Coating for medical instrument

Abstract

A coating for medical instrument, comprising a first coating and a second coating from the interior to the exterior, wherein the first coating comprises a corrosion delaying agent capable of delaying the corrosion of the instrument substrate, and the second coating comprises a safety factor. The coating for medical instrument can not only ensure that the substrate has better mechanical properties before the completion of blood vessel repair, but also achieve rapid degradation after the completion of blood vessel repair, which can effectively reduce the toxicity of instrument components to the cells / tissues around the instrument, thereby improving the efficacy and safety of the instrument.

Description

Coating for medical devices Technical Field

[0001] The present invention relates to the field of implantable medical devices, in particular to a coating for medical devices, and in particular to a degradable metal-based coating for implantable medical devices. Background Art

[0002] Currently, in cardiovascular implant applications, vascular stents are typically made of non-degradable metals. However, these metals are non-degradable, difficult to remove, and can remain in the body for extended periods, leading to numerous adverse events such as late-stage thrombosis and long-term complications. Therefore, biodegradable implantable devices made of biodegradable polymers and corrodible metals hold great promise for future applications.

[0003] However, there are also many challenges in the actual research and development process of degradable implantable devices. First, from the perspective of clinical application, when the degradable implantable device has completed its intended use, the lesion has healed (1-6 months) and restored its normal morphology and function, and under the premise of not causing new biocompatibility issues, the shorter the time it takes for the device to completely degrade and be absorbed by the body, the better. In other words, degradable medical devices need to meet the requirements that their matrix basically does not degrade during the healing period, maintain good mechanical properties, and degrade and absorb rapidly after the healing period; secondly, the device is implanted in the human body and plays a therapeutic role, and it needs to meet the corresponding safety and effectiveness at the same time. Degradable devices need to meet both safety and effectiveness, and their degradation performance also needs to meet the corresponding requirements. However, the currently common degradable substrates either find it difficult to meet the degradation requirements, or even if they meet the degradation requirements, there is still room for optimization in terms of safety and effectiveness. On the one hand, this is because the device itself, as a foreign body, will cause greater stimulation to the implantation site after being implanted in the lesion site, and may even cause certain damage to the tissues surrounding the device, resulting in inflammatory reactions, cell proliferation, and thrombosis near the device implantation site; on the other hand, the degradation products of the device will have more or less toxic side effects on the surrounding tissues, and it will take a certain amount of time for the device to be completely endothelialized after being implanted in the lesion site. During this period, the continuous interaction between the device and its degradation products and the surrounding tissues may further cause late cell proliferation and even lead to cell death, thereby posing a safety hazard and ultimately affecting effectiveness.

[0004] For example, some early polymer stents, after implantation, often caused severe inflammatory reactions due to the local acidic environment created by polymer degradation. This inflammatory reaction, in turn, can easily lead to thrombosis and cell proliferation. If proliferation occurs in the lumen, lumen stenosis is also likely to occur. Therefore, ensuring that biodegradable implantable devices meet the corresponding mechanical performance and degradation rate requirements after implantation in the human body, while also avoiding safety issues such as cell proliferation, thrombosis, inflammation, and fever caused by the device itself or its degradation products, which further affect the effectiveness of the device, remains a difficult issue in current research. Summary of the Invention

[0005] Based on this, the present invention provides a coating for medical devices that can meet the degradation and mechanical performance requirements of the device, ensuring that the device substrate does not degrade or degrades slowly during the healing period and degrades rapidly after the healing period. It can also effectively inhibit serious safety issues such as cell proliferation, thrombosis, inflammation, and fever that occur before the device is fully endothelialized, as well as effectiveness issues caused by safety. The coating for medical devices includes a first coating and a second coating from the inside to the outside, wherein the first coating includes a corrosion retardant that can delay corrosion of the device substrate, and the second coating includes a safety factor that improves the safety of the device. By adding a safety factor to the second coating, the present invention can effectively reduce infection, proliferation, thrombosis, etc. in the tissues surrounding the device. If the lesion area is within the lumen, the lumen stenosis rate can be greatly reduced, thereby improving effectiveness.

[0006] In the above technical solution of the present invention, the corrosion retarder in the first coating can achieve the purpose of no corrosion or less corrosion of the device in the early stage by delaying and / or delaying the corrosion of the substrate, that is, reducing the early corrosion rate of the substrate and / or delaying the corrosion start time of the substrate.

[0007] The "safety factor" described in the present invention is not a drug-like substance in the conventional sense. It does not directly act on tissues to improve the safety and effectiveness of the device. Instead, it indirectly improves the safety and effectiveness of the device by interacting with other components in the coating or related components in the surrounding body fluids after implantation. For example, in some embodiments of the present invention, the safety factor can fully regulate the residual concentration / retention amount of the degradation products released by the first coating near the device, ensuring that the concentration of the degradation products of the first coating near the device remains within a relatively favorable concentration range before the device is endothelialized, thereby effectively preventing toxic reactions such as proliferation and inflammation. In other embodiments of the present invention, the safety factor can fully regulate the residual concentration / retention amount of the degradation products released by the first coating near the device, ensuring that the concentration of the degradation products of the first coating near the device remains within a relatively favorable concentration range before the device is endothelialized, thereby effectively preventing cell proliferation. In other embodiments of the present invention, the safety factor can regulate the release of the drug in the coating, so that the concentration of the drug released from the device can effectively inhibit tissue proliferation during the period from implantation of the device to complete endothelialization. In still other embodiments of the present invention, the safety factor can both ensure that the concentration of the degradation products of the first coating near the device remains within a relatively favorable concentration range before the device is endothelialized, thereby reducing the toxicity of the degradation products of the first coating to cells / tissues, and can also regulate the concentration of the drug in the coating, ultimately effectively and synergistically inhibiting adverse reactions such as tissue proliferation and inflammation.

[0008] In the present invention, "the safety factor can fully regulate the retained concentration of the degradation products of the first coating near the device" means that the safety factor can, on the one hand, regulate the release rate of the degradation products of the first coating, and on the other hand, can also regulate the concentration of the ionic form of the degradation products of the first coating in the physiological solution around the device, thereby ultimately achieving the purpose of regulating the retained concentration of the degradation products of the first coating near the device. The term "regulating the release rate of degradation products of the first coating" means that the safety factor in the present invention can bidirectionally regulate the corrosion rate of the first coating, mainly by reducing the corrosion rate of the first coating in the early and / or mid-stages while accelerating the corrosion rate of the first coating in the late stage. The term "regulating the concentration of ionic degradation products of the first coating in the physiological solution surrounding the device" is mainly achieved by reducing the fluctuation amplitude or dispersion of the concentration of ionic degradation products of the first coating in the tissue surrounding the device at various time points, that is, reducing the deviation or variance of the retained concentration of ionic degradation products of the first coating surrounding the device at various time points, so as to achieve the purpose of always maintaining the concentration of ionic degradation products of the first coating surrounding the device within a relatively safe range, avoiding excessively high or low retained concentrations of ionic degradation products of the first coating near the tissue surrounding the device, leading to cytotoxicity or adverse effects, and ultimately achieving the goal of effectively inhibiting serious safety issues such as cell proliferation, thrombosis, inflammation, and fever in the tissue surrounding the device, thereby improving the effectiveness of the device.

[0009] The term "luminal stenosis" in the present invention refers to the phenomenon that after the device is implanted in the human body, the volume of the cavity is gradually filled with proliferating cells, thereby causing the inner diameter of the cavity to gradually decrease.

[0010] It should be noted that the “safety factor is soluble in acidic solution” means that the safety factor itself has a high solubility in acidic solution or the new substance formed by the safety factor under the action of acidic solution has a high solubility in aqueous solution or physiological solution.

[0011] According to the above technical solution provided by the present invention, the first coating layer is an inorganic coating layer, and the second coating layer is an inorganic coating layer and / or an organic coating layer. In some embodiments of the present invention, the first coating layer is an inorganic coating layer, and the second coating layer is an inorganic coating layer; in other embodiments of the present invention, the first coating layer is an inorganic coating layer, and the second coating layer is an organic coating layer; in still other embodiments of the present invention, the first coating layer is an inorganic coating layer, and the second coating layer is an organic and inorganic coating layer, that is, the second coating layer contains both organic and inorganic substances.

[0012] It should be noted that the "inorganic coating" and "organic coating" in the present invention refer to whether the coating is composed of an inorganic compound or an organic compound. If the coating is composed of an inorganic compound, then the coating is an inorganic coating; if the coating is composed of an organic compound, then the coating is an organic coating; if the coating is composed of both an organic compound and an inorganic compound, then the coating is an organic and inorganic coating, or the coating is an inorganic and organic coating.

