Drug coatings, and medical devices, systems, and manufacturing methods having them.

Abstract

The present invention provides a drug coating, and a medical device, system, and method for manufacturing the drug coating. The drug coating comprises a non-degradable fluoropolymer matrix and a drug dispersed therein, and has inner and outer layers with different drug concentrations along the thickness direction of the drug coating, the drug concentration of the inner layer being 10 wt% or more by weight, the drug concentration of the outer layer being less than 10 wt% by weight, and the thickness of the outer layer being 20 μm or less. The drug coating of the present invention can stably release the drug to the tissue wall in contact with it over a long period of time in order to achieve long-term therapeutic or preventive effects against diseases such as luminal stenosis.

Description

[Technical Field]

[0001] The present invention relates to the technical field of medical devices, and more specifically to drug-carrying devices and coatings that enable long-term drug release, and in particular to implantable medical devices delivered intracavitary, such as drug-eluting stents, and related manufacturing methods. [Background technology]

[0002] A drug-eluting stent (DES) consists of three parts: a metal framework, a polymer coating, and a restenosis prevention drug supported on it. Since the application of DES, the polymer coating has been a crucial component of the DES, functioning as a drug carrier, controlling drug release, and preventing thrombus formation and restenosis within the stent.

[0003] DES are currently classified into two main categories: permanent polymers and biodegradable polymers.

[0004] Biodegradable polymers, primarily made from materials such as polylactic acid, decompose into carbon dioxide and water in human tissue and blood environments once a DES is implanted. The coating decomposes as the drug is released, gradually thinning and eventually disappearing. The in vivo release kinetic profile of the supported drug is generally thought to be influenced by the degradation characteristics of the biodegradable polymer and the drug concentration.

[0005] Permanent polymers, primarily fluoropolymers, do not decompose in the human body and possess good biocompatibility. The release of the supported drug is generally considered to be primarily determined by the drug concentration in the coating. Fluoropolymer coatings are widely used in applications requiring short-term drug release (usually less than 30 days), such as coronary DES. Research and reports on the application of permanent polymer DES to applications requiring long-term drug release (e.g., 30 days or more) are lacking. While biodegradable polymer coatings allow for extended drug release time through the design of the biodegradable polymer's degradation characteristics and appropriate drug load, designing fluoropolymer coatings to achieve long-term drug release is more challenging. Directly increasing the drug concentration in the coating to extend drug release time is generally not considered feasible. This can lead to excessively high and rapid drug release in the early stages of drug release, resulting in drug waste and significant drug toxicity. In the mid-to-late stages of drug release, the amount of drug remaining on the coating decreases or the drug concentration decreases, leading to a reduced drug release rate and a slower release rate. This is insufficient to achieve the necessary effective drug amount within the desired treatment cycle, and thus prevents effective drug release over a long period.

[0006] A prime example of a need for long-term release of DES is the treatment of peripheral arterial disease (PAD). PAD is a chronic disease mainly caused by atherosclerosis and Takayasu's arteritis, and is a systemic disease that presents with symptoms such as narrowing and reduced blood flow in the arteries of the lower and / or upper limbs, posing a serious threat to the human body. DES possess excellent biocompatibility and the ability to carry drugs, and therefore have great potential for broad application in the treatment of peripheral arterial occlusion.

[0007] However, a greater challenge lies in the fact that peripheral arteries in the lower extremities are longer, larger in diameter, and have stronger impact forces due to blood flow compared to other blood vessels such as coronary arteries. For example, the subpericardial coronary artery typically has a diameter of 0.5-5 mm and a blood flow velocity of 10-30 cm / s, while the femoral artery typically has a diameter of 6-9 mm and a blood flow velocity of 70-90 cm / s. To achieve long-term, stable therapeutic effects for lower extremity PAD, it is necessary to load more drug onto the DES, which exacerbates the rapid release of large amounts of drug in a short period of time during the initial stage of drug release (burst release). In medium- to long-term release cycles exceeding 30 days, it demands stricter requirements for uniformity of drug coating and a higher drug release rate; otherwise, it may be difficult to achieve long-term effective therapeutic drug release. [Overview of the project]

[0008] One of the objectives of the present invention is to provide a medical device having a drug coating that achieves a therapeutic or preventive effect by releasing a drug onto a tissue wall that comes into contact with the drug coating.

[0009] Here, the drug coating comprises a non-degradable polymer as a coating matrix and a drug carrier, the drug is dispersed and distributed in the coating matrix, can be released outside the coating during the therapeutic cycle, and the coating matrix is ​​substantially retained.

[0010] The present invention particularly proposes a drug coating or a medical device having the drug coating, wherein the drug coating comprises a non-degradable polymer matrix and a drug dispersed therein, and has an outer layer and an inner layer with different drug concentrations along the thickness direction of the coating, the drug concentration of the inner layer being higher than that of the outer layer. The outer layer is relatively thin, for example, 20 microns or less in thickness. In a preferred embodiment, the thickness of the inner layer is greater than the thickness of the outer layer. The drug coating can be applied to the surface of the medical device body.

[0011] Another object of the present invention is to provide a method for manufacturing a medical device having a drug coating, which first involves applying a first coating composition to a medical device body to form an inner layer of the drug coating, and then applying a second coating composition onto the inner layer to form an outer layer of the drug coating, wherein the drug loading concentration of the inner layer is higher than that of the outer layer.

[0012] It should be understood that the inner layer and the outer layer referred to in the present invention are continuous along the thickness direction of the coating, and there is no visible gap, space, or intermediate layer between the two, and the inner layer is closer to the body than the outer layer. Usually, the inner layer and the outer layer are composed of the same non-degradable polymer matrix.

[0013] As described above, when manufacturing the coating, first, the inner layer can be manufactured, and then the outer layer can be manufactured on the surface of the inner layer. In one embodiment, the inner layer is formed by applying and drying a liquid first coating composition. Then, a liquid second coating composition is applied to the outside of the inner layer and dried to form the outer layer. Further, the weight of the drug in the first coating composition is greater than the weight of the drug in the second coating composition.

[0014] The coating means can adopt any method known in the art, including but not limited to spray coating and dip coating.

[0015] In the process of manufacturing the coating, prior to applying the inner layer to the surface of the device body, a bottom layer is applied to the surface of the device body. That is, first, a bottom layer film-forming substance and a solvent are mixed and dissolved to obtain a bottom layer solution, and the bottom layer solution is applied to the surface of the body to form a bottom layer of the drug coating, thereby improving the adhesion between the drug coating and the body or preventing the drug of the drug coating from migrating to the surface of the device body. In one embodiment, the bottom layer film-forming substance may be poly-n-butyl acrylate and the solvent may be tetrahydrofuran.

[0016] In another aspect, the present invention further provides a drug-eluting stent having a diameter exceeding 5 mm, particularly a drug-eluting stent for peripheral arteries, and can provide applications such as prevention or treatment of large-diameter vascular stenosis and restenosis, treatment of inflammation, etc., and particularly can provide stable drug release over a long period exceeding 30 days.

[0017] As described above, in a blood vessel having a large-diameter lumen such as a peripheral artery, after the stenotic site is expanded with a drug-eluting stent and the blood flow path is enlarged, the drug-eluting stent is placed in an environment under the impact of a large blood flow over a long period. The drug-eluting stent according to the present invention can withstand the impact of a large blood flow over a long period, avoid early excessive release of the drug from the drug coating, and can continuously and stably release the drug in a plurality of small cycles within a relatively long treatment period (for example, 30 days or more, or about 1 year), and is expected to achieve a long-term therapeutic effect or preventive effect.

[0018] In one embodiment, the drug loading amount of the drug coating of the drug-eluting stent is 100 μg / cm 2 , 2 , 2 , 2 , 2 , 0000002, 2 , 2 , 2 or more, for example, 110 μg / cm 2 or 120 μg / cm 2 or 130 μg / cm 2 or 140 μg / cm 2 In one embodiment, the drug loading amount of the drug coating of the drug-eluting stent is 150 μg / cm 2 or more, for example, 160 μg / cm 2 or 180 μg / cm 2 or 200 μg / cm 2 In one embodiment, the drug loading amount of the drug coating of the drug-eluting stent is 200 μg / cm 2 or more, for example, 210 μg / cm 2 or 230 μg / cm 2 or 250 μg / cm 2 or 260 μg / cm 2 or 280 μg / cm 2 In one embodiment, the drug loading amount of the drug coating of the drug-eluting stent is 300 μg / cm2 For example, 310 μg / cm³ 2 , or 330 μg / cm³ 2 , or 350 μg / cm³ 2 , or 380 μg / cm³ 2 Or 400 μg / cm³ 2 In one example, the drug load on the drug coating of the drug-eluting stent was 400 μg / cm³. 2 For example, 410 μg / cm³ 2 , or 450 μg / cm³ 2 , or 480 μg / cm³ 2 , or 500 μg / cm³ 2 That is the case.

