WO2020134542A1

WO2020134542A1 - Drug eluting device and manufacturing method thereof

Info

Publication number: WO2020134542A1
Application number: PCT/CN2019/114702
Authority: WO
Inventors: 林文娇; 胡军
Original assignee: 先健科技(深圳)有限公司
Priority date: 2018-12-25
Filing date: 2019-10-31
Publication date: 2020-07-02
Also published as: CN111358603A

Abstract

A drug eluting device and a manufacturing method thereof, the drug eluting device comprising a base (1) and a drug-carrying layer (3); the base (1) having an outer surface (102), a lateral surface (103) and an inner surface (101); the drug-carrying layer (3) comprising a drug carrier and an active drug (301); the outer surface (102), lateral surface (103) and inner surface (101) of the base (1) all being covered by the drug-carrying layer (3); the active drug (301) only being distributed on at least a portion of the areas of the drug-carrying layer (3) covering the outer surface (102) and lateral surface (103), and, in the depth direction of the at least portion of areas, the concentration of the active drug (301) at a side adjacent to the base (1) being greater than the concentration of the active drug (301) on a side furthest from the base (1), and an area of the drug-carrying layer (3) disposed at the inner surface (101) of the base (1) not containing the active drug (301). The drug eluting device has a relatively long active-drug release period, and has a relatively low risk of blood clots.

Description

Drug eluting apparatus and manufacturing method thereof

Technical field

The invention relates to the field of implantable medical devices, in particular to a drug eluting device and a manufacturing method thereof.

Background technique

The use of drug-eluting stents in the treatment of cardiovascular diseases is becoming more and more widespread. At present, the inner and outer surfaces of most drug-eluting stents are coated with drugs. When a drug-eluting stent is implanted in a blood vessel, only the outer and side surfaces of the stent are in contact with the vessel wall, and the outer surface of the stent The active drugs released from the lateral surface will enter the blood vessel wall to play a therapeutic effect, and the active drugs on the inner surface of the stent will not only play a therapeutic role, but will be released into the blood and circulate to the whole body, which may play a role in other organs. toxic side effect. In addition, active drugs on the inner surface of the stent will also inhibit endothelialization of the stent, thereby increasing the risk of thrombosis.

In addition, the drug release cycle of the existing drug-eluting stent is too short, which makes it difficult to match the release of the drug with the repair process of the diseased tissue, so that it is difficult to effectively play a therapeutic role.

Summary of the invention

Based on this, it is necessary to provide a drug eluting device with a longer release period of active drugs and a lower risk of thrombosis.

A drug eluting device includes a base and a drug-loading layer; the base has an outer surface, a side surface and an inner surface, the drug-loading layer contains a drug carrier and an active drug, and the outer surface, the side surface and the inner of the base The surfaces are covered by the drug-carrying layer; the active drug is only distributed in at least a part of the drug-carrying layer covering the outer surface and the side surface, and in the thickness direction of the at least part of the region, close to the The concentration of the active drug on the side of the substrate is greater than the concentration of the active drug on the side away from the substrate.

In one of the embodiments, in the thickness direction of the at least part of the region, the concentration of the active drug gradually decreases from the side close to the base to the side far from the base.

In one of the embodiments, a groove or micropore is formed on the substrate, the groove or micropore is filled with an active drug, and the drug-carrying layer covers the groove or micropore.

In one of the embodiments, the grooves or micropores are covered by the at least a portion of the drug carrier layer where the active drug is distributed; or,

The groove or micropore is covered by the area of the drug-carrying layer where the active drug is not distributed.

In one of the embodiments, the drug eluting device further includes a pure drug layer, the pure drug layer covers at least part of the outer surface and the side surface of the substrate, and the pure drug layer is carried by the carrier The drug layer is completely covered.

In one embodiment, the active drug in the drug-carrying layer is only distributed in the area of the drug-carrying layer covering the outer surface of the substrate; or, the active drug in the drug-carrying layer is only distributed in the A partial area of the drug-carrying layer covering the outer surface of the substrate; or, the active drug in the drug-carrying layer is distributed in the area of the drug-carrying layer covering the outer surface and the side surface of the substrate; Alternatively, the active drug in the drug-carrying layer is distributed in a region where the drug-carrying layer covers the outer surface of the substrate and at least a part of the side surface.

In one of the embodiments, the thickness of the area covering the outer surface of the substrate and the area covering the side surface of the drug-carrying layer are both greater than the area of the drug-carrying layer covering the inner surface of the substrate thickness of.

In one of the embodiments, the thickness of the drug-carrying layer is 3-20 microns.

In one of the embodiments, the drug carrier is a degradable polymer, and the mass ratio of the degradable polymer to the active drug is 10:1 to 1:3.

A method for manufacturing a drug eluting device, including:

Providing a substrate, the substrate having an outer surface, an inner surface and a side surface;

The active drug is dissolved in the solvent I to form a drug solution, and then the drug solution is coated on at least a part of the outer surface and the side surface of the substrate, and after drying, the outer surface and the outer surface are formed on the substrate Pure drug layer in at least part of the side surface; and,

The drug carrier is dissolved in the solvent II to form a coating solution, and then the coating solution is coated on the outer surface, inner surface and side surface of the substrate, the solvent II dissolves the active drug in the pure drug layer After drying, a drug-carrying layer containing the active drug and a drug carrier is formed on the surface of the substrate, and the outer surface, side surfaces, and inner surface of the substrate are covered by the drug-carrying layer, and the drug-carrying layer The active drug in the layer is distributed in at least a part of the drug-carrying layer covering the outer surface and the side surface, and in the thickness direction of the at least part of the region, the concentration of the active drug on the side close to the substrate It is greater than the concentration of active drug on the side away from the matrix.

The active drug of the drug eluting device is only distributed in at least a part of the area covering the outer surface and the side surface of the base body of the drug-loading layer, while the area of the drug-loading layer covering the inner surface has no distribution of active drug. Therefore, the drug-eluting device can avoid the toxic and side effects of the active drug on other organs, and avoid the inhibitory effect of the active drug on the endothelialization of the device, thereby facilitating the attachment of endothelial cells on the device to reduce the risk of thrombosis. In addition, in the thickness direction of at least part of the region covering the outer surface and the side surface of the substrate, the concentration of the active drug on the side near the substrate is greater than the concentration of the active drug on the side away from the substrate, which is beneficial to prolong the activity The release cycle of the drug is beneficial to match the release of the active drug with the repair process of the diseased tissue and improve the therapeutic effect.

