Medical magnesium alloy composite material and preparation method and application thereof

Abstract

The present application relates to the technical field of medical materials, and particularly relates to a medical magnesium alloy composite material and a preparation method and application thereof. The present application regulates the degradation rate of the medical magnesium alloy composite material by regulating the thickness of the polymer-drug-loaded nanometer microsphere composite coating, the thicker the thickness, the slower the degradation rate, and the thinner the thickness, the faster the degradation rate; the present application regulates the drug release rate of the medical magnesium alloy composite material by regulating the spatial distribution of the drug-loaded nanometer microspheres in the polymer-drug-loaded nanometer microsphere composite coating, so that the drug release can be fast or slow, specifically, the more concentrated (i.e. the more) the spatial distribution of the drug-loaded nanometer microspheres, the faster the drug release. The preparation method of the present application can realize the synergistic regulation of magnesium alloy degradation and drug release, and meet the clinical application requirements of magnesium alloy vascular stent customization, such as slow release, more or less, and fast or slow degradation.

Description

Technical Field

[0001] This invention relates to the field of medical materials technology, and in particular to a medical magnesium alloy composite material, its preparation method, and its application. Background Technology

[0002] Vascular stents are one of the most effective medical interventions for coronary artery stenosis. Their core principle is to repair diseased blood vessels and restore their normal physiological function through mechanical support and biological intervention. Magnesium alloy stents are biodegradable, non-toxic, and have high specific strength, representing the latest development direction in the field of vascular stents. Their high-performance design and manufacturing have become a research hotspot for next-generation vascular stents. However, magnesium alloys have poor corrosion resistance, rapid drug release and stent degradation, and insufficient endothelialization after implantation, which can easily induce intravascular thrombosis, restenosis, and inflammation. Therefore, how to regulate drug release and stent degradation, and further improve biocompatibility, is at the forefront of international cardiovascular disease treatment.

[0003] To achieve the above objectives, the mainstream international approach is to use surface modification methods to improve the degradation performance and biocompatibility of magnesium alloy vascular stents. The principle is to create a physical barrier that isolates the magnesium matrix from corrosive media while simultaneously releasing anti-proliferative drugs. Commonly used surface modification methods include chemical conversion coatings, organic coatings, micro-arc oxidation, and ion implantation. For example, the third-generation magnesium alloy stent, Dreams-2G, improved its degradation time from 6 months to over 12 months with an absorption rate of 95% through surface coating. These methods have preliminarily solved the problems of rapid degradation and poor biocompatibility of magnesium alloy vascular stents.

[0004] With the continuous improvement of medical standards and health requirements, different types of patients have placed new demands on magnesium alloy vascular stents. Patients with high bleeding risk and low ischemia risk require rapid drug release and degradation; patients with low bleeding risk and high ischemia risk require slow drug release and degradation. This poses a severe challenge to the precise control of drug release and stent degradation. Regarding drug release: instability in the release rate directly reduces biocompatibility; mismatch between degradation rate and drug release increases the risk of in-stent thrombosis and restenosis; and the drug release rate is difficult to control in special patients (such as those with high bleeding risk). Regarding stent degradation performance: individual patient differences and local hemodynamics can interfere with the degradation rate of magnesium alloy stents; patients with other underlying conditions (diabetes, renal insufficiency) cannot adapt to the degradation rate of conventional magnesium alloy stents, and the degradation rate cannot be adjusted. Therefore, the conventional surface modification methods for preparing magnesium alloy vascular stents face the challenge of precisely controlling drug release and degradation rate, which has become a technical bottleneck in the clinical application of customized vascular stents in my country. Summary of the Invention

[0005] In view of this, the purpose of this invention is to provide a medical magnesium alloy composite material, its preparation method, and its application. The method of this invention allows for precise control of the degradation rate and drug release rate of the magnesium alloy composite material, thereby enabling the high-performance customized preparation of magnesium alloy vascular stents.

