Expandable self-adhesive hollow tubular structure for treating blood vessels as well as preparation method and application of expandable self-adhesive hollow tubular structure

Abstract

The invention relates to an expandable self-adhesive hollow tubular structure for treating blood vessels, which is a multi-layer composite system and comprises at least the following functional layers: an antifouling drug-loading layer, an expandable drug-loading support layer and a pressure-sensitive biological adhesion layer. Wherein the inner layer of the hollow tubular structure is an antifouling drug-loading layer and a polymer layer with antifouling, anticoagulation and endothelial growth promoting functions, the middle layer is an expandable drug-loading supporting layer, and the outer layer is a biological adhesion layer capable of adhering to the blood vessel wall. The hollow tubular structure can be arranged on the outer surface of an intervention balloon in a sleeving mode, a common balloon serves as a conveying carrier, the balloon dilates the tubular film to be attached to the inner wall of a blood vessel, the inner layer of the hollow tubular structure makes contact with blood, the middle layer is dilated and disengaged, the outer layer is pressed to be attached to the wall of the blood vessel, and precise drug positioning treatment of related lesions in the blood vessel is achieved; and a solution is provided for clinical vascular wall drug release. The invention further relates to a preparation method and application of the hollow tubular structure.

Description

Technical Field

[0001] The invention relates to the technical field of implantable prostheses, and in particular to an expandable self-adhesive hollow tubular structure for treating blood vessels, a preparation method and application thereof. Background Art

[0002] The cause of the most deaths from cardiovascular diseases is still coronary heart disease, which is mainly caused by atherosclerosis. The implementation of coronary artery intervention has greatly improved obstructive coronary artery lesions (atherosclerosis). At home and abroad, it has now developed into coronary artery intervention drug-eluting balloons and coronary artery intervention drug-eluting stents, but these interventional treatments still have certain limitations. Drug-eluting balloons have problems such as difficult control of local drug concentration, crystal embolism and poor long-term effectiveness; while the latest coronary artery stents reduce the occurrence of late and very late thrombotic events, but the incidence of in-stent restenosis remains at 5% to 10%, and patients need to take drugs for a long time. Therefore, exploring new coronary intervention treatment methods is of great significance to reducing the incidence of complications of coronary artery intervention and reducing subsequent treatment. In addition, after the current balloon stent is implanted in the blood vessel, the patient needs to take anticoagulants and other drugs for a long time, which has unnecessary harm to the patient's whole body. Therefore, exploring new, precisely positioned drug implantation treatment methods is of great significance to the improvement of interventional treatment.

[0003] In order to solve the current problems of intravascular restenosis and treatment of vascular lesions after coronary intervention, a multifunctional self-adhesive multilayer degradable drug-loaded expandable tubular membrane has been developed with a simple process and the advantages of the current new drug eluting balloon and drug eluting stent, providing a new solution for minimally invasive coronary intervention and clinical vascular precision drug treatment.

[0004] Chinese invention patent CN202410738680.0 discloses a self-repairing vascular patch and its delivery system, which adopts a double balloon structure. The first balloon is used to block blood flow, and the patch is arranged outside the second balloon. The balloon and the patch have liquid outlet holes. The balloon expands after being delivered to the designated position. The adhesive in the second balloon is delivered to the space between the patch and the blood vessel wall through the liquid outlet hole, so as to achieve the adhesion between the blood vessel and the patch and achieve the purpose of blood vessel repair. The disadvantages of this invention are: (1) The delivery system needs to design a special balloon, including the first balloon and the second balloon, and the balloon surface is designed with holes and filled with liquid, and the balloon structure is complicated. (2) The adhesive in the delivery system cannot guarantee that it will not leak to other locations. The adhesive is in a liquid state. After the balloon expands and is injected from the liquid outlet hole, it cannot guarantee that the adhesive will only stay between the patch and the blood vessel wall. It may leak to the balloon surface, thereby sticking to the balloon, blood vessel and patch, affecting the surgical operation and actual effect.