BRIEF DESCRIPTION

By reading the detailed description of the preferred embodiments below, various other advantages and benefits will become clear to those of ordinary skill in the art. The drawings are only for the purpose of showing the preferred embodiments, and are not considered to limit the present invention. Furthermore, throughout the drawings, the same reference symbols are used to denote the same components. In the drawings:

FIG. 1 is a schematic structural diagram of a drug eluting device according to an embodiment;

2 is a schematic diagram of the structure of a drug eluting device according to another embodiment;

3 is a schematic structural diagram of a drug eluting device according to another embodiment;

4 is a schematic structural diagram of a drug eluting device according to another embodiment;

FIG. 5 is a schematic structural diagram of a drug eluting device according to another embodiment;

FIG. 6 is a schematic structural diagram of a drug eluting device according to another embodiment.

detailed description

Hereinafter, exemplary embodiments of the present disclosure will be described in more detail with reference to the accompanying drawings. Although the exemplary embodiments of the present disclosure are shown in the drawings, it should be understood that the present disclosure can be implemented in various forms and should not be limited by the embodiments set forth herein. Rather, these embodiments are provided to enable a more thorough understanding of the present disclosure and to fully convey the scope of the present disclosure to those skilled in the art.

Referring to FIG. 1, a drug eluting device provided in an embodiment includes a base 1 and a drug carrying layer 3.

The base 1 is a hollow lumen structure. The base 1 has an inner surface 101, an outer surface 102, and a side surface 103. When the drug eluting device is implanted in the blood vessel, the inner surface 101 is the surface directly contacting the blood, the outer surface 102 is the surface directly contacting the blood vessel wall, the inner surface 101 and the outer surface 102 are opposite, and the side surface 103 Connecting inner surface 101 and outer surface 102.

In one embodiment, the substrate 1 can be made of a bioabsorbable material. For example, the substrate 1 is made of iron, iron-based alloy, magnesium, magnesium-based alloy, zinc, zinc-based alloy, or absorbable polymer material. Absorbable polymer materials are polylactic acid, polyglycolic acid, etc. In this embodiment, the base 1 is made of an iron-based alloy with a carbon content of not higher than 2.11 wt.% or the base 1 is made of pure iron.

In other embodiments, the base 1 is made of a material that is not bioabsorbable. For example, the base 1 is made of nickel-titanium alloy, cobalt-chromium alloy or stainless steel.

The drug carrier layer 3 completely covers the inner surface 101, the outer surface 102 and the side surface 103 of the base 1. The drug-carrying layer 3 contains a drug carrier (not shown in FIG. 1) and an active drug 301. The active drug 301 is only distributed in at least a part of the region of the drug-carrying layer 3 covering the outer surface 102 and the side surface 103 of the substrate 1, and the area of the drug-carrying layer 3 covering the inner surface 101 of the substrate 1 does not contain the active drug 301. In this way, the phenomenon that the active drug 301 is contained on the inner surface 101 and causes the active drug 301 to be released into the blood to cause toxic and side effects is avoided. In addition, after the drug-eluting device is implanted into the vascular lesion site, endothelial cells will crawl on the inner surface 101 of the base 1 to form an endothelial cell layer without the inhibitory effect. The inner surface 101 does not contain the active drug 301, which avoids the inhibitory effect of endothelial cell crawling, which is beneficial to the rapid endothelial cell crawling on the inner surface 101 of the base 101 to quickly form an endothelial cell layer, which is conducive to avoiding thrombosis Formation, reducing the risk of blood clots.

In addition, in the thickness direction of the region of the drug-carrying layer 3 covering the outer surface 102 and the side surface 103 of the base 1, the concentration of the active drug 301 on the side closer to the base 1 is greater than that of the active drug 301 on the side away from the base 1 concentration. The concentration of the active drug 301 on the side close to the base 1 is greater than the concentration of the active drug 301 on the side far from the base 1 is beneficial to delay the release cycle of the active drug 301 and avoid the release of the active drug 301 too fast to control the long-acting of the active drug 301 The release promotes the release of the active drug 301 to match the repair process of the diseased tissue, thereby improving the therapeutic effect.

In one embodiment, the concentration of the active drug 301 in the thickness direction of the region of the drug-carrying layer 3 covering the outer surface 102 and the side surface 103 of the base 1 from the side close to the base 1 to the side far from the base 1 The gradual decrease is beneficial to further control the release of the active drug 301 and improve the therapeutic effect.

Wherein, the active drug 301 is only distributed on at least part of the area of the outer surface 102 and the side surface 103 of the drug-carrying layer 3 covering the base 1, which means that the active drug 301 is distributed on the outer surface 102 and the side of the drug-carrying layer 3 covering the base 1 In the entire area of the surface 103, the active drug 301 is not distributed in the area of the drug-loading layer 3 covering the inner surface 101 of the substrate 1; or, the active drug 301 is distributed only in the entire area of the drug-loading layer 3 covering the outer surface 102 of the substrate 1 And part of the side surface 103, the active drug 301 is not distributed in the region of the drug-loading layer 3 covering the inner surface 101 of the substrate 1; or, the active drug 301 is only distributed on the outer surface 102 of the drug-loading layer 3 covering the substrate 1 The active drug 301 is not distributed in the area of the drug carrier layer 3 covering the inner surface 101 and the side surface 103 of the drug carrier layer 3; or, the active drug 301 is only distributed outside the drug carrier layer 3 covering the substrate 1 Part of the area of the surface 102, except for this area, other areas of the drug-loading layer 3 covering the outer surface 102 of the base 1 are not distributed with the active drug 301, and the active drug 301 is on the inner surface 101 of the drug-loading layer 3 covering the inner surface 101 of the base 1 The area and the area of the side surface 103 are not distributed.

In one embodiment, the active drug 301 is selected from at least one of anti-angiogenesis drugs, anti-thrombotic drugs, anti-inflammatory drugs, and anti-sensitizing drugs. Wherein, the angiogenesis-inhibiting drug is selected from at least one of paclitaxel, paclitaxel derivatives, rapamycin and rapamycin derivatives. The antiplatelet drug is cilostazol. The antithrombotic drug is heparin. The anti-inflammatory drug is dexamethasone. Anti-sensitizing drugs selected from diphenhydramine, chlorpheniramine, promethazine, hydrocortisone, triamcinolone, methylprednisolone, loratadine, fexofenadine, levocetine At least one of liazine, mizolastine and ebastine.

In one embodiment, the drug carrier is a degradable polymer. In one embodiment, the degradable polymer is selected from at least one of degradable polyester and degradable acid anhydride.

In one embodiment, the degradable polyester is selected from polylactic acid, polyglycolic acid, polylactic acid glycolic acid copolymer, polycaprolactone, polyacrylate, polyhydroxy fatty acid ester, polysuccinate, polysalicylic acid Anhydride ester, polytrimethylene carbonate, polydioxanone, poly(β-alkanoate), poly(β-hydroxybutyrate), polyethylene glycolate and polyhydroxybutyrate At least one of ester valerate copolymers. The degradable polyanhydride is at least one selected from the group consisting of poly 1,3-bis(p-carboxyphenoxy)propane-gluconic acid, polyerucic acid dimer-gluconic acid, and polyfumaric acid-gluconic acid.

In one embodiment, the degradable polymer is formed by copolymerizing at least two of the monomers forming the above-mentioned degradable polyester and the monomers forming the above-mentioned degradable acid anhydride.

