological material;

Step 2, mixing the adhesive and the dispersant with water;

Step 3, mixing the drug microspheres obtained in step 1 with the solution obtained in step 2;

Step 4, using the needle coating method to apply the solution obtained in step 3 to the balloon surface of the drug-eluting balloon catheter.

The sequence of steps 1 and 2 is not limited.

In some embodiments, the biological material is racemic polylactic acid or polylactic acid-glycolic acid copolymer; the drug is a macrolide immunosuppressant, rapamycin, umelimus, everolimus , rapamycin, a mixture of one or more of zotarolimus; the adhesive is 1,2-dioleoyl-SN-glycero-3-phosphocholine (DOPC), 1,2 -Dipalmitoyl-SN-glycero-3-phosphorylcholine (DPPC), 1,2-Dierucoyl-SN-glycero-3-phosphorylcholine (DEPC), 1,2-dimyristoyl-SN - a mixture of one or more of glycerol-3-phosphorylcholine (DMPC), 1,2-distearoyl-SN-glycero-3-phosphorylcholine (DSPC), cholesterol; the dispersant is 1,2-distearoyl-SN-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-2000 (DSPE-mPEG2000), 1,2-distearoyl-SN- Glycerol-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-1000 (DSPE-mPEG1000), 1,2-dimyristoyl-rac-glycerol-3-methoxypolyethylene glycol 2000 (DMG-PEG2000), a mixture of one or more of polyethylene oxide; the mass ratio of the adhesive to the dispersant is 1:1 to 10:1; the drug microspheres and the step The mass ratio of the adhesive to 2 is 1:0.5˜1:5.

In the technical scheme of the present invention, anti-proliferation drugs are wrapped with degradable biomaterials, made into microspheres, and then the microspheres are coated on the surface of the balloon with excipients; the excipients contain adhesives and dispersants, When the balloon is stretched at the position of vascular lesion, the adhesive agent can adhere the microspheres to the vessel wall, and the dispersant is to fully disperse the microspheres, increase the lubricity of the coating, promote drug absorption, and solve the problem of drug tissue absorption. Poor ability, short retention time in the organization, etc.

Description of drawings

Other characteristics, objects and advantages of the present invention will become more apparent by reading the detailed description of non-limiting embodiments with reference to the following drawings.

Fig. 1 is a schematic diagram of the structure of a balloon catheter according to an embodiment of the present invention;

Fig. 2 is a schematic structural view of the winding of the balloon according to the embodiment of the present invention;

Fig. 3 is a schematic diagram of the microsphere structure of the encapsulated drug of the embodiment of the present invention;

Figure 4 is a scanning electron micrograph of the microspheres prepared in Example 1 of the present invention;

Figure 5 is a scanning electron micrograph of the balloon drug coating prepared in Example 2 of the present invention;

6 is an angiogram of the superficial femoral artery before the balloon implantation according to an embodiment of the present invention;

Fig. 7 is an angiogram of the superficial femoral artery during balloon implantation according to an embodiment of the present invention;

Fig. 8 is an angiogram of the superficial femoral artery after balloon implantation according to an embodiment of the present invention.

Detailed ways

Example embodiments will now be described more fully with reference to the accompanying drawings. Example embodiments may, however, be embodied in many forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the concept of the example embodiments to those skilled in the art. The same reference numerals denote the same or similar structures in the drawings, and thus their repeated descriptions will be omitted.

In an embodiment of the present invention, a drug coating, a drug-eluting balloon catheter and a preparation method thereof are provided.

As shown in FIG. 1 , it is a typical drug-eluting balloon catheter, including a drug-coated balloon. By implanting the balloon into the blood vessel, the drug coating on the balloon is transferred to the vessel wall.

The drug coating on the drug-eluting balloon catheter balloon of the embodiment of the present invention includes drug microspheres, an adhesive and a dispersant. Drug microspheres are made by encapsulating drugs in biological materials.

