CN111358603A

CN111358603A - Medicine eluting apparatus and manufacturing method thereof

Info

Publication number: CN111358603A
Application number: CN201811593382.8A
Authority: CN
Inventors: 林文娇; 胡军
Original assignee: Biotyx Medical Shenzhen Co Ltd
Current assignee: Biotyx Medical Shenzhen Co Ltd
Priority date: 2018-12-25
Filing date: 2018-12-25
Publication date: 2020-07-03
Also published as: WO2020134542A1

Abstract

The invention relates to a drug eluting device and a manufacturing method thereof, wherein the drug eluting device comprises a substrate and a drug-loaded layer; the base body is provided with an outer surface, a side surface and an inner surface, the drug-loaded layer contains a drug carrier and an active drug, and the outer surface, the side surface and the inner surface of the base body are all covered by the drug-loaded layer; the active drug is distributed on at least partial areas of the drug-loaded layer covering the outer surface and the side surfaces, the concentration of the active drug on the side close to the matrix is larger than that on the side far away from the matrix in the thickness direction of the at least partial areas, and the area of the drug-loaded layer on the inner surface of the matrix does not contain the active drug. The drug eluting device has a long release period of active drug and a low risk of thrombosis.

Description

Medicine 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

Drug eluting stents are becoming more widely used in the treatment of cardiovascular diseases. At present, the inner surface and the outer surface of most drug eluting stents are coated with drugs, when the drug eluting stents are implanted into blood vessels, only the outer surface and the side surface of the stent are in contact with the blood vessel wall, active drugs released from the outer surface and the side surface of the stent can enter the blood vessel wall to play a curative effect, and the active drugs on the inner surface of the stent cannot play a therapeutic role, but can be released into blood to circulate to the whole body, and may have toxic and side effects on other organs. In addition, active drugs on the inner surface of the stent also inhibit stent endothelialization, thereby increasing the risk of thrombosis.

In addition, the release period of the drug of the existing drug eluting stent is too short, so that the release of the drug is difficult to match with the repair process of the pathological tissue, and the effective treatment effect is difficult to achieve.

Disclosure of Invention

Based on this, there is a need for a drug eluting device with a longer release period of the active drug and a lower risk of thrombosis.

A drug eluting device comprises a base body and a drug-loaded layer; the substrate is provided with an outer surface, a side surface and an inner surface, the drug-loaded layer contains a drug carrier and an active drug, and the outer surface, the side surface and the inner surface of the substrate are all covered by the drug-loaded layer; the active drug is distributed on at least partial area of the drug-loaded layer covering the outer surface and the side surface, and the concentration of the active drug on the side close to the substrate is larger than that on the side far away from the substrate in the thickness direction of the at least partial area.

In one embodiment, the concentration of the active drug is gradually decreased from a side close to the substrate to a side far from the substrate in the thickness direction of the at least partial region.

In one embodiment, the substrate is formed with a groove or a pore, the groove or the pore is filled with active drug, and the drug-loaded layer covers the groove or the pore.

In one embodiment, the grooves or pores are covered by the at least partial region of the drug-loaded layer where the active drug is distributed; or,

the grooves or micropores are covered by regions of the drug-loaded layer not distributed with the active drug.

In one embodiment, the drug eluting device further comprises a pure drug layer covering at least partial areas of the outer surface and the side surface of the substrate, and the pure drug layer is completely covered by the drug-loaded layer.

In one embodiment, the active drug in the drug-loaded layer is distributed only in the area of the drug-loaded layer covering the outer surface of the substrate; or the active medicament in the medicament-carrying layer is distributed on only partial area of the medicament-carrying layer covering the outer surface of the substrate; or the active medicament in the medicament-carrying layer is distributed in the area of the medicament-carrying layer covering the outer surface and the side surface of the substrate; or the active medicament in the medicament-carrying layer is distributed in the area of the outer surface of the substrate covered by the medicament-carrying layer and at least part of the side surface.

In one embodiment, the thickness of the drug-loaded layer in the area covering the outer surface of the base body and the thickness of the area covering the side surface are both greater than the thickness of the drug-loaded layer in the area covering the inner surface of the base body.

In one embodiment, the thickness of the drug-loaded layer is 3-20 microns.

In one embodiment, 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 of manufacturing a drug eluting device, comprising:

providing a substrate having an outer surface, an inner surface, and a side surface;

dissolving an active drug in a solvent I to form a drug solution, then coating the drug solution on at least partial areas of the outer surface and the side surface of the substrate, and forming a pure drug layer covering at least partial areas of the outer surface and the side surface on the substrate after drying; and a process for the preparation of a coating,

dissolving a drug carrier in a solvent II to form a coating solution, and then coating the coating solution on the outer surface, the inner surface and the side surface of the substrate, wherein the solvent II dissolves the active drug in the pure drug layer, a drug-loaded layer containing the active drug and the drug carrier is formed on the surface of the substrate after drying, the outer surface, the side surface and the inner surface of the substrate are all covered by the drug-loaded layer, the active drug in the drug-loaded layer is distributed in at least partial area of the drug-loaded layer covering the outer surface and the side surface, and in the thickness direction of the at least partial area, the concentration of the active drug on the side close to the substrate is greater than that on the side far away from the substrate.

The active agent of the drug eluting device is distributed only in at least a portion of the area of the drug-loaded layer covering the outer surface and side surfaces of the base, while the area of the drug-loaded layer covering the inner surface is free of distribution of the active agent. Therefore, the medicine elution apparatus can avoid the toxic and side effects of the active medicine on other organs and the inhibition effect of the active medicine on endothelialization of the apparatus, thereby being beneficial to endothelial cells to climb on the apparatus and reducing the risk of thrombus. In addition, in the thickness direction of at least partial areas of the drug-loaded layer covering the outer surface and the side surface of the substrate, the concentration of the active drug on one side close to the substrate is greater than that on one side far away from the substrate, so that the release period of the active drug is prolonged, the release of the active drug is matched with the repair process of the pathological tissue, and the curative effect is improved.

Drawings

Various other advantages and benefits will become apparent to those of ordinary skill in the art upon reading the following detailed description of the preferred embodiments. The drawings are only for purposes of illustrating the preferred embodiments and are not to be construed as limiting the invention. Also, like reference numerals are used to refer to like parts throughout the drawings. In the drawings:

FIG. 1 is a schematic diagram of the structure of one embodiment of a drug eluting device;

FIG. 2 is a schematic structural view of another embodiment of a drug eluting device;

FIG. 3 is a schematic structural view of another embodiment of a drug eluting device;

FIG. 4 is a schematic structural view of another embodiment of a drug eluting device;

FIG. 5 is a schematic structural view of another embodiment of a drug eluting device;

fig. 6 is a schematic structural view of another embodiment drug eluting device.

