KR20210154734A - Drug delivery stent and manufacturing method of the same - Google Patents

Abstract

The present invention relates to a stent for drug delivery that is inserted into a stenosis site in the body in which stenosis is observed or expected, prevents stenosis of the stenosis site and delivers a drug, and a method for manufacturing the same. The stent for drug delivery according to an embodiment of the present invention can include: a stent body having mechanical strength to prevent stenosis of the stenosis site; and a coating film formed on the surface of the stent body, carrying the drug, and releasing the drug.

Description

Drug delivery stent and manufacturing method thereof

The present invention relates to a stent for drug delivery and a method for manufacturing the same, and more particularly, to a stent for drug delivery that is inserted into a stenosis site in the body where stenosis is observed or expected to prevent stenosis of the stenosis and deliver a drug; It relates to a manufacturing method thereof.

In general, a stent is a medical device that is inserted and mounted in a narrowed blood vessel or conduit in a body to maintain normal blood flow by expanding the narrowed blood vessel back to its original size. That is, a stent is a luminal expansion device used to expand a narrowed passage due to stenosis, and is widely used for the treatment of cancer or vascular diseases.

The stent can be generally divided into a metal stent and a drug eluting stent in which a therapeutic component is included in a coating layer of the stent. The drug-releasing stent is coated with a polymer and a therapeutic component to reduce physiological side effects such as restenosis and late thrombosis in stent intervention.

Recently, in order to enhance the therapeutic effect using the stent, a stent capable of delivering a drug such as a thrombolytic agent or an anticancer agent has been developed. That is, a method of coating a drug on the metallic surface of the stent so that the biologically active therapeutic material can penetrate into the damaged tissue and be treated has been studied.

In particular, in the treatment of benign stenosis of the biliary tract, which controls the bile produced by hepatocytes to be properly discharged toward the duodenum, drugs such as anticancer agents, anti-inflammatory agents, and immunosuppressants are continuously released to the damaged tissue in the biliary tract, the damaged tissue Many studies on drug-releasing stents that prevent temporary blockage or stenosis of the biliary tract are ongoing.

Republic of Korea Patent Publication No. 10-1735702

The problem to be solved by the present invention is to provide a stent for drug delivery that is inserted into a stenosis site in the body where stenosis is observed or expected, prevents stenosis of the stenosis site and delivers a drug.

In addition, the problem to be solved by the present invention is to provide a method for manufacturing a stent for drug delivery that is inserted into a stenosis site in the body where stenosis is observed or expected, prevents stenosis of the stenosis site and delivers a drug.

The problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.

The stent for drug delivery that is inserted into a stenosis site in the body where stenosis symptoms are observed or expected to solve the above-mentioned problems and delivers a drug and prevent stenosis of the stenosis site according to an embodiment of the present invention for solving the above problems, the stenosis site A stent body having mechanical strength to prevent stenosis, and a coating film formed on the surface of the stent body, carrying the drug, and releasing the drug.

The stent body may be formed of a metal.

The metal may be any one selected from the group consisting of Mg, Zn, Fe, Na, K, Ca, Mo, W, Cr, Co, Ti, Ni, Fe, and combinations thereof.

The coating layer may include a first membrane formed on the surface of the stent body and a second membrane formed on the first membrane.

The first membrane may include an acrylic resin, a methacryl resin, an epoxy resin, an epoxy-acrylic resin, a urethane resin, a melamine resin, a novolak resin, an unsaturated polyester resin, a vinyl ester resin, a dially phthalate resin, a silicone resin, a furan resin, It may be at least one selected from the group consisting of a ketone resin, a xylene resin, and a curable polyimide.

The second membrane may have biocompatibility, support for the drug, and release performance.

The second membrane may include polyvinyl alcohol, polyethylene glycol, polylactide, polyglycolide, polylactide copolymer, polyethylene oxide, polydioxanone, polycaprolactone, polyphosphazene, polyanhydride, polyamino acid, It may be any one selected from the group consisting of cellulose acetate butyrate, cellulose triacetate, polyacrylate, polyacrylamide, polyurethane, polysiloxane, polyvinylpyrrolidone, and copolymers thereof.

The drugs are sirolimus, everolimus, zotarolimus, xanthorrhizol, docetaxel, cisplatin, camptothecin, paclitaxel ), Tamoxifen, Anasterozole, Gleevec, 5-fluorouracil (5-FU), Floxuridine, Leuprolide, Flutamide ), zoledronate, doxorubicin, vincristine, gemcitabine, streptozotocin, carboplatin, topotecan, belote ( Belotecan), irinotecan, vinorelbine, hydroxyurea, valrubicin, retinoic acid, methotrexate, meclorethamine, Chlorambucil, Busulfan, Doxifluridine, Vinblastin, Mitomycin, Prednisone, Testosterone, Mitoxantrone ), aspirin, salicylates, ibuprofen, naproxen, fenoprofen, indomethacin, phenylbutazone, cyclophospha cyclophosphamide, mechlorethamine, dexamethasone, prednisolone, celecoxy It may be any one selected from the group consisting of celecoxib, valdecoxib, nimesulide, cortisone, triamcinolone, corticosteroids, and combinations thereof.