[0013] Furthermore, the corrosion retarder in the present invention is an inorganic substance, and the safety factor is one of an inorganic substance or an organic substance.

[0014] Furthermore, the corrosion retarder in the present invention is an inorganic substance, and the safety factor is also an inorganic substance.

[0015] Furthermore, in the present invention, the corrosion retarder of the first coating and the safety factor of the second coating are both selected from simple substances, alloys or compounds composed of metal elements.

[0016] Furthermore, the corrosion retarder of the first coating and the safety factor of the second coating in the present invention are selected from elements, alloys, or compounds composed of the same metal element. That is, both the first and second coatings contain metal elements, and the key components of the two coatings are the same metal element. For example, in some embodiments of the present invention, the corrosion retarder of the first coating is a zinc alloy, and the safety factor of the second coating is a zinc carbonate layer; in some embodiments of the present invention, the corrosion retarder of the first coating is elemental zinc, and the safety factor of the second coating is a zinc alloy; in still other embodiments of the present invention, the corrosion retarder of the first coating is elemental zinc, and the safety factor of the second coating is a zinc phosphate layer; in some embodiments of the present invention, the corrosion retarder of the first coating is a zinc alloy, and the safety factor of the second coating is a zinc phosphate layer; in still other embodiments of the present invention, the corrosion retarder of the first coating is elemental zinc, and the safety factor of the second coating is a zinc carbonate layer. By providing the second coating on the first coating in the present invention, the second coating can regulate the release rate of the first coating and the residual concentration or amount of the first coating's degradation products around the device, thereby improving the safety of the device. The second coating in the present invention mainly regulates the amount of degradation products retained near the device in the early and late stages, thereby preventing the amount of degradation products retained near the device from being too high in the early stage and from being too low in the late stage. This ensures that the amount of degradation products retained is always within a range with low toxicity to the tissues surrounding the device, ultimately improving the safety of the device.

[0017] Furthermore, in the present invention, the corrosion retarder of the first coating layer and the safety factor of the second coating layer are selected from elements, alloys, or compounds composed of different metal elements. That is, in the present invention, both the first coating layer and the second coating layer contain metal elements, but the metal elements of the key components of the two coating layers are different. For example, in some embodiments, the metal element contained in the corrosion retarder of the first coating layer is Zn, and the metal element contained in the safety factor of the second coating layer is Na; in some embodiments, the metal element contained in the corrosion retarder of the first coating layer is Cu, and the metal element contained in the safety factor of the second coating layer is Na; in other embodiments, the metal element contained in the corrosion retarder of the first coating layer is Zn, and the metal element contained in the safety factor of the second coating layer is Mg; in still other embodiments, the metal element contained in the corrosion retarder of the first coating layer is Al, and the metal element contained in the safety factor of the second coating layer is Ca; in still other embodiments, the metal element contained in the corrosion retarder of the first coating layer is Mg, and the metal element contained in the safety factor of the second coating layer is K.

[0018] In the above technical solutions provided by the present invention, the key components of the first coating layer and the second coating layer can be at least one of a single substance, an alloy, or a compound, and the first coating layer and the second coating layer can be freely matched. For example, in some embodiments, the first coating layer is a single substance and the second coating layer is a compound; in some embodiments, the first coating layer is an alloy and the second coating layer is a compound; in other embodiments, the first coating layer is a compound and the second coating layer is a compound; in still other embodiments, the first coating layer is a mixture of a single substance and an alloy and the second coating layer is a compound; in still other embodiments, the first coating layer is a mixture of a single substance and a compound and the second coating layer is a compound; in still other embodiments, the first coating layer is a mixture of an alloy and a compound and the second coating layer is a compound; in still other embodiments, the first coating layer is a mixture of a single substance, an alloy, and a compound and the second coating layer is a compound. Compounds include but are not limited to oxides and inorganic salts.

[0019] It should be noted that when a coating layer / a key component is composed of multiple components, the metal elements corresponding to the multiple components may be different or the same. For example, in some embodiments, the first coating layer is composed of zinc alloy and zinc oxide.

[0020] Furthermore, the corrosion retarder includes at least one of a metal element, a metal alloy, a metal oxide, or an inorganic salt; the safety factor includes at least one of an inorganic salt, an organic base, or an inorganic weak base. The first coating and the second coating can be freely combined within the above range. For example, in some embodiments, the first coating is a metal element and the second coating is an inorganic salt; in some embodiments, the first coating is a metal alloy and the second coating is an inorganic salt; in other embodiments, the first coating is a mixture of a metal element and a metal alloy and the second coating is an inorganic salt; in still other embodiments, the first coating is a metal alloy and the second coating is a mixture of an inorganic weak base and an inorganic salt.

[0021] Furthermore, the inorganic salt in the present invention is an inorganic weak acid salt or an inorganic medium strong acid salt.

[0022] In the above-mentioned technical solutions provided by the present invention, the corrosion retardant of the first coating dissolves / releases in body fluids / physiological solutions primarily through electrochemical means, while the safety factor of the second coating dissolves / releases in body fluids / physiological solutions primarily through ionization or galvanic corrosion. When the device of the present invention comprises a degradable metal substrate, in some embodiments, the degradable metal substrate can form a galvanic pair with the first coating to cause galvanic corrosion; in some embodiments, the degradable metal substrate can also form a galvanic pair with the second coating to cause galvanic corrosion; in still other embodiments, the degradable metal substrate can simultaneously form complex galvanic pairs with the first and second coatings, mutually regulating the corrosion rate.

[0023] The "electrochemical method" mentioned in the present invention includes galvanic corrosion and non-galvanic corrosion, wherein non-galvanic corrosion includes ionization or chemical reaction.

[0024] In the above technical solution provided by the present invention, at least one ion released by the safety factor forms an insoluble compound with at least one ion released by the corrosion retarder, and the solubility of the metal element in the insoluble compound in a physiological environment is less than 60 mg / L, or the solubility of the safety factor at 20°C is less than 1.5 g / L. Furthermore, at least one ion released by the safety factor forms an insoluble compound with at least one ion released by the corrosion retarder, and the solubility of the metal element in the insoluble compound in a physiological environment is less than 50 mg / L, 40 mg / L, or 30 mg / L, or the solubility of the safety factor at 20°C is less than 1.2 g / L, 1.0 g / L, 0.8 g / L, or 0.5 g / L. The second coating of the technical solution provided by the present invention forms a primary cell with the substrate, or forms a complex primary cell with both the substrate and the first coating, or changes the electrode potential, electrolyte composition, primary cell medium, cathode to anode area ratio, anode resistance, cathode polarization effect, etc. of the primary cell formed between the first coating and the substrate to ultimately achieve the purpose of regulating the release rate and / or retention concentration of toxic components of cells or tissues, and ultimately achieve the purpose of improving the safety and effectiveness of the device.

[0025] In the present invention, the components of the second coating and the degradation products of the first coating can effectively control the concentration of the degradation products of the first coating near the device within an effective range through complex electrochemical or chemical reactions, thereby effectively improving the safety and effectiveness of the device.

[0026] Furthermore, the safety factor in the second coating has a pKa greater than 3.86 or a pKb greater than 1. In some embodiments, the safety factor in the second coating is an inorganic weak acid salt or an inorganic medium strong acid salt, and the dissociation constant pKa value corresponding to the anion of the inorganic salt is greater than 3.86; in other embodiments, the safety factor in the second coating is at least one of an organic base or an inorganic weak base, in which case the pKb value corresponding to the organic base, the inorganic weak base, or the combination of an inorganic weak base and an organic base is greater than 1. In the present invention, the dissociation constant pKa value corresponding to the anion of the inorganic weak acid salt can be further greater than 4, 4.25, 4.5, 4.75, or 5; the pKb value corresponding to the organic base, the inorganic weak base, or the combination of an inorganic weak base and an organic base can be further greater than 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, or 3.75. The pKa and pKb values ​​of the safety factor can regulate the release rate of degradation products of the first coating and, when the medical device coating provided herein also includes a polymer or drug coating, can also regulate the release rate of the drug. This helps control the release rate of the degradation products of the first coating within an optimal range, while also controlling the release rate of the drug within a relatively optimal range, thereby effectively inhibiting the proliferation of tissue near the device.

