WO2013152713A1

WO2013152713A1 - Drug balloon based on hydrogen-bond interaction and coating method therefor

Info

Publication number: WO2013152713A1
Application number: PCT/CN2013/073941
Authority: WO
Inventors: 郭芳; 谢志永; 卢惠娜; 李孝秀; 张滢涛; 孙芳华; 常孟琪; 宋林飞; 罗七一
Original assignee: 上海微创医疗器械（集团）有限公司
Priority date: 2012-04-10
Filing date: 2013-04-09
Publication date: 2013-10-17
Also published as: CN102657900A

Abstract

Disclosed is a drug coated balloon based on hydrogen-bond interaction and the coating method therefor. The balloon comprises a balloon surface and a drug layer containing an active drug. The balloon surface carries hydrophilic groups as a result of treatment or modification; there is hydrogen-bond interaction between the balloon surface and the drug layer. The hydrogen-bond interaction increases the binding force between the drug layer and the balloon surface, thus ensuring the extensibility of the coated layer and favoring the loading of a drug on the balloon surface.

Description

Drug balloon based on hydrogen bonding and coating method thereof

The invention relates to the field of medical devices. More specifically, the present invention relates to a hydrogen balloon-based drug balloon and a coating method therefor. Background technique

Since the 1970s, intraluminal balloon angioplasty has been widely used to treat stenosis caused by atherosclerosis. Although the immediate therapeutic effect of balloon angioplasty is satisfactory, the incidence of surgical complications, especially restenosis, is high, limiting its clinical application. Endovascular stenting is the implantation of a stent (which can be a bare stent or a drug stent) in the stenosis site while the balloon is dilating. The stent can prevent the stenosis caused by vascular stratification and elastic retraction, and can significantly reduce the acute interventional treatment. Or subacute ischemic complications. However, analysis of clinical results for many years indicates that there are still some complications in this technique, such as inflammation, intimal tear, vascular endothelial cell proliferation, etc., which may lead to vascular restenosis. Drug-coated balloons are an emerging means of endovascular treatment in recent years, which avoids endothelialization disorders caused by continuous drug contact, drug-coated balloons or drug-coated balloon-based bare metal stents. A good prospect. Since the launch of the first generation of drug balloons (product name: SeQuent Please), many drug balloons have been marketed in Europe. The key to a drug balloon is how to achieve an effective bond between the drug coating and the balloon surface. If the adhesion between the drug coating and the balloon surface is small, the balloon is easily detached during folding, or lost during delivery during implantation of the lesion, or expansion prior to contact with the target lesion. The rupture falls off and is washed away. A research hotspot in today's drug balloons is the development of new drug coating methods. The applicant is a patent application of Beijing Tiandi Hexie Technology Co., Ltd.

