Multifunctional intravascular stent for diabetics and preparation method of multifunctional intravascular stent

Abstract

The invention discloses a multifunctional intravascular stent for diabetics and a preparation method of the multifunctional intravascular stent, and relates to the technical field of cardiovascular interventional therapy instruments. The polycitrate is used as a carrier on the surface of the intravascular stent body to form the drug-loaded slow-release coating, and the drug-loaded slow-release coating has high antioxidant content, can provide oxidative stress attenuation continuously for a long time, provides a good microenvironment for cell tissue recovery, and promotes regeneration and repair of blood vessels. The biological immunosuppressor and the diabetes specific drug are loaded in the drug-loaded slow-release coating, the biological immunosuppressor is a drug having an excellent effect on common patients, the diabetes specific drug is a drug having a specific effect on diabetic patients, and the two drugs have a synergistic effect, so that the effect of treating diabetes is achieved; the coating on the surface of the intravascular stent has the effects of resisting inflammation, improving endothelial dysfunction and inhibiting proliferation and migration of smooth muscle cells aiming at diabetic patients so as to promote regeneration and repair of diseased blood vessels of the diabetic patients.

Description

Technical Field

[0001] The present invention relates to the technical field of cardiovascular interventional treatment devices, and in particular to a multifunctional vascular stent for diabetic patients and a preparation method thereof. Background Art

[0002] Cardiovascular disease is the leading cause of death. As one of the most important treatments for cardiovascular disease, interventional therapy with vascular stents can effectively reduce mortality and save the lives of many patients. However, with the widespread clinical application of drug-eluting stents (DES), the following problems have emerged:

[0003] (1) Most of the drug carriers of these drug-eluting stents are biodegradable polylactic acid polymers. After these polymers are degraded in the body, their products will cause oxidative stress reactions, thereby hindering tissue remodeling, aggravating tissue inflammation, and promoting intimal hyperplasia.

[0004] (2) After diabetic patients receive these drug-eluting stents, their vascular late lumen diameter loss rate is accelerated and in-stent restenosis increases.

[0005] Diabetic patients experience differences in inflammation, endothelial dysfunction, platelet dysfunction, coagulation, rheology, and smooth muscle cell proliferation compared to nondiabetic patients. These differences play a unique role in the pathogenesis of atherosclerosis. Current stents designed for widespread atherosclerosis are inadequate when used in diabetic patients and cannot achieve a more potent therapeutic effect.

[0006] Therefore, there is an urgent need to develop multifunctional cardiovascular stents suitable for diabetic patients to solve the above scientific problems.

[0007] In view of this, the present invention is proposed. Summary of the Invention

[0008] The purpose of the present invention is to provide a multifunctional vascular stent for diabetic patients and a preparation method thereof, aiming to provide a multifunctional vascular stent suitable for diabetic patients, which can achieve anti-inflammatory, improve endothelial dysfunction, and inhibit smooth muscle cell proliferation and migration effects for diabetic patients, thereby promoting the regeneration and repair of diseased blood vessels in diabetic patients.

[0009] The present invention is achieved in that:

[0010] In a first aspect, the present invention provides a multifunctional vascular stent for diabetic patients, comprising a vascular stent body, a drug-loaded sustained-release coating on the surface of the vascular stent body, and the drug-loaded sustained-release coating containing a polycitrate carrier, a biological immunosuppressant and a diabetes-specific drug.

[0011] In an optional embodiment, the drug-loaded sustained-release coating contains, by mass fraction, 50%-98% of a polycitrate carrier, 1%-40% of a biological immunosuppressant, and 1%-10% of a diabetes-specific drug;

[0012] and / or, the thickness of the drug-loaded sustained-release coating is 0.1 nm-10000 nm, preferably 5 nm-200 nm, more preferably 5 nm-20 nm;

[0013] And / or, the material of the vascular stent body is selected from at least one of stainless steel, cobalt and its alloys, titanium and its alloys, platinum and its alloys, magnesium and its alloys, iron and its alloys, and zinc and its alloys.

[0014] In an alternative embodiment, the polycitrate carrier is selected from at least one of poly(1,8-octanediol citrate) (MPOC) and methacrylated poly(1,12-dodecanediol citrate) (MPDC).

[0015] In an optional embodiment, the biological immunosuppressant is selected from at least one of glucocorticoids, microbial metabolites, polyclonal or monoclonal anti-lymphocyte antibodies, antimetabolites, and alkylating agents;

[0016] Preferably, the biological immunosuppressant is selected from at least one of cerivastatin, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, pitavastatin, amlodipine atorvastatin and its calcium salt or sodium salt, rapamycin, everolimus, Biolimus A9, Zotarolimus, salvianolic acid B, rosmarinic acid, tacrolimus, pimecrolimus, paclitaxel, estradiol, cilostazol, ticlopidine, triptolide or dexamethasone, fenofibrate, CD34, DAPT and CD40TRAF6 blockers.

