WO2015070814A1

WO2015070814A1 - Drug-eluting balloon and preparation method therefor

Info

Publication number: WO2015070814A1
Application number: PCT/CN2014/091292
Authority: WO
Inventors: 张鹏; 张琳琳; 郭芳; 王长松; 史增佐; 李中华; 罗七一
Original assignee: 微创心脉医疗科技（上海）有限公司
Priority date: 2013-11-15
Filing date: 2014-11-17
Publication date: 2015-05-21
Also published as: CN104623740A; CN104623740B

Abstract

A drug-eluting balloon and a preparation method therefor. The drug-eluting balloon comprises a double-layer balloon, the outer surface whereof is sequentially coated with a water-soluble substrate and a biodegradable polymer layer containing a medicine. During the process of balloon dilatation, physiological saline and related solutions exude through the balloon wall and dissolve the water-soluble substrate, thereby controlling release of the degradable polymer layer containing the medicine.

Description

Medicine balloon and preparation method thereof

Technical field

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

Background technique

Vascular stenosis is the leading cause of morbidity and mortality. The most common treatment currently used is drug-eluting stent (DES) interventional therapy. DES is a drug that is mixed with a polymer matrix and applied to the surface of the stent to form a local drug slow release system. When the stent is implanted into the blood vessel, the drug will be slowly released for several weeks to several months. Together with the support of the stent, it can effectively treat the stenosis or occlusion of the blood vessel. It is one of the most commonly used and most effective interventional devices. However, DES also has many shortcomings. For example, the polymer will produce a local chronic inflammatory reaction; the presence of the stent requires long-term antiplatelet therapy; the drug coating is unevenly distributed; after stent thrombosis, it is not suitable to implant the stent again.

In order to overcome the above-mentioned deficiencies, especially in the search for problems such as in-stent restenosis, lower extremity arterial disease, vascular bifurcation and small blood vessel stenosis, a new type of drug-eluting balloon (DEB) was born. The DEB technique is an improved balloon revascularization technique that attaches a drug to the outer surface of the balloon, delivers the balloon through the catheter to the lesion site, and releases the drug within a short period of time (0-2 min) during balloon expansion. It acts to dilate blood vessels and treat stenosis or occlusion. Even if the lesion vessel is blocked by restenosis, it can be treated twice by DEB.

However, current drug balloons require that the drug used to treat the disease must have the effect that the treatment is treated by a single large dose, and repeated administration is not necessary. This greatly limits the choice of the drug, and the drug enters the circulatory system after a large dose of administration, which is likely to cause acute toxicity.

The current degradable stent partially overcomes the limitations of traditional DES, does not cause inflammatory reactions and re-endothelialization, and can release drugs slowly relative to DEB. But because of its release surface The product is limited, and the support strength of the stent is not ideal, and it is easy to break, and the expected effect cannot be achieved. Therefore, it is necessary to synthesize a uniform drug release in the drug balloon and a long-term slow release in the drug stent to develop a new drug-containing coating.

WO 2012/039884 A1 discloses a transferable polymer coating by dissolving a water-soluble material and a degradable polymer on a surface of a conventional balloon, respectively, and then immersing the entire coating in an aqueous solution for a period of time to dissolve the water solubility of the inner layer. The material forms a structure in which a layer of degradable polymer is nested outside the balloon. The disadvantages of the invention are: (1) the inner layer water-soluble material is tightly coated by the outer layer degradable polymer, and it is difficult for water molecules to cross the outer layer barrier. In many cases, the inner layer water-soluble material cannot be immersed for a long time. Dissolving; on the other hand, even if the water-soluble material in the inner layer is dissolved, its aqueous solution is difficult to completely flow out with water molecules, although the solution has a certain lubricity in the presence of water, but once the coating is dried, The balloon is adhered to the outer layer; (2) even after the immersion treatment, the inner layer is completely removed, and there is no physical connection between the balloon wall and the degradable polymer layer, which directly causes drug coating and late folding crimping During the processing, the polymer layer moves or even falls off; (3) In addition, the polymer layer is a very thin film, which does not support the support like a stent, and does not actively adhere to the wall once the balloon is withdrawn. After the release, the film remaining on the inner wall of the blood vessel is easily washed away by the bloodstream, and not only does not serve the purpose of treating the disease, but even causes severe blood vessel embolism.