In an embodiment of the present invention, the above-mentioned method for preparing a drug-eluting balloon catheter includes the following steps:

Step 1, making microspheres by encapsulating drugs with biomaterials;

Biomaterials are a type of natural or synthetic special functional materials that are used to contact and interact with living systems, and can diagnose, treat, replace, repair, or induce regeneration of their cells, tissues, and organs, also known as biomedical materials. . Preferably, the anti-proliferation drug is wrapped with a degradable biological material and made into a microsphere form.

The degradable biomaterial is preferably racemic polylactic acid (PDLLA), poly(lactic-co-glycolic acid) (75% DL-lactide/25% glycolide copolymer, PLGA). And preferably, the viscosity range of PDLLA is 0.15-0.75 dl/g, and the viscosity range of PLGA is 0.15-0.75 dl/g.

In addition, the drugs that affect the embedding in the microspheres are fat-soluble drugs, which are macrolide immunosuppressants, rapamycin, eulimus, everolimus, rapamycin, and zotarolimus. One or a mixture of two or more of them.

And preferably, the diameter of the microspheres ranges from 1 to 10 μm.

Step 2, mixing the adhesive and the dispersant with water; preferably, the adhesive and the dispersant are placed in a glass vial, added with water, and stirred magnetically for 3-6 hours to mix.

Preferably the adhesive is a phospholipid, and preferably a glycerophospholipid and/or cholesterol. Further preferred are 1,2-dioleoyl-SN-glycero-3-phosphocholine (1,2-Dioleoyl-sn-Glycero-3-Phosphatidylcholine, DOPC), 1,2-dipalmitoyl-SN-glycerol- 3-phosphocholine (1,2-Dipalmitoyl-sn-glycero-3-phosphocholine, DPPC), 1,2-dierucoyl-SN-glycero-3-phosphocholine (1,2-Dioleoyl-sn- Glycero-3-Phosphatidylcholine, DEPC), 1,2-dimyristoyl-SN-glycero-3-phosphocholine (1,2-dimyristoyl-sn-glycero-3-phosphocholine, DMPC), 1,2- One of distearoyl-SN-glycero-3-phosphorylcholine (1,2-Distearoyl-sn-glycero-3-phosphorylcholine, DSPC), cholesterol (Cholesterol) or a mixture of two or more of them .

The phospholipid adhesives of the embodiments of the present invention have amphiphilic properties, absorb water and swell when in contact with water, have good adhesion, and can adhere drugs to the blood vessel wall, and are not easily washed away by blood flow; at the same time, because the cell membrane The main component of phospholipids is phospholipids. Choosing phospholipids as an adhesive has the advantage of good biocompatibility. Phospholipids can allow drugs to pass through the internal hydrophobic core area of the plasma membrane of endothelial cells and promote drug absorption by the blood vessel wall.

Preferred dispersing agents are PEGylated liposomes, ie PEG-liposome derivatives (phospholipids coupled to PEG) and/or polyethylene oxide.

And the preferred dispersant is 1,2-distearoyl-SN-glycerol-3-phosphoethanolamine-N-methoxyl (polyethylene glycol)-2000 (DSPE-mPEG2000), 1,2-distearyl Acyl-SN-glycerol-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-1000 (DSPE-mPEG1000), 1,2-dimyristoyl-rac-glycerol-3-methoxypoly Ethylene glycol 2000 (1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000, DMG-PEG2000), one of polyethylene oxide or a mixture of two or more of them.

The PEGylated liposome of the embodiment of the present invention has better water solubility and can prevent drug aggregation. After the balloon is expanded in the blood vessel, the coating can be evenly dispersed and it is not easy to cause thrombus. At the same time, PEGylated liposomes can reduce the recognition and uptake of the monocyte-macrophage system, and can passively accumulate liposomes in tissues by enhancing the osmotic retention effect. At the same time, polyethylene oxide has good water solubility, swells after absorbing water, and has lubricity, which can prevent drug aggregation and reduce drug loss during delivery.

