Dual process drug eluting stent with fast release and sustained release

Abstract

The application discloses a double-process drug eluting stent with rapid release and sustained release, and relates to the technical field of medical device manufacturing.The double-process drug eluting stent with rapid release and sustained release comprises a stent base body, the surface of the stent base body is provided with a drug loading groove, the bottom wall of the drug loading groove is provided with a plurality of drug loading blind holes, the opening area of each drug loading blind hole is smaller than the bottom wall area of the drug loading groove, the plurality of drug loading blind holes are arranged on the bottom wall of the drug loading groove at intervals, and the drug loading groove and the drug loading blind holes are adapted to accommodate crystalline drugs.The double-process drug eluting stent with rapid release and sustained release according to the embodiment of the application can realize high-concentration drug release in a short time and long-term sustained drug release, so that the drug concentration peak can quickly reach the treatment requirement and locally maintain activity for a long time, and the double-process drug eluting stent has the advantages of preventing intimal hyperplasia, preventing thrombosis, preventing in-stent restenosis and the like.

Description

Technical Field

[0001] This invention relates to the field of medical device manufacturing technology, and more specifically, to a dual-process drug-eluting stent that combines rapid release and sustained release. Background Technology

[0002] Vascular stents are inserted into blocked blood vessels to open the channels and prevent further blockage. However, after stent implantation, the vascular system is highly susceptible to intimal hyperplasia, which can subsequently lead to arterial blockage and blood flow obstruction, a condition known as in-stent restenosis.

[0003] Drug-eluting stents can inhibit stent intimal hyperplasia and prevent in-stent restenosis by administering medication locally.

[0004] Drug-eluting stents include two types: coated drug-eluting stents and polymer-free drug-eluting stents.

[0005] Coated drug-eluting stents use a polymer coating on a metal surface as a drug carrier, with the drug slowly released from the polymer coating into the cardiovascular wall tissue via elution to exert its effect. However, polymer-coated drug carriers are prone to creating a procoagulant and pro-inflammatory environment, leading to increased thrombus formation.

[0006] Bare metal core polymer-free drug-eluting stents can effectively avoid polymer-induced adverse pathological reactions.

[0007] In related technologies, eluting stents are designed with drug-loaded grooves to contain crystalline drugs. After insertion into a blood vessel, the drugs in the drug-loaded grooves are released to inhibit stent intimal hyperplasia. However, only a specific rate of drug release can be achieved. If the release rate is too slow, the local drug concentration peak may not be sufficient to prevent new intimal hyperplasia in a short period of time. If the release rate is too fast, the local drug activity may be insufficient. Summary of the Invention

[0008] This invention aims to at least solve one of the technical problems existing in the prior art. To this end, this invention proposes a dual-process drug-eluting stent that combines rapid release and sustained release. This dual-process drug-eluting stent can achieve high-concentration drug release in a short time and sustained drug release over a long period of time, so that the peak drug concentration can quickly reach the therapeutic requirement and maintain local activity for a long time. It has the advantages of preventing intimal hyperplasia, preventing thrombosis, and preventing in-stent restenosis.

[0009] To achieve the above objectives, an embodiment of the present invention provides a dual-process drug-eluting stent that combines rapid and sustained release. The dual-process drug-eluting stent includes: a stent substrate, the surface of which is provided with a drug-loaded groove, the bottom wall of which is provided with a plurality of drug-loaded blind holes, the opening area of ​​each drug-loaded blind hole being smaller than the bottom wall area of ​​the drug-loaded groove, the plurality of drug-loaded blind holes being spaced apart on the bottom wall of the drug-loaded groove, and the drug-loaded groove and the drug-loaded blind holes being adapted to contain crystalline drugs.

[0010] The dual-process drug-eluting stent with both rapid and sustained release according to embodiments of the present invention can achieve high-concentration drug release in a short time and sustained drug release over a long period of time, so that the peak drug concentration can quickly reach the therapeutic requirement and maintain local activity for a long time. It has the advantages of preventing intimal hyperplasia, preventing thrombosis, and preventing in-stent restenosis.

[0011] In addition, the dual-process drug-eluting stent with both rapid and sustained release according to the above embodiments of the present invention may also have the following additional technical features: According to one embodiment of the present invention, the total opening area of ​​the plurality of drug-loaded blind holes is 5%-50% of the bottom wall area of ​​the drug-loaded groove.

[0012] According to one embodiment of the present invention, the volume ratio of each drug-loaded blind hole to the volume of the drug-loaded groove is 1:20 to 1:200.

