A method for preparing a bifunctional antibacterial anti-inflammatory absorbable coating material, and products and uses thereof

Abstract

The application discloses a preparation method of a dual-function antibacterial and anti-inflammatory absorbable coating material, which comprises the following steps: (1) blending rifampicin, artemisinin and an absorbable polymer A with a mixed solvent to obtain coating solution A; blending minocycline hydrochloride, aspirin and an absorbable polymer B with the mixed solvent to obtain coating solution B; the mixed solvent is selected from hexafluoroisopropanol and ethyl acetate; (2) uniformly spraying the coating solution A and the coating solution B on the surface of a degradable substrate by ultrasonic spraying, and performing drying treatment to obtain the dual-function antibacterial and anti-inflammatory absorbable coating material. According to the preparation method, the proportion of antibiotic active ingredients, anti-inflammatory drug active ingredients and absorbable polymers is regulated, the antibacterial and anti-inflammatory drug coating is uniformly and stably fixed on the surface of the degradable substrate by ultrasonic spraying, and the dual-function absorbable antibacterial and anti-inflammatory coating material with controllable release is prepared by optimizing process parameters.

Description

Technical Field

[0001] This invention relates to the technical field of biomedical materials, and in particular to a method for preparing a bifunctional antibacterial and anti-inflammatory absorbable coating material, its products, and applications. Background Technology

[0002] Medical devices play a vital role in medical practice. Implantable medical devices (such as artificial joints, pacemakers, and artificial valves) are in long-term contact with human tissues and are not only prone to becoming carriers for bacterial adhesion, but are also often accompanied by inflammatory reactions, causing great suffering to patients. Clinical data shows that in the United States alone, the additional medical expenses caused by implantable medical device infections amount to billions of dollars each year [Mcverry B, Polasko A, Rao E, et al. Areadily scalable, clinically demonstrated, antibiofoulingzwitterionic surface treatment for implantable medical devices[J]. Advanced Materials, 2022, 34(20):2200254.].

[0003] Depositing antibacterial or anti-inflammatory coatings on the surface of medical devices is an effective solution. However, existing antibacterial coatings (such as silver-loaded ceramic coatings and quaternary ammonium polymer coatings), while capable of inhibiting bacterial growth in the short term, suffer from problems such as short antibacterial duration, poor broad-spectrum activity, and cytotoxicity due to excessive release of metal ions. For example, the ceramic coating proposed in patent CN100390098C achieves antibacterial function by adding nano-cuprous oxide and titanium dioxide, but its slurry stability is poor, and the coating is prone to forming voids after sintering, leading to rapid loss of antibacterial components, short antibacterial duration, and decreased effectiveness with long-term use. In addition, traditional single antibacterial coatings can only play a role in inhibiting bacterial proliferation. They are powerless against the complex inflammatory response around implants; while existing single anti-inflammatory coatings (such as simple aspirin-loaded coatings) lack antibacterial protection and cannot prevent initial bacterial adhesion, easily forming a vicious cycle of infection and inflammation, leading to an increase in the complication rate of more than 30%.

[0004] Therefore, developing an antibacterial-anti-inflammatory composite coating is particularly important. However, currently, the preparation of antibacterial-anti-inflammatory composite coatings still faces the following bottlenecks:

[0005] 1. Poor component compatibility: If a single solvent (such as ethyl acetate) is chosen, rifampin, artemisinin, and aspirin have good solubility, but the solubility of minocycline hydrochloride will be inhibited; if a water-organic solvent mixture is chosen, the stability of rifampin will be affected by pH and solvent ratio, and partial separation is likely to occur.

[0006] 2. Weak adhesion to substrate: Existing absorbable substrates (such as PLGA, PGA) have low surface energy (<30 mN / m), and the adhesion between traditional coatings and substrates is relatively poor, making them prone to falling off after implantation.