The degradation of the above-mentioned degradable polyester and degradable polyanhydride will produce acidic products around the matrix 1, thereby forming a local low pH environment. When the matrix 1 is formed of an absorbable metal or alloy, it is beneficial to accelerate the later stage of the matrix 1 corrosion.

In one embodiment, the thickness of the drug carrier layer 3 is 3-20 microns. In one embodiment, the mass ratio of the degradable polymer (drug carrier) in the drug carrier layer 3 to the active drug 301 is 10:1 to 1:3. By reasonably setting the mass ratio of the degradable polymer to the active drug 301, the controlled release of the active drug 301 is better achieved, which is beneficial to the matching of the release of the active drug 301 and tissue repair. At the same time, when the substrate 1 is a degradable or corrodible substrate, the thickness of the drug carrier layer 3 is reasonably set so that the degradation cycle of the degradable polymer contained in the drug carrier layer 3 matches the degradation or corrosion cycle of the substrate 1 After the tissue repair is completed, the degradation products of the degradable polymer accelerate the degradation or corrosion of the matrix 1, thereby helping to reduce inflammation and reduce long-term clinical risk.

It should be noted that the thickness of the drug-loading layer 3 is 3-20 μm means that the average thickness of the drug-loading layer 3 is 3-20 μm, that is, the thickness and coverage of the area of the drug-loading layer 3 covering the inner surface 101 of the base 1 The average value of the thickness of the area of the outer surface 102 and the thickness of the area covering the side surface 103 is 3 to 20 μm.

In one embodiment, the thickness of the region covering the outer surface 102 of the base 1 and the thickness covering the side surface 103 of the drug-loading layer 3 are both greater than the thickness of the region covering the inner surface 101 of the base 1 by the drug-loading layer 3. That is, the drug-carrying layer 3 has a layered structure with asymmetric thickness.

In one embodiment, the base 1 is provided with grooves or micro holes. Please refer to FIG. 2. In the embodiment shown in FIG. 2, the base 1 is provided with a groove 104, and the surface where the opening end of the groove 104 is located is coplanar with the outer surface 102 of the base 1. The groove 104 is filled with active medicine. The region of the drug-loading layer 3 containing the active drug 301 covers the groove 104. The active drug filled in the groove 104 and the active drug 301 in the drug-loading layer 3 may be the same or different. Also, the release of the active drug filled in the groove 104 is later than the release of the active drug 301 in the drug-loading layer 3. In this way, the release cycle of the active drug (active drug 301 and active drug filled in the groove 104) is further extended, thereby improving the therapeutic effect.

In another embodiment, the drug-loaded layer 3 covers the groove 104, but the area of the drug-loaded layer 3 where the active drug 301 is distributed does not cover the groove 104, and the area of the drug-loaded layer 3 where the active drug 301 is not distributed covers the recess槽104. In this way, the release of the active drug filled in the groove 104 can also be delayed, thereby facilitating the overall delay of the release of the active drug (active drug 301 and active drug filled in the groove 104) of the drug eluting device.

In one embodiment, the base 1 is made of an absorbable material, and the active drug filled in the groove 104 is different from the active drug 301 in the drug-loading layer 3. Among them, the active drug 301 in the drug-carrying layer 3 is a drug that inhibits vascular proliferation, so as to inhibit vascular proliferation. The active drug filled in the groove 104 is an anti-inflammatory drug. The drug-loading layer 3 gradually degrades, and the active drug 301 gradually releases, which plays a role in inhibiting vascular proliferation. When the repair of the diseased tissue in the blood vessel is completed, the substrate 1 begins to degrade or corrode, and the degradation of the drug-loading layer 3 barely exposes the substrate 1, the substrate 1 The anti-inflammatory response drug filled in the groove 104 is gradually released to exert a curative effect, and the inflammatory response that may be generated due to the degradation or corrosion of the substrate 1 is suppressed.

In one embodiment, the substrate 1 is provided with micropores for filling the active drug. Wherein, the opening direction of the micropores is parallel to the thickness direction of the substrate 1, the micropores extend from the outer surface 102 to the inner surface 101 of the substrate 1, and/or the opening direction of the micropores is perpendicular to the thickness direction of the substrate 1, The micropores extend from the side surface 103 on one side of the base 1 to the side surface 103 on the other side.

Please refer to FIG. 3. In one embodiment, the drug eluting device further includes a pure drug layer 2. The pure drug layer 2 contains only active drugs and does not contain any drug carriers and other substances. The active drug in the pure drug layer 2 is the same as the active drug 301 in the drug carrier layer 3. In the embodiment shown in FIG. 3, the pure drug layer 2 completely covers the outer surface 102 and the side surface 103 of the base 1, and the pure drug layer 2 does not completely cover the inner surface 101 of the base 1. In another embodiment, as shown in FIG. 4, the pure drug layer 2 completely covers the outer surface 102 of the base 1, only partially covering the side surface 103 of the base 1, and the pure drug layer 2 does not completely cover the inside of the base 1 Surface 101. In another embodiment, as shown in FIG. 5, the pure drug layer 2 completely covers the outer surface 102 of the base 1, and the pure drug layer 2 completely does not cover the side surface 103 and the inner surface 101 of the base 1. In another embodiment, the pure drug layer 2 only covers a part of the outer surface 102 of the base 1, and some areas of the outer surface 102 of the base 1 are not covered by the pure drug layer 2, and the pure drug layer 2 does not cover the base at all 1的内面101和侧面103。 1 inner surface 101 and side surface 103. A pure drug layer 2 is provided between the substrate 1 and the drug-loading layer 3, that is, a layer containing active drugs is layered, which is beneficial to further prolong the release period of the active drugs.

When the drug eluting device further includes the pure drug layer 2, the base 1 may be provided with grooves 104 or micro holes for drug loading, or the base 1 may not be provided with any grooves 104 or micro holes. In the embodiment shown in FIG. 6, the drug eluting device includes a pure drug layer 2, and a groove 104 is formed on the base 1, and the pure drug layer 2 covers the groove 104.

The drug-carrying layer 3 of the above-mentioned drug eluting device completely covers the inner surface 101, the outer surface 102 and the side surface 103 of the substrate 1, that is, the drug-carrying layer 3 is a complete and continuous coating, and the complete and continuous coating When the drug is loaded, and the inner surface 101 of the base 1 does not contain the active drug 301, not only the risk of thrombus is low, but also when the drug eluting device is expanded, the drug-loaded layer 3 is not easily separated from the base 1 and falls off the base 1.

Therefore, the release period of the active drug 301 of the drug eluting device is longer, which is beneficial to match the release of the active drug 301 with the repair process of the diseased tissue, thereby improving the therapeutic effect. In addition, the inner surface 101 of the base 1 does not contain the active drug 301, which can avoid the side effects of the active drug 301, and is beneficial for the endothelial cells to crawl on the device to reduce the risk of thrombosis. At the same time, the reliability of the drug-eluting device is high, and the drug-carrying layer 3 is not easily separated from the base body 1 and falls off the base body 1 during the expansion process. After implantation in the body, the release of the active drug 301 is consistent with the tissue repair process, and the degradation of the drug-loaded layer 3 matches the corrosion of the matrix 1 to promote rapid corrosion of the matrix 1 and a low long-term clinical risk.