Detailed Description

Exemplary embodiments of the present disclosure will be described in more detail below with reference to the accompanying drawings. While exemplary embodiments of the present disclosure are shown in the drawings, it should be understood that the present disclosure may be embodied in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the disclosure to those skilled in the art.

Referring to fig. 1, one embodiment provides a drug eluting device comprising a base 1 and a drug-loaded layer 3.

The base body 1 is a hollow-out tube cavity structure. The base body 1 has an inner surface 101, an outer surface 102 and a side surface 103. Wherein, when the drug eluting device is implanted in a blood vessel, the inner surface 101 is a surface in direct contact with blood, the outer surface 102 is a surface in direct contact with a blood vessel wall, the inner surface 101 and the outer surface 102 are opposite, and the side surface 103 connects the inner surface 101 and the outer surface 102.

In one embodiment, the matrix 1 may be made of a bioabsorbable material. For example, the substrate 1 is made of iron, iron-based alloy, magnesium-based alloy, zinc-based alloy, or absorbable polymer material. The absorbable polymer material is polylactic acid, polyglycolic acid and the like. In the present embodiment, the base 1 is made of an iron-based alloy having a carbon content of not more than 2.11 wt.% or the base 1 is made of pure iron.

In other embodiments, the matrix 1 is made of a non-bioabsorbable material. For example, the base body 1 is made of a material such as nickel-titanium alloy, cobalt-chromium alloy, or stainless steel.

The drug-loaded layer 3 completely covers the inner surface 101, the outer surface 102 and the side surface 103 of the base body 1. The drug-loaded layer 3 contains a drug carrier (not shown in fig. 1) and an active drug 301. The active drug 301 is distributed only in the region of the drug-loaded layer 3 covering at least part of the outer surface 102 and the side surface 103 of the base 1, and the region of the drug-loaded layer 3 covering the inner surface 101 of the base 1 does not contain the active drug 301. Thus, the phenomenon that the active medicament 301 is released into the blood to cause toxic and side effects due to the active medicament 301 contained on the inner surface 101 is avoided. After the drug eluting device is implanted into a vascular lesion, endothelial cells may climb on the inner surface 101 of the base 1 to form an endothelial cell layer without inhibiting effects. The inner surface 101 does not contain active drugs 301, so that the inhibition effect on endothelial cell crawling is avoided, the endothelial cells can crawl on the inner surface 101 of the substrate 101 quickly to form an endothelial cell layer quickly, the formation of thrombus is avoided, and the thrombus risk is reduced.

Further, in the thickness direction of the region of the drug-loaded 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 close to the base 1 is greater than the concentration of the active drug 301 on the side far from the base 1. The concentration of the active drug 301 close to one side of the matrix 1 is greater than that of the active drug 301 far away from one side of the matrix 1, so that the release period of the active drug 301 is delayed, the active drug 301 is prevented from being released too fast, the long-acting release of the active drug 301 is controlled, the release of the active drug 301 is promoted to be matched with the repair process of the pathological tissue, and the curative effect is improved.

In one embodiment, the concentration of the active drug 301 gradually decreases from the side close to the substrate 1 to the side far from the substrate 1 in the thickness direction of the region of the drug-loaded layer 3 covering the outer surface 102 and the side surface 103 of the substrate 1, which is beneficial to further control the release of the active drug 301 and improve the therapeutic effect.

Wherein, the active drug 301 is distributed only in at least partial area of the drug-loaded layer 3 covering the outer surface 102 and the side surface 103 of the base body 1, which means that the active drug 301 is distributed in the whole area of the drug-loaded layer 3 covering the outer surface 102 and the side surface 103 of the base body 1, and the active drug 301 is not distributed in the area of the drug-loaded layer 3 covering the inner surface 101 of the base body 1; alternatively, the active drug 301 is distributed only in the entire region of the drug-loaded layer 3 covering the outer surface 102 of the base 1 and in a partial region of the side surface 103, and the active drug 301 is not distributed in the region of the drug-loaded layer 3 covering the inner surface 101 of the base 1; alternatively, the active drug 301 is distributed only in the entire region of the drug-loaded layer 3 covering the outer surface 102 of the base 1, and the active drug 301 is not distributed in both the region of the drug-loaded layer 3 covering the inner surface 101 and the side surface 103 of the base 1; alternatively, the active drug 301 is distributed only in a partial region of the drug-loaded layer 3 covering the outer surface 102 of the base 1, and other regions of the drug-loaded layer 3 covering the outer surface 102 of the base 1 are not distributed with the active drug 301 except for this region, and the active drug 301 is not distributed in both the region of the drug-loaded layer 3 covering the inner surface 101 and the region of the side surface 103 of the base 1.

In one embodiment, the active agent 301 is selected from at least one of a vascular proliferation-inhibiting agent, an antithrombotic agent, an anti-inflammatory agent, and an anti-allergenic agent. Wherein the angiogenesis inhibitor is at least one of paclitaxel, paclitaxel derivatives, rapamycin and rapamycin derivatives. The antiplatelet drug is cilostazol. The antithrombotic drug is heparin. The anti-inflammatory agent is dexamethasone. The anti-sensitization drug is at least one of diphenhydramine, chlorpheniramine, promethazine, hydrocortisone, triamcinolone acetonide, methylprednisolone, loratadine, fexofenadine, levocetirizine, 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 a degradable polyester and a degradable anhydride.

In one embodiment, the degradable polyester is at least one selected from the group consisting of polylactic acid, polyglycolic acid, copolymers of polylactic and glycolic acid, polycaprolactone, polyacrylate, polyhydroxyalkanoate, polybutylene succinate, polyanhydride, polytrimethylene carbonate, polydioxanone, poly (β -alkanoate), poly (β -hydroxybutyrate), polyethylene glycol adipate, and polyhydroxybutyrate valerate copolymers.

In one embodiment, the degradable polymer is copolymerized from at least two of monomers forming the degradable polyester and monomers forming the degradable anhydride.

The degradation of the degradable polyester and the degradable polyanhydride as described above creates acidic products around the substrate 1, thereby creating a localized low pH environment that facilitates accelerated corrosion of the substrate 1 at a later time when the substrate 1 is formed of absorbable metal or alloy.