[0007] 3. Uncontrollable release kinetics: Traditional processes cannot precisely control the drug release rhythm, which can easily lead to problems such as "excessive release in the early stage (release > 90% in 24 hours) causing toxic side effects, and insufficient release in the later stage (release < 10% in 72 hours) causing efficacy decay". Summary of the Invention

[0008] To address the shortcomings of existing technologies, this invention discloses a method for preparing a dual-functional antibacterial and anti-inflammatory absorbable coating material. By controlling the ratio of antibiotic active ingredients, anti-inflammatory drug active ingredients, and absorbable polymers, an antibacterial and anti-inflammatory drug-loaded coating is uniformly and stably fixed on the surface of a biodegradable substrate through ultrasonic spraying. Through process design such as "component synergy + carrier anchoring + layered sustained release", a controllable release dual-functional absorbable antibacterial and anti-inflammatory coating material is prepared by optimizing process parameters.

[0009] The specific technical solution is as follows:

[0010] A method for preparing a bifunctional antibacterial and anti-inflammatory absorbable coating material includes:

[0011] (1) Rifampin, artemisinin, absorbable polymer A and mixed solvent are mixed to obtain coating solution A; minocycline hydrochloride, aspirin, absorbable polymer B and mixed solvent are mixed to obtain coating solution B;

[0012] The absorbable polymer A and the absorbable polymer B are independently selected from one or more of the following: polyglycolic acid, polylactide, polyglycolic acid-co-lactide, polyglycolic acid-co-caprolactone, and tyrosine polyarylate.

[0013] The mixed solvent is selected from hexafluoroisopropanol and ethyl acetate, and the volume percentage of hexafluoroisopropanol in the mixed solvent is not less than 25%.

[0014] (2) Coating solution A and coating solution B are uniformly sprayed onto the surface of the biodegradable substrate by ultrasonic spraying, and the dual-function antibacterial and anti-inflammatory absorbable coating material is obtained by drying.

[0015] This invention discloses a method for preparing a dual-functional antibacterial and anti-inflammatory absorbable coating material. The aim is to solve the core technical bottleneck of existing dual-functional coatings through a three-in-one technical solution of "component synergy + carrier anchoring + layered sustained release", and achieve comprehensive performance of "highly efficient antibacterial, long-lasting anti-inflammatory, strong substrate bonding and controllable release" to meet the stringent requirements of clinical implantable devices.

[0016] The anti-inflammatory drugs selected in this invention are a combination of artemisinin and aspirin, which have the following synergistic advantages:

[0017] 1. Synergistic mechanism: Artemisinin reduces the synthesis of pro-inflammatory factors such as TNF-α and IL-6 upstream, while aspirin can block the production of downstream prostaglandins by inhibiting the activity of cyclooxygenase (COX-1 / COX-2), forming a dual anti-inflammatory pathway of "upstream inhibition-downstream blocking".

[0018] 2. Synergistic effect: The slow release of artemisinin can compensate for the short-acting nature of aspirin, while the rapid release of aspirin can solve the problem of artemisinin's delayed response to acute inflammation.

[0019] Experiments have shown that if all antibacterial and anti-inflammatory drugs are mixed together in a single spraying solution, the resulting coating material after ultrasonic spraying will exhibit a burst release of both drugs, resulting in a relatively uniform release rate and making it difficult to achieve rapid suppression and long-term control. This invention employs a special mixed solvent system, including hexafluoroisopropanol and ethyl acetate. This system is optimized for the dissolution requirements of the dual anti-inflammatory components and offers four major advantages:

[0020] 1. It can simultaneously and efficiently dissolve antibiotics, dual anti-inflammatory components, and absorbable polymers, completely solving the compatibility problem of dual anti-inflammatory components, antibacterial ingredients, and polymers;

[0021] 2. It has a moderate swelling effect on biodegradable substrates (such as PLGA nonwoven fabric), which can enhance the intermolecular bonding force between the coating and the substrate;

[0022] 3. Low boiling point, which facilitates subsequent vacuum drying at room temperature, avoids high temperature damage to drug activity, and avoids solvent residue problems;

[0023] 4. Gradual evaporation during drying (hexafluoroisopropanol evaporates first, followed by ethyl acetate) can prevent the coating from developing pores due to the sudden release of solvent, ensuring that the drug components are tightly embedded in the coating and preventing the drug from being released too quickly in the early stages.

