Degradable and self-adaptive external auditory canal drug stent combined with segmented drug release and preparation method of degradable and self-adaptive external auditory canal drug stent

Abstract

The invention relates to an external auditory canal degradable and self-adaptive drug stent combined with segmented drug release and a preparation method thereof. The drug stent comprises a stent body, antibacterial drug microspheres, antifungal drug microspheres and anti-inflammatory drug microspheres, the stent body comprises a stent inner layer and a stent outer layer, the stent outer layer is a PLGA / PCL composite material layer loaded with antibacterial drug microspheres and antifungal drug microspheres, the stent outer layer is in contact with an external auditory canal, and a GelMA layer loaded with anti-inflammatory drug microspheres is used as the stent inner layer; the drug microsphere comprises a PLGA / PCL composite material shell and a drug inner core. Compared with the prior art, the PLGA / PCL composite material and the GelMA hydrogel are used for constructing the outer layer structure and the inner layer structure of the stent, the PLGA is used for embedding the sterilization, bacteriostasis and anti-inflammatory drugs to prepare corresponding drug microspheres, the drug microspheres are loaded on the corresponding outer layer structure and the inner layer structure, and by means of the degradability of the drug microsphere shell layer and the stent material, the anti-inflammatory and anti-inflammatory stent can be prepared. And segmented sequential release of the bactericidal, bacteriostatic and anti-inflammatory drugs is realized by adjusting the thickness of the structure.

Description

Technical Field

[0001] This invention belongs to the field of medical device technology and relates to a biodegradable, adaptive drug-eluting stent for the external auditory canal that combines segmented drug release and its preparation method. Background Technology

[0002] External auditory canal fungal infection is a common disease in otolaryngology, especially during ear cleaning. Current treatments mainly rely on the topical application of single-component antifungal drugs, such as ketoconazole ear drops and ketoconazole cream. However, single-drug antifungal agents often lead to poor treatment efficacy and patient experience. Furthermore, external auditory canal fungal infections are often accompanied by bacterial otitis externa, requiring concurrent use of antibacterial drugs, such as ofloxacin, to control the spread of infection. Current treatment regimens typically require frequent ear drops or ointments, causing significant inconvenience and ear discomfort for patients. Research has found that the treatment of external auditory canal fungal infections can be divided into three stages: bactericidal (quinolone antibiotics), antifungal (triazole antifungal drugs), and sustained anti-inflammatory (steroids). However, effective drug combinations and segmented release at each stage of treatment for external auditory canal fungal infections are currently unreported.

[0003] Prior art CN 111467100 A provides a shape memory polymer external auditory canal scaffold and its preparation and driving methods, relating to the field of materials medicine manufacturing technology. The external auditory canal scaffold includes a scaffold body and a support body, both of which are made of shape memory polymer. The scaffold body includes an initial state; the external contour of the scaffold body in the initial state is the same as the contour of the external auditory canal, the outer surface of the scaffold body is suitable for contact with the external auditory canal, and the scaffold body is suitable for carrying drugs; the scaffold body has a cavity, and the support body is located in the cavity; the scaffold body has a porous structure. The shape memory polymer external auditory canal scaffold, its preparation and driving methods described in this invention have good shape memory properties, biocompatibility, and biodegradability. It has a certain degree of hardness and mechanical stress, and will not cause rejection after implantation in the human body. While releasing drugs, the external auditory canal scaffold is gradually biodegraded. It is simple to operate, low in cost, and easily accepted by people.

[0004] However, since the medication is directly loaded onto the stent and comes into direct contact with the external auditory canal, it is released synchronously, which cannot meet the needs of staged medication during the treatment of fungal infections in the external auditory canal. Summary of the Invention

[0005] The purpose of this invention is to provide a biodegradable, adaptive drug-eluting scaffold for combined segmented drug release in the external auditory canal and its preparation method, addressing the problem of how to achieve segmented, sequential release of multiple drugs from an external auditory canal scaffold. This invention constructs the outer and inner layers of the scaffold using PLGA / PCL composite materials and GelMA hydrogel. Drug microspheres are prepared by encapsulating bactericidal, bacteriostatic, and anti-inflammatory drugs in PLGA and loading them onto the corresponding outer and inner layers. Utilizing the biodegradability of the drug microsphere shell and scaffold materials, the segmented, sequential release of bactericidal, bacteriostatic, and anti-inflammatory drugs is achieved by adjusting the structural thickness.