In one embodiment, the thickness of the drug-loaded layer 3 is 3-20 μm. In one embodiment, the mass ratio of the degradable polymer (drug carrier) to the active drug 301 in the drug-loaded layer 3 is 10:1 to 1: 3. The mass ratio of the degradable polymer to the active drug 301 is reasonably set to better realize the controlled release of the active drug 301, which is beneficial to matching the release of the active drug 301 with the tissue repair. Meanwhile, when the matrix 1 is degradable or corrodible, the thickness of the drug-loaded layer 3 is reasonably set, so that the degradation period of the degradable polymer contained in the drug-loaded layer 3 is matched with that of the matrix 1, and after the tissue repair is completed, the degradation product of the degradable polymer accelerates the degradation or corrosion of the matrix 1, thereby being beneficial to reducing inflammatory reaction and reducing long-term clinical risk.

The thickness of the drug-loaded layer 3 of 3 to 20 μm means that the average thickness of the drug-loaded layer 3 is 3 to 20 μm, that is, the average of the thickness of the drug-loaded layer 3 in the region covering the inner surface 101 of the base 1, the thickness of the region covering the outer surface 102, and the thickness of the region covering the side surface 103 is 3 to 20 μm.

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

In one embodiment, the substrate 1 is provided with grooves or pores. Referring to fig. 2, in the embodiment shown in fig. 2, a groove 104 is formed on the substrate 1, and a surface of an opening end of the groove 104 is coplanar with the outer surface 102 of the substrate 1. The recess 104 is filled with an active drug. The region of the drug-loaded layer 3 containing the active drug 301 covers the recess 104. The active drug filled in the groove 104 may be the same as or different from the active drug 301 in the drug-loaded layer 3. And the release of the active drug filled in the grooves 104 is later than the release of the active drug 301 in the drug-loaded layer 3. Thus, the release period of the active drug (the active drug 301 and the 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 region of the drug-loaded layer 3 where the active drug 301 is distributed does not cover the groove 104, and the region of the drug-loaded layer 3 where the active drug 301 is not distributed covers the groove 104. In this way, the release of the active drug filled in the groove 104 can be delayed, thereby being beneficial to delaying the release of the active drug (the active drug 301 and the active drug filled in the groove 104) of the drug eluting device as a whole.

In one embodiment, the matrix 1 is made of an absorbable material, and the grooves 104 are filled with an active drug different from the active drug 301 in the drug-loaded layer 3. Wherein, the active drug 301 in the drug-loaded layer 3 is a drug for inhibiting vascular proliferation so as to inhibit vascular proliferation. The active drug filled in the grooves 104 is an anti-inflammatory drug. The drug-loaded layer 3 is gradually degraded, the active drug 301 is gradually released to play a role in inhibiting the proliferation of blood vessels, when the repair of pathological tissues in the blood vessels is finished, the substrate 1 starts to degrade or corrode, the degradation of the drug-loaded layer 3 exposes the substrate 1, the anti-inflammatory reaction drugs filled in the grooves 104 of the substrate 1 are gradually released to play a curative effect, and the inflammatory reaction possibly generated due to the degradation or corrosion of the substrate 1 is inhibited.

In one embodiment, the substrate 1 is provided with micropores for filling with active drugs. Wherein the opening direction of the micropores is parallel to the thickness direction of the substrate 1, the micropores extending 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 extending from the side surface 103 of one side of the substrate 1 to the side surface 103 of the other side.

Referring to fig. 3, in one embodiment, the drug eluting device further includes a pure drug layer 2. The pure drug layer 2 contains only the active drug and does not contain any drug carriers or other substances. The active drug in the pure drug layer 2 is the same as the active drug 301 in the drug-loaded layer 3. In the embodiment shown in fig. 3, the pure chemical layer 2 completely covers the outer surface 102 and the side surface 103 of the base 1, and the pure chemical layer 2 does not cover the inner surface 101 of the base 1 at all. In another embodiment, as shown in fig. 4, the pure chemical layer 2 completely covers the outer surface 102 of the base 1, only partially covers the side surface 103 of the base 1, and the pure chemical layer 2 does not cover the inner surface 101 of the base 1 at all. 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 does not cover the side surface 103 and the inner surface 101 of the base 1 at all. In another embodiment, the pure drug layer 2 covers only a partial area of the outer surface 102 of the base body 1, a partial area of the outer surface 102 of the base body 1 is not covered by the pure drug layer 2, and the pure drug layer 2 does not cover the inner surface 101 and the side surface 103 of the base body 1 at all. The pure drug layer 2 is arranged between the matrix 1 and the drug-loaded layer 3, namely, the layers containing active drugs are arranged in a layered mode, and the release period of the active drugs can be further prolonged.

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

The medicine carrying layer 3 of the medicine elution apparatus completely covers the inner surface 101, the outer surface 102 and the side surface 103 of the substrate 1, namely the medicine carrying layer 3 is a complete and continuous coating, medicine is carried through the complete and continuous coating, the inner surface 101 of the substrate 1 is prevented from containing no active medicine 301, the thrombus risk is low, and the medicine carrying layer 3 is not easy to separate from the substrate 1 and fall off from the substrate 1 when the medicine elution apparatus is expanded.

Therefore, the active drug 301 of the drug eluting device has a longer release period, which is beneficial to matching the release of the active drug 301 with the repair process of the pathological tissue, thereby improving the curative effect. In addition, the inner surface 101 of the matrix 1 does not contain the active drug 301, so that the side effect of the active drug 301 can be avoided, endothelial cells can be favorably attached to the device, and the risk of thrombus is reduced. Meanwhile, the medicine elution apparatus has high reliability, and the medicine-carrying layer 3 is not easy to separate from the matrix 1 and fall off from the matrix 1 in the expansion process. After implantation in vivo, the release of the active drug 301 is consistent with the tissue repair process, and the degradation of the drug-loaded layer 3 is matched with the erosion of the matrix 1 to promote rapid erosion of the matrix 1 with lower long-term clinical risk.

In one embodiment, the surface of the base body 1 is roughened, which is beneficial to the adhesion of the pure drug layer 2 and/or the drug-loaded layer 3 on the base body 1, is beneficial to improving the reliability of the drug eluting device, and avoids the pure drug layer 2 and/or the drug-loaded layer 3 from falling off from the base body 1 during the expansion process.

The drug eluting device may be a drug eluting stent or other devices, including but not limited to cardiovascular stent, cerebrovascular stent, peripheral vascular stent, biliary stent, esophageal stent, airway stent or orthopedic implant, etc.

A method of manufacturing a drug eluting device according to an embodiment, comprising the steps of:

A. a substrate is provided having an outer surface, an inner surface, and a side surface.

In one embodiment, the method further comprises the step of roughening the surface of the substrate and/or forming grooves or micropores in the substrate before the next step.