[0017] In an optional embodiment, the diabetes-specific drug is a drug with specific functions for diabetic patients, and the diabetes-specific drug is selected from at least one of antioxidant drugs, anti-inflammatory drugs, anticoagulant drugs, drugs that inhibit vascular smooth muscle cell proliferation, endothelialization-promoting drugs, and immunosuppressive drugs;

[0018] Preferably, the diabetes-specific drug is selected from at least one of aspirin, benazepril, velipril, sitagliptin, liraglutide, insulin, canagliflozin, liraglutide, dapagliflozin, melatonin, tocopherol, thiazolidinedione, metformin, pioglitazone, dipeptidyl peptidase 4 inhibitors, glucagon-like peptide 1 receptor agonists, sodium-glucose transporter 2 inhibitors, pioglitazone, cilostazol, MCC950, Clinacanthus nutans, Ruboxistaurin and Ferroptosis inhibitors.

[0019] In a second aspect, the present invention provides a method for preparing any of the aforementioned multifunctional vascular stents, comprising: mixing a polycitrate carrier, a biological immunosuppressant, a diabetes-specific drug, an organic solvent, and a photoinitiator to obtain a drug-loaded sustained-release solution;

[0020] A drug-loaded sustained-release coating is formed on the vascular stent body using a drug-loaded sustained-release solution.

[0021] In an optional embodiment, the drug-loaded sustained-release solution is sprayed on the surface of the vascular stent body using ultrasonic atomization spraying technology, and the drug-loaded sustained-release coating is formed after ultraviolet cross-linking and drying.

[0022] In an optional embodiment, during the spraying of the drug-loaded sustained-release solution, the number of spraying cycles is controlled to be 1-30 cycles, the extrusion rate is 0.001 mL / min-0.500 mL / min, and the forward speed is 0.001 cm / min-1.000 cm / min;

[0023] And / or, the UV crosslinking is photocuring under UV light for 1 min to 60 min.

[0024] In an optional embodiment, by regulating the amount of organic solvent, the concentration of the biological immunosuppressant in the drug-loaded sustained-release solution is 0.1 mg / mL-40 mg / mL, the concentration of the diabetes-specific drug is 0.1 mg / mL-10 mg / mL, and the concentration of the photoinitiator is 0.1 mg / mL-5.0 mg / mL.

[0025] In an optional embodiment, the organic solvent is selected from at least one of ethyl acetate, dichloromethane, chloroform, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, acetone, diethyl ether and ethanol;

[0026] And / or, the photoinitiator is at least one selected from Irgacure 2959, Irgacure 369, Irgacure 819, NAP, HBA, Photocleavable Crosslinker and LAP.

[0027] The present invention has the following beneficial effects: the present invention uses polycitrate as a carrier to form a drug-loaded sustained-release coating on the surface of the vascular stent body. The drug-loaded sustained-release coating has a high antioxidant content and can continuously and long-term provide oxidative stress attenuation, providing a good microenvironment for cell tissue recovery and promoting vascular regeneration and repair. The drug-loaded sustained-release coating is loaded with a biological immunosuppressant and a diabetes-specific drug. The biological immunosuppressant is a drug with excellent effects on ordinary patients, and the diabetes-specific drug is a drug with specific effects on diabetic patients. The two drugs act synergistically, so that the surface coating of the vascular stent achieves anti-inflammatory effects, improves endothelial dysfunction, and inhibits smooth muscle cell proliferation and migration in diabetic patients, thereby promoting regeneration and repair of diseased blood vessels in diabetic patients. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for use in the embodiments. It should be understood that the following drawings only illustrate certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other relevant drawings can be obtained based on these drawings without paying any creative work.

[0029] Figure 1 1 is an infrared spectrum of the surface coating of the vascular stent in Example 1 and Comparative Example 1;

[0030] Figure 2 This is the SEM result of the surface coating of the vascular stent in Example 1;

[0031] Figure 3 This is the drug release diagram of the surface coating of the vascular stent in Example 1;

[0032] Figure 4 The graphs are for the endothelial cell activity results of Example 1 and Comparative Examples 1 and 2;

[0033] Figure 5 The smooth muscle cell activity results of Example 1 and Comparative Examples 1 and 2 are shown;

[0034] Figure 6 The figures are macrophage activity and ELISA results of Example 1 and Comparative Examples 1 and 2; (a) shows the macrophage activity result; (b) shows the result of macrophage TNF-α expression; (c) shows the result of macrophage IL-6 expression. DETAILED DESCRIPTION

[0035] To make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are described clearly and completely below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer are used. Where the manufacturer of the reagents or instruments is not specified, all are conventional products that can be purchased commercially.

