A multi-layer coated implantable medical device and method of making the same

Abstract

The application provides a multi-layer coated implantable medical device and a preparation method thereof. The medical device comprises an implant body and a coating, wherein the coating comprises at least an inner release layer, a middle transfer layer and an outer protective layer which are sequentially coated on the implant body. The material of the inner release layer comprises a hydrophilic polymer material, a drug and a drug-loaded carrier. The material of the middle transfer layer comprises a lipophilic or amphiphilic amino acid, a phospholipid and a derivative thereof. The material of the outer protective layer comprises a hydrophilic polymer material. The multi-layer coated implantable medical device and the preparation method thereof can solve the problem that the drug coating of the coated implantable device is easily washed off before reaching the lesion site.

Description

Technical Field

[0001] This invention relates to the field of medical technology, and in particular to a multi-layered coated implantable medical device and its preparation method. Background Technology

[0002] Percutaneous coronary intervention (PCI) has become a primary treatment for coronary artery disease. With the increasing number of stents used, in-stent restenosis (ISR) has become a serious problem. Among current ISR treatment options, coronary artery bypass grafting (CABG) has many risk factors and contraindications, and re-stent placement may lead to repeat ISR and other risks of multiple stent placements. Even after simple balloon angioplasty, the probability of ISR recurrence is as high as 27%. Therefore, existing ISR treatment options are not ideal. In recent years, drug-coated balloons (DCBs) have become increasingly widely used in coronary and peripheral interventional procedures in Europe, and several DCB products have been or are about to be put into clinical use in China. The emergence of DCBs provides a new option for the treatment of coronary artery disease in my country.

[0003] Drug-eluting bronchiectasis (DCB) inhibits intimal hyperplasia by locally releasing anti-proliferative drugs into the coronary artery wall. Compared to drug-eluting stents (DES), DCB has no polymer matrix and no residual metal mesh, reducing intimal inflammation, significantly lowering the risk of thrombosis, and shortening the duration of dual antiplatelet therapy (only 1-3 months of dual antiplatelet therapy is required after DCB). Furthermore, DCB treatment avoids the insertion of foreign bodies, preserving the opportunity for subsequent treatment if necessary.

[0004] Currently, there are more than ten drug-coated balloons (DCBs) on the market globally, most of which use paclitaxel-based drug coatings. Paclitaxel has good lipid solubility and stable anti-proliferative effects. Basic research has confirmed that paclitaxel can block early cell proliferation initiation factors, inhibit cytoskeleton formation, block mitosis, effectively inhibit rapid cell proliferation, and also inhibit smooth muscle cell migration and phenotypic changes, as well as suppress proliferative inflammatory responses in the intima. When a DCB releases the drug, the balloon adheres to the blood vessel wall, providing sufficient drug contact area so that the lipid-soluble paclitaxel can be rapidly taken up by the blood vessel wall tissue. However, DCBs with a simple paclitaxel coating are easily washed away by blood flow during blood vessel crossing, resulting in low bioavailability of the coating. In addition, the paclitaxel coating being washed away by blood flow may lead to thrombosis, and in severe cases, even death, especially in the treatment of peripheral arterial disease (PAD), where the consequences of this washout phenomenon are particularly serious. Therefore, the existing paclitaxel-based drug-coated balloons carry significant risks. Summary of the Invention

[0005] The purpose of this invention is to provide a multi-layer coated implantable medical device and its preparation method, so as to solve the problem that the drug coating of the existing coated implantable device is easily washed off before reaching the lesion site.

[0006] To address the aforementioned technical problems, this invention provides a multi-layered coated implantable medical device, comprising: an implantable body and a coating, wherein the coating comprises at least an inner release layer, a middle transfer layer, and an outer protective layer sequentially coated on the implantable body; the material of the inner release layer comprises a hydrophilic polymer, a drug, and a drug carrier; the material of the middle transfer layer comprises lipophilic or amphiphilic amino acids, phospholipids, and their derivatives; and the material of the outer protective layer comprises a hydrophilic polymer.

[0007] Furthermore, the hydrophilic polymer material is selected from one or more combinations of polyvinylpyrrolidone, polyethylene oxide, polyacrylamide, polyacrylic acid, polyether and its derivatives, urea, polyurethane, polyurethane urea, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, gum arabic and gelatin.

[0008] Furthermore, the drug is selected from one or more combinations of rapamycin, paclitaxel, sirolimus, paclitaxel derivatives, sirolimus derivatives, paclitaxel analogs, sirolimus analogs, repressive RNA, repressive DNA, steroids, and complement inhibitors.

[0009] Furthermore, the drug delivery carrier is selected from one or more combinations of polylactic acid, polylactic acid-glycolic acid copolymer, polyisopropylacrylamide, polyvinylpyrrolidone, and polyethylene glycol-cholesterol copolymer.

[0010] Furthermore, in the inner release layer, the ratio of the hydrophilic polymer material, the drug, and the drug carrier is 5-100:1-50:5-100.

[0011] Furthermore, the amino acid is selected from one or more combinations of glycine, glutamic acid, sarcosine, and alanine.