[0005] Chinese invention patent CN201310572145.4 discloses a drug-coated balloon and its preparation method, and designs a multi-coated drug-coated balloon. By using a special double-layer balloon with micropores on the surface, a coating is applied to the surface of the balloon. After the balloon is delivered to the designated site, the micropores release liquid to dissolve the innermost coating layer, thereby separating the coating from the balloon. Finally, the outermost adhesive layer of the coating is used to adhere to the blood vessel wall to achieve adhesion of the coating to the blood vessel wall. The disadvantages of this invention are: (1) In order to separate the balloon from the coating, a hydrophilic coating and a balloon with a special structure are designed, and a special double-layer microporous balloon is used, resulting in a complex balloon structure. (2) The outermost layer of the balloon coating is an adhesive coating, which cannot be controlled to have adhesiveness only at the lesion site during balloon delivery. It will inevitably adhere to the blood vessels during delivery in the blood, causing difficulties in surgery.

[0006] Therefore, how to develop a hollow tubular structure with simple structure, expandable self-adhesion and anti-pollution to overcome the limitations of existing technologies and provide an effective way for minimally invasive coronary intervention and clinical vascular precision drug treatment is an urgent problem that needs to be solved. Summary of the invention

[0007] In view of the technical problems existing in the prior art, the first object of the present invention is to provide an expandable self-adhesive hollow tubular structure for treating blood vessels.

[0008] The second purpose of the present invention is to provide a method for preparing the above-mentioned hollow tubular structure, using a degradable polymer and an intravascular therapeutic drug as raw materials, adopting a simple dip-coating method to prepare a drug-loaded tubular membrane (composite double-layer structure), and dip-coating pressure-sensitive bioadhesive microcapsules on the outermost layer of the tubular membrane to obtain a three-layer structure.

[0009] The third purpose of the present invention is to provide an application of the above-mentioned hollow tubular structure, which is used for interventional treatment of vascular lesions, providing a new treatment plan for other lesions in blood vessels such as vascular tumors, arterial inflammation, vascular damage, etc., and achieving precise positioning and precise release of drugs at the site of diseased blood vessels through minimally invasive means, which can reduce unnecessary harm to the body of patients from large doses of oral drugs.

[0010] In order to achieve the above object, the present invention adopts the following technical solution:

[0011] An expandable self-adhesive hollow tubular structure for treating blood vessels, wherein the hollow tubular structure is a multi-layer composite system, comprising at least the following functional layers:

[0012] an antifouling drug-carrying layer, which is composed of an anticoagulant-modified polymer material and loaded with an endothelial growth-promoting drug, which can be added according to different therapeutic uses;

[0013] An expandable drug-loaded support layer, which is composed of a plastically deformable degradable polymer and loaded with anti-tumor or anti-intimal hyperplasia drugs;

[0014] The pressure-sensitive bioadhesive layer is composed of multiple pressure-sensitive microcapsules, which trigger the adhesion function through mechanical pressure;

[0015] The hollow tubular structure is delivered in cooperation with an interventional balloon, and the balloon is expanded to make the hollow tubular structure adhere to the inner wall of the blood vessel, and automatically separate from the balloon after expansion.

[0016] Furthermore, the hollow tubular structure is a three-layer structure, comprising:

[0017] The inner layer is defined as the antifouling drug-carrying layer, wherein the anticoagulant modified polymer material is selected from heparin-modified polymers, and the endothelial growth promoting drug is selected from RSNO (resonance stabilized nitroso oxide), GSNO (S-nitrosoglutathione), REDV polypeptide (called arginine-glutamic acid-aspartic acid polypeptide according to its constituent amino acid sequence) or RGD polypeptide (called arginine-glycyl-aspartic acid polypeptide according to its constituent amino acid sequence); the preferred anticoagulant modified polymer is heparin-modified polycaprolactone, and the preferred endothelial growth promoting drug is GSNO;

[0018] The middle layer is defined as the expandable drug-carrying support layer, wherein the degradable polymer is selected from polycaprolactone, polylactide-co-glycolide, polyethylene glycol, polylactic acid, poly-3-hydroxyalkanoate, polyvinyl alcohol, and the anti-tumor or anti-intimal hyperplasia drug is selected from rapamycin, paclitaxel, aspirin or simvastatin; the preferred degradable polymer is polycaprolactone, and the preferred drug is rapamycin;