Chinese Patent Application No. 200610025200.8 discloses a double-layer balloon catheter in which an inner balloon in the two-layer balloon functions to expand a blood vessel, and an outer balloon is made of a unique microporous membrane, which can be treated. The acting gene or drug is infiltrated by the outer balloon into the blood vessel wall and the target organ. The invention effectively overcomes the loss of the drug during the delivery of the contrast catheter, reduces the system toxicity, but does not achieve the purpose of long-term sustained release.

Summary of the invention

In order to solve the above problems, the present invention contemplates a coating of a drug balloon that is combined with a special double layer balloon. During surgery, the inner balloon is first angioplasty, then the outer balloon expansion. During this process, a solution such as physiological saline oozes out from the pores of the outer balloon wall to dissolve the water-soluble underlayer, so that the action of the underlayer changes from the connecting layer to the lubricating layer, and the drug-containing degradable polymer layer (film) ) detaches from the surface of the outer balloon and withdraws the balloon from the body. The drug-containing degradable polymer layer uniformly releases the drug throughout the lesion over a period of minutes to months. The degradable polymer layer (film) may further comprise an adhesive which adheres to the inner wall of the blood vessel and has a certain toughness, and does not break like a stent due to an external force such as compression or torsion of the blood vessel, and does not fall off from the lesion.

In particular, the present invention provides a drug balloon comprising a double-layer balloon, characterized in that a coating layer is provided on the outer balloon surface of the double-layer balloon, and the coating sequentially comprises a water-soluble primer layer. And a biodegradable polymer layer containing the drug.

According to the invention, the drug is dispersed in the biodegradable polymer layer, or the drug-containing biodegradable polymer layer comprises a further coating of a drug layer over the biodegradable polymer layer.

According to the invention, the drug-containing biodegradable polymer layer further contains an adhesive. In this case, the drug-containing biodegradable polymer layer is a layer structure comprising a biodegradable polymer, an adhesive and a drug, or a double layer structure comprising any combination of a polymer, an adhesive and a drug, Or a three-layer structure in which a polymer, an adhesive, and a drug are separately coated.

According to the present invention, the one-layer structure is obtained by blending a biodegradable polymer, an adhesive and a drug together on a water-soluble underlayer.

According to the present invention, the two-layer structure may be arbitrarily combined as long as it includes a biodegradable polymer, an adhesive, and a drug. For example, the two-layer structure may be a structure in which a degradable polymer and an adhesive form a structure, and the drug alone constitutes another layer structure, or the degradable polymer separately constitutes a layer structure, and the adhesive and the drug constitute another layer structure, Or the degradable polymer and the adhesive form a structure, and the drug and the adhesive constitute another structure, or the degradable polymer and the drug form a structure, and the adhesive separately constitutes a structure, or a degradable polymer, an adhesive And the drug constitutes a layer of structure, while the adhesive and / or drug and / or degradable polymerization The object constitutes another layer structure or the like.

According to the present invention, the three-layer structure may be arranged in any order, for example, in turn, a biodegradable polymer structural layer, an adhesive structural layer, and a drug structural layer.

Those skilled in the art can understand that in order to ensure that the two-layer or three-layer structure adheres to the inner wall of the blood vessel, whether it is a two-layer structure or a three-layer structure, the adhesive-containing structural layer is exposed in whole or in part to dissolve in the water-soluble bottom layer. It can be in contact with the inner wall of the blood vessel after release.

The present invention also provides a method of preparing a drug balloon comprising providing a double layer balloon, making a water soluble primer layer on the outer balloon surface thereof, and then forming a biodegradable polymer layer containing the drug and optionally an adhesive.

The biodegradable polymer layer may be attached to the inner wall of the blood vessel of the lesion area to release the drug for a period of several minutes to several months.

The double-layered balloon is completely identical to the balloon disclosed in Chinese Patent Application No. 200610025200.8.

The water-soluble bottom layer, also known as the hydrophilic bottom layer, has a certain adhesive strength in the anhydrous state, and is used for connecting the surface of the balloon and the degradable polymer layer containing the drug and the optional adhesive; Dissolved to form a lubricating layer to smoothly release the degradable polymer layer. The water-soluble materials include natural water-soluble polymers such as starch, cellulose, vegetable gum and animal glue; modified starch and modified cellulose; carboxymethyl starch, acetic acid starch, hydroxymethyl cellulose, and carboxymethyl Chemically modified natural polymers such as cellulose; synthetic polymers such as polyacrylamide (PAM), hydrolyzed polyacrylamide (HPAM), and polyvinylpyrrolidone (PVP).