[0019] In one embodiment, the thickness of the drug coating on the drug-eluting stent is 50 μm or less, and preferably 30 μm or less, for example, 30 μm, 25 μm, 20 μm, 15 μm, or 12 μm.

[0020] To those skilled in the art, adjusting the drug-loaded concentration, coating thickness, and / or drug load of a drug-loaded coating is a common means of regulating and controlling drug release. However, it was not explicitly anticipated by those skilled in the art that a drug coating clinically usable for long-term drug release could be obtained. Surprisingly, the inventors have discovered that by controlling the thickness of the inner and outer layers and / or drug-loaded concentration of the drug coating of the present invention under specific conditions, controlled drug release over long periods from drug-loaded coatings made of non-degradable polymers can be achieved, particularly for clinically safe and controllable drug release that meets therapeutic needs, such as those for PAD treatment, for longer than 30 days or far beyond.

[0021] In the drug coating of the present invention, the drug concentration in the inner layer is higher than that of the outer layer, and the thickness of the outer layer should not be too thick, for example, 20 μm or less, but generally 10 μm or less, and particularly preferably 8 μm or less, for example 6 μm, 5 μm, 4 μm, 3 μm, 2 μm, or 1 μm.

[0022] Preferred options include an outer layer thickness of 1 μm to 8 μm, particularly 1 μm to 3 μm, or 2 μm to 4 μm.

[0023] As described above, drug coating makes it possible to significantly reduce or avoid large, concentrated drug releases within a short period (e.g., 24 hours, 48 ​​hours, or 7 days) in the initial stages of drug release, especially in cases of high drug loads. This avoids drug waste and drug toxicity to tissues due to excessively high initial drug release, and is expected to achieve long-term therapeutic effects by maintaining essentially stable drug release over a relatively long release cycle.

[0024] The present invention further provides a drug coating, in one embodiment, configured such that the drug coating has a drug release rate of 30% or less during the first 24 hours, 48 ​​hours, or 7 days after implantation in a mammalian blood vessel, and a drug release rate of 15% or more during the first 30 days.

[0025] Mammals may be humans, pigs, sheep, rabbits, etc.

[0026] The drug coating having the aforementioned drug-releasing properties may have the drug-loading concentrations and thicknesses of the inner and outer layers as described in any of the options above.

[0027] The inventors believe that the low drug-loading concentration and extremely thin thickness of the outer layer are the main reasons for achieving the aforementioned effects. The inventors hypothesize that, in the initial stages of drug coating release, the low drug-loading concentration of the outer layer directly affects the amount of drug released from the drug coating in the initial stages, while the non-degradable polymer matrix of the outer layer exerts a barrier or blocking effect, delaying the release of the drug from the inner layer, which has a higher drug-loading concentration, to the outside of the coating. However, unexpectedly, after the initial stages of drug coating release, the outer layer, which may have released most of the original drug it was loaded onto, does not have the same properties as a blank non-degradable polymer matrix layer that does not carry any drug, the latter almost completely blocking the release of the drug from the inner layer to the outside of the drug coating. In this case, the outer layer in the embodiment of the present invention forms a function similar to a control valve, allowing the drug loaded on the inner layer to pass through the outer layer and migrate or diffuse out of the drug coating in a stable amount, thus enabling the release of the drug from the drug coating to the outside (e.g., tissue wall) in a stable amount over a long period of time. In some embodiments, the drug release profile over long periods may be substantially linear.

[0028] Despite such assumptions, those skilled in the art understand that the controlled release mechanism of coatings is usually complex and is affected by multiple factors, such as swelling and dissolution of the coating matrix material in the tissue or blood environment, and the solubility, lipophilicity, or hydrophilicity of the drug.

[0029] In preferred embodiments of the present invention, the thickness of the inner layer should be greater than the thickness of the outer layer, and the thickness of the inner layer is generally 10 μm or more. For example, it may be 10 μm to 22 μm. In one embodiment, the selectable range for the thickness of the inner layer is 12 μm to 16 μm.

[0030] For example, the thickness of the outer layer may be 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, or 8 μm, and the thickness of the inner layer may be 12 μm, 13 μm, 14 μm, 15 μm, 16 μm, 17 μm, or 18 μm.

[0031] Making the thickness of the inner layer greater than the thickness of the outer layer contributes to making the drug-loaded concentration in the inner layer higher than that of the outer layer.

[0032] In this invention, the drug-loaded concentration is expressed as a weight percentage, and the drug-loaded concentration can be calculated as follows.

[0033] Drug concentration in the inner layer = Mass of drug in the inner layer / (Sum of the mass of non-degradable polymer in the inner layer and the mass of drug in the inner layer) × 100%

[0034] Drug concentration in the outer layer = Mass of drug in the outer layer / (Sum of the mass of non-degradable polymer in the outer layer and the mass of drug in the outer layer) × 100%

[0035] In embodiments of the present invention, the inner and outer layers of the drug coating typically carry more drug than the total therapeutic dose required for the medical device. For a lumen of a treatment target that is relatively large in both diameter and length, the total drug load of the drug coating is 100 μg / cm³. 2 It may be larger than this; for example, the total drug load may be 110 μg / cm³. 2 ~400 μg / cm³ 2 This may also be the case. Furthermore, the drug loads of the inner and outer layers are usually different, and the drug load of the inner layer is usually significantly higher than that of the outer layer because the drug load concentration of the inner layer is higher than that of the outer layer, or the thickness of the inner layer is greater than that of the outer layer. For example, the drug load of the inner layer may be 100 μg / cm³. 2 ~400 μg / cm³ 2 The drug load on the outer layer is 2 μg / cm³. 2 ~60 μg / cm³ 2 Alternatively, the drug-carrying capacity of the inner layer is 150 μg / cm³. 2 ~350 μg / cm³ 2 The drug load on the outer layer is 2 μg / cm³. 2 ~30 μg / cm³ 2 That is the case.

[0036] In some preferred embodiments of the present invention, the drug-loaded concentration of the inner layer is 10 wt% or more by weight, and the drug-loaded concentration of the outer layer is less than 10 wt% by weight. Here, the thickness of the outer layer may be 10 μm or less.

[0037] For example, in one embodiment, the drug-loaded concentration of the inner layer may be 10 wt% to 45 wt%, and the drug-loaded concentration of the outer layer may be 1 wt% to 8 wt%.

[0038] In one embodiment, the drug-loaded concentration of the inner layer may be 10 wt% to 30 wt%, and the drug-loaded concentration of the outer layer may be 3 wt% to 5 wt%.

[0039] In one embodiment, the drug-loaded concentration of the inner layer may be 10 wt% to 20 wt%, and the drug-loaded concentration of the outer layer may be 3 wt% to 5 wt%.

[0040] In one embodiment, the drug-loaded concentration of the inner layer may be 10 wt% to 20 wt%, and the drug-loaded concentration of the outer layer may be 3 wt% to 4 wt%.

[0041] In one embodiment, the drug-loaded concentration of the inner layer may be 20 wt% to 30 wt%, and the drug-loaded concentration of the outer layer may be 4 wt% to 5 wt%.

[0042] In one embodiment, the drug-loaded concentration of the inner layer may be 15 wt% to 25 wt%, and the drug-loaded concentration of the outer layer may be 3 wt% to 5 wt%.

[0043] In one embodiment, the drug-loaded concentration of the inner layer may be 10 wt%, 13 wt%, 15 wt%, 18 wt%, or 20 wt%, and the drug-loaded concentration of the outer layer may be 3 wt%, 4 wt%, or 5 wt%.

[0044] A further object of the present invention is to provide a drug coating having a specific drug release profile or a medical device having the drug coating, and a treatment method, wherein the drug release profile of the drug coating satisfies the following conditions: the drug release rate in the first 24 hours after implantation in a mammalian blood vessel is 40% or less, and the drug release rate in the first 30 days is 15% or more.

[0045] In one embodiment, the drug coating has a drug release rate of 15% or more, but 60% or less, 50% or less, or 40% or less during the first 30 days after implantation in the blood vessels of a mammal. Preferably, the drug release rate is 40% or less.

[0046] In one embodiment, the drug coating has a drug release rate of 15% or more during the first 14 days after implantation in a mammalian blood vessel, and is 30% or less, 40% or less, or 50% or less. Preferably, the drug release rate is 30% or less.

[0047] In one embodiment, the drug coating exhibited a weekly drug release rate of approximately 6% to 2% from week 2 to week 17 after implantation in the blood vessels of mammals.

[0048] In one embodiment, the drug coating has a drug release rate of 30% or more, or 40% or more, or 50% or more, within 31 to 360 days after implantation in the blood vessels of a mammal. Preferably, the drug release rate is 50% or more.

[0049] In one embodiment, the drug coating has a drug release rate of 15% or less, 20% or less, or 30% or less during the first 24 hours after implantation in a mammalian blood vessel. Preferably, the drug release rate during the first 24 hours is 15% or less.

