Preparation method of absorbable antibacterial coating material capable of slowly releasing antibiotics as well as product and application of absorbable antibacterial coating material

Abstract

The invention discloses a preparation method of an absorbable antibacterial coating material capable of slowly releasing antibiotics. The preparation method comprises the following steps: step 1, blending antibiotics, an absorbable polymer and a mixed solvent to obtain a coating solution; the antibiotics are selected from rifampicin and minocycline hydrochloride; the absorbable polymer is selected from one or more of polyglycolide, polylactide, polyglycolide-co-lactide, polyglycolide-co-caprolactone and tyrosine polyarylester; the absorbable polymer is selected from one or more of polyglycolide, polylactide, polyglycolide-co-lactide, polyglycolide-co-caprolactone and tyrosine polyarylester; the mixed solvent is selected from hexafluoroisopropanol and acetonitrile, and the volume ratio of the hexafluoroisopropanol in the mixed solvent is not less than 25%; and 2, uniformly spraying the coating solution on the surface of the degradable base material through ultrasonic spraying, and then carrying out drying treatment. According to the preparation method disclosed by the invention, the antibiotic, the absorbable polymer and the organic solvent are blended and dissolved and then are attached to the surface of the absorbable material through ultrasonic spraying, and the release of the antibiotic is regulated and controlled while the stability of the coating is ensured by regulating and controlling the ratio of the antibiotic to the polymer and the swelling characteristic of the solvent to the base material.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of biomedical materials, in particular to a preparation method of an absorbable antibacterial coating material with sustained-release antibiotics, and a product and application thereof. BACKGROUND

[0002] Under the background of continuous advancement of medical technology, medical devices have become an indispensable key element in treatment and health maintenance. However, the problem of bacterial infection faced by medical devices in the actual application process has always been a serious challenge to the medical field. For example, implantable medical devices such as artificial joints, cardiac pacemakers and artificial valves will be in direct contact with body tissues after being implanted in the human body. Clinical data shows that in the United States alone, the additional medical expenses caused by implantable medical device infections amount to billions of dollars every year [Mcverry B, Polasko A, Rao E, et al. A readily scalable, clinically demonstrated, antibiofouling zwitterionic surface treatment for implantable medical devices [J]. Advanced Materials, 2022, 34(20): 2200254.]. Once bacteria adhere and breed on the surface of these devices, it is likely to cause infection at the implant site, and in severe cases, it can even endanger the life safety of patients. This not only brings great physical and mental suffering to patients, but also causes high medical costs. It is particularly important to improve the antibacterial performance without affecting the function of medical devices.

[0003] With the rapid development of medical technology, biomaterial science and antibacterial demand, absorbable antibacterial coating materials have shown important application value in the fields of medical devices, wound dressings, tissue engineering, etc.

[0004] Traditional antibacterial coatings usually use organic antibacterial agents or composite antibacterial systems, which have certain antibacterial effect, but have many limitations: some materials are not degradable, which may cause biocompatibility problems during long-term use; antibacterial agents are prone to release, which may lead to drug resistance risk; the coating preparation process is complex, which requires harsh conditions such as high temperature, high pressure or special equipment, making it difficult to achieve large-scale production.

[0005] A preparation method of an antibacterial coating is disclosed in Chinese patent document with application publication number CN105461952A, in which a dopamine hydrochloride solution and a silver nitrate solution are sequentially spin-coated on the surface of a substrate, and an antibacterial coating containing nano-silver on the surface is prepared by layer-by-layer assembly combined with ultraviolet reduction technology. Although the steps are simplified, the long-term stability and potential toxicity of nano-silver still need to be verified.

[0006] Existing absorbable biomaterials, such as polyglycolide (PGA), polylactide (PLA), polyglycolide-co-lactide (PLGA), polyglycolide-co-caprolactone (PGCL), etc. have been used for suture, bone repair materials, etc. However, the antibacterial performance of single material is insufficient, and the antibacterial function needs to be enhanced by coating modification.