[0024] Experiments revealed that replacing other common solvents in the field, such as acetonitrile alone, with the specially formulated mixed solvent of this invention leads to significant aggregation and precipitation of the drug components, affecting their antibacterial and anti-inflammatory effects. Artemisinin and rifampin exhibit reduced solubility in acetonitrile due to hydrophobic aggregation. Ethyl acetate alone presents polymer solubility issues, as the polymer is difficult to completely dissolve in a single ethyl acetate solvent. Replacing it with hexafluoroisopropanol alone causes nozzle clogging during ultrasonic spraying and drug loss during subsequent drying.

[0025] In this invention, the mass ratio of the absorbable polymer to the drug is also very important.

[0026] Preferred:

[0027] The total mass ratio of rifampin and artemisinin to the mass ratio of absorbable polymer A is 1:(2~6); more preferably 1:(2.5~4).

[0028] The total mass ratio of minocycline hydrochloride and aspirin to the mass ratio of absorbable polymer B is 1:(2~6); more preferably 1:(2.5~4).

[0029] The formulation was determined through multiple optimizations based on "drug solubility, polymer encapsulation capacity, and synergistic effect of dual anti-inflammatory agents." When the mass ratio is too low, not only is the antibiotic released too quickly (completely within 24 hours), but the dual anti-inflammatory components, aspirin and artemisinin, also exhibit burst release. When the mass ratio is too high, it leads to excessive local encapsulation of drug concentrations, resulting in slow release of both antibiotics and anti-inflammatory components.

[0030] Preferred:

[0031] The mass ratio of rifampin to artemisinin is 1:(1~2);

[0032] The mass ratio of minocycline hydrochloride to aspirin is 1:(1~2);

[0033] Preferred:

[0034] In the coating solution A, the concentration of absorbable polymer A is 0.02~0.06 g / mL; more preferably 0.03~0.06 g / mL; and even more preferably 0.03~0.04 g / mL.

[0035] In the coating solution B, the concentration of absorbable polymer B is 0.02~0.06 g / mL; more preferably 0.025~0.06 g / mL; and even more preferably 0.025~0.04 g / mL.

[0036] Preferably, the absorbable polymer is selected from polyglycolic acid-co-caprolactone (PGCL).

[0037] Preferably, the volume percentage of hexafluoroisopropanol in the mixed solvent is 25-75%; more preferably 50-75%.

[0038] Experiments have shown that a higher content of hexafluoroisopropanol in the mixed solvent can increase the adhesion between the drug and the coating, thereby controlling the drug release rate.

[0039] Preferably, the blending is carried out at room temperature under light-protected conditions.

[0040] In step (2), the ultrasonic spraying:

[0041] The spraying flow rate is 0.2~0.4 mL / min, the number of sprays is 4~8, the feed speed is 6~10 mm / s, and the nozzle height is 30~50 mm.

[0042] Preferably, the biodegradable substrate is selected from one or more of the following: polyglycolic acid filament, polyglycolic acid nonwoven fabric, polypropylene filament, polypropylene nonwoven fabric, polyglycolic acid-co-propylene filament, polyglycolic acid-co-propylene nonwoven fabric, polyglycolic acid-co-caprolactone filament, and polyglycolic acid-co-caprolactone nonwoven fabric.

[0043] Preferably, the drying process is carried out at room temperature, in the dark, under vacuum.

[0044] Preferred:

[0045] First, spray coating solution A, then spray coating solution B. Experiments showed that if the two were interchanged, the drug release rate was unsatisfactory.

[0046] The present invention also discloses a bifunctional antibacterial and anti-inflammatory absorbable coating material prepared according to the method described.

[0047] The present invention also discloses an implantable medical device, comprising a medical device and a dual-function antibacterial and anti-inflammatory absorbable coating material wrapped around the outer surface of the medical device.