[0036] The inventors have discovered that in actual clinical applications of existing drug-eluting stents, the drug carriers are mostly made of degradable polylactic acid polymers. After such polymers degrade in the body, their products can cause oxidative stress reactions, thereby hindering tissue remodeling, exacerbating tissue inflammation, and promoting intimal hyperplasia. To date, stent surface modifications have been targeted at ordinary patients, and there is no more targeted treatment for atherosclerosis caused by a certain disease. However, for diabetic patients, their inflammation, endothelial dysfunction, platelet dysfunction, coagulation process, rheology, and smooth muscle cell proliferation processes are different from those of ordinary patients. These differences play a special role in the pathogenesis of atherosclerosis. Therefore, the vascular stents currently designed for a wide range of atherosclerosis are insufficient in their functions when used in diabetic patients and cannot achieve a more effective therapeutic effect.

[0037] An ideal cardiovascular stent for diabetic patients should use materials with antioxidant properties as drug carriers. These materials should more specifically improve endothelial damage, inhibit smooth muscle cell proliferation and migration, and suppress inflammation at the lesion site, thereby alleviating oxidative stress at the lesion site and inhibiting platelet adhesion, activation, and thrombosis. Therefore, the technical solution of the present invention is proposed.

[0038] An embodiment of the present invention provides a multifunctional vascular stent for diabetic patients, comprising a vascular stent body, and a drug-loaded sustained-release coating applied to the surface of the vascular stent body. The drug-loaded sustained-release coating comprises a polycitrate carrier, a biological immunosuppressant, and a diabetes-specific drug. The drug-loaded sustained-release coating, constructed using a novel biodegradable elastomer, polycitrate, as a carrier, is loaded with two sustained-release drugs: a biological immunosuppressant and a diabetes-specific drug. The biological immunosuppressant is a drug with excellent efficacy for general patients, while the diabetes-specific drug is a drug with specific efficacy for diabetic patients.

[0039] The embodiments of the present invention optimize the types and ratios of the two drugs to exert their synergistic effect, so that the surface coating of the vascular stent can achieve anti-inflammatory, improve endothelial dysfunction, and inhibit smooth muscle cell proliferation and migration in diabetic patients, thereby promoting the regeneration and repair of diseased blood vessels in diabetic patients.

[0040] In some embodiments, the drug-loaded sustained-release coating comprises, by weight, 50%-98% of a polycitrate carrier, 1%-40% of a biological immunosuppressant, and 1%-10% of a diabetes-specific drug. By regulating the content of the polycitrate carrier, the biological immunosuppressant, and the diabetes-specific drug, the drug-loaded sustained-release coating exhibits a superior sustained-release effect, while also exhibiting superior anti-inflammatory, endothelial dysfunction-improving, and smooth muscle cell proliferation and migration inhibition effects. Specifically, the polycitrate carrier content can be 50%, 60%, 70%, 80%, 90%, 98%, etc.; the biological immunosuppressant content can be 1%, 5%, 10%, 20%, 30%, 40%, etc.; and the diabetes-specific drug content can be 1%, 3%, 5%, 8%, 10%, etc.

[0041] Specifically, the novel biodegradable elastomer polycitrate is a cross-linked copolymer formed by polycondensing non-toxic, readily available, and inexpensive citric acid (a metabolite of the human body through the Kreb's cycle) as a multifunctional monomer with a bifunctional monomer (diol). The drug-loaded sustained-release coating constructed using the novel biodegradable elastomer polycitrate as a carrier has a high antioxidant content, can provide sustained and long-term oxidative stress attenuation, create a favorable microenvironment for cell tissue recovery, and promote vascular regeneration and repair. The polymer also has the advantages of good biocompatibility, non-toxicity, and excellent film-forming properties. The resulting drug-loaded sustained-release coating can achieve long-term controlled drug release.

[0042] In some embodiments, the polycitrate carrier is selected from at least one of poly(1,8-octanediol citrate) (MPOC) and methacrylated poly(1,12-dodecanediol citrate) (MPDC), and the polycitrate carrier can be any one or more of the above.

[0043] In some embodiments, the biological immunosuppressant is selected from at least one of glucocorticoids, microbial metabolites, polyclonal or monoclonal anti-lymphocyte antibodies, antimetabolites, and alkylating agents, and the biological immunosuppressant can be any one or more of the above. In a preferred embodiment, the biological immunosuppressant is selected from at least one of cerivastatin, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, pitavastatin, amlodipine, atorvastatin, and their calcium or sodium salts, rapamycin, everolimus, Biolimus A9, Zotarolimus, salvianolic acid B, rosmarinic acid, tacrolimus, pimecrolimus, paclitaxel, estradiol, cilostazol, ticlopidine, triptolide or dexamethasone, fenofibrate, CD34, DAPT, and CD40TRAF6 blockers, and the biological immunosuppressant can be selected from any one or more of the above, and the above drugs are all commercially available materials. Specifically, Biolimus A9 is an antiproliferative drug used for cardiovascular interventional therapy and is a rapamycin derivative (mTOR inhibitor); Zotarolimus is an antiproliferative drug used for cardiovascular interventional therapy and is a rapamycin derivative (mTOR inhibitor); CD34 is a cell surface glycoprotein molecule, the full name of which is a highly glycosylated type I transmembrane glycoprotein, which is mainly expressed on the surface of hematopoietic stem cells and vascular endothelial cells. It plays a key role in vascular development and hematopoiesis, participating in cell adhesion and signal transduction; DAPT is a small molecule compound, the full name of which is N-[N-(3,5-difluorophenylacetyl)-L-alanyl]-S-phenylglycine tert-butyl ester; CD40TRAF6 blockers are a class of inhibitors targeting the CD40 / TRAF6 signaling pathway, which regulate the immune response by interfering with the interaction between CD40 and its downstream adaptor protein TRAF6 (TNF receptor-associated factor 6).