B. Dissolving an active drug in a solvent I to form a drug solution, coating the drug solution on at least partial areas of the outer surface and the side surface of the substrate, and drying to form a pure drug layer covering at least partial areas of the outer surface and the side surface on the substrate.

The drug solution contains only the active drug and solvent I. Methods of coating include, but are not limited to, spraying, leaching, dipping, rolling, or electrospinning. In the coating process, the inner surface of the substrate is shielded, so that a drug coating is prevented from being formed on the inner surface of the substrate. In one embodiment, a cylindrical inner strut extends into the lumen of the substrate during the coating process to provide a shadow against the inner surface of the substrate.

C. Dissolving a drug carrier in a solvent II to form a coating solution, then coating the coating solution on the outer surface, the inner surface and the side surface of a substrate, dissolving the active drug in the pure drug layer by the solvent II, forming a drug-loaded layer containing the active drug and the drug carrier on the surface of the substrate after drying, wherein the outer surface, the side surface and the inner surface of the substrate are all covered by the drug-loaded layer, the active drug in the drug-loaded layer is distributed in at least partial area of the part of the drug-loaded layer covering the outer surface and the side surface, and in the thickness direction of the at least partial area, the concentration of the active drug on the side close to the substrate is greater than that on the side far away from the substrate.

The coating solution contains only the drug carrier and solvent II, but does not contain any active drug. The solvent II is used for dissolving the active medicament in the pure medicament layer, and the solvent II is used for partially dissolving the active medicament in the pure medicament layer or completely dissolving the active medicament in the pure medicament layer.

By controlling the solid content (concentration of the drug carrier) and the coating speed of the coating solution in step C, it is possible to control whether or not all of the drug in the pure drug layer is dissolved by the solvent II and transferred into the drug-loaded layer, and it is achieved that 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 away from the substrate in the thickness direction of the drug-loaded layer covering at least a partial region of the substrate. Further, the concentration of the active drug is gradually reduced from the side close to the base to the side far from the base in the thickness direction of the drug-loaded layer covering at least a partial region of the base.

After the step B is completed, the cylindrical inner support rod is taken down and then the step C is carried out, so that the drug-loaded layer completely covers the inner surface, the outer surface and the side surface of the substrate.

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

In one embodiment, when the resulting drug eluting device further comprises a pure drug layer, this can be achieved by simultaneously controlling the concentration of the drug carrier in the coating solution, the coating rate and the thickness of the pure drug layer. For example, when the concentration of the drug carrier in the coating solution and the coating rate of the coating solution are fixed, the thickness of the pure drug layer may be increased so that the resulting drug eluting device further comprises a pure drug layer between the substrate and the drug-loaded layer.

The manufacturing method of the drug eluting device comprises the steps of forming a pure drug layer on a base body, transferring active drugs in the pure drug layer into a drug-loaded layer in a solvent transfer mode, enabling the active drugs to be dispersed in drug carriers, enabling the concentration of the active drugs on one side close to the base body to be larger than that of the active drugs on one side far away from the base body in the thickness direction of at least one part of the drug-loaded layer covering the base body, and controlling the long-acting release of the active drugs through the drug carriers of the drug-loaded layer and the concentration distribution of the active drugs. The drug eluting device manufactured by the manufacturing method of the drug eluting device not only has longer release period of the active drug and lower thrombus risk, but also realizes that the inner surface of the matrix does not contain the active drug on one hand by forming the pure drug layer firstly and then transferring the active drug by the solvent to disperse the active drug in the drug carrier, on the other hand, compared with the traditional mode that the active drug and the drug carrier are simultaneously dissolved in the solvent to obtain the coating solution, the inner surface of the matrix is shielded by the inner supporting rod or the blocking rod, and then the coating solution is sprayed on the matrix, no matter the pure drug layer or the drug-carrying layer, the integrity of the coating obtained by the manufacturing method of the drug eluting device is better, and when the device is peeled off from the inner supporting rod or the blocking rod after the coating simultaneously containing the active drug and the drug carrier is formed, causing damage to the coating. Therefore, the manufacturing method of the drug eluting device has high production yield.

The drug eluting device is further illustrated by specific examples using a 30008 gauge drug eluting stent as an example.

30008 Standard drug eluting stents means a nominal diameter of 3mm and a nominal length of 8mm after expansion at a nominal expansion pressure (nominal expansion pressure means the pressure used to expand the stent to the nominal diameter). Wherein, the nominal diameter refers to the inner diameter of the matrix after expansion (the inner diameter of the matrix after being implanted into the blood vessel and the expansion is completed), and the nominal length refers to the length of the matrix after expansion (the length of the matrix after being implanted into the blood vessel and the expansion is completed).

The following description of the test and experimental procedures for specific examples is provided:

I. test methods for drug release cycle:

implanting the drug eluting stent into the iliac artery of a New Zealand rabbit, killing the New Zealand rabbit at a follow-up node X months after implantation, taking out the stent, extracting the drug (such as acetonitrile) in the stent by using a proper solvent, detecting the residual drug amount on the stent by using High Performance Liquid Chromatography (HPLC), and comparing the detection result with the theoretical drug amount of the stent obtained by coating mass calculation before stent implantation to obtain the mass percentage of the residual drug of the stent, wherein if the mass percentage of the residual drug on the stent is less than or equal to 5%, the X months is considered as the drug release period of the stent.

Equipment: agilent high performance liquid chromatograph 1260; a chromatographic column: agilent Zobax SB C184.6 x 150mm 5 μm. The suggested test parameters are: detection wavelength: 278nm, column temperature: 50 ℃, mobile phase: acetonitrile: water 65:35, flow rate: 1.0 mL/min.

II. Stent coating integrity test method:

the drug eluting stent is expanded under rated explosion pressure after being subjected to simulated conveying, and then the expanded stent is magnified by 50 times to 200 times under a microscope to observe the damage and the falling condition of the coating.

III, testing the distribution of the drugs in the stent coating:

the distribution condition of the drug on the surface of the stent can be characterized by Raman spectrum, and the specific characterization method comprises the following steps: the outer surface and the side surface of the coating were subjected to raman spectroscopic analysis using a raman spectrometer of seimer feishel corporation at a wavelength of 532nm, and the test was focused outward in steps (e.g., 1 μm) from the side close to the substrate to the side away from the substrate in the thickness direction of the substrate, and when the intensity of the characteristic peak of the active drug gradually decreased, it was indicated that the intensity of the active drug gradually decreased from the side close to the substrate to the side away from the substrate.

IV: method for testing coating thickness:

the stent was embedded in resin and ground, the cross section of the stent was observed by SEM, and the thickness of the drug coating layer coated on the stent was measured.