[0019] The outer layer is defined as the pressure-sensitive bioadhesive layer, and a plurality of the pressure-sensitive microcapsules form a layered structure and have an adhesive inside, wherein the adhesive is selected from polyurethane, 2-hydroxyethyl acrylate, 2-octyl cyanoacrylate, urea-formaldehyde resin, polymethylene polyphenyl polyisocyanate, polyacrylic acid, chitosan, gelatin, tannic acid or hyaluronic acid, and the preferred adhesive is 2-octyl cyanoacrylate.

[0020] Furthermore, the microcapsule coating of the pressure-sensitive bioadhesive layer ruptures under the balloon expansion pressure to release the adhesive to adhere to the blood vessel wall.

[0021] Furthermore, the thickness of the hollow tubular structure is 20-300 μm, preferably 50 μm, which is achieved by adjusting the concentration of the organic solvent. The thickness of the hollow tubular structure after expansion by the balloon is 10-200 μm.

[0022] A method for preparing the above hollow tubular structure comprises the following steps:

[0023] (1) preparing an antifouling drug-carrying layer: dissolving an anticoagulant-modified polymer material in an organic solvent to form a first polymer solution, adding an endothelial growth-promoting drug, and then dipping and coating the solution on a mold surface after degassing to form an inner layer structure;

[0024] (2) preparing an expandable drug-loaded support layer: mixing an anti-tumor or anti-intimal hyperplasia drug and a degradable polymer to form a second polymer solution, and coating the second polymer solution on the surface of the inner layer structure by dip coating to form an expandable drug-loaded support layer, thereby obtaining a composite double-layer structure;

[0025] (3) Preparing a pressure-sensitive bioadhesive layer: spraying pressure-sensitive microcapsules onto the surface of the composite double-layer structure that is not completely dried to form a pressure-sensitive bioadhesive layer, thereby obtaining a hollow tubular structure.

[0026] Furthermore, in step (1), the anticoagulant modified polymer material is heparin-modified polycaprolactone, the organic solvent is chloroform, the concentration of the first polymer solution is 3-10wt%, preferably 4-5wt%, more preferably 4wt%, the endothelial growth promoting drug loading is 10-20mg, preferably 10-13mg, more preferably 12.9mg; in step (2), The drug is rapamycin, the degradable polymer is polycaprolactone, the solvent is selected from dichloromethane, tetrahydrofuran or chloroform, the preferred solvent is tetrahydrofuran, the concentration of the second polymer solution is 3-20wt%, the preferred second polymer solution concentration is 3-4wt%, and the more preferred second polymer solution concentration is 4wt%, the drug loading is 2-10mg, the preferred drug loading is 2-5mg, and the more preferred drug loading is 4.3mg, and the concentration of the drug in the solvent is 0.1-50mg / ml.

[0027] Furthermore, the mold in step (1) and step (2) is a solid rod, and vertical dipping is performed. After each dipping, a rotary drying process is performed. The number of dipping cycles of the composite double-layer structure is 2-4 times, and the preferred number of dipping cycles is 3 times.

[0028] Furthermore, the pressure-sensitive microcapsules are prepared by the following method:

[0029] (a) reacting toluene diisocyanate and 1,4-butanediol in cyclohexanone at a molar ratio of 2.5:1-3.0:1, under the following reaction conditions: temperature of 70-90° C., nitrogen protection, and for 20-28 hours to obtain a polyurethane prepolymer; wherein the molar ratio of toluene diisocyanate to 1,4-butanediol in cyclohexanone is preferably 2.7:1-2.9:1, more preferably 2.8:1, the preferred temperature is 80° C., and the preferred reaction time is 24 hours.