[0044] For example, when N-[N-(3,5-difluorophenylacetyl)-L-alanyl]-S-phenylglycine tert-butyl ester (DAPT) is selected as a sustained-release drug with excellent effects for ordinary patients, since DAPT is an effective inhibitor of the Notch signaling pathway, it regulates the secretion of inflammation-related cytokines and the phenotypic differentiation of monocytes / macrophages through the Notch signaling pathway, thereby playing a role in regulating inflammation, especially promoting the activation of M2 macrophages. While being beneficial to inflammation, it also has a positive effect on the regression and stabilization of AS plaques. This anti-inflammatory method is exactly what the second-generation DES with Rapamycin derivatives as the mainstream does not have. Therefore, it is preferred to use DAPT as a sustained-release drug to actively regulate the inflammatory response and inhibit the proliferation and migration of SMCs through the Notch signaling pathway.

[0045] In some embodiments, the diabetes-specific drug is a drug with specific functions for diabetic patients, and the diabetes-specific drug is selected from at least one of antioxidant drugs, anti-inflammatory drugs, anticoagulant drugs, drugs that inhibit vascular smooth muscle cell proliferation, endothelialization-promoting drugs, and immunosuppressive drugs. The diabetes-specific drug can be any one or more of the above. In a preferred embodiment, the diabetes-specific drug is selected from at least one of aspirin, benazepril, velipril, sitagliptin, liraglutide, insulin, canagliflozin, liraglutide, dapagliflozin, melatonin, tocopherol, thiazolidinedione, metformin, pioglitazone, dipeptidyl peptidase 4 inhibitor, glucagon-like peptide 1 receptor agonist, sodium-glucose transporter 2 inhibitor, pioglitazone, cilostazol, MCC950, Clinacanthus nutans, Ruboxistaurin and Ferroptosis inhibitor. The diabetes-specific drug can be any one or more of the above, and the above diabetes-specific drugs are all commercially available materials.

[0046] For example, when Ruboxistaurin (methanesulfonic acid hydrate (LY-333531) is an oral protein kinase C inhibitor developed by Eli Lilly and Company) is selected as a sustained-release drug with specific effects on diabetic patients, since LY333531 is a selective inhibitor of the PKCβ signaling pathway, it inhibits the activation of the PKCβ signaling pathway caused by hyperglycemia in diabetic patients to achieve the functions of inhibiting macrophage infiltration, inhibiting macrophage proliferation and migration and the expression of related inflammatory factors, improving endothelial damage, inhibiting the expression of endothelial cell inflammatory factors and regulating vasodilation.

[0047] In some embodiments, the thickness of the drug-loaded sustained-release coating is 0.1 nm to 10,000 nm, such as 0.1 nm, 1.0 nm, 5.0 nm, 10.0 nm, 20.0 nm, 100.0 nm, 200.0 nm, 1000.0 nm, 5000.0 nm, 10000.0 nm, etc. Preferably, it is 5 nm to 200 nm, more preferably 5 nm to 20 nm. By regulating the thickness of the drug-loaded sustained-release coating to keep the thickness within a reasonable range, the pathological microenvironment can be effectively improved, further enhancing the effect of vascular repair.

[0048] In some embodiments, the material of the stent body is selected from at least one of stainless steel, cobalt and its alloys, titanium and its alloys, platinum and its alloys, magnesium and its alloys, iron and its alloys, and zinc and its alloys. The material of the stent body can be any one or more of the above materials, selected based on the usage scenario. These materials have good biocompatibility, certain strength and toughness, and are not prone to cracking or breakage.

[0049] It should be noted that the vascular stent provided in the embodiment of the present invention has a synergistic effect of the two drugs loaded in the drug-loaded sustained-release coating on the stent surface, so that the surface coating of the vascular stent can achieve anti-inflammatory, anti-oxidation, improve endothelial dysfunction, and inhibit smooth muscle cell proliferation and migration effects for diabetic patients, effectively improve the pathological microenvironment, and accelerate vascular repair in diabetic patients.

[0050] The present invention also provides a method for preparing a multifunctional vascular stent. The surface of the vascular stent body is formed with a drug-loaded sustained-release coating using a novel degradable elastomer, polycitrate, as a carrier. The steps are as follows:

[0051] S100, cleaning the vascular stent body

[0052] The stent body is ultrasonically cleaned using organic solvents such as acetone and ethanol, and deionized water, and then dried for later use. Ultrasonic cleaning removes surface impurities and improves the adhesion of the coating.