[0050] The non-degradable polymers referred to in this invention possess biocompatibility and chemical and physical stability, making them suitable for contact with tissue walls of the human body and animal bodies, such as blood vessels. Preferred non-degradable polymers may be fluoropolymers. Those skilled in the art will understand that a fluoropolymer refers to a polymer having a CC chain as its main chain, with one or more fluorine atoms linked to its side chains or branches, and thus entirely composed of fluorine atoms.

[0051] The fluoropolymer can be selected from fluorine-containing copolymers, and the comonomers may be, for example, tetrafluoroethylene (TFE), hexafluoropropylene, chlorotrifluoroethylene, and perfluoroalkyl vinyl ether (PFVE), among which PFVEs include perfluoromethyl vinyl ether (methyl ether), perfluoropropyl vinyl ether (propyl ether), and perfluorodioxol.

[0052] Fluoropolymers are also preferably fluorine-containing acrylic polymers, for example, the comonomer may be perfluoroalkyl (meth)acrylate, heteroatom-containing perfluoroalkyl (meth)acrylate, perfluoroamide (meth)acrylate, and perfluorosulfonamide (meth)acrylate.

[0053] The fluorine-containing copolymer used in the present invention must function as a film-forming polymer and have a molecular weight sufficient to provide adequate toughness so that the film containing such polymer is not scraped off during the stent treatment or implantation process, or that obvious cracking occurs in the coating when the stent or other medical devices such as occluders or vena cava filters are expanded.

[0054] In preferred embodiments, the fluoropolymer is a copolymer of vinylidene fluoride and hexafluoropropylene (PVDF-HFP), wherein the copolymer comprises 50% to 92% vinylidene fluoride and 50% to 8% hexafluoropropylene by weight. This polymer is reported and used, for example, in Chinese Invention Patent Publication No. CN1225292C, the full text of which is incorporated herein. This Chinese Invention Patent discloses a method for producing the aforementioned fluorine-containing polymer coating and a performance test.

[0055] In one embodiment, the non-degradable fluoropolymer is a copolymer of vinylidene fluoride and hexafluoropropylene, and the copolymer contains 55% to 65% by weight of vinylidene fluoride and 45% to 35% by weight of hexafluoropropylene.

[0056] In one embodiment, the non-degradable fluoropolymer is a copolymer of vinylidene fluoride and hexafluoropropylene, and the copolymer contains 70% to 90% by weight of vinylidene fluoride and 30% to 10% by weight of hexafluoropropylene.

[0057] In one embodiment, the drug coating further comprises a drug-free bottom layer, the bottom layer located beneath the inner layer and covering the medical device body, and is used to adhere the drug coating to the medical device body, in which case the inner layer is not directly attached to the surface of the medical device body.

[0058] The bottom layer can be made of one or more of the following: polymethacrylonitrile, polymethyl methacrylate, polyethyl methacrylate, polypropyl methacrylate, poly-n-butyl methacrylate, polyhydroxyethyl methacrylate, and polyhydroxypropyl methacrylate. The bottom layer also has excellent toughness, so the coating will not crack.

[0059] A further object of the present invention is to provide an implantable medical system for interventional procedures, comprising the above-described medical device and a delivery device separable from the medical device, wherein the medical device is suitable for being compressed to a small diameter and delivered via a catheter, such that the body or at least a portion of it has expandable properties. The aforementioned drug coating may be provided on the surface of the expandable portion of the medical device. The drug coating therefore preferably has good elongation and satisfies the requirement that the drug coating remains substantially intact without rupture when the medical device deforms from a compressed state to an unrestrained state.

[0060] In one embodiment, the medical device may be a drug-eluting stent, which may be compressed and grasped to 50% of its diameter in an unrestrained state without the drug coating substantially rupturing.

[0061] In one embodiment, the medical device may be a drug-eluting stent, which may be compressed and grasped to 30% of its diameter in an unrestrained state without the drug coating substantially rupturing.

[0062] In one embodiment, the medical device may be a drug-eluting stent, which may be compressed and grasped to 20% of its diameter in an unrestrained state without the drug coating substantially rupturing.

[0063] Drug-eluting stents typically have a body made of a metallic material such as stainless steel, nickel-titanium alloy, or cobalt-chromium alloy. The drug coating is applied to the surface of the alloy material of the body.

[0064] Based on several embodiments of the present invention, the provided drug coatings are expected to satisfy the function of stable drug release over long periods. In particular, some embodiments provide stable drug release over long periods exceeding 30, 60, 180, or 360 days. The amount of drug released in each release cycle can always be controlled to be above the minimum effective dose, thereby ensuring or improving medical efficacy. [Brief explanation of the drawing]

[0065] [Figure 1] This is a schematic diagram of the structure of a drug-eluting stent according to an embodiment of the present invention. [Figure 2] This is a schematic cross-sectional view of the elongated stem portion of a drug-eluting stent according to an embodiment of the present invention. [Figure 3] This shows the drug release rate in animal studies of drug-eluting stents according to embodiments of the present invention. [Figure 4] These are the results of animal studies on the drug release rate of a drug-eluting stent according to an embodiment of the present invention. [Figure 5] This shows the drug release rate in an in vitro test of a drug-eluting stent according to an embodiment of the present invention. [Figure 6] This is a schematic diagram of the structure of an implantable medical device system for interventional treatment according to an embodiment of the present invention. [Figure 7] This is a magnified view of a portion of Figure 6, showing the assembly position of the drug-eluting stent within the delivery device. [Modes for carrying out the invention]

[0066] The present invention will be further illustrated by the following embodiments, which are illustrative and not intended to limit the scope of protection of the invention, but rather to enable those skilled in the art to understand the invention. Other different forms of modification are possible, and it is not necessary to comprehensively list all embodiments here. It will be understood that all equivalent modifications or variations actually made in accordance with the spirit of the invention are within the scope of protection of the invention.

[0067] The present invention provides one or more examples of drug-eluting stents having a drug coating attached to the surface of the stent, the drug coating may be any of the following or described in the preamble of this specification.

[0068] Drug-eluting stents can be used primarily to treat intravascular diseases such as stenosis, restenosis, and inflammation of peripheral arteries, peripheral veins, cerebrovascular systems, and arteriovenous fistulas. However, those skilled in the art will understand that drug-eluting stents can also be used to treat related intravascular diseases such as those affecting the esophagus and intestines.

[0069] The drug coating is not limited to these examples, and can be applied to other medical devices, such as various occluders and filters that are permanently or temporarily implanted in the body by interventional procedures, or medical devices that require long-term contact with tissue walls without interventional procedures. The drug coating is applied to the surface of the device body to enable drug delivery to the outside.

[0070] The present invention provides several examples of drug coatings that have long-term controlled release functions and characteristics, such as having a drug release profile that delivers the drug to tissue walls over a period of 30 days or more, or 60 days or more, or 120 days or more, or 240 days or more, or 360 days or more, while satisfying the requirement that the average daily release amount or average weekly release amount of the drug within a preset release cycle reaches or exceeds at least the minimum required therapeutic dose.

[0071] In some embodiments, this required minimum therapeutic dose is 1% to 10% of the total drug load on the drug coating. In some embodiments, the drug release profile is such that the average weekly release reaches or exceeds at least 1% to 10% of the total drug load on the drug coating, e.g., 8%, 6%, or at least 1% to 5% of the total drug load on the drug coating, e.g., 1%, 2%, 3%, 4%, or 4%, or exceeds.

[0072] In some embodiments, unlike the average weekly release described above, the drug release profile ensures that the designed weekly release of the drug within this predetermined release cycle (e.g., 4 to 52 weeks) reaches or exceeds the required minimum therapeutic dose, which is at least 1% to 10% of the total drug load on the drug coating. In some embodiments, the drug release profile ensures that the designed weekly release of the drug within this predetermined release cycle reaches or exceeds at least 1% to 6% of the total drug load on the drug coating, e.g., 1%, 2%, 3%, 4%, 5%, or 6%.

[0073] Compared to the average weekly release, the designed weekly release can more reasonably reflect the characteristics of long-term controlled release of a drug, particularly meeting the requirements for long-term controlled release of the minimum therapeutic dose. This is because the average weekly release may not adequately represent or reflect the actual control of weekly drug release. The designed weekly release refers to the controlled release amount of drug required each week from the first to the last week within a predetermined drug release cycle. To ensure long-term therapeutic effect, the designed weekly release must reach or exceed at least the required minimum therapeutic dose.

[0074] The present invention further provides some other embodiments of drug coatings having functions and properties that suppress short-term burst release of high-drug-carrying drug coatings. For example, a high-drug-carrying coating has a drug release rate of 40% or less during the first 24 hours of drug delivery to the tissue wall, and a drug release rate of 15% or more during the first 30 days. In the present invention, the drug release rate described above, herein, and below refers to the ratio of the amount of drug released from the drug coating to the total amount of drug carried on the drug coating, unless otherwise specified.