In addition, it is preferable that the mass ratio of the adhesive agent and the dispersant is 1:1˜10:1.

The order of steps 1 and 2 is not limited.

Step 3, mixing the microspheres obtained in step 1 with the solution obtained in step 2, and ultrasonically dispersing;

And preferably, the mass ratio of the microspheres to the adhesive in step 2 is 1:0.5-1:5.

Needle coating method, that is to use a balloon folding machine to fold the balloon so that the balloon is kept in three or five folded flaps, that is, the cross section of the outer periphery of the balloon has three or five "V" shaped spaces. Balloon diameter ≤ 6.0mm folded into 3 wings, balloon diameter > 6.0mm folded into 5 wings. As shown in FIG. 2 , it is a schematic structural view of the coiled balloon.

Turn the balloon catheter so that each "V" shape faces directly upward in turn; at the same time, use a flat-tip micro-sampler to draw a fixed volume of liquid medicine and inject it into the three "V"-shaped spaces of the balloon in sequence.

Then, the balloon is dried, coiled, and heat-cured to obtain the drug-eluting balloon catheter provided with the drug coating of the embodiment of the present invention.

The drug coating, the drug-eluting balloon catheter provided with the drug coating and the preparation method thereof in the embodiments of the present invention solve the problems of poor drug tissue absorption and short retention time in the tissue.

Describe the present invention with specific embodiment below:

Example 1

Preparation of drug-encapsulated microspheres as shown in Figure 3:

1. Raw materials

1. PLGA (75% DL-lactide/25% glycolide, viscosity 0.2dl/g);

2. Rapamycin;

3. Dichloromethane;

4. Polyvinyl alcohol (PVA) solution: Weigh 20g of polyvinyl alcohol (molecular weight 1.3-23,000 Da, degree of alcoholysis 98%) into a 1L beaker, add 400mL of water, stir in a water bath at 95°C for 30min to dissolve, cool to room temperature, Transfer to a 1L volumetric flask, add water to volume, and store in a 4°C refrigerator.

2. Preparation method

1. Weigh 500.0mg PLGA and 237.5mg rapamycin in 8mL dichloromethane, shake to dissolve.

2. Measure 160mL of PVA solution into a 1000mL plastic beaker, place it in an ice-water bath (the temperature of the water bath is controlled at 4°C throughout the process), and turn on the mixer (1400rpm). Measure 40mL of PVA solution in a 50mL plastic centrifuge tube and homogenize (homogenization speed 18000rpm/min). During the homogenization process, add the polymer solution dropwise into the centrifuge tube within 3min, and continue homogenizing for 5min. After the homogenization is completed, immediately pour the microemulsion in the centrifuge tube into a 1000mL beaker and stir for 2h.

3. After the stirring is completed, transfer the solution to two 100mL centrifuge tubes, centrifuge at 6000rpm for 10min, discard the supernatant, add purified water to shake and wash the micronuclei, centrifuge, and repeat 5 times.

4. Put the microspheres into a vacuum drying oven and dry them at room temperature for 48 hours to prepare the microspheres with a drug loading of 30.2% rapamycin by weight as shown in FIG. 4 .

Example 2

1. Raw materials

1. Microsphere: the rapamycin microsphere that embodiment 1 makes;

2. Binder: 1,2-Dioleoyl-SN-Glycero-3-phosphorylcholine (1,2-Dioleoyl-sn-Glycero-3-Phosphatidylcholine, DEPC); 1,2-Dipalmitoyl- SN-Glycero-3-phosphocholine (1,2-Dipalmitoyl-sn-glycero-3-phosphocholine, DPPC); Cholesterol (Cholesterol);

3. Dispersant: polyethylene oxide;

4. Water, water for injection.

2. Preparation method

1. Weigh 22.5mg DEPC, 22.5mg DPPC and 45mg cholesterol into a glass vial, add 5mL water and 45mg polyethylene oxide, and stir magnetically for 4 hours to obtain solution 1. The mass ratio of DEPC to DPPC, cholesterol and polyethylene oxide is 1:1:2:2;