[0012] Furthermore, the phospholipids and their derivatives are selected from one or more combinations of 1,2-bis(eicosanyl)-sn-glycero-3-phosphate choline, 1,2-dicarachidoyl-sn-glycero-3-phosphate choline, 1,2-disorcinyl-sn-glycero-3-phosphate choline, 1,2-bis(docohexanoyl)-sn-glycero-3-phosphate choline, 1,2-docoenoyl-sn-glycero-3-phosphate choline, and 1,2-dinervonicyl-sn-glycero-3-choline phosphate.

[0013] Furthermore, according to claim 1, the implantable medical device with a multilayer coating is characterized in that the material of the middle transfer layer further includes a lipophilic or amphiphilic surfactant.

[0014] Furthermore, the surfactant is selected from sodium dodecyl sulfate and / or sodium dodecylbenzenesulfonate.

[0015] Furthermore, the material of the intermediate transfer layer also includes fatty acids.

[0016] Furthermore, the fatty acid is selected from one or more combinations of stearic acid, lauric acid, myrcenoic acid, tetradecadienoic acid, and octanoic acid.

[0017] Furthermore, the ratio of the amino acid, the phospholipid and its derivatives, the surfactant and the fatty acid is 1-25:2-35:1-20:1-20.

[0018] Furthermore, the coating is formed by spraying, dipping, roller coating, electrostatic deposition, printing, or pipetting.

[0019] This invention also provides a method for preparing a multi-layer coated implantable medical device, comprising the following steps:

[0020] S1: Provide an implantable subject;

[0021] S2: Prepare solution C corresponding to the inner release layer, solution B corresponding to the middle transfer layer, and solution A corresponding to the outer protective layer;

[0022] S3: Apply solution C, solution B and solution A sequentially to the surface of the implanted subject.

[0023] In summary, compared with the prior art, the multi-layer coated implantable medical device and its preparation method provided by the present invention have the following advantages:

[0024] The multilayer coated implantable medical device of this invention comprises at least three layers. During implantation into the lesion site, when blood or tissue fluid washes away the implanted device, only the outer protective layer is washed away, effectively protecting the middle transfer layer and the inner release layer. This prevents the drug in the inner release layer from being washed away outside the lesion site, avoiding thrombosis. Furthermore, the outer protective layer is made of a hydrophilic polymer material, which, even if washed away during implantation, will be degraded and absorbed, preventing thrombosis. Upon reaching the lesion site, the outer protective layer is washed away, exposing the middle transfer layer. The middle transfer layer is made of a lipophilic or amphiphilic material, positively charged, and can effectively bind to negatively charged vascular wall cells, preventing device displacement. This allows the drug released by the inner release layer to be precisely targeted to the lesion site, improving the bioavailability of the coating.

[0025] Furthermore, the intermediate transfer layer of this invention comprises amino acids and phospholipids and their derivatives. The hydroxyl and carboxyl groups of the amino acids can form hydrogen bonds with the ester bonds of drugs such as sirolimus and rapamycin in the inner release layer, thereby increasing the ester bond binding force between the intermediate transfer layer and the inner release layer. Moreover, the tertiary amine groups in the phospholipids and their derivatives in the intermediate transfer layer are positively charged, while the vascular endothelial cells are negatively charged. This allows the intermediate transfer layer to effectively bind to the vascular wall of the lesion, preventing it from being washed away by blood and causing balloon or stent displacement. Furthermore, since the main component of the cell membrane is a phospholipid bilayer, according to the principle of like dissolves like, the drugs in the inner release layer are more likely to penetrate the membrane and reach the vascular cells, thus aiding in drug absorption.

[0026] Furthermore, the mesotransfer layer may further include surfactants and fatty acids. Surfactants can act as a barrier against elution of the mesotransfer layer by intravascular blood flow and enhance the hydrophilicity of fatty acids. Fatty acids, in turn, serve as the matrix for the surfactants, providing structural strength to aid in barrier formation and better resist elution by blood flow.

[0027] In addition, in the present invention, the ratio of each component in the inner release layer can be adjusted to regulate the hydrogen bonding forces between the ester bonds in the inner release layer and the amino, hydroxyl, and carboxyl groups in the middle transfer layer, thereby adjusting the degree of bonding between the inner release layer and the middle transfer layer. This prevents the middle transfer layer from detaching from the inner release layer due to insufficient bonding force, ensuring that the inner release layer is basically located at the lesion site when releasing the drug, reducing drug loss, and improving the bioavailability of the coating.

[0028] The method for preparing multi-layer coated implantable medical devices provided by this invention has a simple preparation process and is conducive to large-scale production. Attached Figure Description

[0029] Figure 1 A cross-sectional view of a multi-layer coated implantable medical device provided by the present invention.

[0030] The reference numerals in the attached figures are explained as follows:

[0031] 10-Implantation body; 20-Coating; 21-Inner release layer; 22-Middle transfer layer; 23-Outer protective layer. Detailed Implementation

[0032] The following detailed description, in conjunction with the accompanying drawings and specific embodiments, provides a more detailed account of the multi-layered coated implantable medical device and its preparation method according to the present invention. The advantages and features of the present invention will become clearer from the following description.

[0033] In this document, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Without further limitation, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes said element.