[0013] According to one embodiment of the present invention, the number of drug-loaded blind holes is 15-40.

[0014] According to one embodiment of the present invention, a plurality of the drug-loaded blind holes are arranged in an array on the bottom wall of the drug-loaded groove.

[0015] According to one embodiment of the present invention, the plurality of drug-loaded blind holes have equal depths.

[0016] According to one embodiment of the present invention, the plurality of drug-loaded blind holes have equal diameters.

[0017] According to one embodiment of the present invention, the drug-loaded groove is formed on at least one of the inner and outer peripheral surfaces of the stent substrate.

[0018] According to one embodiment of the present invention, the diameter of the drug-loaded blind hole is 5-15 micrometers.

[0019] According to one embodiment of the present invention, the depth of the drug-loaded groove from the surface of the scaffold substrate is 30-50 micrometers, and the depth of the drug-loaded blind hole from the bottom wall of the drug-loaded groove is 30-50 micrometers.

[0020] Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. Attached Figure Description

[0021] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which: Figure 1 This is a schematic diagram of a dual-process drug-eluting stent that combines rapid and sustained release according to an embodiment of the present invention.

[0022] Figure 2 This is a partial structural schematic diagram of a dual-process drug-eluting stent that combines rapid and sustained release according to an embodiment of the present invention.

[0023] Figure 3 This is a partial cross-sectional view of a dual-process drug-eluting stent that combines rapid and sustained release according to an embodiment of the present invention.

[0024] Figure reference numerals: 1. Drug-eluting stent with both rapid and sustained release capabilities; 10. Stent substrate; 11. Drug-loaded groove; 12. Drug-loaded blind hole; 2. Crystallized drug. Detailed Implementation

[0025] This application is based on the findings and understanding of the following facts and issues: In related technologies, eluting stents are designed with drug-loaded grooves to contain crystalline drugs. After insertion into a blood vessel, the drugs in the drug-loaded grooves are released to inhibit stent intimal hyperplasia. However, only a specific rate of drug release can be achieved. If the release rate is too slow, the local drug concentration peak may not be sufficient to prevent new intimal hyperplasia in a short period of time. If the release rate is too fast, the local drug activity may be insufficient.

[0026] Specifically, in the clinical treatment of vascular occlusion, releasing the drug within a relatively short period of time helps to ensure that the local peak drug concentration reaches the treatment requirements as soon as possible and prevents new intimal hyperplasia, while the subsequent slow release of the drug can ensure the long-term local activity of the drug.

[0027] The elution stents in related technologies use a simple groove structure to accommodate crystalline drugs. The drugs can only be released at a linear rate according to the simple groove structure. Due to the limited size of the stent itself, the simple groove is structurally limited and cannot meet the requirement of continuous release while ensuring rapid drug release.

[0028] Embodiments of the present invention are described in detail below. Examples of these embodiments are shown in the accompanying drawings, wherein the same or similar reference numerals denote the same or similar elements or elements having the same or similar functions throughout. The embodiments described below with reference to the accompanying drawings are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0029] In the description of this invention, it should be understood that the terms "center," "longitudinal," "lateral," "length," "width," "thickness," "upper," "lower," "front," "rear," "left," "right," "vertical," "horizontal," "top," "bottom," "inner," "outer," "clockwise," "counterclockwise," "axial," "radial," and "circumferential," etc., indicating orientation or positional relationships, are based on the orientation or positional relationships shown in the accompanying drawings and are only for the convenience of describing the invention and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation, and therefore should not be construed as a limitation of the invention. Furthermore, features defined with "first" or "second" may explicitly or implicitly include one or more of that feature. In the description of this invention, unless otherwise stated, "a plurality of" means two or more. In the description of this invention, it should be noted that, unless otherwise explicitly specified and limited, the terms "installation," "connection," and "linking" should be interpreted broadly. For example, they can refer to a fixed connection, a detachable connection, or an integral connection; they can refer to a mechanical connection or an electrical connection; they can refer to a direct connection or an indirect connection through an intermediate medium; and they can refer to the internal connection of two components. Those skilled in the art can understand the specific meaning of the above terms in this invention according to the specific circumstances.

[0030] The following description, with reference to the accompanying drawings, describes a dual-process drug-eluting stent 1 that combines rapid and sustained release according to an embodiment of the present invention.

[0031] like Figures 1-3 As shown, the dual-process drug-eluting stent 1 with both rapid and sustained release according to an embodiment of the present invention includes a stent matrix 10.