The biodegradable polymer layer containing the drug and optionally the adhesive can be rapidly degraded or dissolved, for example, even a few days after surgery, for example, 5 minutes to 24 hours after surgery. In other cases, the degradable polymer layer may degrade or dissolve slowly, for example from 5 days to 6 months. In this process, the degradable polymer layer is attached to the inner wall of the diseased vessel until the drug is completely absorbed or the coating is completely degraded. Thickness of the drug-containing degradable polymer layer The degree can be appropriately adjusted depending on the desired degradation time, generally less than 10 μm, for example, 0.2 μm to 9 μm or 0.5 μm to 8.5 μm.

The biodegradable polymer may be polyhydroxyalkanoate (PHA), polyhydroxybutyrate compound, poly(glycerol-sebacic acid), polypeptide, polylactic acid (PLA), etc. poly-α- A hydroxy acid compound, a polyglycolic acid (PGA), a polylactic acid-glycolic acid copolymer (PLGA), a polydioxanone, a polylactic acid-polyethylene oxide copolymer, hyaluronic acid or the like.

The adhesive can adhere the polymer layer to the inner wall tissue of the blood vessel to prevent shedding, including gelatin, starch, agar, mannan, alginic acid, polyacrylic acid, polyacrylate adhesive, dextrin, methyl cellulose. , methyl vinyl ether, copolymer of maleic anhydride, gum arabic, scutellaria gum, paulownia gum, locust bean gum, cyanoacrylate adhesive, polyurethane adhesive, silicone adhesive, fibrin Adhesive, mussel mucin adhesive, etc.

The drug is antithrombotic, proliferative, anti-inflammatory, anti-inflammatory, anti-proliferative, anti-tumor, anti-mitotic, cytostatic, cytotoxic, anti-angiogenic, anti-restenosis, inhibition of microtubule, anti-metastatic or antithrombotic Substance, preferably acemetacin, aescin, aminopterin, antimycotics, arsenic trioxide, aristolochic acid, aspirin, berberine, ginkgo phenol, rapamycin and its derivatives, paclitaxel, docei Paclitaxel, antibiotics (especially actinomycin-D), hormones, and antibody-based cancer drugs.

The invention solves the problems that the absorption time of the medicine in the traditional drug balloon is short, the absorption amount is low, and the individual difference is large. After the interventional procedure, the polymer layer carries the drug to the lesion and uniformly releases the drug from 5 minutes to 6 months.

The drug balloon of the invention has the following beneficial effects: (1) the coating is combined with a special double-layer balloon, and a solution such as physiological saline is exuded from the balloon wall during the expansion of the outer balloon to dissolve the water-soluble bottom layer. It converts the connection function into a lubrication function to control the release of the drug-containing degradable polymer layer; (2) the polymer layer can uniformly release the drug to the entire diseased tissue for a long time, and maintain sufficient surrounding of the diseased cells for a long period of time. Drug concentration; (3) degradable polymer layer (film) may also contain Adhesive, which is more conducive to adhesion to the inner wall of the blood vessel and has certain toughness, and will not break like a stent due to external forces such as compression and torsion of the blood vessel; (4) no stent exists in the human body for a long time, and the coating can be relatively short. Degradation or dissolution in time does not affect re-endothelialization; (5) Compared with the conventional drug-eluting balloon technique, the present invention reduces the amount of drug loss, increases the amount of drug absorption, requires less drug loading, and has less toxicity to the system.

DRAWINGS

In order to more clearly describe the technical solution of the present invention, a brief description will be made below with reference to the accompanying drawings. It is apparent that these drawings are only some of the specific embodiments described herein. The invention includes, but is not limited to, the drawings.

FIG. 1 is a schematic view showing a cross-sectional structure of a drug balloon after an inner balloon is expanded according to an embodiment of the present invention. As shown, the inner balloon acts as an angioplasty, in which case the degradable polymer layer remains firmly bonded to the outer wall of the balloon.

2 is a schematic view showing a cross-sectional structure of a drug balloon according to an embodiment of the present invention, in which the inner and outer balloons are expanded. As shown, when the outer balloon is dilated, its expansion fluid (such as saline) can penetrate the pores in the outer wall of the balloon to dissolve the water-soluble bottom layer, thereby degrading the polymer layer containing the drug and optional adhesive. Separated from the balloon.