[0034] The purpose of this invention is to provide a multi-layer coated implantable medical device and its preparation method, so as to solve the problem that the drug coating of the existing coated implantable device is easily washed off before reaching the lesion site, resulting in thrombosis.

[0035] like Figure 1 As shown, the present invention provides a multi-layer coated implantable medical device, comprising: an implantable body 10 and a coating 20, wherein the coating 20 comprises at least an inner release layer 21, a middle transfer layer 22 and an outer protective layer 23 sequentially coated on the implantable body 10; the material of the inner release layer 21 includes a hydrophilic polymer, a drug and a drug carrier; the material of the middle transfer layer 22 includes lipophilic or amphiphilic amino acids, phospholipids and their derivatives; and the material of the outer protective layer 23 includes a hydrophilic polymer.

[0036] In the present invention, the implantable medical device can be a drug-eluting balloon or a stent. The coating 20 is applied to the surface of the expandable portion of the balloon or stent. During the implantation of the balloon or stent into the lesion, when blood or tissue fluid washes away the balloon or stent, only the outer protective layer 23 is washed away, which can effectively protect the middle transfer layer 22 and the inner release layer 21. In this way, the drug in the inner release layer 21 will not be washed away in non-lesion sites, thus avoiding the formation of thrombi. Moreover, the outer protective layer 23 is made of a hydrophilic polymer material, which will be degraded and absorbed even if it is washed away during implantation, and will not cause thrombi to form. Once the balloon or stent reaches the lesion site, the outer protective layer 23 is washed away, exposing the middle transfer layer 22. The middle transfer layer 22 is made of a lipophilic or amphiphilic material, generally positively charged, which can effectively bind to negatively charged vascular wall cells, preventing balloon or stent displacement. This allows the drug released by the inner release layer 21 to be precisely targeted to the lesion site, improving the bioavailability of the coating. Of course, those skilled in the art should understand that the coating 20 of this invention is not limited to the three layers mentioned above; more functional coatings can be added. For example, the intermediate layer can be multi-layered. Furthermore, the inner release layer 21 can also be configured with a gradient coating according to the drug concentration to achieve a controlled release effect.

[0037] In this invention, the hydrophilic polymer material in the outer protective layer 23 and the inner release layer 21 can be selected from one or a combination of several of the following: polyvinylpyrrolidone, polyethylene oxide, polyacrylamide, polyacrylic acid, polyether and its derivatives, urea, polyurethane, polyurethane urea, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, gum arabic and gelatin.

[0038] In this invention, the inner release layer 21 serves as a drug carrier, loading the drug and dispersing it within a hydrophilic polymer material. The drug can be an anti-cell migration, anti-mitosis, or anti-proliferation agent, effectively treating problems such as ISR (Infectious Disease Reduction). For example, the drug of this invention can be selected from one or more combinations of rapamycin, paclitaxel, sirolimus, paclitaxel derivatives, sirolimus derivatives, paclitaxel analogs, sirolimus analogs, repressive RNA, repressive DNA, steroids, and complement inhibitors.

[0039] Drug delivery carriers are generally made of synthetically produced polymers with low toxicity and good biocompatibility. For example, they can be selected from one or a combination of several of polylactic acid, polylactic acid-glycolic acid copolymer, polyisopropylacrylamide, polyvinylpyrrolidone, and polyethylene glycol-cholesterol copolymer.

[0040] Furthermore, in the inner release layer 21, the ratio of the hydrophilic polymer material, the drug, and the drug carrier is 5-100:1-50:5-100. By adjusting the ratio of each component in the inner release layer 21, the hydrogen bonding forces between the ester bonds in the inner release layer 21 and the amino, hydroxyl, and carboxyl groups in the middle transfer layer 22 can be adjusted, thereby regulating the degree of bonding between the inner release layer 21 and the middle transfer layer 22. This prevents the middle transfer layer 22 from detaching from the inner release layer 21 due to insufficient bonding, ensuring that the inner release layer 21 releases the drug primarily at the lesion site, reducing drug loss, and improving the bioavailability of the coating.

[0041] In the material selected for the intermediate transfer layer 22 of the present invention, the lipophilic or amphiphilic amino acids may be selected from one or more combinations of glycine, glutamic acid, sarcosine, and alanine. The phospholipids and their derivatives are selected from one or more combinations of 1,2-bis(eicosanyl)-sn-glycero-3-phosphate choline, 1,2-dicarachidoyl-sn-glycero-3-phosphate choline, 1,2-disorcinyl-sn-glycero-3-phosphate choline, 1,2-bis(docohexanoyl)-sn-glycero-3-phosphate choline, 1,2-docoenoyl-sn-glycero-3-phosphate choline, and 1,2-dinervonicyl-sn-glycero-3-choline phosphate. Specifically, the hydroxyl and carboxyl groups of amino acids in the intermediate transfer layer 22 can form hydrogen bonds with the ester bonds of drugs such as sirolimus and rapamycin in the inner release layer 21, thereby increasing the ester bond binding force between the intermediate transfer layer 22 and the inner release layer 21. Moreover, the tertiary amine groups of phospholipids and their derivatives in the intermediate transfer layer 22 are positively charged, while the vascular endothelial cells are negatively charged. This allows the intermediate transfer layer 22 to effectively bind to the vascular wall of the lesion, preventing it from being washed away by blood and causing balloon or stent displacement. Furthermore, since the main component of the cell membrane is a phospholipid bilayer, according to the principle of "like dissolves like," the drugs in the inner release layer 21 are more likely to penetrate the membrane and reach the vascular cells, thus aiding in drug absorption.