[0006] The objective of this invention can be achieved through the following technical solutions: A first aspect of the present invention provides an antifungal drug-eluting stent for the external auditory canal, comprising a stent body, antibacterial drug microspheres, antifungal drug microspheres, and anti-inflammatory drug microspheres; The stent body includes an inner stent layer and an outer stent layer. The outer stent layer is a lactic acid-glycolic acid copolymer / polycaprolactone composite material layer that contacts the external auditory canal. The inner stent layer is a methacrylamide gelatin layer. The bactericidal drug microspheres, antifungal drug microspheres, and anti-inflammatory drug microspheres comprise a lactic acid-glycolic acid copolymer / polycaprolactone composite material shell and a corresponding drug core; the shell thickness of the bactericidal drug microspheres is greater than that of the antifungal drug microspheres. The antibacterial drug microspheres and antifungal drug microspheres are loaded on the outer layer of the scaffold; The anti-inflammatory drug microspheres are loaded onto the inner layer of the scaffold.

[0007] This invention effectively achieves the following by employing an inner and outer layer support structure: 1. Segmented release: Different drugs are released at different stages of the disease. Simultaneous application will result in simultaneous release, and the efficacy and release rate of different drugs will be affected under the same pH environment, leading to poor drug effect. 2. Single-dose administration avoids the discomfort in the patient's ear canal and the inconvenience of repeated medical visits caused by multiple doses.

[0008] In some specific embodiments, the bactericidal drug microspheres use quinolone antibiotics, preferably ofloxacin.

[0009] In some specific embodiments, the antifungal drug used in the antifungal drug microspheres is a triazole antifungal drug, preferably ketoconazole.

[0010] In some specific embodiments, the anti-inflammatory drug used in the anti-inflammatory drug microspheres is a hormone-based anti-inflammatory drug, preferably mometasone furoate.

[0011] In some specific embodiments, the support body has a spiral layered cylindrical structure.

[0012] In some specific embodiments, the thickness of the outer layer of the stent is 150~250 μm; the thickness of the inner layer of the stent is 30~80 μm.

[0013] A second aspect of the present invention provides a method for preparing an antifungal drug-eluting scaffold in the external auditory canal, comprising: A mixed solution containing lactic acid-glycolic acid copolymer and polycaprolactone was prepared, and bactericidal drug microspheres and antifungal drug microspheres were added to obtain a spinning solution. Electrospinning was then performed to obtain an outer layer structure loaded with bactericidal drug microspheres and antifungal drug microspheres. A photoinitiator, methacrylamide gelatin, chitosan, and anti-inflammatory drug microspheres were mixed to obtain a coating, which was then coated onto the inner surface of the outer layer of the scaffold. The coating was then cross-linked and cured under ultraviolet light to obtain an inner layer structure loaded with anti-inflammatory drug microspheres. After that, the structure was fixed and shaped by plasma treatment to obtain the final product.

[0014] In some specific embodiments, the mass ratio of lactic acid-glycolic acid copolymer to polycaprolactone in the mixed solution is 8:(1~3), and the total concentration of both is 8~10 g / mL; The concentration of bactericidal drug microspheres and the concentration of antifungal drug microspheres in the spinning solution are 8-12 wt%. In the electrospinning process, the voltage is 16~20 kV, the flow rate is 1~1.5 mL / h, and the receiving distance is 12~18 cm.