No.200910084768.0 (Publication No. CN101549186) relates to a balloon-expanding catheter carrying a drug. The balloon dilatation catheter includes a balloon and a plurality of drugs coated on the balloon, wherein one of the drugs is probucol. Since probucol can not only greatly increase the absorption rate of drugs by intravascular cells, but also reduce the loss of other therapeutic drugs during blood transport, the multi-drug-carrying balloon dilatation catheter described in the present application has Compared with balloon dilatation catheters, it is more effective in preventing and treating restenosis. It is especially suitable for the treatment of in-stent restenosis of coronary, carotid, renal artery and other blood vessels, or to replace the existing drug stents. A mild lesion with a mild degree of stenosis and a small number of stenotic vessels. The patent application focuses on one of the coated drugs, Probucol, which does not disclose or imply that the drug and the additive are firmly applied to the surface of the balloon by hydrogen bonding forces. The applicant's patent application No. 200710150413.8 (publication number CN101264347) of Tianjin Baichang Medical Device Technology Co., Ltd. relates to a drug coating applied to the surface of a balloon catheter balloon for relieving vascular restenosis, and particularly relates to a postoperative relief A drug coating applied to the surface of the balloon in the balloon catheter by restenosis of the blood vessel and reducing free radical damage. The drug coating is composed of 1%-99% of a drug and 1%-99% of a drug carrier, and the drug may be selected from a single antioxidant drug, a mixture of a plurality of antioxidant drugs, and a single or multiple antibodies. A combination of an oxidizing drug and a combination of anti-vascular restenosis drugs. The drug is uniformly applied to the surface of the balloon by a mixed or layered coating method, and the topical drug can effectively alleviate and reduce the damage of free cells to human cells and tissues after myocardial ischemia and reperfusion. Treat heart dysfunction. The patent application focuses on the combination of drug and carrier, and does not disclose or suggest balloon surface treatment or modification and addition of low molecular weight hydrophilic additives. The applicant's patent application No. 201010121627.4 (publication number CN101785900A) of Chengdu Weide Medical Devices Co., Ltd. relates to a drug balloon catheter and a preparation method thereof. The outer surface of the balloon of the drug balloon catheter is a non-planar structure having irregularities. The drug balloon catheter uses ultraviolet laser grinding to process the outer surface of the balloon, so that the outer surface of the balloon forms a non-planar structure with irregularities. No contact, no processing heat due to laser grinding Characteristics, the balloon still maintains its original strength after processing. The drug balloon catheter has a non-planar structure with irregularities on the outer wall surface of the balloon, so that the drug adsorption and storage capacity is fundamentally improved, that is, the amount of adsorbed drugs is greatly increased, and the second is that the drug adsorbed by the balloon is in the blood vessel. By reaching the lesion site, the drug adsorbed on the outer wall of the balloon can be prevented from being washed away by the blood in the blood vessel as much as possible, and can be effectively transported through the balloon to the lesion site, thereby effectively treating the disease. The drug balloon catheter can be applied not only to coronary heart disease, but also to various other diseases in which various ducts are narrowed, such as stenosis and occlusion of lower extremity arteries due to diabetes. The focus of this patent application is that in order to increase the drug loading, the outer surface of the balloon of the drug balloon catheter is a non-planar structure having irregularities. The applicant's patent application No. 200920268650.9 (publication number CN201524344U) of Dongguan Dikai Precision Pipe Co., Ltd. relates to a novel balloon catheter carrying a drug microcapsule. The balloon catheter consists of a proximal tube, a distal tube, a balloon, a drug microcapsule, and a flexible tip. The balloon is a memory folding balloon and is coated with a microcapsule in a folded balloon using a special infiltration technique. The inner surface of the pleats. The folded balloon can be a two-, three-, and five-flap folded balloon. The drug encapsulated in the drug microcapsule is a traditional Chinese medicine extract for preventing and treating vascular restenosis, such as water extract of Salvia miltiorrhiza. After concentration, the corresponding auxiliary material is added. It is made into powdery granular drug microcapsules. The utility model has the advantages of enhancing the targeting of the carrier drug, accurately positioning, slowly releasing the drug at a regular time, realizing the purpose of long-term treatment, and fundamentally preventing the occurrence of vascular restenosis. The focus of the utility model is on the use of folding technology to wrap the drug. In order to improve the performance of the drug balloon, the prior art has been improved from many aspects such as drug and balloon structure. However, there is still a need to find a breakthrough in other aspects, such as the combination of balloon surface and drug. Summary of the invention

