Medical devices with a drug-coated layer, methods for preparing and using the same, and drug-coated layer and its use.

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] This disclosure relates to the technical field of medical devices, and more specifically to medical devices with drug-coated layers, methods for preparing and using the same, and drug-coated layers and their use. Cross-reference of related applications This disclosure claims priority based on a Chinese patent application filed with the China Patent Office on March 21, 2022, with application number CN202210276877.8, titled "Medical device with drug coating layer, method of preparation and use thereof, and drug coating layer and its use," the entirety of which is incorporated by reference in this disclosure. [Background technology]

[0002] Macrolide antibiotics, such as sirolimus, everolimus, tacrolimus, and zotarolimus, have excellent growth inhibitory effects and can be carried on the surface of intravascular implantable devices. By being released slowly over a certain period, they can suppress the proliferation of vascular smooth muscle cells and prevent restenosis. However, the presence of the implant in the blood vessel can have negative effects. Therefore, there is a need for a device that can deliver these drugs to the occluded or narrowed lesion vessel while simultaneously opening it, and that can retain these drugs in the lesion vessel for a sufficient period after the device is removed following treatment, thereby preventing restenosis.

[0003] Because such drugs have a certain degree of solubility in the blood, it is necessary to transfer a sufficient amount of the drug into the blood vessel wall within a short treatment time (generally less than 60 seconds) during which the instrument surface is in contact with the blood vessel wall, and it is required that a certain level of effective tissue concentration can still be maintained even after a relatively long period of time post-operatively (e.g., 4 weeks). This presents a significant technical challenge. According to previous literature, restenosis can be effectively prevented if the drug concentration in the tissue is 1 ng / mg or higher after 4 weeks post-operatively. Therefore, it is important to develop drug-carrying medical devices that can transfer a sufficient amount of the drug into the blood vessel wall within a short treatment time during which the instrument surface is in contact with the blood vessel wall, and that can still maintain a certain level of effective tissue concentration even after a relatively long period of time post-operatively.

[0004] Furthermore, conventional technologies typically involve complex and lengthy process steps for preparing medical devices containing pharmaceuticals, resulting in wasted time and effort, and high costs. [Overview of the Initiative]

[0005] This disclosure provides a drug-coated medical device. The drug-coated medical device can transfer a sufficient amount of drug to the blood vessel wall while in contact with the blood vessel wall, and can maintain a certain level of drug concentration in the blood vessel wall tissue even after a relatively long period of time has passed since the drug-coated medical device was removed.

[0006] This disclosure provides a method for preparing a drug-coated medical device. This preparation method has advantages such as being easy to operate, requiring mild conditions, having fewer process steps, saving time, reducing costs, and being suitable for mass production.

[0007] This disclosure provides the use of the above-mentioned drug-coated medical device in the preparation of drugs or medical devices for the treatment of atherosclerotic disease, prevention of restenosis, and prevention of local tissue proliferation.

[0008] This disclosure provides a drug coating layer.

[0009] The present disclosure provides a medical device.

[0010] The present disclosure provides a medicated coating layer medical device. The medicated coating layer medical device includes a carrier and a medicated coating layer that partially or completely covers the carrier. The medicated coating layer is 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 medicated coating layer 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 after removing the medicated coating layer medical device.

[0013] As the macrolide drug, any common macrolide drug can be used and can be obtained by direct purchase. The state of the macrolide drug may be a crystalline state, a powder state, or a granular state.

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

[0015] In the present invention, the coating solution is a suspension obtained by directly distributing a macrolide-based agent in a dispersion medium; that is, in the coating solution according to the present invention, the macrolide-based agent includes a solid macrolide-based agent that is not dissolved in the dispersion and reprecipitationd.

[0016] Optionally, the mass ratio of the macrolide drug to the dispersion medium is 20-100 (which may be 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, or 100): 100-6000 (which may 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] By adopting the above mass ratio, it is possible to obtain medical devices with a drug-coated layer that have better performance.