The stenosis symptom may be any one of stenosis, restenosis, arteriosclerosis, atherosclerosis, tube occlusion, vascular constriction, and aneurysm.

The method of manufacturing a stent for drug delivery that is inserted into a stenosis site in the body where stenosis symptoms are observed or expected according to another embodiment of the present invention to solve the above problems, prevents the stenosis of the stenosis site and delivers a drug, It may include providing a stent body having mechanical strength to prevent stenosis of the stenosis site, and forming a coating film on the surface of the stent body to carry the drug and release the drug.

The stent body may be formed of a metal.

The metal may be any one selected from the group consisting of Mg, Zn, Fe, Na, K, Ca, Mo, W, Cr, Co, Ti, Ni, Fe, and combinations thereof.

The forming of the coating film may include forming a first membrane on the surface of the stent body, and forming a second membrane on the first membrane.

The forming of the first membrane may include forming a first solution for forming the first membrane.

The first solution is acrylic resin, methacrylic resin, epoxy resin, epoxy-acrylic resin, urethane resin, melamine resin, novolak resin, unsaturated polyester resin, vinyl ester resin, dially phthalate resin, silicone resin, furan resin, It may be formed by dissolving at least one selected from the group consisting of a ketone resin, a xylene resin, and a curable polyimide in a first solvent.

The first solvent is acetic acid, water, ethanol, methanol, propanol, butanol, hexane, methylene chloride, ethyl acetate, propylene glycol, butylene glycol, dipropylene glycol, glycerin, ketone, acetone, dimethyl sulfoxide, dimethylformamide, It may be any one selected from the group consisting of toluene, tetrahydrofuran, acetonitrile, and combinations thereof.

The forming of the first membrane may further include coating the first solution on the surface of the stent body to form a first film, and drying the first film.

The forming of the second membrane may include forming a second solution for forming the second membrane.

The second solution is polyvinyl alcohol, polyethylene glycol, polylactide, polyglycolide, polylactide copolymer, polyethylene oxide, polydioxanone, polycaprolactone, polyphosphazene, polyanhydride, polyamino acid, It can be formed by dissolving at least one selected from the group consisting of cellulose acetate butyrate, cellulose triacetate, polyacrylate, polyacrylamide, polyurethane, polysiloxane, polyvinylpyrrolidone, and copolymers thereof in a second solvent. have.

The second solvent is acetic acid, water, ethanol, methanol, propanol, butanol, hexane, methylene chloride, ethyl acetate, propylene glycol, butylene glycol, dipropylene glycol, glycerin, ketone, acetone, dimethyl sulfoxide, dimethylformamide, It may be any one selected from the group consisting of toluene, tetrahydrofuran, acetonitrile, and combinations thereof.

The forming of the second membrane may further include coating the second solution on the surface of the first membrane to form a second film, and drying the second film.

The drugs are sirolimus, everolimus, zotarolimus, xanthorrhizol, docetaxel, cisplatin, camptothecin, paclitaxel ), Tamoxifen, Anasterozole, Gleevec, 5-fluorouracil (5-FU), Floxuridine, Leuprolide, Flutamide ), zoledronate, doxorubicin, vincristine, gemcitabine, streptozotocin, carboplatin, topotecan, belote ( Belotecan), irinotecan, vinorelbine, hydroxyurea, valrubicin, retinoic acid, methotrexate, meclorethamine, Chlorambucil, Busulfan, Doxifluridine, Vinblastin, Mitomycin, Prednisone, Testosterone, Mitoxantrone ), aspirin, salicylates, ibuprofen, naproxen, fenoprofen, indomethacin, phenylbutazone, cyclophospha cyclophosphamide, mechlorethamine, dexamethasone, prednisolone, celecoxy It may be any one selected from the group consisting of celecoxib, valdecoxib, nimesulide, cortisone, triamcinolone, corticosteroids, and combinations thereof.

According to the present invention, there is provided a stent for drug delivery that is inserted into a stenosis site in the body where stenosis is observed or expected, prevents stenosis of the stenosis site and delivers a drug.

In addition, there is provided a method of manufacturing a stent for drug delivery, which is inserted into a stenosis site in the body where stenosis is observed or expected, prevents stenosis of the stenosis site and delivers a drug.