[0053] S200, preparing drug-loaded sustained-release solution

[0054] The polycitrate carrier, the biological immunosuppressant, the diabetes-specific drug, the organic solvent and the photoinitiator are mixed to obtain a drug-loaded sustained-release solution for standby use.

[0055] In some embodiments, 5598 parts of a polycitrate carrier, 140 parts of a biological immunosuppressant, 1-10 parts of a diabetes-specific drug, and 1-5 parts of a photoinitiator are mixed, and then an organic solvent is added and stirred for 1200 hours. By regulating the amount of organic solvent, the concentration of the biological immunosuppressant in the drug-loaded sustained-release solution is 0.1 mg / mL-40 mg / mL (such as 0.1 mg / mL, 1.0 mg / mL, 10.0 mg / mL, 20.0 mg / mL, 30.0 mg / mL, 40.0 mg / mL, etc.), the concentration of the diabetes-specific drug is 0.1 mg / mL-10 mg / mL (such as 0.1 mg / mL, 1.0 mg / mL, 3.0 mg / mL, 5.0 mg / mL, 8.0 mg / mL, 10.0 mg / mL, etc.), and the concentration of the photoinitiator is 0.1 mg / mL-5.0 mg / mL (such as 0.1 mg / mL, 1.0 mg / mL, 3.0 mg / mL, 5.0 mg / mL, etc.).

[0056] In some embodiments, the organic solvent is selected from at least one of ethyl acetate, dichloromethane, chloroform, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, acetone, ether, and ethanol, and any one or more of the above can be used. The photoinitiator is selected from at least one of Irgacure 2959, Irgacure 369, Irgacure 819, NAP, HBA, Photocleavable Crosslinker, and LAP, and any one or more of the above can be used.

[0057] S300, spraying drug-loaded sustained-release solution to form a coating

[0058] The drug-loaded sustained-release coating is formed on the vascular stent body using the drug-loaded sustained-release solution, and the formation method is not limited.

[0059] In some embodiments, a drug-loaded sustained-release solution can be sprayed onto the surface of the stent using ultrasonic atomization spraying technology. After UV crosslinking and drying, a drug-loaded sustained-release coating is formed. In actual operation, the stent is placed on a custom fixture, and the solution is sprayed onto the outer surface of the stent using ultrasonic atomization spraying. The solution is then cured under UV light for 1-60 minutes (e.g., 1 minute, 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, etc.), followed by drying.

[0060] Furthermore, during the spraying of the drug-loaded sustained-release solution, the number of spraying cycles is controlled to be 1-30 cycles, such as 1 time, 5 times, 10 times, 15 times, 20 times, 25 times, 30 times, etc.; the extrusion rate is 0.001 mL / min-0.500 mL / min, such as 0.001 mL / min, 0.010 mL / min, 0.050 mL / min, 0.100 mL / min, 0.200 mL / min, 0.300 mL / min, 0.400 mL / min, 0.500 mL / min, etc.; the forward speed is 0.001 cm / min-1.000 cm / min, such as 0.001 cm / min, 0.010 cm / min, 0.100 cm / min, 0.300 cm / min, 0.500 cm / min, 0.800 cm / min, 1.000 cm / min, etc.

[0061] The features and performance of the present invention are further described in detail below with reference to the embodiments.

[0062] Example 1

[0063] This embodiment provides a multifunctional vascular stent for diabetic patients, and the preparation method thereof is as follows:

[0064] S100, ultrasonically clean the stainless steel stent body with acetone, ethanol, and deionized water for 50 minutes in sequence, and blow dry in a nitrogen environment to obtain a clean stainless steel stent body for use.

[0065] S200, a drug-loaded sustained-release solution was prepared with a DAPT concentration of 0.6 mg / mL, a LY333531 concentration of 0.15 mg / mL, a MPOC concentration of 2 mg / mL, and an Irgacure 819 concentration of 0.04 mg / mL in tetrahydrofuran. DAPT was purchased from Aladdin, LY333531 from MCE, and Irgacure 819 from Sigma.

[0066] S300. Place the sample obtained in S100 on a customized fixture, spray the drug solution onto the outer surface of the stent using ultrasonic atomization spraying technology, place the sprayed stent under a 365nm ultraviolet lamp for photocuring for 5 minutes, and obtain the vascular stent after drying.

[0067] In the vascular stent of this embodiment, the thickness of the drug-loaded sustained-release coating is 8 μm, the number of spraying cycles is 15 cycles, the extrusion rate is 0.035 mL / min, and the forward speed is 0.035 cm / min.

[0068] Example 2

[0069] This embodiment provides a multifunctional vascular stent for diabetic patients. The preparation method thereof is different from that of Example 1 in the following aspects:

[0070] In step S200 , the prepared drug-loaded sustained-release solution contains 0.6 mg / mL DAPT, 0.2 mg / mL tocopherol, 2 mg / mL MPOC, and 0.02 mg / mL Irgacure 2959, and the solvent is chloroform.