[0027] Furthermore, the first coating layer has a higher density and / or a higher hardness than the second coating layer. In some embodiments of the present invention, the first coating layer has a higher density than the second coating layer; in other embodiments of the present invention, the first coating layer has a higher hardness than the second coating layer; in still other embodiments of the present invention, the first coating layer has both a higher density and a higher hardness than the second coating layer.

[0028] In the above-mentioned technical solution provided by the present invention, the crystallinity of the first coating is greater than or equal to 50%. By controlling the overall crystallinity of the coating, the release rate of the coating itself can be effectively controlled. Therefore, the crystallinity of the first coating in the present invention is generally controlled to be above 50%. Furthermore, the crystallinity of the first coating in the present invention is generally controlled to be above 55%, 60%, 65%, 70%, or 75%. Furthermore, the crystallinity of the first coating in the present invention can even be controlled to be greater than or equal to 80%, thereby minimizing the concentration of degradation products of the first coating retained near the device.

[0029] In the above-mentioned technical solution provided by the present invention, the second coating layer can be crystalline, amorphous, or a mixture of the two. Furthermore, the crystallinity of the second coating layer can be greater than or equal to 0%. In other words, there is no specific requirement for the crystallinity of the second coating layer in this application; the effect of the second coating layer on the degradation of other coating layers can be comprehensively controlled by combining the crystallinity and coating thickness. The higher the crystallinity of the second coating layer, the slower its degradation rate. In the present invention, the crystallinity of the second coating layer can be controlled to control its release rate in the physiological fluid environment of the body, thereby improving its control over the degradation of the first coating layer and reducing the amount of the coating layer used. Therefore, in the present invention, the crystallinity of the second coating layer is generally controlled to be 1% or above; in the present invention, the crystallinity of the second coating layer is further controlled to be 10%, 20%, 30%, 40%, 48%, 55%, 60%, 65%, 70%, or even above 75%; further, the crystallinity of the second coating layer can even be controlled to be above 80% or 90%.

[0030] In some embodiments of the present invention, the crystallinity of the first coating layer is higher than that of the second coating layer; in other embodiments of the present invention, the crystallinity of the first coating layer is equal to that of the second coating layer; in still other embodiments of the present invention, the crystallinity of the first coating layer is less than that of the second coating layer.

[0031] In the above technical solution provided by the present invention, the content of the corrosion retarder in the first coating layer is greater than or equal to 20% wt.; further, the content of the corrosion retarder in the first coating layer is greater than or equal to 25% wt., 30% wt., 35% wt., 40% wt., 45% wt., or 50% wt.; further, the content of the corrosion retarder in the second coating layer is greater than or equal to 55% wt., 60% wt., 70% wt., 75% wt., 80% wt., 85% wt., 95% wt., or 99% wt. In the present invention, the mass content of the corrosion retarder in the first coating layer can be any value greater than 20%. The higher the content of the corrosion retarder, the lower the content of other components in the first coating layer, such as binders, thickeners, and other additives or some alloying elements. When the mass content of the main component reaches 100%, it can be considered that there are no other additives, impurities, or alloying elements.

[0032] According to the above technical solution, the safety factor content in the second coating layer is ≥ 10% wt., that is, the safety factor content in the second coating layer is 10% wt. to 100% wt. by weight. Since a relatively effective cytotoxicity reduction effect is achieved only when the safety factor content reaches a certain level, when the safety factor content in the second coating layer is less than 10% by weight, the cytotoxicity reduction effect may be poor due to the low safety factor content. Furthermore, the safety factor content in the second coating layer is 15% wt. to 100% wt., 20% wt. to 100% wt., or 30% wt. to 100% wt.; further, the safety factor content in the second coating layer is 35% wt. to 100% wt., 45% wt. to 100% wt., 55% wt. to 100% wt., 60% wt. to 100% wt., 65% wt. to 100% wt., or 90% wt. to 100% wt. The safety factor content of the second coating layer in the present invention can be any value above 10% wt., 15% wt., 18% wt., or 25% wt. In some embodiments of the present invention, the safety factor content of the second coating layer is 12% wt., 18% wt., 25% wt., 28% wt., 30% wt., 32.5% wt., 37.5% wt., 40% wt., 42.5% wt., 45% wt., 47.5% wt., 50% wt., or 52.5% wt. , 55% wt., 57.5% wt., 60% wt., 62.5% wt., 65% wt., 67.5% wt., 70% wt., 72.5% wt., 75% wt., 77.5% wt. or 80% wt.; in some other embodiments of the present invention, the content of the safety factor in the second coating is 82.5% wt., 85% wt., 87.5% wt., 90% wt., 92.5% wt., 95% wt., 97.5% wt. or 100% wt.

[0033] In the above technical solution provided by the present invention, when the content of the safety factor in the second coating is lower, the content of the additive is higher; when the content of the safety factor in the second coating is higher, the content of the additive is lower; when the content of the safety factor in the second coating is 100%, it can be considered that there are no other additives.

[0034] "Additives" in the present invention include, but are not limited to, binders and thickeners. In one embodiment of the present invention, the binder and thickener can enhance the film-forming effect of the safety factor in the second coating. The binder is selected from at least one of polyethylene glycol, polyvinyl alcohol, starch, cyclodextrin, or a water-soluble inorganic salt; the thickener is selected from at least one of gelatin, polyvinyl pyrrolidone (PVP), or sodium carboxymethyl cellulose (CMC).

[0035] It should be noted that the content of a component in a coating refers to the percentage of that component in the coating that plays a key role. In this invention, "content" generally refers to mass content, that is, the proportion of a component's mass in a coating or the entire device. For example, in a certain embodiment, when the component that plays a key role in corrosion retardation in the first coating is a certain metal element, the content of the corrosion retarder refers to the proportion of the mass of the metal element in the overall mass of the coating; in a certain embodiment, when the component that plays a key role in corrosion retardation in the first coating is an alloy of a certain metal element A, and the metal element A is the cause of the corrosion retardation effect, then the content of the corrosion retarder refers to the proportion of the mass of the metal element A in the overall mass of the coating; in a certain embodiment, when the component that plays a key role in reducing cytotoxicity is a certain compound or a certain part of a compound (such as an anion or a cation), then the content of the safety factor in a certain coating refers to the ratio of the mass of the compound to the overall mass of the coating; in some other embodiments, when the key role is played by the synergistic effect of multiple substances, then the content of a certain key component (such as the safety factor) in a certain coating refers to the ratio of the sum of the masses of these multiple substances to the overall mass of the coating.

[0036] Furthermore, in a certain embodiment, the first coating is an iron-zinc alloy, and the key element in the coating is zinc, that is, the main element in the alloy that plays a role in corrosion retardation / delay is zinc. In this case, the content of the corrosion retarder in the first coating refers to the ratio of the mass of zinc in the iron-zinc alloy to the total mass of the iron-zinc alloy in the entire first coating; in another embodiment, the second coating is phosphate, and the key element is phosphate. In this case, the content of the main component refers to the ratio of the mass of phosphate to the overall mass of the second coating.

[0037] In the above-mentioned solution provided by the present invention, the moisture content of the first coating layer is less than or equal to 5% wt. Further, the moisture content of the first coating layer is less than or equal to 4% wt.; further, the moisture content of the first coating layer is less than or equal to 3% wt.; further, the moisture content of the first coating layer is less than or equal to 2% wt.; further, the moisture content of the first coating layer is less than or equal to 1% wt.; further, the moisture content of the first coating layer is less than or equal to 0.5% wt.; further, the moisture content of the first coating layer is less than or equal to 0.2% wt. In some embodiments of the present invention, the moisture content in the first coating is 4.5% wt., 4% wt., 3.5% wt., 2.5% wt., 2% wt., 1.5% wt., 1% wt., 0.5% wt., 0.2% wt. or 0.1% wt.; in other embodiments of the present invention, the moisture content in the first coating is 4.8% wt., 4.2% wt., 3.8% wt., 3.2% wt., 2.8% wt., 2.2% wt. t., 1.8%wt., 1.25%wt., 0.9%wt., 0.8%wt., 0.7%wt., 0.6%wt., 0.4%wt., 0.3%wt., 0.2%wt., 0.1%wt. , 0.08%wt., 0.06%wt., 0.05%wt., 0.04%wt., 0.03%wt., 0.02%wt., 0.01%wt., 0.002%wt. or 0.001%wt.