[0007] As disclosed in the Chinese patent document with the application publication number CN117860950A, an antibacterial coating gel is disclosed, the raw materials of which include an antibacterial agent, a stearate, a glycolide / lactide copolymer, a polyhydroxybutyrate, and an organic solvent. The coating gel has better antibacterial performance, but the preparation system thereof may limit biocompatibility, and the preparation process involves multi-step heating reflux, which has high process complexity.

[0008] Therefore, it is a key technical problem to be solved in the industry to develop a coating material with absorbability, long-acting antibacterial performance, and simple preparation process. SUMMARY

[0009] In view of the deficiencies of the prior art, the present application discloses a preparation method of an absorbable antibacterial coating material for slow-release of antibiotics. After the antibiotic, the absorbable polymer, and the organic solvent are blended and dissolved, they are attached to the surface of an absorbable material by ultrasonic spraying. By adjusting the ratio of the antibiotic to the polymer and the swelling properties of the solvent to the substrate, the stability of the coating is ensured while the release of the antibiotic is regulated.

[0010] The specific technical solutions are as follows:

[0011] The preparation method of the absorbable antibacterial coating material for slow-release of antibiotics comprises:

[0012] Step 1: blending an antibiotic, an absorbable polymer, and a mixed solvent to obtain a coating solution;

[0013] The antibiotic is selected from rifampicin and minocycline hydrochloride;

[0014] The absorbable polymer is selected from one or more of polyglycolide, polylactide, polyglycolide-co-lactide, polyglycolide-co-caprolactone, and tyrosine polyarylate;

[0015] The mixed solvent is selected from hexafluoroisopropanol and acetonitrile, and the volume fraction of hexafluoroisopropanol in the mixed solvent is not less than 25%;

[0016] Step 2: uniformly spraying the coating solution on the surface of a degradable substrate by ultrasonic spraying, and then drying to obtain the absorbable antibacterial coating material for slow-release of antibiotics.

[0017] The preparation method disclosed in this invention uses two antibiotics, rifampin and minocycline, and an absorbable polymer as a drug carrier. A mixed solvent composed of hexafluoroisopropanol and acetonitrile is used to dissolve the antibiotics and absorbable polymer. Utilizing the swelling properties of this specially formulated mixed solvent on the surface of a biodegradable substrate, atomized antibiotic-loaded microparticles are uniformly and stably fixed onto the surface of the biodegradable substrate through an ultrasonic spraying process. Simultaneously, the atomized microparticles are insufficient to damage the substrate surface. Through ultrasonic spraying and the inherent properties of the solvent, the antibiotics and absorbable polymer are embedded into the surface of the biodegradable substrate, thus preparing an absorbable antibacterial material with sustained-release antibiotics. This process is simple, can be mass-produced, and has a significant price advantage.

[0018] Experiments revealed that replacing the special mixed solvent composition of this invention with acetonitrile alone or other common solvents in the art, such as ethyl acetate or tetrahydrofuran, caused the antibiotics to detach from the surface of the biodegradable substrate, failing to achieve stable antibacterial properties. Replacing it with hexafluoroisopropanol alone resulted in nozzle clogging during ultrasonic spraying, preventing successful spraying.

[0019] In step one:

[0020] Preferably, the mass ratio of rifampicin to minocycline hydrochloride in the antibiotic is (0.3~3.0):1; more preferably 1:1.

[0021] Preferably, the mass ratio of antibiotic to absorbable polymer is 1:(1~3).

[0022] Experiments have shown that if the mass ratio of the two components is too large, such as 1:1, the antibiotic cannot be effectively encapsulated, resulting in excessively rapid release of the antibiotic and making it difficult to achieve effective controlled release. If the mass ratio is too small, such as 1:4, the absorbable polymer almost completely encapsulates the antibiotic, making it difficult to release it effectively.

[0023] In step one:

[0024] Preferably, the concentration of antibiotics in the coating solution is (0.5~1.5) wt%

[0025] Preferably, the volume percentage of hexafluoroisopropanol in the mixed solvent is 25-75%.