[0030] (b) vacuum drying the polyurethane prepolymer at 90-110° C. for 4-8 hours, preferably at 100° C., and preferably for 6 hours;

[0031] (c) preparing an aqueous solution containing a surfactant, heating it to 35-45° C., preferably a surfactant is Pluronic F-68 (block polyether F-68), and preferably heating it to 40° C.;

[0032] (d) dissolving the product of step (b) in methyl ethyl ketone to form a first oil phase at a concentration of 0.2-0.4 g / mL, preferably 0.3 g / mL;

[0033] (e) dissolving cyanoacrylate in methyl isobutyl ketone, and then adding p-toluenesulfonic acid monohydrate to form a second oil phase, wherein the concentration of cyanoacrylate is 0.4-0.6 g / mL, preferably 0.5 g / mL, and the concentration of p-toluenesulfonic acid monohydrate is 1.0-2.0 wt %, preferably 1.5 wt %;

[0034] (f) injecting the first oil phase and the second oil phase into the aqueous phase solution, controlling the stirring speed to 300-1500 rpm and the temperature to 25-50° C.;

[0035] (g) adding 1,4-butanediol dropwise and reacting for 1-3 hours, then washing and filtering to obtain a core-shell structured pressure-sensitive microcapsule.

[0036] Furthermore, in the step (a), the molar ratio of toluene diisocyanate to 1,4-butanediol is 2.7:1-2.9:1; in the step (f), the stirring speed is controlled from 300 rpm to 1500 rpm, and the temperature is controlled from 25° C. to 50° C.; in the step (g), the average particle size of the pressure-sensitive microcapsules is 20-250 μm, and this size is achieved by adjusting the synthesis process such as stirring rate and monomer concentration.

[0037] An application of the hollow tubular structure in interventional treatment of vascular lesions, such as vascular tumors, arterial inflammation, vascular damage and other lesions.

[0038] The present invention has the following advantages:

[0039] The present invention provides a hollow tubular repair structure adapted to an interventional balloon, which uses a three-layer composite membrane system to achieve therapeutic function integration: the outer layer is a pressure-sensitive bioadhesive layer, which triggers the rupture of microcapsules to release adhesives through balloon expansion, thereby achieving covalent bond binding with the blood vessel wall; the middle layer is an expandable drug-loaded support layer, which uses a degradable polymer as a carrier to encapsulate anti-proliferative drugs, provide mechanical support and continuously release drugs; the inner layer is an anti-fouling drug-loaded layer, which is loaded with anti-coagulation, anti-protein deposition and endothelial growth-promoting drugs to accelerate endothelial cell coverage. This structure is adapted to a standard interventional balloon, and after expansion, the diameter increases to 1.2-1.5 times and does not retract, and the balloon can be recovered after automatic separation.

[0040] After the hollow tubular structure of the present invention is expanded by balloon delivery, it has an ultra-thin feature, which is conducive to the endothelialization and degradation absorption of the implanted material, compared with the high thickness of the coronary stent to maintain mechanical properties. The outermost layer uses a pressure-sensitive bioadhesive layer in the form of microcapsules (microcapsules contain bioadhesives inside), which is not adhesive under normal conditions. After the balloon is expanded, the structure is compressed, and the microcapsules in the pressure-sensitive bioadhesive layer on the outer surface of the structure are broken to release the adhesive, thereby achieving the combination of the structure and the blood vessel wall.

[0041] Compared with existing vascular interventional devices, the present invention has the following innovations: (1) a uniform tubular membrane is prepared by dip-coating, replacing the complex weaving process of traditional stents, reducing costs and improving batch stability; (2) a drug-loaded hollow tubular structure is adopted, and the drug is carried by a degradable polymer. The drug-eluting balloon currently used in clinical practice only uses a mechanical embedding method to embed the drug into the inner wall of the blood vessel, which is washed by the blood flow and has problems such as difficult control of drug concentration, drug crystal shedding and embolism, and poor long-term effectiveness. The multifunctional tubular membrane prepared by the present invention can release drugs continuously, linearly and for a long time after being implanted in the lesion site, thereby reducing intimal hyperplasia and effectively reducing the incidence of restenosis; (3) After the hollow tubular structure is transported to the lesion site, it can realize accurate and low-dose release of drugs, which is safe and convenient compared to the large-dose regular drug administration after surgery of the current balloon stent; (4) It eliminates the risk of drug crystal shedding and solves the problem of blood flow flushing of drug-eluting balloons; the synergistic effect of dual drug sustained release significantly reduces the restenosis rate, and the degradation characteristics avoid the long-term complications of metal stents; no special modified balloon is required, and it is fully compatible with conventional interventional devices. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 It is a comparison diagram of the composite double-layer structure prepared in Example 1 of the present invention before and after expansion.