[0038] In the above technical solution provided by the present invention, the thickness of the second coating is 0.01-20 μm 。 Furthermore, the thickness of the second coating is 0.01-5.5 μm. When the thickness of the second coating is less than 0.01 μm, the amount of the safety factor is too small to effectively play the corresponding role; when the thickness of the second coating is greater than 20 μm, the coating thickness is too thick, resulting in the implant device being too large and having little practical application value. In addition, when the coating thickness is too thick, it will also affect the effect of reducing cytotoxicity. Furthermore, the thickness of the second coating is 0.1-10 μm or 0.1-5 μm; furthermore, the thickness of the second coating is 0.2-4 μm, 0.5-3.5 μm, 0.8-3 μm or 0.8-2 μm. When the thickness of the second coating in the present invention is moderate, the process difficulty coefficient of the entire coating is small, and the effect of reducing cytotoxicity is also better.

[0039] Furthermore, the second coating provided by the present invention has a relatively uniform thickness, with a thickness variation of less than 1 micron across the entire coating. Furthermore, the thickness variation of the second coating is less than 0.5 microns; and even more preferably, the thickness variation of the second coating is less than 0.2 microns. The more uniform the thickness of the second coating, the better it inhibits tissue proliferation and also helps improve the uniformity of corrosion on the device substrate.

[0040] It should be noted that the “thickness difference” here refers to the difference between the thickness of the thickest part and the thickness of the thinnest part of the coating.

[0041] Furthermore, the thickness of the first coating is 0.05-25 μm. When the thickness of the first coating is too thin, less than 0.05 μm, the corrosion-retarding effect is not significant, and it cannot ensure that the device will not degrade or degrade slowly during the healing period of the lesion, thereby having better mechanical properties. When the thickness of the first coating is greater than 25 μm, on the one hand, the overall size of the implanted device and the amount of material used are too large, affecting the overall mechanical properties and delivery performance of the device. On the other hand, it is easy to cause the matrix to not be quickly degraded and absorbed after the lesion has healed, and furthermore, it will affect the safety of the tissue surrounding the device. Further, the thickness of the first coating in the present invention is 0.05-20μm, 0.05-15μm, 0.05-10μm, 0.05-8μm, 0.05-6μm, 0.05-5μm, 0.05-4μm; further, the thickness of the first coating in the present invention is 0.4-20μm, 0.4-15μm, 0.4-10μm, 0.4-8μm, 0.4-6μm, 0.4-5μm, 0.4-4μm; further, the thickness of the first coating in the present invention is 0.5-20μm, 0.5-15μm, 0.5-10μm, 0.5-8μm, 0.5-6μm, 0.5-5μm, 0.5-4μm.

[0042] Furthermore, the thickness of the second coating layer is 0.01-20 μm. Furthermore, the thickness of the second coating layer is 0.01-15 μm, 0.01-10 μm, 0.01-8 μm, 0.01-6 μm, 0.01-5.5 μm, 0.01-5 μm, 0.01-4 μm; furthermore, the thickness of the second coating layer is 0.05-15 μm, 0.05-10 μm, 0.05-8 μm, 0.05-6 μm, 0.05-5.5 μm, 0.05-5 μm, 0.05-4 μm.

[0043] According to the above technical solution provided, the mass ratio of the second coating layer to the first coating layer is [0.01, 10]:1.

[0044] Unless otherwise specified, the "thickness of the coating" in the present invention refers to the average thickness of the coating.

[0045] In the above technical solution provided by the present invention, the metallic activity of at least one metal element in the corrosion retarder of the first coating layer is greater than or equal to Fe. For example, when the first coating layer is a metal alloy, at least one metal element in the alloy is more active than iron.

[0046] In the above technical solution provided by the present invention, the corrosion retarder includes at least one of pure zinc, zinc alloy, zinc-containing compound, pure magnesium, magnesium alloy, pure aluminum, aluminum alloy, and aluminum-containing compound; the safety factor in the second coating includes at least one of weak acid salts and weak inorganic bases.

[0047] In the above technical solution provided by the present invention, the weak acid salt includes at least one of carbonate, basic carbonate, bicarbonate, phosphate, metaphosphate, monohydrogen phosphate, dihydrogen phosphate, oxalate, hydrogen oxalate, sulfite, ethylenediaminetetraacetate, benzoate, sorbate, chlorosorbate, borate, silicate, metasilicate, citrate, metaphosphite, pyrophosphate, monohydrogen pyrophosphate, polyphosphate, polyhydrogen phosphate, hydrogen citrate, carboxylate, and glycerophosphate; and the weak inorganic base includes at least one of calcium hydroxide, aluminum hydroxide, zinc hydroxide, metaaluminate, monohydrogen phosphate, and sulfide.

[0048] Furthermore, the weak acid salt is at least one of a sodium salt, a potassium salt, a calcium salt, a magnesium salt, and a zinc salt. The carbonate salt of the present invention is at least one selected from the group consisting of sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, zinc carbonate, basic zinc carbonate, sodium bicarbonate, potassium bicarbonate, magnesium bicarbonate, and calcium bicarbonate; and the phosphate salt is at least one selected from the group consisting of sodium phosphate, potassium phosphate, magnesium phosphate, calcium phosphate, zinc phosphate, sodium monohydrogen phosphate, potassium monohydrogen phosphate, magnesium monohydrogen phosphate, calcium monohydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, magnesium dihydrogen phosphate, and calcium dihydrogen phosphate.

[0049] In the above technical solution provided by the present invention, the second coating covers at least 50% of the surface of the first coating. In some embodiments of the present invention, the second coating covers more than 55% or 60% of the surface of the first coating; in other embodiments of the present invention, the second coating covers more than 65% or 70% of the surface of the first coating; in other embodiments of the present invention, the second coating covers more than 75% or 80% of the surface of the first coating; further, the second coating covering the surface of the first coating here refers to covering the outer surface of the first coating. The proportion of the second coating covering the surface of the first coating will directly affect the release rate of the first coating and thus improve the effect of inhibiting tissue proliferation near the device.

[0050] Furthermore, the particle size of the safety factor in the second coating layer is less than or equal to 1000 nm. In some embodiments of the present invention, the particle size of the safety factor in the second coating layer is 1-100 nm; in other embodiments of the present invention, the particle size of the safety factor in the second coating layer is 100-250 nm; in other embodiments of the present invention, the particle size of the safety factor in the second coating layer is 250-500 nm; in still other embodiments of the present invention, the particle size of the safety factor in the second coating layer is 500-1000 nm. The particle size of the safety factor not only affects its own release rate, but also affects the degradation rate of other coatings.

[0051] In the above technical solution provided by the present invention, the coating further comprises a degradable polymer layer disposed outside the second coating layer; the total thickness of the degradable polymer layer is 1-30 μm. Furthermore, the total thickness of the degradable polymer layer is 2-25 μm, 5-25 μm, 10-25 μm, or 10-20 μm. The degradable polymer layer comprises a degradable polymer selected from at least one of degradable polyesters, degradable polyanhydrides, degradable polyamino acids, and binary or multi-component degradable copolymers formed by copolymerizing monomers corresponding to degradable polyesters, degradable polyanhydrides, and degradable polyamino acids, as well as derivatives thereof. In some embodiments of the present invention, the degradable polymer may be any one or more of degradable polyesters, degradable polyanhydrides, and degradable polyamino acids; it may also be at least one of a binary or multi-degradable copolymer and a derivative thereof copolymerized with monomers corresponding to degradable polyesters, degradable polyanhydrides, and degradable polyamino acids; it may also be a combination of at least one of a degradable polyester, a degradable polyanhydride, and a degradable polyamino acid and at least one of a binary or multi-degradable copolymer and a derivative thereof copolymerized with monomers corresponding to degradable polyesters, degradable polyanhydrides, and degradable polyamino acids.

[0052] Furthermore, the degradable polymer included in the degradable polymer layer of the present invention may be one type or a mixture of two or more types.

[0053] In some embodiments of the present invention, the degradable polymer is one or more degradable polyesters; in some embodiments of the present invention, the degradable polymer is one or more degradable polyanhydrides; in some embodiments of the present invention, the degradable polymer is a binary or multi-component degradable copolymer formed by the monomers of two or more degradable polyesters; in other embodiments of the present invention, the degradable polymer is a binary or multi-component degradable copolymer formed by the copolymerization of monomers of two or more degradable polyanhydrides; in other embodiments of the present invention, the degradable polymer is a binary or multi-component degradable copolymer formed by the copolymerization of monomers of at least one degradable polyester and at least one degradable polyanhydride; in other embodiments of the present invention, the degradable polymer includes at least two of the following: degradable polyesters, degradable polyanhydrides, degradable polyamino acids, copolymers formed by monomers of degradable polyesters and / or degradable polyanhydrides, that is, in some embodiments of the present invention, the degradable polymer includes both degradable polyesters and degradable polyanhydrides; in some embodiments of the present invention, it includes both degradable polyesters and degradable polyanhydrides, and copolymers formed by monomers of degradable polyesters and / or degradable polyanhydrides.