[0026] Experiments have shown that the release of antibiotics in the prepared absorbable antibacterial coating material can be controlled by adjusting the volume ratio of hexafluoroisopropanol in the mixed solvent to meet different application requirements.

[0027] In step two:

[0028] Preferably, an organic filter is used to filter the antibiotic solution and transfer it into a syringe. The syringe is fixed to an injection pump and connected to an ultrasonic nozzle via a polytetrafluoroethylene tube.

[0029] The ultrasonic spraying:

[0030] Preferably, 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.

[0031] Further optimizations were made regarding the following parameters: spray flow rate: 0.4 mL / min, number of sprays: 4, feed rate: 10 mm / s, and nozzle height: 30 mm.

[0032] In step two:

[0033] 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.

[0034] Preferably, the drying process is carried out at room temperature, in the dark, under vacuum.

[0035] The present invention also discloses an absorbable antibacterial coating material for sustained-release antibiotics prepared according to the above method.

[0036] The present invention also discloses an implantable medical device, comprising a medical device and an absorbable antibacterial coating material for sustained-release antibiotics wrapped around the outer surface of the medical device.

[0037] The absorbable antibacterial 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.

[0038] Compared with the prior art, the present invention has the following beneficial effects:

[0039] This invention discloses a method for preparing absorbable antibacterial materials for sustained-release antibiotics. It employs rifampicin and minocycline as antibiotics, using an absorbable polymer as a drug carrier. The method innovatively utilizes a special mixed solvent (hexafluoroisopropanol and acetonitrile) to induce a swelling mechanism. Leveraging the swelling-binding effect of this solvent system, the moderate swelling of the biodegradable substrate by hexafluoroisopropanol in the mixed solvent creates a microporous structure on the substrate surface. After atomization, the coating solution penetrates into this microporous structure. Once the solvent evaporates, the antibiotic-loaded polymer forms a tight interfacial bond with the substrate, significantly enhancing the binding force between the drug and the material. This method allows for the physical integration of antibiotics and polymers in different proportions on the surface of the biodegradable substrate, and the degree of swelling is controllable (adjusted by the volume ratio of hexafluoroisopropanol to acetonitrile). This avoids excessive swelling that could damage the substrate surface structure and also allows for adjustment of the antibiotic release rate to suit different application scenarios.

[0040] The preparation method disclosed in this invention allows for easy adjustment of solvent ratio and ultrasonic spraying parameters (flow rate, number of times, etc.), making it suitable for industrial mass production. Furthermore, the raw materials are low in cost and readily available.

[0041] The absorbable antibacterial material for sustained-release antibiotics prepared by this invention has long-lasting sustained-release properties. Relying on the above-mentioned swelling and binding mechanism, the antibiotics form a "gradient loading" structure on the substrate surface. In vitro release experiments show that the release of rifampin and minocycline in this material can be sustained for more than 8 hours. In vivo release experiments in rats show that the release of rifampin and minocycline in this material can be sustained for more than 14 days. This avoids the problem of drug burst release in traditional spraying processes, can match the high infection risk window in the early stage of medical device implantation, and meet the long-lasting sustained-release antibacterial needs after medical device implantation. Attached Figure Description

[0042] Figure 1 SEM images of the absorbable antibacterial coating materials prepared in Examples 1-3 are shown, and PGA nonwoven fabric substrates without spraying treatment are given as a comparison.

[0043] Figure 2 Microscopic cross-sections of the absorbable antibacterial coating material prepared in Example 1 at different magnifications (middle and lower images), and a PGA nonwoven fabric substrate without coating treatment is given as a comparison (top image).

[0044] Figure 3 The in vitro release curves of rifampin on the surface of the absorbable antibacterial coating materials prepared in Examples 1-5 in PBS buffer are shown.

[0045] Figure 4 The in vitro release curves of minocycline hydrochloride on the surface of the absorbable antibacterial coating materials prepared in Examples 1-5 in PBS buffer are shown.

