CN116712619B

CN116712619B - Drug coating for medical devices

Info

Publication number: CN116712619B
Application number: CN202310477330.9A
Authority: CN
Inventors: 王静; 李亮
Original assignee: Beijing Xinlitai Medical Equipment Co ltd
Current assignee: Beijing Xinlitai Medical Equipment Co ltd
Priority date: 2023-04-27
Filing date: 2023-04-27
Publication date: 2024-01-19
Anticipated expiration: 2043-04-27
Also published as: CN117298359A; CN116712619A

Abstract

The present invention provides a drug coating for a medical device comprising a non-degradable fluorinated polymer matrix and a drug dispersed therein, and forming an outer layer and an inner layer having different drug loading concentrations in a thickness direction of the drug coating, the outer layer having a thickness of not more than 10 μm, the drug coating being configured such that a drug release rate at the first 24 hours after implantation of a blood vessel of a mammal is not more than 40% and a drug release rate at the first 30 days is not less than 15%. The medicine coating can release medicine to the contacted tissue wall for a long time and stably, so as to achieve the long-term treatment or prevention effect on diseases such as lumen stenosis and the like.

Description

Drug coating for medical devices

Technical Field

The present invention relates to the technical field of medical devices, in particular drug-loaded devices and coatings for achieving long-term drug release, in particular to implantable medical devices for transluminal delivery, such as drug eluting stents, and related methods of manufacture.

Background

Drug-eluting stent (DES) consists of three parts: a metal matrix, a polymer coating, and an anti-restenosis drug carried thereon. Since DES applications, polymeric coatings have been an important component in DES, and are used as carriers for drugs to control drug release and prevent thrombosis and restenosis within stents.

DES is currently largely classified as either permanent or biodegradable.

The biodegradable polymer is mainly made of polylactic acid and other materials, and is degraded into carbon dioxide and water in human tissues and blood environment after DES implantation, the coating is degraded gradually thinner and finally disappears along with drug release, and the in vivo release dynamics curve of the loaded drug is generally considered to be influenced by the degradation characteristic and drug loading concentration of the biodegradable polymer.

Permanent polymers are predominantly fluorinated polymers, are not degradable in humans and have good biocompatibility, and drug delivery is generally considered to be determined primarily by the drug loading concentration of the coating. Fluorinated polymer coatings are widely used in permanent polymer DES with short-term (typically less than 30 days) drug release requirements, such as coronary DES, and long-term (e.g., greater than 30 days) drug release requirements, lacking research and reports. Compared with the biodegradable polymer coating, the purpose of prolonging the effective release time of the drug can be achieved by designing the degradation characteristic and the adaptive drug loading capacity of the biodegradable polymer, and the design of the fluorinated polymer coating for realizing the long-term effective release of the drug is more challenging: directly increasing the drug loading concentration of the coating to extend the drug release time is not generally considered feasible because it results in excessive and fast drug release at the early stages of drug release resulting in wasted drug or significant drug toxicity, while in the middle and late stages of drug release, the drug retained by the coating is reduced or drug loading concentration is reduced resulting in lower drug release and lower release rates, insufficient to achieve the necessary drug onset in the desired treatment period, and ineffective drug release over a long period of time.

A typical example of the need for long-term release DES is the treatment of peripheral arterial disease (peripheral arterial disease, PAD), which is a chronic disorder mainly caused by atherosclerosis, polyarteritis, etc., a systemic disease, PAD often manifesting as narrowing of the lower and/or upper limb arteries, reduced blood flow, and constitutes a great threat to the health of the human body. DES is expected to have a broad application prospect in peripheral arterial occlusive lesions due to its good biocompatibility and drug carrying properties.

However, the lower extremity peripheral arterial vessels are more challenging than other vessels such as coronary vessels, are longer, have larger diameters, have stronger blood flow impact, e.g. epicardial coronary artery diameters typically between 0.5 and 5mm, blood flow rates between 10 and 30cm/s, and femoral artery diameters typically between 6 and 9mm, blood flow rates between 70 and 90cm/s, and DES is necessary to carry larger amounts of drug in order to achieve long-term stable therapeutic effects on lower extremity PAD, which exacerbates the large amount of drug release (burst) in the early stages of drug release over a short period of time, and places more stringent demands on drug coating uniformity and larger drug release rates over medium and long-term release periods of greater than 30 days, which may otherwise be difficult to achieve long-term effective therapeutic drug release.

Disclosure of Invention

It is an object of the present invention to provide a medical device comprising a drug coating with which the drug coating is used to release a drug to a tissue wall in contact therewith to achieve a therapeutic or prophylactic effect.

Wherein the drug coating comprises a non-degradable polymer as a coating matrix and a drug carrier, the drug being dispersed in the coating matrix and releasing the drug out of the coating during the treatment cycle and substantially retaining the coating matrix.

The present invention particularly proposes a drug coating comprising a non-degradable polymer matrix and a drug dispersed therein, and forming an outer layer and an inner layer having different drug loading concentrations in the thickness direction of the coating, the inner layer having a drug loading concentration greater than that of the outer layer, or a medical device having the drug coating. The outer layer has a smaller thickness, for example no greater than 20 microns. In a preferred embodiment, the thickness of the inner layer is greater than the thickness of the outer layer. The drug coating may be applied to the surface of the body of the medical device.

It is also an object of the present invention to provide a method for preparing the aforementioned medical device comprising a drug coating, comprising: the method comprises the steps of coating an inner layer of a medical device body with a first coating composition to form a drug coating, and coating an outer layer of the drug coating with a second coating composition on the inner layer, wherein the drug loading concentration of the inner layer is larger than that of the outer layer.

It should be understood that the present invention is directed to an inner layer and an outer layer that are continuous along the thickness of the coating, with no visible separation, gap or interlayer between them, the inner layer being closer to the body than the outer layer. Typically, the inner and outer layers are composed of the same non-degradable polymer matrix.

As before, during the coating preparation process, the inner layer may be prepared first and the outer layer may be prepared on the surface of the inner layer. In certain embodiments, the inner layer is formed by coating with the first coating composition in liquid form and then drying, and the outer layer is formed by continuing to coat the outer side of the inner layer with the second coating composition in liquid form and then drying. And the weight of the drug in the first coating composition is greater than the weight of the drug in the second coating composition.

The coating means may be in a form known in the art, including, but not limited to, spray coating, dip coating, for example.

In the preparation process of the coating, a bottom layer can be coated on the surface of the device body before the inner layer is coated on the surface of the device body, namely, a bottom layer film forming substance and a solvent are mixed and dissolved to obtain a bottom layer solution, the bottom layer solution is coated on the surface of the device body to form a bottom layer of the drug coating, so that the adhesiveness between the drug coating and the device body is better, or the migration of the drug coating to the surface of the device body is prevented. In one embodiment, the underlying film-forming material may be n-butyl polyacrylate and the solvent may be tetrahydrofuran.

In another aspect, the invention also provides a drug eluting stent having a diameter of greater than 5 mm, particularly a drug eluting stent suitable for use in peripheral arteries, which provides for uses such as prevention or treatment of large diameter intravascular stenosis and restenosis, treatment of inflammation, and the like, particularly for long term and stable amounts of drug release over 30 days.

In the present invention, the present invention provides a drug eluting stent which can withstand the long-term impact of a large flow of blood, prevent excessive early release of the drug from the drug coating, and have continuous and stable release of the drug in a plurality of smaller cycles over a long treatment period (for example, 30 days or more, or even about 1 year) in order to achieve a long-term treatment or prevention effect.

In certain embodiments, the drug-eluting stent has a drug-loaded drug-loading of no less than 100 μg/cm ² For example 110. Mu.g/cm ² 、120μg/cm ² Or 130. Mu.g/cm ² Or 140. Mu.g/cm ² . In certain embodiments, the drug-eluting stent has a drug-loaded drug-loading amount of no less than 150 μg/cm ² For example 160. Mu.g/cm ² Or 180. Mu.g/cm ² Or 200. Mu.g/cm ² . In certain embodiments, the drug-eluting stent has a drug-loaded drug-loading amount of no less than 200 μg/cm ² For example 210. Mu.g/cm ² Or 230. Mu.g/cm ² Or 250. Mu.g/cm ² Or 260. Mu.g/cm ² Or 280. Mu.g/cm ² . In certain embodiments, the drug-eluting stent has a drug-loaded drug-loading of not less than 300 μg/cm ² For example 310. Mu.g/cm ² Or 330. Mu.g/cm ² Or 350. Mu.g/cm ² Or 380. Mu.g/cm ² Or 400. Mu.g/cm ² . In certain embodiments, the drug-eluting stent has a drug-loaded drug-loading of not less than 400 μg/cm ² For example 410. Mu.g/cm ² Or 450. Mu.g/cm ² Or 480. Mu.g/cm ² Or 500. Mu.g/cm ² 。

In certain embodiments, the drug-eluting stent has a drug coating thickness of no more than 50 μm, and preferably, the drug coating thickness is no more than 30 μm, which may be, for example, 30 μm, 25 μm, 20 μm, 15 μm, or 12 μm.

While it is a common practice for those skilled in the art to regulate drug loading concentration, coating thickness, and/or drug loading of a drug-loaded coating to regulate drug release, it is not specifically contemplated by those skilled in the art that a drug coating that can be clinically used for long-term drug release can be obtained by this common practice. The inventors have surprisingly found that based on the control of the thickness and/or drug loading concentration of the inner and outer layers of the drug coating according to the invention under specific conditions, a long-term controlled drug release of the non-degradable polymeric drug-loaded coating, in particular a controlled drug release of more than or substantially more than 30 days clinically, with safety and meeting therapeutic needs, e.g. PAD therapeutic needs, can be achieved.

For the drug coating of the present invention, the drug loading concentration of the inner layer is greater than the drug loading concentration of the outer layer while the thickness of the outer layer is selected to be not too great, e.g. not greater than 20 μm, but generally not greater than 10 μm, particularly preferred, the thickness of the outer layer is not greater than 8 μm, e.g. 6 μm, 5 μm, 3 μm, 2 μm, 1 μm.

The thickness of the outer layer is preferably chosen to be 1 μm to 8. Mu.m, in particular 1 μm to 3. Mu.m, or 2 μm to 4. Mu.m.

Based on the above-mentioned drug coating, it is possible to achieve a substantial reduction in the initial drug release period or to avoid a large and concentrated release of the drug in a short period of time (e.g., 24 hours, 48 hours, or 7 days) under high drug loading conditions, which avoids the waste of the drug or dose toxicity to tissues that may result from an excessively high initial drug release, and to maintain a substantially stable drug release over a longer release period in order to achieve a long-term therapeutic effect.

The present invention also provides a drug coating, in certain embodiments thereof, configured to have a drug release rate of no greater than 30% for the first 24 hours or 48 hours or 7 days after intravascular implantation in a mammal, and a drug release rate of no less than 15% for the first 30 days.

Wherein the mammal can be human, pig, sheep, rabbit, etc.

The drug coating of the aforementioned drug release characteristics may be provided with a drug loading concentration and thickness of any of the aforementioned selected inner and outer layers.

The inventors believe that an outer layer of small drug loading and very thin thickness may be the primary reason for achieving the aforementioned effects. The inventor speculates that in the initial release stage of the drug coating, on one hand, the low drug-carrying concentration of the outer layer directly influences the drug release amount of the drug coating in the initial release stage, and on the other hand, the non-degradable polymer matrix of the outer layer forms a shielding or blocking-like effect and delays the release of the inner-layer drug with high drug-carrying concentration to the outside of the coating; after the initial release of the drug coating, unexpectedly, the outer layer that has been largely released may not have properties similar to a non-drug-loaded blank non-degradable polymer matrix layer that almost completely blocks the release of the drug from the inner layer to the outside of the drug coating, while the outer layer of embodiments of the present invention functions like a control valve, and the drug loaded from the inner layer can migrate or diffuse out of the drug coating through the outer layer in a stable amount, allowing for a stable amount of drug release of the drug coating to the outside (e.g., tissue wall) over a long period. In certain embodiments, the drug amount release profile over a long period may be substantially linear.

Despite this conjecture, those skilled in the art will appreciate that the mechanism of controlled release of the coating is often complex, e.g., affected by swelling, dissolution of the coating matrix material in the tissue or blood environment, and multiple factors such as drug solubility, lipophilic or hydrophilic properties.

In a preferred embodiment of the invention, the thickness of the inner layer is chosen to be greater than the thickness of the outer layer, which is typically not less than 10 μm. For example, it may be selected to be 10 μm to 22. Mu.m. In some embodiments, the thickness of the inner layer is selected to be in the range of 12 μm to 16 μm.

For example, the thickness of the outer layer may be selected to be 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, while the thickness of the inner layer may be selected to be 12 μm, 13 μm, 14 μm, 15 μm, 16 μm, 17 μm, 18 μm.

The thickness of the inner layer is selected to be larger than that of the outer layer, so that the medicine carrying concentration of the inner layer is favorable to be larger than that of the outer layer.

The drug loading concentration indicated by the invention is expressed in weight percent and can be calculated as follows:

drug loading concentration of inner layer = mass of drug contained in inner layer/(sum of mass of non-degradable polymer of inner layer and mass of drug contained in inner layer) ×100%;

drug loading concentration of the outer layer = mass of drug contained in the outer layer/(sum of mass of non-degradable polymer of the outer layer and mass of drug contained in the outer layer) ×100%.

In the embodiment of the invention, the inner layer and the outer layer of the drug coating layer are generally loaded with the drugs with the total treatment amount not smaller than the total treatment amount required by the medical device, and the total drug loading amount of the drug coating layer can be more than 100 mug/cm for the treatment lumen with larger diameter and length ² For example, the total drug load may be 110 μg/cm ² ～400μg/cm ² . And the drug loading of the inner layer and the drug loading of the outer layer are usually different, and the drug loading of the inner layer is usually obviously larger than the drug loading of the outer layer because the drug loading concentration of the inner layer is larger than the drug loading concentration of the outer layer or the thickness of the inner layer is larger than the thickness of the outer layer. For example, the inner layer may have a drug loading of 100 μg/cm ² ～400μg/cm ² The drug loading of the outer layer is 2 mug/cm ² ～60μg/cm ² The method comprises the steps of carrying out a first treatment on the surface of the Alternatively, the inner layer has a drug loading of 150 μg/cm ² ～350μg/cm ² The drug loading of the outer layer is 2 mug/cm ² ～30μg/cm ² 。

In some preferred embodiments of the present invention, the inner layer has a drug loading concentration of not less than 10wt%, and the outer layer has a drug loading concentration of less than 10wt%. Wherein the outer layer thickness may be selected to be no greater than 10 μm.

For example, in some embodiments, the drug loading concentration of the inner layer may be 10wt% to 45wt% and the drug loading concentration of the outer layer may be 1wt% to 8wt%.

In some embodiments, the drug loading concentration of the inner layer is 10wt% -30 wt%, and the drug loading concentration of the outer layer is 3wt% -5 wt%.

In some embodiments, the drug loading concentration of the inner layer is 10wt% -20 wt%, and the drug loading concentration of the outer layer is 3wt% -5 wt%.

In some embodiments, the drug loading concentration of the inner layer is 10wt% -20 wt%, and the drug loading concentration of the outer layer is 3wt% -4 wt%;

in some embodiments, the drug loading concentration of the inner layer is 20wt% -30 wt%, and the drug loading concentration of the outer layer is 4wt% -5 wt%;

in some embodiments, the drug loading concentration of the inner layer is 15wt% -25 wt%, and the drug loading concentration of the outer layer is 3wt% -5 wt%.

In certain embodiments, the inner layer has a drug loading concentration of 10wt%, 13wt%, 15wt%, 18wt%, or 20wt% and the outer layer has a drug loading concentration of 3wt%, 4wt%, or 5wt%.

It is still another object of the present invention to provide a drug coating having a specific drug release profile, or a medical device containing the same, and a therapeutic method, wherein the drug coating has a release profile satisfying the drug release rate of not more than 40% at the first 24 hours after intravascular implantation in a mammal, and a drug release rate of not less than 15% at the first 30 days.

In certain embodiments, the drug coating has a drug release rate of no less than 15% and no greater than 60%, or no greater than 50%, or no greater than 40% over the first 30 days after intravascular implantation in the mammal. Preferably, the drug release rate is not more than 40%.

In certain embodiments, the drug coating has a drug release rate of no less than 15%, and no greater than 30%, or no greater than 40%, or no greater than 50% for the first 14 days after intravascular implantation in a mammal. Preferably, the drug release rate is not more than 30%.

In certain embodiments, the drug coating has a drug release rate of about 6% to about 2% from the second week to the seventeenth week after intravascular implantation in the mammal.

In certain embodiments, the drug coating has a drug release rate of not less than 30%, or not less than 40%, or not less than 50% on days 31 to 360 following intravascular implantation of the mammal. Preferably, the drug release rate is not less than 50%.

In certain embodiments, the drug coating has a drug release rate of no greater than 15%, or no greater than 20%, or no greater than 30% at the first 24 hours after intravascular implantation in a mammal. Preferably, the drug release rate for the first 24 hours is no more than 15%.

The non-degradable polymer referred to in the present invention is biocompatible and chemically physically stable and is suitable for contact with tissue walls of the human or animal body, such as blood vessels, etc. The preferred non-degradable polymer may be a fluorinated polymer. Fluorinated polymers (Fluoropolymers) are understood by those skilled in the art to be polymers having a main chain of C-C chains, to which one or more, or even all, fluorine atoms are attached in side chains or branches.

Fluorinated polymers may be considered to be fluorocopolymers, and the comonomers may be, for example, tetrafluoroethylene (TFE), hexafluoropropylene, chlorotrifluoroethylene, and perfluoroalkyl vinyl ethers (PFVE), among others, where PFVE is perfluoromethyl vinyl ether (methyl ether), perfluoropropyl vinyl ether (propyl ether), and perfluorodioxole, among others.

The fluorinated polymer may also be preferably selected from fluorinated acrylate polymers, and for example, the comonomer may be perfluoroalkyl (meth) acrylate, heteroatom-containing perfluoroalkyl (meth) acrylate, perfluoroamide (meth) acrylate, perfluorosulfonamide (meth) acrylate, or the like.

The fluorocopolymers used in the present invention as film-forming polymers should have a molecular weight high enough to provide sufficient toughness so that films containing such polymers will not rub off during stent handling or installation or so that the coating will not exhibit significant cracking when the stent or other medical device such as occluder, vena cava filter is expanded.

In a preferred embodiment, the fluorinated polymer is a copolymer of vinylidene fluoride and hexafluoropropylene (PVDF-HFP) and the copolymer comprises, by weight, 50% to 92% vinylidene fluoride and 50% to 8% hexafluoropropylene. This polymer has been reported and used, for example, in chinese patent publication No. CN1225292C, which is incorporated in its entirety into the present specification, which discloses the preparation method and performance test of the aforementioned fluoropolymer coating.

In certain embodiments, the non-degradable fluorinated polymer is a copolymer of vinylidene fluoride and hexafluoropropylene, and the copolymer comprises 55% to 65% vinylidene fluoride and 45% to 35% hexafluoropropylene by weight.

In certain embodiments, the non-degradable fluorinated polymer is a copolymer of vinylidene fluoride and hexafluoropropylene, and the copolymer comprises 70% to 90% vinylidene fluoride and 30% to 10% hexafluoropropylene by weight.

In certain embodiments, the drug coating further comprises a non-drug-carrying bottom layer underlying the inner layer and overlying the medical device body for attaching the drug coating to the medical device body, wherein the inner layer is not directly attached to a surface of the medical device body.

The bottom layer can be one or more of polymethyl acrylonitrile, polymethyl methacrylate, polyethyl methacrylate, polypropylene methacrylate, poly-n-butyl methacrylate, polyhydroxyethyl methacrylate and polyhydroxypropyl methacrylate. The bottom layer also has good toughness, so that the coating does not crack.

It is a further object of the present invention to provide an implantable medical system for interventional procedures comprising a medical device as described above and a delivery device separable from the medical device, the body of the medical device or at least a portion thereof being expandable in nature and adapted to be delivered through a catheter upon compression to a smaller diameter. The aforementioned drug coating may be disposed on a surface of the expandable portion of the medical device. Thus, the preferred drug coating has good elongation, yet is substantially complete without rupture when the medical device is deformed from a compressed state to an unconstrained state.

In certain embodiments, the medical device may be a drug eluting stent that may be crimped to 50% of its diameter in the unconstrained state without substantial rupture of the drug coating.

In certain embodiments, the medical device may be a drug eluting stent that may be crimped to 30% of its diameter in the unconstrained state without substantial rupture of the drug coating.

In certain embodiments, the medical device may be a drug eluting stent that may be crimped to 20% of its diameter in the unconstrained state without substantial rupture of the drug coating.

The drug eluting stent may generally be a body of a metal, such as stainless steel, nitinol, or cobalt chrome. The drug coating is arranged on the surface of the alloy material of the body.

Based on some embodiments of the present invention, it is contemplated that the provided drug coating has a function of satisfying long-term stable drug release, and in particular, some embodiments provide long-term and stable drug release for more than 30 days, 60 days, 180 days or 360 days, and the drug release amount in the release period can be always controlled to be above the minimum effective dose, ensuring or improving the medical effect.

Drawings

FIG. 1 is a schematic diagram of a drug eluting stent in accordance with an embodiment of the present invention;

FIG. 2 is a schematic cross-sectional view of an elongate stem portion of a drug eluting stent in accordance with an embodiment of the present invention;

FIG. 3 is a graph showing the results of drug release rate of the drug eluting stent of the present invention in animal experiments;

FIG. 4 is a graph showing the drug release rate results of a drug eluting stent in accordance with an embodiment of the present invention in an animal test;

FIG. 5 is a graph showing the results of drug release rate in vitro tests of a drug eluting stent according to an embodiment of the present invention;

FIG. 6 is a schematic diagram of an implantable medical device system for interventional procedures according to an embodiment of the present invention;

fig. 7 is an enlarged view of a portion of fig. 6 showing the drug eluting stent in an assembled position of the delivery device.

Detailed Description

The invention will be further illustrated by the following examples, which are merely exemplary and are intended to enable those skilled in the art to understand the invention without limiting its scope. Variations in forms other than the embodiments are possible and need not be exhaustive of all embodiments. It is understood that all equivalent changes or modifications made in accordance with the spirit of the present invention are intended to be included within the scope of the present invention.

The present invention provides one or more embodiments of a drug eluting stent having a drug coating attached to the surface of the stent, which may be any of those described below or in the foregoing description.

The drug eluting stent may be mainly used for the treatment of diseases in the lumen of blood vessels, such as stenosis, restenosis, inflammation, etc. of peripheral arteries, peripheral veins, cerebral nerve vessels, arteriovenous fistulae, etc. However, it will be appreciated by those skilled in the art that the drug eluting stent may also be adapted for the treatment of intra-luminal related diseases such as the esophagus, intestine, etc.

Without being limited thereto, the drug coating may also be applied to other medical devices, such as various occluders, filters, etc. which may be permanently or temporarily placed in the body through an intervention, or medical devices which require prolonged contact with the tissue wall without an intervention, the drug coating being attached to the surface of the device body in order to achieve the drug coating delivery of the drug outwards.

The present invention provides some embodiments of drug coatings having long-acting controlled release functional properties, such as drug release profiles that deliver drug to the tissue wall for up to 30 days and more, or 60 days and more, or 120 days and more, or 240 days and more, or 360 days and more, while meeting at least a desired minimum therapeutic dose for the average daily or average weekly release of drug over the preset release period.

In certain embodiments, the minimum therapeutic dose required is 1% to 10% of the total drug loading of the drug coating. In certain embodiments, the drug release profile meets an average weekly release of at least 1% to 10%, e.g., 8%, 6%, or at least 1% to 5%, e.g., 1%, 2%, 3%, 4% of the total drug loaded by the drug coating.

In certain embodiments, the drug release profile meets a weekly design release of drug that at least meets or exceeds a desired minimum therapeutic dose that is 1% to 10% of the total drug loading of the drug coating over the preset release period (e.g., 4 to 52 weeks), as distinguished from the aforementioned weekly average release. In certain embodiments, the drug release profile satisfies that the weekly designed release of drug over the preset release period is at least 1% to 6%, such as 1%, 2%, 3%, 4%, 5%, 6% of the total drug loaded by the drug coating.

The weekly design release, which is the amount of controlled release drug required weekly from the first week to the last week over a preset drug release period, is more reasonable than the weekly average release, particularly to meet the long-term release control requirements of the minimum therapeutic dose, since the weekly average release may not be sufficient to truly reflect or reflect the control of the weekly actual drug release. In order to ensure that a long-term therapeutic effect is achieved, it is apparent that the weekly design release amount is at least at or above the minimum therapeutic dosage required.

The present invention also provides another partial embodiment of a drug coating having the functional property of inhibiting short-term fulminant release of a high-load drug coating, for example, a high-load drug coating having a drug release rate of no greater than 40% for the first 24 hours and no less than 15% for the first 30 days of drug delivery to the tissue wall. The drug release rates referred to herein before, herein and hereinafter of the present invention mean, unless otherwise specified, the ratio of the amount of drug released by the drug coating to the total amount of drug carried by the drug coating.

In certain embodiments, the high drug load coating has a drug release rate of no greater than 30%, or no greater than 20%, or no greater than 10%, for the first 24 hours of drug delivery to the tissue wall, while the drug release rate for the first 30 days is no less than 15%, or no less than 20%, or no less than 30%, or no less than 40%.

It has been demonstrated that the coating of the drug with a further barrier layer, in particular, helps to suppress the short-term burst release of the drug from the drug coating. The barrier layer may be an additional coating, the same or different from the drug coating matrix, and is typically not loaded with a drug, and may be referred to as a blank barrier layer, however, the blank barrier layer of the non-degradable polymer matrix makes it difficult for the drug coating below it to release the drug out of the coating, and the release period may not allow for the release of a drug that maintains a minimum therapeutic dose over a prolonged period of time. Thus, one direction of improvement is to select a matrix material that can be rapidly ruptured, dissolved, as a sacrificial barrier layer to provide a barrier to drug release prior to or at the beginning of the drug release cycle, and to effect removal of the barrier during the release cycle, for example by dissolution, degradation, fluid flushing, and the like.

In contrast, the drug coating according to the embodiment of the invention realizes short-term and long-term drug release control mainly through the double-layer drug-carrying layer with gradient concentration, and particularly aims at the drug coating with high drug-carrying capacity.

Coronary drug eluting stents used in comparison to small diameter vessels typically have a drug loading of 10 μg/cm ² The level of the drug loading of the high drug loading drug coating layer according to the invention can be generally not less than 50 mug/cm ² In particular not less than 100. Mu.g/cm ² 。

In certain preferred embodiments of the present invention, the aforementioned long-acting controlled release functional properties are both met, along with the ability to inhibit short-term burst release of a high drug load drug coating.

Wherein, in certain embodiments, the drug coating has a drug release rate of no less than 15% and no greater than 60%, or no greater than 50%, or no greater than 40% over the first 30 days after intravascular implantation in a mammal.

In certain embodiments, the drug coating has a drug release rate of no less than 15%, and no greater than 30%, or no greater than 40%, or no greater than 50% for the first 14 days after intravascular implantation in a mammal.

In certain embodiments, the drug coating has a drug release rate of not less than 30%, or not less than 40%, or not less than 50% on days 31 to 360 following intravascular implantation of the mammal.

In certain embodiments, the drug coating has a drug release rate of no greater than 15%, or no greater than 20%, or no greater than 30% at the first 24 hours after intravascular implantation in a mammal.

A significant feature of the drug coating of the present embodiments is the provision of a thinner outer layer, and an inner layer of significant thickness as opposed thereto. Typically, the outer layer has a lower drug loading and/or drug loading concentration, while the inner layer has a higher drug loading and/or drug loading concentration.

In one embodiment, the outer layer has a thickness selected in the range of 1 μm to 6 μm, while the inner layer having a significant thickness has a thickness selected in the range of 10 μm to 18 μm.

The present invention also provides a drug eluting stent embodiment with the aforementioned drug coating, which is particularly suitable for peripheral intra-arterial implantation.

Among these, some embodiments of the drug eluting stent suitable for peripheral intra-arterial implantation may be selected to have a length of 15mm to 200mm and a diameter of 3mm to 12mm. The drug eluting stent of certain embodiments may optionally have a length L of 20mm to 150mm and a diameter of 5mm to 10mm.

In one embodiment, the drug eluting stent has a length of 20mm and a diameter of 5mm, and in another embodiment, the drug eluting stent has a length of 150mm and a diameter of 8mm, both of which can be delivered through a sheath of 7F outer diameter.

Wherein the drug coating may be entirely coated on the surface of the aforementioned stent body, however, it is not limited thereto, and one skilled in the art may alternatively coat the stent body at portions thereof, for example, the stent body may have a bare surface of the uncoated drug coating at some portions. The stent body is typically metallic and has good elastic deformation characteristics to provide good support and crimping properties.

One significant advantage of the drug eluting stent embodiment of the present invention for peripheral arterial implantation is that it provides lower trauma and more effective treatment of peripheral arteries during treatment.

The drug eluting stent can be delivered to a lesion site in a blood vessel by a delivery device in a state of being pressed and held to a smaller diameter, the delivery device is operated to release the drug eluting stent into a lumen of the blood vessel, the drug eluting stent can be self-expanded or balloon-expanded to contact with the wall of the blood vessel and support the wall of the vessel with radial force to expand the wall of the blood vessel, and an antiproliferative drug carried by a drug coating can be released to the lesion site to prevent and reduce restenosis of the lumen of the blood vessel.

In one embodiment, as shown in fig. 6 and 7, the drug eluting stent 3 may be fitted to a delivery device. Referring to fig. 7, the drug eluting stent 3 is sleeved on an inner sheath tube 4 of a delivery device, an outer sheath tube 5 is slidably sleeved outside the inner sheath tube 4 to bind the drug eluting stent 3 on the inner sheath tube 4, a distal end 1 of the inner sheath tube 4 is a conical head, a developing ring 2 is arranged at a position close to the distal end 1, a proximal end of the inner sheath tube 4 is connected with a front handle 7, and a stress diffusion tube 6 is arranged at a distal end of the front handle 7 to improve the strength of a tube body. In the operation process, the conveying device injects normal saline through the joint 12 at the proximal end to flush the tube body, the guide channel established by the guide wire is conveyed into a human body, when the distal end of the inner sheath tube 4 reaches a designated lesion position, an operator takes down the limit of the stop piece 10 on the knob 8, holds the front handle 7, withdraws (moves proximally) along the screw 11 through the locking operation knob 8 between the release button 9 and the screw 11, and drives the outer sheath tube 5 to withdraw to release the drug eluting stent 3. Fig. 7 shows the drug eluting stent 3 exposed after the sheath 5 has been slid proximally such that the drug eluting stent 3 is not constrained by the sheath 5. During the release process, the self-expandable stent is no longer radially constrained by the outer sheath 5 from the distal end to the proximal end, and thus gradually expands, tending to resume its preset shape and supporting the stenosed vessel lumen within the vessel.

Some drug eluting stent embodiments have the advantage of inhibiting drug burst phenomena that occur during the initial stages of stent implantation, which is highly advantageous in most cases.

For example, for selecting a drug coating loaded with rapamycin or the like, in the initial postoperative period of angioplasty, platelet adhesion, aggregation and secretion are caused by damage to endothelial cells, tearing and exposure of vascular intima, reduction of vascular endothelial barrier and protective function, vascular stretch and impact of blood flow due to stent expansion, and at this time, released drugs such as rapamycin may not have a significant effect, and thus, the drug release amount is not preferably excessively large. For drug coatings selected to carry paclitaxel and the like, during the initial post-operative period of angioplasty, for the same reasons as described above, large amounts of paclitaxel intensively released in a short period of time may exhibit severe cytotoxicity, causing additional damage to the tissue of the vessel wall or other tissues of the systemic circulation.

Although there have been studies on the higher incidence of restenosis in peripheral arterial vessels, such as in the vicinity of one year in which the superficial femoral artery is dilated, see ostamu et al, 2011, published in the university & Cardiovascular Interventions Official Journal ofthe Society for Cardiac Angiography & Interventions journal (time of restenosis after placement of the superficial femoral artery nitinol stent and factors related to early and late restenosis), timing ofthe restenosis following nitinol stenting in the superficial femoral artery and the factors associated with early and late restenoses (time of restenosis after placement of the superficial femoral artery nitinol stent and factors related to early and late restenosis) in the university journal of Catheterization & Cardiovascular Interventions Official Journal ofthe Society for Cardiac Angiography, however, no suitable peripheral arterial drug eluting stent has been proposed to address this clinical problem.

It is therefore an object of the present invention to also provide a method for the prevention or treatment of restenosis as described above and a drug eluting stent for use in the method.

The drug eluting stent may be the example described above or below and it is sufficient that, in one embodiment, a drug eluting arterial stent implanted in a peripheral arterial vessel stenosis has a drug release period of more than 3 months.

In another embodiment, a drug-eluting arterial stent implanted in a peripheral arterial vessel stenosis has a drug release period of greater than 6 months.

In a preferred embodiment, the drug-eluting arterial stent implanted in a peripheral arterial vessel stenosis has a drug release period of substantially about 12 months. This is because, considering that the aforementioned study surface restenosis time appears to have a steep peak for about 12 months, in order to effectively reduce the restenosis rate, the entire drug release period of the drug eluting stent is designed to be one year, and the release of an effective dose of the drug for inhibiting stenosis can be maintained for a long period of time to more effectively increase the patency rate of the lumen for 12 months, and in particular, the effect of preventing or reducing restenosis can be better to maintain the effective dose release of the drug for a period of time before the stent having a high occurrence probability of restenosis is implanted for 12 months. In certain embodiments, the drug eluting stent releases from 10% to 40%, e.g., about 30%, of the total drug loading of the drug coating at month 7-12 after implantation.

The following is an illustration of the drug coating using polyvinylidene fluoride copolymer (PVDF-HFP) as the fluorinated polymer matrix. However, without limitation, one skilled in the art may select other suitable fluorinated polymer matrices.

Referring to fig. 1, there is shown an embodiment of a drug eluting stent 100 having a cylindrical configuration of mesh-like bodies that provide radial support to a vessel lumen.

Referring again to fig. 2, a drug coating 32 is shown covering the surface of the body 1 of the drug eluting stent 100 or other similar device body 1, the drug coating 32 may substantially circumferentially surround the body 1. The cross-section of the elongate stem of the stent body 1 is shown as a quadrilateral, however, in some embodiments, the cross-section may be circular, oval or arcuate in shape.

Without limitation, the drug coating need not circumferentially surround the body 1. In some embodiments, the drug coating may cover only 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, the outer circumferential surface of the stent body 1 may be provided with grooves, and the drug coating may alternatively cover only the grooves or cover the entire outer circumferential surface of the stent body 1 at the same time.

In some embodiments, the outer and inner circumferential surfaces of the stent body 1 may be covered with drug coatings of the same or different thickness. In certain embodiments, the thickness of the drug coating covered by the outer circumferential surface of the stent body 1 is greater than the thickness of the drug coating covered by the inner circumferential surface.

The body 1 of the bracket can be made of non-biodegradable materials, in particular metals, such as 316L stainless steel, cobalt-chromium alloy, magnesium alloy, iron alloy, zinc alloy, nickel-titanium alloy, nickel-iron alloy and the like, which have good biocompatibility, memory property, support property and the like. However, without being limited thereto, the stent body 1 material may also be a polymer, such as polyamide, polyolefin, non-absorbent polyester, or the like. Without being limited thereto, the body 1 of the stent may alternatively be made of a biodegradable or bioabsorbable material and be substantially or largely undegraded or absorbed during the drug release period, although such a choice may not be preferred.

The drug coated substrate of the embodiment of fig. 1 is selected from polyvinylidene fluoride copolymer (PVDF-HFP) which is copolymerized from vinylidene fluoride and hexafluoropropylene. The polymer has excellent biocompatibility, and stable chemical property ensures that the drug can be stably released, and meanwhile, the risk of generating acidic degradation substances to increase inflammatory reaction is avoided. The medicine loaded by the medicine coating can be anti-proliferation medicines such as rapamycin and derivatives thereof, taxol, heparin and the like. In the embodiment shown in fig. 1, the drug is rapamycin, which has the effects of inhibiting cell proliferation and migration, reducing local vascular wall cytokine production and inflammatory cell activation, inhibiting apoptosis, promoting re-endothelialization of damaged vascular sites, and the like. Restenosis is primarily caused by excessive intimal hyperplasia following stent implantation, and rapamycin inhibits cell proliferation and migration, thereby inhibiting restenosis.

The drug coating 32 of the embodiment of fig. 2 comprises an inner layer 321 of polyvinylidene fluoride copolymer as a matrix and an outer layer 322 of the same polyvinylidene fluoride copolymer as a matrix, the inner layer 321 and the outer layer 322 carrying a different concentration of rapamycin drug, wherein the drug loading concentration of the inner layer 321 is greater than the drug loading concentration of the outer layer 322. Referring to fig. 2, the thickness of the inner layer 321 is shown to be greater than the thickness of the outer layer 322. The thickness of the outer layer 322 should be selected not to be too great, for example not greater than 20 μm, but generally not greater than 10 μm, in this embodiment, the thickness of the outer layer 322 is between 1 μm and 8 μm. The overall thickness of the inner 321 and outer 322 layers is generally no greater than 50 μm, preferably no greater than 30 μm.

In some embodiments, the overall thickness of the inner layer 321 and the outer layer 322 may be selected to be 11 μm to 27 μm.

For example, the thickness of the inner layer 321 is 10 μm to 22 μm, the thickness of the outer layer 322 is 1 μm to 5 μm, the thickness of the inner layer 321 may be 2 times or more the thickness of the outer layer 322, for example, the coating thickness ratio of the inner layer 321 to the outer layer 322 is about 22:1 to 10: 1. For another 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 coating thickness ratio of the inner layer 321 to the outer layer 322 is about 16:1 to 12: 1.

The drug coating 32 of the embodiment of fig. 1 also includes a non-drug-carrying bottom layer 33, although this is not required, and in some cases it is preferred to include a bottom layer 33. An 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. The choice of a suitable primer layer 33 may enhance the adhesion of the drug coating 32 to the stent, and the material of the primer layer 33 may be, for example, a non-biodegradable polymer such as poly (acrylonitrile), poly (methyl methacrylate), poly (ethyl methacrylate), poly (propyl methacrylate), poly (n-butyl methacrylate), poly (hydroxyethyl methacrylate), poly (hydroxypropyl methacrylate), etc., which does not substantially cause tissue rejection and tissue inflammation due to degradation. In this embodiment, poly-n-butyl methacrylate (PBMA) is used as the bottom layer 33, and has a strong adhesion to the metal material of the body 31 of the stent, and good compatibility with the drug-loaded fluorocopolymer, so that the contact interface between the inner layer 321 and the bottom layer 33 can perform a "locking" function, so as to form a stable and high-bonding-strength coating system on the stent.

The thickness of the bottom layer 33 is not excessively large, and may be selected as desired by those skilled in the art. In this embodiment, the thickness of the underlayer 33 is 0.5 μm to 1.5 μm, for example, 0.5 μm, 1 μm, 1.5 μm.

It will be appreciated that the release of drug molecules carried by the inner layer 321 adjacent the surface of the stent body 31 must migrate a longer distance out of the coating, and that as the drug is released, the concentration differential between the drug eluting stent and the blood or tissue gradually decreases and the release gradually slows.

Thus, in this embodiment, the drug concentration of at least a portion of the inner layer 321 is greater than the drug concentration of at least a portion of the outer layer 322 in the thickness direction of the coating, forming a gradient concentration bilayer drug coating 32 arrangement. It will be apparent that in the preferred embodiment, the inner layer 321 and the outer layer 322 each have a relatively uniform drug concentration, and that the drug concentration is greater in all areas of the inner layer 321 than in all areas of the outer layer 322, which is particularly advantageous for controlling the release of the entire drug coating 32.

In this embodiment, the drug loading concentration of the inner layer 321 may be 10wt% to 45wt%, and the drug loading concentration of the outer layer 322 may be 1wt% to 8wt%. Preferably, the drug loading concentration of the inner layer 321 can be selected to be 10-30wt% and the drug loading concentration of the outer layer 322 is 3-5wt%; alternatively, the drug loading concentration of the inner layer 321 is 10-20wt% and the drug loading concentration of the outer layer 322 is 3-5wt%; alternatively, the drug loading concentration of the inner layer 321 is 10wt% to 20wt%, and the drug loading concentration of the outer layer 322 is 3wt% to 4wt%. More preferably, the drug loading concentration of the inner layer 321 may be selected to be 10wt%, 13wt%, 15wt%, 18wt% or 20wt%, while the drug loading concentration of the outer layer 322 may be selected to be 3wt%, 4wt% or 5wt%.

In one embodiment of the invention, the drug release rate is greater than or equal to 98% after the drug eluting stent is implanted for 12 months, the initial release is substantially free of burst and long-term release in the middle and late stages is maintained.

The implementation isThe drug coating 32 of the example is loaded with a sufficient amount of drug to be required, for example, at 160 μg/cm ² ～500μg/cm ² 。

Obviously, the above-mentioned embodiments of the drug eluting stent are not limited to peripheral arteries, but can be applied to other arteries or veins where the blood flow is fast or where the vessel is thick and long-term release is required.

Examples of the preparation of the aforementioned drug eluting stent are provided below.

Example 1

The preparation method of the drug eluting stent comprises the following steps:

1) Providing a net tubular support body, and carrying out ultrasonic cleaning and drying;

2) A primer for non-drug delivery is provided, comprising:

and mixing and dissolving the bottom layer film forming substance and the solvent to obtain a bottom layer solution. Specifically, the preparation method of the bottom layer solution comprises the following steps: 0.40g of poly (n-butyl acrylate) was weighed into a 250ml volumetric flask, 60ml of tetrahydrofuran was added to the flask, and stirred until completely dissolved.

3) Forming a bottom layer on the stent body, comprising:

filling a bottom layer solution into ultrasonic spraying equipment (an ultrasonic atomization spraying system TLS-2000), cleaning and drying the bracket body, placing the bracket body under ultrasonic spraying after the liquid flows out of a spray head, spraying to form a bottom layer with the thickness of 0.5-1.5 mu m, and drying in an oven at 50 ℃ for 2 hours after the spraying is finished.

4) The preparation method of the drug-loaded drug coating comprises the following steps:

weighing 4g of PVDF-HFP (75% -25%) solid, placing the solid into a 50ml volumetric flask, adding methyl ethyl ketone to fix the volume, stirring until the solid is completely dissolved, obtaining a carrier stock solution, and storing the carrier stock solution at a temperature lower than room temperature.

Taking 5ml of each carrier stock solution, putting into a 100ml volumetric flask, respectively adding 16.5mg and 100mg of rapamycin solid, fixing the volume by methyl ethyl ketone, and stirring until dissolution is completed, thus preparing the coating solution of the outer layer and the inner layer of the drug coating.

5) Forming a drug-loaded drug coating on a bottom layer of a stent, comprising:

after the bottom layer is formed, a drug-loaded coating is sprayed on the bottom layer to form an inner layer and an outer layer. Firstly, spraying an inner layer: filling 1mg/mL of inner layer coating solution into ultrasonic spraying equipment (an ultrasonic atomization spraying system TLS-2000), spraying the support under ultrasonic spraying after the liquid flows out of a spray head, forming an inner layer with the thickness of 12-16 mu m, and drying in a drying oven at 40 ℃ for 12 hours after the spraying is finished;

and then spraying an outer layer: and (3) filling 0.165mg/mL of outer coating solution into the ultrasonic spraying equipment, spraying the bracket under ultrasonic spraying after the liquid flows out from the spray head, forming an outer layer with the thickness of 2-4 mu m, and drying in a drying oven at 40 ℃ for 12 hours after the spraying is finished.

The drug eluting stent of the embodiment is obtained by the steps, wherein the drug loading concentration of the inner layer is 20wt%, the drug loading concentration of the outer layer is 4wt%, and the drug loading of the inner layer is 200 mug/cm ² ～268μg/cm ² The drug loading of the outer layer is 7 mug/cm ² ～14μg/cm ² The thickness of the inner layer is 12-16 μm, and the thickness of the outer layer is 2-4 μm.

In other embodiments, the drug eluting stent may not include an underlayer. After the stent body is cleaned and dried, the inner layer and the outer layer of solution are sequentially sprayed to form the corresponding inner layer and the corresponding outer layer, so that the drug coating carrying the drug can be directly attached to the surface of the stent body through the inner layer.

Obviously, the steps of the present embodiment are not limited to the above-mentioned example sequence, and for example, the bottom layer solution, the inner layer solution or the outer layer solution may be configured at the same time, and then the corresponding solution may be selected to be sprayed on the stent body according to the need.

Example 2

Referring to the preparation method of example 1, this example prepared a drug eluting stent having a different drug loading concentration than example 1. The bottom layer in this embodiment is the same as that in embodiment 1, and will not be described here again.

The preparation method of the coating solution of the inner layer and the outer layer of the drug coating comprises the following steps:

9g of PVDF-HFP (50% -50%) solid is weighed, placed into a 50ml volumetric flask, methyl ethyl ketone is added to fix the volume, stirred until the solid is completely dissolved, and a carrier stock solution is obtained and stored below room temperature.

Taking 1ml of each carrier stock solution, putting into a 100ml volumetric flask, respectively adding 6mg and 20mg of rapamycin solid, fixing the volume by methyl ethyl ketone, and stirring until dissolution is completed, thus preparing the coating solution of the outer layer and the inner layer of the drug coating.

Firstly, spraying an inner layer, filling 20mg/mL of inner layer coating solution into ultrasonic spraying equipment (an ultrasonic atomization spraying system TLS-2000), spraying an inner layer with the thickness of 14-18 mu m on a bottom layer under ultrasonic spraying after a nozzle flows out of liquid, and drying in a drying oven at 40 ℃ for 12 hours after the spraying is finished;

and then spraying an outer layer: and (3) filling 6mg/mL of outer layer coating solution into the ultrasonic spraying equipment, placing the bracket under ultrasonic spraying after the liquid flows out from the spray head, spraying to form an outer layer with the thickness of 1-3 mu m, and drying in a vacuum oven at 40 ℃ for 12h after the spraying is finished.

The drug eluting stent of the embodiment is obtained by the steps, wherein the drug loading concentration of the inner layer is 10wt%, the drug loading concentration of the outer layer is 3wt%, and the drug loading of the inner layer is 126 mug/cm ² ～162μg/cm ² The drug loading of the outer layer is 3 mug/cm ² ～9μg/cm ² The thickness of the inner layer is 14-18 μm, and the thickness of the outer layer is 1-3 μm.

Example 3

Referring to the preparation method of example 1, this example prepares another drug-eluting stent having a different drug loading concentration as compared to examples 1 and 2. The bottom layer in this embodiment is the same as that in embodiment 1, and will not be described here again.

weighing 5g of PVDF-HFP (60% -40%) solid, placing the solid into a 50ml volumetric flask, adding methyl ethyl ketone to fix the volume, stirring until the solid is completely dissolved, obtaining a carrier stock solution, and storing the carrier stock solution at a temperature lower than room temperature.

Taking 1mL of each carrier stock solution, putting into a 100mL volumetric flask, respectively adding 5.3mg and 44mg of rapamycin solid, fixing the volume by methyl ethyl ketone, and stirring until dissolution is completed, thereby preparing an inner layer coating solution with the concentration of 5.3 mug/mL of the outer layer of the drug coating and 440 mug/mL of the inner layer coating solution.

Firstly, spraying an inner layer, filling 400 mug/mL of inner layer coating solution into ultrasonic spraying equipment (an ultrasonic atomization spraying system TLS-2000), spraying the inner layer with the thickness of 10-12 mu m on a bottom layer under ultrasonic spraying after a spray head flows out of liquid, and drying in a vacuum oven at 40 ℃ for 12 hours after the spraying is finished;

and then spraying an outer layer: and (3) filling 21.5 mu g/mL of outer coating solution into the ultrasonic spraying equipment, placing the support under ultrasonic spraying after the liquid flows out from the spray head, forming an outer layer with the thickness of 3-5 mu m by spraying, and drying in a vacuum oven at 40 ℃ for 12h after the spraying is finished.

The drug eluting stent of the embodiment is obtained by the steps, wherein the drug loading concentration of the inner layer is 30wt%, the drug loading concentration of the outer layer is 5wt%, and the drug loading of the inner layer is 264 mug/cm ² ～316μg/cm ² The drug loading of the outer layer is 13 mug/cm ² ～22μg/cm ² The thickness of the inner layer is 10-12 μm, and the thickness of the outer layer is 3-5 μm.

Animal test example

With miniature Bama pigs as animal models, 33 miniature pigs were randomly allocated and implanted with 66 sets of drug eluting stents of example 1, and each pig was implanted with 1 set of drug stent in the left and right iliac (femoral) arteries. And taking out 2 sets of stents implanted in three pigs at each of 11 time points after implantation, analyzing the drug residue in the drug coating of the stent by liquid chromatography, measuring and calculating the average drug residue of the drug coating at each time point to obtain the drug release rate data of the drug eluting stent of the embodiment 1 at each time point, wherein the data are shown in the following table 1, and a drug release rate curve and a release rate curve can be drawn according to the data, and are shown in fig. 3 and 4.

Still taking miniature Bama pigs as animal models, randomly distributing and implanting 6 sets of drug eluting stents of the example 2 into 3 miniature pigs, and implanting 1 set of drug stents into left and right iliac (femoral) arteries of each pig. And taking out 2 sets of stents implanted in one pig at each of 3 time points after implantation, analyzing the drug residue in the drug coating of the stent by liquid chromatography, measuring and calculating the average drug residue of the drug coating at each time point, and obtaining the drug release rate data of the drug eluting stent of the example 2 at each time point, wherein the drug release rate data is shown in the table 1 below.

Similarly, 3 minipigs were randomly allocated with 6 drug-eluting stents of example 3, and 1 stent was implanted in each of the left and right iliac (femoral) arteries of each pig. And taking out 2 sets of stents implanted in one pig at each of 3 time points after implantation, analyzing the drug residue in the drug coating of the stent by liquid chromatography, measuring and calculating the average drug residue of the drug coating at each time point, and obtaining the drug release rate data of the drug eluting stent of the embodiment 3 at each time point, wherein the data are shown in the table 1 below.

Table 1: release rate of drug in miniature Bama pig

Time point	Example 1	Example 2	Example 3
				4h	5.70％		9.98％
24h	6.36％	1.23％	-
				7d	15.33％	-
14d	21.13％	-	-
				30d	31.72％	24.88％
60d	48.58％	-	55.50％
				90d	58.50％	-
120d	67.31％	60.56％	-
				180d	71.34％	-	88.61％
270d	87.24％
				369d	98.52％	-	-

From the above data and figures, it can be seen that the drug release of the drug coating of example 1 described above covers the entire restenosis period (369 days) and has a release rate of up to 90% or more, and the drug is a relatively fast release rate within months 1-2 of the relatively fast smooth muscle proliferation, and after about 50 days, the drug release rate enters the relatively plateau and the drug remains at a steady release rate until the drug is completely released.

According to the above data, the drug coatings of the examples have the following action processes in the restenosis development process:

(1) Within 1-12 h after angioplasty, platelets adhere, aggregate and secrete due to injury of angioplasty to endothelial cells, tearing and exposure of vascular intima, reduction of vascular endothelial barrier and protective function, vascular stretch and impact of blood flow, at this time, rapamycin does not have a remarkable effect, so that the release amount is not excessively large, and the release rate of the drug eluting stent in the embodiment is controlled to be about 10% at the initial stage, so that drug burst is avoided, and sufficient drug storage at the later stage is ensured to be released.

(2) Immediately after operation, the period of time can last for 7 days, and is also caused by endothelial cell injury, the rapamycin at this stage mainly inhibits inflammation and does not play an antiproliferative role, so the rapamycin at this stage has no remarkable effect, and the release rate of the drug eluting stent in the embodiment can be controlled to be lower than 20% at this stage, so that premature waste and loss of drugs are avoided.

(3) The smooth muscle proliferation peak is reached after 7-14 days and can last for 1-2 months, and in two months, the smooth muscle proliferation peak stage causes intimal thickening to cause late restenosis, and at this stage, the embodiment releases about 50% of the medicine, namely, the peak stage is reached to release enough medicine to meet the treatment requirement, and meanwhile, smooth and stable release at this stage is ensured.

(4) Finally, the blood vessel adapts to the self-adjustment of the external environment change, so as to adapt to the change of the hemodynamics and the blood vessel wall structure under different physiological and pathological states, and the sustained release of the medicine can be maintained at the middle and later stages, for example, 270 days, and the release rate reaches more than 80 percent until the maximum release from a time node to the whole release period is completed.

In vitro test case

Although the foregoing animal tests exist, in vitro accelerated test tests may also generally be employed to generally evaluate the release characteristics of the drug coating of a drug eluting stent. In vitro accelerated release experiments, the release medium may be selected to have solvents or combinations thereof that release the drug more readily than blood, to obtain an evaluation of different drug coatings in a shorter time, as a basis for improvement.

Thus, the invention also provides a method for in vitro drug release testing of drug eluting stents comprising using a buffer solution system of a trace amount of water soluble nonionic surfactant mixed with acetonitrile as a release medium. For example, a buffer solution system of about 0.1% to 1% water-soluble nonionic surfactant mixed with about 10% acetonitrile is used as the release medium. The pH of the release medium can be adjusted to about 7.4.

Taking the drug eluting stent of example 1 as an example, the procedure for the in vitro drug release test was performed:

1) Configuration of release medium: 20mL of acetonitrile and 1.8mL of 70% Triton (Triton X-405) are taken in a volumetric flask of 200mL, PBS solution (38.0 g of sodium dihydrogen phosphate and 5.04g of disodium hydrogen phosphate are taken and added with water to form 1000mL of the mixture) is used for constant volume, shaking is carried out, and the pH value is regulated to 7.4+/-0.1 by hydrochloric acid or sodium hydroxide, so that a release medium of 10% acetonitrile mixed with 0.9% Triton X-405 is obtained.

2) Release testing was performed: placing a drug eluting stent to be detected in a release medium, maintaining a water bath at 37+/-2 ℃, selecting a vibration frequency of 60r/min, simulating to release the drug, taking out the drug eluting stent at the moment point of 5min, 10min, 30min, 60min, 90min, 180min, 240min, 480min, 1200min and 1440min respectively, placing the drug eluting stent into a dissolution bottle containing acetonitrile, performing ice bath ultrasound for 30min, completely dissolving the residual rapamycin of the drug eluting stent into the acetonitrile of the dissolution bottle, quantifying, and detecting the dissolved drug in the dissolution bottle according to a chromatographic method.

The measured release profile is shown in figure 5. It can be seen that the release rate reached more than 90% at the late 1440min and approached 100% at 1800 min.

Comparative example

With reference to the method of example 1, a comparative drug eluting stent was prepared comprising a bottom layer overlying the stent body, a drug-loaded layer overlying the bottom layer, and a clear barrier layer overlying the drug-loaded layer. The bottom layer was the same as in example 1 and the drug-loaded layer and the empty barrier layer were the same fluorinated polymer as in example 1.

In the comparative example, the drug-carrying layer is a drug-coating layer containing a single concentration, the drug-carrying concentration is 10 to 20wt%, the thickness of the drug-carrying layer is 12 to 15 μm, and the barrier layer is 2 to 4 μm. The blank barrier layer is a non-drug loaded fluorinated polymer coating.

The results of in vivo or in vitro drug release curves show that the comparative example reduces the burst release phenomenon in the initial stage of release, but the release amount of the drug in the middle and later stages is obviously insufficient, the release rate is far below 15% after 30 days, and the therapeutic effect is difficult to achieve.

Although the present invention has been described in terms of the preferred embodiments, it is not intended to be limited to the embodiments, and any person skilled in the art can make any possible variations and modifications to the technical solution of the present invention by using the methods and technical matters disclosed above without departing from the spirit and scope of the present invention, so any simple modifications, equivalent variations and modifications to the embodiments described above according to the technical matters of the present invention are within the scope of the technical matters of the present invention.

Claims

1. A drug coating for a medical device, the drug coating for placement on a drug eluting stent having a diameter of greater than 5mm, the drug coating comprising a non-degradable fluorinated polymer matrix and a drug dispersed therein and forming an outer layer and an inner layer having different drug loading concentrations along a thickness direction of the drug coating, the drug coating being configured to have a drug release rate of no greater than 40% at a first 24 hours after vascular implantation of a mammal and a drug release rate of no less than 15% for a first 30 days, the drug release rate being no less than 40% or no less than 50% from day 31 to day 360 after implantation;

the non-degradable fluorinated polymer is a copolymer of vinylidene fluoride and hexafluoropropylene, and the copolymer comprises 50-92% of vinylidene fluoride and 50-8% of hexafluoropropylene by weight percent;

the drug is selected from rapamycin;

the drug loading concentration of the inner layer is 10-30wt% and the drug loading concentration of the outer layer is 3-5wt%;

the thickness of the inner layer is 10-18 mu m, and the thickness of the outer layer is 1-6 mu m;

the total drug loading is 110 mug/cm ² ～500μg/cm ² 。

2. The drug coating of claim 1, wherein the drug loading concentration of the inner layer is 10wt% to 20wt%;

Or the drug loading concentration of the inner layer is 20-30wt%, and the drug loading concentration of the outer layer is 4-5wt%;

alternatively, the drug loading concentration of the inner layer is 10wt%, 13wt%, 15wt%, 18wt% or 20wt%, and the drug loading concentration of the outer layer is 3wt%, 4wt% or 5wt%.

3. The drug coating of claim 2, wherein the inner layer has a thickness of 12-16 μm and the outer layer has a thickness of 2-4 μm;

alternatively, the thickness of the inner layer is 14-18 μm, and the thickness of the outer layer is 1-3 μm;

alternatively, the thickness of the inner layer is 10-12 μm, and the thickness of the outer layer is 3-5 μm;

alternatively, the thickness of the outer layer is 1 μm to 3 μm, or 2 μm to 4 μm, or 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm.

4. A drug coating according to claim 3, wherein the drug loading of the inner layer is 100 μg/cm ² ～400μg/cm ² The drug loading of the outer layer is 2 mug/cm ² ～60μg/cm ² 。

5. The pharmaceutical coating according to any one of claims 1-4, wherein the mammal is a human or a pig.

6. The drug coating of claim 4, wherein the drug coating is configured to have a drug release rate of no greater than 60%, or no greater than 50%, or no greater than 40% over the first 30 days after intravascular implantation in a mammal.

7. The drug coating of claim 4, wherein the drug coating is configured to have a drug release rate of no less than 10% and no more than 30%, or no more than 40%, or no more than 50% for the first 14 days after intravascular implantation in a mammal.

8. The drug coating of claim 6 or 7, wherein the drug coating is configured to have a drug release rate of no greater than 15%, or no greater than 20%, or no greater than 30% at the first 24 hours after intravascular implantation in a mammal.

9. The drug coating of claim 8, further comprising a drug-free bottom layer underlying the inner layer and overlying the body of the drug-eluting stent.