[0054] It should be noted that the "binary or multi-component degradable copolymer formed by copolymerization of monomers of degradable polyester and / or degradable polyanhydride" can be a binary or multi-component degradable copolymer formed by copolymerization of monomers of two or more degradable polyesters, a binary or multi-component degradable copolymer formed by copolymerization of monomers of two or more degradable polyanhydrides, or a binary or multi-component degradable copolymer formed by copolymerization of at least one monomer of a degradable polyester and at least one monomer of a degradable polyanhydride.

[0055] Furthermore, the degradable polyester in the present invention is selected from at least one of polylactic acid, polyglycolic acid, polylactic glycolic acid, polycaprolactone, polyhydroxyalkanoate, polyacrylate, polysuccinate, poly(β-hydroxybutyrate), polyethylene adipate, and polyhydroxybutyrate valerate copolymer; the degradable polyanhydride is selected from at least one of poly 1,3-bis(p-carboxyphenoxy)propane-sebacic acid, polyerucic acid dimer-sebacic acid, or polyfumaric acid-sebacic acid; the degradable polyamino acid includes at least one of polyglycine, polyalanine, polyvaline, polyleucine, polyisoleucine, polymethionine, polyproline, polytryptophan, polyserine, polytyrosine, polycysteine, polyphenylalanine, polyasparagine, polyglutamine, polythreonine, polyarginine, polyhistidine, polyselenocysteine, polypyrroline, polyglutamic acid, polyaspartic acid, polyornithine, polylysine, and derivatives thereof.

[0056] Furthermore, the degradable polymer layer includes an active drug, and the degradable polymer layer can release the active drug during the degradation process. The active drug is selected from at least one of drugs that inhibit angiogenesis, antiplatelet drugs, antithrombotic drugs, anti-inflammatory drugs, and anti-allergic drugs; wherein the drug that inhibits angiogenesis includes at least one of paclitaxel, rapamycin and its derivatives; the antiplatelet drug includes cilostazol; the antithrombotic drug includes heparin; the anti-inflammatory drug includes dexamethasone; and the anti-allergic drug includes at least one of calcium gluconate, chlorpheniramine and cortisone.

[0057] When a polymer drug coating is present in the coating provided by the present invention, the second coating can also regulate the release of the active drug, effectively regulating the release rate of the drug in the early and late stages, so that the amount of drug near the device can be maintained within a range that effectively inhibits tissue proliferation.

[0058] In the above-mentioned technical solutions provided by the present invention, the drug can be evenly distributed in the degradable polymer layer or unevenly distributed in the polymer layer. For example, in some embodiments, the polymer layer is a single layer, and the drug is substantially evenly distributed in the polymer coating. In other embodiments, the drug is encapsulated in the middle of the polymer layer, i.e., the upper and lower layers are the polymer coating, and the middle layer is the drug layer. In other embodiments, the polymer layer is divided into three layers, and the drug is primarily or entirely distributed in the polymer layer located in the middle. In other embodiments, the polymer layer is divided into two layers, and the drug is primarily or entirely dispersed in the layer closest to the device substrate. In still other embodiments, the polymer layer is divided into four layers, and the drug is primarily or entirely dispersed in the middle two layers or the bottom three layers.

[0059] The degradable polymer coating of the present invention can comprehensively regulate the degradation of the device substrate, primary coating, secondary coating, and drug. The degradation of the degradable polymer coating can drive drug release, while its degradation products can also promote / accelerate the corrosion / degradation of the substrate, primary coating, and secondary coating.

[0060] It should be noted that the "alloy" in the present invention refers to a mixture of a certain metal and other metals and / or non-metals, and the type, quantity, and content of the other metal elements or non-metal elements are not limited. Furthermore, the "alloy" in the present invention is an alloy in which the content of the metal element is greater than or equal to 0.25%. For example, the ferroalloy described in the present invention refers to a mixture of iron metal and other metal elements or non-metal elements, and the mass / volume content of the iron element in the alloy is greater than or equal to 0.25%. Furthermore, the iron alloys in the present application include, but are not limited to, iron-manganese alloys, iron-zinc alloys, iron-magnesium alloys, iron-calcium alloys, iron-zirconium alloys, iron-manganese-carbon alloys, iron-molybdenum alloys, iron-manganese-copper alloys, iron-manganese-silicon-carbon alloys, iron-silicon-manganese alloys, iron-copper alloys, iron-copper-manganese-carbon alloys, iron-gold alloys, iron-silver alloys, iron-manganese-silver alloys, iron-magnesium alloys, iron-hydrogen alloys, iron-phosphorus alloys, iron-sulfur alloys, iron-boron alloys, iron-titanium alloys, iron-titanium-carbon alloys, iron-carbon alloys, iron-manganese-nitrogen alloys, iron-nitrogen alloys, iron-manganese-carbon-nitrogen alloys, and the like. In addition, the iron content in the iron alloys may be 1.5%, 5%, 10%, 95%, or even 99.5%. For another example, zinc alloys include, but are not limited to, zinc-aluminum alloys, zinc-silver alloys, zinc-iron alloys, zinc-copper alloys, and zinc-iron-calcium alloys; and for another example, magnesium alloys include, but are not limited to, magnesium-manganese alloys, magnesium-zinc alloys, magnesium-aluminum alloys, and magnesium-iron alloys.

[0061] On the other hand, the present invention also provides a medical device, which includes any of the aforementioned coatings and a substrate. Furthermore, the substrate is a degradable substrate; further, the substrate is a degradable metal substrate; further, the electronegativity of the degradable metal substrate is higher than the electronegativity of the first coating; further, the degradable metal substrate is a degradable iron substrate, and the degradable iron substrate is one of pure iron or an iron alloy. The present invention uses the coating provided by the above technical solution on a degradable metal substrate. On the one hand, it can control the degradation of the degradable metal substrate so that it does not degrade or degrades less in the early stage and degrades rapidly in the late stage. At the same time, it can also control the release amount of the cell-toxic components in the coating and the retained concentration of its products around the device within a relatively safe range, thereby reducing the toxicity of the degradation products of the coating to the tissues around the device and ultimately reducing the severity of tissue hyperplasia, fever, thrombosis and inflammation of the device, thereby improving the safety and effectiveness of the device. In addition, the above coating can be combined with the drug release rate to control adverse reactions such as proliferation of tissues around the device, and ultimately effectively reduce the device's lumen stenosis rate, intimal hyperplasia rate, etc., thereby improving the device's effectiveness.

[0062] In the coating provided in this application, each layer of coating interacts with each other, regulating or affecting the degradation or release rate of other coatings, and ultimately achieving an effect with relatively good comprehensive performance. Furthermore, the coating provided in this application interacts with the substrate. While regulating the degradation of the substrate, the coating also ensures that the concentration released by the components of the coating itself is always within a safe range, which can not only ensure that the substrate is not corroded or less corroded in the first 3-6 months and has good mechanical properties, but also ensure that the entire device has the characteristics of good safety and effectiveness. In addition, the substrate also cooperates with some coatings to control the release rate of other coatings, further improving the safety and effectiveness of the entire device.

[0063] The coating of the present invention can be applied to a variety of medical devices, including vascular stents, orthopedic implants, gynecological implants, andrological implants, or respiratory implants. The device is formed by applying the coating of the present invention to its substrate. Furthermore, the medical device is a biodegradable medical device; further, the medical device is a magnesium-based, zinc-based, or iron-based medical device; and further, the substrate of the medical device is at least one of pure magnesium, a magnesium alloy, pure zinc, a zinc alloy, pure iron, or an iron alloy.

[0064] It should be noted that "A / B" in the present invention represents A or B, and "A and / or B" represents A and B or A or B. For example, "retention concentration / retention amount" represents retention concentration or retention amount, and so on.

[0065] Pure metal in this application means that the total content of other impurities in the metal is less than or equal to 0.5 wt.%. For example, pure iron means that the total amount of other metals and / or non-metals other than iron in the metal is less than or equal to 0.5 wt.%.