In one embodiment, the surface of the substrate 1 is roughened, which is conducive to the adhesion of the pure drug layer 2 and/or the drug-loading layer 3 on the substrate 1, which is beneficial to improve the reliability of the drug eluting device and avoid expansion. During the process, the pure drug layer 2 and/or the drug-loading layer 3 fall off from the substrate 1.

The drug eluting device may be other devices such as drug eluting stents, including but not limited to cardiovascular stents, cerebrovascular stents, peripheral vascular stents, biliary stents, esophageal stents, airway stents, orthopedic implants, etc.

A method for manufacturing a drug eluting device according to an embodiment includes the following steps:

A. Provide a base, the base having an outer surface, an inner surface, and a side surface.

In one embodiment, before performing the next step, the method further includes the steps of roughening the surface of the substrate and/or opening grooves or micropores in the substrate.

B. Dissolve the active drug in solvent I to form a drug solution, and then apply the drug solution to at least part of the outer surface and side surface of the substrate, and after drying, form at least part of the area covering the outer surface and side surface on the substrate Pure medicine layer.

The drug solution contains only the active drug and solvent I. The coating method includes but is not limited to spraying, leaching, dipping, rolling or electrospinning. During the coating process, the inner surface of the substrate is shielded to avoid the formation of a drug coating on the inner surface of the substrate. In one embodiment, during the coating process, a cylindrical inner brace is extended into the inner cavity of the base body to shield the inner surface of the base body.

C. Dissolve the drug carrier in the solvent II to form a coating solution, and then apply the coating solution to the outer surface, inner surface and side surface of the substrate. The solvent II dissolves the active drug in the pure drug layer and dries on the surface of the substrate A drug-carrying layer containing an active drug and a drug carrier is formed, and the outer surface, the side surface, and the inner surface of the substrate are covered by the drug-carrying layer, and the active drug in the drug-carrying layer is distributed on the part of the drug-carrying layer covering the outer surface and the side surface At least part of the region, and in the thickness direction of the at least part of the region, the concentration of the active drug on the side close to the substrate is greater than the concentration of the active drug on the side far from the substrate.

The coating solution contains only the drug carrier and solvent II, and does not contain any active drug. The solvent II dissolves the active drug in the pure drug layer means that the solvent II partially dissolves the active drug in the pure drug layer or completely dissolves the active drug in the pure drug layer.

By controlling the solid content (concentration of drug carrier) and coating speed of the coating solution in step C, it can be controlled whether the drug in the pure drug layer is completely dissolved by the solvent II and transferred to the drug carrier layer, and the In the thickness direction of the layer covering at least a part of the base, the concentration of the active drug on the side close to the base is greater than the concentration of the active drug on the side far from the base. Further, in the thickness direction where the drug-loading layer covers at least a part of the base, the concentration of the active drug gradually decreases from the side close to the base to the side far from the base.

After completing step B, first remove the cylindrical inner brace and then proceed to step C, so that the drug-carrying layer completely covers the inner surface, outer surface, and side surfaces of the substrate.

In one embodiment, the concentration of the drug carrier in the coating solution is 1 mg/mL to 15 mg/mL, and the coating speed is 0.01 mL/min to 0.20 mL/min.

In one embodiment, when the final drug eluting device further includes a pure drug layer, it can be achieved by simultaneously controlling the concentration of the drug carrier in the coating solution, the coating speed, and the thickness of the pure drug layer. For example, when the concentration of the drug carrier in the coating solution and the coating speed of the coating solution are fixed, the thickness of the pure drug layer can be increased, so that the resulting drug eluting device further includes a layer between the substrate and the drug carrier layer Pure medicine layer.

The manufacturing method of the above drug eluting device first forms a pure drug layer on the substrate, and then transfers the active drug in the pure drug layer to the drug carrier layer by means of solvent transfer, so that the active drug is dispersed in the drug carrier, and In the thickness direction of the drug carrier layer covering at least part of the substrate, the concentration of the active drug on the side near the substrate is greater than the concentration of the active drug on the side away from the substrate, the concentration of the drug carrier and the active drug passing through the drug carrier layer Distribution controls the long-acting release of active drugs. The drug-eluting device manufactured by the manufacturing method of the drug-eluting device not only has a longer release period of the active drug and a lower risk of thrombosis, but also disperses the active drug by forming a pure drug layer and then transferring the active drug through the solvent The way in the drug carrier, on the one hand, realizes that the inner surface of the matrix does not contain the active drug, on the other hand, compared with the traditional method of dissolving the active drug and the drug carrier in the solvent at the same time to obtain a coating solution, and using an internal strut or barrier After the rod covers the inner surface of the substrate, the coating solution is sprayed on the substrate. Whether it is a pure drug layer or a drug-loaded layer, the integrity of the coating obtained by the above-mentioned drug eluting device manufacturing method is better It will not cause damage to the coating when the device is separated from the inner brace or barrier after the coating containing both active drug and drug carrier is formed. Therefore, the production yield of the above-mentioned drug eluting device manufacturing method is high.

Taking the drug eluting stent of 30008 size as an example, the above drug eluting device will be further described through specific examples.

The 30008 drug eluting stent refers to the nominal expansion pressure (the nominal expansion pressure refers to the pressure used when expanding the stent to the nominal diameter), the nominal diameter after expansion is 3 mm, and the nominal length is 8 mm. Among them, the nominal diameter refers to the inner diameter of the matrix after expansion (implanted into the blood vessel and the expansion of the inner diameter of the matrix), the nominal length is the length of the matrix after expansion (implanted into the blood vessel and the expansion is completed, the length of the matrix).

The following describes the detection and experimental methods of the specific embodiments as follows:

I. Test method of drug release cycle:

The drug-eluting stent was implanted into the iliac artery of New Zealand rabbits, and the New Zealand rabbits were sacrificed at the follow-up node X months after implantation, the stent was removed, and the drug (such as acetonitrile) in the stent was extracted with a suitable solvent, using high performance liquid chromatography (HPLC) The remaining drug amount on the stent is tested, and the test result is compared with the theoretical drug amount of the stent obtained by the coating quality calculation before the stent is implanted to obtain the mass percentage of the remaining drug of the stent, such as the remaining drug on the stent If the mass percentage is ≤5%, it is considered that X months is the drug release cycle of the stent.

Equipment: Agilent High Performance Liquid Chromatograph 1260; Column: Agilent Zobax SB C18 4.6*150mm 5μm. Suggested test parameters: detection wavelength: 278nm, column temperature: 50℃, mobile phase: acetonitrile: water = 65:35, flow rate: 1.0mL/min.

II. Test method of stent coating integrity:

The drug-eluting stent is expanded under the rated burst pressure after simulated delivery, and then the expanded stent is magnified under a microscope to observe the damage and peeling of the coating from 50 times to 200 times.