2. Weigh 60 mg of PLGA microspheres in solution 1, and ultrasonically disperse the microspheres to obtain a coating solution with a concentration of 12.0 mg/mL;

3. Fold the balloon into 3 wings with a folding machine.

4. Apply the coating solution to the V-shaped groove of the folded balloon by needle coating;

5. At room temperature, the coating was dried for 16 hours to obtain a drug-coated balloon catheter, as shown in FIG. 5 , the drug-loaded amount of rapamycin per unit external area of the balloon was 2.0 μg/mm ² .

Example 3

1. Raw materials

1. Microsphere: the rapamycin microsphere that embodiment 1 makes;

2. Binder: 1,2-dioleoyl-SN-glycero-3-phosphocholine (1,2-Dioleoyl-sn-Glycero-3-Phosphatidylcholine, DOPC); 1,2-dipalmitoyl-SN - glycerol-3-phosphocholine (1,2-Dipalmitoyl-sn-glycero-3-phosphocholine, DPPC); cholesterol (Cholesterol);

3. Dispersant: polyethylene oxide;

4. Water, water for injection.

2. Preparation method

1. Weigh 22.5mg DOPC, 22.5mg DPPC and 45mg cholesterol into a glass vial, add 5mL water and 45mg polyethylene oxide, stir magnetically for 4 hours to obtain solution 1. The mass ratio of DOPC to DPPC, cholesterol and polyethylene oxide is 1:1:2:2;

3. Fold the balloon into 3 wings with a folding machine;

5. The drug-coated balloon catheter was obtained after the coating was dried for 16 hours at room temperature, and the drug-loaded amount of rapamycin per unit external area of the balloon was 2.0 μg/mm ² .

Example 4

1. Raw materials

1. Microsphere: the rapamycin microsphere that embodiment 1 makes;

3. Water, water for injection.

2. Preparation method

1. Weigh 22.5mg DOPC, 22.5mg DPPC and 45mg cholesterol into a glass vial, add 5mL water, stir magnetically for 4 hours to obtain solution 1. The mass ratio of DOPC to DPPC and cholesterol polymer is 1:1:2;

3. Fold the balloon into 3 wings with a folding machine;

Example 5

1. Raw materials

1. Microsphere: the rapamycin microsphere that embodiment 1 makes;

2. Binder: 1,2-Dioleoyl-SN-Glycero-3-Phosphorylcholine (1,2-Dioleoyl-sn-Glycero-3-Phosphatidylcholine, DEPC); Cholesterol;

3. Dispersant: 1,2-dimyristoyl-rac-glycerol-3-methoxypolyethylene glycol-2000 (1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000, DMG-PEG2000) ;

4. Water, water for injection.

2. Preparation method

1. Weigh 45mg DEPC, 45mg DMG-PEG2000 and 45mg cholesterol into a glass vial, add 5mL water, stir magnetically for 4 hours to obtain solution 1. The mass ratio of DEPC, DMG-PEG2000, and cholesterol is 1:1:1;

3. Fold the balloon into 3 wings with a folding machine;

Example 6

1. Raw materials

1. Microsphere: the rapamycin microsphere that embodiment 1 makes;

3. Dispersant: polyethylene oxide;

4. Water, water for injection.

2. Preparation method

1. Weigh 45mg of DEPC, 45mg of polyethylene oxide and 45mg of cholesterol into a glass vial, add 5mL of water, and magnetically stir for 4 hours to obtain solution 1. The mass ratio of DEPC to polyethylene oxide and cholesterol poly is 1:1:1;