[0046] Figure 5The in vivo release curves of rifampicin on the surface of the absorbable antibacterial coating materials prepared in Examples 1-3 in SD rats are shown.

[0047] Figure 6 The in vivo release curves of minocycline hydrochloride on the surface of the absorbable antibacterial coating materials prepared in Examples 1-3 in SD rats are shown.

[0048] Figure 7 The in vitro release curves of rifampin on the surface of the absorbable antibacterial coating materials prepared in Comparative Example 1 and Comparative Example 2 in PBS buffer.

[0049] Figure 8 The in vitro release curves of minocycline hydrochloride on the surface of the absorbable antibacterial coating materials prepared in Comparative Example 1 and Comparative Example 2 in PBS buffer are shown.

[0050] Figure 9 The image shows the appearance of the absorbable antibacterial coating material prepared in Example 1 after implantation in a rat.

[0051] Figure 10 The images show the antibacterial activity of the absorbable antibacterial coating materials prepared in Examples 1-3 against Staphylococcus aureus, and a biodegradable PGA nonwoven fabric without coating treatment is provided as a comparison. 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] 1) Rifampicin, minocycline hydrochloride and polyglycolic acid (PGA) were dissolved in a mixed solvent of hexafluoroisopropanol and acetonitrile (volume ratio 3:1). The mixture was stirred under light-protected conditions until completely dissolved to obtain a coating solution. The mass ratio of rifampicin, minocycline hydrochloride and PGA was 1:1:2. The concentration of antibiotics in the coating solution was 1.0 wt%.

[0055] 2) After filtering the above coating solution through a 0.22 μm organic filter, transfer it to a 10 mL syringe. Fix the syringe to the injection pump connected to the ultrasonic spraying instrument. Connect the syringe to the ultrasonic nozzle through a 1 mm diameter polytetrafluoroethylene tube so that the solution in the syringe can flow stably through the ultrasonic nozzle.

[0056] 3) Adjust the process parameters of ultrasonic spraying: spraying flow rate: 0.4 mL / min, spraying times: 4 times, feed speed: 10 mm / s, nozzle height: 30 mm, and spray the coating solution evenly and stably onto the surface of the PGA nonwoven fabric material. The PGA nonwoven fabric material has evenly arranged circular holes with a diameter of 1 mm and a distance of 1 mm between the holes.

[0057] 4) After the PGA nonwoven fabric material is sprayed, it is transferred to a vacuum drying oven and dried at room temperature and in the dark for 10 h to prepare an absorbable antibacterial coating material for sustained-release antibiotics.

[0058] The absorbable antibacterial coating material for sustained-release antibiotics prepared in this embodiment was cut into sheets with a diameter of 1x1 cm using a mold. The average device weight was 30 mg. Three 1x1 cm sheets were placed in separate vials, and 10 mL of a mixture of methanol and deionized water (volume ratio 1:1) 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 and minocycline hydrochloride were analyzed by HPLC. The average value was taken as the drug loading per unit area of ​​the coating material. The drug loading of rifampin and minocycline hydrochloride per unit area of ​​the absorbable antibacterial coating material prepared in this embodiment is listed in Table 1 below.

[0059] Example 2

[0060] The preparation process is basically the same as in Example 1, except for step 1):

[0061] Replacing the mass ratio of rifampin, minocycline hydrochloride, and PGA with 1:1:4 does not change the concentration of antibiotics in the resulting coating solution.

[0062] Using the same testing method as in Example 1, the drug loading data per unit area of ​​the absorbable antibacterial coating material were obtained and are listed in Table 1 below.

[0063] Example 3

[0064] The preparation process is basically the same as in Example 1, except for step 1):

[0065] Replacing the mass ratio of rifampin, minocycline hydrochloride, and PGA with 1:1:6 does not change the concentration of antibiotics in the resulting coating solution.

[0066] Using the same testing method as in Example 1, the drug loading data per unit area of ​​the absorbable antibacterial coating material were obtained and are listed in Table 1 below.