[0048] The bifunctional antibacterial and anti-inflammatory absorbable coating material disclosed in this invention has universal applicability to medical devices and can be used in various medical devices commonly found in this field, such as pacemakers, artificial heart valves, vascular stents, defibrillators, or spinal cord stimulators, etc.

[0049] Compared with the prior art, the present invention has the following beneficial effects:

[0050] This invention discloses a method for preparing a bifunctional antibacterial and anti-inflammatory absorbable coating material. The method involves compounding antibacterial agents (rifampicin, minocycline hydrochloride) with anti-inflammatory agents (aspirin, artemisinin), and optimizing the ratio of polymer components to prepare homogeneous and stable coating solutions A and B, respectively. Subsequently, an ultrasonic spraying process is used to coat the coating solutions onto the surface of an absorbable nonwoven fabric substrate, constructing a functional coating. During the coating preparation process, the swelling effect of the coating solvent on the absorbable nonwoven fabric substrate significantly enhances the adhesion between the coating and the substrate, while effectively controlling the sustained-release rate and amount of the antibacterial and anti-inflammatory agents.

[0051] The resulting coating material (i.e., absorbable nonwoven fabric with a functional coating on its surface) possesses both excellent antibacterial and anti-inflammatory properties, and its drug loading capacity is significantly increased compared to traditional coatings, enabling more efficient suppression of wound infection risks during the application of implantable medical devices. Therefore, this invention, through the synergistic design of dual anti-inflammatory components, customized innovation of the solvent system, and precise control of process parameters, focuses on overcoming the challenges of synergistic, stable release, and adhesion of antibacterial and anti-inflammatory components, solving the core technical bottlenecks of existing dual-functional coatings. It provides an efficient, stable, and safe technical solution for surface modification of implantable medical devices, exhibiting significant advantages in controlling both acute and chronic inflammation in addition to its antibacterial properties, thus providing key technical support for the research and development of functional coatings for implantable medical devices. Detailed Implementation

[0052] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially. The features and performance of the present invention will be further described in detail below with reference to the embodiments.

[0053] Example 1

[0054] Step 1: Dissolve rifampicin (0.1g), artemisinin (0.2g), and polyglycolic acid-co-caprolactone (PGCL, 0.8g) in a mixed solvent of hexafluoroisopropanol (10mL) and ethyl acetate (10mL). Stir at 500 rpm for 30 min at room temperature in the dark to obtain a homogeneous and transparent coating solution A. Dissolve minocycline (0.1g), aspirin (0.1g), and polyglycolic acid-co-caprolactone (PGCL, 0.5g) in a mixed solvent of hexafluoroisopropanol (10mL) and ethyl acetate (10mL). Stir at 500 rpm for 30 min at room temperature in the dark to obtain a homogeneous and transparent coating solution B.

[0055] Step 2: After filtering coating solution A and coating solution B through a 0.22 μm organic filter, transfer them to the syringe. Set the spray flow rate to 0.4 mL / min, the number of sprays to 6, the feed speed to 8 mm / s, and the nozzle height to 30 mm. First, apply coating solution A to the surface of the PLGA nonwoven fabric. Then, apply coating solution B to the nonwoven fabric surface coated with coating solution A under the same spraying conditions to ensure uniform coating.

[0056] Step 3: Transfer the sprayed nonwoven fabric to a light-proof vacuum drying oven (vacuum degree -0.1 MPa) and dry at room temperature for 10 h to obtain the coating material.

[0057] Example 2

[0058] Step 1: Dissolve rifampicin (0.1g), artemisinin (0.1g), and polyglycolic acid-co-caprolactone (PGCL, 0.6g) in a mixed solvent of hexafluoroisopropanol (15mL) and ethyl acetate (5mL). Stir at 500 rpm for 30 min at room temperature in the dark to obtain a homogeneous and transparent coating solution A. Then, dissolve minocycline (0.1g), aspirin (0.1g), and polyglycolic acid-co-caprolactone (PGCL, 0.6g) in a mixed solvent of hexafluoroisopropanol (15mL) and ethyl acetate (5mL). Stir at 500 rpm for 30 min at room temperature in the dark to obtain a homogeneous and transparent coating solution B.