[0071] In the vascular stent of this embodiment, the thickness of the drug-loaded sustained-release coating is 10 μm, the number of spraying cycles is 18 cycles, the extrusion rate is 0.075 mL / min, and the forward speed is 0.075 cm / min.

[0072] Example 3

[0073] This embodiment provides a multifunctional vascular stent for diabetic patients. The main differences between the preparation method of the stent and that of Example 1 are as follows:

[0074] In step S200, the prepared drug-loaded sustained-release solution contains 1 mg / mL of rapamycin, 0.2 mg / mL of dapagliflozin, 5 mg / mL of MPOC, and 0.06 mg / mL of HBA, and the solvent is dichloromethane.

[0075] The vascular stent of this embodiment has a drug-loaded sustained-release coating with a thickness of 7 μm, a spraying cycle number of 12 cycles, an extrusion rate of 0.075 mL / min, and a forward speed of 0.05 cm / min.

[0076] Example 4

[0077] This embodiment provides a multifunctional vascular stent for diabetic patients. The main differences between the preparation method and that of Example 1 are as follows:

[0078] In step S200 , the prepared drug-loaded sustained-release solution contains 1 mg / mL of rosmarinic acid, 0.5 mg / mL of thiazolidinedione, 2 mg / mL of MPOC, and 0.05 mg / mL of photocleavable crosslinker, and the solvent is acetone.

[0079] The vascular stent of this embodiment has a drug-loaded sustained-release coating with a thickness of 10 μm, a spraying cycle number of 12 cycles, an extrusion rate of 0.035 mL / min, and a forward speed of 0.035 cm / min.

[0080] Example 5

[0081] This embodiment provides a multifunctional vascular stent for diabetic patients. The main differences between the preparation method and that of Example 1 are as follows:

[0082] In step S200 , a drug solution containing 0.6 mg / mL dexamethasone, 0.6 mg / mL melatonin, 5 mg / mL MPDC, and 0.06 mg / mL photocleavable crosslinker in tetrahydrofuran as the solvent is used.

[0083] The vascular stent of this embodiment has a drug-loaded sustained-release coating with a thickness of 15 μm, 18 spraying cycles, an extrusion rate of 0.035 mL / min, and a forward speed of 0.05 cm / min.

[0084] Example 6

[0085] The only difference from Example 1 is that in step S200 , DAPT is replaced with an equal amount of paclitaxel.

[0086] Example 7

[0087] The only difference from Example 1 is that in step S200 , DAPT is replaced with an equal amount of atorvastatin.

[0088] Example 8

[0089] The only difference from Example 1 is that in step S200, LY333531 is replaced by an equal amount of canagliflozin.

[0090] Example 9

[0091] The only difference from Example 1 is that in step S200, LY333531 is replaced by an equal amount of metformin.

[0092] Example 10

[0093] The only difference from Example 1 is that in step S200 , the concentration of DAPT is replaced with 0.8 mg / mL.

[0094] Example 11

[0095] The only difference from Example 1 is that in step S200 , the concentration of DAPT is replaced with 0.6 mg / mL.

[0096] Example 12

[0097] The only difference from Example 1 is that in step S200 , the concentration of DAPT is replaced with 0.4 mg / mL.

[0098] Example 13

[0099] The only difference from Example 1 is that in step S200, the concentration of LY333531 is replaced with 0.1 mg / mL.

[0100] Comparative Example 1

[0101] This comparative example provides another vascular stent, the preparation method of which is as follows:

[0102] S100. Ultrasonic cleaning of a stainless steel stent body with acetone, ethanol, and deionized water for 50 minutes in sequence, and drying in a nitrogen environment to obtain a clean stainless steel stent body for use.

[0103] S200: Prepare a drug solution containing 0.75 mg / mL of LY333531, 2 mg / mL of MPOC, and 0.04 mg / mL of Irgacure 819 in tetrahydrofuran. The sample obtained in S100 is placed on a custom fixture, and the drug solution is sprayed onto the stent's exterior using ultrasonic atomization. After drying, the vascular stent is obtained.

[0104] The stent in this comparative example contained only LY333531 in its sprayed drug solution. The drug-loaded sustained-release coating had a thickness of 8 μm, 15 spraying cycles, an extrusion rate of 0.035 mL / min, and a forward velocity of 0.035 cm / min.

[0105] Comparative Example 2

[0106] This comparative example provides another vascular stent, the preparation method of which is as follows:

[0107] S100, ultrasonically clean the stainless steel stent body with acetone, ethanol, and deionized water for 50 minutes in sequence, and blow dry in a nitrogen environment to obtain a clean stainless steel stent body for use.

[0108] S200: Prepare a drug solution containing 0.2 mg / mL tocopherol, 2 mg / mL MPOC, and 0.04 mg / mL Irgacure 819 in tetrahydrofuran. The sample obtained in S100 is placed on a custom fixture. The drug solution is then sprayed onto the outer surface of the stent using ultrasonic atomization. The sprayed stent is then cured under a 365nm UV lamp for 5 minutes. After drying, the vascular stent is obtained.