[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0007] This invention provides a method for preparing medical-grade magnesium alloy composite materials, comprising the following steps:

[0008] The medical magnesium alloy substrate was immersed in hydrofluoric acid solution, and an in-situ reaction was carried out on the surface of the magnesium alloy to form a MgF2 coating, thus obtaining an intermediate.

[0009] An antiplatelet drug is dissolved in a first organic solvent to obtain a drug solution; the drug solution is then loaded onto gelatin nanospheres to obtain drug-loaded nanospheres.

[0010] The biodegradable polymer is dissolved in a second organic solvent to obtain a polymer solution;

[0011] Several portions of the drug-loaded nanospheres were dispersed into the polymer solution to obtain several groups of drug-loaded nanosphere-polymer composite coatings;

[0012] Each group of drug-loaded nanosphere-polymer composite coatings is coated onto the surface of the intermediate to form a polymer-drug-loaded nanosphere composite coating, thereby obtaining a medical magnesium alloy composite material.

[0013] The degradation rate of medical magnesium alloy composite materials can be controlled by adjusting the thickness of the polymer-drug-loaded nanosphere composite coating; the drug release rate of medical magnesium alloy composite materials can be controlled by adjusting the spatial distribution of drug-loaded nanospheres in the polymer-drug-loaded nanosphere composite coating.

[0014] Preferably, the spatial distribution of drug-loaded nanospheres in the polymer-drug-loaded nanosphere composite coating is controlled by adjusting the concentration of drug-loaded nanospheres in each group of drug-loaded nanosphere-polymer composite coatings and the order of coating, thereby controlling the spatial distribution of drug-loaded nanospheres in the polymer-drug-loaded nanosphere composite coating.

[0015] Preferably, the control of the thickness of the polymer-drug-loaded nanosphere composite coating includes controlling the thickness of the polymer-drug-loaded nanosphere composite coating by controlling the number of coating layers.

[0016] Preferably, the coating comprises ultrasonic atomization spraying.

[0017] Preferably, the antiplatelet drug includes one or more of ticagrelor, clopidogrel, and aspirin.

[0018] Preferably, the degradable polymer comprises poly(L-lactide) and / or polylactic-co-glycolic acid copolymer.

[0019] Preferably, the gelatin nanospheres have a particle size of 100-200 nm and the drug-loaded nanospheres have a drug loading capacity of 130-140 μg / mg.

[0020] Preferably, the concentration of the polymer solution is 1 to 3 wt%.

[0021] The present invention provides a medical magnesium alloy composite material prepared by the preparation method described above, comprising a medical magnesium alloy matrix, a MgF2 coating generated by in-situ reaction on the surface of the medical magnesium alloy matrix, and a polymer-drug-loaded nanosphere composite coating coated on the surface of the MgF2 coating.

[0022] This invention provides the application of the medical magnesium alloy composite material described above in the preparation of vascular stents.

[0023] This invention provides a method for preparing medical magnesium alloy composite materials, which can precisely control the degradation rate and drug release rate of the magnesium alloy composite materials, thereby meeting the high-performance customized requirements of magnesium alloy vascular stents. Specifically, the degradation rate of the medical magnesium alloy composite materials is controlled by adjusting the thickness of the polymer-drug-loaded nanosphere composite coating. Essentially, this involves controlling the polymer thickness; a thicker polymer results in a slower degradation rate, while a thinner polymer results in a faster degradation rate. Furthermore, this invention controls the drug release rate of the medical magnesium alloy composite materials by regulating the spatial distribution of the drug-loaded nanospheres in the polymer-drug-loaded nanosphere composite coating. This allows for both fast and slow drug release; specifically, a denser spatial distribution of the drug-loaded nanospheres (i.e., a greater number) results in faster drug release, meeting diverse clinical needs.