[0066] The medical devices in the present invention include at least one of a luminal stent, an occluder, a gasket, an artificial blood vessel, a dental implant, a vascular clamp, a dental implant, a suture, a gynecological implant, an andrological implant, a respiratory implant or an orthopedic implant; the orthopedic implant includes at least one of a bone screw, a bone plate, a joint, an intramedullary nail, an anchor, a bolt, and an intervertebral fusion device; the luminal stent includes at least one of a vascular stent, a tracheal stent, a urethral stent, a neural stent, a biliary stent, an esophageal stent, an intestinal stent, and a pancreatic stent; the vascular stent includes stents used in all blood vessels, including but not limited to stents for heart valves, coronary stents, pulmonary artery stents, covered stents, peripheral stents, vertebral artery stents, and renal artery stents. BRIEF DESCRIPTION OF THE DRAWINGS

[0067] FIG1 is a schematic diagram of a medical device according to Example 7, wherein 10 is a metal substrate, 11 is a first coating, and 12 is a second coating located on the first coating.

[0068] FIG2 is a schematic diagram of the medical device of Example 1, wherein 10 is a metal substrate, 11 is a first coating, 12 is a second coating located on the first coating, and 13 is a degradable polymer layer located on the second coating.

[0069] FIG3 is an OCT image of the medical device of Example 6 implanted in a dog's coronary artery 2 months later.

[0070] FIG4 is a schematic diagram of the medical device of Comparative Example 1, wherein 10 is a metal substrate; 11 is a first coating. DETAILED DESCRIPTION

[0071] To make the above-mentioned objects, features, and advantages of the present invention more readily apparent, specific embodiments of the present invention are described in detail below with reference to the accompanying drawings. The following description sets forth numerous specific details to facilitate a full understanding of the present invention. However, the present invention can be implemented in many other ways than those described herein, and those skilled in the art may make similar modifications without departing from the scope of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0072] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in this specification of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0073] Test Method

[0074] The test / characterization methods of various parameters in the present invention are as follows:

[0075] 1. Coating particle size test method

[0076] The particle size of the coating is tested using a scanning electron microscope. If there is a polymer coating on the coating, it is necessary to first soak it in an organic solvent to remove the polymer and then test the particle size of the coating.

[0077] 2. Test method for coating thickness

[0078] The coating thickness was measured using a scanning electron microscope. The device was first embedded and fixed with resin, and then a cross section was cut along the axial direction. The coating thickness was observed using a scanning electron microscope on this section.

[0079] 3. Stenosis rate detection method:

[0080] Vascular stents were implanted into the blood vessels of experimental animals, and the vascular lumen area was measured using optical coherence tomography (OCT) at time zero and at follow-up time points. Stenosis rate = (lumen area at time zero - lumen area at follow-up) / lumen area at time zero × 100%.

[0081] Example 1

[0082] A pure iron-based vascular stent has a first coating of an iron-zinc alloy with a zinc content of 20 wt.%, a crystallinity of 100%, and a thickness of 1 micron. A second coating of sodium bicarbonate with a sodium bicarbonate content of 100 wt.%, a crystallinity of 50%, a particle size of 100 nm, and a thickness of 0.1 micron. The second coating covers 80% of the first coating surface. The second coating is topped with a polylactic acid coating with a molecular weight of 200,000 and a thickness of 10 microns. After implantation in a dog's coronary artery, optical coherence tomography (OCT) measurements showed a stenosis rate of 20% after two months.

[0083] Example 2

[0084] A nitrided iron-based intestinal stent has a first coating of an iron-manganese alloy with a manganese content of 50 wt.%, a crystallinity of 100%, and a thickness of 8 microns. A second coating of zinc carbonate-sodium carboxymethylcellulose has a zinc carbonate content of 50 wt.%, a crystallinity of 100%, a particle size of 1 micron, and a thickness of 5 microns. The second coating covers 50% of the first coating surface. The second coating is topped with a polylactic acid coating with a molecular weight of 200,000 and a thickness of 10 microns. Implanted in a dog's coronary artery, the stenosis rate measured by optical coherence tomography (OCT) after two months was 20%.

[0085] Example 3

[0086] A nitrided iron-based vascular stent, wherein the first coating is a zinc single layer, wherein the zinc content is 100wt.%, the crystallinity is 100%, and the thickness is 1 micron. The second coating is a sodium bicarbonate-polyvinyl alcohol coating, wherein the sodium bicarbonate content is 50wt.%, the crystallinity is 10%, the particle size is 10nm, and the thickness is 2 microns. The second coating covers 100% of the surface of the first coating. The second coating has a sirolimus-polylactic acid coating, wherein the mass ratio of sirolimus to polylactic acid is 1:5, the molecular weight of polylactic acid is 200,000, and the coating thickness is 10 microns. Implanted in a dog's coronary artery, the stenosis rate measured by optical coherence tomography (OCT) after 2 months was 8%.

[0087] Example 4

[0088] A nitrided iron-based vascular stent, wherein the first coating is a single zinc layer, wherein the zinc content is 100wt.%, the crystallinity is 100%, and the thickness is 1 micron. The second coating is a sodium bicarbonate layer, wherein the sodium bicarbonate content is 100wt.%, the crystallinity is 100%, the particle size is 100nm, and the thickness is 1 micron. The second coating covers 100% of the surface of the first coating. The second coating has a sirolimus-polylactic acid coating, wherein the mass ratio of sirolimus to polylactic acid is 1:5, the molecular weight of the polylactic acid is 200,000, and the coating thickness is 10 microns. Implanted in a dog's coronary artery, the stenosis rate measured by optical coherence tomography (OCT) after 2 months was 8%.

[0089] Example 5

[0090] A nitrided iron-based vascular stent, wherein the first coating is a zinc single layer, wherein the zinc content is 100wt.%, the crystallinity is 90%, and the thickness is 0.5 microns. The second coating is a potassium dihydrogen phosphate layer, wherein the potassium dihydrogen phosphate content is 100wt.%, the crystallinity is 70%, the particle size is 100nm, and the thickness is 2 microns. The second coating covers 100% of the surface of the first coating. The second coating has a sirolimus-polylactic acid coating, wherein the mass ratio of sirolimus to polylactic acid is 1:5, the molecular weight of polylactic acid is 200,000, and the coating thickness is 10 microns. Implanted in a dog's coronary artery, the stenosis rate measured by OCT after 2 months was 12%.

[0091] Example 6

[0092] A nitrided iron-based neural stent, wherein the first coating is a zinc alloy-zinc oxide layer, wherein the zinc content is 70wt.%, the crystallinity is 80%, and the thickness is 5 microns. The second coating is a zinc phosphate-cyclodextrin layer, wherein the zinc phosphate content is 20wt.%, the crystallinity is 90%, the particle size is 1 micron, and the thickness is 15 microns. The second coating covers 100% of the surface of the first coating. The second coating has a sirolimus-polylactic acid coating, wherein the mass ratio of sirolimus to polylactic acid is 1:5, the molecular weight of polylactic acid is 200,000, and the coating thickness is 10 microns. Implanted in a dog's coronary artery, the stenosis rate measured by OCT after 2 months was 10%.

[0093] Example 7

[0094] A nitrided iron-based biliary stent has a primary coating consisting of a single aluminum layer with an aluminum content of 100 wt.%, a crystallinity of 50%, and a thickness of 0.2 microns. A secondary coating consists of a calcium silicate-polyethylene glycol layer with a calcium silicate content of 40 wt.%, a crystallinity of 30%, a particle size of 200 nm, and a thickness of 8 microns. The secondary coating covers 100% of the primary coating. Implanted in a dog's coronary artery, the stenosis rate measured by optical coherence tomography (OCT) at two months was 20%.

[0095] Example 8

[0096] A nitrided iron-based esophageal stent has a primary coating consisting of a magnesium-copper alloy layer with an 80 wt.% magnesium content, 50% crystallinity, and a thickness of 10 microns. The secondary coating consists of a zinc hydroxide-starch layer with a 10 wt.% zinc hydroxide content, 0% crystallinity, a particle size of 200 nm, and a thickness of 10 microns. The secondary coating covers 60% of the primary coating. After implantation in a dog's coronary artery, optical coherence tomography (OCT) measurements at two months revealed a 20% stenosis rate.