[0042] Furthermore, the material of the intermediate transfer layer 22 of the present invention may also include a lipophilic or amphiphilic surfactant. The surfactant is selected from sodium dodecyl sulfate and / or sodium dodecylbenzene sulfonate. Furthermore, the material of the intermediate transfer layer 22 may also include fatty acids. The fatty acids are selected from one or more combinations of stearic acid, lauric acid, myrcenoic acid, tetradecadienoic acid, and octanoic acid. The surfactant can act as a barrier against elution of the intermediate transfer layer 22 by intravascular blood flow and enhance the hydrophilicity of the fatty acids. The fatty acids, as the matrix of the surfactant, provide a certain structural strength to assist in the formation of the barrier, thus better resisting elution by blood flow.

[0043] In the present invention, when the intermediate transfer layer 22 comprises only amino acids and phospholipids and their derivatives, the ratio of the amino acids to the phospholipids and their derivatives can be 2-45:3-55. When the intermediate transfer layer 22 further comprises amino acids, phospholipids and their derivatives, and surfactants, the ratio of the amino acids, the phospholipids and their derivatives, and the surfactants is 1.5-3.5:2.5-45:1-20. When the intermediate transfer layer comprises amino acids, phospholipids and their derivatives, surfactants, and fatty acids, the ratio of the amino acids, the phospholipids and their derivatives, the surfactants, and the fatty acids is 1-25:2-35:1-20:1-20.

[0044] In the present invention, the coating 20 can be formed by spraying, dipping, rolling, electrostatic deposition, printing, pipetting or dispensing.

[0045] This invention also provides a method for preparing a multi-layered coated implantable medical device, comprising the following steps:

[0046] S1: Provide an implantable body 10; for example, the implantable body can be a balloon or a stent, and the coating is applied to the surface of the expandable portion of the balloon or stent.

[0047] S2: Prepare solution C corresponding to the inner release layer 21, solution B corresponding to the middle transfer layer 22, and solution A corresponding to the outer protective layer 23. During preparation, the components corresponding to each layer are dissolved in a solvent to obtain the corresponding solutions. The solvent can be selected from diethyl ether, formic acid, acetic acid, acetone, dichloromethane, pentane, hexane, heptane, alcohol, or a mixture of alcohol and water.

[0048] S3: Apply solutions C, B, and A sequentially to the surface of the implanted body. Specifically, first, apply solution C corresponding to the inner release layer 21 to the surface of the expandable portion of the balloon or stent using the aforementioned coating methods such as spraying, dipping, roller coating, electrostatic deposition, printing, pipetting, or dispensing to form the inner release layer 21. After the solvent evaporates and the corresponding inner layer dries, solution B corresponding to the middle transfer layer 22 can be applied to the surface of the inner release layer 21 using the aforementioned coating methods to form the middle transfer layer 22. Similarly, after the solvent evaporates, apply the outer protective layer 23 to the dried middle layer surface. To ensure the thickness of the coating, the solution corresponding to each coating can be applied multiple times. For example, when forming the inner release layer 21, a coating is first formed on the surface of the implant with solution C. After the coating dries, solution C is applied again, and the coating is allowed to dry. This process is repeated multiple times to finally form the inner release layer 21 with a certain thickness. The middle transfer layer 22 and the outer protective layer 23 are also coated multiple times in a similar manner. Preferably, each solution can be coated 2-20 times.

[0049] The fabrication process of the multi-layer coated implantable medical device of the present invention is roughly as follows:

[0050] Take an appropriate amount of hydrophilic polymer material and add it to 20-100 mL of solvent. Mix and stir evenly to obtain solution A corresponding to the outer protective layer 23. The mass volume fraction of the hydrophilic polymer material in the prepared solution A is 0.5%-10%.

[0051] Take appropriate amounts of amino acids, phospholipids and their derivatives, surfactants and fatty acids, add them to 20-100 mL of solvent, mix and stir evenly to obtain solution B corresponding to the middle transfer layer 22; wherein, in the prepared solution B, the mass volume fraction of amino acids is 0.12%-2.5%, the mass volume fraction of phospholipids and their derivatives is 0.2%-3.5%, the mass volume fraction of surfactants is 0.1%-2%, and the mass volume fraction of fatty acids is 0.1%-2%.

[0052] Add an appropriate amount of hydrophilic polymer material to 20-100 mL of solvent, mix and stir evenly, then add the drug carrier loaded with the drug to the solution, mix evenly to obtain solution C; wherein, in the prepared solution C, the mass volume fraction of hydrophilic polymer material is 0.5%-10%, the mass volume fraction of drug carrier is 0.5%-10%, and the mass volume fraction of drug is 0.1%-5%.

[0053] Next, in sequence, solutions C, B, and A are applied to the surface of the expandable portion of the balloon or stent by spraying, dipping, rolling, electrostatic deposition, printing, pipetting, or dispensing, using the improved coating preparation method described above. Each solution is applied 2-20 times. After each application, the solution is allowed to stand for 30-60 seconds to allow the solvent to evaporate.