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

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

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

[0021] Optionally, the antioxidant may include at least one of a water-soluble antioxidant and a lipid-soluble antioxidant.

[0022] Optionally, the water-soluble antioxidant may include 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-hydroxybutanediic acid. It has three isomers: L-malic acid, D-malic acid, and DL-malic acid. Malic acid is a colorless needle-shaped crystal or a white crystalline powder, odorless, and has a distinctive and pleasant sour taste.

[0024] Chlorogenic acid is an organic compound with the chemical formula C 16 H 18 It is O9 and has effects such as antibacterial, antiviral, leukocytosis, hepatoprotection, bile secretion promotion, antitumor, blood pressure reduction, blood lipid reduction, radical scavenging, and central nervous system stimulation.

[0025] Procyanidins are a general term for a type of polyphenol compound widely found in plants, possessing strong 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 crystalline or crystalline powder, odorless, acidic, and its color turns yellowish over time. It is readily soluble in water, acidic, and slightly soluble in ethanol.

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

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

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

[0030] Optionally, the lipid-soluble antioxidant may include at least one of the following: vitamin E, dibutylhydroxytoluene, butylhydroxyanisole, ascorbyl palmitate, tocopherol, propucol, propyl gallate, and tert-butylhydroquinone.

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

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

[0033] Butylhydroxyanisole, also known as t-butylhydroxyanisole, t-butyl-p-hydroxyanisole, butylated hydroxyanisole, or tert-butyl-4-hydroxyanisole, is a white to slightly yellowish crystalline or waxy solid with a somewhat distinctive odor and can be used as a food antioxidant.

[0034] Ascorbyl palmitate is formed by esterifying palmitic acid with natural components such as L-ascorbic acid, and its chemical formula is C 22 H 38 It is O7, and is a highly efficient oxygen scavenger and efficacy enhancer.

[0035] Tocopherol is a hydrolyzed vitamin E product that can enhance the antioxidant effect of cells, maintain and promote reproductive function, possess some anti-aging effects, improve lipid metabolism, prevent arteriosclerosis, and lower blood lipid levels.

[0036] Probucol is a white or pseudo-white crystalline powder with a distinctive odor and possesses 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 crystal, odorless, slightly bitter, odorless in aqueous solution, hygroscopic, its decomposition is accelerated by light irradiation, sparingly soluble in water, but readily soluble in hot water, ethanol, diethyl ether, propylene glycol, glycerin, cottonseed oil, peanut oil, and lard.

[0038] Tert-butylhydroquinone, also known as tertiary butylhydroquinone, is abbreviated as TBHQ. Tert-butylhydroquinone is a white, powdery crystalline substance with a distinctive odor. It is readily soluble in ethanol and diethyl ether, soluble in oils and fats, and insoluble in water.

[0039] Because macrolide drugs are susceptible to oxidation in air, this disclosure shows that by adding antioxidants, the storage stability of the product can be improved and the shelf life of drug-coated medical devices can be extended.

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

[0041] Optionally, if the dispersion medium in the coating solution is water, the antioxidant used in the coating solution is a water-soluble antioxidant; or if the dispersion medium in the coating solution is an organic solvent, the antioxidant used in the coating solution is a lipid-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 either a water-soluble antioxidant or a lipid-soluble antioxidant, or a mixture of a water-soluble antioxidant and a lipid-soluble antioxidant may be used.

[0043] Optionally, the coating solution may further contain polymer materials.

[0044] Polymer materials act as both a binder and a dispersion stabilizer.

[0045] Using polymer materials as a binder can improve the adhesion between the mixed materials and the support.

[0046] Furthermore, by using polymer materials as dispersion stabilizers, macrolide-based drugs can be stably dispersed in the dispersion medium, contributing to coating.