The present invention provides a drug balloon based on hydrogen bonding, comprising a balloon surface and a drug layer containing an active drug, wherein the balloon surface is treated or modified to carry a hydrophilic group, and There is hydrogen bonding between the balloon surface and the drug layer. By chemically modifying the active drug to carry more hydrophilic groups, and/or further containing a hydrophilic group-containing additive through the drug layer, hydrogen bonding exists between the balloon surface and the drug layer, thereby Increases the adhesion, maintains the ductility of the coating, and facilitates the loading of the drug on the surface of the balloon. The present invention also provides a method for coating a drug balloon based on hydrogen bonding, comprising: treating or modifying a surface of a balloon with a hydrophilic group; and administering an active drug and optionally a hydrophilic agent The additive of the group is dissolved in an organic solvent to form a mixed solution; and the mixed solution is applied to the surface of the balloon by spraying or dipping to form a drug coating. According to the present invention, the surface of the balloon is treated or modified to have a hydrophilic group and a hydrophilicity without affecting the physical and chemical properties of the matrix of the balloon material. The balloon material is a polymer material such as nylon, Pebax, polyethylene, etc. well known to those skilled in the art. Preferably, the surface of the expandable balloon is subjected to low temperature plasma surface modification, and after the balloon material is treated with ammonia, oxygen or water plasma, various hydrophilic groups such as an amino group, a hydroxyl group and a carboxyl group are introduced on the surface of the material. Preferably, the balloon material is placed in an ozone atmosphere to introduce a layer of peroxyactive groups onto the surface. Preferably, the high-energy radiation such as a, β, γ-ray and x-ray is used to generate a radical or ionized active center on the surface or the body of the material, and the reactive group is used as a reaction site for graft polymerization or coupling, so that the surface is provided with Hydrophilic group. Preferably, the surface of the material is irradiated with ultraviolet light or visible light (wavelength of 200-800 nm) to cause a polymerization active center on the surface of the material to introduce a corresponding hydrophilic functional group. A resin which forms a resin layer with a hydrophilic group. Preferably, the polycarboxylic acid may be selected from one or more of polymers of acrylic acid, methacrylic acid, maleic acid, aspartic acid or glutamic acid, starch, cellulose, alginic acid, pectin and the like. . Preferably, the active drug is a fat-soluble drug. Preferably, the fat-soluble drug is selected from one or more of an anticancer drug, an anticoagulant, a microbial immunosuppressive agent, and other anti-restenosis drugs, including but not limited to paclitaxel, rapamycin or a derivative thereof. Things and so on. The anticancer drug is selected from the group consisting of methotrexate, anthraquinone, pyrimidine, plant alkaloid, epothilone, tripterygium wilfordii compound, antibiotic (especially actinomycin-D), hormone, antibody treatment One or more of cancer drugs. Preferably, the plant alkali anticancer drug is paclitaxel. The anticoagulant is selected from one or more of heparin, aspirin, hirudin, colchicine, and an anti-platelet GP lI b/IIIa receptor antagonist, said anti-platelet GP lI b/IIIa receptor The antagonist is selected from one or more of tirofiban, abciximab, and eptifibatide. The microbial immunosuppressive agent is selected from the group consisting of cyclosporine A, tacrolimus and homologues, desperin, enzymatic phenolic acid ester, rapamycin and its derivatives, strain of strain Streptomyces FR900520, chain Mold strains FR900523, daclizumab, valeramide, claramycin, sclarin, lycopene 25c, tranilast, myriocin, cyclosporine, bracemycin, mycophenol One or more of acid, brefeldin A, ketone corticosteroid. The other anti-restenosis drug is selected from the group consisting of bamastat, metalloproteinase inhibitor, 17β-estradiol, NO donor, 2-chlorodeoxyadenosine, 2-deoxy-assisin, fingolimod , mycophenolate sodium, cyclosporin A derivative ISA (TX) 247, acesulfab, sanipiride, basiliximab, antithymocyte, everolimus, methotrexate, neola , cyclophosphamide, benzoquina One or more of sodium, leflunomide, and imidazolyl. Preferably, the active drug is chemically modified without affecting the drug effect, such as by esterification, amidation, salt formation modification, ring formation or ring opening modification of the drug molecular structure, etc. The chemical structure carries more hydrophilic groups. Preferably, the additive is mainly a hydrophilic organic substance, including but not limited to a carboxylic acid containing a hydroxyl group -OH, an amino group -NH ₂ , an amide group -CONH - , a sulfonic acid group -SO ₃ H, a carboxylic acid group -COOH One or more functional groups of water-soluble organic matter. Preferably, the additive is water-soluble, such as a non-ionic water-soluble polymer having a molecular weight of less than 50,000, including but not limited to PVP, PEG (Mn<5000), PEO, Tween 20, PEO-PPO-PEO, PVA, Polyurea, polyester, etc. Preferably, the additive is a bio-soluble plasticizer. In addition to improved adhesion, the plasticizer can also increase the ductility of the coating to prevent brittle cracking of the coating during folding or expansion. The additives include, but are not limited to, triethyl citrate, trihexyl citrate, diisononyl cycline-1,2-dicarboxylate, ethyl lactate, benzyl alcohol, citric acid, triacetic acid anhydride, etc. One or more. Preferably, the additive is a monosaccharide, a polysaccharide, a cellulose, etc., and some monosaccharides can reduce the hygroscopic effect of the hygroscopic additive on the active drug, and some anionic polysaccharides can also increase the adhesion between the drug and the cell. Some water soluble celluloses increase the strength and toughness of the coating. Such additives include, but are not limited to, dextran, sulfonated dextran, sodium hyaluronate, hyaluronic acid, pectin, mannitol, methylcellulose, vinylcellulose, hydroxypropylcellulose, and the like. Preferably, the weight ratio of the active drug to the additive is between 1:0.01-50. Preferably, the weight ratio is between 1:0.1 and 3. Preferably, the active drug and the additive are dissolved in an organic solvent to form a mixed solution, including but not limited to methanol, ethanol, acetone, tetrahydrofuran, dimethylformamide, isopropanol, acetonitrile, ethyl acetate, etc. One or more mixtures with water. Preferably, the drug coating can be applied to the surface of the balloon by spraying or dipping. In a specific embodiment, the expandable balloon surface of the present invention is provided with a drug layer composed of an active drug and an additive, wherein the balloon surface is treated or modified to be coated before the drug is applied to the surface of the balloon. The hydrophilic group is simultaneously selected, and the hydrophilic additive is selected to increase the adhesion between the drug layer and the balloon surface by utilizing the hydrogen bonding between the balloon surface and the additive. In another embodiment, the active drug is directly chemically modified without affecting the efficacy of the drug, so that the chemical structure of the drug carries more hydrophilic groups, thereby utilizing the surface of the balloon and the active drug. The hydrogen bonding between the two increases the adhesion between the drug and the balloon surface. With regard to the latter embodiment, if necessary, various additives described above may be added to the drug layer, and the effects are also expected. 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 the drawings are only specific embodiments of the present application and are not intended to be limiting. Figure 1 shows an optical electron micrograph of the drug balloon a of Example 1;