[0054] To further understand the present invention, preferred embodiments will be described below in more detailed and specific terms to highlight the features and characteristics of the multi-layered coated implantable medical device and its preparation method provided by the present invention. These descriptions are merely illustrative of the features and advantages of the method of the present invention and are not intended to limit the scope of protection of the present invention.

[0055] Example 1

[0056] The preparation method of the multi-layer coated implantable medical device provided in Example 1 is as follows:

[0057] Take an appropriate amount of polyvinylpyrrolidone and add it to 20 mL of ethanol solution. Mix and stir evenly to obtain solution A corresponding to the outer protective layer 23, wherein the mass volume fraction of polyvinylpyrrolidone is 0.5%.

[0058] An appropriate amount of glycine and 1,2-bis(eicosenoyl)-sn-glycero-3-phosphocholine were added to 20 mL of solvent, mixed and stirred evenly to obtain solution B corresponding to the middle layer transfer layer 22, wherein the mass volume fraction of glycine was 0.1% and the mass volume fraction of 1,2-bis(eicosenoyl)-sn-glycero-3-phosphocholine was 0.2%.

[0059] Dissolve an appropriate amount of polyvinylpyrrolidone in 20 mL of ethanol and mix well. Then, load paclitaxel with polylactic acid. Next, add the paclitaxel-loaded polylactic acid to the above-mentioned polyvinylpyrrolidone alcohol solution and disperse it evenly to obtain the C solution corresponding to the inner release layer. The mass volume fraction of polyvinylpyrrolidone is 0.5%, the mass volume fraction of polylactic acid is 0.5%, and the mass volume fraction of paclitaxel is 0.1%.

[0060] The C, B, and A solutions were sequentially applied to the expandable portion of the balloon or stent using a dip-coating method. Each solution was applied twice, and after each application, the surface was allowed to stand for 30 seconds to evaporate. After all three solutions were applied, the multi-layered implantable medical device of Example 1 was obtained.

[0061] Example 2

[0062] The preparation method of the multi-layer coated implantable medical device provided in Example 2 is as follows:

[0063] Take an appropriate amount of polyethylene glycol and add it to 40 mL of water. Mix and stir until homogeneous to obtain solution A corresponding to the outer protective layer 23, wherein the mass volume fraction of polyethylene glycol is 2%.

[0064] An appropriate amount of glutamic acid and 1,2-diarachido-sn-glycero-3-phosphocholine were added to 40 mL of acetic acid, mixed and stirred evenly to obtain solution B corresponding to the middle layer transfer layer 22, wherein the mass-volume fraction of glutamic acid was 0.5% and the mass-volume fraction of 1,2-diarachido-sn-glycero-3-phosphocholine was 0.75%.

[0065] An appropriate amount of polyethylene glycol was dissolved in 40 mL of acetone and mixed evenly. Then, rapamycin was loaded onto polylactic acid-glycolic acid copolymer. Next, the polylactic acid-glycolic acid copolymer loaded with rapamycin was added to the above solution and dispersed evenly to obtain solution C corresponding to the inner release layer. The mass volume fraction of polyethylene glycol was 2%, the mass volume fraction of polylactic acid-glycolic acid copolymer was 2%, and the mass volume fraction of rapamycin was 0.9%.

[0066] Solution C, solution B, and solution A were sequentially applied to the surface of the expandable portion of the balloon or stent using a spraying method. Each solution was applied six times, and after each application, the surface was allowed to stand for 35 seconds to evaporate. After all three solutions were applied, the multi-layered implantable medical device of Example 2 was obtained.

[0067] Example 3

[0068] The preparation method of the multi-layer coated implantable medical device provided in Example 3 is as follows:

[0069] Take an appropriate amount of polyvinyl alcohol and add it to 50 mL of water. Mix and stir evenly to obtain solution A corresponding to the outer protective layer 23, wherein the mass volume fraction of polyethylene glycol is 3.5%.

[0070] Appropriate amounts of sarcosine, 1,2-diergoyl-sn-glycero-3-phosphocholine, and stearic acid were added to 50 mL of diethyl ether, mixed, and stirred until homogeneous to obtain solution B corresponding to the intermediate transfer layer 22. The mass-volume fraction of sarcosine was 0.9%, the mass-volume fraction of 1,2-diergoyl-sn-glycero-3-phosphocholine was 1.3%, and the mass-volume fraction of stearic acid was 3.5%.

[0071] Dissolve an appropriate amount of polyvinyl alcohol in 50 mL of water and mix well. Then, load siromos onto polyisopropylacrylamide. Next, add the polyisopropylacrylamide loaded with siromos to the above solution and disperse it evenly to obtain solution C corresponding to the inner release layer. The mass volume fraction of polyvinyl alcohol is 3.5%, the mass volume fraction of polyisopropylacrylamide is 3.5%, and the mass volume fraction of siromos is 1.7%.

[0072] Solution C, solution B, and solution A were sequentially coated onto the expandable portion of the balloon or stent using a roller coating method. Each solution was coated 10 times, and after each coating, the surface was allowed to stand for 40 seconds to evaporate. After all three solutions were coated, the multi-layered implantable medical device of Example 3 was obtained.