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

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

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

[0050] When water is used as the dispersion medium, most macrolide agents are poorly soluble in water, so the coating solution containing the macrolide agent and the dispersion medium is generally a suspension. In some optional embodiments of this disclosure, the coating solution is made into a suspension by means of stirring, vortexing, sonication, or homogenization (performed with a homomixer), that is, the small granules of the solid agent in the coating solution are suspended in the liquid. In this way, when coating is performed, the macrolide agent can uniformly coat the surface of the carrier.

[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, since macrolide drugs are soluble in organic solvents, the coating solution prepared in this case is in a solution state. When the additive solution containing water and the coating solution are coated together, the macrolide drug reprecipitations upon contact with water during coating, exhibiting a crystalline, powdery, or granular form. This prevents the crystal form of the macrolide drug from being affected in the subsequent drying process.

[0052] Optionally, the additive solution may further include at least one of a water-soluble antioxidant and a polymer material.

[0053] Optionally, the additive solution mainly consists of, in parts by weight, 80 to 1200 parts (including any one of 85 parts, 90 parts, 95 parts, 100 parts, 105 parts, 110 parts, 115 parts, 200 parts, 500 parts, 800 parts, 1000 parts, 1100 parts, or values within a range consisting of any two of these values, but not limited thereto) of water, 0 to 100 parts (including any one of 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, or values within a range consisting of any two of these values, but not limited thereto) of a water-soluble antioxidant, and 0 to 300 parts (including any one of 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, or values within a range consisting of any two of these values, but not limited thereto) of a polymer material.

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

[0055] In some selectable embodiments of the present disclosure, the coating concentration of the coating solution, expressed in terms of macrolide drugs, is 0.05 μg / mm 2 ~50 μg / mm 2 and includes any one of 0.1 μg / mm [[ID=*13]] 2 , 0.5 μg / mm 2 , 1 μg / mm 2 , 3 μg / mm 2 , 5 μg / mm 2 , 8 μg / mm 2 , 10 μg / mm 2 , 15 μg / mm 2 , 20 μg / mm 2 , 25 μg / mm 2 , 30 μg / mm 2 , 35 μg / mm 2 , 40 μg / mm 2 , 45 μg / mm 2 or values within a range consisting of any two of these values, but not limited thereto.

[0056] This disclosure further provides a method for preparing the above-described drug-coated medical device. The preparation method includes the step of applying a coating solution containing a macrolide drug and a dispersion medium to the surface of the carrier to obtain the drug-coated medical device.

[0057] The preparation method described herein is simple, easy to implement, has few process steps, operates under mild conditions, saves a great deal of time, reduces costs, and is suitable for mass production.

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

[0059] Conventional techniques involve complex methods for preparing drug-coated medical devices. For example, the carrier may be pre-treated to hydrophilize it, or a specific material may be applied to the surface of the carrier to obtain an undercoat, or drug crystals may be grown directly on the carrier.

[0060] The preparation method described herein is very easy to operate, has few process steps, requires little time, and the drug-coated medical device prepared by this method can transfer a sufficient amount of drug to the blood vessel wall. Furthermore, even after a relatively long period of time has passed since the removal of the drug-coated medical device, a certain level of drug concentration can still be maintained in the blood vessel wall tissue.Optionally, the drug concentration in the tissue can be 1 ng / mg or higher four weeks post-operatively, meeting the needs of the medical field.

[0061] Optionally, the D50 particle size of the macrolide drug is less than 200 μm and includes, but is not limited to, values ​​within the range of any one or any two values ​​from 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, and 0.05 μm.

[0062] Optionally, the coating concentration of the coating solution may be expressed as 0.05 μg / mm³ in terms of chemicals. 2 ~50μg / mm 2Therefore, 0.1 μg / mm 2 , 0.5 μg / mm³ 2 , 1 μg / mm 2 3 μg / mm³ 2 5 μg / mm³ 2 , 8 μg / mm 2 , 10 μg / mm 2 , 15 μg / mm³ 2 , 20 μg / mm³ 2 , 25 μg / mm³ 2 , 30 μg / mm³ 2 , 35 μg / mm³ 2 , 40 μg / mm³ 2 , 45 μg / mm³ 2 This includes, but is not limited to, any one or any two of the values ​​within a range of values.