[0024] Furthermore, the medical magnesium alloy composite material prepared by this invention has an inner layer of MgF2 chemical coating, which can effectively establish an anti-corrosion barrier and slow down the degradation of magnesium alloy; and an outer layer of polymer-drug-loaded nanosphere composite coating, which loads antiplatelet drugs into the composite coating to meet the long-term clinical needs for antiplatelet therapy. Attached Figure Description

[0025] Figure 1 The weight loss ratio of different samples after soaking in SBF solution for 15 days;

[0026] Figure 2 The graph shows the elemental changes of different samples before (A) and after (B) immersion in SBF solution for 15 days.

[0027] Figure 3SEM images of different samples after soaking in SBF solution for 15 days, where a) Bare Mg, b) HF-Mg, c) PLLA(1)-HF-Mg, d) PLLA(5)-HF-Mg, e) PLLA(10)-HF-Mg, f) PLLA(15)-HF-Mg;

[0028] Figure 4 The sustained-release curve of ticagrelor nanospheres;

[0029] Figure 5 The drug release curves are for different PLLA-HF-Mg samples. Detailed Implementation

[0030] This invention provides a method for preparing medical-grade magnesium alloy composite materials, comprising the following steps:

[0031] The medical magnesium alloy substrate was immersed in hydrofluoric acid solution, and an in-situ reaction was carried out on the surface of the magnesium alloy to form a MgF2 coating, thus obtaining an intermediate.

[0032] An antiplatelet drug is dissolved in a first organic solvent to obtain a drug solution; the drug solution is then loaded onto gelatin nanospheres to obtain drug-loaded nanospheres.

[0033] The biodegradable polymer is dissolved in a second organic solvent to obtain a polymer solution;

[0034] Several portions of the drug-loaded nanospheres were dispersed into the polymer solution to obtain several groups of drug-loaded nanosphere-polymer composite coatings;

[0035] Each group of drug-loaded nanosphere-polymer composite coatings is coated onto the surface of the intermediate to form a polymer-drug-loaded nanosphere composite coating, thereby obtaining a medical magnesium alloy composite material.

[0036] The degradation rate of medical magnesium alloy composite materials can be controlled by adjusting the thickness of the polymer-drug-loaded nanosphere composite coating; the drug release rate of medical magnesium alloy composite materials can be controlled by adjusting the spatial distribution of drug-loaded nanospheres in the polymer-drug-loaded nanosphere composite coating.

[0037] Unless otherwise specified, all raw materials used in this invention are commercially available products well known in the art.

[0038] This invention involves immersing a medical-grade magnesium alloy substrate in a hydrofluoric acid solution to form an in-situ MgF2 coating on the magnesium alloy surface, thereby obtaining an intermediate.

[0039] The present invention does not have any special requirements for the medical magnesium alloy, and any medical magnesium alloy well known in the art can be used. In the embodiments of the present invention, AZ31 magnesium alloy is specifically used.

[0040] Before immersion, the present invention preferably pre-treats the medical magnesium alloy substrate; the pre-treatment preferably includes grinding, polishing, cleaning, and drying in sequence. In the present invention, the grinding preferably includes grinding with 600-grit, 1200-grit, and 2000-grit sandpaper in sequence until the surface is smooth and free of obvious scratches. The present invention has no special requirements for the polishing, cleaning, and drying; well-known procedures in the art can be used. The present invention removes impurities and oxide films from the surface of the magnesium alloy substrate through pre-treatment, resulting in a smooth and flat surface, which is beneficial for coating preparation.

[0041] In this invention, the mass concentration of the hydrofluoric acid solution is preferably 40-50%, and in specific embodiments it can be 40%, 45%, or 50%; the soaking time is preferably 2-7 days, and in specific embodiments it can be 2, 3, 4, 5, 6, or 7 days. In this invention, the soaking is preferably carried out at room temperature. This invention forms a MgF2 coating on the magnesium alloy surface through in-situ reaction during soaking. In this invention, the thickness of the MgF2 coating is preferably 0.8-1.0 μm. The MgF2 coating serves as a corrosion barrier, slowing down the degradation of the magnesium alloy, and also improves the bonding strength between the magnesium alloy substrate and the polymer-drug-loaded nanosphere composite coating. After the soaking is completed, this invention preferably removes the medical-grade magnesium alloy substrate and air-dries it naturally in the air for 24 hours to obtain an intermediate.