[0067] Figure 1SEM images of the absorbable antibacterial coating materials prepared in Examples 1-3 are shown, with PGA nonwoven fabric material without spraying treatment provided for comparison. The comparison reveals that the structure of the PGA nonwoven fabric was not damaged after spraying treatment according to the present invention, and the prepared coating surface was smooth and flat.

[0068] Figure 2 Microscopic sections of the absorbable antibacterial coating material prepared in Example 1 at different magnifications are shown (middle and lower images), with an uncoated PGA nonwoven fabric substrate provided for comparison (top image). The comparison reveals that…

[0069] Example 4

[0070] The preparation process is basically the same as in Example 1, except for step 1):

[0071] By replacing the volume ratio of hexafluoroisopropanol and acetonitrile in the mixed solvent to 1:1, the concentration of antibiotics in the coating solution remains unchanged.

[0072] Using the material system described in this embodiment, ultrasonic spraying can be achieved smoothly and stably.

[0073] Using the same testing method as in Example 1, the drug loading data per unit area of ​​the absorbable antibacterial coating material were obtained and are listed in Table 1 below.

[0074] Example 5

[0075] The preparation process is basically the same as in Example 1, except for step 1):

[0076] The volume ratio of hexafluoroisopropanol to acetonitrile in the mixed solvent was replaced with 1:3, while the concentration of antibiotics in the coating solution remained unchanged.

[0077] Using the material system described in this embodiment, ultrasonic spraying can be achieved smoothly and stably.

[0078] Using the same testing method as in Example 1, the drug loading data per unit area of ​​the absorbable antibacterial coating material were obtained and are listed in Table 1 below.

[0079] Comparative Example 1

[0080] The preparation process is basically the same as in Example 1, except for step 1):

[0081] Replacing the mass ratio of rifampin, minocycline hydrochloride, and PGA with 1:1:1 does not change the concentration of antibiotics in the resulting coating solution.

[0082] Using the same testing method as in Example 1, the drug loading data per unit area of ​​the absorbable antibacterial coating material prepared in this comparative example are listed in Table 1 below.

[0083] Comparative Example 2

[0084] The preparation process is basically the same as in Example 1, except for step 1):

[0085] Replacing the mass ratio of rifampin, minocycline hydrochloride, and PGA with 1:1:8 does not change the concentration of antibiotics in the resulting coating solution.

[0086] Comparative Examples 3-6

[0087] The preparation process is basically the same as in Example 1, except for step 1):

[0088] The mixed solvent was replaced sequentially with acetonitrile, dimethyl sulfoxide, ethyl acetate, and tetrahydrofuran, while the concentration of antibiotics in the coating solution remained unchanged.

[0089] Using the raw material system in the above comparative example, ultrasonic spraying can be successfully achieved.

[0090] Using the same testing method as in Example 1, the drug loading data per unit area of ​​the absorbable antibacterial coating material obtained for each comparative example are listed in Table 1 below.

[0091] Comparative Example 7

[0092] The preparation process is basically the same as in Example 1, except for step 1):

[0093] Replacing the mixed solvent with hexafluoroisopropanol alone does not change the concentration of antibiotics in the coating solution.

[0094] Using the raw material system in this comparative example, during ultrasonic spraying, antibiotics are prone to precipitate and accumulate at the nozzle, causing nozzle blockage and preventing successful spraying.

[0095] Using the same testing method as in Example 1, the drug loading data per unit area of ​​the absorbable antibacterial coating material prepared in this comparative example are listed in Table 1 below.

[0096] Table 1

[0097]

[0098] Comparing the data in Table 1, it can be seen that the hexafluoroisopropanol / acetonitrile mixed solvent disclosed in this invention in Examples 1-5 and Comparative Examples 1-2 can achieve stable intercalation of antibiotic-loaded polymers on the surface of biodegradable substrates, significantly enhance the adhesion between the drug-loaded coating and the substrate, and stabilize the antibiotic loading rate, laying the foundation for subsequent stable and continuous antibacterial effects.