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

[0064] Optionally, the spray coating may include an ultrasonic spray coating.

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

[0066] Optionally, the process may include drying, packaging, and sterilization steps, performed sequentially after the coating.

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

[0068] Optionally, the additive solution further comprises at least one of a water-soluble antioxidant and a polymer material. 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, and the polymer material comprises at least one of polyethylene glycol, polyethylene oxide, hyaluronic acid, carboxymethylcellulose, collagen, polyvinylpyrrolidone, and polyvinyl alcohol.

[0069] In this disclosure, simultaneous application means that the coating solution and the additive solution are applied to the surface of the carrier at the same time, and that the application positions of the coating solution and the additive solution are the same. When using spray coating, the coating solution and the additive solution are spray-coated to the surface of the carrier from two directions simultaneously, forming an intersection point on the surface of the carrier during spray coating. In this way, the macrolide-based drug reprecipitation occurs when it comes into contact with water, so the crystal form of the macrolide-based drug is not affected in the subsequent drying process, and this contributes to ensuring the effectiveness of the drug.

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

[0071] This 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 drugs or medical devices for the treatment of atherosclerotic disease, prevention of restenosis and prevention of local tissue proliferation.

[0072] This disclosure further provides a drug coating layer comprising a macrolide drug and a water-soluble antioxidant.

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

[0074] Optionally, the water-soluble antioxidant may include 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 agent is 0.01 to 10 (0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, or 9):1.

[0076] This disclosure further provides a medical device, the medical device comprising the drug coating layer described above.

[0077] Compared to prior art, this disclosure has the following beneficial effects.

[0078] (1) The drug-coated medical device relating to this disclosure can transfer a sufficient amount of drug to the blood vessel wall while in contact with the blood vessel wall, and can maintain a certain level of drug concentration in the blood vessel wall tissue even after a relatively long period of time has passed since the drug-coated medical device was removed.

[0079] (2) The method for preparing a drug-coated medical device according to this disclosure has advantages such as being easy to operate, requiring mild conditions, having few process steps, requiring little time, reducing costs, and being suitable for mass production.

[0080] (3) The method for preparing a drug-coated medical device according to this disclosure involves simultaneously applying a coating solution containing a macrolide drug and a dispersion medium to the surface of a carrier, along with an additive solution containing water, and, based on the premise of significantly simplifying the preparation process, it is possible to maintain a relatively high drug concentration in the vascular wall tissue even after a relatively long period of time has passed since the drug-coated medical device was removed.

[0081] To more clearly illustrate the embodiments of this disclosure or the technical concepts in the prior art, the drawings used in the embodiments or the prior art are briefly described below. The drawings described illustrate several embodiments of this disclosure. Those skilled in the art can obtain other relevant drawings based on these drawings without employing inventive capabilities. [Brief explanation of the drawing]

[0082] [Figure 1] This is an SEM image of a drug-coated medical device according to Example 1 of this disclosure. [Figure 2] This is an SEM image of a drug-coated medical device according to Example 2 of this disclosure. [Modes for carrying out the invention]

[0083] The technical proposal of this disclosure will be clearly and completely described below with reference to embodiments. As those skilled in the art will see, the embodiments described are only a selection of embodiments of this disclosure, not all embodiments, and are for illustrative purposes only, and do not limit the scope of this disclosure. Based on the embodiments in this disclosure, those skilled in the art will also see that all other embodiments obtained without inventive ability are also within the scope of this disclosure. Where specific conditions are not specified in the embodiments, it is possible to perform them under conventional conditions or conditions recommended by the manufacturer. Where the manufacturer is not specified for reagents or instruments, it is possible to use commercially available conventional products.