V: endothelialization rate test methods:

endothelialization rate test: implanting the drug eluting device into the iliac artery of a rabbit, taking out the blood vessel where the drug eluting device is located after a certain time, soaking the blood vessel with glutaraldehyde (for example, 6h), drying, then cutting the blood vessel along the axial direction, spraying gold, measuring and observing the endothelial coverage rate of the drug eluting device by SEM, and when the coverage rate reaches more than 90%, indicating that the drug eluting device completes endothelialization.

VI: inflammatory response integral test method

Implanting the drug eluting stent into the iliac artery of a rabbit, taking out the blood vessel where the drug eluting stent is positioned, and soaking the blood vessel with formalin. The formalin-fixed tissue specimen was chemically treated to remove the stent, embedded in paraffin, sliced with a Leica 2135 microtome, 4-5 μm thick, HE stained, and examined for pathology.

Inflammation integral calculation: 0 minute: there were no inflammatory cells (lymphocytes, eosinophils, macrophages, etc.) around the media and intima. 1 minute: infiltrated by a small number of inflammatory cells around the media and intima. And 2, dividing: the tunica intima, tunica media and tunica adventitia have moderate inflammatory cell infiltration, and account for 25% -50% of the area of blood vessels. And 3, dividing: there are a large number of inflammatory cells in the intima, media and adventitia. Surrounding the whole blood vessel, occupying more than 50% of the blood vessel area, and calculating the average value through multiple observations. The larger the integral, the more severe the inflammation.

It should be noted that the method for testing the parameters or the performance is not limited to the above-mentioned method, and any method known to those skilled in the art can be used for testing.

Example 1

Firstly, respectively preparing an ethyl acetate solution of rapamycin with the concentration of 5mg/mL and an ethyl acetate solution of poly-racemic lactic acid with the concentration of 3 mg/mL; a30008-sized base body formed of pure iron is prepared and is fitted over the inner strut, and the base body is slightly compressed so that the inner surface of the base body is closely fitted to the inner strut. Then, spraying an ethyl acetate solution of rapamycin onto the substrate through ultrasonic spraying, drying, and then taking down the inner support rod to obtain the stent containing the pure drug layer, wherein the pure drug layer completely covers the outer surface and the side surface of the substrate; and then spraying the ethyl acetate solution of the poly-dl-lactic acid on the inner surface, the outer surface and the side surface of the stent, wherein the coating speed of the step is 0.03mL/min, the ethyl acetate in the ethyl acetate solution of the poly-dl-lactic acid completely dissolves the rapamycin in the pure drug layer into the poly-dl-lactic acid coating, and drying is carried out to obtain the drug eluting stent, the drug eluting stent comprises an iron-based matrix and a drug-loaded layer, the drug-loaded layer covers the outer surface, the inner surface and the side surface of the iron-based matrix, and the rapamycin content in the regions of the drug-loaded layer covering the outer surface and the side surface is gradually reduced from one side close to the matrix to one side far away from the matrix along the thickness direction. Wherein the mass ratio of the rapamycin to the poly-racemic lactic acid on the stent is 1:3, and the average thickness of the drug-loaded layer is 10 μm.

After the bracket is subjected to simulated conveying in vitro, the bracket is expanded under rated blasting pressure, and the result shows that the medicine-carrying layer is complete without peeling and spalling; the stent is completely endothelialized after being implanted into the iliac artery of a New Zealand rabbit for 1 month, and the release period of the active drug is 12 months.

Example 2

Firstly, respectively preparing an ethyl acetate solution of rapamycin with the concentration of 5mg/mL and an ethyl acetate solution of poly-racemic lactic acid with the concentration of 10 mg/mL; a30008-sized base body formed of pure iron is prepared and is fitted over the inner strut, and the base body is slightly compressed so that the inner surface of the base body is closely fitted to the inner strut. Then, spraying an ethyl acetate solution of rapamycin onto the substrate through ultrasonic spraying, drying, and then taking down the inner support rod to obtain the stent containing the pure drug layer, wherein the pure drug layer completely covers the outer surface and the side surface of the substrate; and then spraying an ethyl acetate solution of the poly-dl-lactic acid on the inner surface, the outer surface and the side surface of the stent, wherein the coating speed of the step is 0.10mL/min, rapamycin in the pure drug layer is partially dissolved into the poly-dl-lactic acid coating by the ethyl acetate in the ethyl acetate solution of the poly-dl-lactic acid, and the drug eluting stent is obtained after drying, and comprises an iron-based matrix, a pure drug layer and a drug-loaded layer, wherein the pure drug layer completely covers the outer surface and the side surface of the iron-based matrix, the drug-loaded layer completely covers the pure drug layer, the drug-loaded layer covers the outer surface, the inner surface and the side surface of the iron-based matrix, and the rapamycin content is gradually reduced from one side close to the matrix to one side far away from the matrix in the thickness direction of the matrix in the region of the drug. Wherein the mass ratio of the rapamycin to the poly-racemic lactic acid on the stent is 1:3, and the average thickness of the drug-loaded layer is 10 μm.

After the bracket is subjected to simulated conveying in vitro, the bracket is expanded under rated blasting pressure, and the result shows that the medicine-carrying layer is complete without peeling and spalling; the stent is completely endothelialized after being implanted into the iliac artery of a New Zealand rabbit for 1 month, and the release period of the active drug is 15 months.

Example 3

Firstly, respectively preparing an ethyl acetate solution of rapamycin with the concentration of 5mg/mL and an ethyl acetate solution of poly-racemic lactic acid with the concentration of 10 mg/mL; preparing a 30008-standard base body formed by pure iron, roughening the surface of the base body, forming a groove in the base body, enabling the plane where the opening end of the groove is located to be coplanar with the outer surface of the base body, sleeving the base body on the inner supporting rod, and slightly compressing the base body to enable the inner surface of the base body to be tightly attached to the inner supporting rod. Then, spraying an ethyl acetate solution of rapamycin onto the substrate through ultrasonic spraying, drying, and then taking down the inner support rod to obtain the stent containing the pure drug layer, wherein the rapamycin is filled in the groove of the substrate, and the pure drug layer completely covers the outer surface and the side surface of the substrate; and then spraying an ethyl acetate solution of the poly-dl-lactic acid on the inner surface, the outer surface and the side surface of the stent, wherein the coating speed of the step is 0.08mL/min, rapamycin in the pure drug layer is partially dissolved into the poly-dl-lactic acid coating by ethyl acetate in the ethyl acetate solution of the poly-dl-lactic acid, and the drug eluting stent is obtained after drying, and comprises an iron-based matrix, a pure drug layer and a drug-loaded layer, rapamycin is filled in a groove of the iron-based matrix, the pure drug layer completely covers the outer surface and the side surface of the iron-based matrix, the drug-loaded layer completely covers the pure drug layer, the drug-loaded layer covers the outer surface, the inner surface and the side surface of the iron-based matrix, and the content of rapamycin is gradually reduced from one side close to the matrix to one side far away from the matrix along the thickness direction of the matrix in the regions. Wherein the mass ratio of the rapamycin to the poly-racemic lactic acid on the stent is 1:3, and the average thickness of the drug-loaded layer is 10 μm.