[0043] Figure 2 It is a comparison diagram of the composite double-layer structure prepared in Example 2 of the present invention before and after expansion.

[0044] Figure 3It is a comparison diagram of the composite double-layer structure prepared in Example 3 of the present invention before and after expansion.

[0045] Figure 4 It is a comparison diagram of the composite double-layer structure prepared in Example 4 of the present invention before and after expansion.

[0046] Figure 5 It is a comparison diagram of the composite double-layer structure prepared in Example 5 of the present invention before and after expansion.

[0047] Figure 6 It is a comparison diagram of the composite double-layer structure prepared in Example 6 of the present invention before and after expansion.

[0048] Figure 7 It is a stress-strain curve diagram of the polycaprolactone material used in Examples 1-6 of the present invention, showing its mechanical properties.

[0049] Figure 8 This is a diagram of the hollow tubular structure of Example 9 of the present invention being used for simulated vascular interventional treatment of a porcine cardiovascular system. DETAILED DESCRIPTION

[0050] The present invention is further described in detail below in conjunction with the examples, but the embodiments of the present invention are not limited thereto. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the field of the present technology. The test methods for which specific experimental conditions are not specified in the following examples are generally in accordance with conventional experimental conditions. Unless otherwise specified, the reagents and raw materials used in the present invention can be obtained commercially. Among them, the degradable polymers are purchased from Sigma-Aldrich and McLean, and other raw materials and organic solvents are purchased from McLean. The degradable polyethylene glycol, rapamycin, and GSNO in all the examples are purchased from McLean; the polycaprolactone in the examples is purchased from Sigma-Aldrich, chloroform is purchased from Guangzhou Tongyuan Chemical Technology Co., Ltd., tetrahydrofuran is purchased from Tianjin Komeo Chemical Reagent Co., Ltd., and TDI, cyclohexanone, and 1,4-butanediol are all purchased from McLean.

[0051] Example 1

[0052] Preparation of composite double-layer structures

[0053] (1) mixing and dissolving the heparin-modified polycaprolactone in chloroform to form a first polymer solution with a concentration of 4 wt %, and performing a degassing treatment;

[0054] (2) Use a solid bar as a mold and fix the solid bar with an electric rotating fixture;

[0055] (3) immersing the solid rod in the first polymer solution of step (2), performing dipping cycles twice, and naturally air-drying to form an inner layer structure, i.e., an antifouling drug-carrying layer, on the surface of the solid rod;

[0056] (4) dissolving the degradable polycaprolactone in tetrahydrofuran to obtain a second polymer solution having a concentration of 3 wt %, and performing a degassing treatment;

[0057] (5) The inner layer structure obtained in step (3) is dipped into the second polymer solution obtained in step (4), and naturally air-dried to obtain a composite double-layer structure having an antifouling drug-carrying layer and an expandable drug-carrying support layer, with a thickness of 30 μm and a thickness error of 10 μm. This structure does not have a bioadhesion function.

[0058] Example 2

[0059] The difference between this embodiment and embodiment 1 is that the dip coating in step (3) is cycled 3 times, the concentration of the second polymer solution in step (4) is 4 wt %, the thickness of the composite double-layer structure in step (5) is 50 μm, the thickness error is 10 μm, and the unmentioned parts are the same as in embodiment 1.

[0060] Example 3

[0061] The difference between this embodiment and embodiment 1 is that the concentration of the first polymer solution in step (1) is 5 wt %, the dip coating in step (3) is cycled 3 times, the thickness of the composite double-layer structure in step (5) is 80 μm, the thickness error is 20 μm, and the unmentioned parts are the same as in embodiment 1.