[0059] Step 2: After filtering coating solution A and coating solution B through a 0.22 μm organic filter, transfer them to the syringe. Set the spray flow rate to 0.4 mL / min, the number of sprays to 8, the feed speed to 8 mm / s, and the nozzle height to 30 mm. First, apply coating solution A to the surface of the PLGA nonwoven fabric. Then, apply coating solution B to the nonwoven fabric surface coated with coating solution A under the same spraying conditions to ensure uniform coating.

[0060] Step 3: Transfer the sprayed nonwoven fabric to a light-proof vacuum drying oven (vacuum degree -0.1 MPa) and dry at room temperature for 10 h to obtain the coating material.

[0061] Example 3

[0062] Step 1: Dissolve rifampicin (0.1g), artemisinin (0.1g), and polyglycolic acid-co-caprolactone (PGCL, 0.8g) in a mixed solvent of hexafluoroisopropanol (15mL) and ethyl acetate (5mL). Stir at 500 rpm for 30 min at room temperature in the dark to obtain a homogeneous and transparent coating solution A. Then, dissolve minocycline (0.1g), aspirin (0.1g), and polyglycolic acid-co-caprolactone (PGCL, 0.6g) in a mixed solvent of hexafluoroisopropanol (15mL) and ethyl acetate (5mL). Stir at 500 rpm for 30 min at room temperature in the dark to obtain a homogeneous and transparent coating solution B.

[0063] Step 2: After filtering coating solution A and coating solution B through a 0.22 μm organic filter, transfer them to the syringe. Set the spray flow rate to 0.4 mL / min, the number of sprays to 6, the feed speed to 8 mm / s, and the nozzle height to 30 mm. First, apply coating solution A to the surface of the PLGA nonwoven fabric. Then, apply coating solution B to the nonwoven fabric surface coated with coating solution A under the same spraying conditions to ensure uniform coating.

[0064] Step 3: Transfer the sprayed nonwoven fabric to a light-proof vacuum drying oven (vacuum degree -0.1 MPa) and dry at room temperature for 10 h to obtain the coating material.

[0065] Example 4

[0066] The preparation process is basically the same as in Example 1, with the only difference being:

[0067] In step one, the mass of PGCL in coating solution A is replaced with 1g, and the mass of PGCL in coating solution B is replaced with 0.8g.

[0068] Example 5

[0069] The preparation process is basically the same as in Example 1, with the only difference being:

[0070] In step one, the mass of PGCL in coating solution A is replaced with 1.2g, and the mass of PGCL in coating solution B is replaced with 1.2g.

[0071] Example 6

[0072] The preparation process is basically the same as in Example 1, with the only difference being:

[0073] In step two, ultrasonic spraying is first performed using spraying solution B, and then ultrasonic spraying is performed using spraying solution A. The spraying process remains unchanged.

[0074] Comparative Example 1

[0075] Other conditions are basically the same as in Example 1, with the following differences:

[0076] In step one, rifampin (0.1g), minocycline (0.1g), artemisinin (0.2g), aspirin (0.1g), and polyglycolic acid co-caprolactone (PGCL, 1.3g) were dissolved in a mixed solvent of hexafluoroisopropanol (10mL) and ethyl acetate (10mL). The solution was stirred at 500 rpm for 30 min at room temperature in the dark to obtain a uniform and transparent coating solution.

[0077] Comparative Example 2

[0078] The preparation process is basically the same as in Example 1, except that:

[0079] In step one, the mixed solvent used to prepare coating solution A and coating solution B is replaced with 20 mL of a single solvent, hexafluoroisopropanol (ethyl acetate alone cannot dissolve PGCL).

[0080] Experiments revealed that solutes accumulated at the nozzle during the spraying process, resulting in an uneven coating.

[0081] Comparative Example 3

[0082] The preparation process is basically the same as in Example 1, with the only difference being:

[0083] In step one, the mixed solvent used to prepare spray solution A and spray solution B is replaced with 20 mL of the single solvent acetonitrile.