1 is a cross-sectional view of a stent for drug delivery according to an embodiment of the present invention.
2 is a flowchart illustrating a method of manufacturing a stent for drug delivery according to the present invention.
3 is a graph examining drug uniformity by location of a stent according to an embodiment of the present invention.
4 is a photograph showing the stent manufactured according to the present embodiment.
5 is a scanning electron microscope photograph of the coating film prepared by the spray coating method.
Figure 6 shows the drug release test results of the stent according to the embodiment of the present invention.
7 is a result of measuring the weight change of pigs treated with the stent according to the present invention.
8 shows blood biochemical test results of pigs treated with a stent according to the present invention.
9 shows the blood test results of pigs treated with the stent according to the present invention.
10 is a photograph of the result of the stenosis in the control group.
11 is a photograph of the result of the stenosis in the steroid (steroid) 1-fold loading group.
12 is a photograph of the result of the stenosis in the steroid 2 times loading group.
13 is a comparison photograph of the stenosis site between the control group (A), the steroid 1 times (B) loading, and the steroid (steroid) 2 times (C) loading.
14 is a photograph of the macroscopic findings of the stenosis site (white arrow) in the biliary tract of a pig sacrificed 4 weeks after the procedure in the control group (A), steroid 1x (B), and steroid 2x (C).
15 is a photograph of Mason's trichrome staining of the stenosis site. The thickness of the fiber wall (Fibrous wall thickeness) represents the average value by measuring the thickness of the collagen fibers (collagenous fibrosis) from the muscle layer to the adipose tissue in three places.
16 is a photograph showing pathological confirmation of the stenosis site 3 days, 2 weeks, and 4 weeks after the procedure in the control group (A), steroid 1x (B) loading, and steroid 2x loading group (C).
17 is a result showing the fiber wall thickness measured quantitatively in the control group (A), steroid 1 times (B), and steroid 2 times (C) loading group.

Advantages and features of the present invention and methods of achieving them will become apparent with reference to the embodiments described below in detail in conjunction with the accompanying drawings. However, the present invention is not limited to the embodiments disclosed below, but may be implemented in various different forms, and only the present embodiments allow the disclosure of the present invention to be complete, and those of ordinary skill in the art to which the present invention pertains. It is provided to fully understand the scope of the present invention to those skilled in the art, and the present invention is only defined by the scope of the claims.

The terminology used herein is for the purpose of describing the embodiments and is not intended to limit the present invention. In this specification, the singular also includes the plural unless specifically stated otherwise in the phrase. As used herein, “comprises” and/or “comprising” does not exclude the presence or addition of one or more other components in addition to the stated components. Like reference numerals refer to like elements throughout, and "and/or" includes each and every combination of one or more of the recited elements. Although "first", "second", etc. are used to describe various elements, these elements are not limited by these terms, of course. These terms are only used to distinguish one component from another. Accordingly, it goes without saying that the first component mentioned below may be the second component within the spirit of the present invention.

Unless otherwise defined, all terms (including technical and scientific terms) used herein will have the meaning commonly understood by those of ordinary skill in the art to which this invention belongs. In addition, terms defined in a commonly used dictionary are not to be interpreted ideally or excessively unless specifically defined explicitly.

Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings.

Before the description, the meaning of the terms used in this specification will be briefly described. However, it should be noted that, since the description of the term is for the purpose of helping the understanding of the present specification, it is not used in the meaning of limiting the technical idea of the present invention unless explicitly described as limiting the present invention.

Hereinafter, a stent for drug delivery and a manufacturing method thereof according to an embodiment of the present invention will be described.

1 is a cross-sectional view showing a stent for drug delivery according to an embodiment of the present invention, Figure 2 is a flowchart showing a method of manufacturing a stent for drug delivery according to an embodiment of the present invention.

First, referring to FIG. 1 , the stent 10 for drug delivery according to an embodiment of the present invention is inserted into a stenosis site in the body where stenosis is observed or expected, and the function of preventing the stenosis of the stenosis and delivering a drug has To this end, the stent 10 for drug delivery according to an embodiment of the present invention includes a stent body 101 having mechanical strength to prevent stenosis of the stenotic site, and is formed on the surface of the stent body, and carries the drug. , it may include a coating film 200 that releases the drug.

The stent body 101 may be inserted or implanted in the stenosis region to expand the stenosis region. To this end, the stent body 101 must have sufficient mechanical strength by itself in order to provide a function of preventing and expanding the stenosis site.

To this end, the stent body 101 is preferably formed of a metal material. The metal material may be any one selected from the group consisting of Mg, Zn, Fe, Na, K, Ca, Mo, W, Cr, Co, Ti, Ni, Fe, and combinations thereof. Alternatively, as a material of the stent body 101, stainless steel, chromium cobalt alloy, or the like may be used.

The stent body 101 may be, for example, a cylindrical shape that is open above and below, and preferably has a diameter of about 2 mm. The shape of the stent body 101 may be a reticulated or lattice-type tubular.

The coating film 200 is formed on the surface of the stent body 101 . The coating may be formed to surround the surface of the stent body 101 . The coating film 200 may carry a drug, and the loaded drug may be released to the stenosis site where the stent 10 is inserted and operated. By releasing the drug from the coating film 200, the drug for treatment can be delivered to the stenosis site.

The coating film 200 may include a first membrane 201 formed on the surface of the stent body 101 and a second membrane 202 formed on the first membrane 201 .

The first membrane 201 is formed on the surface of the stent body 101, is flexible even in a dry state in which the film is formed, is not easily damaged, and can be formed of a material having biocompatibility. The first membrane 201 is preferably formed with a relatively uniform thickness on the surface of the stent body (101).