After the bracket is subjected to simulated conveying in vitro, the bracket is expanded under rated blasting pressure, and the result shows that the medicine-carrying layer is complete without peeling and spalling; the stent is completely endothelialized after being implanted into the iliac artery of a New Zealand rabbit for 1 month, and the release period of the active drug is 18 months.

Example 4

Firstly, respectively preparing an ethyl acetate solution of rapamycin with the concentration of 5mg/mL and an ethyl acetate solution of polycaprolactone with the concentration of 10 mg/mL; a30008-sized base body formed of pure iron is prepared and is fitted over the inner strut, and the base body is slightly compressed so that the inner surface of the base body is closely fitted to the inner strut. Then, spraying an ethyl acetate solution of rapamycin onto the substrate through ultrasonic spraying, drying, and then taking down the inner support rod to obtain the stent containing the pure drug layer, wherein the pure drug layer completely covers the outer surface of the substrate and does not cover the side surface of the substrate completely; and then spraying the ethyl acetate solution of polycaprolactone onto the inner surface, the outer surface and the side surface of the stent, wherein the coating speed of the step is 0.20mL/min, the rapamycin in the pure drug layer is partially dissolved into the poly-racemic lactic acid coating by the ethyl acetate in the ethyl acetate solution of polycaprolactone, and the drug eluting stent is obtained after drying and comprises an iron-based matrix, a pure drug layer and a drug-loaded layer, wherein the pure drug layer only covers the outer surface of the iron-based matrix, the drug-loaded layer completely covers the pure drug layer, the drug-loaded layer covers the outer surface, the inner surface and the side surface of the iron-based matrix, and the content of the rapamycin is gradually reduced from one side close to the matrix to one side far away from the matrix in the thickness direction of the matrix in the region of the drug-loaded layer covering the outer surface. Wherein the mass ratio of the rapamycin to the poly-racemic lactic acid on the stent is 1:10, and the average thickness of the drug-loaded layer is 10 μm.

Example 5

Firstly, respectively preparing an ethyl acetate solution of paclitaxel with the concentration of 5mg/mL and an ethyl acetate solution of poly-racemic lactic acid with the concentration of 15 mg/mL; a30008-sized base body formed of pure magnesium is prepared and is fitted over the inner strut, and the base body is slightly compressed so that the inner surface of the base body is closely fitted to the inner strut. Then, spraying an ethyl acetate solution of paclitaxel on the matrix through ultrasonic spraying, drying, and then taking down the inner support rod to obtain the stent containing the pure drug layer, wherein the pure drug layer completely covers the outer surface of the matrix and partially covers the side surface of the matrix; and spraying an ethyl acetate solution of the poly-dl-lactic acid on the inner surface, the outer surface and the side surface of the stent, wherein the coating speed of the step is 0.1mL/min, the ethyl acetate in the ethyl acetate solution of the poly-dl-lactic acid dissolves the paclitaxel in the pure drug layer partially into the poly-dl-lactic acid coating, and drying is carried out to obtain the drug eluting stent, the drug eluting stent comprises a magnesium-based matrix, a pure drug layer and a drug-loaded layer, the pure drug layer completely covers the outer surface of the magnesium-based matrix and partially covers the side surface of the matrix, the drug-loaded layer completely covers the pure drug layer, the drug-loaded layer covers the outer surface, the inner surface and the side surface of the magnesium-based matrix, and the content of the paclitaxel is gradually reduced from the side close to the matrix to the side far from the matrix along the thickness direction of the matrix. Wherein the mass ratio of the paclitaxel to the poly-racemic lactic acid on the stent is 1:1, and the average thickness of the drug-loaded layer is 3 μm.

After the bracket is subjected to simulated conveying in vitro, the bracket is expanded under rated blasting pressure, and the result shows that the medicine-carrying layer is complete without peeling and spalling; the stent is completely endothelialized after being implanted into the iliac artery of a New Zealand rabbit for 1 month, and the release period of the active drug is 6 months.

Example 6

Firstly, respectively preparing a heparin aqueous solution with the concentration of 5mg/mL and a poly-racemic-lactic-acid ethyl acetate solution with the concentration of 3 mg/mL; a30008-sized matrix formed of L-polylactic acid is prepared, and the matrix is fitted over the inner strut, and the matrix is slightly compressed so that the inner surface of the matrix is in close contact with the inner strut. Then, spraying a heparin aqueous solution on the substrate through ultrasonic spraying, drying, and then taking down the inner support rod to obtain the stent containing the pure medicine layer, wherein the pure medicine layer completely covers the outer surface and the side surface of the substrate; and then spraying an ethyl acetate solution of the poly-dl-lactic acid on the inner surface, the outer surface and the side surface of the stent, wherein the coating speed of the step is 0.02mL/min, the ethyl acetate in the ethyl acetate solution of the poly-dl-lactic acid completely dissolves the heparin in the pure drug layer into the poly-dl-lactic acid coating, and drying is carried out to obtain the drug eluting stent, the drug eluting stent comprises a levorotatory polylactic acid matrix and a drug-loaded layer, the drug-loaded layer covers the outer surface, the inner surface and the side surface of the levorotatory polylactic acid matrix, and the content of the heparin is gradually reduced from one side close to the matrix to one side far away from the matrix along the thickness direction of the matrix in the region of the drug-loaded layer covering the outer surface and the side surface. Wherein the mass ratio of the heparin to the poly-dl-lactic acid on the stent is 3:1, and the average thickness of the drug-loaded layer is 20 μm.

After the bracket is subjected to simulated conveying in vitro, the bracket is expanded under rated blasting pressure, and the result shows that the medicine-carrying layer is complete without peeling and spalling; the stent is completely endothelialized after being implanted into iliac artery of New Zealand rabbit for 2 months, and the release period of active drug is 6 months.