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

[0085] Optionally, the suspension may further include at least one of a water-soluble antioxidant and a polymer material.

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

[0087] Optionally, the mixed solution may further contain a lipid-soluble antioxidant.

[0088] Optionally, the additive solution may further include at least one of a water-soluble antioxidant and a polymer material.

[0089] The sirolimus, everolimus, and tacrolimus used in each of the following examples and comparative examples of this disclosure were all purchased. [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, manufactured by Hua Bei Pharmaceutical) was added to 1000 mg of distilled water, and a stable suspension (suspension temperature 20°C) was formed by ultrasonic vibration. Then, the above suspension was taken and applied to the surface of a drug balloon, and the drug concentration on the surface of the drug balloon was set to 4 μg / mm³. 2 The medical device was coated using ultrasonic spray coating, and after drying, a drug-coated layer was obtained.

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

[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 stirred until completely dissolved. Then, 25 mg of sirolimus (D50 particle size less than 200 μm, manufactured by Wuhan NEWBIO PHARM-TECH Co., Ltd.) was added and stirred at high speed using a homomixer to form a suspension (the suspension temperature was 25°C). The suspension was then placed in an ultrasonic cleaner and vibrated to maintain a stable suspension state.

[0095] Take the above suspension and apply the drug concentration of 3 μg / mm³ to the surface of the drug balloon. 2 The device was lashed in this manner, and after drying, a drug-coated layer was obtained.

[0096] In this embodiment, a drug coating layer was further obtained, and this drug coating layer consisted of a macrolide drug (sirolimus) and ascorbic acid.

[0097] SEM measurements were performed on the drug-coated medical device, and the measurement results are shown in Figure 2. As shown in Figure 2, the drug is clearly distributed on the surface of the device in a 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, manufactured by Zhongmei Huadong Pharmaceutical Co., Ltd.) was weighed and dissolved in 1000 mg of ethanol to obtain a topical solution (at a temperature of 25°C).

[0100] 50 mg of L-malic acid was added to 1000 mg of distilled water and stirred until completely dissolved, obtaining an additive solution (at a temperature of 25°C).

[0101] The above coating solution and additive solution are simultaneously applied to the surface of the drug balloon, bringing the sirolimus concentration on the surface of the drug balloon to 2.5 μg / mm³. 2 The concentration of L-malic acid is 1.3 μg / mm³. 2 An ultrasonic spray coating was applied to form a white powdery coating layer. After drying, a drug-coated medical device was obtained.

[0102] In this embodiment, a drug coating layer was further obtained, and this drug coating layer 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 20000) was added to 1000 mg of distilled water and stirred until completely dissolved. Then, 25 mg of sirolimus (D50 particle size less than 200 μm, manufactured by Hisun Pharmaceutical) was added and stirred at high speed using a homomixer to form a stable suspension (suspension temperature 30°C). The above suspension was taken and applied to the surface of a drug balloon, with the drug concentration on the surface of the drug balloon set to 1 μg / mm³. 2 The medical device was coated using ultrasonic spray coating, and after drying, a drug-coated layer 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 less than 200 μm, manufactured by Xinchang Pharmaceutical Factory) was weighed and dissolved in 5000 mg of propanol to obtain a topical solution (at a temperature of 35°C).

[0107] 30 mg of calcium pantothenate was added to 1000 mg of distilled water and stirred until completely dissolved, obtaining an additive solution (at a temperature of 35°C).

[0108] The above coating solution and additive solution are simultaneously applied to the surface of the drug balloon, and the sirolimus drug concentration on the surface of the drug balloon is set to 5 μg / mm³. 2 The concentration of L-malic acid is 4.8 μg / mm³. 2 An ultrasonic spray coating was applied 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, manufactured by Hubei Jiuzhou Kangda Biotechnology Co., Ltd.) was added to 3000 mg of distilled water, and a stable suspension (suspension temperature 65°C) was formed by ultrasonic vibration. Then, a drug balloon was used, and the drug concentration of everolimus on the surface of the drug balloon was set to 10 μg / mm³. 2 The devices were then immersed in the above suspension. Furthermore, after drying, packaging, and sterilization, a drug-coated medical device was obtained.