[0075] In one embodiment, the high-drug-carrying coating has a drug release rate of 30% or less, or 20% or less, or 10% or less, during the first 24 hours of drug delivery to the tissue wall, and a drug release rate of 15% or more, or 20% or more, or 30% or more, or 40% or more, during the first 30 days.

[0076] Adding a blocking layer to a drug coating has proven particularly effective in suppressing short-term burst releases of drugs from the drug coating. The blocking layer may be an additional coating identical or different from the drug coating matrix, and is typically drug-free, and can be called a blank blocking layer. However, a blank blocking layer of a non-degradable polymer matrix may hinder drug release from the underlying drug coating to the outside of the coating, potentially failing to maintain a minimum therapeutic dose release over a long period during the release cycle. Therefore, one improvement method involves selecting a matrix material that can be rapidly broken down or dissolved as a sacrificial blocking layer to inhibit drug release before drug release or early in the release cycle, and then removing the blocking layer during the release cycle, for example, by dissolution, decomposition, or fluid flushing.

[0077] Unlike the above, the drug coatings of the embodiments of the present invention primarily achieve short-term and long-term controlled drug release through two drug-carrying layers having a concentration gradient, in high-drug-carrying drug coatings.

[0078] The typical drug load is 10 μg / cm³. 2 Compared to coronary artery drug-eluting stents used in small-diameter blood vessels, the high-drug-carrying drug coating described in the present invention typically has a drug-carrying capacity of 50 μg / cm³. 2 In particular, 100 μg / cm³ 2 The above may be the case.

[0079] In one preferred embodiment of the present invention, the functions and characteristics of long-term controlled release described above are simultaneously provided with the functions and characteristics of suppressing short-term burst release of high-drug-carrying drug coatings.

[0080] In one embodiment, the drug coating has a drug release rate of 15% or more, but 60% or less, 50% or less, or 40% or less during the first 30 days after implantation in the blood vessels of a mammal.

[0081] In one embodiment, the drug coating has a drug release rate of 15% or more, but 30% or less, 40% or less, or 50% or less, during the first 14 days after implantation in the blood vessels of a mammal.

[0082] In one embodiment, the drug coating exhibited a weekly drug release rate of approximately 6% to 2% from week 2 to week 17 after implantation in the blood vessels of mammals.

[0083] In one embodiment, the drug coating exhibits a drug release rate of 30% or more, or 40% or more, or 50% or more, within 31 to 360 days after implantation in the blood vessels of a mammal.

[0084] In one embodiment, the drug coating has a drug release rate of 15% or less, 20% or less, or 30% or less during the first 24 hours after implantation in the blood vessels of a mammal.

[0085] One notable feature of the drug coating in the embodiments of the present invention is the provision of a relatively thin outer layer and an inner layer having a significantly greater thickness. Typically, the outer layer has a low drug load and / or drug load concentration, while the inner layer has a high drug load and / or drug load concentration.

[0086] In one embodiment, the selectable thickness range for the outer layer is 1 μm to 6 μm, while the selectable thickness range for the inner layer, which has a significantly greater thickness, is 10 μm to 18 μm.

[0087] The present invention further provides examples of drug-eluting stents having the aforementioned drug coating, which are particularly suitable for implantation in peripheral arteries.

[0088] In some embodiments of drug-eluting stents suitable for implantation in peripheral arteries, the length may be 15 mm to 200 mm and the diameter 3 mm to 12 mm. In one embodiment, the drug-eluting stent may have a length L of 20 mm to 150 mm and a diameter of 5 mm to 10 mm.

[0089] In one embodiment, the drug-eluting stent has a length of 20 mm and a diameter of 5 mm, and in another embodiment, the drug-eluting stent has a length of 150 mm and a diameter of 8 mm, all of which can be delivered via a sheath with an outer diameter of 7 F.

[0090] Here, the drug coating can be applied to the entire surface of the stent body, but is not limited to this. Those skilled in the art may choose to apply the drug coating to only a portion of the stent body. For example, certain parts of the stent body may have exposed surfaces that are not coated with the drug coating. The stent body is usually made of metal and has excellent elastic deformation properties, thereby providing good support and compressive gripping force.

[0091] One of the notable advantages of the embodiment of the drug-eluting stent implanted in the peripheral artery of the present invention is that it reduces damage to the peripheral artery during the treatment process and results in a more effective therapeutic effect.

[0092] Drug-eluting stents can be delivered to the lesion site within the blood vessel by a delivery device while compressed and grasped in a small diameter state. When the drug-eluting stent is released into the blood lumen by manipulating the delivery device, it expands on its own or by balloon expansion to contact the blood vessel wall. Using its radial force, it supports and expands the narrowed blood vessel wall, releasing antiproliferative agents and other substances carried on the drug coating to the lesion site, thereby preventing or reducing restenosis of the blood lumen.

[0093] In one embodiment, a drug-eluting stent 3 can be incorporated into a delivery device, as shown in Figures 6 and 7. Referring to Figure 7, the drug-eluting stent 3 is fitted onto an inner sheath 4 of the delivery device, and an outer sheath 5 may be slidably fitted outside the inner sheath 4 to restrain the drug-eluting stent 3 in the inner sheath 4. The distal end 1 of the inner sheath 4 is a tapered head, and a marker 2 is provided near the distal end 1. The proximal end of the inner sheath 4 is connected to a front handle 7, and a stress-diffusing tube 6 is provided at the distal end of the front handle 7 to increase the strength of the tube body. During operation, the delivery device injects saline solution via a connector 12 at the proximal end, flushes the tube body, and delivers the drug into the human body via an introduction channel established by a guidewire. When the distal end of the inner sheath 4 reaches the designated lesion site, the operator releases the restriction of the stopper 10 on the knob 8, grasps the front handle 7, and releases the lock between the button 9 and the screw 11, thereby operating the knob 8 to retract (move towards the proximal end) along the screw 11, driving the outer sheath 5 to retract and release the drug-eluting stent 3. Figure 7 shows how the outer sheath 5 slides toward the proximal end to expose the drug-eluting stent 3 and release the drug-eluting stent 3 from the outer sheath 5. During release, the self-expanding stent is no longer radially constrained by the outer sheath 5 from the distal end to the proximal end, and gradually expands to restore its preset shape, supporting and expanding the narrowed blood lumen within the blood vessel.

[0094] Some examples of drug-eluting stents suppress the burst release of drugs that occurs in the early stages of stent implantation, which is highly advantageous in most cases.

[0095] For example, in the case of drug coatings carrying rapamycin or its analogues, in the early stages after angioplasty, platelet adhesion, aggregation, and secretion occur due to endothelial cell damage from stent expansion, laceration and exposure of the vascular intima, decreased barrier and protective function of the vascular endothelium, and impact from vascular stretching and blood flow. In this situation, the release of drugs such as rapamycin may not show a significant effect. Therefore, it is necessary to avoid releasing too much drug. In the case of drug coatings carrying paclitaxel, for the same reasons as above, if a large amount of paclitaxel is released in a short period of time in the early stages after angioplasty, it may show severe cytotoxicity and cause further damage to vascular wall tissue and other tissues in the systemic circulation.

[0096] Studies have shown that the incidence of restenosis in peripheral arteries, such as the superficial femoral artery, is high within one year of stenting (see "Timing of the restenosis following nitinol stenting in the superficial femoral artery and the factors associated with early and late restenoses" by Osamu et al., published in 2011 in the Catheterization & Cardiovascular Interventions Official Journal of the Society for Cardiac Angiography & Intervention). No peripheral artery drug-eluting stent has been proposed that is suitable to address this clinical problem.

[0097] Therefore, one object of the present invention is to provide a method for preventing or treating the aforementioned restenosis, and a drug-eluting stent used in the method.

[0098] The drug-eluting stent may be any of the examples described above or below, and in one embodiment, the drug-eluting arterial stent implanted in the narrowed portion of a peripheral artery satisfies the requirement that it has a drug release cycle of more than three months.

[0099] In another embodiment, a drug-eluting arterial stent implanted in a narrowed peripheral artery has a drug release cycle of more than 6 months.

[0100] In preferred embodiments, drug-eluting arterial stents implanted in narrowed peripheral arteries have a drug release cycle of approximately 12 months. This is because, given that previous studies have shown a sharp peak in restenosis time at approximately 12 months, the entire drug release cycle of drug-eluting stents is designed to be one year in order to effectively reduce the restenosis rate. Since the drug that inhibits stenosis can maintain the release of an effective dose over a long period, the patency rate of the lumen after 12 months can be more effectively improved. In particular, maintaining the release of an effective dose of the drug during the period up to 12 months after stent implantation, when the incidence of restenosis is high, is highly effective in preventing or reducing restenosis. In one embodiment, the amount of drug released by the drug-eluting stent 7 to 12 months after implantation is 10% to 40%, for example, about 30%, of the total drug-carrying amount of the drug coating.

[0101] The following description of drug coatings will use polyvinylidene fluoride copolymer (PVDF-HFP) as a fluoropolymer matrix, but the explanation is not limited to this, and those skilled in the art can select other suitable fluoropolymer matrices.