III. Test method of drug distribution in stent coating:

The distribution of drugs on the surface of the stent can be characterized by Raman spectroscopy. The specific characterization method is: using the Raman spectrometer of Thermo Fisher Scientific Corporation to perform Raman spectroscopy on the outer surface and the side surface of the coating at a wavelength of 532 nm According to the analysis, in the thickness direction of the matrix, from the side close to the matrix to the side away from the matrix, focus out the test step by step with a certain step length (for example, 1 μm). When the intensity of the characteristic peak of the active drug gradually weakens, it means that the active drug It gradually decreases from the side close to the base to the side far from the base.

IV: Test method for coating thickness:

The stent was embedded in resin to grind the sample, the section of the stent was observed by SEM, and the thickness of the drug coating applied on the stent was measured.

V: Endothelialization speed test method:

Endothelialization speed test: the drug-eluting device is implanted into the rabbit iliac artery. After a certain period of time, the blood vessel where the drug-eluting device is located is taken out, soaked with glutaraldehyde (such as 6h), dried, then cut along the axial direction, and gold sprayed , SEM measurement and observation of drug-eluting device endothelial coverage, when the coverage rate reached more than 90%, indicating that the drug-eluting device has completed endothelialization.

VI: Inflammatory response integral test method

The drug-eluting stent was implanted into the rabbit iliac artery. After a certain period of time, the blood vessel containing the drug-eluting stent was removed and soaked with formalin. Formalin-fixed tissue specimens were removed by chemical treatment, then the paraffin was embedded, paraffin-embedded, sliced with Leica 2135 microtome, slice thickness 4-5μm, and then HE stained to observe pathology.

Inflammation score calculation: 0 points: There are no inflammatory cells (lymphocytes, eosinophils, macrophages, etc.) around the media and intima. 1 point: Infiltrated by a small amount of inflammatory cells around the media and intima. 2 points: moderate infiltration of inflammatory cells in the intima, media and adventitia, accounting for 25%-50% of the vascular area. 3 points: There are a large number of inflammatory cells in the intima, media and adventitia. Surround the entire blood vessel, occupying more than 50% of the blood vessel area, and calculate the average value through multiple observations. The larger the score, the more severe the inflammation.

It should be noted that the test methods for the above parameters or performance are not limited to the methods listed above, and any method mastered by those skilled in the art can be used for testing.

Example 1

First prepare an ethyl acetate solution of rapamycin at a concentration of 5 mg/mL and an ethyl acetate solution of poly-racic lactic acid at a concentration of 3 mg/mL; prepare a matrix of pure iron with a specification of 30008, and cover the matrix On the inner strut, slightly compress the base body so that the inner surface of the base body is close to the inner strut. Then, the ethyl acetate solution of rapamycin is sprayed onto the substrate by ultrasonic spraying, and after drying, the inner brace is removed to obtain a stent containing a pure drug layer, wherein the pure drug layer completely covers the outer surface and the side surface of the substrate; Spray the ethyl acetate solution of polyracemic lactic acid on the inner surface, outer surface and side surface of the stent. The coating speed in this step is 0.03mL/min. Dissolve all the rapamycin in the pure drug layer into the poly racemic lactic acid coating, and dry to obtain a drug-eluting stent. The drug-eluting stent contains an iron-based matrix and a drug-carrying layer. The drug-loading layer covers the iron-based matrix The outer surface, inner surface and side surface of the drug carrier layer covering the outer surface and the side surface, along the thickness direction of the substrate, the content of rapamycin gradually decreases from the side near the substrate to the side away from the substrate small. Among them, the mass ratio of rapamycin to polyracemic lactic acid on the stent is 1:3, and the average thickness of the drug-loaded layer is 10 μm.

After the simulated delivery in vitro, the stent was expanded under the rated blasting pressure. The results showed that the drug-loaded layer was intact without peeling or peeling; the stent was completely endothelialized after 1 month of implantation in the New Zealand rabbit iliac artery, and the active drug was released. The period is 12 months.

Example 2

First prepare an ethyl acetate solution of rapamycin at a concentration of 5 mg/mL and an ethyl acetate solution of poly-racic lactic acid at a concentration of 10 mg/mL; prepare a matrix of pure iron with a size of 30008 and coat the matrix On the inner strut, slightly compress the base body so that the inner surface of the base body is close to the inner strut. Then, the ethyl acetate solution of rapamycin is sprayed onto the substrate by ultrasonic spraying, and after drying, the inner brace is removed to obtain a stent containing a pure drug layer, wherein the pure drug layer completely covers the outer surface and the side surface of the substrate; Spray the ethyl acetate solution of polyracemic lactic acid on the inner surface, outer surface and side surface of the stent, the coating speed of this step is 0.10mL/min, the ethyl acetate in the ethyl acetate solution of polyracic lactic acid The rapamycin in the pure drug layer is partially dissolved into the polyracemic lactic acid coating, and after drying, a drug-eluting stent is obtained. The drug-eluting stent includes an iron-based matrix, a pure drug layer, and a drug-loading layer. The pure drug layer The outer surface and the side surface of the iron-based substrate are completely covered, the drug-loaded layer completely covers the pure drug layer, and the drug-loaded layer covers the outer surface, the inner surface and the side surface of the iron-based substrate, and the drug-loaded layer covers the outer surface and the side surface In the area, along the thickness direction of the substrate, the content of rapamycin gradually decreases from the side near the substrate to the side away from the substrate. Among them, the mass ratio of rapamycin to polyracemic lactic acid on the stent is 1:3, and the average thickness of the drug-loaded layer is 10 μm.

After the simulated delivery in vitro, the stent was expanded under the rated burst pressure. The results showed that the drug-loaded layer was complete without peeling and peeling; the stent was completely endothelialized after 1 month of implantation in the New Zealand rabbit iliac artery, and the active drug release cycle For 15 months.

Example 3

First prepare an ethyl acetate solution of rapamycin at a concentration of 5 mg/mL and an ethyl acetate solution of poly-racic lactic acid at a concentration of 10 mg/mL; prepare a matrix made of pure iron of 30008 size, and the surface of the matrix passes In the roughening process, a groove is formed on the base body, the plane where the opening end of the groove is located is coplanar with the outer surface of the base body, the base body is sleeved on the inner strut, and the base body is slightly compressed so that the inner surface of the base body is close to the inner strut. Then, the ethyl acetate solution of rapamycin is sprayed on the substrate by ultrasonic spraying, and after drying, the inner brace is removed to obtain a stent containing a pure drug layer, and the groove of the substrate is filled with rapamycin, pure drug layer Fully cover the outer surface and side surface of the substrate; then spray the ethyl acetate solution of polyracemic lactic acid on the inner surface, outer surface and side surface of the stent, the coating speed of this step is 0.08mL/min, polyracemic The ethyl acetate in the ethyl acetate solution of lactic acid dissolves the rapamycin in the pure drug layer into the poly racemic lactic acid coating, and after drying, a drug-eluting stent is obtained. The drug-eluting stent contains an iron-based matrix, Pure drug layer and drug-loaded layer, and the groove of the iron-based substrate is filled with rapamycin, the pure drug layer completely covers the outer surface and side surface of the iron-based substrate, the drug-loaded layer completely covers the pure drug layer, and the drug-loaded layer The layer covers the outer surface, inner surface and side surface of the iron-based substrate. On the area of the drug-loaded layer covering the outer surface and the side surface, along the thickness direction of the substrate, the content of rapamycin is from the side close to the substrate to far away from the substrate The side gradually decreases. Among them, the mass ratio of rapamycin to polyracemic lactic acid on the stent is 1:3, and the average thickness of the drug-loaded layer is 10 μm.