[0042] The present invention dissolves an antiplatelet drug in a first organic solvent to obtain a drug solution; and loads the drug solution onto gelatin nanospheres to obtain drug-loaded nanospheres.

[0043] In this invention, the first organic solvent is preferably chloromethane, more preferably dichloromethane or trichloromethane; the antiplatelet drug preferably includes one or more of ticagrelor, clopidogrel, and aspirin. In this invention, the concentration of the drug solution is preferably 30-50 μg / mL, and in specific embodiments it can be 30, 35, 40, 45, or 50 μg / mL.

[0044] In this invention, the preferred particle size of the gelatin nanospheres is 100-200 nm. This invention does not specify a particular method for preparing the gelatin nanospheres; any method well-known in the art can be used. In an embodiment of this invention, the preparation method is as follows: 1) Add 1.25 g of type A gelatin to 25 mL of distilled water, and continuously heat and stir at 50°C to obtain a 5% w / v gelatin solution; 2) Then add 25 mL of acetone and let stand at room temperature for 1 h; 3) Discard the supernatant, add another 25 mL of distilled water, and heat and stir at 50°C; 4) After the solution cools to room temperature, add 2 M hydrochloric acid to adjust the pH to 2.5; 5) Vigorously stir the gelatin solution at 40°C, 50°C, and 60°C respectively, and continuously and slowly add a total of 80 mL of acetone; 6) Continue stirring at room temperature, and after cooling, add 740 μL of a 25% glutaraldehyde aqueous solution dropwise, stirring at room temperature. Crosslinking for 16 h; 7) Add 105 mL of glycine solution (concentration 100 mM) and stir at room temperature for 1 h; 8) Dispense the gelatin solution into centrifuge tubes, centrifuge at 10000 r / min for 10 min, and discard the supernatant; 9) Resuspend in deionized water, centrifuge, and repeat centrifugation 3 times to obtain wet gelatin nanospheres; 10) Resuspend the gelatin nanospheres in acetone-water (1:3, V / V), dispense, pre-freeze in a -80℃ freezer, and freeze-dry in a vacuum freeze dryer to obtain dry gelatin nanosphere powder for later use.

[0045] This invention does not have any special requirements regarding the method of loading the drug solution onto the gelatin nanospheres; any loading method well-known in the art can be used. In an embodiment of this invention, the drug solution is specifically added dropwise onto the gelatin nanospheres (dry powder) and placed in a refrigerator at 4°C overnight to allow the drug to be fully loaded into the gelatin nanospheres.

[0046] In this invention, the drug loading of the drug-loaded nanospheres is preferably 130~140μg / mg (meaning that the drug content loaded on each 1mg of gelatin nanospheres is 130~140μg), and in specific embodiments it can be 130, 132, 134, 136, 138 or 140μg / mg.

[0047] The present invention dissolves a biodegradable polymer in a second organic solvent to obtain a polymer solution.

[0048] In this invention, the second organic solvent is preferably chloromethane, more preferably dichloromethane or trichloromethane; the degradable polymer preferably includes poly(L-lactide) (PLLA) and / or polylactic-co-glycolic acid copolymer (PLGA). In this invention, the concentration of the polymer solution is preferably 1-3 wt%, and in specific embodiments it can be 1, 1.5, 2, 2.5 or 3 wt%.

[0049] After obtaining the polymer solution and the drug-loaded nanospheres, the present invention disperses several portions of the drug-loaded nanospheres into the polymer solution to obtain several groups of drug-loaded nanosphere-polymer composite coatings.