FIG. 3 is a schematic structural view of a longitudinal section of a drug balloon according to an embodiment of the present invention.

FIG. 4 is a schematic structural view of a drug balloon in a process of withdrawing a balloon according to an embodiment of the present invention. As shown, the balloon is withdrawn from the body and a layer of degradable polymer containing the drug and optional adhesive adheres to the inner wall of the blood vessel, releasing the drug to adjacent tissue over a period of minutes to months of dissolution or degradation.

detailed description

In order to further understand the present invention, the preferred embodiments of the present invention will be described below in conjunction with the embodiments. These descriptions are merely illustrative of the features and advantages of the drug balloon of the present invention, rather than limiting it. The scope of protection of the invention.

Example 1

1. Double balloon preparation

A double-layered balloon was prepared according to the method described in Chinese Patent Application No. 200610025200.8 owned by the present applicant.

2. Coating preparation

2 g of polyvinylpyrrolidone (PVP, molecular weight 10,000) was weighed, added to 5 ml of isopropyl alcohol (IPA) solution, and stirred well until PVP was completely dissolved. The inner layer of the double-layer balloon was expanded, immersed in the above solution, and then dried in an oven at 40 ° C to form a water-soluble bottom layer, and the outer diameter of the middle portion of the balloon was measured to be 30.109 mm.

2 g of polylactic acid-glycolic acid copolymer (PLGA) (50/50), 0.01 g of cyanoacrylate and 300 mg of paclitaxel were dissolved in 10 ml of tetrahydrofuran (THF) solution, and stirred well until all the ingredients were completely dissolved. The balloon coated with the water-soluble primer layer was then immersed in the above solution, dried in an oven at 40 ° C, and repeatedly immersed 3 times. After drying, the outer diameter of the middle portion of the balloon was measured by a caliper to be 30.121 mm.

As a result of calculation, the thickness of the degradable polymer layer was 6 μm.

Example 2

1. Double balloon preparation

2. Coating preparation

2 g of PVP (molecular weight 10,000) was weighed, added to 5 ml of IPA solution, and stirred well until PVP was completely dissolved. The inner layer of the double-layer balloon was expanded, immersed in the above solution, and then dried in an oven at 40 ° C to form a water-soluble bottom layer, and the outer diameter of the middle portion of the balloon was measured to be 30.109 mm.

Weigh 2g PLGA (50/50), 0.01g cyanoacrylate dissolved in 10ml THF solution, charge Stir until the ingredients are completely dissolved. The balloon coated with the water-soluble primer layer was continuously dipped in the above solution, and then dried in an oven at 40 ° C, repeatedly immersed twice, and completely dried. Finally, a layer of paclitaxel was sprayed on the surface of the polymer layer by ultrasonic spraying. To ensure effective adhesion of the polymer coating to the blood vessel, a length of 1 mm was reserved at both ends of the coating without spraying the drug. The caliper measures the outer diameter of the middle part of the balloon to be 30.126 mm.

As a result of calculation, the thickness of the degradable polymer layer including the drug layer was 8.5 μm in total.

Example 3

The isolated porcine artery vascular segment, which is similar in diameter to the balloon, was immediately immersed in pig blood supplemented with anticoagulant, kept at 37 ° C, and the drug balloon was passed through the 6F catheter in a folded state for 1 minute, then the balloon entered the blood vessel. In the inner cavity, the inner balloon first expands (12 atm) to achieve the purpose of blood vessel formation, and then the outer balloon is infused with physiological saline, and the water-soluble bottom layer dissolves and disappears (about 1 minute) to withdraw the balloon, and the degradable polymer layer forms a The layer film adheres to the inner wall of the blood vessel.

Another latex hose with a diameter similar to that of the balloon was immersed in a 37 ° C constant temperature phosphate buffer (PBS, pH = 7.4). The drug balloon entered the lumen of the latex hose in a folded state, and the inner balloon first expanded (12 atm). Then, the outer balloon is infused with physiological saline, and after the water-soluble bottom layer dissolves and disappears (about 1 minute), the balloon is withdrawn, and the polymer layer is degraded to form a film adhered to the inner cavity of the latex tube, and the latex tube is degradable. The film was placed in a basket of a drug dissolution apparatus, and the dissolution medium was a constant temperature PBS (pH=7.4) at 37 ° C ± 0.5 ° C, and the number of rotations was 100 rpm. After sampling at intervals of 1 hour, the drug was dissolved by HPLC. As a result, the degradable polymer layer releases about 40% of the drug during the first 24 hours.