[0032] The surface of the scaffold substrate 10 is provided with a drug-carrying groove 11, and the bottom wall of the drug-carrying groove 11 is provided with a plurality of drug-carrying blind holes 12. The opening area of ​​each drug-carrying blind hole 12 is smaller than the bottom wall area of ​​the drug-carrying groove 11. The plurality of drug-carrying blind holes 12 are spaced apart on the bottom wall of the drug-carrying groove 11. The drug-carrying groove 11 and the drug-carrying blind holes 12 are suitable for accommodating crystalline drug 2.

[0033] It is important to understand here that the bottom wall of the drug-carrying groove 11 refers to the surface opposite the open surface of the drug-carrying groove 11.

[0034] Specifically, the scaffold substrate 10 can be a mesh structure or a corrugated structure, and can be made of metal, ceramic, or polymer materials. The drug-carrying groove 11 can be one or more of the following: cylindrical groove, elliptical cylindrical groove, and rectangular groove.

[0035] The scaffold substrate 10 can be used to crystallize and store drugs in the drug-loaded grooves 11 and drug-loaded blind holes 12 by solution crystallization.

[0036] After the dual-process drug-eluting stent 1, which combines rapid and sustained release, is implanted into the blood vessel, the crystalline drug 2 in the drug-loaded groove 11 begins to be released. Because the drug-loaded groove 11 has a relatively larger size, the crystalline drug 2 can be released rapidly, allowing the drug concentration to reach its peak quickly. After the crystalline drug 2 in the drug-loaded groove 11 has been released, the crystalline drug 2 in the drug-loaded blind hole 12 begins to be released. Because the drug-loaded blind hole 12 has a relatively smaller size, the crystalline drug 2 can be released slowly and continuously, allowing the drug to maintain long-term local activity.

[0037] For example, the scaffold substrate 10 has a radial thickness of 200 μm, and drug-loaded grooves 11 and drug-loaded blind holes 12 can be machined on the inner and outer surfaces of the unit grid and connecting rods. Figure 2 As shown, a rectangular drug-loading groove is machined on the scaffold substrate 10, with a width of 80 μm, a length of 250 μm, and a depth of 40 μm. Twenty-seven drug-loading blind holes 12, each with a diameter of 20 μm and a depth of 40 μm, are evenly distributed at the bottom of the groove. The total opening area of ​​the drug-loading blind holes 12 accounts for 42.41% of the bottom wall area of ​​the drug-loading groove 11, and the ratio of the volume of each drug-loading blind hole 12 to the volume of the drug-loading groove 11 is 1:63.7.

[0038] In Example 1, 5 mg of retchimica was dissolved in an appropriate amount of acetonitrile solution, and the mass fraction of retchimica in the mixed solution was diluted to 5 μg / mL. The prepared retchimica solution was sprayed dropwise into the drug-loaded groove and placed in a vacuum drying oven. The drying temperature was set to 50°C. After the solution evaporated, the spraying was repeated until the drug-loaded blind hole 12 and the drug-loaded groove 11 were completely deposited with crystallized drug. The in vitro release test medium was a 1% sodium dodecyl sulfate aqueous solution, the in vitro release test temperature was 37°C, and the magnetic stirrer speed was controlled at 200 rpm. Samples were taken for testing at 1 h, 5 h, 12 h, 1 d, 3 d, 7 d, 14 d, and 24 d.

[0039] In Example 2, 5 mg of retchimica was dissolved in an appropriate amount of acetonitrile solution to dilute the retchimica mass fraction in the mixed solution to 2 μg / mL. The prepared retchimica solution was then sprayed dropwise into the drug-loaded groove and placed in a vacuum drying oven at a drying temperature of 50°C. After the solution evaporated, the spraying was repeated until the drug-loaded blind hole 12 and the drug-loaded groove 11 were completely deposited with crystallized drug. The in vitro release test medium was a 1% sodium dodecyl sulfate aqueous solution, the in vitro release test temperature was 37°C, and the magnetic stirrer speed was controlled at 200 rpm. Samples were taken for testing at 1 h, 5 h, 12 h, 1 d, 3 d, 7 d, 14 d, and 24 d.

