Drug-coated medical devices, methods for preparing and using same, and drug-coated layers and uses thereof

Abstract

The present disclosure belongs to the technical field of medical devices, and specifically relates to a drug-coated medical device, its preparation method and use, and a drug-coated layer and its use. The drug-coated medical device includes a carrier and a drug-coated layer that partially or completely covers the carrier, and the drug-coated layer is obtained by coating with a coating solution that mainly contains a macrolide drug and a dispersion medium, and the dispersion medium contains at least one of water and an organic solvent, and the organic solvent contains at least one of ethanol, propanol, methylene chloride, 1,4-dioxane, tetrahydrofuran, and toluene. The drug-coated medical device according to the present disclosure can transfer sufficient drug to the blood vessel wall while in contact with the blood vessel wall, and can still maintain a certain drug concentration in the blood vessel wall tissue even after a relatively long time has passed after the drug-coated medical device is removed.

Description

[Technical field]

[0001] FIELD OF THE DISCLOSURE The present disclosure is in the field of medical devices, and specifically relates to drug coated medical devices, methods for their preparation and use, as well as drug coated layers and their uses. CROSS REFERENCE TO RELATED APPLICATIONS This disclosure claims priority to a Chinese application filed with the China Patent Office on March 21, 2022, bearing application number CN202210276877.8 and entitled "Drug-Coated Medical Device, Its Preparation Method and Use, and Drug-Coated Layer and Its Use," the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Macrolide drugs, such as sirolimus, everolimus, tacrolimus and zotarolimus, have good antiproliferative effects, and can be supported on the surface of an intravascular implantation device, and can play a role in inhibiting the proliferation of vascular smooth muscle cells and suppressing restenosis by sustained release for a certain period of time. However, there are also negative effects due to the presence of an implant in the blood vessel. For this reason, it is expected that these drugs can be delivered to the lesioned blood vessel while opening the obstructed or stenosed lesioned blood vessel, and that these drugs can be retained in the lesioned blood vessel for a sufficient period of time after the treatment is completed and the device is removed, thereby playing a role in preventing restenosis.

[0003] Since such drugs have a certain degree of solubility in blood, it is necessary to transfer a sufficient amount of the drug into the blood vessel wall within a short treatment time (generally 60 seconds or less) during which the surface of the device contacts the blood vessel wall, and it is also required that a certain degree of effective tissue concentration can be maintained even after a relatively long time (e.g., 4 weeks) has passed since the operation. This is a major technical challenge. According to the description in the prior art, if the drug concentration in the tissue is 1 ng / mg or more 4 weeks after the operation, restenosis can be effectively prevented. For this reason, it is important to develop a drug-loaded medical device that can transfer a sufficient amount of the drug into the blood vessel wall within a short treatment time during which the surface of the device contacts the blood vessel wall, and that can maintain a certain degree of effective tissue concentration even after a relatively long time has passed since the operation.

[0004] In addition, in the prior art, the preparation method of the drug-loaded medical device is usually complicated, has long process steps, is time-consuming and labor-intensive, and has high costs. Summary of the Invention

[0005] The present disclosure provides a drug-coated medical device that is capable of transferring sufficient drug to the vessel wall while in contact with the vessel wall, and still maintaining some drug concentration in the vessel wall tissue even after a relatively long time period after the drug-coated medical device is removed.

[0006] The present disclosure provides a method for preparing a drug-coated medical device, which has the advantages of simple operation, mild conditions, few process steps, time saving, cost reduction, and suitable for mass production.

[0007] The present disclosure provides the use of the drug coated medical device described above in the preparation of a medicament or medical device for the treatment of atherosclerotic disease, the prevention of restenosis and the prevention of local tissue proliferation.

[0008] The present disclosure provides a drug coat layer.

[0009] The present disclosure provides a medical device.

[0010] The present disclosure provides a drug-coated medical device, the drug-coated medical device comprising a carrier and a drug coating layer partially or completely coating the carrier, the drug coating layer being obtained by coating with a coating solution mainly containing a macrolide drug and a dispersion medium; The dispersion medium includes at least one of water and an organic solvent. That is, as the dispersion medium, only water may be selected, only an organic solvent may be selected, or both water and an organic solvent may be selected.

[0011] The organic solvent includes at least one of ethanol, propanol, methylene chloride, 1,4-dioxane, tetrahydrofuran, and toluene.

[0012] The drug-coated medical device of the present disclosure can transfer sufficient drug to the vessel wall while in contact with the vessel wall, and can still maintain a certain drug concentration in the vessel wall tissue even after a relatively long time has passed since the drug-coated medical device was removed.

[0013] As the macrolide drug, any common macrolide drug can be used and can be directly purchased. The state of the macrolide drug may be in a crystalline state, a powder state, or a granular state.

[0014] A system obtained by dispersing one (or more) substance in another (or more) substance is called a dispersion system, the former being the substance to be dispersed and called the dispersoid, and the latter playing a role of surrounding and supporting the dispersoid and called the dispersion medium. In the present disclosure, the dispersion medium refers to the substance that plays a role of surrounding and supporting the dispersoid.