3. Fold the balloon into 3 wings with a folding machine;

Example 7

1. Raw materials

1. Microsphere: the rapamycin microsphere that embodiment 1 makes;

2. Binder: 1,2-dioleoyl-SN-glycero-3-phosphocholine (1,2-Dioleoyl-sn-Glycero-3-Phosphatidylcholine, DOPC); 1,2-dimyristoyl- SN-glycero-3-phosphocholine (1,2-dimyristoyl-sn-glycero-3-phosphocholine, DMPC); cholesterol (Cholesterol);

3. Dispersant: polyethylene oxide;

4. Water, water for injection.

2. Preparation method

1. Weigh 22.5mg DOPC, 22.5mg DMPC and 45mg cholesterol into a glass vial, add 5mL water and 90mg polyethylene oxide, stir magnetically for 4 hours to obtain solution 1. The mass ratio of DOPC, DMPC, cholesterol and polyethylene oxide is 1:1:2:4;

3. Fold the balloon into 3 wings with a folding machine;

Example 8

1. Raw materials

1. Microsphere: the rapamycin microsphere that embodiment 1 makes;

2. Binder: 1,2-Dioleoyl-SN-Glycero-3-phosphorylcholine (1,2-Dioleoyl-sn-Glycero-3-Phosphatidylcholine, DEPC); 1,2-Dioleoyl-sn-Glycero-3-Phosphatidylcholine, DEPC); -SN-glycero-3-phosphocholine (1,2-dimyristoyl-sn-glycero-3-phosphocholine, DMPC); cholesterol (Cholesterol);

3. Dispersant: polyethylene oxide;

4. Water, water for injection.

2. Preparation method

1. Weigh 22.5mg DEPC, 22.5mg DMPC and 45mg cholesterol into a glass vial, add 5mL water and 9mg polyethylene oxide, and stir magnetically for 4 hours to obtain solution 1. The mass ratio of DEPC, DMPC, cholesterol and polyethylene oxide is 5:5:10:2;

3. Fold the balloon into 3 wings with a folding machine;

5. At room temperature, the drug-coated balloon catheter was obtained after the coating was dried for 16 hours, and the drug-loaded amount of rapamycin per unit external area of the balloon was 2.0 μg/mm2.

Example 9

1. Raw materials

1. Microsphere: the rapamycin microsphere that embodiment 1 makes;

2. Binder: 1,2-dipalmitoyl-SN-glycero-3-phosphorylcholine (DPPC), 1,2-dierucoyl-SN-glycero-3-phosphorylcholine (DEPC); cholesterol (Cholesterol);

3. Dispersant: 1,2-distearoyl-SN-glycerol-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-2000 (DSPE-mPEG2000);

4. Water, water for injection.

2. Preparation method

1. Weigh 7.5mg DEPC, 7.5mg DPPC and 15mg cholesterol into a glass vial, add 5mL water and 3mg DSPE-mPEG2000, stir magnetically for 4 hours to obtain solution 1. The mass ratio of DEPC to DPPC, cholesterol and DSPE-mPEG2000 is 5:5:10:2;

2. Weigh 60 mg of PLGA microspheres into solution 1, and ultrasonically disperse the microspheres to obtain a coating solution with a concentration of 12.0 mg/mL. The mass ratio of the adhesive to the microspheres is 1:0.5;

3. Fold the balloon into 3 wings with a folding machine;

Example 10

1. Raw materials

1. Microsphere: the rapamycin microsphere that embodiment 1 makes;

2. Binder: 1,2-dipalmitoyl-SN-glycero-3-phosphocholine (DPPC), 1,2-dioleoyl-SN-glycero-3-phosphocholine (DOPC); cholesterol ( Cholesterol);

3. Dispersant: 1,2-distearoyl-SN-glycerol-3-phosphoethanolamine-N-methoxy (polyethylene glycol)-1000 (DSPE-mPEG1000);

4. Water, water for injection.

2. Preparation method

1. Weigh 75mg DEPC, 75mg DPPC and 150mg cholesterol into a glass vial, add 5mL water and 30mg DSPE-mPEG1000, stir magnetically for 4 hours to obtain solution 1. The mass ratio of DEPC to DPPC, cholesterol and DSPE-mPEG1000 is 5:5:10:2;