After the simulated delivery in vitro, the stent was expanded under the rated blasting pressure. The results showed that the drug-loaded layer was intact without peeling or peeling; the stent was completely endothelialized after 1 month of implantation in the New Zealand rabbit iliac artery, and the active drug was released. The period is 18 months.

Example 4

First prepare an ethyl acetate solution of rapamycin at a concentration of 5 mg/mL and an ethyl acetate solution of polycaprolactone at a concentration of 10 mg/mL; prepare a matrix of pure iron with a size of 30008 and coat the matrix On the inner strut, slightly compress the base body so that the inner surface of the base body is close to the inner strut. Then, the ethyl acetate solution of rapamycin is sprayed onto the substrate by ultrasonic spraying, and after drying, the inner brace is removed to obtain a stent containing a pure drug layer, wherein the pure drug layer completely covers the outer surface of the substrate and does not cover the substrate at all Side surface; spraying the ethyl acetate solution of polycaprolactone onto the inner surface, outer surface and side surface of the stent, the coating speed of this step is 0.20mL/min, the ethyl acetate solution of polycaprolactone The ethyl acetate in the solution dissolves part of the rapamycin in the pure drug layer into the poly racemic lactic acid coating. After drying, a drug-eluting stent is obtained. The pure drug layer only covers the outer surface of the iron-based substrate, the drug-loaded layer completely covers the pure drug layer, and the drug-loaded layer covers the outer surface, inner surface, and side surfaces of the iron-based substrate, and the drug-loaded layer covers the area of the outer surface Above, along the thickness direction of the substrate, the content of rapamycin gradually decreases from the side near the substrate to the side away from the substrate. Among them, the mass ratio of rapamycin to polyracemic lactic acid on the stent is 1:10, and the average thickness of the drug-carrying layer is 10 μm.

After the simulated delivery in vitro, the stent was expanded under the rated blasting pressure. The results showed that the drug-loaded layer was intact without peeling or peeling; the stent was completely endothelialized after 1 month of implantation in the New Zealand rabbit iliac artery, and the active drug was released. The period is 15 months.

Example 5

First prepare an ethyl acetate solution of paclitaxel at a concentration of 5 mg/mL and an ethyl acetate solution of poly-racic lactic acid at a concentration of 15 mg/mL; prepare a matrix of pure magnesium with a size of 30008, and put the matrix in the inner support On the rod, the base body is slightly compressed so that the inner surface of the base body is close to the inner brace. Then, the ethyl acetate solution of paclitaxel is sprayed onto the substrate by ultrasonic spraying, and after drying, the inner brace is removed to obtain a stent containing a pure drug layer, wherein the pure drug layer completely covers the outer surface of the substrate and partially covers the side surface of the substrate; Then spray the ethyl acetate solution of polyracemic lactic acid on the inner surface, outer surface and side surface of the stent. The coating speed of this step is 0.1mL/min. The ester partially dissolves the paclitaxel in the pure drug layer into the poly racemic lactic acid coating, and after drying, a drug-eluting stent is obtained. The drug-eluting stent includes a magnesium-based matrix, a pure drug layer, and a drug-loading layer, and the pure drug layer is completely covered. The outer surface of the magnesium-based substrate partially covers the side surface of the substrate, the drug-loading layer completely covers the pure drug layer, and the drug-loading layer covers the outer surface, inner surface, and side surfaces of the magnesium-based substrate, and the area of the drug-loading layer covering the outer surface And on the partial area covering the side surface, the content of paclitaxel gradually decreases from the side close to the base to the side away from the base along the thickness direction of the base. Among them, the mass ratio of paclitaxel and polyracemic lactic acid on the stent is 1:1, and the average thickness of the drug-loaded layer is 3 μm.

After the simulated delivery in vitro, the stent was expanded under the rated blasting pressure. The results showed that the drug-loaded layer was intact without peeling or peeling; the stent was completely endothelialized after 1 month of implantation in the New Zealand rabbit iliac artery, and the active drug was released. The period is 6 months.

Example 6

First prepare an aqueous solution of heparin with a concentration of 5 mg/mL and an ethyl acetate solution of polyracemic lactic acid with a concentration of 3 mg/mL; prepare a matrix formed of L-polylactic acid with a size of 30008 and put the matrix on the inner brace , Slightly compress the base body so that the inner surface of the base body close to the inner strut. Then, the aqueous solution of heparin is sprayed onto the substrate by ultrasonic spraying, and after drying, the inner brace is removed to obtain a stent containing a pure drug layer, wherein the pure drug layer completely covers the outer surface and the side surface of the substrate; The ethyl acetate solution is sprayed onto the inner surface, outer surface and side surface of the stent. The coating speed in this step is 0.02mL/min. The heparin is completely dissolved in the poly-racemic lactic acid coating, and after drying, a drug-eluting stent is obtained. The drug-eluting stent includes a L-lactic acid matrix and a drug-carrying layer, and the drug-loading layer covers the outer surface and the inner surface of the L-lactic acid matrix. And the side surface, the area of the drug-carrying layer covering the outer surface and the side surface, along the thickness direction of the base, the content of heparin gradually decreases from the side close to the base to the side away from the base. Among them, the mass ratio of heparin on the stent to polyracemic lactic acid is 3:1, and the average thickness of the drug-loaded layer is 20 μm.

The stent was expanded under the rated blast pressure after simulated delivery in vitro, and the results showed that the drug-loaded layer was intact without peeling or peeling; the stent was completely endothelialized after 2 months of implantation in the New Zealand rabbit iliac artery, and the active drug was released The period is 6 months.