[0015] In some specific embodiments, the photoinitiator content relative to methacrylamide gelatin is 0.3~0.8 g / 100 mL; the chitosan content relative to methacrylamide gelatin is 0.8~1.2 g / 100 mL; The mass ratio of the bactericidal drug in the bactericidal drug microspheres, the antifungal drug in the antifungal drug microspheres, and the anti-inflammatory drug in the anti-inflammatory drug microspheres is 1:(0.5~1.5):(1.5~2.5), preferably 1:1:2.

[0016] In some specific embodiments, the plasma treatment has a treatment power of 30-100 W, a treatment time of 20-40 s, a treatment atmosphere of oxygen / helium mixture, an oxygen / helium volume ratio of (2-4):1, a flow rate of 25-35 sccm, and a pressure of 40-60 Pa; preferably, the oxygen / helium volume ratio is 3:1, the flow rate is 30 sccm, and the pressure is 50 Pa. The fixing and shaping process includes wrapping the support around the rod, hot air treatment, cooling, and sterilization.

[0017] In some specific embodiments, the processing temperature of the hot air treatment is 40~80 ℃.

[0018] The external auditory canal support in this invention employs a layered electrospinning process, using biodegradable and shape-memory materials. During the electrospinning process, different spinning solutions are changed or parameters are adjusted to deposit fibers of different materials layer by layer, forming a multi-layered structure. Each layer has a different function, such as drug release, mechanical support, or shape adaptation.

[0019] Compared with the prior art, the present invention has the following beneficial effects: 1) Segmented and Sequential Drug Release: This invention provides a drug-eluting scaffold that conforms to the external auditory canal. PLGA / PCL composite material and GelMA hydrogel are used as the main materials for the outer and inner layers of the scaffold. PLGA is used to encapsulate quinolone antibiotics, triazole antifungal drugs, and hormonal drugs, forming corresponding drug microspheres. Quinolone antibiotic microspheres and triazole antifungal drug microspheres are loaded onto the outer layer of the scaffold, while hormonal drugs are loaded onto the inner layer. Utilizing the biodegradability of the drug microsphere shell and the scaffold, the release timing of the drugs within the patient's ear canal is controlled by adjusting the shell thickness and the thickness of the corresponding scaffold structural layers. This achieves segmented and sequential drug release. The PLGA / PCL base layer (degrades in 4 weeks) provides mid-term support, while the GelMA hydrogel layer (degrades in 2 weeks) releases the drug early, covering the entire infection-inflammation process of external auditory canal fungal treatment in stages. This scaffold has advantages such as simple structure, ease of operation, and stable therapeutic effect. 2) Drug Separation and Release: Due to the pH sensitivity conflict between ketoconazole (optimal drug pH: 3.0-5.0) and corticosteroids (optimal drug pH: 5.5-7.0), and the pH concentration of the ear canal being 6.0-7.5, mixing both on the same carrier will lead to a decrease in the antifungal efficiency of ketoconazole and an increase in the rate of local hydrolytic irritation side effects of mometasone. To solve this technical problem, this invention uses different materials to encapsulate different drugs. Specifically, PLGA is used to encapsulate ketoconazole, utilizing the slightly acidic environment (pH 4.5-5.5) generated by PLGA degradation to maintain its solubility and stability; mometasone furoate is loaded onto a GelMA layer containing chitosan (pH 6.0-6.5), utilizing the adsorption of H+ by chitosan... + Or release OH - Dynamically adjusting the local microenvironment pH to maintain a relatively stable pH value of 6.0-6.5 ensures transdermal absorption, resulting in approximately a 50% improvement in synergistic efficacy compared to mixed drug delivery systems. 3) Adaptive scaffold: A gelatin-methacryloyl (GelMA) hydrogel layer is introduced into PLGA, which expands in volume by 20-30% after absorbing water, helping to fit the ear canal and reducing the pressure on the ear canal after expansion; 4) Ribbon-shaped support structure: It is not a traditional hollow spiral support, but adopts a spiral makeup-shaped support shape, with a larger direct area, ensuring that the radial pressure after the support expands is <15 kPa. Attached Figure Description