Fig. 2 shows an optical electron micrograph of the drug balloon b of Example 1. 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 only illustrative of the features and advantages of the invention and are not intended to limit the scope of the invention. Example 1

75 mg of paclitaxel, 30 mg of trihexyl citrate, dissolved in 4 ml of acetone and an aqueous solution (acetone: water = 7.5:1), and sonicated for 10 min to form a uniformly dispersed mixed solution. The above solution was sprayed on five non-treated nylon-based balloons (3.0*20) to make the drug loading amount to about 3 g/mm ² , dried, and folded to obtain a drug balloon a. The above solution was sprayed on 5 nylon-based balloon surfaces (3.0*20) which were previously subjected to plasma oxygen treatment for 5 minutes, and the drug loading amount was about 3 g/mm ² , dried, and folded to obtain a drug balloon b. The balloon was observed by electron microscopy. It was found that during the folding process of the balloon, the drug balloon a had some drug shedding phenomenon. When the folded balloon a was expanded again, the drug collapsed at the balloon fold (as shown in Fig. 1). The drug balloon b has no drug shedding during the folding process, and the balloon surface is smooth and uniform after being expanded again (as shown in Fig. 2). Example 2

The nylon-based balloon was ozonized for 10 min to give the balloon a -OO group; 75 mg of paclitaxel and 45 mg of PEG (Mw < 5000) were dissolved in 4 ml of acetone and ethanol (acetone:ethanol = 3:1) The mixture is formed in the mixture, and the solution is sprayed on the surface of the balloon, dried, and folded to obtain a drug balloon. Example 3

X-ray treatment of nylon-based balloon for 3 min; dissolving 75 mg of rapamycin and 45 mg of PEG (Mw<5000) in 4 ml of acetone and ethanol (acetone:ethanol = 3:1) to form a mixture The solution is sprayed on the surface of the balloon, dried, and folded to obtain a drug balloon. Example 4