Example 7

Firstly, respectively preparing an ethyl acetate solution of dexamethasone with the concentration of 5mg/mL and an ethyl acetate solution of polylactic acid-glycolic acid copolymer with the concentration of 10 mg/mL; preparing a 30008-standard base body formed by pure zinc, roughening the surface of the base body, forming a groove in the base body, enabling the plane where the opening end of the groove is located to be coplanar with the outer surface of the base body, sleeving the base body on the inner support rod, and slightly compressing the base body to enable the inner surface of the base body to be tightly attached to the inner support rod. Then, spraying ethyl acetate solution of dexamethasone onto the matrix through ultrasonic spraying, drying, and then taking down the inner support rod to obtain the bracket containing the pure drug layer, wherein the groove of the matrix is filled with the dexamethasone, and the pure drug layer completely covers the outer surface and the side surface of the matrix; and then the bracket is sleeved on a clamp with a blocking rod, the diameter of the blocking rod is smaller than the inner diameter of the bracket, the ethyl acetate solution of the polylactic acid-glycolic acid copolymer is sprayed on the bracket, and the medicine-carrying layer is obtained after drying. The barrier rod partially shields the inner surface of the base body, so that the thickness of the obtained region of the drug-loaded layer covering the outer surface of the base body and the thickness of the region covering the side surface are both larger than the thickness of the region of the drug-loaded layer covering the inner surface of the base body, the coating speed of the step is 0.08mL/min, dexamethasone in the pure drug layer is partially dissolved into the poly (lactic-co-glycolic acid) coating by ethyl acetate in an ethyl acetate solution of the poly (lactic-co-glycolic acid), the drug-eluting stent is obtained after drying, the drug-eluting stent comprises a zinc-based base body, a pure drug layer and the drug-loaded layer, the groove of the zinc-based base body is filled with dexamethasone, the pure drug layer covers the outer surface and the side surface of the zinc-based base body, the drug-loaded layer completely covers the pure drug layer, the drug-loaded layer covers the outer surface, the inner surface and the side surface of, the content of dexamethasone gradually decreases from the side close to the matrix to the side far from the matrix along the thickness direction of the matrix. Wherein the mass ratio of the dexamethasone on the bracket to the polylactic acid-glycolic acid copolymer is 1:1, and the average thickness of the drug-loaded layer is 5 μm.

After the bracket is subjected to simulated conveying in vitro, the bracket is expanded under rated blasting pressure, and the result shows that the medicine-carrying layer is complete without peeling and spalling; the stent is completely endothelialized after being implanted into iliac artery of New Zealand rabbit for 2 months, and the release period of active drug is 9 months.

Example 8

Firstly, respectively preparing an ethyl acetate solution of loratadine with the concentration of 5mg/mL and an ethyl acetate solution of poly-L-lactic acid with the concentration of 1 mg/mL; preparing a 30008-standard base body formed by pure iron, roughening the surface of the base body, forming a groove in the base body, enabling the plane where the opening end of the groove is located to be coplanar with the outer surface of the base body, sleeving the base body on the inner support rod, and slightly compressing the base body to enable the inner surface of the base body to be tightly attached to the inner support rod. Then, spraying an ethyl acetate solution of loratadine on the base body through ultrasonic spraying, drying, and then taking down the inner support rod to obtain the bracket containing the pure medicine layer, wherein the pure medicine layer completely covers the outer surface and the side surface of the base body; and then spraying the ethyl acetate solution of the poly-L-lactic acid onto the inner surface, the outer surface and the side surface of the stent, wherein the coating speed of the step is 0.03mL/min, the ethyl acetate in the ethyl acetate solution of the poly-L-lactic acid completely dissolves the loratadine in the pure drug layer into the poly-L-lactic acid coating, and the drug eluting stent is obtained after drying, and comprises an iron-based matrix and a drug carrying layer, wherein the drug carrying layer covers the outer surface, the inner surface and the side surface of the iron-based matrix, and the content of the loratadine is gradually reduced from one side close to the matrix to one side far away from the matrix in the thickness direction of the matrix in the area of the drug carrying layer covering the outer surface and the side surface. Wherein the mass ratio of the loratadine to the poly-L-lactic acid on the stent is 1:6, and the average thickness of the drug-loaded layer is 15 mu m.

After the stent is subjected to simulated conveying in vitro, the stent is expanded under a rated explosion pressure, and the result shows that the stent coating is complete and has no peeling or spalling; the stent is completely endothelialized after being implanted into the iliac artery of a New Zealand rabbit for 1 month, and the drug release period of the stent is 15 months.

Example 9

Firstly, respectively preparing a dexamethasone ethyl acetate solution with the concentration of 5mg/mL, a rapamycin ethyl acetate solution with the concentration of 5mg/mL and a poly-racemic lactic acid ethyl acetate solution with the concentration of 3 mg/mL; preparing a 30008-standard base body formed by pure iron, roughening the surface of the base body, forming a groove in the base body, enabling the plane where the opening end of the groove is located to be coplanar with the outer surface of the base body, sleeving the base body on the inner support rod, and slightly compressing the base body to enable the inner surface of the base body to be tightly attached to the inner support rod. Then, spraying an ethyl acetate solution of dexamethasone into a groove on the substrate by ultrasonic spraying, continuously spraying an ethyl acetate solution of rapamycin onto the substrate after drying, and taking down the inner supporting rod after drying to obtain the stent containing a pure drug layer, wherein the groove contains the dexamethasone, and the pure drug layer (only containing rapamycin) completely covers the outer surface and the side surface of the substrate; and then spraying the ethyl acetate solution of the poly-dl-lactic acid on the inner surface, the outer surface and the side surface of the stent, wherein the coating speed of the step is 0.01mL/min, the ethyl acetate in the ethyl acetate solution of the poly-dl-lactic acid completely dissolves the rapamycin in the pure drug layer into the poly-dl-lactic acid coating, and the drug eluting stent is obtained after drying, and comprises an iron-based matrix, a drug-loaded layer and dexamethasone in a groove, wherein the drug-loaded layer covers the outer surface, the inner surface and the side surface of the iron-based matrix, and the rapamycin content in the regions of the drug-loaded layer covering the outer surface and the side surface is gradually reduced from one side close to the matrix to one side far away from the matrix along the thickness direction of the matrix. Wherein the mass ratio of dexamethasone, rapamycin and poly-racemic lactic acid on the stent is 1:2:6, and the average thickness of the drug-loaded layer is 10 μm.

After the stent is subjected to simulated conveying in vitro, the stent is expanded under a rated explosion pressure, and the result shows that the stent coating is complete and has no peeling or spalling; the stent is completely endothelialized after being implanted into iliac arteries of a New Zealand rabbit for 1 month, the rapamycin release period of the stent is 12 months, and the inflammatory reaction integral of 12 months is 1 point.