[0050] In this invention, the concentration of drug-loaded nanospheres in each group of drug-loaded nanosphere-polymer composite coatings can be the same or different. This invention does not impose specific limitations on the concentration of drug-loaded nanospheres in each group of drug-loaded nanosphere-polymer composite coatings, as long as it meets the requirements of the subsequent coating process. When the coating is ultrasonic atomization spraying, the concentration of drug-loaded nanospheres in each group of drug-loaded nanosphere-polymer composite coatings is preferably independently 0.5~5 mg / mL.

[0051] In this invention, the number of groups of the drug-loaded nanosphere-polymer composite coating is determined according to the number of subsequent coating layers. Specifically, when coating one layer, one group of drug-loaded nanosphere-polymer composite coating is prepared; when coating two layers, two groups of drug-loaded nanosphere-polymer composite coating are prepared. In the embodiments of this invention, the specific number of groups is 1, 5, 10, or 15.

[0052] After obtaining the drug-loaded nanosphere-polymer composite coating, the present invention coats each group of drug-loaded nanosphere-polymer composite coatings onto the surface of the intermediate to form a polymer-drug-loaded nanosphere composite coating, thereby obtaining a medical magnesium alloy composite material.

[0053] In this invention, the coating preferably includes ultrasonic atomization spraying; the conditions for ultrasonic atomization spraying preferably include: a spraying flow rate of 0.001~0.002 mL / min and a spraying speed of 0.1~0.2 mL / min.

[0054] This invention regulates the degradation rate of medical magnesium alloy composite materials by controlling the thickness of the polymer-drug-loaded nanosphere composite coating; furthermore, it controls the thickness of the polymer-drug-loaded nanosphere composite coating by controlling the number of coating layers. In this invention, controlling the thickness of the polymer-drug-loaded nanosphere composite coating essentially means controlling the thickness of the polymer; the thicker the polymer, the slower the degradation rate, and the thinner the polymer, the faster the degradation rate.

[0055] This invention regulates the drug release rate of medical magnesium alloy composite materials by controlling the spatial distribution of drug-loaded nanospheres in polymer-drug-loaded nanosphere composite coatings; furthermore, it regulates the spatial distribution of drug-loaded nanospheres in polymer-drug-loaded nanosphere composite coatings by controlling the concentration of drug-loaded nanospheres in each group of drug-loaded nanosphere-polymer composite coatings and the order of coating.

[0056] In this invention, the denser the spatial distribution of the drug-loaded nanospheres (i.e., the greater their number), the faster the drug release rate. In this invention, the spatial distribution of the drug-loaded nanospheres in the polymer-drug-loaded nanosphere composite coating is preferably denser inside and sparser outside. Based on the principle of initial burst release followed by sustained release of the drug in the coating, this invention adopts a denser-inside-sparser-outside distribution, enabling the composite coating to stably and sustainably release the drug.

[0057] In this invention, after one layer is coated, there is no need to dry it; the next layer can be coated directly.

[0058] This invention stacks single layers of polymer-drug-loaded nanosphere composite coatings containing different numbers of drug-loaded nanospheres, so that the drug-loaded nanospheres exhibit different spatial gradient distributions.

[0059] The present invention provides a medical magnesium alloy composite material prepared by the preparation method described above, comprising a medical magnesium alloy matrix, a MgF2 coating generated by in-situ reaction on the surface of the medical magnesium alloy matrix, and a polymer-drug-loaded nanosphere composite coating coated on the surface of the MgF2 coating.

[0060] This invention regulates the degradation rate of medical magnesium alloy composite materials by adjusting the thickness of the polymer-drug-loaded nanosphere composite coating, and regulates the drug release rate by adjusting the spatial distribution of the drug-loaded nanospheres. The degradation of magnesium alloy and drug release are synergistically regulated, meeting the customized clinical application needs of magnesium alloy vascular stents that allow for both high and low sustained release and fast and slow degradation.

[0061] This invention provides the application of the medical magnesium alloy composite material described above in the preparation of vascular stents.