The first membrane 201 may include acrylic resin, methacrylic resin, epoxy resin, epoxy-acrylic resin, urethane resin, melamine resin, novolak resin, unsaturated polyester resin, vinyl ester resin, dially phthalate resin, silicone resin, It may be at least one selected from the group consisting of furan resin, ketone resin, xylene resin, and curable polyimide. Here, it is preferable that a silicone resin and/or a xylene resin be selected as the material for forming the first membrane 201 .

The second membrane 202 may have biocompatibility, excellent drug loading and release performance. The second membrane 202 may be formed on the surface of the first membrane 201 . The second membrane 202 is preferably formed on the surface of the first membrane 201 with a relatively uniform thickness.

The second membrane 202 includes polyvinyl alcohol, polyethylene glycol, polylactide, polyglycolide, polylactide copolymer, polyethylene oxide, polydioxanone, polycaprolactone, polyphosphazene, polyanhydride, poly It may be any one selected from the group consisting of amino acids, cellulose acetate butyrate, cellulose triacetate, polyacrylate, polyacrylamide, polyurethane, polysiloxane, polyvinylpyrrolidone, and copolymers thereof. Here, polyurethane is preferably selected as the material for forming the second membrane 202 .

Meanwhile, the drug carried on the second membrane 202 may be selected according to the symptoms of the stenosis site into which the stent 10 is inserted. Here, the drug is sirolimus, everolimus, zotarolimus, xanthorrhizol, docetaxel, cisplatin, camptothecin, paclitaxel ( paclitaxel), tamoxifen, anasterozole, Gleevec, 5-fluorouracil (5-FU), floxuridine, leuprolide, flotamide ( Flutamide), zoledronate, doxorubicin, vincristine, gemcitabine, streptozotocin, carboplatin, topotecan, belote (Belotecan), Irinotecan, Vinorelbine, hydroxyurea, Valrubicin, retinoic acid, Methotrexate, Meclorethamine , Chlorambucil, Busulfan, Doxifluridine, Vinblastin, Mitomycin, Prednisone, Testosterone, Mitosanthrone ( Mitoxantron, aspirin, salicylates, ibuprofen, naproxen, fenoprofen, indomethacin, phenylbutazone, cyclophos cyclophosphamide, mechlorethamine, dexamethasone, prednisolone, celery It may be any one selected from the group consisting of coxib (celecoxib), valdecoxib (valdecoxib), nimesulide, cortisone, triamcinolone, corticosteroids, and combinations thereof .

For example, fibrosis of the stenosis site is a problem, and in order to induce antifibrosis of the stenosis site and surrounding tissues, the drug is preferably selected as a corticosteroid. Corticosteroids are effective in preventing fibrosis of the stenotic site. Accordingly, corticosteroids can function as an antifibrotic agent in the stenotic site.

The stent 10 for drug delivery according to an embodiment of the present invention is inserted into a stenosis site in the body where stenosis is observed or expected, thereby preventing the stenosis of the stenosis and delivering the drug. The stenosis symptom may be any one of stenosis, restenosis, arteriosclerosis, atherosclerosis, vascular obstruction, vascular constriction, and aneurysm.

Next, a method for manufacturing a stent for drug delivery according to an embodiment of the present invention will be described.

First, the method for manufacturing a stent for drug delivery according to the present invention is inserted into a stenosis site in the body where stenosis is observed or expected to prevent stenosis of the stenosis site and to deliver a drug. it is for

The method for manufacturing a stent for drug delivery according to the present invention includes the steps of providing a stent body having mechanical strength to prevent stenosis of the stenosis site (S10), and the surface of the stent body so that the drug is loaded and the drug is released It may include forming a coating film on the (S20).

The stent body 101 may be prepared and provided as follows.

The stent body 101 has a cylindrical shape, a mesh shape, a tubular shape, and is preferably formed of a metal material. The metal material may be any one selected from the group consisting of Mg, Zn, Fe, Na, K, Ca, Mo, W, Cr, Co, Ti, Ni, Fe, and combinations thereof. Alternatively, as a material of the stent body 101, stainless steel, chromium cobalt alloy, or the like may be used.

Subsequently, a coating film is formed on the stent body 101 (S20).

Forming the coating film 200, forming a first membrane 201 on the surface of the stent body 10, and forming a second membrane 202 on the first membrane 201 may include the step of

First, forming the first membrane 201 may include forming a first solution for forming the first membrane 201 .

The first solution is acrylic resin, methacrylic resin, epoxy resin, epoxy-acrylic resin, urethane resin, melamine resin, novolac resin, unsaturated polyester resin, vinyl ester resin, dially phthalate resin, silicone resin, furan resin, ketone It may be formed by dissolving at least one selected from the group consisting of a resin, a xylene resin, and a curable polyimide in a first solvent. Here, the first solvent is acetic acid, water, ethanol, methanol, propanol, butanol, hexane, methylene chloride, ethyl acetate, propylene glycol, butylene glycol, dipropylene glycol, glycerin, ketone, acetone, dimethyl sulfoxide, dimethylformamide , toluene, tetrahydrofuran, acetonitrile, and may be any one selected from the group consisting of combinations thereof.