[0099] When Comparative Examples 3-6 replaced the specific mixed solvent in this invention with other common organic solvents, the bonding force between the drug-loaded polymer and the substrate decreased significantly, resulting in easy detachment of antibiotics, a significant decrease in drug loading, and an impact on the stability of the process. When using pure hexafluoroisopropanol in Comparative Example 7, the nozzle was easily clogged during the spraying process due to the rapid evaporation of the solvent, making it difficult to operate effectively for a long time and resulting in uneven spraying.

[0100] Detection of antibiotics on the surface of absorbable antibacterial coating materials

[0101] High performance liquid chromatography (HPLC) conditions: Column: C18 column; Mobile phase: Methanol:acetonitrile:0.075 mol / L potassium dihydrogen phosphate solution:1 mol / L citric acid (30:30:36:4) as the mobile phase, pH adjusted to approximately 7 with 10 mol / L NaOH; Detection wavelength: 254 nm; Injection volume: 10 µL.

[0102] Method for establishing standard curves (methanol / water solution) for rifampin and minocycline hydrochloride: Weigh 10 mg of minocycline hydrochloride and rifampin separately on an electronic balance and place them in centrifuge tubes. Add them to a mixed solution of methanol and deionized water (volume ratio 1:1), stir to dissolve, and prepare a solution with a mass concentration of 1 mg / mL. Quantitatively dilute the solution to the following mass concentrations: 0.5, 1, 5, 10, 15, 20 µg / mL. Detect the absorbance values ​​of minocycline hydrochloride and rifampin at 254 nm and plot the standard curves.

[0103] Method for establishing standard curves (PBS solution) for rifampin and minocycline hydrochloride: Weigh 10 mg of minocycline hydrochloride and rifampin separately on an electronic balance and place them in centrifuge tubes. Add PBS buffer solution (pH=7.4), stir to dissolve, and prepare a solution with a mass concentration of 1 mg / mL. Quantitatively dilute the solution to the following mass concentrations: 0.5, 1, 5, 10, 15, 20 µg / mL. Detect the absorbance values ​​of minocycline hydrochloride and rifampin at 254 nm and plot the standard curves.

[0104] I. In vitro release assay of rifampin and minocycline hydrochloride:

[0105] The absorbable antibacterial coating material was cut into 1x1 cm sheets, weighed, and placed in 20 mL of PBS buffer solution (pH=7.4). The sheets were then shaken at 110 rpm in a 37°C incubator. Samples were taken periodically, and the drug concentration released into the medium was determined by high-performance liquid chromatography (HPLC) at 5 min, 10 min, 30 min, 1 h, and 2 h. After each sampling, 15 mL, 10 mL, 5 mL, and 2 mL of new buffer solution were used to maintain a concentration detectable by the instrument. The percentage of drug release at different time points was determined according to a standard curve.

[0106] II. In vivo release assay of rifampin and minocycline hydrochloride:

[0107] Sample preparation: The absorbable antibacterial coating material was cut into 1 cm diameter sheets using a 1 cm diameter mold. The antibacterial coating material was first freeze-dried to constant weight and then weighed using an analytical balance.

[0108] Experimental groups: Rifampin:minocycline hydrochloride:PGA (1:1:2, Group I), Rifampin:minocycline hydrochloride:PGA (1:1:4, Group II), and Rifampin:minocycline hydrochloride:PGA (1:1:6, Group III), with 15 rats in each group, for a total of 45 rats. Two samples were implanted in each rat. Three rats were sacrificed on days 1, 3, 5, 7, and 14. After removing the antibacterial coating material, the surface moisture was dried, and excess tissue was removed. The antibiotics on the surface of the antibacterial coating material were washed off with a mixture of methanol and water (volume ratio 1:1). The residual drug loading in the coating was detected by UV-Vis spectrophotometer.

[0109] The surgical implantation procedure is as follows, and the appearance of the implanted tissue is shown in the image. Figure 9 As shown:

[0110] Material sterilization: The antibacterial coating material is sterilized by irradiation in a UV sterilization chamber for 30 minutes before implantation.