[0097] Example 9

[0098] A tracheal stent with an Fe-Mn alloy matrix, wherein the first coating is a magnesium-aluminum alloy layer, wherein the magnesium content is 90wt.%, the crystallinity is 100%, and the thickness is 25 microns. The second coating is a potassium aluminate-starch layer, wherein the potassium aluminate content is 30wt.%, the crystallinity is 80%, the particle size is 250nm, and the thickness is 20 microns. The second coating covers 90% of the surface of the first coating. The second coating has a sirolimus-polylactic acid coating, wherein the mass ratio of sirolimus to polylactic acid is 1:5, the molecular weight of polylactic acid is 200,000, and the coating thickness is 10 microns. Implanted in a dog's coronary artery, the stenosis rate measured by optical coherence tomography (OCT) after 2 months was 18%.

[0099] Example 10

[0100] A nitrided iron-based vascular stent, wherein the first coating is a single zinc layer, wherein the zinc content is 100wt.%, the crystallinity is 100%, and the thickness is 0.6 microns. The second coating is a zinc carbonate layer, wherein the zinc content is 100wt.%, the crystallinity is 80%, the particle size is 50nm, and the thickness is 0.2 microns. The second coating covers 100% of the surface of the first coating. The second coating has a sirolimus-polylactic acid coating, wherein the mass ratio of sirolimus to polylactic acid is 1:5, the molecular weight of the polylactic acid is 200,000, and the coating thickness is 10 microns. Implanted in a dog's coronary artery, the stenosis rate measured by optical coherence tomography after 2 months was 6%.

[0101] Example 11

[0102] A nitrided iron-based vascular stent, wherein the first coating is a zinc single layer, wherein the zinc content is 100wt.%, the crystallinity is 100%, and the thickness is 0.8 microns. The second coating is a zinc carbonate layer, wherein the zinc carbonate content is 100wt.%, the crystallinity is 100%, the particle size is 100nm, and the thickness is 0.01 microns. The second coating covers 100% of the surface of the first coating. The second coating has a sirolimus-polylactic acid coating, wherein the mass ratio of sirolimus to polylactic acid is 1:5, the molecular weight of polylactic acid is 200,000, and the coating thickness is 10 microns. Implanted in a dog's coronary artery, the stenosis rate measured by optical coherence tomography (OCT) after 2 months was 10%.

[0103] Example 12

[0104] A nitrided iron-based vascular stent, wherein the first coating is a zinc single layer, wherein the zinc content is 100wt.%, the crystallinity is 100%, and the thickness is 0.8 microns. The second coating is a magnesium-containing layer, wherein the magnesium content is 100wt.%, the crystallinity is 100%, the particle size is 100nm, and the thickness is 2 microns. The second coating covers 100% of the surface of the first coating. The second coating has a sirolimus-polylactic acid coating, wherein the mass ratio of sirolimus to polylactic acid is 1:5, the molecular weight of polylactic acid is 200,000, and the coating thickness is 10 microns. Implanted in a dog's coronary artery, the stenosis rate measured by optical coherence tomography (OCT) after 2 months was 15%.

[0105] Example 13

[0106] A nitrided iron-based vascular stent, wherein the first coating is a magnesium-sodium carboxymethylcellulose layer, wherein the magnesium content is 40wt.%, the crystallinity is 100%, and the thickness is 3 microns. The second coating is a calcium silicate-sodium carboxymethylcellulose layer, wherein the calcium silicate content is 40wt.%, the crystallinity is 30%, the particle size is 200nm, and the thickness is 8 microns. The second coating covers 100% of the surface of the first coating. The second coating has a sirolimus-polylactic acid coating, wherein the mass ratio of sirolimus to polylactic acid is 1:5, the molecular weight of polylactic acid is 200,000, and the coating thickness is 10 microns. Implanted in a dog's coronary artery, the stenosis rate measured by OCT after 2 months was 15%.

[0107] Example 14

[0108] A vascular stent with an iron-calcium alloy matrix, wherein the first coating is a zinc hydroxide-polyethylene glycol layer, wherein the zinc content is 50wt.%, the crystallinity is 60%, and the thickness is 0.3 microns. The second coating is a sodium bicarbonate layer, wherein the sodium bicarbonate content is 100wt.%, the crystallinity is 50%, the particle size is 100nm, and the thickness is 3 microns. The second coating covers 100% of the surface of the first coating. The second coating has a sirolimus-polylactic acid coating, wherein the mass ratio of sirolimus to polylactic acid is 1:5, the molecular weight of the polylactic acid is 200,000, and the coating thickness is 10 microns. Implanted in a dog's coronary artery, the stenosis rate measured by optical coronary computed tomography (OCT) after 2 months was 7%.

[0109] Example 15

[0110] A nitrided iron-based pancreatic stent, wherein the first coating is a magnesium-containing layer, wherein the magnesium content is 100wt.%, the crystallinity is 100%, and the thickness is 3 microns. The second coating is a potassium dihydrogen phosphate layer, wherein the potassium dihydrogen phosphate content is 100wt.%, the crystallinity is 70%, the particle size is 100nm, and the thickness is 2 microns. The second coating covers 100% of the surface of the first coating. The second coating has a sirolimus-polylactic acid coating, wherein the mass ratio of sirolimus to polylactic acid is 1:5, the molecular weight of polylactic acid is 200,000, and the coating thickness is 10 microns. Implanted in a dog's coronary artery, the stenosis rate measured by OCT after 2 months was 15%.

[0111] Example 16

[0112] A vascular stent with an Fe-Mn-C alloy matrix, wherein the first coating is a basic copper carbonate-polyvinyl pyrrolidone layer, wherein the copper content is 30wt.%, the crystallinity is 80%, and the thickness is 0.2 microns. The second coating is a potassium dihydrogen phosphate layer, wherein the potassium dihydrogen phosphate content is 100wt.%, the crystallinity is 10%, the particle size is 10nm, and the thickness is 2 microns. The second coating covers 100% of the surface of the first coating. The second coating has a sirolimus-polylactic acid coating, wherein the mass ratio of sirolimus to polylactic acid is 1:5, the molecular weight of polylactic acid is 200,000, and the coating thickness is 10 microns. Implanted in a dog's coronary artery, the stenosis rate measured by OCT after 2 months was 15%.

[0113] Example 17

[0114] A nitrided iron-based vascular stent, wherein the first coating is a zinc single layer, wherein the zinc content is 100wt.%, the crystallinity is 100%, and the thickness is 1 micron. The second coating is a sodium bicarbonate layer, wherein the sodium bicarbonate content is 100wt.%, the crystallinity is 10%, the particle size is 10nm, and the thickness is 2 microns. The second coating covers 50% of the surface of the first coating. The second coating has a sirolimus-polylactic acid coating, wherein the mass ratio of sirolimus to polylactic acid is 1:5, the molecular weight of polylactic acid is 200,000, and the coating thickness is 10 microns. Implanted in a dog's coronary artery, the stenosis rate measured by optical coherence tomography (OCT) after 2 months was 18%.

[0115] Comparative Example 1

[0116] A pure iron-based vascular stent has a first coating of an iron-zinc alloy layer with a zinc content of 20 wt.%, a crystallinity of 100%, and a thickness of 1 micron. After implantation in a dog's coronary artery, optical coherence tomography (OCT) measurements showed a stenosis rate of 60% after two months.

[0117] Comparative Example 2

[0118] A nitrided iron-based vascular stent has a primary coating of elemental zinc with a zinc content of 100% by weight, a crystallinity of 100%, and a thickness of 1 micron. The primary coating is topped with a sirolimus-polylactic acid coating, with a sirolimus-to-PLA weight ratio of 1:5, a molecular weight of 200,000, and a coating thickness of 10 microns. After implantation in a dog's coronary artery, optical coherence tomography (OCT) measurements showed a stenosis rate of 40% after two months.

[0119] Comparative Example 3

[0120] A nitrided iron-based vascular stent, wherein the first coating is a single zinc layer, wherein the zinc content is 100wt.%, the crystallinity is 100%, and the thickness is 1 micron. The second coating is a sodium bicarbonate layer, wherein the sodium bicarbonate content is 100wt.%, the crystallinity is 10%, the particle size is 10nm, and the thickness is 0.001 micron. The second coating covers 100% of the surface of the first coating. The second coating has a sirolimus-polylactic acid coating, wherein the mass ratio of sirolimus to polylactic acid is 1:5, the molecular weight of the polylactic acid is 200,000, and the coating thickness is 10 microns. Implanted in a dog's coronary artery, the stenosis rate measured by optical coherence tomography (OCT) after 2 months was 35%.