[0062] Example 4

[0063] The difference between this embodiment and embodiment 1 is that the concentration of the first polymer solution in step (1) is 5wt%, the dip coating in step (3) is cycled 3 times, the concentration of the second polymer solution in step (4) is 5wt%, the thickness of the composite double-layer structure in step (5) is 150μm, the thickness error is 20μm, and the unmentioned parts are the same as embodiment 1.

[0064] Example 5

[0065] The difference between this embodiment and embodiment 1 is that the concentration of the first polymer solution in step (1) is 8wt%, the dip coating in step (3) is cycled 3 times, the concentration of the second polymer solution in step (4) is 6wt%, the thickness of the composite double-layer structure in step (5) is 200μm, the thickness error is 20μm, and the unmentioned parts are the same as embodiment 1.

[0066] Example 6

[0067] The difference between this embodiment and embodiment 1 is that the concentration of the first polymer solution in step (1) is 8wt%, the dip coating in step (3) is cycled 3 times, the concentration of the second polymer solution in step (4) is 8wt%, the thickness of the composite double-layer structure in step (5) is 300μm, the thickness error is 20μm, and the unmentioned parts are the same as embodiment 1.

[0068] refer to Figure 1-6 , which shows the comparison of the composite double-layer structures prepared in Examples 1-6 before and after expansion. It can be seen that, under the condition of ensuring expansion without rupture, the tubular membrane with the smallest thickness is sought. Example 1 is the minimum thickness that can be achieved, but the tubular membrane of Example 1 has cracks and ruptures after expansion. In addition, since the thickness of Examples 5 and 6 is too large, the composite double-layer structure cannot be expanded by balloon pressure expansion. Figure 7 , which shows the stress-strain curve of polycaprolactone, a polymer material, which has excellent mechanical properties and can undergo plastic deformation. Therefore, the thickness of 50 μm in Example 2 is the best thickness that can be achieved.

[0069] Example 7

[0070] Preparation of hollow tubular structures

[0071] (1) mixing and dissolving the heparin-modified polycaprolactone in chloroform to form a first polymer solution with a concentration of 4 wt %, and performing a degassing treatment;

[0072] (2) Use a solid bar as a mold and fix the solid bar with an electric rotating fixture;

[0073] (3) immersing the solid rod in the first polymer solution of step (2), performing dipping cycles for 3 times, and naturally air-drying to form an inner layer structure, i.e., an antifouling drug-carrying layer, on the surface of the solid rod;

[0074] (4) dissolving the degradable polycaprolactone in tetrahydrofuran, and then adding rapamycin dissolved in tetrahydrofuran to obtain a second polymer solution with a concentration of 4 wt %, and performing a degassing treatment;

[0075] (5) The inner layer structure obtained in step (3) is dipped into the second polymer solution obtained in step (4), and naturally air-dried to form an expandable drug-loaded support layer, thereby obtaining a composite double-layer structure with a thickness of 50 μm and a drug loading of 4.3 mg of rapamycin.

[0076] (6) Spraying the pressure-sensitive microcapsules onto the surface of the composite double-layer structure that is not completely dried in step (5) to form a pressure-sensitive bioadhesive layer, thereby obtaining a hollow tubular structure.

[0077] (7) The hollow tubular structure is sheathed on the outside of a commercial interventional balloon. The hollow tubular structure conforms to the balloon and is delivered to the lesion site and expanded through minimally invasive means. The hollow tubular structure is automatically separated from the balloon, and the outermost pressure-sensitive bioadhesive layer of the structure is destroyed by pressure to release the adhesive, thereby achieving adhesion to the blood vessel wall.