[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, manufactured by Wuhan Biocar Biopharmaceutical 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 (suspension temperature 40°C) was formed by ultrasonic vibration. The above suspension was then applied to the surface of a drug-eluting stent, and the drug concentration on the surface of the drug-eluting stent was set to 50 μg / mm³. 2 The device was then ultrasonically spray-coated. Following drying, packaging, and sterilization, a drug-coated layer was obtained for the medical device.

[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, manufactured by Jinan Jage Biotechnology Co., Ltd.) was weighed and dissolved in 100 mg of methylene chloride, and then 150 mg of vitamin E was added to obtain a topical solution (at a temperature of 20°C).

[0115] The above coating solution and 200 mg of distilled water (i.e., additive solution) are applied to the surface of the drug-eluting stent, and the sirolimus drug concentration on the surface of the drug-eluting stent is set to 8 μg / mm³. 2 The surface was simultaneously ultrasonically spray-coated to form a white powdery coating layer. After drying, a drug-coated medical device was obtained.

[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, manufactured by Hisun Pharmaceutical) was weighed and dissolved in 1000 mg of toluene to obtain a coating solution (at a temperature of 25°C).

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

[0119] The above coating solution and additive solution are simultaneously applied to the surface of the drug balloon, and the sirolimus drug concentration on the surface of the drug balloon is set to 2 μg / mm³. 2 The concentration of L-malic acid is 1 μg / mm³. 2 The concentration of carboxymethylcellulose is 3 μg / mm³. 2 An ultrasonic spray coating was applied 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 stirred until completely dissolved. Then, 25 mg of rapamycin (D50 particle size less than 200 μm, manufactured by Yibin Weixi Pharmaceutical Co., Ltd.) was added and stirred at high speed using a homomixer to form a suspension (the suspension temperature was 25°C). The suspension was then placed in an ultrasonic cleaner and vibrated to maintain a stable suspension state.

[0122] Take the above suspension and apply it to the surface of the drug balloon, aiming for a drug concentration of 10 μg / mm³ on the surface of the drug balloon. 2 The surface was lashed in this manner. After drying, a drug-coated layer was obtained on the medical device.

[0123] In this embodiment, a drug coating layer was further obtained, and this drug coating layer consisted of a macrolide drug (rapamycin) and chlorogenic acid.

[0124] Comparative Example 1 The method for preparing the drug-coated medical device in this comparative example is almost the same as in Example 1, differing only in 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 in this comparative example is almost the same as in Example 1, differing only in that the D50 particle size of sirolimus was set to over 200 μm.

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

[0127] Comparative Example 4 The method for preparing the drug-coated medical device in this comparative example is almost the same as in Example 3, differing only in that the step of "ultrasonic spray coating the surface of the drug balloon with the above coating solution and additive solution simultaneously" in Example 3 is replaced with the step of "uniformly mixing the above coating solution and additive solution, and then ultrasonically spray coating the surface of the drug balloon."

[0128] Experimental example Animal experiments were conducted using drug-coated medical devices obtained in each of the above examples and comparative examples. The method was as follows: Under the guidance of DSA (digital subtraction angiography), drug-coated medical devices were inserted into the coronary arteries of pigs, dilated at 6 atmospheres for 60 seconds, depressurized, and the drug-coated medical devices were removed. After rearing for 4 weeks, the animals died, and the coronary arteries of the experimental animals were weighed, homogenized, and extracted. The drug concentration in the tissue was measured using a liquid chromatography-mass spectrometer, and 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 example of this disclosure is 1 ng / mg or higher, and therefore, restenosis can be prevented.