Subsequently, after forming the first solution, the first solution is coated on the surface of the stent body 101 to form a first film. At this time, as a coating method for forming the first film, a spray method of coating the stent body 101 on the stent body 101 by a spray device or an immersion method in which the stent body 101 is immersed in the first solution to coat it. can be used

After forming the first film, the first film is dried to form the first membrane 201 . Drying may be performed in a temperature atmosphere of 50° C. to 160° C. for 30 minutes to 100 minutes.

Continuing, forming the second membrane 202 may include forming a second solution for forming the second membrane 202 .

The second solution is polyvinyl alcohol, polyethylene glycol, polylactide, polyglycolide, polylactide copolymer, polyethylene oxide, polydioxanone, polycaprolactone, polyphosphazene, polyanhydride, polyamino acid, cellulose It may be formed by dissolving at least one selected from the group consisting of acetate butyrate, cellulose triacetate, polyacrylate, polyacrylamide, polyurethane, polysiloxane, polyvinylpyrrolidone, and copolymers thereof in a second solvent. . Here, the second solvent is acetic acid, water, ethanol, methanol, propanol, butanol, hexane, methylene chloride, ethyl acetate, propylene glycol, butylene glycol, dipropylene glycol, glycerin, ketone, acetone, dimethyl sulfoxide, dimethylformamide , toluene, tetrahydrofuran, acetonitrile, and may be any one selected from the group consisting of combinations thereof.

Subsequently, after forming the second solution, the second solution is coated on the surface of the first membrane 201 to form a second film. At this time, as a coating method for forming the second film, a dipping method in which the stent body 101 on which the first membrane 201 is formed is immersed in a second solution or a second solution is applied to the first membrane ( 201), a spray method of coating on it may be used.

After forming the second film, the second film is dried to form the second membrane 202 . Drying may be performed in a temperature atmosphere of 50° C. to 160° C. for 30 minutes to 100 minutes.

Meanwhile, the drug carried on the second membrane 202 may be selected according to the symptoms of the stenosis site into which the stent 10 is inserted. Here, the drug is sirolimus, everolimus, zotarolimus, xanthorrhizol, docetaxel, cisplatin, camptothecin, paclitaxel ( paclitaxel), tamoxifen, anasterozole, Gleevec, 5-fluorouracil (5-FU), floxuridine, leuprolide, flotamide ( Flutamide), zoledronate, doxorubicin, vincristine, gemcitabine, streptozotocin, carboplatin, topotecan, belote (Belotecan), Irinotecan, Vinorelbine, hydroxyurea, Valrubicin, retinoic acid, Methotrexate, Meclorethamine , Chlorambucil, Busulfan, Doxifluridine, Vinblastin, Mitomycin, Prednisone, Testosterone, Mitosanthrone ( Mitoxantron, aspirin, salicylates, ibuprofen, naproxen, fenoprofen, indomethacin, phenylbutazone, cyclophos cyclophosphamide, mechlorethamine, dexamethasone, prednisolone, celery It may be any one selected from the group consisting of coxib (celecoxib), valdecoxib (valdecoxib), nimesulide, cortisone, triamcinolone, corticosteroids, and combinations thereof .

Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .

Example - Preparation of Stents

1) Preparation of coating solution

First, in order to form a coating film on the surface of the stent body, a coating solution was prepared.

Silicone Solution Preparation (Solution A): Mix ^{Part A and Part B of silicone (MED-6640A, Nusil TM} ) and xylene in a ratio of 1:1:0.4, respectively, and dissolve in tetrahydrofuran (THF) to contain silicone A solution was prepared.

Preparation of polyurethane solution (solution B): polyurethane was completely dissolved by stirring in THF (Tetrahydrofuran) at a concentration of 25 mg/mL for 24 hours to prepare a polyurethane solution.

Preparation of Triamcinolone Solution (Solution C): 40 mg/mL of triamcinolone was added to THF, stirred for 1 hour, and completely dissolved to prepare a solution.

For the first membrane coating, solution A was used, and for the second membrane coating, solutions A, B, and C were mixed in a ratio of 1: 1: 1.