Example 10

Firstly, respectively preparing an ethyl acetate solution of rapamycin with the concentration of 5mg/mL and an ethyl acetate solution of poly-racemic lactic acid with the concentration of 10 mg/mL; preparing a 30008-standard base body formed by pure iron, roughening the surface of the base body, forming a groove in the base body, enabling the plane where the opening end of the groove is located to be coplanar with the outer surface of the base body, spraying ethyl acetate solution of rapamycin onto a local area of the outer surface of the base body through an ink-jet printer, drying, then taking down an inner support rod to obtain a bracket containing a pure drug layer, filling rapamycin into the groove of the base body, and completely covering the outer surface and the side surface of the base body with the pure drug layer; and then spraying an ethyl acetate solution of the poly-dl-lactic acid on the inner surface, the outer surface and the side surface of the stent, wherein the coating speed of the step is 0.08mL/min, rapamycin in the pure drug layer is partially dissolved into the poly-dl-lactic acid coating by ethyl acetate in the ethyl acetate solution of the poly-dl-lactic acid, and the drug eluting stent is obtained after drying, and comprises an iron-based matrix, a pure drug layer and a drug-loaded layer, rapamycin is filled in a groove of the iron-based matrix, the pure drug layer only partially covers the outer surface of the iron-based matrix, the drug-loaded layer of the iron-based matrix completely covers the pure drug layer, the drug-loaded layer covers the outer surface, the inner surface and the side surface of the iron-based matrix, and the content of rapamycin is gradually reduced from one side close to one side far away from the matrix along the thickness direction of the matrix in the areas covering the outer. Part of the groove of the iron-based matrix is covered by the area of the drug-loaded layer, which is not distributed with the active drug. Wherein the mass ratio of the rapamycin to the poly-racemic lactic acid on the stent is 1:3, and the average thickness of the drug-loaded layer is 10 μm.

Comparative example 1

Firstly, preparing a mixed solution of ethyl acetate with the mass ratio of rapamycin to poly-racemic lactic acid being 1: 3; preparing an iron-based matrix with the specification of 30008, sleeving the iron-based matrix on the inner support rod, and slightly compressing the iron-based matrix to enable the inner surface of the iron-based matrix to be tightly attached to the inner support rod. And then spraying the mixed solution onto an iron-based matrix by ultrasonic spraying, drying, and then taking down the inner support rod to obtain the stent containing the drug-loaded layer. The bracket comprises an iron-based matrix and a drug-loaded layer, wherein the drug-loaded layer covers the outer surface and the side surface of the iron-based matrix. Wherein the mass ratio of the rapamycin to the poly-racemic lactic acid on the stent is 1:3, and the average thickness of the drug-loaded layer is 10 μm.

After the bracket is subjected to simulated conveying in vitro, the bracket is expanded under a rated explosion pressure, and the result shows that the medicine-carrying layer is damaged and partial area of the medicine-carrying layer falls off; the stent is completely endothelialized after being implanted into the iliac artery of a New Zealand rabbit for 1 month, the release period of the active drug is 3 months, and the inflammatory reaction integral of 12 months is 2 points.

Comparative example 2

Firstly, preparing a mixed solution of ethyl acetate with the mass ratio of rapamycin to poly-racemic lactic acid being 1: 1; an iron-based matrix of 30008 gauge was prepared. And spraying the mixed solution onto an iron-based matrix by ultrasonic spraying, and drying to obtain the bracket containing the drug-loaded layer, wherein the bracket comprises the iron-based matrix and the drug-loaded layer, and the drug-loaded layer completely coats the surface of the iron-based matrix. The average thickness of the drug-loaded layer was 20 μm.

After the bracket is subjected to simulated conveying in vitro, the bracket is expanded under rated blasting pressure, and the result shows that the medicine-carrying layer is complete without peeling and spalling; the stent is completely endothelialized after being implanted into the iliac artery of a New Zealand rabbit for 3 months, and the release period of the active drug is 3 months.

It is to be understood that the terminology used herein is for the purpose of describing particular example embodiments only, and is not intended to be limiting. As used herein, the singular forms "a", "an" and "the" may be intended to include the plural forms as well, unless the context clearly indicates otherwise. The terms "comprises," "comprising," "including," and "having" are inclusive and therefore specify the presence of stated features, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and/or groups thereof. The method steps, processes, and operations described herein are not to be construed as necessarily requiring their performance in the particular order described or illustrated, unless specifically identified as an order of performance. It should also be understood that additional or alternative steps may be used.

The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the appended claims.

Claims

1. A drug eluting device, which is characterized by comprising a basal body and a drug-loaded layer; the substrate is provided with an outer surface, a side surface and an inner surface, the drug-loaded layer contains a drug carrier and an active drug, and the outer surface, the side surface and the inner surface of the substrate are all covered by the drug-loaded layer; the active drug is distributed on at least partial area of the drug-loaded layer covering the outer surface and the side surface, and the concentration of the active drug on the side close to the substrate is larger than that on the side far away from the substrate in the thickness direction of the at least partial area.

2. The drug eluting device of claim 1, wherein the concentration of the active drug decreases gradually from a side near the matrix to a side away from the matrix in a thickness direction of the at least partial region.

3. A drug eluting device according to claim 1 or 2, wherein the matrix has grooves or pores formed therein, the grooves or pores being filled with an active drug, and the drug loaded layer covering the grooves or pores.

4. A drug eluting device according to claim 3, wherein the grooves or pores are covered by the at least partial area of the drug carrying layer where the active drug is distributed; or,

5. A drug eluting device according to claim 1 or 2, wherein: the drug eluting device further comprises a pure drug layer, wherein the pure drug layer coats at least partial areas of the outer surface and the side surface of the substrate, and the pure drug layer is completely covered by the drug-loaded layer.

6. A drug eluting device according to claim 1 or 2, wherein the active drug in the drug-loaded layer is distributed only in the region of the drug-loaded layer covering the outer surface of the matrix; or the active medicament in the medicament-carrying layer is distributed on only partial area of the medicament-carrying layer covering the outer surface of the substrate; or the active medicament in the medicament-carrying layer is distributed in the area of the medicament-carrying layer covering the outer surface and the side surface of the substrate; or the active medicament in the medicament-carrying layer is distributed in the area of the outer surface of the substrate covered by the medicament-carrying layer and at least part of the side surface.

7. A drug eluting device according to claim 1 or 2, wherein the region of the drug-loaded layer covering the outer surface of the base body and the region covering the side surface each have a thickness greater than the thickness of the region of the drug-loaded layer covering the inner surface of the base body.

8. The drug eluting device according to claim 1, wherein the drug loaded layer has a thickness of 3 to 20 microns.

9. The drug eluting device of 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.

10. A method of manufacturing a drug eluting device, comprising: