A multilayer dissolving microneedle patch for oral mucosa disease treatment and a preparation method and application thereof

Abstract

The application discloses a multilayer dissolving microneedle patch for oral mucosa disease treatment and a preparation method and application thereof. The microneedle patch comprises a microneedle array and a backing layer, the microneedle array is composed of a plurality of microneedles, the microneedle tip is composed of drug-loaded polydopamine nanoparticles and polyvinylpyrrolidone, and the drug is concentrated on the tip to realize precise delivery; the backing layer comprises a polyvinyl alcohol adhesive layer and an ethyl cellulose waterproof layer, the base of the microneedle array is fixed to one side surface of the polyvinyl alcohol adhesive layer, and the ethyl cellulose waterproof layer covers the other side surface of the polyvinyl alcohol adhesive layer. The preparation method of the application adopts a one-step casting method to prepare the microneedle array and a two-step uniform coating method to prepare the backing layer. The application has the advantages of precise drug delivery, rapid and efficient release, prevention of saliva flushing, high mechanical strength, good biocompatibility, minimally invasive and painless, and the like, and provides a novel solution for oral mucosa disease treatment.

Description

Technical Field

[0001] This invention belongs to the field of drug delivery technology, specifically relating to a multilayer dissolving microneedle patch for the treatment of oral mucosal diseases, its preparation method, and its application. Background Technology

[0002] Oral mucosal diseases are common conditions affecting human health, including recurrent aphthous ulcers, oral mucositis, oral herpes, and oral candidiasis. These diseases can cause varying degrees of pain, discomfort, and anxiety, severely impacting patients' quality of life. In the clinical treatment of oral mucosal diseases, corticosteroids, anti-inflammatory drugs, analgesics, and healing-promoting factors are commonly used medications, and topical administration is an important treatment approach.

[0003] Traditional local oral treatments mainly include submucosal injection and transmucosal drug delivery. Submucosal injections often cause pain, reduce patient compliance, require professional medical personnel to perform, and generate sharps waste. Transmucosal drug delivery includes forms such as gels, ointments, mouthwashes, and patches; however, drug penetration efficiency is limited due to the physiological permeability barrier formed by the outermost layer of the oral mucosa. Furthermore, the flow of saliva in the mouth can cause drugs to be swallowed prematurely before being fully absorbed by the mucosa, resulting in ineffective drug delivery. Therefore, developing a novel oral drug delivery system that can achieve efficient, painless, and precise local drug delivery is of significant clinical importance.

[0004] Over the past two decades, microneedles have received widespread attention as a novel drug delivery system. Microneedles can form micropores in the oral mucosa to break down physiological barriers, delivering drugs directly to the submucosal tissue. Compared to traditional transmucosal drug delivery, this significantly improves drug permeability, enabling highly efficient local or systemic drug delivery. Current research reports the use of microneedles for oral mucosal drug or vaccine delivery. For example, Chinese patent application CN116059521A discloses a soluble microneedle patch for oral mucosal drug delivery, which uses a structure where microneedles are snapped into a drug layer, with a drug-retaining cavity in the center of the microneedles, and achieves oral mucosal drug delivery through a combination of an adsorption film and a waterproof film. Chinese patent application CN120585736A discloses a supramolecular hydrogel microneedle patch for treating oral mucositis, which uses guanosine, metal ions, and phenylboronic acid lactones as raw materials, forming hydrogel microneedles through self-assembly to achieve deep drug delivery. Chinese patent application CN121102119A discloses a microneedle patch for accelerating the healing of oral mucosal wounds. It uses methacrylamide gelatin loaded with the DAPK1 small molecule inhibitor HS-38 and sodium hyaluronate as a substrate to prepare microneedles through photocrosslinking, thereby achieving local sustained release of the drug.

[0005] However, existing microneedle technology still has the following shortcomings: (1) Drug distribution and delivery efficiency: Most existing microneedles disperse the drug throughout the needle body or set up an independent drug storage cavity (such as CN116059521A). Due to the elasticity of the oral mucosa, the microneedle often cannot be fully inserted into the tissue, resulting in the drug in the needle root or drug storage cavity not being able to enter the submucosa, causing drug waste and inaccurate actual delivery dose. Although some microneedles can achieve sustained drug release (such as CN121102119A), the drug release site does not match the needle tip insertion depth, affecting the accurate delivery effect. (2) Oral environment adaptability: The oral surface is moist and covered by saliva. The flow of saliva can easily wash away the drug deposited in the tissue. Although existing microneedles have attempted to set up a waterproof layer or an adsorption layer (such as the waterproof film in CN116059521A), their backing structure mostly adopts a multi-layer combination method, the preparation process is complicated, and the synergistic effect of the waterproof layer and the adsorption layer is limited. In addition, some microneedles require complex processes such as ultraviolet photocrosslinking (e.g., CN121102119A), which increases the difficulty and cost of preparation. (3) Drug loading materials and functional integration issues: Most existing microneedles use single polymer materials (e.g., hyaluronic acid, gelatin, etc.) as the matrix, and the drug loading method is mainly physical mixing or embedding, lacking synergistic regulation of drug release behavior and needle tip mechanical strength. Some studies have attempted to introduce nanoparticles or functional modifications (e.g., guanosine supramolecular assembly in CN120585736A), but their systems are complex and have limited versatility. In addition, microneedle systems that combine high mechanical strength, rapid dissolution, precise release and anti-saliva erosion functions are still rare.

[0006] In conclusion, developing a microneedle patch that enables concentrated drug delivery at the needle tip, rapid and efficient release, good adhesion and water resistance, simple preparation process, and excellent biocompatibility has significant clinical value and application prospects for the treatment of oral mucosal diseases. Summary of the Invention

[0007] To address the shortcomings of existing technologies, this invention provides a multilayer dissolving microneedle patch for the treatment of oral mucosal diseases, its preparation method, and its application. It achieves precise and rapid drug delivery through concentrated drug loading at the needle tip, and combines the strong adhesion and anti-erosion functions of the double-layer backing, providing a highly efficient, minimally invasive, and biocompatible treatment solution for oral mucosal diseases.

[0008] This invention is achieved through the following technical solution:

[0009] A multilayer dissolving microneedle patch for the treatment of oral mucosal diseases includes a microneedle array and a backing layer. The microneedle array consists of a plurality of microneedles. The tips of the microneedles are composed of drug-loaded polydopamine nanoparticles and polyvinylpyrrolidone. The backing layer includes a polyvinyl alcohol adhesive layer and an ethyl cellulose waterproof layer. The substrate of the microneedle array is fixed to one side surface of the polyvinyl alcohol adhesive layer, and the ethyl cellulose waterproof layer covers the other side surface of the polyvinyl alcohol adhesive layer.

[0010] Preferably, the microneedle array consists of n 2 It consists of microneedles arranged in an n×n pattern, where n is 4 to 12.

[0011] Preferably, the total height H of the microneedles is 400~1000 μm, the bottom diameter D is 180~750 μm, and the distance L between adjacent microneedles is 200~600 μm.

[0012] Preferably, the thickness of both the polyvinyl alcohol adhesive layer and the ethyl cellulose waterproof layer is 400~750 μm, and the shape of the backing layer is circular or square, with the diameter of the circle or the side length of the square being 5~10 mm.

[0013] Preferably, the drug is any one or more of triamcinolone acetonide, dexamethasone, recombinant human epidermal growth factor, watermelon frost, acyclovir, lidocaine, ibuprofen, fluconazole, rosmarinic acid, and prednisolone.

[0014] Preferably, the polydopamine nanoparticles have a particle size of 10-180 nm; and the polyvinylpyrrolidone has a molecular weight of 50-60 kDa.

[0015] The above-mentioned method for preparing multilayer dissolving microneedle patches for the treatment of oral mucosal diseases includes the following steps:

[0016] Step 1) Mix the drug-loaded polydopamine nanoparticle solution and polyvinylpyrrolidone aqueous solution, fill the mold by centrifugation or vacuuming, and dry to form a microneedle array;

[0017] Step 2) Aqueous solutions of polyvinyl alcohol, sodium carboxymethyl cellulose and glycerin are uniformly coated on the substrate surface of the microneedle array and dried to form a polyvinyl alcohol adhesion layer, so that the substrate of the microneedle array is embedded and fixed in the polyvinyl alcohol adhesion layer.

[0018] Step 3) Apply the ethyl cellulose ethanol solution evenly to the surface of the polyvinyl alcohol adhesive layer away from the microneedle array, and dry to form an ethyl cellulose waterproof layer;

[0019] Step 4) Demolding, thus obtaining the multilayer dissolving microneedle patch.

[0020] Preferably, in step 1), the concentration of the drug is 10-100 mg / mL, the concentration of the polydopamine nanoparticles is 80-120 mg / mL, and the concentration of the polyvinylpyrrolidone is 200-350 mg / mL; in step 2), the concentration of the polyvinyl alcohol is 60-75 mg / mL, the concentration of the sodium carboxymethyl cellulose is 5-10 mg / mL, and the concentration of the glycerol is 10-15 mg / mL; and in step 3), the concentration of the ethyl cellulose is 80-120 mg / mL.

[0021] Preferably, in step 1), the centrifugation speed is 3000~5000 rpm, the time is 15~25 min, and the temperature is 4℃; the vacuuming time is 10~20 min; the drying temperature is 40~60℃ and the time is 0.5~2 h; and in steps 2) and 3), the drying temperature is 20~30℃ and the time is 5~8 h.

[0022] The above-mentioned multilayer dissolving microneedle patch is used in the preparation of a drug delivery system for treating oral mucosal diseases.

[0023] The beneficial effects of this invention are as follows:

[0024] (1) This invention concentrates the drug in the tip of the microneedle, using polydopamine nanoparticles as the drug carrier, and combining them with polyvinylpyrrolidone to form the tip body. When the microneedle is inserted into the oral mucosa, the tip can completely enter the mucosal tissue and dissolve rapidly, achieving precise release of the drug in the submucosa or basal layer. This effectively overcomes the problem of drug waste caused by the inability of the microneedle to be fully inserted due to the elasticity of the mucosa, and ensures accurate dosage.

[0025] (2) The microneedle tip of the present invention uses polyvinylpyrrolidone as the matrix material, which has good mechanical strength and can effectively penetrate the oral mucosal epithelial barrier, avoiding tip breakage or bending. At the same time, the tip can dissolve rapidly after penetrating the tissue, and the drug is then released from the polydopamine nanoparticles, significantly improving drug permeability and bioavailability, and achieving rapid onset of action.

[0026] (3) In the microneedle patch of the present invention, the backing layer adopts a double-layer structure design: the polyvinyl alcohol adhesive layer has good bioadhesion and can be firmly fixed to the oral mucosa surface; the ethyl cellulose waterproof layer has excellent hydrophobic properties and can effectively resist the scouring effect of saliva flow on the patch and the drug. This structure enables the microneedle patch to maintain stable adhesion in the moist oral environment, prolong the drug action time, and avoid drug loss.

[0027] (4) The microneedles of the present invention are reasonably designed in size (height 400~1000 μm, bottom diameter 180~750 μm), which can penetrate the mucosal epithelial layer without touching the deep nerve endings, so as to achieve minimally invasive and painless drug delivery. All materials used have good biocompatibility, can be safely degraded or metabolized in the body, have no toxic residues, and patients can operate on their own, with high compliance.

[0028] (5) The polydopamine nanoparticles used in this invention can efficiently load various types of drugs (including small molecule drugs, traditional Chinese medicine extracts and biological macromolecules), and are suitable for the treatment needs of different oral mucosal diseases. The preparation adopts a one-step casting method combined with a two-step uniform coating method. The process is simple, requires no complicated equipment, has mild operating conditions, is easy to scale up, and is inexpensive. Attached Figure Description

[0029] Figure 1 This is a schematic diagram of the structure of the multilayer dissolving microneedle patch (circular) for the treatment of oral mucosal diseases according to the present invention;

[0030] Figure 2 This is a schematic diagram of the structure of the multilayer dissolving microneedle patch (square) for the treatment of oral mucosal diseases according to the present invention;

[0031] Figure 3 This is a side view of the multilayer dissolving microneedle patch for the treatment of oral mucosal diseases according to the present invention;

[0032] Figure 4 This is a schematic diagram of the preparation process of the microneedle solution;

[0033] Figure 5 This is a schematic diagram showing the dimensions of adjacent microneedles;

[0034] Figure 1-5 In the middle: 1. Microneedle array; 2. Backing layer; 3. Microneedles; 4. Drug; 5. Polydopamine nanoparticles; 6. Polyvinylpyrrolidone; 7. Polyvinyl alcohol adhesive layer; 8. Ethyl cellulose waterproof layer;

[0035] Figure 6 The UV-Vis absorption spectra of polydopamine nanoparticles before and after drug loading in Example 1 are shown.

[0036] Figure 7 This is a scanning electron microscope image of drug-loaded polydopamine particles in the microneedle patch prepared in Example 1;

[0037] Figure 8 This is a photograph of the microneedle patch prepared in Example 1.

[0038] Figure 9 This is a front scanning electron microscope image of the microneedle patch prepared in Example 1;

[0039] Figure 10This is a side scanning electron microscope image of the microneedle patch prepared in Example 1;

[0040] Figure 11 HE staining images of rat liver and kidney tissues after treatment with the microneedle patch prepared in Example 1;

[0041] Figure 12 The effect of the drug-loaded microneedle patch prepared in Example 1 on the healing area of ​​oral ulcers in rats. Detailed Implementation

[0042] The present invention will now be described in further detail with reference to the accompanying drawings and specific embodiments.

[0043] Unless otherwise specified, the technical means used in the following embodiments are all conventional means well known to those skilled in the art, and the experimental methods without specific conditions are all conventional methods in the art.

[0044] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0045] A multilayer dissolving microneedle patch for the treatment of oral mucosal diseases, such as Figure 1-3 As shown, it includes a microneedle array 1 and a backing layer 2, wherein the microneedle array 1 consists of n 2 It consists of 3 microneedles arranged in an n×n pattern, where n is 4 to 12.

[0046] like Figure 4 As shown, the tip of the microneedle 3 is composed of polydopamine nanoparticles 5 and polyvinylpyrrolidone 6 carrying drug 4. Drug 4 is concentrated in the tip area to achieve precise and rapid delivery.

[0047] like Figure 5 As shown, the total height H of the microneedles 3 is 400~1000 μm, the bottom diameter D (not shown in the figure) is 180~750 μm, and the distance L between adjacent microneedles 3 is 200~600 μm.

[0048] like Figure 1-3 As shown, the backing layer 2 includes a polyvinyl alcohol adhesive layer 7 and an ethyl cellulose waterproof layer 8; the substrate of the microneedle array 1 is fixed to one side surface of the polyvinyl alcohol adhesive layer 7, and the ethyl cellulose waterproof layer 8 covers the other side surface of the polyvinyl alcohol adhesive layer 7, forming a sandwich structure of "microneedle array-polyvinyl alcohol adhesive layer-ethyl cellulose waterproof layer".

[0049] In a preferred embodiment, the thickness of both the polyvinyl alcohol adhesive layer 7 and the ethyl cellulose waterproof layer 8 is 400~750 μm, and the backing layer 2 is circular in shape. Figure 1 ) or square ( Figure 2The diameter of the circle or the side length of the square is 5~10 mm.

[0050] In a preferred embodiment, the drug 4 is any one or more of triamcinolone acetonide, dexamethasone, recombinant human epidermal growth factor, watermelon frost, acyclovir, lidocaine, ibuprofen, fluconazole, rosmarinic acid, and prednisolone.

[0051] In a preferred embodiment, the polydopamine nanoparticles 5 have a particle size of 10-180 nm; and the polyvinylpyrrolidone 6 has a molecular weight of 50-60 kDa.

[0052] The preparation method of the above-mentioned multilayer dissolving microneedle patch for the treatment of oral mucosal diseases includes the following specific steps:

[0053] (1) such as Figure 4 As shown, a solution of polydopamine nanoparticles 5 loaded with drug 4 and an aqueous solution of polyvinylpyrrolidone 6 were mixed and filled into a mold by centrifugation (centrifugation at 3000~5000 rpm for 15~25 min at 4℃) or vacuuming (10~20 min). After drying at 40~60℃ for 0.5~2 h, a microneedle array 1 was formed.

[0054] In a preferred embodiment, the concentration of drug 4 is 10-100 mg / mL, the concentration of polydopamine nanoparticles 5 is 80-120 mg / mL, and the concentration of polyvinylpyrrolidone 6 is 200-350 mg / mL.

[0055] (2) Aqueous solutions of polyvinyl alcohol, sodium carboxymethyl cellulose and glycerin are uniformly coated on the substrate surface of microneedle array 1 and dried at 20~30℃ for 5~8 h to form polyvinyl alcohol adhesive layer 7, so that the substrate of microneedle array 1 is embedded and fixed in the polyvinyl alcohol adhesive layer 7.

[0056] In a preferred embodiment, the concentration of polyvinyl alcohol is 60-75 mg / mL, the concentration of sodium carboxymethyl cellulose is 5-10 mg / mL, and the concentration of glycerol is 10-15 mg / mL.

[0057] (3) Apply ethyl cellulose ethanol solution evenly to the surface of the polyvinyl alcohol adhesive layer 7 away from the microneedle array 1, and dry at 20~30℃ for 5~8 h to form ethyl cellulose waterproof layer 8.

[0058] In a preferred embodiment, the concentration of the ethyl cellulose is 80-120 mg / mL.

[0059] (4) Demolding, thus obtaining the multilayer dissolving microneedle patch.

[0060] Example 1

[0061] A method for preparing a multilayer dissolving microneedle patch for the treatment of oral mucosal diseases (recurrent oral ulcers) includes the following steps:

[0062] 1. Fabrication of microneedle arrays

[0063] (1) Preparation of microneedle solution

[0064] Rosmarinic acid was added to a solution of polydopamine nanoparticles with a particle size of 160 nm to make the concentration of polydopamine nanoparticles 80 mg / mL and the drug concentration 10 mg / mL, and the nanoparticles were fully dissolved and mixed. Polyvinylpyrrolidone with a molecular weight of 55 kDa was dissolved in ultrapure water to prepare a solution with a concentration of 200 mg / mL.

[0065] The polydopamine nanoparticle dispersions before and after drug loading were analyzed by UV-Vis absorption spectroscopy. Figure 6 As shown, the polydopamine nanoparticles exhibit a characteristic absorption peak at approximately 280 nm before drug loading, and new absorption peaks appear at approximately 250 nm and 350 nm after drug loading, indicating that rosmarinic acid was successfully loaded onto the surface of the polydopamine nanoparticles. Simultaneously, the morphology of the drug-loaded polydopamine nanoparticles was observed using scanning electron microscopy, as shown... Figure 7 As shown, the nanoparticles are spherical, with uniform particle size distribution, smooth surface, and good dispersibility.

[0066] (2) Fabrication of microneedle array

[0067] 50 μL of drug-loaded polydopamine nanoparticle solution and 100 μL of polyvinylpyrrolidone solution were thoroughly mixed and then filled into a polydimethylsiloxane mold (49 microcavities, microneedle array arranged in a 7×7 pattern) by centrifugation. The mixture was centrifuged at 3000 rpm for 15 min at 4 °C, and excess solution was scraped off and recovered. The mold containing the solution was then dried in a 40 °C oven for 0.5 h to form the needle tip. The resulting microneedle height H was 800 μm, the bottom diameter D was 360 μm, and the spacing L between adjacent microneedles was 400 μm.

[0068] 2. Preparation of the backing layer

[0069] (1) Preparation of polyvinyl alcohol adhesive layer

[0070] Polyvinyl alcohol (molecular weight 31–50 kDa, degree of hydrolysis 87–89%), sodium carboxymethyl cellulose, and glycerol were dissolved in ultrapure water at mass-volume ratios of 60 mg / mL, 5 mg / mL, and 10 mg / mL, respectively, and stirred until completely dissolved and free of bubbles. This solution was then uniformly coated onto the substrate surface of the microneedle array to a height of 400 μm and dried at 20 °C for 5 h, allowing the microneedle array substrate to embed and fix within the polyvinyl alcohol adhesive layer.

[0071] (2) Preparation of ethyl cellulose waterproof layer

[0072] Ethyl cellulose was dissolved in anhydrous ethanol to prepare a solution with a concentration of 80 mg / mL. This solution was then uniformly coated onto the surface of the polyvinyl alcohol adhesive layer away from the microneedle array to a height of 400 μm and dried at 20 °C for 5 h.

[0073] 3. Demolding

[0074] Demolding the entire structure yields a multilayer dissolvable microneedle patch.

[0075] 4. Experimental Results and Analysis

[0076] (1) Morphological characteristics

[0077] The backing layer of the microneedle patch prepared in this embodiment is circular in shape, such as... Figure 8 As shown, the diameter is 8.5 mm. The morphology of the microneedle patch was observed using a scanning electron microscope. Figure 9 and Figure 10 These are SEM images of the front and side views of the microneedle patch, respectively. Figure 9 As can be seen, the microneedle array is neatly arranged, with complete and sharp needle tips, uniform shape, and no breaks or defects; Figure 10 As can be seen, the microneedle body is smooth, and the backing layer is firmly bonded to the microneedle substrate.

[0078] (2) Biocompatibility evaluation

[0079] Eight-week-old SD rats were used to establish an oral ulcer model, and the rats were randomly divided into three groups. The blank microneedle patch (without drug loading) and the drug-loaded microneedle patch prepared in this embodiment were applied to the oral ulcer surface, respectively. A control group without any treatment was also included. After 7 days of treatment, liver and kidney tissues were collected from each group of rats, fixed, sectioned, and then stained with hematoxylin and eosin (H&E) for observation.

[0080] like Figure 11 As shown, compared with the control group, no obvious pathological changes were observed in the liver and kidney tissues of rats in both the blank microneedle patch group and the drug-loaded microneedle patch group. The hepatocytes were normal in morphology, and the glomeruli and renal tubules were intact. No abnormal phenomena such as inflammatory infiltration, necrosis or fibrosis were observed, indicating that the microneedle patch of the present invention has good biocompatibility and in vivo safety.

[0081] (3) Pharmacodynamic evaluation

[0082] Using the above-mentioned oral ulcer model rats, the oral ulcer area of ​​each group of rats was measured on days 1, 3, 5 and 7 after treatment, and the healing status was calculated.

[0083] like Figure 12As shown, compared with the control group and the blank microneedle patch group, the drug-loaded microneedle patch group showed a significant reduction in ulcer area on day 3, a significant reduction in ulcer area on day 5, and near-complete healing of ulcers on day 7. The results indicate that the drug-loaded microneedle patch of this invention has a good effect on promoting the healing of oral ulcers.

[0084] Example 2

[0085] A method for preparing a multilayer dissolving microneedle patch for the treatment of oral mucosal diseases (allergic oral mucosal diseases), the specific steps of which are as follows:

[0086] 1. Fabrication of microneedle arrays

[0087] (1) Preparation of microneedle solution

[0088] Dexamethasone was added to a solution of polydopamine nanoparticles with a particle size of 10 nm to make the concentration of polydopamine nanoparticles 120 mg / mL and the drug concentration 100 mg / mL, and the nanoparticles were fully dissolved and mixed. Polyvinylpyrrolidone with a molecular weight of 60 kDa was dissolved in ultrapure water to prepare a solution with a concentration of 350 mg / mL.

[0089] (2) Fabrication of microneedle array

[0090] 50 μL of drug-loaded polydopamine nanoparticle solution and 100 μL of polyvinylpyrrolidone solution were thoroughly mixed and then filled into a polystyrene mold (144 microcavities, microneedle array arranged in a 12×12 pattern) by centrifugation. The mixture was centrifuged at 5000 rpm for 25 min at 4 °C, and excess solution was scraped off and recovered. The mold containing the solution was then dried in a 60 °C forced-air drying oven for 2 h to form the needle tip. The resulting microneedles had a height H of 500 μm, a bottom diameter D of 200 μm, and a spacing L of 300 μm between adjacent microneedles.