[0111] Implantation method: Subcutaneous implantation, chest incision (1~2 cm), implantation of a 1 cm diameter antibacterial coated sheet material, and suturing of the muscle layer and skin.

[0112] Implant placement: The 1 cm diameter antibacterial coated sheet material is placed directly into the subcutaneous tissue of the chest.

[0113] Suturing and closing the wound: After implantation, wipe the wound with an iodine-soaked cotton swab to remove blood and tissue debris. Suture the subcutaneous tissue with silk sutures, and finally suture the skin with silk sutures. During suturing, ensure the wound is neatly aligned and avoid leaving dead space.

[0114] After timely removal of the antibacterial coating material, any unreleased rifampicin and minocycline hydrochloride on the surface are washed off, and the antibiotic content is calculated after measurement with a UV-Vis spectrophotometer.

[0115] Antimicrobial zone experiment of absorbable antimicrobial coating materials

[0116] All consumables to be used (centrifuge tubes, pipette tips, etc.) and culture media should be sterilized by high temperature and high pressure in advance;

[0117] Prepare bacterial culture: Pick a single colony with an inoculation loop and place it in a 15 mL centrifuge tube containing 5 mL of sterile LB liquid medium (or 15 mL of medium for a 50 mL centrifuge tube). Incubate overnight (15-20 h) at 37°C and 150 rpm on a shaker.

[0118] Dilution and Spreading: Dilute Staphylococcus aureus solution to 0.5 McFarland turbidity (10⁸ CFU / mL) with sterile physiological saline / LB liquid medium. Spread Staphylococcus aureus solution evenly on LB agar plates using a sterile cotton swab and let stand for 5 min. After standing, place a 1 cm diameter PGA nonwoven fabric sample on top, and then let the agar plate stand in a clean bench for 30 min. Place the plate in a self-sealing bag (unsealed) and invert it in a 37 ℃ oven for overnight incubation. Observe the size of the inhibition zone.

[0119] Experimental results

[0120] 1. In vitro release performance: In Examples 1-5, the in vitro release percentages of rifampin in the first 2 hours were 82%, 48%, 18%, 80%, and 85%, respectively, and stabilized at 88%, 54%, 20%, 86%, and 91% after 8 hours; the release percentages of minocycline hydrochloride in the first 2 hours were 83%, 53%, 22%, 81%, and 86%, respectively, and stabilized at 88%, 55%, 24%, 86%, and 91% after 8 hours. The in vitro release curves are shown below. Figures 3-4 As shown.

[0121] Therefore, it can be seen that the in vitro release rate of antibiotics in the absorbable antibacterial coating material prepared by this invention is inversely proportional to the PGA content, and remains stable after reaching a certain value (incompletely released antibiotics are no longer released further). This is because PGA encapsulates some antibiotics, making them difficult to release. The encapsulated antibiotics are released slowly only as PGA degrades, resulting in a superior long-lasting antibacterial mechanism. The solvent ratio also affects antibiotic release, mainly due to the increased swelling properties of hexafluoroisopropanol on the substrate, which enhances the binding force between some antibiotics and the substrate. However, this effect is far less significant than the influence of the polymer-to-antibiotic ratio on the release rate.

[0122] In Comparative Examples 1 and 2, the release percentages of rifampin and minocycline hydrochloride in the first 0.5 h were 94% (rifampin), 95% (minocycline hydrochloride), and 5% (rifampin), 6% (minocycline hydrochloride), respectively; after 2 h, they were approximately 100% and 7%, respectively. This indicates that when the PGA content is below a certain value, the antibiotic cannot be effectively encapsulated, leading to excessively rapid release and difficulty in achieving effective controlled release; when the PGA content is above a certain value, the PGA almost completely encapsulates the antibiotic, making effective release difficult. The in vitro release curves are as follows: Figures 7-8As shown, the specific data are listed in Table 2 below (the release data of the antibiotics rifampin and minocycline hydrochloride are similar, so only the release data of rifampin is used as an example, and the same applies below). The table also provides the in vitro release data of comparative examples 3 to 6.