Irradiation of the Pebax-based balloon surface with ultraviolet light having a wavelength of 400 nm for 5 min; 37.5mg of rapamycin and 30mg of glycerol are dissolved in 2-4ml of acetone and water (acetone: water = 7.5: 1) to form a mixture, spray the above solution on the surface of the balloon, dry, fold, then Get a drug balloon. Example 5

At room temperature, the Pebax-based balloon was immersed in a 1 mol/L aqueous solution of acrylic acid in lOmin and vacuum-dried; 75 mg of rapamycin and 30 mg of PVP were dissolved in 4 ml of acetone and water (acetone:water = 7.5: 1) A mixed solution is formed, and the above solution is sprayed on the surface of the balloon, dried, and folded to obtain a drug balloon. In the drug balloon of Example 2-5, no drug was peeled off during the folding process, and after the balloon was expanded again, the surface of the balloon was smooth and uniform, and the same effect as that of the drug balloon b of Example 1 was obtained. 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 make several improvements and modifications to the present invention without departing from the principles of the present invention, but such modifications and modifications are also within the scope of the claims of the present invention. .

Claims

Claim

A drug balloon based on hydrogen bonding, comprising a balloon surface and a drug layer containing an active drug, wherein the balloon surface is treated or modified to carry a hydrophilic group, and the ball There is hydrogen bonding between the surface of the capsule and the drug layer.

2. The drug balloon of claim 1, wherein the drug layer further comprises an additive having a hydrophilic group.

The drug balloon according to claim 1 or 2, wherein the active drug is modified by a chemical structure to carry more hydrophilic groups without affecting the drug effect.

4. The drug balloon of any of the preceding claims, wherein the material of the balloon is selected from the group consisting of nylon, Pebax and polyethylene.

The drug balloon of any of the preceding claims, wherein the active drug is a fat-soluble drug, including but not limited to paclitaxel, rapamycin or a derivative thereof.

6. A method of coating a drug balloon based on hydrogen bonding, comprising:

Treating or modifying the surface of the balloon with a hydrophilic group;

Dissolving the active drug and optionally the hydrophilic group-containing additive in an organic solvent to form a mixed solution;

The mixed solution is applied to the surface of the balloon by spraying or dipping to form a drug coating.

7. The method of claim 6 wherein the step of treating or modifying the surface of the balloon is selected from:

(1) The surface of the expandable balloon is subjected to low temperature plasma surface modification, and the balloon material is treated with ammonia, oxygen, water plasma to introduce an amino group, a hydroxyl group, a carboxyl group hydrophilic group on the surface of the material; (2) placing the balloon material in an ozone atmosphere to introduce a layer of peroxyactive group on the surface;

(3) Using a, β, γ-rays and X-rays to generate free radicals or ionized active centers on the surface or bulk of the material, graft polymerization or coupling with reactive groups as reaction sites, and having hydrophilic groups on the surface Mission

(4) illuminating the surface of the material with ultraviolet light or visible light to cause a polymerization active center on the surface of the material to introduce a corresponding hydrophilic functional group;

(5) A negatively chargeable resin polycarboxylic acid or a polycarboxylic acid derivative is coated on the surface of the balloon to form a resin layer having a hydrophilic group.

The method according to claim 6 or 7, wherein said additive is (1) water-soluble one or more functional groups containing -ΟΗ, -ΝΗ ₂ , -CONH -, -SO ₃ H, -COOH An organic substance, preferably a nonionic water-soluble polymer having a molecular weight of less than 50,000, including but not limited to PVP, PEG (Mn < 5000), PEO, Tween 20, PEO-PPO-PEO, PVA, polyurea, polyester; (2) biological Soluble plasticizers, including but not limited to triethyl citrate, trihexyl citrate, diisononyl cyclohexane-1,2-dicarboxylate, ethyl lactate, benzyl alcohol, citric acid, triacetic anhydride One or more of oils and fats; and/or (3) monosaccharides, polysaccharides and cellulose, including but not limited to dextran, sulfonated dextran, sodium hyaluronate, hyaluronic acid, pectin, mannitol , methyl cellulose, vinyl cellulose, hydroxypropyl cellulose.

The method according to any one of claims 6-8, wherein the weight ratio between the active drug and the additive is between 1:0.01 and 50, preferably between 1:0.1 and 3.