[0015] In the present invention, the coating solution is a suspension obtained by directly adding a macrolide drug to a dispersion medium, i.e., in the coating solution according to the present invention, the macrolide drug includes a solid macrolide drug that is not dissolved in a dispersion solution and then reprecipitated.

[0016] Optionally, the mass ratio of the macrolide to the dispersion medium is 20-100 (which can be 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, or 100):100-6000 (which can be 110, 120, 150, 170, 200, 230, 250, 300, 400, 500, 600, 700, 800, 900, 1000, 1300, 1500, 1800, 2000, 2300, 2500, 2800, 3000, 4000, 5000, or 5500).

[0017] The adoption of the above mass ratio can contribute to obtaining a drug-coated medical device with better performance.

[0018] Optionally, the macrolide comprises at least one of everolimus, tacrolimus, zotarolimus, rapamycin (sirolimus), temsirolimus, biolimus, 7-O-demethyl rapamycin, ridaforolimus, 32-deoxyrapamycin, and 42-O-(2-ethoxyethyl)rapamycin.

[0019] Optionally, the carrier comprises at least one of a drug balloon and a drug eluting stent.

[0020] Optionally, the coating solution further comprises an antioxidant.

[0021] Optionally, the antioxidant comprises at least one of a water soluble antioxidant and a fat soluble antioxidant.

[0022] Optionally, the water soluble antioxidant comprises at least one of malic acid, chlorogenic acid, procyanidin, ascorbic acid, sodium ascorbate, calcium ascorbate, potassium ascorbate, calcium pantothenate, and vitamin E polyethylene glycol succinate.

[0023] Malic acid is also known as 2-hydroxybutanedioic acid. There are three isomers: L-malic acid, D-malic acid, and DL-malic acid. Malic acid appears as colorless needle-like crystals or a white crystalline powder, is odorless, and has a distinctive, pleasantly sour taste.

[0024] Chlorogenic acid is an organic compound with the chemical formula C 16 H 18 It is O9 and has antibacterial, antiviral, white blood cell-increasing, liver-protecting, bile secretion-promoting, antitumor, blood pressure-lowering, blood lipid-lowering, radical scavenging, and central nervous system stimulating effects.

[0025] Procyanidin is a general term for a type of polyphenolic compound that is widely found in plants and has high antioxidant and radical scavenging properties.

[0026] Ascorbic acid, also known as Vitamin C, is a polyhydroxy compound with the chemical formula C6H8O6. It is a white crystal or crystalline powder, odorless, acidic, turns yellowish over time, soluble in water, acidic, and slightly soluble in ethanol.

[0027] Sodium ascorbate, whose chemical formula is C6H7O6Na, is a white to slightly yellow crystalline powder or granule, odorless, slightly salty in taste, easily soluble in water, and can be used as a food antioxidant.

[0028] Calcium ascorbate is a white to pale yellow crystalline powder, is odorless, soluble in water, slightly soluble in ethanol, insoluble in diethyl ether, and is more stable than Vc and has a superior antioxidant effect than Vc.

[0029] Calcium pantothenate is an organic substance with the chemical formula C 18 H 32 O 10 It is N2Ca and is freely soluble in water and glycerin.

[0030] Optionally, the fat-soluble antioxidant comprises at least one of vitamin E, dibutylhydroxytoluene, butylhydroxyanisole, ascorbyl palmitate, tocopherol, probucol, propyl gallate, and tert-butylhydroquinone.

[0031] Vitamin E is a fat-soluble vitamin that contains four tocopherols and four tocotrienols and is an antioxidant.

[0032] Dibutylhydroxytoluene (BHT) has antioxidant and preservative properties.

[0033] Butyl hydroxyanisole, also known as t-butyl hydroxyanisole, t-butyl-p-hydroxyanisole, butylated hydroxyanisole, or tert-butyl 4-hydroxyanisole, is a white to slightly yellow crystalline or waxy solid with a slightly peculiar smell and can be used as a food antioxidant.

[0034] Ascorbyl palmitate is formed by esterifying natural ingredients such as palmitic acid and L-ascorbic acid, and has the chemical formula C 22 H 38 O7, a highly efficient oxygen scavenger and potentiator.

[0035] Tocopherol is a hydrolysate of vitamin E. It can enhance the antioxidant effect of cells, maintain and promote reproductive function, have a certain degree of anti-aging effect, improve lipid metabolism, prevent arteriosclerosis, and lower blood lipids.

[0036] Probucol is a white or pseudo-white crystalline powder with a special odor and blood lipid regulating and anti-lipid peroxidation effects.

[0037] Propyl gallate is a white to pale yellowish brown crystalline powder or milky white needle-shaped crystals, is odorless, has a slightly bitter taste, its aqueous solution is odorless, is hygroscopic, its decomposition is accelerated by irradiation with light, is poorly soluble in water, and is easily soluble in hot water, ethanol, diethyl ether, propylene glycol, glycerin, cottonseed oil, peanut oil, and lard.

[0038] Tertiary butylhydroquinone (TBHQ) is a white powdery crystal with a special odor, easily soluble in ethanol and diethyl ether, soluble in oils and fats, and insoluble in water.

[0039] Since macrolide drugs are susceptible to oxidation in air, the present disclosure provides the ability to add antioxidants to improve the storage stability of the product and extend the shelf life of drug-coated medical devices.

[0040] Optionally, the weight ratio of the antioxidant to the macrolide is 0.01-10 (which can be 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, or 9):1.

[0041] Optionally, when the dispersion medium in the coating liquid is water, the antioxidant used in the coating liquid is a water-soluble antioxidant, or when the dispersion medium in the coating liquid is an organic solvent, the antioxidant used in the coating liquid is a fat-soluble antioxidant.

[0042] When both water and an organic solvent are used as the dispersion medium in the coating solution, the antioxidant used in the coating solution may be one of a water-soluble antioxidant and an oil-soluble antioxidant, or a mixture of a water-soluble antioxidant and an oil-soluble antioxidant may be used.

[0043] Optionally, the coating fluid further comprises a polymeric material.

[0044] The polymer material acts, on the one hand, as a binder and, on the other hand, as a dispersion stabilizer.

[0045] The use of a polymeric material as a binder can improve the adhesion between the mixed material and the carrier.

[0046] Furthermore, if a polymeric material is used as a dispersion stabilizer, the macrolide drug can be stably dispersed in the dispersion medium, which contributes to coating.

[0047] Optionally, the polymeric material comprises at least one of polyethylene glycol, polyethylene oxide, hyaluronic acid, carboxymethylcellulose, collagen, polyvinylpyrrolidone, and polyvinyl alcohol.

[0048] Optionally, the mass ratio of the polymeric material to the dispersion medium is 0.1-30 (which can be 0.5, 1, 2, 3, 4, 5, 6, 7, 8 or 9):100-1000 (which can be 120, 150, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800 or 900).

[0049] Optionally, when the dispersion medium in the coating solution is an organic solvent, the drug coating layer is obtained by coating a coating solution containing a macrolide drug and a dispersion medium together with an additive solution containing water.

[0050] When water is used as a dispersion medium, since most macrolide drugs are poorly soluble in water, the coating liquid containing the macrolide drug and the dispersion medium is generally a suspension. In some optional embodiments of the present disclosure, the coating liquid is made into a suspension state by means of stirring, vortexing, ultrasonication, or homogenization (performed with a homomixer), i.e., small granules of the solid drug in the coating liquid are suspended in the liquid. In this way, the macrolide drug can uniformly cover the surface of the carrier when coating is performed.

[0051] When an organic solvent is used as the dispersion medium in the coating solution, the drug coating layer is obtained by coating a coating solution containing a macrolide drug and a dispersion medium together with an additive solution containing water. Generally, macrolide drugs are soluble in organic solvents, so the coating solution prepared in this case is in a solution state. If the additive solution containing water and the coating solution are coated together, the macrolide drug will reprecipitate upon contact with water during coating to assume a crystalline, powdery or small granular form. In this way, the crystal form of the macrolide drug will not be affected in the subsequent drying process.

[0052] Optionally, the additive solution further comprises at least one of a water soluble antioxidant and a polymeric material.

[0053] Optionally, the additive solution may be, by weight, primarily comprised of 80 to 1200 parts (including, but not limited to, any one or any two of the following ranges of values: 85 parts, 90 parts, 95 parts, 100 parts, 105 parts, 110 parts, 115 parts, 200 parts, 500 parts, 800 parts, 1000 parts, 1100 parts) of water, 0 to 100 parts (5 parts, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts, 60 parts, 70 parts, 80 parts, 90 parts, 100 parts, 110 parts, 120 parts, 130 parts, 140 parts, 150 parts, 160 parts, 170 parts, 180 parts, 190 parts, 200 parts, 210 parts, 220 parts, 230 parts, 240 parts, 250 parts, 260 parts, 270 parts, 280 parts, 290 parts, 300 parts, 310 parts, 320 parts, 330 parts, 340 parts, 350 parts, 360 parts, 370 parts, 380 parts, 390 parts, 400 parts, 410 parts, 420 parts, 430 parts, 440 parts, 450 parts, 460 parts, 470 parts, 480 parts, 490 parts, 500 parts, 510 parts, 520 parts, 530 parts, 540 parts, 550 parts, 560 parts, 570 parts, 580 parts, 590 parts, 600 parts, 610 parts, , 80 parts, 90 parts) of a water-soluble antioxidant; and 0 to 300 parts (including but not limited to any one or any two of the following ranges: 10 parts, 30 parts, 50 parts, 80 parts, 100 parts, 130 parts, 150 parts, 180 parts, 200 parts, 230 parts, 250 parts, 270 parts, 290 parts) of a polymeric material.

[0054] Optionally, the weight ratio of the coating solution to the additive solution is 1-7 (can be 2, 3, 4, 5 or 6):1-7 (can be 2, 3, 4, 5 or 6).

[0055] In some optional embodiments of the present disclosure, the coating concentration of the coating solution is 0.05 μg / mm 2 ~50μg / mm 2 and 0.1 μg / mm 2 , 0.5 μg / mm 2 , 1μg / mm 2 , 3 μg / mm 2 , 5 μg / mm 2 , 8 μg / mm 2 , 10μg / mm 2 , 15μg / mm 2 , 20μg / mm 2 , 25 μg / mm 2 , 30 μg / mm 2 , 35 μg / mm 2 , 40 μg / mm 2 , 45 μg / mm 2 The present invention is not limited to the above, and includes any one or any two of the following values:

[0056] The present disclosure further provides a method for preparing the drug-coated medical device, comprising the steps of applying a coating solution containing a macrolide drug and a dispersion medium to a surface of the carrier to obtain a drug-coated medical device.

[0057] The preparation method according to the present disclosure is simple, easy to carry out, has few process steps, mild conditions, can save a lot of time, reduce costs, and is suitable for mass production.

[0058] Optionally, in the present disclosure, the drug is applied directly to the surface of the carrier in the form of small granules.

[0059] In the prior art, the preparation methods of drug-coated medical devices are complicated, for example, the carrier is subjected to a hydrophilic treatment in advance, or a specific material is applied to the surface of the carrier to obtain a primer layer, or, for example, drug crystals are directly grown on the carrier.

[0060] The preparation method of the present disclosure is very simple to operate, has few process steps, and requires a short time, and the drug-coated medical device prepared by this method can transfer sufficient drug to the blood vessel wall and can still maintain a certain drug concentration in the blood vessel wall tissue even after a relatively long time has passed since the drug-coated medical device was removed, and optionally, the drug concentration in the tissue is 1 ng / mg or more 4 weeks after surgery, thereby meeting the needs of the medical field.

[0061] Optionally, the macrolide has a D50 particle size of less than 200 μm, including, but not limited to, any one or any two of the following ranges: 190 μm, 180 μm, 170 μm, 160 μm, 150 μm, 130 μm, 110 μm, 100 μm, 80 μm, 60 μm, 50 μm, 30 μm, 20 μm, 10 μm, 5 μm, 3 μm, 1 μm, 0.5 μm, 0.3 μm, 0.1 μm, 0.05 μm.

[0062] Optionally, the coating concentration of the coating solution is, in terms of drug, 0.05 μg / mm 2 ~50μg / mm 2and 0.1 μg / mm 2 , 0.5 μg / mm 2 , 1μg / mm 2 , 3 μg / mm 2 , 5 μg / mm 2 , 8 μg / mm 2 , 10μg / mm 2 , 15μg / mm 2 , 20μg / mm 2 , 25 μg / mm 2 , 30 μg / mm 2 , 35 μg / mm 2 , 40 μg / mm 2 , 45 μg / mm 2 The present invention is not limited to the above, and includes any one or any two of the following values:

[0063] Optionally, the method of application includes at least one of spray coating, dip coating, drop coating, and brushing.

[0064] Optionally, the spray coat comprises an ultrasonic spray coat.

[0065] Ultrasonic spray coating is a spray coating process that uses ultrasonic atomization technology, and the material to be spray coated can be a solution or suspension. Ultrasonic spray coating has the advantages of high uniformity of the coating layer, high raw material utilization rate, little liquid splashing, and easy control of the amount of spray coating.

[0066] Optionally, said application is followed by drying, packaging and sterilization steps carried out in sequence.

[0067] Optionally, when the dispersion medium in the coating liquid is an organic solvent, the coating method includes a step of simultaneously coating a coating liquid containing a macrolide drug and a dispersion medium and an additive solution containing water onto the surface of the carrier.

[0068] Optionally, the additive solution further comprises at least one of a water-soluble antioxidant and a polymeric material, the water-soluble antioxidant comprising at least one of malic acid, chlorogenic acid, procyanidin, ascorbic acid, sodium ascorbate, calcium ascorbate, potassium ascorbate, calcium pantothenate, and vitamin E polyethylene glycol succinate, and the polymeric material comprising at least one of polyethylene glycol, polyethylene oxide, hyaluronic acid, carboxymethylcellulose, collagen, polyvinylpyrrolidone, and polyvinyl alcohol.

[0069] In the present disclosure, simultaneous application means that the coating liquid and the additive solution are applied to the surface of the carrier at the same time, and the coating liquid and the additive solution are applied at the same position. When spray coating is used, the coating liquid and the additive solution are spray-coated onto the surface of the carrier at the same time from two directions, and an intersection is formed on the surface of the carrier during spray coating. In this way, the macrolide drug is reprecipitated when it comes into contact with water, so that the crystal form of the macrolide drug is not affected in the subsequent drying process, which contributes to ensuring the efficacy of the drug.

[0070] Optionally, the temperature of at least one of the coating solution and the additive solution is less than 70°C, including, but not limited to, any one or any two of the following values: 60°C, 50°C, 40°C, 30°C, 20°C, 10°C, 5°C.

[0071] The present disclosure further provides the use of the above-described drug-coated medical device, or a drug-coated medical device prepared by the above-described method for preparing a drug-coated medical device, in the preparation of a medicament or medical device for the treatment of atherosclerotic disease, the prevention of restenosis, and the prevention of localized tissue proliferation.

[0072] The present disclosure further provides a drug coating layer, the drug coating layer comprising a macrolide drug and a water-soluble antioxidant.

[0073] Optionally, the macrolide comprises at least one of everolimus, tacrolimus, zotarolimus, rapamycin, temsirolimus, biolimus, 7-O-demethylrapamycin, ridaforolimus, 32-deoxyrapamycin, and 42-O-(2-ethoxyethyl)rapamycin.

[0074] Optionally, the water soluble antioxidant comprises at least one of malic acid, chlorogenic acid, procyanidin, ascorbic acid, sodium ascorbate, calcium ascorbate, potassium ascorbate, calcium pantothenate, and vitamin E polyethylene glycol succinate.

[0075] Optionally, the mass ratio of the water-soluble antioxidant to the macrolide is 0.01-10 (0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, or 9):1.

[0076] The present disclosure further provides a medical device, said medical device comprising a drug coating layer as described above.

[0077] Compared with the prior art, the present disclosure has the following beneficial effects:

[0078] (1) The drug-coated medical device of the present disclosure is capable of transferring sufficient drug to the blood vessel wall while in contact with the blood vessel wall and is capable of still maintaining a certain drug concentration in the blood vessel wall tissue even after a relatively long time has passed since the drug-coated medical device was removed.

[0079] (2) The method for preparing a drug-coated medical device according to the present disclosure has the advantages of being simple in operation, requiring mild conditions, having few process steps, requiring a short time, reducing costs, and being suitable for mass production.

[0080] (3) The method for preparing a drug-coated medical device according to the present disclosure comprises simultaneously applying a coating solution containing a macrolide drug and a dispersion medium, and an additive solution containing water, to the surface of a carrier, thereby significantly simplifying the preparation process, and is capable of maintaining a relatively high drug concentration in the vascular wall tissue even after a relatively long time has passed since the drug-coated medical device was removed.

[0081] In order to more clearly describe the embodiments of the present disclosure or the technical solutions in the prior art, the drawings used in the embodiments or the prior art are briefly described below. The drawings described show some embodiments of the present disclosure. Those skilled in the art can obtain other related drawings based on these drawings without using their inventive abilities. [Brief description of the drawings]

[0082] [Figure 1] 1 is a SEM photograph of a drug-coated medical device according to Example 1 of the present disclosure. [Diagram 2] 1 is a SEM photograph of a drug-coated medical device according to Example 2 of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0083] The technical solutions of the present disclosure will be described clearly and completely below with reference to the embodiments. As those skilled in the art will understand, the described examples are only some of the examples of the present disclosure, not all of the examples, and are only for illustrating the present disclosure and do not limit the scope of the present disclosure. Based on the examples in the present disclosure, all other examples obtained by those skilled in the art without using inventive abilities also belong to the scope of protection of the present disclosure. In the examples, the specific conditions are not specified, and they can be carried out under conventional conditions or conditions recommended by the manufacturer. For reagents or instruments whose manufacturers are not specified, conventional products available on the market can be used.

[0084] In one embodiment of the present disclosure, the method for preparing the drug-coated medical device includes applying a suspension (suspension) containing a macrolide drug and water to a surface of a carrier to obtain a drug-coated medical device (a medical device having a drug coating layer).

[0085] Optionally, the suspension further comprises at least one of a water soluble antioxidant and a polymeric material.

[0086] In another embodiment of the present disclosure, the method for preparing the drug-coated medical device includes the steps of simultaneously applying a mixed solution containing a macrolide drug and an organic solvent and an additive solution containing water to a surface of a carrier such that the application areas of the mixed solution and the additive solution are the same, thereby obtaining a drug-coated medical device.

[0087] Optionally, the mixture further comprises a fat-soluble antioxidant.

[0088] Optionally, the additive solution further comprises at least one of a water soluble antioxidant and a polymeric material.

[0089] Sirolimus, everolimus, and tacrolimus used in the following examples and comparative examples of the present disclosure were all purchased commercially. EXAMPLES

[0090] Example 1 The method for preparing a drug-coated medical device according to this embodiment includes the following steps.

[0091] 30 mg of sirolimus (D50 particle size 200 μm, manufacturer: Huabei Pharmaceutical) was added to 1000 mg of distilled water, and a stable suspension (temperature of the suspension was 20°C) was formed by ultrasonic vibration. Then, the above suspension was taken and applied to the surface of the drug balloon, so that the drug concentration on the surface of the drug balloon was 4 μg / mm 2 After drying, a drug-coated medical device was obtained.

[0092] The drug-coated medical device was subjected to SEM measurement, and the results are shown in Figure 1. As shown in Figure 1, the drug is distributed in a granular form on the surface of the device.

[0093] Example 2 The method for preparing a drug-coated medical device according to this embodiment includes the following steps.

[0094] 30 mg of ascorbic acid was added to 1000 mg of distilled water and completely dissolved by stirring, and then 25 mg of sirolimus (D50 particle size less than 200 μm, manufacturer Wuhan NEWBIO PHARM-TECH Co., Ltd.) was added thereto, and a suspension was formed by high-speed stirring using a homomixer (the temperature of the suspension was 25° C.), and the suspension was placed in an ultrasonic cleaner and vibrated to maintain a stable suspension state.

[0095] The above suspension was taken and applied to the surface of the drug balloon so that the drug concentration on the surface of the drug balloon was 3 μg / mm 2 After drying, a drug-coated medical device was obtained.

[0096] This example further provided a drug coating layer, which consisted of a macrolide drug (sirolimus) and ascorbic acid.

[0097] The drug-coated medical device was subjected to SEM measurement, and the measurement results are shown in Figure 2. As shown in Figure 2, the drug is distributed on the surface of the device in an obvious granular form.

[0098] Example 3 The method for preparing a drug-coated medical device according to this embodiment includes the following steps.

[0099] 30 mg of sirolimus (D50 particle size less than 200 μm, manufacturer was Zhongmei Huadong Pharmaceutical Co., Ltd.) was weighed and dissolved in 1000 mg of ethanol to obtain a coating solution (temperature was 25° C.).

[0100] 50 mg of L-malic acid was added to 1000 mg of distilled water and completely dissolved by stirring to obtain an additive solution (temperature was 25° C.).

[0101] The above coating solution and additive solution were simultaneously applied to the surface of the drug balloon, and the drug concentration of sirolimus on the surface of the drug balloon was set to 2.5 μg / mm 2 and the concentration of L-malic acid was 1.3 μg / mm 2 The coated layer was then ultrasonically spray-coated to form a white powdery coating layer. After drying, a drug-coated medical device was obtained.

[0102] This example further provided a drug coating layer, which consisted of a macrolide drug (sirolimus) and L-malic acid.

[0103] Example 4 The method for preparing a drug-coated medical device according to this embodiment includes the following steps.

[0104] 25 mg of polyethylene glycol (molecular weight was 20,000) was added to 1,000 mg of distilled water and completely dissolved by stirring, and 25 mg of sirolimus (D50 particle size was less than 200 μm, manufacturer was Hisun Pharmaceutical) was added thereto and stirred at high speed using a homomixer to form a stable suspension (temperature of the suspension was 30°C). The above suspension was applied to the surface of the drug balloon, so that the drug concentration on the surface of the drug balloon was 1 μg / mm 2 After drying, a drug-coated medical device was obtained.

[0105] Example 5 The method for preparing a drug-coated medical device according to this embodiment includes the following steps.

[0106] 30 mg of sirolimus (D50 particle size was less than 200 μm, manufacturer was Xinchang Pharmaceutical Factory) was weighed and dissolved in 5000 mg of propanol to obtain a coating solution (temperature was 35° C.).

[0107] 30 mg of calcium pantothenate was added to 1000 mg of distilled water and completely dissolved by stirring to obtain an additive solution (temperature was 35° C.).

[0108] The above coating solution and additive solution were simultaneously applied to the surface of the drug balloon, and the drug concentration of sirolimus on the surface of the drug balloon was set to 5 μg / mm 2 The concentration of L-malic acid was 4.8 μg / mm 2 The coated layer was then ultrasonically spray-coated to form a white powdery coating layer. After drying, a drug-coated medical device was obtained.

[0109] Example 6 The method for preparing a drug-coated medical device according to this embodiment includes the following steps.

[0110] 30 mg of everolimus (D50 particle size less than 200 μm, manufacturer was Hubei Jiuzhou Kangda Biotechnology Co., Ltd.) was added to 3000 mg of distilled water, and a stable suspension (temperature of suspension was 65°C) was formed by ultrasonic vibration. Then, the drug balloon was placed in a 10 μg / mm 2 tube so that the drug concentration of everolimus on the surface of the drug balloon was 10 μg / mm 2 . 2 The drug-coated medical device was then immersed in the above suspension so as to be completely coated with the drug. The device was then dried, packaged and sterilized to obtain a drug-coated medical device.

[0111] Example 7 The method for preparing a drug-coated medical device according to this embodiment includes the following steps.

[0112] 100 mg of everolimus (D50 particle size less than 200 μm, manufacturer was Wuhan Biocar Biological Pharmaceutical Co., Ltd.), 1 mg of hyaluronic acid and 300 mg of sodium ascorbate were added to 1000 mg of distilled water, and a stable suspension (temperature of the suspension was 40°C) was formed by ultrasonic vibration. Then, the above suspension was applied to the surface of the drug-eluting stent, and the drug concentration on the surface of the drug-eluting stent was 50 μg / mm 2 The drug-coated medical device was then ultrasonically spray-coated to obtain a drug-coated layer.

[0113] Example 8 The method for preparing a drug-coated medical device according to this embodiment includes the following steps.

[0114] 30 mg of tacrolimus (D50 particle size less than 200 μm, manufacturer Jinan Jiage Biotechnology Co., Ltd.) was weighed and dissolved in 100 mg of methylene chloride, and 150 mg of vitamin E was added to obtain a coating solution (temperature was 20° C.).

[0115] The above coating solution and 200 mg of distilled water (i.e., additive solution) were applied to the surface of the drug-eluting stent, and the drug concentration of sirolimus on the surface of the drug-eluting stent was adjusted to 8 μg / mm 2 At the same time, ultrasonic spray coating was performed so as to coat the surface of the drug-coated medical device with the drug-coated layer.

[0116] Example 9 The method for preparing a drug-coated medical device according to this embodiment includes the following steps.

[0117] 100 mg of tacrolimus (D50 particle size less than 200 μm, manufacturer Hisun Pharmaceutical) was weighed and dissolved in 1000 mg of toluene to obtain a coating solution (temperature was 25° C.).

[0118] 100 mg of L-malic acid and 250 mg of carboxymethylcellulose were added to 1000 mg of distilled water and completely dissolved by stirring to obtain an additive solution (temperature was 25° C.).

[0119] The above coating solution and additive solution were simultaneously applied to the surface of the drug balloon, and the drug concentration of sirolimus on the surface of the drug balloon was set to 2 μg / mm 2 The concentration of L-malic acid was set at 1 μg / mm 2 The concentration of carboxymethylcellulose was set at 3 μg / mm 2 The coated layer was then ultrasonically spray-coated to form a white powdery coating layer. After drying, a drug-coated medical device was obtained.

[0120] Example 10 The method for preparing a drug-coated medical device according to this embodiment includes the following steps.

[0121] 30 mg of chlorogenic acid was added to 1000 mg of distilled water and completely dissolved by stirring, and then 25 mg of rapamycin (D50 particle size less than 200 μm, manufacturer: Yibin Weixi Pharmaceutical Co., Ltd.) was added thereto, and a suspension was formed by high-speed stirring using a homomixer (the temperature of the suspension was 25° C.), and the suspension was placed in an ultrasonic cleaner and vibrated to maintain a stable suspension state.

[0122] The above suspension was applied to the surface of the drug balloon, and the drug concentration on the surface of the drug balloon was set to 10 μg / mm 2 After drying, a drug-coated medical device was obtained.

[0123] This example further provided a drug coating layer, which consisted of a macrolide drug (rapamycin) and chlorogenic acid.

[0124] Comparative Example 1 The method for preparing the drug-coated medical device according to this comparative example was substantially the same as that of Example 1, except that an equal mass of ethanol was used instead of distilled water.

[0125] Comparative Example 2 The method for preparing the drug-coated medical device according to this comparative example was almost the same as that of Example 1, and differed from Example 1 only in that the D50 particle size of sirolimus was made to exceed 200 μm.

[0126] Comparative Example 3 The method for preparing the drug-coated medical device of this comparative example was almost the same as that of Example 1, and differed from Example 1 only in that the mass of sirolimus was 100 mg.

[0127] Comparative Example 4 The method for preparing the drug-coated medical device according to this comparative example is almost the same as that of Example 3, except that the step in Example 3 of “ultrasonic spray coating the above-mentioned coating liquid and additive solution simultaneously onto the surface of the drug balloon” is changed to a step of “uniformly mixing the above-mentioned coating liquid and additive solution, and then ultrasonically spray coating the surface of the drug balloon.”

[0128] Experimental Example Animal experiments were carried out using the drug-coated medical devices obtained from each of the above examples and comparative examples. The method was as follows. The drug-coated medical device was inserted into the coronary artery of a pig under the guidance of DSA angiography (digital subtraction angiography), and the pressure was released by dilating the device at 6 atmospheric pressure for 60 seconds, and the drug-coated medical device was removed. After 4 weeks of breeding, the animals were killed, and the coronary arteries of the experimental animals were weighed, homogenized, and extracted, and the drug concentration in the tissue was measured using a liquid chromatography mass spectrometer. The results are shown in Table 1 below.

[0129] [Table 1]

[0130] As can be seen from Table 1, the drug concentration in the tissue of each embodiment of the present disclosure is 1 ng / mg or more, and therefore, the prevention of restenosis can be ensured.

[0131] Although the present disclosure has been described using examples, the above examples are merely for illustrating the technical solutions of the present disclosure and are not intended to limit the same. As will be understood by those skilled in the art, the technical solutions described in the above examples may be modified or some or all of the technical features may be equivalently replaced without departing from the spirit and scope of the present disclosure. These modifications or replacements do not deviate from the scope of the technical solutions of the embodiments of the present disclosure in accordance with the spirit of the corresponding technical solutions. Therefore, the appended claims include all replacements and modifications that fall within the scope of the present disclosure.