[0131] While the present disclosure has been illustrated with examples, these examples are merely illustrative and not limiting. As those skilled in the art will see, it is possible to modify the technical concepts described in the above examples, or to substitute some or all of their technical features, without departing from the spirit and scope of the present disclosure. Such modifications or substitutions will not cause the spirit of the applicable technical concept to deviate from the scope of the technical concepts of the examples of the present disclosure. For this reason, the claims are included to encompass all substitutions and modifications that fall within the scope of the present disclosure. Exemplary embodiments of the present invention are described below. <1> The carrier comprises a drug coating layer that partially or completely covers the carrier, The aforementioned drug coating layer was obtained by coating with a coating solution mainly containing a macrolide-based drug and a dispersion medium. The dispersion medium comprises at least one of water and an organic solvent, the organic solvent comprising at least one of ethanol, propanol, methylene chloride, 1,4-dioxane, tetrahydrofuran, and toluene. A medical device characterized by a drug-coated layer. <2> The mass ratio of the macrolide drug to the dispersion medium is 20-100:100-6000. Preferably, the macrolide drug includes at least one of everolimus, tacrolimus, zotarolimus, rapamycin, temsirolimus, biolimus, 7-O-demethylrapamycin, ridafololimus, 32-deoxyrapamycin, and 42-O-(2-ethoxyethyl)rapamycin. Preferably, the carrier includes at least one of a drug balloon and a drug-eluting stent. Characterized by <1> A medical device with a drug-coated layer as described above. <3> The aforementioned coating solution further contains an antioxidant, Preferably, the antioxidant comprises at least one of a water-soluble antioxidant and a lipid-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 lipid-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 agent is 0.01 to 10:1. Preferably, when the dispersion medium in the coating solution is water, the antioxidant used in the coating solution is a water-soluble antioxidant, or when the dispersion medium in the coating solution is an organic solvent, the antioxidant used in the coating solution is a lipid-soluble antioxidant. Characterized by <1> A medical device with a drug-coated layer as described above. <4> The aforementioned coating solution further contains a polymer material, Preferably, the polymer 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 to 30:100 to 1000. Characterized by <1> A medical device with a drug-coated layer as described above. <5> 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. A drug-coated medical device according to any one of <1 to 4>, characterized by the above. <6> The additive solution further comprises at least one of a water-soluble antioxidant and a polymer material. Preferably, the additive solution consists of, by weight, mainly 80 to 1200 parts water, 0 to 100 parts water-soluble antioxidant, and 0 to 300 parts polymer material. Characterized by <5> A medical device with a drug-coated layer as described above. <7> The step includes applying a coating solution containing a macrolide drug and a dispersion medium to the surface of the carrier to obtain a drug-coated medical device. Characterized by <1> ~ <6> A method for preparing a drug-coated medical device as described in any one of the items. <8> The D50 particle size of the macrolide drug is less than 200 μm. Preferably, the coating concentration of the coating solution is 0.05 μg / mm³ when expressed as a macrolide agent. 2 ~50μg / mm 2 And, Preferably, the application method includes at least one of spray coating, dip coating, drop coating, and brushing. Preferably, the process includes a drying step, a packaging step, and a sterilization step, which are performed in order after the coating. Characterized by <7> The preparation method described above. <9> The aforementioned coating method is The method further includes the step of simultaneously applying a coating solution containing a macrolide-based agent and a dispersion medium, and an additive solution containing water, to the surface of the carrier. Preferably, the temperature of at least one of the coating solution and the additive solution is below 70°C. Characterized by <7> The preparation method described above. <10> In the preparation of drugs or medical devices for the treatment of atherosclerotic disease, prevention of restenosis, and prevention of local tissue proliferation, <1> ~ <6> A drug-coated medical device as described in any one of the items, or <7> ~ <9> Use of a drug-coated medical device prepared by the method for preparing drug-coated medical devices described in any one of the items. <11> It consists of macrolide antibiotics and water-soluble antioxidants. A drug coating layer characterized by the following features. <12> The macrolide drugs include at least one of everolimus, tacrolimus, zotarolimus, rapamycin, temsirolimus, biolimus, 7-O-demethylrapamycin, ridafololimus, 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 mass ratio of the water-soluble antioxidant to the macrolide agent is 0.01 to 10:1. Characterized by <11> The drug coating layer described above. <13> <11> or <12> A medical device containing the drug coating layer described above.