[0102] Referring to Figure 1, an embodiment of a drug-eluting stent 100 is shown, which has a cylindrical structure formed by a mesh-like body and can support the lumen of a blood vessel in the radial direction.

[0103] Continuing to refer to Figure 2, a drug coating 32 is shown covering the surface of the body 1 of the drug-eluting stent 100 or a similar device body 1. The drug coating 32 can surround the body 1 in a substantially circumferential direction. The cross-section of the elongated stem portion of the stent body 1 is shown as rectangular, but in some embodiments, the cross-section may be circular, elliptical, or arc-shaped.

[0104] The drug coating is not restrictive and does not necessarily have to surround the stent body 1 circumferentially. In some embodiments, the drug coating may be applied only to the outer circumferential surface of the stent body 1, i.e., the surface of the stent body 1 that is in contact with the tissue wall. In some embodiments, grooves may be provided on the outer circumferential surface of the stent body 1, and the drug coating may be applied only to the grooves, or simultaneously to the entire outer circumferential surface of the stent body 1.

[0105] In one embodiment, the outer and inner surfaces of the stent body 1 may be coated with a drug coating of the same or different thicknesses. In one embodiment, the thickness of the drug coating on the outer surface of the stent body 1 is greater than the thickness of the drug coating on the inner surface.

[0106] The stent body 1 may be made of a non-biodegradable material, particularly a metal, such as 316L stainless steel, cobalt-chromium alloy, magnesium alloy, iron alloy, zinc alloy, nickel-titanium alloy, or nickel-iron alloy, which has excellent biocompatibility and possesses good memory and support properties. However, the material of the stent body 1 is not limited to these, and may also be a polymer such as polyamide, polyolefin, or non-absorbable polyester. Although not limited to this, the stent body 1 may be made of a biodegradable or bioabsorbable material and is substantially or largely not decomposed or absorbed within the drug release cycle, but this choice may not be preferable.

[0107] The drug coating matrix in the example shown in Figure 1 is polyvinylidene fluoride copolymer (PVDF-HFP), which is a copolymer of vinylidene fluoride and hexafluoropropylene. This polymer has excellent biocompatibility and stable chemical properties, ensuring stable drug release without generating acidic degradation substances that increase the risk of inflammatory responses. The drug supported on the drug coating may be an antiproliferative agent such as rapamycin and its derivatives, paclitaxel, or heparin. In the example shown in Figure 1, rapamycin is selected as the supported drug. Rapamycin plays a role in inhibiting cell proliferation and migration, as well as suppressing cytokine production and inflammatory cell activation in the local vascular wall, inhibiting cell apoptosis, and promoting reendothelialization at the site of vascular injury. Restenosis is mainly caused by excessive proliferation of the vascular intima after stent implantation. Rapamycin suppresses the occurrence of restenosis by inhibiting cell proliferation and migration.

[0108] The drug coating 32 in the example shown in Figure 2 comprises an inner layer 321 with polyvinylidene fluoride copolymer as the matrix and an outer layer 322 also with polyvinylidene fluoride copolymer as the matrix, with different concentrations of rapamycin supported on the inner layer 321 and the outer layer 322, where the drug concentration on the inner layer 321 is higher than that on the outer layer 322. Referring to Figure 2, it is shown that the thickness of the inner layer 321 is greater than the thickness of the outer layer 322. The thickness of the outer layer 322 should not be too thick, for example, it should be 20 μm or less, and generally 10 μm or less. In this example, the thickness of the outer layer 322 is 1 μm to 8 μm. The total thickness of the inner layer 321 and the outer layer 322 is generally 50 μm or less, preferably 30 μm or less.

[0109] In one embodiment, the total thickness of the inner layer 321 and the outer layer 322 may be 11 μm to 27 μm.

[0110] For example, the thickness of the inner layer 321 is 10 μm to 22 μm, and the thickness of the outer layer 322 is 1 μm to 5 μm. The thickness of the inner layer 321 may be more than twice the thickness of the outer layer 322, for example, the ratio of the coating thickness of the inner layer 321 to the outer layer 322 is between approximately 22:1 and 10:1. Alternatively, for example, the thickness of the inner layer 321 is 12 μm to 16 μm, the thickness of the outer layer 322 is 1 μm to 3 μm, and the ratio of the coating thickness of the inner layer 321 to the outer layer 322 is between approximately 16:1 and 12:1, or the thickness of the inner layer 321 is 12 μm to 16 μm, the thickness of the outer layer 322 is 2 μm to 4 μm, and the ratio of the coating thickness of the inner layer 321 to the outer layer 322 is between approximately 16:2 and 12:2.

[0111] The drug coating 32 in the embodiment shown in Figure 1 further includes a bottom layer 33 that does not support the drug. This is not essential, but in some cases, it is preferable to include the bottom layer 33. The inner layer 321 of the drug coating 32 is attached to the surface of the bottom layer 33, and the bottom layer 33 is directly attached to the surface of the stent body 31. By selecting an appropriate bottom layer 33, the adhesion of the drug coating 32 to the stent can be increased. The material of the bottom layer 33 may be a non-biodegradable polymer such as polymethacrylonitrile, polymethyl methacrylate, polyethyl methacrylate, polypropyl methacrylate, poly-n-butyl methacrylate, polyhydroxyethyl methacrylate, or polyhydroxypropyl methacrylate. These do not fundamentally cause tissue rejection or tissue inflammation due to degradation. In this embodiment, poly-n-butyl methacrylate (PBMA) is used as the bottom layer 33. Poly-n-butyl methacrylate exhibits strong adhesion to the metal material of the stent body 31 and has good compatibility with the drug-supported fluorine-containing copolymer. As a result, the contact interface between the inner layer 321 and the bottom layer 33 is mixed and acts as a "lock" between them, forming a stable, highly bonded coating system on the stent.

[0112] The thickness of the bottom layer 33 should not be too thick, and a person skilled in the art can select the appropriate thickness as needed. In this embodiment, the thickness of the bottom layer 33 is 0.5 μm to 1.5 μm, for example, 0.5 μm, 1 μm, and 1.5 μm.

[0113] It can be understood that drug molecules supported on the inner layer 321 near the surface of the stent body 31 need to travel a long distance to be released outside the coating, and that as the drug is released, the drug concentration difference between the drug-eluting stent and the blood or tissue gradually decreases, and the release rate gradually slows down.

[0114] Therefore, in this embodiment, a two-layer drug coating 32 is formed with a concentration gradient, where the drug concentration in at least a portion of the inner layer 321 is higher than the drug concentration in at least a portion of the outer layer 322 along the thickness direction of the coating. Naturally, in a preferred embodiment, the inner layer 321 and the outer layer 322 each have relatively uniform drug concentrations, and the drug concentration in the entire area of ​​the inner layer 321 is higher than the drug concentration in the entire area of ​​the outer layer 322, which is particularly advantageous for controlling the release of the entire drug coating 32.

[0115] In this embodiment, the drug-loaded concentration of the inner layer 321 may be 10 wt% to 45 wt%, and the drug-loaded concentration of the outer layer 322 may be 1 wt% to 8 wt%. Preferably, the drug-loaded concentration of the inner layer 321 may be 10 wt% to 30 wt%, and the drug-loaded concentration of the outer layer 322 may be 3 wt% to 5 wt%, or the drug-loaded concentration of the inner layer 321 may be 10 wt% to 20 wt%, and the drug-loaded concentration of the outer layer 322 may be 3 wt% to 5 wt%, or the drug-loaded concentration of the inner layer 321 may be 10 wt% to 20 wt%, and the drug-loaded concentration of the outer layer 322 may be 3 wt% to 4 wt%. More preferably, the drug-loaded concentration of the inner layer 321 may be 10 wt%, 13 wt%, 15 wt%, 18 wt%, or 20 wt%, and the drug-loaded concentration of the outer layer 322 may be 3 wt%, 4 wt%, or 5 wt%.

[0116] In one embodiment of the present invention, the drug-eluting stent exhibits a drug release rate of 98% or more 12 months after implantation, with virtually no burst release phenomena in the initial stages of release, and sustained release for extended periods in the middle and later stages.

[0117] The drug coating 32 in this embodiment adequately carries the required amount of drug, for example, 110 μg / cm³. 2 ~500 μg / cm³ 2 That is also acceptable.

[0118] Naturally, the above examples of drug-eluting stents are not limited to peripheral arteries, but can also be applied to other arteries or veins with high blood flow velocity, large vessel diameters, or requiring long-term release.

[0119] The following provides examples of the manufacturing of the aforementioned drug-eluting stent.

[0120] Example 1 The method for manufacturing a drug-eluting stent includes the following steps:

[0121] 1) A mesh tube-shaped stent body was provided, which was ultrasonically cleaned and dried.