Example 7

First prepare the ethyl acetate solution of dexamethasone with a concentration of 5 mg/mL and the ethyl acetate solution of a polylactic acid-glycolic acid copolymer with a concentration of 10 mg/mL; prepare a matrix made of pure zinc with a specification of 30008. The surface is roughened, and a groove is formed on the base body. The plane of the open end of the groove is coplanar with the outer surface of the base body. The base body is sleeved on the inner brace bar, and the base body is slightly compressed to make the inner surface of the base body close to the inner brace. Rod. Then, the ethyl acetate solution of dexamethasone was sprayed onto the substrate by ultrasonic spraying. After drying, the inner brace was removed to obtain a stent containing a pure drug layer, and the groove of the substrate was filled with dexamethasone, which was completely covered by the pure drug layer. The outer surface and the side surface of the substrate; then put the bracket on the fixture with the blocking rod, the diameter of the blocking rod is smaller than the inner diameter of the bracket, spray the ethyl acetate solution of the polylactic acid-glycolic acid copolymer onto the bracket, and dry it to get the load Medicine layer. The blocking rod partially blocks the inner surface of the base body, so that the thickness of the region covering the outer surface of the base body and the area covering the side surface of the obtained drug-loading layer are both greater than the thickness of the area of the drug-loading layer covering the inner surface of the base body, the The coating speed in the step is 0.08 mL/min. The ethyl acetate in the ethyl acetate solution of the polylactic acid-glycolic acid copolymer will partially dissolve the dexamethasone in the pure drug layer into the polylactic acid-glycolic acid copolymer coating After drying, a drug-eluting stent is obtained. The drug-eluting stent includes a zinc-based matrix, a pure drug layer, and a drug-carrying layer, and the groove of the zinc-based matrix is filled with dexamethasone, and the pure drug layer covers the outside of the zinc-based matrix. On the surface and side surfaces, the drug-loading layer completely covers the pure drug layer, and the drug-loading layer covers the outer surface, inner surface, and side surface of the zinc-based substrate. The area of the drug-loading layer covering the outer surface and the side surface, along the thickness of the substrate In the direction, the content of dexamethasone gradually decreased from the side close to the substrate to the side away from the substrate. Among them, the mass ratio of dexamethasone and polylactic acid-glycolic acid copolymer on the stent is 1:1, and the average thickness of the drug-loading layer is 5 μm.

The stent was expanded under the rated blast pressure after simulated delivery in vitro, and the results showed that the drug-loaded layer was intact without peeling or peeling; the stent was completely endothelialized after 2 months of implantation in the New Zealand rabbit iliac artery, and the active drug was released The period is 9 months.

Example 8

First prepare the ethyl acetate solution of loratadine with a concentration of 5 mg/mL and the ethyl acetate solution of poly-L-lactic acid with a concentration of 1 mg/mL; prepare a matrix made of pure iron with a size of 30008. The surface of the matrix is roughened The base body is provided with a groove, the plane where the opening end of the groove is located is coplanar with the outer surface of the base body, and the base body is sleeved on the inner brace bar, and the base body is slightly compressed so that the inner surface of the base body is close to the inner brace bar. Then, the ethyl acetate solution of loratadine is sprayed onto the substrate by ultrasonic spraying, and after drying, the inner brace is removed to obtain a stent containing a pure drug layer, wherein the pure drug layer completely covers the outer surface and the side surface of the substrate; Spray the ethyl acetate solution of poly-L-lactic acid on the inner surface, outer surface and side surface of the stent. The coating speed in this step is 0.03mL/min. The ethyl acetate in the ethyl acetate solution of poly-L-lactic acid will be pure The loratadine in the drug layer is completely dissolved in the poly-L-lactic acid coating, and the drug-eluting stent is obtained after drying. The drug-eluting stent includes an iron-based substrate and a drug-carrying layer, and the drug-loading layer covers the outer surface of the iron-based substrate On the surface, inner surface and side surface, the area of the drug-carrying layer covering the outer surface and the side surface, along the thickness direction of the substrate, the content of loratadine gradually decreases from the side near the substrate to the side away from the substrate. Among them, the mass ratio of loratadine and poly-L-lactic acid on the stent is 1:6, and the average thickness of the drug-carrying layer is 15 μm.

The stent was expanded under the rated blasting pressure after simulated delivery in vitro, and the results showed that the stent coating was complete without peeling and peeling; the stent was completely endothelialized after implantation of the New Zealand rabbit iliac artery for 1 month, and the stent drug was released The period is 15 months.

Example 9

Prepare an ethyl acetate solution of dexamethasone at a concentration of 5 mg/ml, an ethyl acetate solution of rapamycin at a concentration of 5 mg/mL, and an ethyl acetate solution of poly-racic lactic acid at a concentration of 3 mg/mL; Prepare a base made of pure iron of 30008 size, the surface of the base is roughened, and a groove is formed on the base, the plane of the opening of the groove is coplanar with the outer surface of the base, and the base is sleeved on the inner brace On the top, the base is slightly compressed so that the inner surface of the base is in close contact with the inner brace. Then, the ethyl acetate solution of dexamethasone was sprayed into the groove on the substrate by ultrasonic spraying. After drying, the ethyl acetate solution of rapamycin was sprayed onto the substrate. After drying, the inner brace was removed to obtain the pure drug. The layer of the stent, and the groove contains dexamethasone, wherein the pure drug layer (containing only rapamycin) completely covers the outer surface and the side surface of the substrate; then the ethyl acetate solution of polyracic lactic acid is sprayed onto the stent On the inner surface, outer surface and side surface, the coating speed of this step is 0.01mL/min. The ethyl acetate in the ethyl acetate solution of polyracemic lactic acid will completely dissolve the rapamycin in the pure drug layer to the poly In the racemic lactic acid coating, a drug-eluting stent is obtained after drying. The drug-eluting stent includes an iron-based substrate, a drug-loading layer, and dexamethasone in the groove, and the drug-loading layer covers the outer surface and inner surface of the iron-based substrate And the side surface, the area of the drug-carrying layer covering the outer surface and the side surface, along the thickness direction of the substrate, the content of rapamycin gradually decreases from the side near the substrate to the side away from the substrate. Among them, the mass ratio of dexamethasone, rapamycin and polyracemic lactic acid on the stent is 1:2:6, and the average thickness of the drug-loaded layer is 10 μm.

After the simulated delivery in vitro, the stent was expanded under the rated burst pressure. The results showed that the stent coating was complete without peeling and peeling; the stent was completely endothelialized after implantation of the New Zealand rabbit iliac artery for 1 month. The release period of the mycocin is 12 months, and the inflammatory response score of 12 months is 1 point.

Example 10

First prepare an ethyl acetate solution of rapamycin at a concentration of 5 mg/mL and an ethyl acetate solution of poly-racic lactic acid at a concentration of 10 mg/mL; prepare a matrix made of pure iron of 30008 size, and the surface of the matrix passes Roughening treatment, a groove is formed on the substrate, the plane of the opening end of the groove is coplanar with the outer surface of the substrate, and the ethyl acetate solution of rapamycin is sprayed onto a local area on the outer surface of the substrate by an inkjet printer , After drying, remove the inner brace to obtain the stent containing the pure drug layer, and the groove of the base is filled with rapamycin, the pure drug layer completely covers the outer surface and the side surface of the base; The ethyl ester solution is sprayed onto the inner surface, outer surface and side surface of the stent. The coating speed in this step is 0.08mL/min. Paromycin is partially dissolved in the polyracemic lactic acid coating, and after drying, a drug-eluting stent is obtained. The drug-eluting stent includes an iron-based matrix, a pure drug layer, and a drug-carrying layer, and the grooves of the iron-based matrix are filled with Rapamycin, the pure drug layer only partially covers the outer surface of the iron-based substrate, and the drug-loaded layer of the iron-based substrate completely covers the pure drug layer, and the drug-loaded layer covers the outer surface, inner surface, and side surfaces of the iron-based substrate, On the area of the drug-carrying layer covering the outer surface and the side surface, the content of rapamycin gradually decreases from the side close to the base to the side away from the base along the thickness direction of the base. Part of the groove of the iron-based substrate is covered by the area of the drug-carrying layer where the active drug is not distributed. Among them, the mass ratio of rapamycin to polyracemic lactic acid on the stent is 1:3, and the average thickness of the drug-loaded layer is 10 μm.