2. Weigh 60 mg of PLGA microspheres into solution 1, and ultrasonically disperse the microspheres to obtain a coating solution with a concentration of 12.0 mg/mL. The mass ratio of the adhesive to the microspheres is 1:5;

3. Fold the balloon into 3 wings with a folding machine;

Comparative example 1

1. Raw materials

1. Rapamycin API (crystal form, particle size 30-120 μm);

2. Excipient: polyethylene oxide (molecular weight 1 million)

3. Water, water for injection.

2. Preparation method

1. Weigh 100mg rapamycin API, add 100mL water, use PSI-40 (Y type) high-pressure micro-jet homogenizer to homogenize, centrifuge at 15000rpm for 30min, discard the supernatant, and transfer the lower layer rapamycin The crystals were vacuum-dried at room temperature for 48 hours to obtain small crystals of rapamycin with a particle size of 2-5 μm;

2. Weigh 40 mg of rapamycin crystals into a 10 mL glass vial, add 10 mL of water, cover the bottle, vortex and sonicate until the rapamycin crystals are completely dispersed;

3. Weigh 160mg of polyethylene oxide with a molecular weight of 1 million into a 10mL glass vial, add 10mL of water, cover the bottle, vortex, and then magnetically stir until the PEO is completely dissolved.

4. Combine the solutions of Step 2 and Step 3, vortex to mix, and ultrasonically disperse until the rapamycin crystals are completely dispersed.

5. Fold the balloon into 3 wings with a folding machine;

6. Apply the coating solution to the V-shaped groove of the folded balloon by needle coating;

7. At room temperature, the drug-coated balloon catheter was obtained after the coating was dried for 16 hours, and the drug-loaded amount of rapamycin per unit external area of the balloon was 2.0 μg/mm2.

Controlled trial

1. Materials

The drug-coated balloon catheters prepared in Examples 2 to 6 and Comparative Example 1 above were folded and wound, covered with a protective sleeve, and sterilized by ethylene oxide for animal experiments. Choose the bare balloon as a control to evaluate the safety of the drug coating. Evaluate the drug transfer/delivery characteristics at 1h, 1d, 7d, and 28d time points and the target tissue uptake of the drug in vivo.

2. Experimental objects and equipment

1. Experimental animals

Experimental animal: white pig for experiment; gender: male or female; body weight 35-40kg.

The total number of experimental animals: 12 cases.

2. Experimental location

Shanghai Mingke Medical Technology Co., Ltd.

3. Drug balloon

Model specification: DCB-4040, DCB-5040

3. Experimental method

1. Surgical procedure

In 12 pigs, 2 drug balloons were implanted in each pig, a total of 20 drug balloons and 4 control drug balloons. Implantation sites for each pig included:

(1) Superficial femoral artery of left hind leg

(2) Deep femoral artery of left hind leg

(3) The superficial femoral artery of the right hind leg

(4) Deep femoral artery of right hind leg

Select a suitable balloon according to the overexpansion ratio of 1.20 to 1.30, expand the balloon for 120 seconds, and then withdraw it.

2. Animal Handling

Blood routine and biochemical tests were performed at each time point before and after surgery. After balloon implantation, double-antibody drug therapy was given until the end of the experiment. Tissue samples were taken at each time point, and the sample site: the blood vessel at the balloon implantation site, and the length of the sample was greater than 0.5 cm before and after the implanted blood vessel site. As shown in Figs. 6-8, they are angiograms of the superficial femoral artery before, during, and after implantation of the balloon, respectively.

4. Tissue detection

After sampling at each time point, vessels were immediately stored on dry ice and sent to a third-party testing facility for analysis.

1. Testing location

Shanghai Runnuo Biotechnology Co., Ltd.