[0122] 2) Prepare a bottom layer coating material that does not support a drug, which includes the following:

[0123] The bottom layer solution was obtained by mixing and dissolving the bottom layer film-forming material with a solvent. Specifically, the method for preparing the bottom layer solution was as follows: 0.40 g of poly-n-butyl acrylate was weighed and added to a 250 ml volumetric flask, 60 ml of tetrahydrofuran was added to the flask, and the mixture was stirred until completely dissolved.

[0124] 3) A bottom layer is formed on the stent body, which includes the following:

[0125] The bottom layer solution was introduced into an ultrasonic spray coating device (ultrasonic atomizing spray coating system TLS-2000). After cleaning and drying the stent body, the liquid flowed out of the nozzle, and the stent body was subjected to ultrasonic spray coating to form a bottom layer with a thickness of 0.5 to 1.5 μm. After the spray coating was completed, it was dried in a 50°C oven for 2 hours.

[0126] 4) Prepare a coating material for a drug-supported drug coating, which specifically includes the following:

[0127] 4 g of PVDF-HFP (75%~25%) solid was weighed, placed in a 50 ml volumetric flask, methyl ethyl ketone was added to the final volume, and the mixture was stirred until completely dissolved to obtain the carrier stock solution, which was stored at room temperature or below.

[0128] 5 ml each of the above carrier stock solutions was taken and placed in a 100 ml volumetric flask. 16.5 mg and 100 mg of rapamycin solid were added to each flask, and the solution was diluted to the final volume with methyl ethyl ketone. The mixture was stirred until completely dissolved to prepare the coating solutions for the outer and inner layers of the drug coating.

[0129] 5) A drug coating is formed on the bottom layer of the stent, which includes the following:

[0130] After forming the bottom layer, a drug-supported drug coating was further spray-coated onto the bottom layer to form the inner and outer layers. First, the inner layer was spray-coated. Specifically, a 1 mg / mL inner layer coating solution was introduced into an ultrasonic spray coating device (ultrasonic atomizing spray coating system TLS-2000). As the liquid flowed out of the nozzle, the stent was placed in the ultrasonic spray coating device and spray-coated to form an inner layer with a thickness of 12-16 μm. After the spray coating was completed, the stent was vacuum-dried in an oven at 40°C for 12 hours.

[0131] Next, the outer layer was spray-coated. Specifically, a 0.165 mg / mL outer layer coating solution was placed in the aforementioned ultrasonic spray-coating apparatus. As the liquid flowed out of the nozzle, the stent was subjected to ultrasonic spray coating to form an outer layer with a thickness of 2-4 μm. After the spray coating was completed, the stent was vacuum-dried in an oven at 40°C for 12 hours.

[0132] Through the above steps, the drug-loaded concentration in the inner layer is 20 wt%, the drug-loaded concentration in the outer layer is 4 wt%, and the drug-loaded amount in the inner layer is 200 μg / cm³. 2 ~268 μg / cm², drug load in the outer layer is 7 μg / cm² to 14 μg / cm². 2 In this embodiment, a drug-eluting stent was obtained with an inner layer thickness of 12 μm to 16 μm and an outer layer thickness of 2 μm to 4 μm.

[0133] In other embodiments, the drug-eluting stent may not include a bottom layer. After cleaning and drying the stent body, the inner layer solution and outer layer solution are spray-coated sequentially to form the corresponding inner and outer layers, allowing the drug-supported drug coating to adhere directly to the surface of the stent body via the inner layer.

[0134] Naturally, the steps of this embodiment are not limited to the order illustrated above. For example, the bottom layer solution, inner layer solution, or outer layer solution may be prepared simultaneously, and then the corresponding solution may be selected and spray-coated onto the stent body as needed.

[0135] Example 2 Referring to the manufacturing method of Example 1, this example produced a drug-eluting stent with a different drug-loading concentration than that of Example 1. The bottom layer in this example is the same as that of Example 1 and will not be described in detail here.

[0136] The method for preparing the coating solutions for the inner and outer layers of the drug coating is as follows:

[0137] 9 g of PVDF-HFP (50%~50%) solid was weighed, placed in a 50 ml volumetric flask, methyl ethyl ketone was added to the final volume, and the mixture was stirred until completely dissolved to obtain the carrier stock solution, which was stored at room temperature or below.

[0138] One ml each of the aforementioned carrier stock solutions was taken and placed in a 100 ml volumetric flask. Six mg and 20 mg of rapamycin solid were added to each flask, and the flasks were diluted to the final volume with methyl ethyl ketone. The mixture was stirred until completely dissolved to prepare the coating solutions for the outer and inner layers of the drug coating.

[0139] First, the inner layer was spray-coated. Specifically, a 20 mg / mL inner layer coating solution was introduced into an ultrasonic spray coating device (ultrasonic atomizing spray coating system TLS-2000). As the liquid flowed out of the nozzle, the stent was subjected to ultrasonic spray coating, spray-coating an inner layer with a thickness of 14-18 μm onto the bottom layer. After the spray coating was completed, the stent was vacuum-dried in an oven at 40°C for 12 hours.

[0140] Next, the outer layer was spray-coated. Specifically, a 6 mg / mL outer layer coating solution was placed in the aforementioned ultrasonic spray-coating apparatus. Once the liquid flowed out of the nozzle, the stent was subjected to ultrasonic spray coating to create an outer layer with a thickness of 1-3 μm. After the spray coating was complete, the stent was vacuum-dried in an oven at 40°C for 12 hours.

[0141] Through the above steps, the drug-loaded concentration in the inner layer is 10 wt%, the drug-loaded concentration in the outer layer is 3 wt%, and the drug-loaded amount in the inner layer is 126 μg / cm³. 2 ~162 μg / cm², drug load in the outer layer is 3 μg / cm² 2 ~9 μg / cm³ 2 In this embodiment, a drug-eluting stent was obtained with an inner layer thickness of 14 μm to 18 μm and an outer layer thickness of 1 μm to 3 μm.

[0142] Example 3 Referring to the manufacturing method of Example 1, this example manufactured a different drug-eluting stent having a different drug-loading concentration than that of Examples 1 and 2. The bottom layer in this example is the same as in Example 1 and will not be described in detail here.

[0143] The method for preparing the coating solutions for the inner and outer layers of the drug coating is as follows:

[0144] 5 g of PVDF-HFP (60%~40%) solid was weighed, placed in a 50 ml volumetric flask, methyl ethyl ketone was added to the final volume, and the mixture was stirred until completely dissolved to obtain the carrier stock solution, which was stored at room temperature or below.

[0145] One ml each of the aforementioned carrier stock solutions was taken and placed in a 100 ml volumetric flask. 5.3 mg and 44 mg of rapamycin solid were added to each, and the solution was diluted to the final volume with methyl ethyl ketone. The mixture was stirred until completely dissolved, and these were used to obtain an outer layer coating solution with a concentration of 5.3 μg / ml and an inner layer coating solution with a concentration of 440 μg / ml.

[0146] First, the inner layer was spray-coated. Specifically, a 400 μg / mL inner layer coating solution was introduced into an ultrasonic spray coating device (ultrasonic atomizing spray coating system TLS-2000). As the liquid flowed out of the nozzle, the stent was subjected to ultrasonic spray coating, and an inner layer with a thickness of 10-12 μm was spray-coated onto the bottom layer. After the spray coating was completed, the stent was vacuum-dried in an oven at 40°C for 12 hours.

[0147] Next, the outer layer was spray-coated. Specifically, a 21.5 μg / mL outer layer coating solution was placed in the aforementioned ultrasonic spray coating apparatus. Once the liquid flowed out of the nozzle, the stent was subjected to ultrasonic spray coating to create an outer layer with a thickness of 3-5 μm. After the spray coating was complete, the stent was vacuum-dried in an oven at 40°C for 12 hours.

[0148] As a result of the above steps, the drug-loaded concentration in the inner layer is 30 wt%, the drug-loaded concentration in the outer layer is 5 wt%, and the drug-loaded amount in the inner layer is 264 μg / cm³. 2~316 μg / cm³ 2 The drug-loading capacity of the outer layer is 13 μg / cm³. 2 ~22 μg / cm³ 2 In this embodiment, a drug-eluting stent was obtained having an inner layer thickness of 10 μm to 12 μm and an outer layer thickness of 3 μm to 5 μm.

[0149] Examples of animal testing Using the Bama miniature pig as an animal model, 66 sets of drug-eluting stents from Example 1 were randomly assigned to 33 miniature pigs and implanted. One set of drug-eluting stents was implanted in each pig's left and right iliac (femoral) arteries. At each of the 11 time points after implantation, two sets of stents implanted in three pigs were removed, and the drug residue in the drug coating of the stents was analyzed by liquid chromatography. The average amount of drug residue in the drug coating at each time point was measured and calculated to obtain drug release rate data for the drug-eluting stents of Example 1 at each time point, which are shown in Table 1 below. Based on this, drug release rate profiles and release rate profiles were created as shown in Figures 3 and 4.