[0020] Figure 1 This is a front view schematic diagram of a biodegradable, adaptive drug-eluting stent for combined drug segmentation release in the external auditory canal, as described in the embodiment. Figure 2 This is a schematic diagram of the left-side structure of a biodegradable, adaptive drug-eluting stent for combined drug segmentation release in the external auditory canal, as described in the embodiment. Figure 3 The sustained-release curves of ofloxacin thin-walled microspheres, ketoconazole thin-walled microspheres, and mometasone furoate thick-walled microspheres prepared in the examples are shown. Figure 4 The example demonstrates the anti-Staphylococcus aureus effect of the ofloxacin thin-walled microspheres prepared against Staphylococcus aureus. Figure 5 The anti-Candida albicans effect of the ketoconazole thin-walled microspheres prepared in the examples is shown. Detailed Implementation

[0021] The present invention will now be described in detail with reference to the accompanying drawings and specific embodiments. The following embodiments are based on the above-described technical solutions of the present invention, providing detailed implementation methods and specific operating procedures. However, the scope of protection of the present invention is not limited to the following embodiments.

[0022] It should be noted that similar labels and letters in the following figures indicate similar items. Therefore, once an item is defined in one figure, it does not need to be further defined and explained in subsequent figures.

[0023] The following detailed description of some embodiments of the present invention is provided in conjunction with the accompanying drawings. Unless otherwise specified, the following embodiments and features described herein can be combined with each other.

[0024] Example: A biodegradable, adaptive drug-eluting scaffold for segmented drug release in the external auditory canal, the structure of which is as follows: Figure 1 and Figure 2 As shown, the scaffold comprises a spiral-shaped, layered, cylindrical structure with an outer diameter of 5 mm, a width of 4 mm, and a helical spacing of 1.5 mm. The outer layer of the scaffold, in contact with the skin, is composed of PLGA / PCL composite fibers loaded with ofloxacin and ketoconazole thin-walled microspheres for rapid release of antibacterial and antifungal drugs, inhibiting acute infection. The inner layer of the scaffold is composed of PLGA / GelMA composite fibers loaded with mometasone furoate thick-walled microspheres for sustained-release anti-inflammatory effects, releasing the drug later in the degradation process (the degradation cycle of PLGA / GelMA is 4-5 weeks). The specific preparation method includes the following steps: S1: Material composition of layered electrospinning ① Base layer material: Lactic acid-glycolic acid copolymer (PLGA): Evonik (model 503H), lactic acid (LA):glycolic acid (GA) = 75:25 (molar ratio), Mw = 30 kDa, providing controllable degradation; Polycaprolactone (PCL): Sigma-Aldrich (440744), molecular weight Mw=80 kDa, enhances flexibility.

[0025] ② Drug carrier: Ofloxacin / ketoconazole PLGA microspheres: PLGA (LA:GA=50:50, molar ratio) encapsulates the drug, with a microsphere particle size of 5-10 μm; the three drugs are encapsulated in PLGA microspheres (particle size 5-10 μm), mixed in proportion, and then embedded in the scaffold matrix. The drug diffusion rate of the PLGA microspheres is controlled by a wall thickness gradient (ofloxacin and ketoconazole microspheres have a wall thickness of 5 μm, while mometasone furoate microspheres have a wall thickness of 10 μm) (ofloxacin and ketoconazole microspheres, with their thinner walls, are preferentially released). Specific preparation steps for ofloxacin / ketoconazole PLGA microspheres: ① Material preparation Polymer solution preparation: PLGA: Evonik (model 503H) (lactic acid: glycolic acid = 50:50, molar ratio) dissolved in dichloromethane (DCM) at a concentration of 8% w / v (4g PLGA / 50mL DCM).

[0026] Drug phase: Ofloxacin: soluble in 0.01M hydrochloric acid (pH 2.0), concentration 20 mg / mL; Ketoconazole: Dissolved in DCM (concentration 10 mg / mL) + 1% Span 80 (mass / volume percentage, 1 gram of sorbitan monooleate Span 80 corresponds to 100 mL of DCM, which acts as a solubilizer, the same below).