[0073] Example 4

[0074] The preparation method of the multi-layer coated implantable medical device provided in Example 4 is as follows:

[0075] Take an appropriate amount of polyacrylamide and add it to 60 mL of acetic acid. Mix and stir evenly to obtain solution A corresponding to the outer protective layer 23, wherein the mass volume fraction of polyacrylamide is 5%.

[0076] Appropriate amounts of alanine, 1,2-bis(docosahexaenoyl)-sn-glycero-3-phosphocholine, and sodium dodecyl sulfate were added to 60 mL of heptane, mixed, and stirred until homogeneous to obtain solution B corresponding to the intermediate transfer layer 22. The mass-volume fraction of alanine was 1.3%, the mass-volume fraction of 1,2-bis(docosahexaenoyl)-sn-glycero-3-phosphocholine was 1.85%, and the mass-volume fraction of sodium dodecyl sulfate was 0.5%.

[0077] Dissolve an appropriate amount of polyacrylamide in 60 mL of acetic acid and mix well. Then, use polyvinylpyrrolidone to load and inhibit RNA. Next, add the polyvinylpyrrolidone loaded with inhibiting RNA to the above solution and disperse it evenly to obtain solution C corresponding to the inner release layer. The mass volume fraction of polyacrylamide is 5%, the mass volume fraction of polyvinylpyrrolidone is 5%, and the mass volume fraction of inhibiting RNA is 2.5%.

[0078] Electrostatic deposition was used to sequentially deposit solutions C, B, and A onto the surface of the expandable portion of the balloon or stent. Each solution was applied 12 times, and after each application, the surface was allowed to stand for 45 seconds to evaporate. After all three solutions were applied, the multi-layered implantable medical device of Example 4 was obtained.

[0079] Example 5

[0080] The preparation method of the multi-layer coated implantable medical device provided in Example 5 is as follows:

[0081] Add an appropriate amount of urea to 70 mL of methanol, mix and stir evenly to obtain solution A corresponding to the outer protective layer 23, wherein the mass-volume fraction of urea is 6.5%.

[0082] Appropriate amounts of glycine, alanine, 1,2-eicosenoyl-sn-glycero-3-phosphocholine, sodium dodecylbenzenesulfonate, stearic acid, and lauric acid were added to 70 mL of hexane, mixed, and stirred until homogeneous to obtain solution B corresponding to the intermediate transfer layer 22. The mass-volume fractions of glycine, alanine, 1,2-eicosenoyl-sn-glycero-3-phosphocholine, sodium dodecylbenzenesulfonate, stearic acid, and lauric acid were all present.

[0083] Dissolve an appropriate amount of urea in 70 mL of methanol and mix thoroughly. Then, load paclitaxel and sirolimus derivatives onto a polyethylene glycol-cholesterol copolymer. Next, add the polyethylene glycol-cholesterol copolymer loaded with paclitaxel and sirolimus derivatives to the above solution and disperse it evenly to obtain solution C corresponding to the inner release layer. The mass-volume fraction of urea is 6.5%, the mass-volume fraction of polyethylene glycol-cholesterol copolymer is 6.5%, and the mass-volume fraction of paclitaxel and sirolimus derivatives is 3.3%, with a ratio of 1:1 between the two drugs.

[0084] Electrostatic deposition was used to sequentially deposit solutions C, B, and A onto the surface of the expandable portion of the balloon or stent. Each solution was applied 16 times, and after each application, the surface was allowed to stand for 50 seconds to evaporate. After all three solutions were applied, the multi-layered implantable medical device of Example 5 was obtained.

[0085] Example 6

[0086] The preparation method of the multi-layer coated implantable medical device provided in Example 6 is as follows:

[0087] Take an appropriate amount of gum arabic and add it to 100 mL of water. Mix and stir evenly to obtain solution A corresponding to the outer protective layer 23, wherein the mass volume fraction of gum arabic is 10%.

[0088] Appropriate amounts of glutamic acid and sarcosine, 1,2-eicosenoyl-sn-glycero-3-phosphocholine and 1,2-dinervonicyl-sn-glycero-3-choline phosphate, sodium dodecylbenzenesulfonate, myrcenoic acid, tetradecadienoic acid, and octanoic acid were added to 100 mL of pentane, mixed, and stirred until homogeneous to obtain solution B corresponding to the middle layer transfer layer 22. The mass-volume fraction of glutamic acid was 1%, sarcosine was 1.5%, 1,2-eicosenoyl-sn-glycero-3-phosphocholine was 1.5%, 1,2-dinervonicyl-sn-glycero-3-choline phosphate was 2.5%, sodium dodecylbenzenesulfonate was 2%, myrcenoic acid was 0.5%, tetradecadienoic acid was 0.5%, and octanoic acid was 1%.

[0089] Dissolve an appropriate amount of gum arabic in 100 mL of water and mix well. Then, load complement inhibitors and steroid drugs onto polylactic acid and polylactic acid-glycolic acid copolymer. Next, add the polylactic acid and polylactic acid-glycolic acid copolymer loaded with complement inhibitors and steroid drugs to the above solution and disperse it evenly to obtain solution C corresponding to the inner release layer. The mass volume fraction of gum arabic is 10%, the mass volume fraction of polylactic acid and polylactic acid-glycolic acid copolymer is 10%, the mass volume fraction of complement inhibitors and steroid drugs is 5%, and the ratio of the two drugs is 1:1.