[0084] Experiments revealed that the loading of antibiotics and anti-inflammatory components was low, possibly due to poor adhesion between the coating and the substrate, which made the coating prone to peeling off.

[0085] Comparative Example 4

[0086] Step 1: Dissolve aspirin (0.1g), artemisinin (0.2g), and polyglycolic acid-co-caprolactone (PGCL, 0.8g) in a mixed solvent of hexafluoroisopropanol (10mL) and ethyl acetate (10mL). Stir at 500 rpm for 30 min at room temperature in the dark to obtain a homogeneous and transparent coating solution A. Dissolve minocycline (0.1g), rifampin (0.1g), and polyglycolic acid-co-caprolactone (PGCL, 0.5g) in a mixed solvent of hexafluoroisopropanol (10mL) and ethyl acetate (10mL). Stir at 500 rpm for 30 min at room temperature in the dark to obtain a homogeneous and transparent coating solution B.

[0087] Step two is exactly the same as in Example 1.

[0088] Comparative Example 5

[0089] The preparation process is basically the same as in Example 1, except that:

[0090] In step one, the mass of PGCL in both coating solution A and coating solution B is replaced with 0.3g.

[0091] Comparative Example 6

[0092] The preparation process is basically the same as in Example 1, with the only difference being:

[0093] In step two, the number of spraying times is changed to 10.

[0094] Performance testing:

[0095] I. Testing of Coating Drug Loading

[0096] Test Method: The absorbable coating materials prepared in each embodiment or comparative example were cut into sheets with a diameter of 1×1 cm using a membrane cutter. Three 1×1 cm sheets were placed in separate vials, and 10 mL of a mixture of methanol and deionized water (volume ratio 7:3) was added. The vials were placed in a constant temperature shaker at 37°C for 4 h for elution. Samples were taken and the contents of rifampin, minocycline hydrochloride, artemisinin, and aspirin were analyzed by HPLC. The average value was taken as the drug loading per unit area of ​​the substrate. Specific values ​​are shown in Table 1. HPLC test conditions for rifampin, minocycline hydrochloride, and artemisinin:

[0097] Chromatographic column: C18 column;

[0098] The mobile phase consisted of methanol, acetonitrile, 0.075 mol / L potassium dihydrogen phosphate solution, and 1 mol / L citric acid (30:30:36:4). The pH was adjusted to approximately 7 using 10 mol / L NaOH.

[0099] Detection wavelength: 254 nm;

[0100] Injection volume: 10 µL. Aspirin high-performance liquid chromatography test conditions:

[0101] Chromatographic column: C18 column;

[0102] Mobile phase: methanol:acetic acid:water (40:1:60);

[0103] Detection wavelength: 276 nm;

[0104] Injection volume: 10 µL.

[0105] Table 1

[0106]

[0107] II. Drug Release Performance Test

[0108] Test method: The coating material (2cm × 2cm) was placed in 20 mL of PBS buffer (pH 7.4) and shaken at 37℃ (110 rpm). Samples were taken periodically (5 min, 10 min, 30 min, 1 h, 2 h, 24 h, 48 h, 72 h). The drug concentration was determined by high performance liquid chromatography, and the cumulative release rate was calculated. The release rate data are listed in Table 2 below.

[0109] Table 2

[0110]

[0111] Results Analysis: Examples 1-3 all achieved synergistic release of antibiotics and anti-inflammatory components. Aspirin and minocycline hydrochloride were rapidly released first from the inner and outer layers after 48 hours, quickly suppressing acute inflammation and providing antibacterial effects. Artemisinin and rifampin were released slowly from the inner layer, providing long-term control of chronic inflammation and sustained antibacterial effects. The release rate of antibiotics and anti-inflammatory components was greatly related to the content of polymers and the solvent ratio. The higher the content of PGCL, the higher the drug encapsulation content. The higher the content of hexafluoroisopropanol, the greater the binding force between the drug and the coating, and the slightly reduced the release rate.