[0109] The vascular stent of this comparative example contained only tocopherol in the sprayed drug solution. The vascular stent of this comparative example had a drug-loaded sustained-release coating thickness of 8 μm, 15 spraying cycles, an extrusion rate of 0.035 mL / min, and a forward velocity of 0.035 cm / min.

[0110] Comparative Example 3

[0111] This comparative example provides another vascular stent, the preparation method of which is as follows:

[0112] S100, ultrasonically clean the stainless steel stent body with acetone, ethanol, and deionized water for 50 minutes in sequence, and blow dry in a nitrogen environment to obtain a clean stainless steel stent body for use.

[0113] In S200, a drug solution containing 0.75 mg / mL DAPT, 2 mg / mL MPOC, and 0.04 mg / mL Irgacure 819 was prepared in tetrahydrofuran. The sample obtained in S100 was placed on a custom fixture, and the drug solution was sprayed onto the outer surface of the stent using ultrasonic atomization spray technology. The sprayed stent was then cured under a 365 nm UV lamp for 5 minutes and allowed to dry to obtain the vascular stent.

[0114] The stent in this comparative example contained only DAPT in its sprayed drug solution. The drug-loaded sustained-release coating had a thickness of 8 μm, 15 spraying cycles, an extrusion rate of 0.035 mL / min, and a forward velocity of 0.035 cm / min.

[0115] Test example

[0116] 1. Spectral test

[0117] The infrared spectra of the outer surface of the vascular stent in Example 1 and Comparative Example 1 were measured using a Fourier transform infrared spectrometer. Figure 1 As shown; Figure 1 The horizontal axis is the wavelength of light in nm, and the vertical axis is the reflectance in arbitrary units (au).

[0118] Figure 1 In the figure, the upper spectral curve is the infrared spectrum of the outer surface of the vascular stent in Comparative Example 1, and the lower spectral curve is the infrared spectrum of the outer surface of the vascular stent in Example 1. Figure 1 It can be seen that the outer wall of the stent was successfully sprayed with a DAPT and LY333531 mixed drug-loaded sustained-release coating.

[0119] 2. Morphology Test

[0120] Scanning electron microscope (SEM) was used to test the coverage of the drug-loaded coating on the outer surface of the vascular stent in Example 1. Figure 2 As shown, Figure 2 This is the scanning result of spraying DAPT and LY333531 mixed drug-loaded sustained-release coating.

[0121] As can be seen from the figure, the outer surface of Example 1 is successfully covered with the drug-loaded sustained-release coating.

[0122] 3. Cell Experiment

[0123] Endothelial cells, smooth muscle cells and macrophages were respectively 4 cells / cm 2 , 2×10 4 cells / cm 2 , 5×104cells / cm 2 The cell density of Example 1 and Comparative Example 2 was planted on the sample surface. After the cells were cultured on the sample surface for 24 hours and 72 hours respectively, the cell proliferation and activity were detected and analyzed using the CCK 8 kit method. Figure 3 , Figure 4 , Figure 5 As shown, Example 1 has a better ability to promote endothelial cell proliferation and inhibit smooth muscle cell and macrophage proliferation. At the same time, the supernatant of macrophages was extracted and its anti-inflammatory properties were tested using ELISA reagent kit. The results are as follows Figure 6 As shown, Example 1 has a better ability to inhibit the secretion of pro-inflammatory factors IL-6 and TNFα.

[0124] In addition, we conducted comparative experiments on each embodiment and comparative example. According to the above-mentioned cell culture method, the CCK value of each group of modeled cells after culturing on the sample surface for 1 day was detected, and the expression level of the pro-inflammatory factor IL-6 was analyzed. All experiments were performed with 316L SS as the control, where 316L SS- represented the normal cell group, and 316L SS+ represented the diabetes combined with atherosclerosis model cell group induced by oxidized low-density lipoprotein, high sugar and palmitic acid. The experimental results of each group are summarized in Table 1. The experimental results show that the vascular stent of Example 1 has the most significant therapeutic effect in improving the activity of model cells and inhibiting inflammation, showing good comprehensive regulatory ability. The other embodiments also showed a certain degree of improvement in biological activity, but the effect was relatively inferior. In contrast, the samples containing only a single drug in the comparative example showed a relatively limited therapeutic effect, and it was difficult to take into account the improvement of multiple cell states at the same time, showing its limitations in synergistic treatment.

[0125] Table 1 Comparison of cells and anti-inflammatory properties of examples and comparative examples

[0126]

[0127]

[0128] In summary, the vascular stent can provide sustained and long-term oxidative stress attenuation, creating a favorable microenvironment for cell tissue recovery and promoting vascular regeneration and repair. The two drugs act synergistically, enabling the stent surface coating to achieve anti-inflammatory effects, improve endothelial dysfunction, and inhibit smooth muscle cell proliferation and migration, thereby promoting regeneration and repair of diseased blood vessels in diabetic patients. Furthermore, the vascular stent possesses the advantages of multifunctionality and wide applicability, and its preparation method is easy to operate and low-cost.