[0090] Electrostatic deposition was used to sequentially deposit solutions C, B, and A onto the surface of the expandable portion of the balloon or stent. Each solution was applied 20 times, and after each application, the surface was allowed to stand for 60 seconds to evaporate. After all three solutions were applied, the multi-layered implantable medical device of Example 6 was obtained.

[0091] To evaluate the performance of the multi-layered coated implantable medical devices prepared in Examples 1-6 of this invention, a control group experiment was also established. The control group was tested together with the multi-layered coated implantable medical devices obtained from the embodiments of this invention to assess their performance indicators. The specific technical solution for the control group is as follows.

[0092] control group

[0093] The control group's implantable medical device consisted of two layers: an inner layer containing the drug and an outer layer containing a hydrophilic material. Its preparation method is as follows:

[0094] Add an appropriate amount of polyvinylpyrrolidone to 20 mL of ethanol, mix and stir evenly to prepare the outer layer corresponding to solution D, wherein the mass-volume fraction of the hydrophilic material polyvinylpyrrolidone is 0.5%;

[0095] Add an appropriate amount of polyvinylpyrrolidone to 20 mL of ethanol and mix well. Then add the drug paclitaxel and disperse evenly to obtain the inner layer E solution. The mass-volume fraction of the hydrophilic material polyvinylpyrrolidone is 0.5%, and the mass-volume fraction of the drug paclitaxel is 0.1%.

[0096] Solution E and solution D were sequentially applied to the surface of the expandable portion of the balloon or stent using a dip-coating method. Each solution was applied twice, and after each application, the surface was allowed to stand for 30 seconds to evaporate until both solutions were completely applied. This yielded the implantable medical device for the control group.

[0097] The implantable medical devices obtained in Examples 1-6 of the present invention and the control group were tested for performance indicators, focusing on drug transfer rate, drug loss rate, and drug absorption rate. The comparative test results are shown in Table 1 below.

[0098] The testing method is as follows: the dissected vascular tissue is applied to the circulatory vascular model, and the coated balloon is passed from one end of the vascular model to the lesion site for compression and expansion. Then, HPLC is used to detect the drug concentration on the balloon, the drug concentration in the eluent in the model, and the drug concentration on the vascular tissue at the lesion site to obtain the drug transfer rate, drug loss rate, and drug absorption rate.

[0099] Table 1. Comparison of performance indicators between Examples 1-6 and the control group.

[0100] Example 1 74 52 27 Example 2 68 55 22 Example 3 84 57 14 Example 4 88 65 17 Example 5 87 62 11 Example 6 92 74 9 control group 53 50 38

[0101] As shown in Table 1, the implantable medical devices of Examples 1-6 of this invention are significantly superior to the control group in terms of drug transfer rate, drug loss rate, and drug absorption rate. In particular, the multi-layer coated implantable medical device provided by Example 6 of this invention has the best experimental results in the three test indicators.

[0102] In summary, compared with the prior art, the multi-layer coated implantable medical device and its preparation method provided by the present invention have the following advantages:

[0103] The multilayer coated implantable medical device of this invention comprises at least three layers. During implantation into the lesion site, when blood or tissue fluid washes away the implanted device, only the outer protective layer is washed away, effectively protecting the middle transfer layer and the inner release layer. This prevents the drug in the inner release layer from being washed away outside the lesion site, avoiding thrombosis. Furthermore, the outer protective layer is made of a hydrophilic polymer material, which, even if washed away during implantation, will be degraded and absorbed, preventing thrombosis. Upon reaching the lesion site, the outer protective layer is washed away, exposing the middle transfer layer. The middle transfer layer is made of a lipophilic or amphiphilic material, positively charged, and can effectively bind to negatively charged vascular wall cells, preventing device displacement. This allows the drug released by the inner release layer to be precisely targeted to the lesion site, improving the bioavailability of the coating.

[0104] Furthermore, the intermediate transfer layer of this invention comprises amino acids and phospholipids and their derivatives. The hydroxyl and carboxyl groups of the amino acids can form hydrogen bonds with the ester bonds of drugs such as sirolimus and rapamycin in the inner release layer, thereby increasing the ester bond binding force between the intermediate transfer layer and the inner release layer. Moreover, the tertiary amine groups in the phospholipids and their derivatives in the intermediate transfer layer are positively charged, while the vascular endothelial cells are negatively charged. This allows the intermediate transfer layer to effectively bind to the vascular wall of the lesion, preventing it from being washed away by blood and causing balloon or stent displacement. Furthermore, since the main component of the cell membrane is a phospholipid bilayer, according to the principle of like dissolves like, the drugs in the inner release layer are more likely to penetrate the membrane and reach the vascular cells, thus playing an auxiliary role in drug absorption.

[0105] Furthermore, the mesotransfer layer may further include surfactants and fatty acids. Surfactants can act as a barrier against elution of the mesotransfer layer by intravascular blood flow and enhance the hydrophilicity of fatty acids. Fatty acids, in turn, serve as the matrix for the surfactants, providing structural strength to aid in barrier formation and better resist elution by blood flow.