The above description of the embodiments is merely for helping to understand the core idea of the present invention. It should be noted that those skilled in the art can also make several improvements and modifications to the drug coating of the balloon of the present invention and the preparation method thereof without departing from the principle of the present invention, but these improvements and modifications also fall. It is within the scope of the claims of the present invention.

Claims

A drug balloon, comprising a double-layer balloon, characterized in that a coating layer is disposed on an outer balloon surface of the double-layer balloon, the coating sequentially comprising a water-soluble primer layer and a biodegradable drug-containing substance Polymer layer.
The drug balloon according to claim 1, wherein the drug is dispersed in the biodegradable polymer layer, or the drug-containing biodegradable polymer layer is included on the biodegradable polymer layer Another layer of drug is applied.
The drug balloon of claim 1 wherein said drug-containing biodegradable polymer layer further comprises an adhesive.
The drug balloon according to claim 3, wherein the drug-containing biodegradable polymer layer is a layer structure comprising a biodegradable polymer, an adhesive, and a drug, or comprises a polymer, an adhesive, and The two-layer structure of any combination of drugs, or a three-layer structure in which a polymer, an adhesive, and a drug are separately coated.
The drug balloon according to any one of claims 1 to 4, wherein the water-soluble primer layer is made of a water-soluble material selected from the group consisting of natural water-soluble polymers, modified starches, and modified Cellulose, chemically modified natural polymer or synthetic polymer.
The drug balloon according to claim 5, wherein the natural water-soluble material is selected from the group consisting of starch, cellulose, vegetable gum or animal glue, and the chemically modified natural polymer is selected from the group consisting of carboxymethyl starch and acetic acid. Starch, hydroxymethylcellulose or carboxymethylcellulose, and the synthetic polymer is selected from the group consisting of polyacrylamide, hydrolyzed polyacrylamide or polyvinylpyrrolidone.
The drug balloon according to any one of claims 1 to 4, wherein the drug-containing biodegradable polymer layer has a thickness of less than 10 μm.
The drug balloon according to claim 7, wherein the drug-containing biodegradable polymer layer has a thickness of from 0.2 μm to 9 μm.
The drug balloon according to claim 8 wherein said drug-containing organism is The thickness of the degraded polymer layer is from 0.5 μm to 8.5 μm.
The drug balloon according to any one of claims 1 to 4, wherein the biodegradable polymer is selected from the group consisting of polyhydroxyalkanoates, polyhydroxybutyrate compounds, and poly(glycerol-oxime). Diacid), polypeptide, polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, polydioxanone, polylactic acid-polyethylene oxide copolymer or hyaluronic acid.
The drug balloon according to claim 3 or 4, wherein the adhesive is selected from the group consisting of gelatin, starch, agar, mannan, alginic acid, polyacrylic acid, polyacrylate adhesive, dextrin, and methyl fiber. , methyl vinyl ether, copolymer of maleic anhydride, gum arabic, scutellaria gum, paulownia gum, locust bean gum, cyanoacrylate adhesive, polyurethane adhesive, silicone adhesive, fiber Protein adhesive or mussel mucin adhesive.
The drug balloon according to any one of claims 1 to 4, wherein the drug is selected from the group consisting of antithrombotic, anti-inflammatory, anti-inflammatory, anti-proliferative, anti-tumor, anti-mitotic, cytostatic, cytotoxic, anti-drug Angiogenesis, anti-restenosis, inhibition of microtubules, anti-metastatic or antithrombotic substances.
The drug balloon according to claim 12, wherein the drug is selected from the group consisting of acemetacin, aescin, aminopterin, antimycotics, arsenic trioxide, aristolochic acid, aspirin, berberine, Ginkgo phenol, rapamycin and its derivatives, paclitaxel, docetaxel, antibiotics, hormones or antibody cancer drugs.
The drug balloon according to claim 13, wherein the antibiotic is actinomycin D.
A method of preparing a drug balloon according to any of the preceding claims, comprising providing a double-layered balloon, making a water-soluble bottom layer on the outer balloon surface thereof, and then producing a biodegradable drug-containing and optional adhesive Polymer layer.