[0027] External aqueous phase: 1% PVA (mass / volume percentage, 1 g / 100 mL water, polyvinyl alcohol, Mw=30 kDa) solution, pre-cooled to 4°C.

[0028] ② Preparation of PLGA drugs: (Prepare them separately first, then mix them) Ofloxacin PLGA microspheres (OFL-PLGA) use PLGA 50:50 (Mw=30kDa) as the carrier material, with a drug loading of 10% w / w (OFL:PLGA=1:9). The organic phase is a chloroform solution containing 10 mg / mL OFL and 90 mg / mL PLGA, and the aqueous phase is a 1% PVA (Mw=30kDa, pH 7.4) solution. Emulsification is carried out by high-speed homogenization (15,000 rpm, 2 minutes), followed by solvent evaporation by magnetic stirring (500 rpm, 4 hours).

[0029] Ketoconazole PLGA microspheres (KET-PLGA) use PLGA 75:25 (Mw=15kDa) as the carrier, with a drug loading of 10% w / w (KET:PLGA=1:9). The organic phase is a chloroform solution containing 10 mg / mL KET and 90 mg / mL PLGA, and the aqueous phase is a mixed solution of 1% PVA and 0.1% Span 80. The emulsion is prepared by ultrasonic emulsification (20 kHz, 100 W, 1 min) and then the solvent is evaporated by rotary evaporation (40 °C, 200 mbar, 1 h).

[0030] ③Drying and post-treatment Freeze-drying: Microspheres were suspended in 5% mannitol (w / v ratio, 5 g / 100 mL water, freeze-drying protectant), pre-frozen at -80°C for 12 hours, and freeze-dried for 24 hours to obtain ofloxacin / ketoconazole PLGA microspheres. Sterilization: irradiation with gamma rays (25 kGy).

[0031] Table 1 Microsphere Formulation and Process Parameters Methacrylamide gelatin (GelMA, Sigma-Aldrich, 924504); Mometasone furoate microspheres: directly dispersed in GelMA prepolymer solution (Swedish Cellink, GelMA-100). Additive: Chitosan (Japan Fuji, Chitosan 100): Added to the GelMA layer (1 g / 100 mL) to enhance adhesion; The specific preparation steps of mometasone furoate microspheres are as follows: ① Material preparation Polymer solution: PLGA Evonik (model 503H), lactic acid (LA): glycolic acid (GA) = 75:25 (molar ratio) dissolved in ethyl acetate (EA), concentration 6% w / v (3g PLGA / 50mL EA).

[0032] Drug phase: Mometasone furoate dissolved in EA (containing 1% Span 80), concentration 5 mg / mL.

[0033] External aqueous phase: 0.5% hydroxypropyl methylcellulose (mass / volume percentage, 0.5 g / 100 mL water, HPMC, viscosity 4000 cP) aqueous solution, pre-cooled to 4°C.

[0034] ② Preparation of colostrum (O / W) Mixed Drug-Polymer Phase: Mometasone furoate-EA solution and PLGA-EA solution were mixed at a volume ratio of 1:5 (total drug amount: mometasone furoate 50mg / 3g PLGA). Emulsification: A homogeneous O / W emulsion was formed at a volume flow ratio of 1:10 (organic phase: aqueous phase) and the temperature was controlled at 15℃.

[0035] ③ Solvent evaporation and microsphere curing Evaporation conditions: Transfer the emulsion to a rotary evaporator (40°C, 200 mbar, 30 min) to quickly remove EA and avoid drug crystallization. Solid-liquid separation: Centrifuge (8,000 rpm, 10 min) to collect microspheres, and wash three times with 0.1% Tween 80 aqueous solution (0.1 g Tween 80: 100 mL water).