[0129] The foregoing description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention are intended to be within the scope of protection of the present invention.

Claims

1. A multifunctional vascular stent for diabetic patients, characterized in that: The invention comprises a vascular stent body, the surface of which is loaded with a drug-loaded sustained-release coating, wherein the drug-loaded sustained-release coating contains a polycitrate carrier, a biological immunosuppressant and a diabetes-specific drug.

2. The multifunctional vascular stent according to claim 1, characterized in that: Calculated by mass, the drug-loaded sustained-release coating contains 50%-98% of a polycitrate carrier, 1%-40% of a biological immunosuppressant, and 1%-10% of a diabetes-specific drug; and / or, the thickness of the drug-loaded sustained-release coating is 0.1 nm-10000 nm, preferably 5 nm-200 nm, more preferably 5 nm-20 nm; And / or, the material of the vascular stent body is selected from at least one of stainless steel, cobalt and its alloys, titanium and its alloys, platinum and its alloys, magnesium and its alloys, iron and its alloys, and zinc and its alloys.

3. The multifunctional vascular stent according to claim 1 or 2, characterized in that: The polycitrate carrier is selected from at least one of poly(1,8-octanediol citrate) and methacrylated poly(1,12-dodecanediol citrate).

4. The multifunctional vascular stent according to claim 1 or 2, characterized in that: The biological immunosuppressant is selected from at least one of glucocorticoids, microbial metabolites, polyclonal or monoclonal anti-lymphocyte antibodies, antimetabolites and alkylating agents; Preferably, the biological immunosuppressant is selected from at least one of cerivastatin, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, pitavastatin, amlodipine atorvastatin and its calcium salt or sodium salt, rapamycin, everolimus, Biolimus A9, Zotarolimus, salvianolic acid B, rosmarinic acid, tacrolimus, pimecrolimus, paclitaxel, estradiol, cilostazol, ticlopidine, triptolide or dexamethasone, fenofibrate, CD34, DAPT and CD40TRAF6 blockers.

5. The multifunctional vascular stent according to claim 1 or 2, characterized in that: The diabetes-specific drug is a drug with specific functions for diabetic patients, and the diabetes-specific drug is selected from at least one of antioxidant drugs, anti-inflammatory drugs, anticoagulant drugs, drugs that inhibit vascular smooth muscle cell proliferation, endothelialization-promoting drugs, and immunosuppressant drugs; Preferably, the diabetes-specific drug is selected from at least one of aspirin, benazepril, velipril, sitagliptin, liraglutide, insulin, canagliflozin, liraglutide, dapagliflozin, melatonin, thiazolidinedione, tocopherol, metformin, pioglitazone, dipeptidyl peptidase 4 inhibitor, glucagon-like peptide 1 receptor agonist, sodium-glucose transporter 2 inhibitor, pioglitazone, cilostazol, MCC950, Clinacanthus nutans, Ruboxistaurin and Ferroptosis inhibitor.

6. A method for preparing the multifunctional vascular stent according to any one of claims 1 to 5, characterized in that: include: Mixing the polycitrate carrier, the biological immunosuppressant, the diabetes-specific drug, an organic solvent, and a photoinitiator to obtain a drug-loaded sustained-release solution; The drug-loaded sustained-release solution is used to form a drug-loaded sustained-release coating on the vascular stent body.

7. The preparation method according to claim 6, characterized in that The drug-loaded sustained-release solution is sprayed on the surface of the vascular stent body by adopting ultrasonic atomization spraying technology, and the drug-loaded sustained-release coating is formed after ultraviolet cross-linking and drying.

8. The preparation method according to claim 7, characterized in that During the spraying of the drug-loaded sustained-release solution, the number of spraying cycles is controlled to be 1-30 cycles, the extrusion rate is 0.001 mL / min-0.500 mL / min, and the forward speed is 0.001 cm / min-1.000 cm / min; And / or, the UV crosslinking is photocuring under UV light for 1 min to 60 min.

9. The preparation method according to claim 6, characterized in that By regulating the amount of the organic solvent, the concentration of the biological immunosuppressant in the drug-loaded sustained-release solution is 0.1 mg / mL-40 mg / mL, the concentration of the diabetes-specific drug is 0.1 mg / mL-10 mg / mL, and the concentration of the photoinitiator is 0.1 mg / mL-5.0 mg / mL.

10. The preparation method according to claim 9, characterized in that The organic solvent is selected from at least one of ethyl acetate, dichloromethane, chloroform, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, acetone, ether and ethanol; And / or, the photoinitiator is at least one selected from Irgacure 2959, Irgacure 369, Irgacure 819, NAP, HBA, Photocleavable Crosslinker and LAP.

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