[0150] Next, using Bama miniature pigs as an animal model, six sets of drug-eluting stents from Example 2 were randomly assigned to three miniature pigs and implanted. One set of drug-eluting stents was implanted in the left and right iliac (femoral) arteries of each pig. After implantation, the two sets of stents implanted in one pig were removed at three time points, and the drug residue in the drug coating of the stents was analyzed by liquid chromatography. The average amount of drug residue in the drug coating at each time point was measured and calculated to obtain the drug release rate data for the drug-eluting stents from Example 2 at each time point, which are shown in Table 1 below.

[0151] Similarly, the six drug-eluting stents from Example 3 were randomly assigned to three miniature pigs and implanted, with one set of drug-eluting stents implanted in the left and right iliac (femoral) arteries of each pig. After implantation, the two sets of stents implanted in one pig were removed at three time points, and the drug residue in the drug coating of the stents was analyzed by liquid chromatography. The average amount of drug residue in the drug coating at each time point was measured and calculated to obtain the drug release rate data for the drug-eluting stents from Example 3 at each time point, which are shown in Table 1 below.

[0152] [Table 1]

[0153] According to the above data and drawings, the drug release of the drug coating in Example 1 covered the entire restenosis cycle (369 days), and the release rate was high at over 90%. It was found that the drug release rate was relatively fast during the first 1-2 months when smooth muscle proliferation was relatively rapid, and after about 50 days, the drug release rate entered the platform relatively quickly and maintained a stable release rate until the drug was completely released.

[0154] According to the data above, the drug coatings in these examples have the following action processes during the progression of restenosis.

[0155] (1) Within 1 to 12 hours after angioplasty, platelet adhesion, aggregation, and secretion occur due to endothelial cell damage, rupture and exposure of the vascular intima, decreased barrier and protective function of the vascular endothelium, and impact from vascular stretching and blood flow. At this time, rapamycin may not show a significant effect. Therefore, it is necessary to avoid releasing too much. The drug-eluting stent in the above example controls the release rate to about 10% in the initial stage to avoid burst release of the drug and to ensure that sufficient drug is stored for later release.

[0156] (2) Immediately after surgery (lasting approximately 7 days), due to endothelial cell damage, rapamycin primarily exhibits an anti-inflammatory effect, and its antiproliferative effect has not yet been exerted. Therefore, at this stage, rapamycin does not exert a significant effect. The drug-eluting stent in the above example controls the drug release rate to less than 20% at this stage, avoiding premature waste or loss of the drug.

[0157] (3) After 7-14 days, the peak of smooth muscle proliferation is reached, which can last for 1-2 months. Within 2 months, intimal thickening occurs due to the peak of smooth muscle proliferation, which can lead to restenosis in the later stages. At this stage, the above example releases approximately 50% of the drug, meaning that at the peak stage, sufficient drug is released to meet the therapeutic needs while ensuring a smooth and stable release at this stage.

[0158] (4) Finally, the blood vessels self-regulate to adapt to changes in the external environment, thereby making corresponding adjustments to adapt to changes in hemodynamics and vascular wall structure under different physiological and pathological conditions. In the mid-to-late stages, for example, on day 270, the drug is released continuously, reaching a release rate of over 80% until the maximum release is completed from the time node to the end of the release cycle.

[0159] In vitro test example Despite the aforementioned animal studies, to roughly evaluate the release characteristics of drug coatings on drug-eluting stents, an in vitro accelerated release test can usually be performed first. In in vitro accelerated release experiments, a solvent or composition that releases drugs more readily than blood can be selected as the release medium, thereby allowing evaluation results for different drug coatings to be obtained in a shorter time.

[0160] Accordingly, the present invention further provides a method for testing in vitro drug release of a drug-eluting stent, which includes using a buffer system comprising a mixture of a small amount of water-soluble nonionic surfactant and acetonitrile as the release medium. For example, a buffer system comprising about 0.1% to 1% water-soluble nonionic surfactant and about 10% acetonitrile is used as the release medium. The pH value of the release medium can be adjusted to about 7.4.

[0161] Taking the drug-eluting stent of Example 1 as an example, the steps for conducting an in vitro drug release test are as follows:

[0162] 1) Preparation of release medium: 20 mL of acetonitrile and 1.8 mL of 70% Triton (Triton X-405) were placed in a 200 mL volumetric flask, and the volume was adjusted with PBS solution (38.0 g of sodium dihydrogen phosphate and 5.04 g of disodium hydrogen phosphate, to which water was added up to 1000 mL). The mixture was shaken well, and the pH was adjusted to 7.4 ± 0.1 with hydrochloric acid or sodium hydroxide to obtain a release medium consisting of a mixture of 0.9% Triton X-405 and 10% acetonitrile.

[0163] 2) Release Test: The drug-eluting stent to be detected was placed in a release medium and held in a water bath at 37°C ± 2°C. A vibration frequency of 60 r / min was selected to simulate drug release. At 5, 10, 30, 60, 90, 180, 240, 480, 1200, and 1440 minutes, the drug-eluting stent was removed and placed in an elution flask containing acetonitrile. The flask was sonicated in an ice bath for 30 minutes to completely dissolve the rapamycin remaining in the drug-eluting stent in the acetonitrile in the elution flask. After quantification, chromatography was used to inject the eluted drug from the elution flask for detection.

[0164] The measured emission profile is shown in Figure 5. It was found that the emission rate reached over 90% in the latter half of 1440 minutes and approached 100% by 1800 minutes.

[0165] Here, multiple stents from Example 1 were manufactured, and one stent was removed at each time point for drug elution detection.

[0166] Using the same manufacturing method as described above, other examples of drug-eluting stents with different drug coatings were produced, as shown in the following table. TIFF2026514507000003.tif55164

[0167] Comparative Example A comparative drug-eluting stent was prepared by referring to the method of Example 1, comprising a bottom layer coated on the stent body, a drug-carrying layer coated on the bottom layer, and a blank barrier layer coated on the drug-carrying layer. The bottom layer was the same as in Example 1, and the drug-carrying layer and blank barrier layer were the same fluoropolymers as in Example 1.

[0168] In the comparative example, the drug-loaded layer is a drug coating with a single concentration, the drug-loaded concentration being 10 wt% to 20 wt%, the thickness of the drug-loaded layer being 12 μm to 15 μm, and the barrier layer being 2 μm to 4 μm. The blank barrier layer is a drug-free fluoropolymer coating.

[0169] Studies of in vivo and in vitro drug release profiles revealed that, in the comparative example, while burst release phenomena decreased in the early stages of release, drug release was clearly insufficient in the mid-to-late stages. The 30-day release rate was significantly below 15%, making it difficult to achieve therapeutic efficacy.

[0170] Using the same or a similar manufacturing method, a comparative drug-eluting stent was also manufactured, comprising a bottom layer covering the stent body and a drug-carrying layer covering the bottom layer, wherein no blocking layer or other drug-carrying layer was provided on the drug-carrying layer. The bottom layer was the same as in Example 1, and the drug-carrying layer was the same fluoropolymer as in Example 1.

[0171] Comparative Examples 1-4 were manufactured by setting the parameters of the drug-carrying layer as shown in the table below. TIFF2026514507000004.tif46164

[0172] In vitro release comparative experiment In vitro drug release tests were performed using the drug-eluting stents of Examples 4-8 and Comparative Examples 1-4 as examples.

[0173] To observe the release of the drug-eluting stent over a longer period, the release medium used in the in vitro drug release test was prepared using the following method: 8 mL of acetonitrile and 0.6 mL of Tween-20 were placed in a 200 mL volumetric flask, and the volume was adjusted with PBS solution (38.0 g of sodium dihydrogen phosphate and 5.04 g of disodium hydrogen phosphate, to which water was added up to 1000 mL). The mixture was shaken well, and the pH was adjusted to 7.4 ± 0.1 with hydrochloric acid or sodium hydroxide to obtain a release medium consisting of a mixture of 0.3% Tween-20 and 4% acetonitrile.

[0174] The drug-eluting stent to be detected was placed in a release medium and held in a water bath at 37°C ± 2°C. A vibration frequency of 60 r / min was selected to simulate drug release. At several corresponding points in time, the stent was removed and placed in a dissolution flask containing acetonitrile. The stent was sonicated in an ice bath for 30 minutes to completely dissolve the rapamycin remaining in the drug-eluting stent in the acetonitrile in the dissolution flask. After quantification, chromatography was employed to inject and detect the eluted drug in the dissolution flask. The measured corresponding drug release results are shown in the table below. TIFF2026514507000005.tif100164

[0175] In each example and comparative example, multiple stents were manufactured, and in the above example, one stent was removed at each time point for drug elution detection.

[0176] At intermediate points such as 10 hours, the release rate of the present invention reached 40%, and even in Example 4, it reached over 50%. This is significantly different from Comparative Examples 1 and 2, which only reached a release rate of approximately 26% to 29%, and also significantly different from Comparative Examples 3 and 4, which showed a tendency toward burst release.