[0036] ④ Drying and post-treatment Spray drying: Microspheres are suspended in a 2% mannitol solution (2 g mannitol: 100 mL water), with an inlet air temperature of 80℃ and an outlet air temperature of 45℃, and a particle size controlled at 5-20 μm. Sterilization: Ethylene oxide sterilization. The inlet and outlet air are used to ensure that the residual moisture content of the resulting microspheres is <3%. Specifically, the inlet air rapidly evaporates the moisture in the droplets using hot air; the outlet air reflects the drying endpoint, ensuring that the moisture content of the microspheres meets the target while maintaining drug activity.

[0037] Photoinitiator (Irgacure, 2959): Premixed in GelMA (0.5 g / 100 mL) for UV crosslinking.

[0038] S2: Layered electrospinning process ①Preparation of spinning solution: Base layer solution: PLGA (Evonik, model 503H, lactic acid:glycolic acid = 50:50, molar ratio) and PCL were dissolved in chloroform (purity ≥ 99%) at a ratio of 8:2 (mass ratio), with a total PLGA / PCL concentration of 8 g / ml. The mixture was magnetically stirred at room temperature for 24 hours until completely dissolved. Ofloxacin / ketoconazole PLGA microspheres (10% w / w, a mixture of ofloxacin PLGA microspheres and ketoconazole PLGA microspheres, with the total mass of the mixed microspheres accounting for 10% of the total mass of the PLGA / PCL polymer) were added and ultrasonically dispersed for 10 minutes (power 100W). (1) Formula calculation (taking the preparation of 100mL solution as an example) Table 2 Preparation of PLGA / PCL mixed solution and microsphere integration (2) Operating steps 1. Dissolve PLGA / PCL: Add 64g PLGA and 16g PCL to chloroform and stir magnetically at room temperature (800rpm, 24 hours) until a clear, viscous liquid is formed. 2. Add microspheres: Weigh 8g of ofloxacin microspheres + 8g of ketoconazole microspheres, slowly sprinkle them into the solution and stir at low speed (200 rpm, 1 hour) to avoid breaking the microspheres; 3. Homogenization: Ultrasonic treatment (40kHz, 100W, 10 minutes) was used to eliminate microsphere agglomeration, resulting in a PLGA microsphere (containing ofloxacin and ketoconazole) mixed spinning solution.

[0039] Functional layer solution: GelMA premixed with photoinitiator was mixed with mometasone furoate microspheres (2:1 volume ratio) and then mixed with chitosan (GelMA mometasone furoate microspheres and chitosan, 1:1 volume ratio). The mixture was dissolved by shaking in a water bath at 37°C. It was stored away from light to avoid preactivation of the photoinitiator. ② Electrospinning equipment parameters: For base layer (PLGA / PCL) spinning, the voltage is set to 18kV, the flow rate is 1.2mL / h, the ambient temperature is 25℃, 40% RH, and a rotating drum (800rpm) is used for receiving, with a receiving distance of 15cm; ③ Base layer spinning: PLGA microspheres (containing ofloxacin and ketoconazole) mixed spinning solution were injected into the spinning syringe, and electrospinning was started after setting the above parameters. The resulting fiber layer deposition thickness was 200 μm (spinning time 2 hours), and the solvent was removed by vacuum drying for 48 hours; ④ Functional layer spraying and crosslinking: Spray the GelMA-drug mixture (containing mometasone furoate) onto the inner surface of the base layer (spraying thickness 50μm); UV crosslinking (365nm, 10mW / cm) 2 (×60s) Cured GelMA layer; Three drug combinations and ratios: mometasone furoate, ketoconazole and ofloxacin in a mass ratio of 2:1:1; ⑤ Interlayer strengthening treatment: Plasma treatment was performed on the surface of the base layer (treatment power of 65W, treatment time of 24s, treatment atmosphere of oxygen / helium mixed atmosphere (volume ratio of 3:1), flow rate of 30sccm (standard cubic centimeters / minute, pressure of 50 Pa) to enhance the adhesion of the GelMA layer; secondary vacuum drying was performed to remove residual moisture.