[0078] Wherein, the pressure-sensitive microcapsules are prepared by the following method:

[0079] (a) reacting toluene diisocyanate (TDI) and 1,4-butanediol in a molar ratio of 2.8:1 in cyclohexanone under the following reaction conditions: stirring in an oil bath at 80° C., nitrogen protection, and reaction time of 24 hours to obtain a polyurethane prepolymer;

[0080] (b) drying the polyurethane prepolymer in a vacuum oven at 100° C. for 6 hours to remove impurities;

[0081] (c) dissolving 2 g of Pluronic F-68 (block polyether F-68) surfactant in deionized water, stirring for 1 hour, and heating to 40° C. to obtain an aqueous phase solution;

[0082] (d) dissolving the polyurethane prepolymer of step (b) in methyl ethyl ketone to form a first oil phase at a concentration of 0.3 g / mL;

[0083] (e) dissolving 2-octyl cyanoacrylate in methyl isobutyl ketone at a concentration of 0.5 g / mL, and adding p-toluenesulfonic acid monohydrate to form a second oil phase at a concentration of 1.5 wt %;

[0084] (f) injecting the first oil phase and the second oil phase into the aqueous phase solution and uniformly mixing them, and controlling the stirring rate from 300 rpm to 1500 rpm and the temperature from 25° C. to 50° C.;

[0085] (g) 1,4-butanediol is slowly added to the mixed stirring solution of step (f) using a syringe. After reacting for 2 hours, the capsule suspension is rinsed with deionized water and vacuum filtered to obtain pressure-sensitive microcapsules with a core material of 2-octyl cyanoacrylate and a shell material of polyurethane, and the average diameter is 20-250 μm.

[0086] Example 8

[0087] The difference between this embodiment and embodiment 7 is that the endothelial growth promoting drug GSNO is added to the first polymer solution in step (1) at a concentration of 20 mg / ml, the thickness of the composite double-layer structure is 50 μm, the drug loading of rapamycin is 4.3 mg, and the drug loading of GSNO, a NO-releasing endothelial growth promoting drug, is 12.9 mg. The unmentioned parts are the same as those in embodiment 7.

[0088] Example 9

[0089] The difference between this embodiment and embodiment 8 is that in step (7), a purchased wet pig cardiovascular segment is used as a prosthesis simulation, and an interventional balloon with a hollow tubular structure is inserted into the pig cardiovascular segment. Figure 8 As shown, the balloon pressure expands, and after 30 seconds the balloon contracts, the hollow tubular structure is separated from the balloon, thereby achieving the combination of the hollow tubular structure and the pig blood vessel. The unmentioned parts are the same as those in Example 8.

[0090] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. An expandable self-adhesive hollow tubular structure for treating blood vessels, characterized in that: The hollow tubular structure is a multi-layer composite system, comprising at least the following functional layers: The antifouling drug-carrying layer is composed of an anticoagulant-modified polymer material and loaded with an endothelial growth-promoting drug; An expandable drug-loaded support layer, which is composed of a plastically deformable degradable polymer and loaded with anti-tumor or anti-intimal hyperplasia drugs; The pressure-sensitive bioadhesive layer is composed of multiple pressure-sensitive microcapsules, which trigger the adhesion function through mechanical pressure; The hollow tubular structure is delivered in cooperation with an interventional balloon, and the balloon is expanded to make the hollow tubular structure adhere to the inner wall of the blood vessel, and automatically separate from the balloon after expansion.

2. The expandable self-adhesive hollow tubular structure for treating blood vessels according to claim 1, characterized in that: The hollow tubular structure is a three-layer structure, comprising: The inner layer is defined as the antifouling drug-carrying layer, wherein the anticoagulant modified polymer material is selected from heparin-modified polymers, and the endothelial growth-promoting drug is selected from RSNO, GSNO, REDV polypeptide or RGD polypeptide; the middle layer is defined as the expandable drug-carrying support layer, wherein the degradable polymer is selected from polycaprolactone, polylactide-co-glycolide copolymer, polyethylene glycol, polylactic acid, poly 3-hydroxyalkanoate, polyvinyl alcohol, and the anti-tumor or anti-intimal hyperplasia drug is selected from rapamycin, paclitaxel, aspirin or simvastatin; the outer layer is defined as the pressure-sensitive bioadhesive layer, and a plurality of the pressure-sensitive microcapsules form a layered structure and have an adhesive inside, wherein the adhesive is selected from polyurethane, 2-hydroxyethyl acrylate, 2-octyl cyanoacrylate, urea-formaldehyde resin, polymethylene polyphenyl polyisocyanate, polyacrylic acid, chitosan, gelatin, tannic acid or hyaluronic acid.