[0112] Comparing Examples 4-5 and Comparative Example 5, it can be seen that the main factor affecting the release rate of the anti-inflammatory component is the ratio of polymer to drug. When the ratio is high, it is easy to cause complete encapsulation, which makes it difficult to release in the short term. If the ratio is low, it is difficult to form effective encapsulation, which can easily cause burst release and make it difficult to achieve a sustained anti-inflammatory effect.

[0113] Comparing Example 1 with Comparative Example 1, it was found that without gradient coating design, the antibiotics and anti-inflammatory components were mixed and sprayed in one go, resulting in the release of antibiotics and anti-inflammatory components outside the coating, forming a burst release. The release rate was relatively uniform, making it difficult to achieve the effect of rapid suppression and long-term control.

[0114] Comparative Examples 2 and 3 used hexafluoroisopropanol and acetonitrile as solvents, respectively. When using hexafluoroisopropanol as the sole solvent, the solute accumulated at the nozzle during spraying, resulting in an uneven coating and hindering experimental repeatability, making it difficult to obtain effective data. When using acetonitrile as the sole solvent, the drug content in the coating was lower under the same conditions, especially the minocycline and aspirin content in the outer layer, which was significantly lower. This may be because the adhesion between acetonitrile solvent and the substrate is weak, making the coating easy to peel off. The faster drug release during in vitro release compared to Example 1 is also due to this reason.

[0115] Comparing Example 1 and Comparative Example 4, it was found that in Comparative Example 4, the anti-inflammatory component was sprayed first, followed by the antibacterial component. Due to the rapid release of the antibacterial component, the excessively fast release rate made it difficult to achieve the purpose of long-lasting antibacterial action. The anti-inflammatory component was released relatively slowly, and its effect was limited in the early stage. This combined coating resulted in an excessively high local concentration of the antibacterial component during the early stage of release, while the effect of the anti-inflammatory component was not obvious. It was difficult to achieve the synergistic effect of the antibacterial and anti-inflammatory components, and the purpose of "short-term + long-term" antibacterial and anti-inflammatory effects could not be achieved.

[0116] Comparing Example 1 and Comparative Example 5, it was found that the polymer content in Comparative Example 5 was too low, making it difficult for most of the drug to be effectively loaded into the complex, resulting in a rapid burst release and making it difficult to achieve a sustained release effect.

[0117] Comparing Example 1 and Comparative Example 6, it was found that increasing the number of spraying times in Comparative Example 6 resulted in a coating material with a minocycline hydrochloride and aspirin loading of 148 µg / cm³. 2 The value did not reach the expected value of 158 µg / cm. 2 The lower levels of minocycline hydrochloride and aspirin may be due to the outer coating peeling off during cutting, which is caused by the thick coating. The stability of the coating may also result in a faster release of minocycline hydrochloride and aspirin.

[0118] III. Antibacterial Performance Test

[0119] Sample preparation: The coating materials prepared in each example and comparative example were cut into 2cm×2cm sheet samples and sterilized by ultraviolet radiation.

[0120] Antibacterial rate test: Following ISO 22196-2011, Staphylococcus aureus (ATCC 6538) and Escherichia coli (ATCC 25922) were inoculated at a bacterial concentration of 1×10⁻⁶. 5 CFU / mL. After the sample has been in contact with the bacterial culture for 24 hours, it is eluted and cultured for counting.

[0121] Formula for calculating antibacterial rate:

[0122] Antibacterial rate = (number of colonies in blank group - number of colonies in sample group) / number of colonies in blank group × 100%.

[0123] The antibacterial rate test results for each sample are shown in Table 3.

[0124] Table 3

[0125]

[0126] Comparative examples and comparative examples show that the initial inhibition rate of the coating materials against both pathogenic bacteria is >90%. The results analysis shows that the presence of anti-inflammatory components does not affect the antibacterial properties of the coating materials. Although the in vitro release rates of different coating materials vary greatly, the inhibition rates against Staphylococcus aureus and Escherichia coli are not significantly different. This is mainly because the inhibition rate of the coating materials is more affected by the concentration of antibiotics.