2. Instruments and equipment

Instrument: triple quadrupole mass spectrometer (LC/MS/MS), model: AB Sciex QTRAP 5500

Chromatographic column: Kinetex 2.6μC18 100A (50mm×3.00mm)

Mobile phase: mobile phase A: 5mM ammonium acetate (containing 0.05% formic acid); mobile phase B: acetonitrile (containing 0.05% formic acid);

3. Test results

The drug absorption results are shown in Table 1.

Table 1: Drug tissue absorption results

As can be seen from Table 1, the time point 1 hour after implantation is mainly to investigate the performance of the coating on the blood vessel wall (anti-blood flow erosion ability). The drug concentration in the tissue of Comparative Example 1 is 38.1 μg/g, and the technical solution Example 2 The tissue drug concentration was 502.9μg/g;

The drug absorption effect was mainly investigated at the time point of implantation 1 day. The tissue drug concentration in Comparative Example 1 was 5.4 μg/g, and the tissue drug concentration in Example 2 of the technical solution was 244.0 μg/g;

After 7 days of balloon implantation, the tissue drug concentration in Comparative Example 1 was 0.061 μg/g, and the tissue drug concentration in Example 2 of the technical solution was 56.1 μg/g;

After balloon implantation 28d, comparative example 1 tissue drug was not detected, and the tissue drug concentration of embodiment 2 of the technical solution was 35.1 μ g/g.

In the experiment, the drug concentration in the tissue of Example 4 was low because no dispersant was added, the microspheres aggregated, and the coating was uneven; the drug concentration in the tissue of Example 5 was low because DMG-PEG2000 was too water-soluble, and the adhesion of the coating was not outstanding ; Embodiment 6 tissue drug concentration is low because only used adhesive DEPC and cholesterol, coating adhesion is not outstanding. However, compared with Comparative Example 1, the release time of rapamycin can be prolonged, so that the retention time of rapamycin in tissues can be prolonged.

At the same time, it can be seen that the drug coating of the technical solution of the embodiment of the present invention has good blood vessel adhesion and strong anti-blood flow erosion ability. With the gradual degradation of PLGA microspheres, rapamycin is slowly released, and the retention time in tissues Longer, at 28 days, the tissue drug concentration is still as high as 35.1μg/g.

In summary, a drug-coated, drug-eluting balloon catheter and a preparation method thereof according to an embodiment of the present invention adopt "oleoyl lecithin + palmitoyl lecithin + cholesterol + polyethylene oxide + rapamycin Microspheres", the coating has a better ability to adhere to the blood vessel wall; use different types of phospholipids and hydrophilic compounds, optimize their optimal ratio, and obtain a drug coating that resists blood flow erosion and has good adhesion performance ; The coating can firmly adhere the microspheres to the blood vessel wall without being washed away by the blood flow, and can promote the entry of the microspheres into the vessel wall; rapamycin and PLGA form microspheres in the form of doping, Ray Pamycin is evenly distributed inside the PLGA microspheres. With the continuous degradation of PLGA, rapamycin is released slowly and the drug release time is prolonged; the hydrophilic compound is polyethylene oxide, which can increase the coating Lubricity, and polyethylene oxide swells with water, has strong adhesion properties, solves the problem that rapamycin in the prior art cannot quickly penetrate into the blood vessel wall, and wraps rapamycin Embedded in degradable materials and made into microspheres, the release time of rapamycin can be extended and the retention time of rapamycin in tissues can be extended. For peripheral blood vessels, due to the long stenosis length and slow endothelial healing, it is necessary for the drug to remain in the tissue for a long time. The technical solution of the embodiment of the present invention can make rapamycin remain in the tissue for a long time, which has wide application value.

The above content is a further detailed description of the present invention in conjunction with specific preferred embodiments, and it cannot be assumed that the specific implementation of the present invention is limited to these descriptions. For those of ordinary skill in the technical field of the present invention, without departing from the concept of the present invention, some simple deduction or replacement can be made, which should be regarded as belonging to the protection scope of the present invention.