[0040] In Example 3, 5 mg of retchimica was dissolved in an appropriate amount of acetonitrile solution, and the mass fraction of retchimica in the mixed solution was diluted to 0.5 μg / mL. The prepared retchimica solution was sprayed dropwise into the drug-loaded groove and placed in a vacuum drying oven. The drying temperature was set to 50°C. After the solution evaporated, the spraying was repeated until the drug-loaded blind hole 12 and the drug-loaded groove 11 were completely deposited with crystallized drug. The in vitro release test medium was a 1% sodium dodecyl sulfate aqueous solution, the in vitro release test temperature was 37°C, and the magnetic stirrer speed was controlled at 200 rpm. Samples were taken for testing at 1 h, 5 h, 12 h, 1 d, 3 d, 7 d, 14 d, and 24 d.

[0041] In the comparative example, the vascular stent used had a rectangular drug-loading groove with a width of 80 μm, a length of 250 μm, and a thickness of 40 μm. It had no drug-loading blind hole 12 at the bottom. A control experiment was carried out according to the above-mentioned drug crystallization method and in vitro release test.

[0042] In Examples 1, 2, and 3, the in vitro drug release exhibited two distinct phases: a short-term high-concentration release and a long-term sustained release. The short-term drug release rates within one day reached 87.5%, 85.2%, and 86.3%, respectively, while the sustained release time exceeded 14 days. In the comparative example, the in vitro drug release rate reached 95.3% within one day, with no obvious sustained release phase.

[0043] The results show that the dual-process drug-eluting stent 1 with both rapid and sustained release according to the embodiments of the present invention, through the structural arrangement of the drug-loaded groove 11 and the drug-loaded blind hole 12, controls the cumulative drug concentration released over time, realizing dual-process drug delivery of high local drug concentration release in a short time and sustained drug release over a long period of time. This can effectively ensure that the local peak drug concentration reaches the treatment requirements and prevent new intimal hyperplasia, while the subsequent slow release of the drug can ensure the long-term local activity of the drug.

[0044] According to an embodiment of the present invention, a dual-process drug-eluting stent 1 that combines rapid release and sustained release can accommodate crystalline drugs by providing a drug-loaded groove 11 and a drug-loaded blind hole 12, and release the drugs after implantation into a blood vessel.

[0045] Furthermore, by making the opening area of ​​each drug-loaded blind hole 12 smaller than the bottom wall area of ​​the drug-loaded groove 11, the drug-loaded groove 11 can quickly release the drug so that the peak drug concentration can quickly reach the treatment requirements and prevent new intimal hyperplasia. Moreover, the drug-loaded blind hole 12 can slowly and continuously release the drug so that the drug can maintain local activity for a long time.

[0046] Furthermore, by forming drug-loaded blind holes 12 on the bottom wall of drug-loaded grooves 11, the drug in the drug-loaded blind holes 12 can be released after the crystalline drug 2 in the drug-loaded grooves 11 has been released, which can further increase the drug release time and make it easier for the drug to maintain its activity for a long time.

[0047] Meanwhile, since the drug is contained only through the structure of the drug-carrying groove 11 and the drug-carrying blind hole 12, there is no need to use a polymer structure, which can avoid adverse pathological effects such as procoagulation and inflammation caused by drug loading with polymer coating.

[0048] Therefore, the dual-process drug-eluting stent 1, which combines rapid and sustained release, can effectively reduce the probability of in-stent restenosis and re-intervention.

[0049] Therefore, the dual-process drug-eluting stent 1 with both rapid and sustained release according to embodiments of the present invention can achieve high-concentration drug release in a short time and sustained drug release over a long period of time, so that the peak drug concentration can quickly reach the treatment requirements and maintain local activity for a long time, and has the advantages of preventing intimal hyperplasia, preventing thrombosis, and preventing in-stent restenosis.

[0050] The following description, with reference to the accompanying drawings, describes a dual-process drug-eluting stent 1 that combines rapid and sustained release according to a specific embodiment of the present invention.

[0051] In some specific embodiments of the present invention, such as Figures 1-3 As shown, the dual-process drug-eluting stent 1 with both rapid and sustained release according to an embodiment of the present invention includes a stent matrix 10.

[0052] Advantageously, the total opening area of ​​the multiple drug-loaded blind holes 12 is 5%-50% of the bottom wall area of ​​the drug-loaded groove 11. This can further control the release rate of the crystalline drug 2 within the drug-loaded blind holes 12, and facilitate the extension of the drug activity retention time.

[0053] More advantageously, the volume ratio of each drug-loaded blind hole 12 to the volume of the drug-loaded groove 11 is 1:20 to 1:200. This facilitates control over the size of each drug-loaded blind hole 12, facilitates control over the release rate of the crystalline drug 2 from each drug-loaded blind hole 12, and facilitates prolonging the retention time of drug activity.