3. An expandable self-adhesive hollow tubular structure for treating blood vessels according to claim 1 or 2, characterized in that: The microcapsule coating of the pressure-sensitive bioadhesive layer ruptures under the balloon expansion pressure to release the adhesive to adhere to the blood vessel wall.

4. An expandable self-adhesive hollow tubular structure for treating blood vessels according to claim 1 or 2, characterized in that: The thickness of the hollow tubular structure is 20-300 μm, and the thickness of the hollow tubular structure after being expanded by the balloon is 10-200 μm.

5. A method for preparing a hollow tubular structure according to any one of claims 1 to 4, characterized in that: The following steps are involved: (1) preparing an antifouling drug-carrying layer: dissolving an anticoagulant modified polymer material in an organic solvent to form a first polymer solution, and then dipping the first polymer solution on a mold surface after degassing to form an inner layer structure; (2) preparing an expandable drug-loaded support layer: mixing an anti-tumor or anti-intimal hyperplasia drug and a degradable polymer to form a second polymer solution, and coating the second polymer solution on the surface of the inner layer structure by dip coating to form an expandable drug-loaded support layer, thereby obtaining a composite double-layer structure; (3) Preparing a pressure-sensitive bioadhesive layer: spraying pressure-sensitive microcapsules onto the surface of the composite double-layer structure that is not completely dried to form a pressure-sensitive bioadhesive layer, thereby obtaining a hollow tubular structure.

6. The preparation method according to claim 5, characterized in that: The anticoagulant modified polymer material in step (1) is heparin-modified polycaprolactone, the organic solvent is chloroform, the concentration of the first polymer solution is 3-10wt%, and the drug loading of the endothelial growth promoting drug is 10-20mg; the drug in step (2) is rapamycin, the degradable polymer is polycaprolactone, the solvent is tetrahydrofuran, the concentration of the second polymer solution is 3-20wt%, and the drug loading is 2-10mg.

7. The preparation method according to claim 5, characterized in that: The mold in step (1) and step (2) is in the shape of a solid rod, and vertical dipping is performed. After each dipping, a rotary drying process is performed. The number of dipping cycles of the composite double-layer structure is 2-4 times.

8. The preparation method according to claim 5, characterized in that: The pressure-sensitive microcapsules are prepared by the following method: (a) reacting toluene diisocyanate and 1,4-butanediol in a molar ratio of 2.5:1-3.0:1 in cyclohexanone under the following reaction conditions: temperature of 70-90° C., nitrogen protection, and for 20-28 hours to obtain a polyurethane prepolymer; (b) vacuum drying the polyurethane prepolymer at 90-110° C. for 4-8 hours; (c) preparing an aqueous solution containing a surfactant and heating it to 35-45° C.; (d) dissolving the product of step (b) in methyl ethyl ketone to form a first oil phase at a concentration of 0.2-0.4 g / mL; (e) dissolving 2-octyl cyanoacrylate in methyl isobutyl ketone, and then adding p-toluenesulfonic acid monohydrate to form a second oil phase, wherein the concentration of 2-octyl cyanoacrylate is 0.4-0.6 g / mL, and the concentration of p-toluenesulfonic acid monohydrate is 1.0-2.0 wt %; (f) injecting the first oil phase and the second oil phase into the aqueous phase solution, controlling the stirring speed to 300-1500 rpm and the temperature to 25-50° C.; (g) adding 1,4-butanediol dropwise and reacting for 1-3 hours, then washing and filtering to obtain a core-shell structured pressure-sensitive microcapsule.

9. The preparation method according to claim 7, characterized in that: In the step (a), the molar ratio of toluene diisocyanate to 1,4-butanediol is 2.7:1-2.9:1; in the step (f), the stirring speed is controlled from 300 rpm to 1500 rpm, and the temperature is controlled from 25° C. to 50° C.; in the step (g), the average particle size of the pressure-sensitive microcapsules is 20-250 μm.

10. Use of the hollow tubular structure according to any one of claims 1 to 4 in interventional treatment of vascular lesions.

Images