Comparative Example 1

First prepare a mixed solution of rapamycin and poly-racic acid with a mass ratio of 1:3 ethyl acetate; prepare an iron-based matrix of 30008 size, and sleeve the iron-based matrix on the inner brace bar, slightly compress the iron-based matrix The base makes the inner surface of the iron-based base close to the inner brace. Then, the above mixed solution is sprayed onto the iron-based substrate by ultrasonic spraying, and after drying, the inner brace is removed to obtain the stent containing the drug-loaded layer. The stent includes an iron-based substrate and a drug-carrying layer, and the drug-loading layer covers the outer surface and the side surface of the iron-based substrate. Among them, the mass ratio of rapamycin to polyracemic lactic acid on the stent is 1:3, and the average thickness of the drug-carrying layer is 10 μm.

After the simulated delivery in vitro, the stent was expanded under the rated blasting pressure. The results showed that the drug-loaded layer was damaged and part of the drug-loaded layer fell off; the stent was completely endothelialized after 1 month of implantation in the New Zealand rabbit iliac artery, and the active drug The release period is 3 months, and the 12-month inflammatory response score is 2 points.

Comparative Example 2

First prepare a mixed solution of rapamycin and poly-racemic acid with a mass ratio of 1:1 ethyl acetate; prepare an iron-based matrix of 30008 size. The above mixed solution is sprayed onto the iron-based substrate by ultrasonic spraying, and after drying, a stent containing a drug-loaded layer is obtained. The stent includes the iron-based substrate and the drug-loaded layer, wherein the drug-loaded layer completely covers the surface of the iron-based substrate. The average thickness of the drug carrier layer is 20 μm.

After the simulated delivery in vitro, the stent was expanded under the rated blasting pressure. The results showed that the drug-loaded layer was complete without peeling and peeling; the stent was completely endothelialized after 3 months of implantation in the New Zealand rabbit iliac artery, and the active drug was released. The period is 3 months.

It should be understood that the terminology used herein is for the purpose of describing particular example embodiments only, and is not intended to be limiting. Unless the context clearly indicates otherwise, the singular forms "a", "an", and "said" as used herein may also mean including the plural forms. The terms "including", "comprising", "containing" and "having" are inclusive and therefore indicate the presence of stated features, steps, operations, elements and/or components, but do not exclude the presence or addition of one or Various other features, steps, operations, elements, components, and/or combinations thereof. The method steps, processes, and operations described herein are not to be construed as requiring that they be performed in the specific order described or illustrated unless the order of execution is clearly indicated. It should also be understood that additional or alternative steps may be used.

The above are only preferred specific embodiments of the present invention, but the scope of protection of the present invention is not limited to this. Any person skilled in the art can easily think of changes or changes within the technical scope disclosed by the present invention. Replacement should be covered within the protection scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims

A drug eluting device, characterized in that it includes a base body and a drug carrying layer; the base body has an outer surface, side surfaces and an inner surface, the drug carrying layer contains a drug carrier and an active drug, the outer surface of the base body, Both the side surface and the inner surface are covered by the drug carrier layer; the active drug is only distributed in at least a part of the drug carrier layer covering the outer surface and the side surface, and in the thickness direction of the at least part of the region Above, the concentration of the active drug on the side close to the base is greater than the concentration of the active drug on the side far from the base.
The drug eluting device according to claim 1, characterized in that, in the thickness direction of the at least part of the area, from the side close to the base to the side far from the base, the concentration of the active drug Gradually decreases.
The drug eluting device according to claim 1 or 2, wherein a groove or a micro hole is formed on the substrate, the groove or the micro hole is filled with an active drug, and the drug loading layer is covered The groove or micro hole.
The drug eluting device according to claim 3, characterized in that the grooves or micropores are covered by the at least a portion of the drug carrier layer where the active drug is distributed; or,

The groove or micropore is covered by the area of the drug-carrying layer where the active drug is not distributed.
The drug eluting device according to claim 1 or 2, characterized in that the drug eluting device further comprises a pure drug layer, the pure drug layer covering at least part of the outer surface and the side surface of the substrate , And the pure drug layer is completely covered by the drug-loading layer.
The drug eluting device according to claim 1 or 2, wherein the active drug in the drug-carrying layer is distributed only in the region of the drug-carrying layer covering the outer surface of the substrate; or, the The active drug in the drug-carrying layer is only distributed in a part of the drug-carrying layer covering the outer surface of the substrate; or, the active drug in the drug-carrying layer is distributed in the drug-carrying layer covering the substrate The area of the outer surface and the area of the side surface; or, the active drug in the drug-carrying layer is distributed in the area of the drug-carrying layer covering the outer surface of the substrate and at least part of the side surface area.
The drug eluting device according to claim 1 or 2, wherein the thickness of the region covering the outer surface of the base and the thickness of the region covering the side surface of the drug-carrying layer are both greater than the load The thickness of the region where the drug layer covers the inner surface of the substrate.
The drug eluting device according to claim 1, wherein the thickness of the drug carrying layer is 3-20 microns.
The drug eluting device according to claim 1, wherein the drug carrier is a degradable polymer, and the mass ratio of the degradable polymer to the active drug is 10:1 to 1:3.
A method for manufacturing a drug eluting device, characterized in that it includes:

Providing a substrate, the substrate having an outer surface, an inner surface and a side surface;

The active drug is dissolved in the solvent I to form a drug solution, and then the drug solution is coated on at least a part of the outer surface and the side surface of the substrate, and after drying, the outer surface and the outer surface are formed on the substrate Pure drug layer in at least part of the side surface; and,

The drug carrier is dissolved in the solvent II to form a coating solution, and then the coating solution is coated on the outer surface, inner surface and side surface of the substrate, the solvent II dissolves the active drug in the pure drug layer After drying, a drug-carrying layer containing the active drug and a drug carrier is formed on the surface of the substrate, and the outer surface, side surfaces, and inner surface of the substrate are covered by the drug-carrying layer, and the drug-carrying layer The active drug in the layer is distributed in at least a part of the drug-carrying layer covering the outer surface and the side surface, and in the thickness direction of the at least part of the region, the concentration of the active drug on the side close to the substrate It is greater than the concentration of active drug on the side away from the matrix.