Claims

A drug coating is characterized in that it includes drug microspheres, an adhesive and a dispersion agent, and the drug microspheres are made by encapsulating drugs with biological materials.
The drug coating according to claim 1, characterized in that: the biological material is racemic polylactic acid or polylactic acid-glycolic acid copolymer.
The drug coating according to claim 1, characterized in that: the drug is a fat-soluble drug.
The drug coating according to claim 3, characterized in that: the drug is a macrolide immunosuppressant, rapamycin, omelimus, everolimus, rapamycin, zotaramole One or a combination of these.
The drug coating according to claim 1, characterized in that: the adhesive is phospholipid and/or cholesterol.
The drug coating according to claim 5, characterized in that: the adhesive is 1,2-dioleoyl-SN-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl- SN-glycero-3-phosphocholine (DPPC), 1,2-dierucoyl-SN-glycero-3-phosphorylcholine (DEPC), 1,2-dimyristoyl-SN-glycerol-3- A mixture of one or more of phosphorylcholine (DMPC), 1,2-distearoyl-SN-glycero-3-phosphocholine (DSPC), and cholesterol.
The drug coating according to claim 1, characterized in that: the dispersant is PEGylated liposome and/or polyethylene oxide.
The drug coating according to claim 7, characterized in that: the dispersant is 1,2-distearoyl-SN-glycerol-3-phosphoethanolamine-N-methoxyl (polyethylene glycol) -2000(DSPE-mPEG2000), 1,2-distearoyl-SN-glycerol-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-1000(DSPE-mPEG1000), 1,2- A mixture of one or more of dimyristoyl-rac-glycerol-3-methoxypolyethylene glycol 2000 (DMG-PEG2000) and polyethylene oxide.
The drug coating according to claim 1, characterized in that: the mass ratio of the adhesive to the dispersant is 1:1˜10:1.
The drug coating according to claim 1, characterized in that: the mass ratio of the drug microspheres to the adhesive is 1:0.5-1:5.
A drug-eluting balloon catheter, comprising a balloon, characterized in that the drug coating according to any one of claims 1-10 is provided on the balloon.
A method for preparing a drug-eluting balloon catheter according to claim 11, characterized in that: comprising the following steps:

Step 1, making the drug microspheres by encapsulating the drug with the biological material;

Step 2, mixing the adhesive and the dispersant with water;

Step 3, mixing the drug microspheres obtained in step 1 with the solution obtained in step 2;

Step 4, using the needle coating method to apply the solution obtained in step 3 to the balloon surface of the drug-eluting balloon catheter.
The preparation method of drug-eluting balloon catheter according to claim 12, characterized in that: the biological material is racemic polylactic acid or polylactic acid-glycolic acid copolymer; the drug is a macrolide immunosuppressant agent, rapamycin, omelimus, everolimus, rapamycin, zotarolimus in one or more of the mixture; the adhesive is 1,2-dioleoyl-SN -Glycero-3-phosphocholine (DOPC), 1,2-Dipalmitoyl-SN-glycero-3-phosphocholine (DPPC), 1,2-Dierucoyl-SN-glycero-3-phosphocholine base (DEPC), 1,2-dimyristoyl-SN-glycero-3-phosphorylcholine (DMPC), 1,2-distearoyl-SN-glycero-3-phosphorylcholine (DSPC), A mixture of one or more of cholesterol; the dispersant is 1,2-distearoyl-SN-glycerol-3-phosphoethanolamine-N-methoxyl (polyethylene glycol)-2000 (DSPE -mPEG2000), 1,2-Distearoyl-SN-Glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-1000 (DSPE-mPEG1000), 1,2-Dimyristoyl -rac-glycerol-3-methoxy polyethylene glycol 2000 (DMG-PEG2000), the mixing of one or more of polyethylene oxide; the mass ratio of the adhesive and dispersant is 1: 1-10:1; the mass ratio of the drug microspheres to the adhesive in step 2 is 1:0.5-1:5.