[0177] As can be seen from the table above, the drug-carrying layers of Examples 4-8 were able to release the drug uniformly and slowly, achieving long-term sustained release. Compared to Comparative Examples 2 and 3, which did not have a blocking layer, no burst release was observed in the initial stages. Compared to Comparative Example 1, which had a blank blocking layer, the drug was released in a stable amount over a long period of time, and the release rate in the later stages was significantly improved.

[0178] While the present invention has been disclosed as preferred embodiments as described above, this does not limit the invention. Those skilled in the art can make possible changes and modifications to the technical solutions of the invention by utilizing the methods and technical content disclosed above, without departing from the spirit and scope of the invention. Accordingly, any simple modifications, equivalent changes, and modifications made to the above embodiments based on the technical substance of the invention without departing from the content of the technical solutions of the invention are all within the scope of protection of the technical solutions of the invention.

Claims

1. A drug coating, wherein the drug coating is provided on a medical device, and the drug coating comprises a non-degradable fluoropolymer matrix and a drug dispersed therein, and an outer layer and an inner layer with different drug-carrying concentrations are formed along the thickness direction of the drug coating, wherein the drug-carrying concentration of the inner layer is higher than that of the outer layer, and the thickness of the outer layer is 20 μm or less.

2. The drug coating according to claim 1, characterized in that the drug coating is configured such that the drug release rate during the first 24 hours after implantation in a mammalian blood vessel is 40% or less, and the drug release rate during the first 30 days is 15% or more.

3. The drug coating according to claim 1 or 2, characterized in that the mammal is a human or a pig.

4. The drug-bearing concentration of the inner layer is 10 wt% or more by weight, and the drug-bearing concentration of the outer layer is less than 10 wt% by weight. Alternatively, the drug-loaded concentration of the inner layer is 10 wt% to 45 wt%, and the drug-loaded concentration of the outer layer is 1 wt% to 8 wt%, Alternatively, the drug-loaded concentration of the inner layer is 10 wt% to 30 wt%, and the drug-loaded concentration of the outer layer is 3 wt% to 5 wt%, Alternatively, the drug-loaded concentration of the inner layer is 10 wt% to 20 wt%, and the drug-loaded concentration of the outer layer is 3 wt% to 5 wt%, Alternatively, the drug-loaded concentration of the inner layer is 10 wt% to 20 wt%, and the drug-loaded concentration of the outer layer is 3 wt% to 4 wt%, Alternatively, the drug-loaded concentration of the inner layer is 20 wt% to 30 wt%, and the drug-loaded concentration of the outer layer is 4 wt% to 5 wt%, Alternatively, the drug coating according to any one of claims 1 to 3, characterized in that the drug-loaded concentration of the inner layer is 10 wt%, 13 wt%, 15 wt%, 18 wt%, or 20 wt%, and the drug-loaded concentration of the outer layer is 3 wt%, 4 wt%, or 5 wt%.

5. The drug coating according to any one of claims 1 to 4, characterized in that the thickness of the outer layer is 1 μm or more and 10 μm or less, or the thickness of the outer layer is 1 μm to 8 μm.

6. The drug coating according to any one of claims 1 to 5, characterized in that the thickness of the inner layer is greater than the thickness of the outer layer, or the thickness of the inner layer is 10 μm to 22 μm.

7. The drug coating according to any one of claims 1 to 6, characterized in that the thickness of the inner layer is 12 μm to 16 μm, and the thickness of the outer layer is 2 μm to 4 μm.

8. The total amount of drug loaded in the drug coating is 110 μg / cm³. 2 ~500 μg / cm² 2 A drug coating according to any one of claims 1 to 7, characterized in that it is the drug coating according to any one of claims 1 to 7.

9. The drug coating according to any one of claims 1 to 8, characterized in that the amount of drug carried in the inner layer is greater than the amount of drug carried in the outer layer.

10. The drug loading amount of the inner layer is 100 μg / cm 2 to 400 μg / cm 2 and the drug loading amount of the outer layer is 2 μg / cm 2 to 60 μg / cm 2 ; alternatively, the drug loading amount of the inner layer is 150 μg / cm 2 to 350 μg / cm 2 and the drug loading amount of the outer layer is 2 μg / cm 2 to 30 μg / cm 2 The drug coating according to any one of claims 1 to 9, characterized in that it is so.

11. The drug coating according to any one of claims 1 to 10, characterized in that the drug is selected from paclitaxel, rapamycin, heparin, probucol, dexamethasone, or an analog of the aforementioned drug.

12. The drug coating according to any one of claims 1 to 11, characterized in that the drug is selected from lipophilic drugs.

13. The drug coating according to any one of claims 1 to 12, characterized in that the drug coating is configured such that the drug release rate during the first 30 days after implantation in a mammalian blood vessel is 15% or more, and is 60% or less, 50% or less, or 40% or less.

14. The drug coating according to any one of claims 1 to 13, characterized in that the drug coating is configured such that the drug release rate during the first 14 days after implantation in a mammalian blood vessel is 10% or more, and is 30% or less, 40% or less, or 50% or less.

15. The aforementioned drug coating exhibits a weekly drug release rate of 6% to 2% from week 2 to week 17 after implantation in the blood vessels of mammals. Alternatively, the drug coating according to any one of claims 1 to 14, characterized in that it is configured such that the drug release rate is 30% or more, or 40% or more, or 50% or more, within 31 to 360 days after implantation.

16. The drug coating according to any one of claims 1 to 15, characterized in that the drug coating is configured such that the drug release rate during the first 24 hours after implantation in a mammalian blood vessel is 15% or less, 20% or less, or 30% or less.

17. The drug coating according to any one of claims 1 to 16, characterized in that the non-degradable fluoropolymer is a copolymer of vinylidene fluoride and hexafluoropropylene, and the copolymer contains 50% to 92% vinylide fluoride and 50% to 8% hexafluoropropylene by weight percentage.

18. The drug coating according to any one of claims 1 to 17, characterized in that the non-degradable fluoropolymer is a copolymer of vinylidene fluoride and hexafluoropropylene, and the copolymer contains 55% to 65% by weight of vinylidene fluoride and 45% to 35% by weight of hexafluoropropylene.

19. The drug coating according to any one of claims 1 to 18, characterized in that the non-degradable fluoropolymer is a copolymer of vinylidene fluoride and hexafluoropropylene, and the copolymer contains 70% to 90% by weight of vinylidene fluoride and 30% to 10% by weight of hexafluoropropylene.

20. A drug coating according to any one of claims 1 to 19, further comprising a drug-free bottom layer, wherein the inner layer is attached to the bottom layer.

21. The drug coating according to any one of claims 1 to 20, characterized in that the bottom layer is made of one or more of the following: polymethacrylonitrile, polymethyl methacrylate, polyethyl methacrylate, polypropyl methacrylate, poly-n-butyl methacrylate, polyhydroxyethyl methacrylate, and polyhydroxypropyl methacrylate.

22. A medical device having a drug coating, comprising a medical device body and a drug coating according to any one of claims 1 to 21, wherein the drug coating is provided on the surface of the body.

23. The medical device according to claim 22, characterized in that the medical device body has an expandable portion, and the drug coating is provided on the surface of the expandable portion.

24. The medical device according to claim 22 or 23, wherein the medical device is a drug-eluting stent, a closure plug, or a filter, and the medical device has a body made of metal.

25. The medical device according to any one of claims 22 to 24, characterized in that the drug coating is provided on the surface of a portion of the main body with a diameter of 5 mm or more.

26. The medical device is a drug-eluting stent for treating peripheral artery stenosis, and the drug-eluting stent is characterized in that it has a length of 15 mm to 200 mm and a diameter of 3 mm to 12 mm, as described in any one of claims 22 to 25.

27. An implantable medical device system comprising a medical device according to any one of claims 22 to 26 and a delivery device detachable from the medical device, wherein during transport, the medical device is fitted into the delivery device in a compressed state, and upon reaching the lesion site, the delivery device detaches from the medical device, allowing the medical device to contact the tissue wall in an expanded state.

28. A method for manufacturing a medical device having a drug coating, wherein the manufacturing method is used to manufacture the medical device according to any one of claims 22 to 26, and the manufacturing method is The steps include providing the medical device itself, The steps include preparing a first solution and a second solution for forming drug coatings with different drug-loading concentrations, First, the first solution is applied to the main body to form the inner layer of the drug coating, Next, the step of applying the second solution onto the inner layer to form the outer layer of the drug coating is included, A manufacturing method characterized in that the drug-loaded concentration of the first solution is higher than the drug-loaded concentration of the second solution, and the thickness of the inner layer is greater than the thickness of the outer layer.

29. The above method further, The process involves preparing a bottom layer solution, where the bottom layer film-forming material and solvent are mixed and dissolved to obtain the bottom layer solution, The steps include: applying the bottom layer solution to the surface of the main body to form the bottom layer, and then applying the first solution onto the bottom layer of the main body to form the inner layer of the drug coating; The manufacturing method according to claim 28, characterized by including

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