2) Formation of a coating film on the stent body - using the spray coating method

For smooth adhesion between the surface of the stent body and the solution A, it was immersed in MED-163, a pretreatment solution, for 1 minute, and dried in an oven at 50° C. for 30 minutes. After setting the conditions of the spray coating machine as shown in Table 1 below, after filling the sample injection part with the first solution (solution A) for forming the first membrane, the first solution is sprayed on the surface of the stent body, It was dried at room temperature for 30 minutes. After filling the secondary solution (solutions A, B, and C) for forming the secondary membrane, the secondary solution is sprayed on the surface of the stent body, 30 min at room temperature, 45 min in a 70 ℃ oven, 150 ℃ in an oven Drying was carried out for 90 min.

primary coating secondary coating 1. Injection flow per second (g/sec) 0.025 0.015 2. Injection time (sec) 16.7 3. line speed (mm/sec) 3 4. rotation rate (RPM) 55

Experimental Example - Confirmation of drug content and uniformity

A mobile phase was prepared by mixing ACN (Acetonitrile) and distilled water 1:1 with reference to United States Pharmacopeia (USP) Triamcinolone acetonide injectable suspension, and a drug-carrying stent (n = 6) was prepared and completely dissolved by stirring in THF for 2 h. . Since the stock solution is THF, it should be diluted to a concentration that can be analyzed while matching the ratio with the mobile phase as much as possible. Therefore, 200 μL of the solution was taken and diluted at a ratio of 1/5 of the mobile phase and analyzed by HPLC (Agilent).

A mobile phase was prepared by mixing ACN and distilled water 1:1 with reference to USP Triamcinolone acetonide injectable suspension, and the drug release behavior was observed for 120 hours in PBS containing 1% Tween 20 in a shaking incubator at 37 ° C. did

When the coating was performed using a spray coating machine, drug uniformity was investigated for each stent location, and relatively uniform results were obtained (FIG. 3). Accordingly, it was uniformly formed on the coating film on the surface of the stent, and the drug release is expected to be uniform from the front surface of the stent. On the other hand, the stent prepared according to this example is shown in FIG. 4, and as a result of measuring the coating film prepared by the spray coating method with a scanning electron microscope, it was confirmed that the thickness was about 50.48 μm (FIG. 5).

Each drug-supported capsule stent was fabricated using five types of polyurethane. The drug release of the stent coated with hydrophobic polyurethane is about 12% slower than that of the stent coated with hydrophilic polyurethane, and the drug release is completed within 120 hours of the stent coated with hydrophilic polyurethane. confirmed to be. In addition, it was confirmed that the release was continued slowly for 120 hours using the hydrophobic polyurethane (FIG. 6).

Experimental Example - Animal Experiment

1) Test method

Experimental animals were fasted for 12 hours before the procedure, and the supply of drinking water was stopped from the morning of the day of the procedure. After endotracheal intubation, the experimental animal was inhaled with an inhalation anesthetic 0.5-2% isoflurane with oxygen, 1:1 (5-10 ml/kg/min)]) implemented. By performing bile duct insertion with a sphincter sphincter, it was confirmed whether there was a difference between Version 1.0 and 1.1 in the ease of bile duct insertion. A radiofrequency ablation catheter was inserted through the duodenoscope forceps hole and placed in the common bile duct, followed by radiofrequency ablation. Immediately after the procedure, follow-up cholangiography was performed.

In an experimental animal model in which common bile duct stenosis occurred 4 weeks after bile duct radiofrequency resection, benign common bile duct stenosis was confirmed using an ERCP duodenum (TJF, Olympus Co., Japan), and the diameter and length of the stenosis were measured. . In 3 large animals, a general stent that was not loaded with drugs was inserted, and in 9 large animals, a metal stent loaded with corticosteroids was inserted into the common bile duct stenosis while observing fluoroscopy through a stent delivery system.

In order to block the lower detachment of the inserted stent during the stent indwelling period, immediately after insertion of the stent into the bile duct, the main papilla, the entrance to the bile duct, was clipped using an upper gastrointestinal endoscope equipped with a transparent cap and a hemostatic clip and the nipple entrance was ligated.

Two days after stent insertion, one animal in each group was autopsied, and endoscopic retrograde cholangiopancreatography was performed at week two. At the 4th week, the target animals were sacrificed and the benign bile duct stenosis was confirmed through pathological analysis after bile duct extraction.

2) Experiment result

(1) Weighing

Upon acquisition, the body weight of each individual was measured once a week during the acclimatization period and once a week during the test period. In particular, weight measurement during the test period was measured using the same scale on the same day of the week and at the same time period (around 4 pm) in order to minimize the error in each measurement. As a result of weight measurement, there was no statistical difference before and after the experiment, so there were no systemic side effects due to the drug-releasing stent (FIG. 7).

(2) Abdominal X-ray examination

In order to check whether the inserted stent was dislodged, simple abdominal photos were taken every 2 weeks after stent insertion, and there was no stent disengagement.

(3) blood test

Blood biochemical tests were performed by requesting an external institution (KNOTUS, Notus) before the procedure and at the 1st, 2nd, and 4th weeks of the procedure. A portion of blood is injected into a 5 mL Vacutainer tube containing Clot activator, left at room temperature for 15 to 20 minutes to coagulate, and then centrifuged for 10 minutes (3000 rpm, MF 600, Hanil, Korea) to obtain serum from the upper layer. Aspartate transaminase (AST), Alanine transaminase (ALT), Alkaline phosphate (ALP), and T-bilirubin (T-Bil) were measured using an automatic blood biochemical analyzer (7180, HITACHI, JAPAN) to confirm the results. There was no statistical difference between each group in the blood biochemical test. Overall, it increased after the creation of the stenosis site, but showed a decreasing trend after stent insertion (FIG. 8).