[0062] The following detailed description of the medical magnesium alloy composite material, its preparation method, and its application provided by the present invention, with reference to specific embodiments, should not be construed as limiting the scope of protection of the present invention.

[0063] Example 1

[0064] AZ31 magnesium alloy plates with a thickness of 2 mm were wire-cut into 10×10 mm samples. These samples were then successively polished with 600-grit, 1200-grit, and 2000-grit sandpaper until the surface was smooth and free of obvious scratches. After polishing, they were ultrasonically cleaned for 10 minutes and then dried in a vacuum drying oven. At room temperature, the cleaned and dried magnesium alloy samples (denoted as Bare Mg) were immersed in 40% hydrofluoric acid for 2 days, resulting in a MgF2 coating (approximately 0.9 μm thick). The coating was then air-dried for 24 hours before use and denoted as HF-Mg.

[0065] Dissolve 1g of PLLA in 64g of dichloromethane to obtain a PLLA solution with a concentration of 1.5wt%.

[0066] Gelatin nanospheres were prepared using a two-stage coagulation method. The specific steps were as follows: 1) 1.25 g of type A gelatin was added to 25 mL of distilled water and heated and stirred continuously at 50 °C to obtain a 5% w / v gelatin solution; 2) 25 mL of acetone was then added, and the solution was allowed to stand at room temperature for 1 h; 3) The supernatant was discarded, and another 25 mL of distilled water was added, followed by heating and stirring at 50 °C; 4) After the solution cooled to room temperature, 2 M hydrochloric acid was added to adjust the pH to 2.5; 5) The gelatin solution was vigorously stirred for 15 min at 40 °C, 50 °C, and 60 °C respectively, and 80 mL of acetone was slowly added dropwise; 6) Stirring was continued at room temperature, and after cooling, 740 μL of a 25% glutaraldehyde aqueous solution was added dropwise, and the solution was allowed to stand at room temperature. 7) Add 105 mL of glycine solution (concentration 100 mM) and stir at room temperature for 1 h; 8) Dispense the gelatin solution into centrifuge tubes, centrifuge at 10000 r / min for 10 min, and discard the supernatant; 9) Resuspend in deionized water, centrifuge, and repeat centrifugation 3 times to obtain wet gelatin nanospheres; 10) Resuspend the gelatin nanospheres in acetone-water (1:3, V / V), dispense, pre-freeze in a -80℃ freezer, and freeze-dry in a vacuum freeze dryer to obtain dry gelatin nanosphere powder for later use.

[0067] Ticagrelor was dissolved in dichloromethane to prepare a 50 μg / mL solution. This ticagrelor solution was then dropped onto 40 mg of gelatin nanosphere powder and placed in a refrigerator at 4°C overnight to allow the drug to fully load onto the gelatin nanospheres (drug loading capacity: 140 μg / mg). Five composite coatings were obtained by adding 40, 50, 60, 70, and 80 mg of ticagrelor nanospheres to 40 mL of PLLA solution, with specific concentrations of C1 (1 mg / mL), C2 (1.25 mg / mL), C3 (1.5 mg / mL), C4 (1.75 mg / mL), and C5 (2 mg / mL), respectively. The mixtures were then magnetically stirred until homogeneous.

[0068] A ticagrelor nanosphere-PLLA composite coating was prepared on the surface of AZ31 magnesium alloy samples using ultrasonic atomization spraying. The ultrasonic spraying width was controlled at 10 mm, the spraying flow rate was set at 0.001 mL / min, and the spraying speed was set at 0.1 mL / min. The ultrasonic precision instrument was used to perform spraying once (concentration C5), five times (concentrations C5, C4, C3, C2, C1), ten times (concentrations C5 twice, C4 twice, C3 twice, C2 twice, C1 twice), and fifteen times (concentrations C5 three times, C4 three times, C3 three times, C2 three times, C1 three times), resulting in magnesium alloy samples with different coating thicknesses and gradients, denoted as PLLA(1)-HF-Mg, PLLA(5)-HF-Mg, PLLA(10)-HF-Mg, and PLLA(15)-HF-Mg, respectively. Note: The numbers in parentheses represent the number of spraying times.