[0106] In addition, in the present invention, the ratio of each component in the inner release layer can be adjusted to regulate the hydrogen bonding forces between the ester bonds in the inner release layer and the amino, hydroxyl, and carboxyl groups in the middle transfer layer, thereby adjusting the degree of bonding between the inner release layer and the middle transfer layer. This prevents the middle transfer layer from detaching from the inner release layer due to insufficient bonding force, ensuring that the inner release layer is basically located at the lesion site when releasing the drug, reducing drug loss, and improving the bioavailability of the coating.

[0107] The method for preparing multi-layer coated implantable medical devices provided by this invention has a simple preparation process and is conducive to large-scale production.

[0108] The above description is merely a description of preferred embodiments of the present invention and is not intended to limit the scope of the invention in any way. Any changes or modifications made by those skilled in the art based on the above disclosure are within the scope of the claims. Obviously, those skilled in the art can make various modifications and variations to the invention without departing from the spirit and scope of the invention. Therefore, if these modifications and variations of the invention fall within the scope of the claims and their equivalents, the invention also intends to include these modifications and variations.

Claims

1. A multi-layered coated implantable medical device, characterized in that, include: The implant body and the coating, wherein the coating comprises at least an inner release layer, a middle transfer layer, and an outer protective layer sequentially coated on the implant body. The material of the inner release layer includes a hydrophilic polymer, a drug, and a drug delivery carrier. The drug is selected from one or more combinations of paclitaxel, sirolimus, paclitaxel derivatives, sirolimus derivatives, repressive RNA, repressive DNA, and complement inhibitors, and the drug contains ester bonds. The material of the intermediate transfer layer includes amino acids and phospholipids and their derivatives; the amino acids are selected from one or more combinations of glycine, glutamic acid, sarcosine and alanine; The outer protective layer is made of hydrophilic polymer materials.

2. The implantable medical device with a multi-layer coating according to claim 1, characterized in that, The hydrophilic polymer material is selected from one or more combinations of polyvinylpyrrolidone, polyethylene oxide, polyacrylamide, polyacrylic acid, polyether and its derivatives, urea, polyurethane, polyurethane urea, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, gum arabic and gelatin.

3. The implantable medical device with a multi-layer coating according to claim 1, characterized in that, The drug delivery carrier is selected from one or more combinations of polylactic acid, polylactic acid-glycolic acid copolymer, polyisopropylacrylamide, polyvinylpyrrolidone, and polyethylene glycol-cholesterol copolymer.

4. The implantable medical device with a multi-layer coating according to claim 1, characterized in that, In the inner release layer, the ratio of the hydrophilic polymer material, the drug, and the drug carrier is 5-100:1-50:5-100.

5. The implantable medical device with a multi-layer coating according to claim 1, characterized in that, The phospholipids and their derivatives are selected from one or more combinations of 1,2-bis(eicosanyl)-sn-glycero-3-phosphocholine, 1,2-dicarachido-sn-glycero-3-phosphocholine, 1,2-disorcinyl-sn-glycero-3-phosphocholine, 1,2-bis(docohexanoyl)-sn-glycero-3-phosphocholine, 1,2-docoenoyl-sn-glycero-3-phosphocholine, and 1,2-dinervonicyl-sn-glycero-3-choline phosphate.

6. The implantable medical device with a multi-layer coating according to claim 1, characterized in that, The material of the intermediate transfer layer also includes lipophilic or amphiphilic surfactants.

7. The implantable medical device with a multi-layer coating according to claim 6, characterized in that, The surfactant is selected from sodium dodecyl sulfate and / or sodium dodecylbenzenesulfonate.

8. The implantable medical device with a multi-layer coating according to claim 6, characterized in that, The material of the intermediate transfer layer also includes fatty acids.

9. The implantable medical device with a multi-layer coating according to claim 8, characterized in that, The fatty acid is selected from one or a combination of stearic acid, lauric acid, myrcenoic acid, tetradecadienoic acid, and octanoic acid.

10. The implantable medical device with a multi-layer coating according to claim 8, characterized in that, The ratio of the amino acid, the phospholipid and its derivatives, the surfactant and the fatty acid is 1-25:2-35:1-20:1-20.

11. The implantable medical device with a multi-layer coating according to claim 1, characterized in that, The coating is formed by spraying, dipping, roller coating, electrostatic deposition, printing, or pipetting.

12. A method for preparing an implantable medical device with a multilayer coating as described in any one of claims 1-11, characterized in that, Includes the following steps: S1: Provide an implantable subject; S2: Prepare solution C corresponding to the inner release layer, solution B corresponding to the middle transfer layer, and solution A corresponding to the outer protective layer; solution C is obtained by dissolving the material of the inner release layer in a solvent, solution B is obtained by dissolving the material of the middle transfer layer in a solvent, and solution A is obtained by dissolving the material of the outer protective layer in a solvent. The solvent is selected from diethyl ether, formic acid, acetic acid, acetone, dichloromethane, pentane, hexane, heptane, alcohol, or a mixture of alcohol and water. S3: Apply solution C, solution B and solution A sequentially to the surface of the implanted subject.

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