Hematological tests are measured before the procedure and at the 1st, 2nd, and 4th weeks of the procedure. It was performed by requesting an external organization (KNOTUS, Notus). 3 mL of the collected blood was injected into a tube containing EDTA, mixed well, and the levels of white blood cell (WBC) and hemoglobin (HGB) were measured using a hemocytometer (ADVIA 2120, SIEMENS, USA) to confirm the results. . Overall, it increased after the creation of the stenosis site, but showed a decreasing trend after stent insertion (FIG. 9).

These results showed that the liver and inflammation levels increased due to biliary obstruction by the stenotic site, but it was judged that the improvement was improved with the opening of the biliary tract after stent insertion.

(4) Autopsy results

As a result of the autopsy after the fourth experiment, it was confirmed that the treatment effect of the stenosis site was greater in the steroid-supported stent group than in the control group ( FIGS. 10 to 12 ), and in particular, the effect was higher in the steroid-loaded stent group ( FIG. 13 ). In the experiment up to the 4th week, no perforation or necrosis by the stent was seen, confirming the stability of the steroid-supported stent.

(5) biopsy results

It can be seen that the stenosis site in the pig biliary tract sacrificed 4 weeks after the procedure is treated in proportion to the steroid concentration (FIG. 14).

As a result of measuring the fiber film thickness and the level of inflammation over time after the procedure in the control group (A), steroid 1x (B), and steroid 2x (C), the results showed that, unlike the control group, the steroid-loaded stent of the present invention was treated. In the experimental group, it was confirmed that the fiber wall thickness and the level of inflammation were decreased in proportion to time and steroid concentration (FIG. 16).

The quantitatively measured fiber wall thickness did not change with time in the control group, but showed a tendency to decrease with time in the steroid-administered group once, and significantly decreased until week 4 in the steroid-administered group twice. could confirm that It was confirmed that the fiber wall thickness decreased in proportion to the steroid concentration and decreased with time.

As mentioned above, although embodiments of the present invention have been described with reference to the accompanying drawings, those skilled in the art to which the present invention pertains know that the present invention may be embodied in other specific forms without changing the technical spirit or essential features thereof. you will be able to understand Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive.

Claims (22)