[0069] Characterization:

[0070] Different samples (pure magnesium alloy Bare Mg, fluorinated samples HF-Mg, PLLA(1)-HF-Mg, PLLA(5)-HF-Mg, PLLA(10)-HF-Mg, PLLA(15)-HF-Mg) were immersed in simulated body fluid (SBF solution) for 15 days, and the weight loss ratio was tested. The results are shown in […]. Figure 1 .Depend on Figure 1 It can be seen that the weight loss ratios of Bare Mg, HF-Mg, PLLA(1)-HF-Mg, PLLA(5)-HF-Mg, PLLA(10)-HF-Mg, and PLLA(15)-HF-Mg are 11%, 5%, 3.8%, 0.9%, 0.7%, and 0.6%, respectively. Compared with Bare Mg and HF-Mg, the weight loss ratio of PLLA-HF-Mg is significantly lower, indicating that the ticagrelor nanosphere-PLLA composite coating can effectively slow down the degradation of magnesium alloys. Comparing the weight loss ratios of PLLA(1)-HF-Mg, PLLA(5)-HF-Mg, PLLA(10)-HF-Mg, and PLLA(15)-HF-Mg, it can be seen that the degradation rate is related to the coating thickness.

[0071] Figure 2 The elemental changes of different samples (pure magnesium alloy Bare Mg, fluorinated sample HF-Mg, PLLA(1)-HF-Mg, PLLA(5)-HF-Mg, PLLA(10)-HF-Mg, PLLA(15)-HF-Mg) before (A) and after (B) immersion in SBF solution for 15 days are shown. Figure 2 The results showed that after immersion in SBF, the highest O content on the magnesium alloy surface was 53%, significantly exceeding the Mg content of 32%. The O content also changed dramatically before and after corrosion, increasing from 3% to 53%, indicating that the magnesium alloy was severely corroded. The O content in HF-Mg increased from 5.9% to 31.6%, indicating that HF-Mg corrosion was relatively severe. The O content in PLLA(1)-HF-Mg increased from 15.6% to 29.5%, indicating that corrosion was still relatively severe. The C and O contents in PLLA(5)-HF-Mg and PLLA(10)-HF-Mg did not change significantly. EDS analysis of PLLA(10)-HF-Mg and PLLA(15)-HF-Mg groups showed that the F and O contents were still extremely low, indicating that the magnesium alloy matrix of PLLA(10)-HF-Mg and PLLA(15)-HF-Mg groups was almost undegraded. The PLLA / MgF2 coating can effectively protect the surface of the magnesium alloy sample and reduce its degradation rate.

[0072] The samples soaked in SBF solution for 15 days were observed by scanning electron microscopy (SEM). The results are shown in the figure. Figure 3, among them, a) Bare Mg, b) HF-Mg, c) PLLA(1)-HF-Mg, d) PLLA(5)-HF-Mg, e) PLLA(10)-HF-Mg, f) PLLA(15)-HF-Mg. Depend on Figure 3 It can be seen that the magnesium alloy group has a rough surface and is full of cracks; the HF-Mg surface is relatively smooth with fewer cracks, and the corroded magnesium alloy substrate is visible; a small amount of PLLA coating is visible in the PLLA(1)-HF-Mg group, and PLLA(5)-HF-Mg, PLLA(10)-HF-Mg, and PLLA(15)-HF-Mg groups still have PLLA coating and a very small number of micro cracks; PLLA(10)-HF-Mg and PLLA(15)-HF-Mg groups have almost no cracks, and the PLLA coverage is relatively complete, indicating the slightest corrosion.