[0040] 2.5 Bracket Forming Shape memory shaping: The support is wound around a 2mm diameter mandrel, treated with hot air at 60℃ for 1 hour, and then fixed in a compressed state after cooling (radius of curvature ≥ 2mm, pitch 1.5mm, suitable for the external auditory canal). Sterilization: Ethylene oxide gas sterilization (temperature ≤ 40℃, humidity 60%, ventilation time 4 hours).

[0041] Application Example 1: Effect of Combined Drug Fragmentation Release Ofloxacin is rapidly released in the early stage (75% release in 7 days) to inhibit bacterial infection; ketoconazole is released in the early to mid-stage (70% release in 14 days) to target the fungal proliferation phase; and mometasone furoate is released slowly in the long stage (92% release in 14 days) to provide sustained anti-inflammatory effects.

[0042] like Figure 3 The figure shows a comparison of the cumulative release rates of ofloxacin PLGA microspheres, ketoconazole PLGA microspheres, and mometasone furoate GelMA microspheres in PBS solution at 37℃±0.5℃, 95±5% RH, and pH 6.0~6.5 after 24 hours, 48 ​​hours, 7 days, and 14 days.

[0043] like Figure 4 , Figure 5 The figures show a comparison of the 7-day inhibition zone diameters of ofloxacin PLGA microspheres and the control group (ofloxacin alone) against Staphylococcus aureus and Candida albicans at the same concentration. The characterization methods included: using the agar diffusion method, 1×10⁻⁶ microspheres were used to disperse the microspheres. 6 CFU / mL suspensions of Staphylococcus aureus and Candida albicans were plated onto LB and Saburg agar plates, respectively. 200 μL of microsphere suspension containing equal amounts of drug and drug-only solution were added to Oxford cups. Bacteria were incubated at 37°C for 24 h, and fungi at 30°C for 48 h. The diameter of the inhibition zone was measured using the cross-hatching method, and the average value of three parallel samples was taken.

[0044] Application Example 2: Structural Strength of the Support The compressive modulus (E) of the support material (helical cylinder, 6 mm in diameter and 12 mm in height) was measured to be 45 ± 5 MPa using universal testing. Test parameters included: using an Instron 5967 universal testing machine (100 N sensor) at 37 ± 0.5℃ and 95 ± 5% RH. The specimens were 5 parallel helical cylinders (6 mm in diameter and 12 mm in height), preloaded with 5 N, and compressed at a rate of 2 mm / min to a strain of 0.5%–5%. Stress-strain data were collected at 100 Hz, and the compressive modulus of 45 ± 5 MPa was calculated using the slope of the linear phase.

[0045] Comparative example: Traditional drug-loaded coatings There are currently no ear canal stents in clinical use. Currently, in clinical practice, antifungal creams (such as miconazole nitrate ointment (brand name: Daktarin)) or liquid drops (such as fluconazole ear drops) are used compared to: 1) Enhanced efficacy. The drug-loaded stent in this embodiment uses ofloxacin (antibacterial), ketoconazole (antifungal), and mometasone furoate (anti-inflammatory), which have broad-spectrum antibacterial, antifungal, and anti-inflammatory effects. In contrast, previous creams or drops used single-drug formulations, thus solving the problems of mixed infections and poor treatment outcomes.

[0046] 2) Improved patient comfort. Traditional creams and drops require repeated administration through the ear canal, which can easily cause a feeling of ear blockage and temporary hearing loss in some patients, resulting in significant discomfort after administration. This invention uses a cylindrical support structure made of PGLA and GelMA materials, providing a single dose with a long-lasting gradient release that conforms to the ear canal wall, making it more comfortable.

[0047] The above description of the embodiments is provided to enable those skilled in the art to understand and use the invention. It will be apparent to those skilled in the art that various modifications can be made to these embodiments, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the present invention is not limited to the above embodiments, and any improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the invention should be within the protection scope of the present invention.