Claims

1. The carrier comprises a drug coating layer that partially or completely covers the carrier, The aforementioned drug coating layer is obtained by coating with a coating solution containing a macrolide-based drug and a dispersion medium. The dispersion medium comprises at least one of water and an organic solvent, the organic solvent comprising at least one of ethanol, propanol, methylene chloride, 1,4-dioxane, tetrahydrofuran, and toluene. A medical device characterized by a drug-coated layer, The macrolide drug includes at least one of everolimus, tacrolimus, and rapamycin. The D50 particle size of the macrolide drug is less than 200 μm. When the dispersion medium in the coating solution is an organic solvent, the drug coating layer is obtained by spray coating the coating solution and an additive solution containing water together. Medical devices with a drug-coated layer.

2. The mass ratio of the macrolide agent to the dispersion medium is 20 to 100:100 to 6000, and / or The carrier includes at least one of a drug balloon and a drug-eluting stent. A drug-coated medical device according to feature 1.

3. The aforementioned coating solution further contains an antioxidant, The antioxidant comprises at least one of a water-soluble antioxidant and a lipid-soluble antioxidant. 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. The lipid-soluble antioxidant comprises at least one of the following: vitamin E, dibutylhydroxytoluene, butylhydroxyanisole, ascorbyl palmitate, tocopherol, probucol, propyl gallate, and tert-butylhydroquinone. A drug-coated medical device according to feature 1.

4. The mass ratio of the antioxidant to the macrolide agent is 0.01 to 10:1, and / or If the dispersion medium in the coating solution is water, the antioxidant used in the coating solution is the water-soluble antioxidant; or, if the dispersion medium in the coating solution is an organic solvent, the antioxidant used in the coating solution is the lipid-soluble antioxidant. A drug-coated medical device according to claim 3.

5. The aforementioned coating solution further contains a polymer material, The polymer material comprises at least one of polyethylene glycol, polyethylene oxide, hyaluronic acid, carboxymethylcellulose, collagen, polyvinylpyrrolidone, and polyvinyl alcohol, and / or The mass ratio of the polymer material to the dispersion medium is 0.1 to 30:100 to 1000. A drug-coated medical device according to feature 1.

6. The additive solution further comprises at least one of a water-soluble antioxidant and a polymer material. The additive solution consists of 80 to 1200 parts by weight of water, 0 to 100 parts by weight of a water-soluble antioxidant, and 0 to 300 parts by weight of a polymer material. A drug-coated medical device according to feature 1.

7. The step includes applying a coating solution 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 a drug-coated medical device according to any one of claims 1 to 6, characterized by: The dispersion medium comprises at least one of water and an organic solvent, the organic solvent comprising at least one of ethanol, propanol, methylene chloride, 1,4-dioxane, tetrahydrofuran, and toluene. The macrolide drug includes at least one of everolimus, tacrolimus, and rapamycin. The D50 particle size of the macrolide drug is less than 200 μm. If the dispersion medium in the coating solution is an organic solvent, the step includes applying the coating solution and an additive solution containing water together by spray coating. Preparation method.

8. The coating concentration of the coating solution is 0.05 μg / mm³ when expressed as a macrolide agent. ２ ~50 μg / mm³ ２ and / or, The aforementioned application method includes at least one of spray coating, dip coating, drop coating, and brushing, and / or The following steps are performed in order after the coating: a drying step, a packaging step, and a sterilization step. The preparation method according to feature 7.

9. The temperature of at least one of the coating solution and the additive solution in the coating process is less than 70°C. The preparation method according to feature 7.

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

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