[0127] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. The specific examples used above to illustrate the present invention are only for the purpose of helping to understand the present invention and are not intended to limit the present invention. Those skilled in the art to which this invention pertains can make several simple deductions, modifications, substitutions, or combinations based on the concept of the present invention. These deductions, modifications, substitutions, or combinations also fall within the scope of the claims of the present invention.

Claims

1. A method for preparing a bifunctional antibacterial and anti-inflammatory absorbable coating material, characterized in that, include: (1) Rifampin, artemisinin, absorbable polymer A and mixed solvent are blended to obtain coating solution A; Coating solution B is obtained by blending minocycline hydrochloride, aspirin, absorbable polymer B, and a mixed solvent. The absorbable polymer A and the absorbable polymer B are independently selected from one or more of the following: polyglycolic acid, polylactide, polyglycolic acid-co-lactide, polyglycolic acid-co-caprolactone, and tyrosine polyarylate. The mixed solvent is selected from hexafluoroisopropanol and ethyl acetate, and the volume percentage of hexafluoroisopropanol in the mixed solvent is not less than 25%. (2) Coating solution A and coating solution B are uniformly sprayed onto the surface of the biodegradable substrate by ultrasonic spraying, and the dual-function antibacterial and anti-inflammatory absorbable coating material is obtained by drying.

2. The method for preparing the bifunctional antibacterial and anti-inflammatory absorbable coating material according to claim 1, characterized in that, In step (1): The mass ratio of rifampin to artemisinin is 1:(1~2); The total mass ratio of rifampin and artemisinin to the mass ratio of absorbable polymer A is 1:(2~6). The concentration of absorbable polymer A in the coating solution A is 0.02~0.06 g / mL.

3. The method for preparing the bifunctional antibacterial and anti-inflammatory absorbable coating material according to claim 1, characterized in that, In step (1): The mass ratio of minocycline hydrochloride to aspirin is 1:(1~2); The total mass ratio of minocycline hydrochloride and aspirin to the mass ratio of absorbable polymer B is 1:(2~6). The concentration of absorbable polymer B in the coating solution B is 0.02~0.06 g / mL.

4. The method for preparing the bifunctional antibacterial and anti-inflammatory absorbable coating material according to claim 1, characterized in that, In step (1): In the mixed solvent, hexafluoroisopropanol accounts for 50-75% by volume; The blending was carried out at room temperature under light-protected conditions.

5. The method for preparing the bifunctional antibacterial and anti-inflammatory absorbable coating material according to claim 1, characterized in that, In step (2), the ultrasonic spraying: The spraying flow rate is 0.2~0.4 mL / min, the number of sprays is 4~8, the feed speed is 6~10 mm / s, and the nozzle height is 30~50 mm.

6. The method for preparing the bifunctional antibacterial and anti-inflammatory absorbable coating material according to claim 1, characterized in that, In step (2): First, spray coating solution A, then spray coating solution B.

7. The method for preparing the bifunctional antibacterial and anti-inflammatory absorbable coating material according to claim 1, characterized in that, In step (2): The biodegradable substrate is selected from one or more of the following: polyglycolic acid filament, polyglycolic acid nonwoven fabric, polypropylene filament, polypropylene nonwoven fabric, polyglycolic acid-co-propylene filament, polyglycolic acid-co-propylene nonwoven fabric, polyglycolic acid-co-caprolactone filament, and polyglycolic acid-co-caprolactone nonwoven fabric. The drying process is carried out at room temperature, in the dark, and under vacuum.

8. A bifunctional antibacterial and anti-inflammatory absorbable coating material prepared by the method according to any one of claims 1 to 7.

9. An implantable medical device, characterized in that, Includes a medical device and a bifunctional antibacterial and anti-inflammatory absorbable coating material according to claim 8, which is wrapped around the outer surface of the medical device.

10. The implantable medical device according to claim 9, characterized in that, The medical device is selected from cardiac pacemakers, artificial heart valves, vascular stents, defibrillators, or spinal cord stimulators.

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