[0073] Ticagrelor nanospheres were placed in SBF simulated body fluid, and drug release curves were plotted daily as follows: Figure 4 As shown. By Figure 4 It is known that ticagrelor is initially released rapidly and later released gradually. Therefore, the drug-releasing coating prepared in this invention is sparse on the outside and dense on the inside. Different samples (PLLA(1)-HF-Mg, PLLA(5)-HF-Mg, PLLA(10)-HF-Mg, PLLA(15)-HF-Mg) were immersed in SBF simulated body fluid, and the drug release was measured daily to plot the curves as shown. Figure 5 As shown. By Figure 5 It can be seen that PLLA(1)-HF-Mg and PLLA(5)-HF-Mg still exhibit burst release in the early stages of degradation, while PLLA(10)-HF-Mg and PLLA(15)-HF-Mg can release ticagrelor steadily and slowly. This indicates that the present invention can regulate the drug release rate of medical magnesium alloy composite materials by controlling the spatial distribution of drug-loaded nanospheres.

[0074] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing a medical magnesium alloy composite material, characterized in that, Includes the following steps: The medical magnesium alloy substrate was immersed in hydrofluoric acid solution, and an in-situ reaction was carried out on the surface of the magnesium alloy to form a MgF2 coating, thus obtaining an intermediate. An antiplatelet drug is dissolved in a first organic solvent to obtain a drug solution; the drug solution is then loaded onto gelatin nanospheres to obtain drug-loaded nanospheres. The biodegradable polymer is dissolved in a second organic solvent to obtain a polymer solution; Several portions of the drug-loaded nanospheres were dispersed into the polymer solution to obtain several groups of drug-loaded nanosphere-polymer composite coatings; Each group of drug-loaded nanosphere-polymer composite coatings is coated onto the surface of the intermediate to form a polymer-drug-loaded nanosphere composite coating, thereby obtaining a medical magnesium alloy composite material. The degradation rate of medical magnesium alloy composite materials can be regulated by controlling the thickness of the polymer-drug-loaded nanosphere composite coating; the drug release rate of medical magnesium alloy composite materials can be regulated by controlling the spatial distribution of drug-loaded nanospheres in the polymer-drug-loaded nanosphere composite coating. The regulation of the spatial distribution of drug-loaded nanospheres in the polymer-drug-loaded nanosphere composite coating includes: regulating the concentration of drug-loaded nanospheres in each group of drug-loaded nanosphere-polymer composite coatings and the order of coating, thereby regulating the spatial distribution of drug-loaded nanospheres in the polymer-drug-loaded nanosphere composite coating. The spatial distribution of the drug-loaded nanospheres in the polymer-drug-loaded nanosphere composite coating is dense inside and sparse outside. The coating is applied by ultrasonic atomization spraying.

2. The preparation method according to claim 1, characterized in that, The control of the thickness of the polymer-drug-loaded nanosphere composite coating includes controlling the number of coating layers to control the thickness of the polymer-drug-loaded nanosphere composite coating.

3. The preparation method according to claim 1, characterized in that, The antiplatelet drugs include one or more of ticagrelor, clopidogrel, and aspirin.

4. The preparation method according to claim 1, characterized in that, The degradable polymers include poly-L-lactide and / or polylactic-co-hydroxyacetic acid copolymer.

5. The preparation method according to claim 1, characterized in that, The gelatin nanospheres have a particle size of 100-200 nm; the drug-loaded nanospheres have a drug loading capacity of 130-140 μg / mg.

6. The preparation method according to claim 1 or 4, characterized in that, The concentration of the polymer solution is 1~3wt%.

7. The medical magnesium alloy composite material prepared by the preparation method according to any one of claims 1 to 6 includes a medical magnesium alloy matrix, a MgF2 coating generated by in-situ reaction on the surface of the medical magnesium alloy matrix, and a polymer-drug-loaded nanosphere composite coating coated on the surface of the MgF2 coating.

8. The application of the medical magnesium alloy composite material of claim 7 in the preparation of vascular stents.

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