Claims

1. A drug-eluting stent for external auditory canal, characterized in that, It includes the scaffold body, antibacterial drug microspheres, antifungal drug microspheres, and anti-inflammatory drug microspheres; The stent body includes an inner stent layer and an outer stent layer. The outer stent layer is a lactic acid-glycolic acid copolymer / polycaprolactone composite material layer that contacts the external auditory canal. The inner stent layer is a methacrylamide gelatin layer. The bactericidal drug microspheres, antifungal drug microspheres, and anti-inflammatory drug microspheres comprise a lactic acid-glycolic acid copolymer / polycaprolactone composite material shell and a corresponding drug core; the shell thickness of the bactericidal drug microspheres is greater than that of the antifungal drug microspheres. The antibacterial drug microspheres and antifungal drug microspheres are loaded on the outer layer of the scaffold; The anti-inflammatory drug microspheres are loaded onto the inner layer of the scaffold.

2. The external auditory canal antifungal drug-eluting stent according to claim 1, characterized in that, The bactericidal drug microspheres contain quinolone antibiotics, preferably ofloxacin.

3. The external auditory canal antifungal drug-eluting stent according to claim 1, characterized in that, The antifungal drug microspheres used are triazole antifungal drugs, preferably ketoconazole.

4. The external auditory canal antifungal drug-eluting stent according to claim 1, characterized in that, The anti-inflammatory drug microspheres used are steroidal anti-inflammatory drugs, preferably mometasone furoate.

5. The external auditory canal antifungal drug-eluting stent according to claim 1, characterized in that, The support body has a spiral layered cylindrical structure.

6. The external auditory canal antifungal drug-eluting stent according to claim 1, characterized in that, The outer layer of the stent has a thickness of 150~250 μm; the inner layer of the stent has a thickness of 30~80 μm.

7. A method for preparing an antifungal drug-eluting scaffold in the external auditory canal, characterized in that, The method includes: A mixed solution containing lactic acid-glycolic acid copolymer and polycaprolactone was prepared, and bactericidal drug microspheres and antifungal drug microspheres were added to obtain a spinning solution. Electrospinning was then performed to obtain an outer layer structure loaded with bactericidal drug microspheres and antifungal drug microspheres. A photoinitiator, methacrylamide gelatin, chitosan, and anti-inflammatory drug microspheres were mixed to obtain a coating, which was then coated onto the inner surface of the outer layer of the scaffold. The coating was then cross-linked and cured under ultraviolet light to obtain an inner layer structure loaded with anti-inflammatory drug microspheres. After that, the structure was fixed and shaped by plasma treatment to obtain the final product.

8. The method for preparing an antifungal drug-eluting scaffold in the external auditory canal according to claim 7, characterized in that, In the mixed solution, the mass ratio of lactic acid-glycolic acid copolymer to polycaprolactone is 8:(1~3), and the total mass-volume ratio of the two is 8~10 g / mL; The concentration of bactericidal drug microspheres and the concentration of antifungal drug microspheres in the spinning solution are 8-12 wt%. In the electrospinning process, the voltage is 16~20 kV, the flow rate is 1~1.5 mL / h, and the receiving distance is 12~18 cm.

9. The method for preparing an antifungal drug-eluting scaffold in the external auditory canal according to claim 7, characterized in that, The photoinitiator content relative to methacrylamide gelatin is 0.3~0.8 g / 100 mL; the chitosan content relative to methacrylamide gelatin is 0.8~1.2 g / 100 mL; The mass ratio of the bactericidal drug in the bactericidal drug microspheres, the antifungal drug in the antifungal drug microspheres, and the anti-inflammatory drug in the anti-inflammatory drug microspheres is 1:(0.5~1.5):(1.5~2.5).

10. The method for preparing an antifungal drug-eluting scaffold in the external auditory canal according to claim 7, characterized in that, In the plasma treatment, the treatment power is 30~100 W, the treatment time is 20~40 s, the treatment atmosphere is an oxygen / helium mixed atmosphere, the volume ratio of oxygen / helium is (2~4):1, the flow rate is 25~35 sccm, and the pressure is 40~60 Pa; the fixing and shaping includes winding the support around the rod, hot air treatment, cooling, and sterilization.

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