In the stent for drug delivery that is inserted into a stenosis site in the body where stenosis symptoms are observed or expected, and prevents stenosis of the stenosis site and delivers a drug,
a stent body having mechanical strength to prevent stenosis of the stenosis site; and
A stent for drug delivery comprising a coating film formed on the surface of the stent body, carrying the drug, and releasing the drug. According to claim 1,
The stent body is a stent for drug delivery, characterized in that formed of metal. 3. The method of claim 2,
The metal is Mg, Zn, Fe, Na, K, Ca, Mo, W, Cr, Co, Ti, Ni, Fe, and a stent for drug delivery, characterized in that any one selected from the group consisting of combinations thereof. According to claim 1,
The coating film is a stent for drug delivery, characterized in that it comprises a first membrane formed on the surface of the stent body and a second membrane formed on the first membrane. 5. The method of claim 4,
The first membrane may include an acrylic resin, a methacryl resin, an epoxy resin, an epoxy-acrylic resin, a urethane resin, a melamine resin, a novolak resin, an unsaturated polyester resin, a vinyl ester resin, a dially phthalate resin, a silicone resin, a furan resin, A stent for drug delivery, characterized in that it is at least one selected from the group consisting of a ketone resin, a xylene resin, and a curable polyimide. 5. The method of claim 4,
The second membrane is a stent for drug delivery, characterized in that it has biocompatibility, bearing capacity for the drug, and release performance. 7. The method of claim 6,
The second membrane may include polyvinyl alcohol, polyethylene glycol, polylactide, polyglycolide, polylactide copolymer, polyethylene oxide, polydioxanone, polycaprolactone, polyphosphazene, polyanhydride, polyamino acid, A stent for drug delivery, characterized in that it is any one selected from the group consisting of cellulose acetate butyrate, cellulose triacetate, polyacrylate, polyacrylamide, polyurethane, polysiloxane, polyvinylpyrrolidone, and copolymers thereof. According to claim 1,
The drugs are sirolimus, everolimus, zotarolimus, xanthorrhizol, docetaxel, cisplatin, camptothecin, paclitaxel ), Tamoxifen, Anasterozole, Gleevec, 5-fluorouracil (5-FU), Floxuridine, Leuprolide, Flutamide ), zoledronate, doxorubicin, vincristine, gemcitabine, streptozotocin, carboplatin, topotecan, belote ( Belotecan), irinotecan, vinorelbine, hydroxyurea, valrubicin, retinoic acid, methotrexate, meclorethamine, Chlorambucil, Busulfan, Doxifluridine, Vinblastin, Mitomycin, Prednisone, Testosterone, Mitoxantrone ), aspirin, salicylates, ibuprofen, naproxen, fenoprofen, indomethacin, phenylbutazone, cyclophospha cyclophosphamide, mechlorethamine, dexamethasone, prednisolone, celecoxib For drug delivery, characterized in that any one selected from the group consisting of valdecoxib, nimesulide, cortisone, triamcinolone, corticosteroid, and combinations thereof stent. According to claim 1,
The stenosis symptom is any one of stenosis, restenosis, arteriosclerosis, atherosclerosis, tube occlusion, vascular constriction, and an aneurysm. In the method for manufacturing a stent for drug delivery that is inserted into a stenosis site in the body where stenosis is observed or expected, and prevents stenosis of the stenosis site and delivers a drug,
providing a stent body having mechanical strength to prevent stenosis of the stenosis site;
A method of manufacturing a stent for drug delivery comprising the step of forming a coating film on the surface of the stent body so that the drug is loaded and the drug is released. 11. The method of claim 10,
The stent body is a method of manufacturing a stent for drug delivery, characterized in that formed of metal. 12. The method of claim 11,
The metal is any one selected from the group consisting of Mg, Zn, Fe, Na, K, Ca, Mo, W, Cr, Co, Ti, Ni, Fe, and combinations thereof. manufacturing method. 11. The method of claim 10,
Forming the coating film, forming a first membrane on the surface of the stent body, Manufacturing of a stent for drug delivery, characterized in that it comprises the steps of forming a second membrane on the first membrane Way. 14. The method of claim 13,
The forming of the first membrane is a method of manufacturing a stent for drug delivery, characterized in that it comprises the step of forming a first solution for forming the first membrane. 15. The method of claim 14,
The first solution is acrylic resin, methacrylic resin, epoxy resin, epoxy-acrylic resin, urethane resin, melamine resin, novolak resin, unsaturated polyester resin, vinyl ester resin, dially phthalate resin, silicone resin, furan resin, A method of manufacturing a stent for drug delivery, characterized in that it is formed by dissolving at least one selected from the group consisting of a ketone resin, a xylene resin, and a curable polyimide in a first solvent. 16. The method of claim 15,
The first solvent is acetic acid, water, ethanol, methanol, propanol, butanol, hexane, methylene chloride, ethyl acetate, propylene glycol, butylene glycol, dipropylene glycol, glycerin, ketone, acetone, dimethyl sulfoxide, dimethylformamide, A method of manufacturing a stent for drug delivery, characterized in that any one selected from the group consisting of toluene, tetrahydrofuran, acetonitrile, and combinations thereof. 15. The method of claim 14,
Forming the first membrane, coating the first solution on the surface of the stent body to form a first film, and the step of drying the first film, the drug characterized in that it further comprises Method of manufacturing a stent for delivery. 14. The method of claim 13,
The forming of the second membrane comprises forming a second solution for forming the second membrane. 19. The method of claim 18,
The second solution is polyvinyl alcohol, polyethylene glycol, polylactide, polyglycolide, polylactide copolymer, polyethylene oxide, polydioxanone, polycaprolactone, polyphosphazene, polyanhydride, polyamino acid, What is formed by dissolving at least one selected from the group consisting of cellulose acetate butyrate, cellulose triacetate, polyacrylate, polyacrylamide, polyurethane, polysiloxane, polyvinylpyrrolidone, and copolymers thereof in a second solvent Method of manufacturing a stent for drug delivery, characterized in that. 20. The method of claim 19,
The second solvent is acetic acid, water, ethanol, methanol, propanol, butanol, hexane, methylene chloride, ethyl acetate, propylene glycol, butylene glycol, dipropylene glycol, glycerin, ketone, acetone, dimethyl sulfoxide, dimethylformamide, A method of manufacturing a stent for drug delivery, characterized in that any one selected from the group consisting of toluene, tetrahydrofuran, acetonitrile, and combinations thereof. 19. The method of claim 18,
Forming the second membrane, coating the second solution on the surface of the first membrane to form a second film, characterized in that further comprising the steps of drying the second film Method for manufacturing a stent for drug delivery. 11. The method of claim 10,
The drugs are sirolimus, everolimus, zotarolimus, xanthorrhizol, docetaxel, cisplatin, camptothecin, paclitaxel ), Tamoxifen, Anasterozole, Gleevec, 5-fluorouracil (5-FU), Floxuridine, Leuprolide, Flutamide ), zoledronate, doxorubicin, vincristine, gemcitabine, streptozotocin, carboplatin, topotecan, belote ( Belotecan), irinotecan, vinorelbine, hydroxyurea, valrubicin, retinoic acid, methotrexate, meclorethamine, Chlorambucil, Busulfan, Doxifluridine, Vinblastin, Mitomycin, Prednisone, Testosterone, Mitoxantrone ), aspirin, salicylates, ibuprofen, naproxen, fenoprofen, indomethacin, phenylbutazone, cyclophospha cyclophosphamide, mechlorethamine, dexamethasone, prednisolone, celecoxib For drug delivery, characterized in that any one selected from the group consisting of valdecoxib, nimesulide, cortisone, triamcinolone, corticosteroid, and combinations thereof A method for manufacturing a stent.

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