[0054] Furthermore, the number of drug-loaded blind wells 12 is 15-40. This facilitates control over the size of each drug-loaded blind well 12, increases the overall storage capacity of the crystalline drug 2 in multiple drug-loaded blind wells 12, and extends the retention time of drug activity.

[0055] Specifically, such as Figure 2 and Figure 3 As shown, multiple drug-loaded blind holes 12 are arranged in an array on the bottom wall of the drug-loaded groove 11. This not only facilitates the processing of the drug-loaded blind holes 12, but also allows for more uniform drug release.

[0056] More specifically, such as Figure 2 and Figure 3 As shown, the multiple drug-loaded blind holes 12 have the same depth. This further facilitates the processing of the drug-loaded blind holes 12.

[0057] Furthermore, such as Figure 2 and Figure 3 As shown, the diameters of the multiple drug-loaded blind holes 12 are equal. This further facilitates the machining of the drug-loaded blind holes 12.

[0058] Optionally, the drug-loaded groove 11 is formed on at least one of the inner and outer peripheral surfaces of the scaffold substrate 10. This facilitates the release of the crystalline drug 2.

[0059] Optionally, the diameter of the drug-loaded blind hole 12 is 5-15 micrometers. This further facilitates control over the size of the drug-loaded blind hole 12, ensuring its volume and facilitating a longer release time.

[0060] Furthermore, the depth of the drug-loaded groove 11 from the surface of the scaffold substrate 10 is 30-50 micrometers, and the depth of the drug-loaded blind hole 12 from the bottom wall of the drug-loaded groove 11 is 30-50 micrometers. This facilitates control over the depth of the drug-loaded groove 11 and the drug-loaded blind hole 12, ensures the volume of the drug-loaded groove 11 and the drug-loaded blind hole 12, ensures the capacity of the crystalline drug 2, facilitates the rapid achievement of peak drug concentration for treatment, and facilitates the prolongation of drug release time.

[0061] Other configurations and operations of the dual-process drug-eluting stent 1 that combines rapid and sustained release according to embodiments of the present invention are known to those skilled in the art and will not be described in detail here.

[0062] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "illustrative embodiment," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0063] Although embodiments of the invention have been shown and described, those skilled in the art will understand that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the claims and their equivalents.

Claims

1. A dual-process drug-eluting stent that combines rapid and sustained release, characterized in that, include: The stent substrate has a drug-loaded groove on its surface and a plurality of drug-loaded blind holes on the bottom wall of the drug-loaded groove. The opening area of ​​each drug-loaded blind hole is smaller than the bottom wall area of ​​the drug-loaded groove. The plurality of drug-loaded blind holes are spaced apart on the bottom wall of the drug-loaded groove. The drug-loaded groove and the drug-loaded blind holes are adapted to contain crystalline drugs.

2. The dual-process drug-eluting stent with both rapid and sustained release as described in claim 1, characterized in that, The total opening area of ​​the plurality of drug-loaded blind holes is 5%-50% of the bottom wall area of ​​the drug-loaded groove.

3. The dual-process drug-eluting stent with both rapid and sustained release as described in claim 1, characterized in that, The volume of each drug-loaded blind hole is in a ratio of 1:20 to 1:200 to the volume of the drug-loaded groove.

4. The dual-process drug-eluting stent with both rapid and sustained release as described in claim 1, characterized in that, The number of drug-loaded blind holes is 15-40.

5. The dual-process drug-eluting stent with both rapid and sustained release as described in claim 1, characterized in that, Multiple drug-loaded blind holes are arranged in an array on the bottom wall of the drug-loaded groove.

6. The dual-process drug-eluting stent with both rapid and sustained release as described in claim 1, characterized in that, The depths of the multiple drug-loaded blind holes are equal.

7. The dual-process drug-eluting stent with both rapid and sustained release as described in claim 1, characterized in that, The diameters of the multiple drug-loaded blind holes are equal.

8. The dual-process drug-eluting stent with both rapid and sustained release as described in claim 1, characterized in that, The drug-loaded groove is formed on at least one of the inner and outer peripheral surfaces of the stent substrate.

9. The dual-process drug-eluting stent with both rapid and sustained release as described in claim 1, characterized in that, The diameter of the drug-loaded blind hole is 5-15 micrometers.

10. The dual-process drug-eluting stent with both rapid and sustained release as described in claim 1, characterized in that, The depth of the drug-loaded groove from the surface of the scaffold substrate is 30-50 micrometers, and the depth of the drug-loaded blind hole from the bottom wall of the drug-loaded groove is 30-50 micrometers.

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