Claims

1. The present invention includes a carrier and a drug coating layer that partially or completely covers the carrier, The drug coating layer is obtained by applying a coating solution containing mainly a macrolide drug and a dispersion medium, The dispersion medium includes at least one of water and an organic solvent, and the organic solvent includes at least one of ethanol, propanol, methylene chloride, 1,4-dioxane, tetrahydrofuran, and toluene. A drug-coated medical device comprising:

2. the mass ratio of the macrolide drug to the dispersion medium is 20-100:100-6000; Preferably, the macrolide comprises at least one of everolimus, tacrolimus, zotarolimus, rapamycin, temsirolimus, biolimus, 7-O-demethylrapamycin, ridaforolimus, 32-deoxyrapamycin and 42-O-(2-ethoxyethyl)rapamycin; Preferably, the carrier comprises at least one of a drug balloon and a drug eluting stent.

2. The drug-coated medical device of claim 1.

3. The coating solution further contains an antioxidant, Preferably, the antioxidant comprises at least one of a water-soluble antioxidant and a fat-soluble antioxidant, Preferably, the water-soluble antioxidant comprises at least one of malic acid, chlorogenic acid, procyanidin, ascorbic acid, sodium ascorbate, calcium ascorbate, potassium ascorbate, calcium pantothenate, and vitamin E polyethylene glycol succinate; Preferably, the fat-soluble antioxidant comprises at least one of vitamin E, dibutylhydroxytoluene, butylhydroxyanisole, ascorbyl palmitate, tocopherol, probucol, propyl gallate, and tert-butylhydroquinone; Preferably, the mass ratio of the antioxidant to the macrolide is 0.01 to 10:1; Preferably, when the dispersion medium in the coating liquid is water, the antioxidant used in the coating liquid is a water-soluble antioxidant, or when the dispersion medium in the coating liquid is an organic solvent, the antioxidant used in the coating liquid is a fat-soluble antioxidant.

2. The drug-coated medical device of claim 1.

4. The coating solution further contains a polymer material, Preferably, the polymeric material comprises at least one of polyethylene glycol, polyethylene oxide, hyaluronic acid, carboxymethylcellulose, collagen, polyvinylpyrrolidone and polyvinyl alcohol; Preferably, the mass ratio of the polymer material to the dispersion medium is 0.1-30:100-1000.

2. The drug-coated medical device of claim 1.

5. When the dispersion medium in the coating liquid is an organic solvent, the drug coating layer is obtained by coating a coating liquid containing a macrolide drug and a dispersion medium together with an additive solution containing water. The drug-coated medical device according to any one of claims 1 to 4.

6. The additive solution further comprises at least one of a water-soluble antioxidant and a polymeric material; Preferably, the additive solution consists essentially of, by weight, 80-1200 parts water, 0-100 parts water-soluble antioxidant, and 0-300 parts polymeric material.

6. The drug-coated medical device of claim 5.

7. The method includes the step of applying a coating liquid containing a macrolide drug and a dispersion medium to the surface of the carrier to obtain a drug-coated medical device. A method for preparing the drug-coated medical device according to any one of claims 1 to 6.

8. The macrolide has a D50 particle size of less than 200 μm; Preferably, the coating concentration of the coating solution is 0.05 μg / mm in terms of macrolide drug. ２ ~50μg / mm ２ and Preferably, the application method includes at least one of spray coating, dip coating, drop coating, and brushing, Preferably, said coating step is followed by a drying step, a packaging step and a sterilization step, which are carried out in sequence.

8. The method according to claim 7 .

9. The coating method includes: The method further includes a step of simultaneously applying a coating solution containing a macrolide drug and a dispersion medium and an additive solution containing water to a surface of the carrier, Preferably, the temperature of at least one of the coating liquid and the additive solution is less than 70° C.

8. The method according to claim 7 .

10. Use of a drug-coated medical device according to any one of claims 1 to 6, or a drug-coated medical device prepared by the method for preparing a drug-coated medical device according to any one of claims 7 to 9, in the preparation of a medicament or medical device for the treatment of atherosclerotic disease, the prevention of restenosis, and the prevention of local tissue proliferation.

11. It consists of a macrolide drug and a water-soluble antioxidant. A drug coating layer characterized by:

12. the macrolide drug comprises at least one of everolimus, tacrolimus, zotarolimus, rapamycin, temsirolimus, biolimus, 7-O-demethylrapamycin, ridaforolimus, 32-deoxyrapamycin, and 42-O-(2-ethoxyethyl)rapamycin; Preferably, the water-soluble antioxidant comprises at least one of malic acid, chlorogenic acid, procyanidin, ascorbic acid, sodium ascorbate, calcium ascorbate, potassium ascorbate, calcium pantothenate, and vitamin E polyethylene glycol succinate; Preferably, the weight ratio of the water-soluble antioxidant to the macrolide drug is 0.01 to 10:

1. The drug coating layer of claim 11.

13. A medical device comprising a drug coating layer according to claim 11 or 12.

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