[0121] Comparative Example 4

[0122] A nitrided iron-based vascular stent, wherein the first coating is a zinc single layer, wherein the zinc content is 100wt.%, the crystallinity is 100%, and the thickness is 0.1 micron. The second coating is a sodium bicarbonate layer, wherein the sodium bicarbonate content is 100wt.%, the crystallinity is 10%, the particle size is 10nm, and the thickness is 30 microns. The second coating covers 100% of the surface of the first coating. The second coating has a sirolimus-polylactic acid coating, wherein the mass ratio of sirolimus to polylactic acid is 1:5, the molecular weight of the polylactic acid is 200,000, and the coating thickness is 10 microns. Implanted in a dog's coronary artery, the stenosis rate measured by optical coherence tomography (OCT) after 2 months was 34%.

[0123] Comparative Example 5

[0124] A nitrided iron-based vascular stent has a primary coating consisting of a zinc-zinc oxide layer with a zinc content of 70 wt.%, a crystallinity of 80%, and a thickness of 5 microns. The primary coating also includes a sirolimus-polylactic acid coating, with a sirolimus to polylactic acid weight ratio of 1:5, a polylactic acid molecular weight of 200,000, and a coating thickness of 10 microns. After implantation in a dog's coronary artery, optical coherence tomography (OCT) measurements of stenosis at two months revealed a 37% rate.

[0125] Comparative Example 6

[0126] A zinc alloy-based vascular stent, comprising a substrate covered with a magnesium-containing layer having a magnesium content of 100 wt.%, a crystallinity of 100%, and a thickness of 3 microns. After implantation in a dog's coronary artery, optical coherence tomography (OCT) measurements revealed a stenosis rate of 45% after two months.

[0127] Comparative Example 7

[0128] A zinc alloy-based vascular stent, comprising a substrate covered with a sodium bicarbonate coating having a sodium bicarbonate content of 100 wt.%, a crystallinity of 10%, and a thickness of 2 microns. After implantation in a dog's coronary artery, optical coherence tomography (OCT) measurements at two months revealed a stenosis rate of 50%.

[0129] The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, not all possible combinations of the technical features in the above-mentioned embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0130] The above-described embodiments merely illustrate several implementations of the present invention, and while their descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the patent. It should be noted that a person skilled in the art would be able to make numerous variations and improvements without departing from the spirit of the present invention, all of which fall within the scope of protection of the present invention. Therefore, the scope of protection of the patent for this invention shall be determined by the appended claims.

Claims

1. A coating for a medical device, the coating comprising a first coating and a second coating from the inside to the outside, characterized in that, The first coating includes a corrosion retardant that can delay the corrosion of the instrument substrate, and the second coating includes a safety factor that improves the safety of the medical device.

2. The coating according to claim 1, characterized in that, The safety factor is soluble in an acidic solution; the first coating is an inorganic coating, and the second coating is an inorganic and / or organic coating.

3. The coating according to claim 1 or 2, characterized in that, The corrosion retardant and the safety factor are selected from elements, alloys or compounds including different metal elements; or the corrosion retardant and the safety factor are selected from elements, alloys or compounds including the same metal element.

4. The coating according to any one of claims 1 to 3, characterized in that, The corrosion retardant includes at least one of a metal element, a metal alloy, a metal oxide or an inorganic salt; the safety factor includes at least one of an inorganic salt, an organic base or an inorganic weak base.

5. The coating according to any one of claims 1-4, characterized in that, The corrosion retardant is mainly dissolved / released in a body fluid / physiological solution by an electrochemical method, and the safety factor is mainly dissolved / released in a body fluid / physiological solution by ionization or galvanic corrosion.

6. The coating according to any one of claims 1-5, characterized in that, At least one ion released by the safety factor forms an insoluble compound with at least one ion released by the corrosion retardant, and the solubility of the metal element in the insoluble compound in a physiological environment is less than 60 mg / L; or the solubility of the safety factor at 20 °C is less than 1.5 g / L.

7. The coating according to any one of claims 1 to 6, characterized in that The pKa of the safety factor > 3.86 or pKb > 1; the particle size of the safety factor is less than or equal to 1000 nm.

8. The coating according to any one of claims 1-7, characterized in that, The density of the first coating is higher than that of the second coating; the crystallinity of the first coating is higher than that of the second coating; the crystallinity of the first coating ≥ 50%.

9. The coating according to any one of claims 1 - 8, characterized in that, The content of the corrosion retardant in the first coating is greater than or equal to 20 wt.%; the content of the safety factor in the second coating is greater than or equal to 10 wt.%.

10. The coating according to any one of claims 1-9, characterized in that, The thickness of the first coating is 0.05 - 25 μm; the thickness of the second coating is 0.01 - 20 μm.

11. The coating according to any one of claims 1 to 10, characterized in that, The thickness of the first coating is 0.05 - 8 μm; the thickness of the second coating is 0.01 - 5.5 μm; the mass ratio of the second coating to the first coating is [0.01, 10]:

1.

12. The coating according to any one of claims 1-11, characterized in that, The metallic activity of at least one metal element in the first coating ≥ Fe.

13. The coating according to any one of claims 1-12, characterized in that, The corrosion retardant includes at least one of pure zinc, a zinc alloy, a zinc-containing compound, pure magnesium, a magnesium alloy, pure aluminum, an aluminum alloy, and an aluminum-containing compound; the safety factor includes at least one of weak acid salts and weak inorganic bases.

14. The coating according to any one of claims 1-13, characterized in that, The weak acid salts include at least one of phosphates, metaphosphates, monohydrogen phosphates, dihydrogen phosphates, oxalates, hydrogen oxalates, sulfites, ethylenediaminetetraacetates, benzoates, carbonates, bicarbonates, sorbates, sorbate chlorides, borates, silicates, metasilicates, citrates, metaphosphites, pyrophosphates, monohydrogen pyrophosphates, polyphosphates, polyhydrogen phosphates, hydrogen citrates, carboxylates, and glycerophosphates; the weak inorganic bases include at least one of calcium hydroxide, aluminum hydroxide, zinc hydroxide, aluminate, monohydrogen phosphate, and sulfide.

15. The coating according to any one of claims 1-14, characterized in that, The second coating covers at least 50% of the surface of the first coating.

16. The coating according to any one of claims 1 to 15, characterized in that, The coating further includes a degradable polymer layer disposed outside the second coating; the total thickness of the degradable polymer layer is 1-30 μm.

17. The coating according to any one of claims 1-16, characterized in that, The degradable polymer layer includes a degradable polymer selected from at least one of degradable polyesters, degradable polyanhydrides, degradable polyamino acids, and binary or multi-component degradable copolymers formed by copolymerizing monomers corresponding to the degradable polyesters, degradable polyanhydrides, and degradable polyamino acids. The degradable polyester is selected from at least one of polylactic acid, polyglycolic acid, polylactic acid-glycolic acid, polycaprolactone, polyhydroxy fatty acid ester, polyacrylate, polybutanedioate, poly(β-hydroxybutyrate), polyethylene adipate, and polyhydroxybutyrate valerate; the degradable polyanhydride is selected from at least one of poly(1,3-bis(p-carboxyphenoxy)propane-sebacate), polyerucic acid dimer-sebacate, or poly(fumaric acid-sebacate); the degradable polyamino acid includes at least one of polyglycine, polyalanine, polyvaline, polyleucine, polyisoleucine, polymethionine, polyproline, polytryptophan, polyserine, polytyrosine, polycysteine, poly(phenylalanine), polyasparagine, polyglutamine, polythreonine, polyarginine, polyhistidine, poly(selenocysteine), polypyrroline, polyglutamic acid, polyaspartic acid, polyornithine, polylysine, and their derivatives.

18. The coating according to any one of claims 1-17, characterized in that, The degradable polymer layer includes an active drug. The active drug is selected from at least one of drugs for inhibiting angiogenesis, antiplatelet drugs, antithrombotic drugs, anti-inflammatory drugs, and anti-allergy drugs. The drug for inhibiting angiogenesis is selected from at least one of paclitaxel, rapamycin, and their derivatives; the antiplatelet drug is cilostazol; the antithrombotic drug is heparin; the anti-inflammatory drug is dexamethasone; the anti-allergy drug is selected from at least one of calcium gluconate, chlorpheniramine, and cortisone.

19. A medical device, characterized in that, The medical device includes the coating and the substrate as described in any one of claims 1-18.

20. The medical device according to claim 19, wherein, The substrate of the medical device includes a degradable metal substrate; the medical device includes a lumen stent, a occluder, a gasket, an artificial blood vessel, a dental implant device, a vascular clip, a dental implant, a suture, a gynecological implant, a urological implant, a respiratory implant, or an orthopedic implant.

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