[0123] Table 2

[0124]

[0125] Based on the above results, it can be seen that the ratio of absorbable polymer to antibiotic in the coating solution of Comparative Examples 1 and 2 has a significant impact on the release rate of antibiotics. When the ratio of antibiotic to polymer is smaller, the antibiotic is released faster, while when the ratio is larger, the release rate of antibiotics is extremely slow. In addition to the ratio of absorbable polymer to antibiotic in the coating solution, the solvent also has a significant impact on the release rate of antibiotics. Using a single reagent that does not have swelling properties on the substrate not only results in unstable coating process and easy coating peeling, but also excessively fast release rate of antibiotics. This is mainly due to the weak adhesion between the coating and the substrate, which makes the coating easy to peel off during the in vitro release experiment.

[0126] 2. In vivo release performance: In Examples 1-3, the release percentages of rifampin in SD rats on day 1 were 85%, 48%, and 12%, respectively, reaching 95%, 84%, and 73% after 14 days; the release percentages of minocycline hydrochloride on day 1 were 79%, 46%, and 11%, respectively, reaching 92%, 83%, and 72% after 14 days. The in vivo release curves are shown below. Figures 5-6 As shown above, the results indicate that the in vivo release rate of antibiotics from the surface of the absorbable antibacterial coating material prepared in this invention is much lower than that in vitro. However, with the passage of time, the percentage of release in vivo increases significantly compared to in vitro and no longer remains at a fixed value. This is because PGA is easily degraded and absorbed in vivo, and the encapsulated antibiotics are released accordingly.

[0127] 3. Antibacterial Properties: Antibacterial experiments showed that the uncoated biodegradable PGA nonwoven fabric had no significant inhibition zone, indicating insufficient antibacterial performance. In contrast, the absorbable antibacterial coating materials prepared in Examples 1-3 of this invention had inhibition zones of 3.82 cm, 3.80 cm, and 3.79 cm, respectively, demonstrating significant antibacterial properties. (Antibacterial diagrams are shown below.) Figure 10 As shown.

[0128] 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 an absorbable antibacterial coating material for sustained-release antibiotics, characterized in that, include: Step 1: Blend antibiotics, absorbable polymers, and mixed solvents to obtain a coating solution; The antibiotic was selected from rifampin and minocycline hydrochloride; The absorbable polymer is selected from one or more of 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%. Step 2: The coating solution is uniformly sprayed onto the surface of the biodegradable substrate by ultrasonic spraying, and then dried to obtain the absorbable antibacterial coating material of the sustained-release antibiotic.

2. The method for preparing the absorbable antibacterial coating material for sustained-release antibiotics according to claim 1, characterized in that, In step one: In the antibiotic, the mass ratio of rifampin to minocycline hydrochloride is (0.3~3.0):1; The mass ratio of antibiotic to absorbable polymer is 1:(1~3).

3. The method for preparing the absorbable antibacterial coating material for sustained-release antibiotics according to claim 1, characterized in that, In step one: The concentration of antibiotics in the coating solution is (0.5~1.5) wt% In the mixed solvent, hexafluoroisopropanol accounts for 25-75% by volume.

4. The method for preparing the absorbable antibacterial coating material for sustained-release antibiotics according to claim 1, characterized in that, In step two, 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.

5. The method for preparing the absorbable antibacterial coating material for sustained-release antibiotics according to claim 1, characterized in that, In step two: 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.

6. The method for preparing the absorbable antibacterial coating material for sustained-release antibiotics according to claim 1, characterized in that, In step two: The drying process is carried out at room temperature, in the dark, and under vacuum.

7. An absorbable antibacterial coating material for a sustained-release antibiotic prepared according to any one of claims 1 to 6.

8. An implantable medical device, characterized in that, Includes a medical device and an absorbable antibacterial coating material of the sustained-release antibiotic according to claim 7, which is wrapped around the outer surface of the medical device.

9. The implantable medical device according to claim 8, 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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