[0091] 2. Preparation of the backing layer

[0092] (1) Preparation of polyvinyl alcohol adhesive layer

[0093] Polyvinyl alcohol (molecular weight 31-50 kDa, degree of hydrolysis 87-89%), sodium carboxymethyl cellulose, and glycerol were dissolved in ultrapure water at mass-volume ratios of 75 mg / mL, 10 mg / mL, and 15 mg / mL, respectively, and stirred until completely dissolved and free of bubbles. This solution was then uniformly coated onto the substrate surface of the microneedle array to a height of 750 μm and dried at 30 °C for 8 h, allowing the microneedle array substrate to embed and fix within the polyvinyl alcohol adhesive layer.

[0094] (2) Preparation of ethyl cellulose waterproof layer

[0095] Ethyl cellulose was dissolved in anhydrous ethanol to prepare a solution with a concentration of 120 mg / mL. This solution was then uniformly coated onto the surface of the polyvinyl alcohol adhesive layer away from the microneedle array to a height of 750 μm and dried at 30 °C for 8 h.

[0096] 3. Demolding

[0097] The entire structure was demolded to obtain a multilayer dissolution microneedle patch.

[0098] In the microneedle patch prepared in this embodiment, the backing layer is circular in shape and has a diameter of 10 mm.

[0099] Example 3

[0100] A method for preparing a multilayer dissolving microneedle patch for the treatment of oral mucosal diseases (infectious oral mucosal diseases), the specific steps of which are as follows:

[0101] 1. Fabrication of microneedle arrays

[0102] (1) Preparation of microneedle solution

[0103] Acyclovir was added to a solution of polydopamine nanoparticles with a particle size of 50 nm to make the concentration of polydopamine nanoparticles 100 mg / mL and the drug concentration 50 mg / mL, and the nanoparticles were fully dissolved and mixed. Polyvinylpyrrolidone with a molecular weight of 50 kDa was dissolved in ultrapure water to prepare a solution with a concentration of 280 mg / mL.

[0104] (2) Fabrication of microneedle array

[0105] 50 μL of drug-loaded polydopamine nanoparticle solution and 100 μL of polyvinylpyrrolidone solution were thoroughly mixed and then filled into a polystyrene mold (64 microcavities, microneedle array arranged in an 8×8 pattern) using a vacuum method. The vacuuming time was 15 min, and excess solution was scraped off and recovered. The mold containing the solution was placed in a 50℃ forced-air drying oven and dried for 1 h to form the needle tip. The resulting microneedle height H was 450 μm, the bottom diameter D was 190 μm, and the spacing L between adjacent microneedles was 250 μm.

[0106] 2. Preparation of the backing layer

[0107] (1) Preparation of polyvinyl alcohol adhesive layer

[0108] Polyvinyl alcohol (molecular weight 31–50 kDa, degree of hydrolysis 87–89%), sodium carboxymethyl cellulose, and glycerol were dissolved in ultrapure water at mass-volume ratios of 65 mg / mL, 7.5 mg / mL, and 12.5 mg / mL, respectively, and stirred until completely dissolved and free of bubbles. This solution was then uniformly coated onto the substrate surface of the microneedle array to a height of 600 μm and dried at 25 °C for 6.5 h, allowing the microneedle array substrate to embed and fix within the polyvinyl alcohol adhesive layer.

[0109] (2) Preparation of ethyl cellulose waterproof layer

[0110] Ethyl cellulose was dissolved in anhydrous ethanol to prepare a solution with a concentration of 100 mg / mL. This solution was then uniformly coated onto the surface of the polyvinyl alcohol adhesive layer away from the microneedle array to a height of 600 μm and dried at 25 °C for 6.5 h.

[0111] 3. Demolding

[0112] The entire structure was demolded to obtain a multilayer dissolution microneedle patch.

[0113] In the microneedle patch prepared in this embodiment, the backing layer is square in shape with a side length of 5 mm.

[0114] Example 4

[0115] A method for preparing a multilayer dissolving microneedle patch for the treatment of oral mucosal diseases (oral ulcers and infectious oral mucosal diseases), the specific steps of which are as follows:

[0116] 1. Fabrication of microneedle arrays

[0117] (1) Preparation of microneedle solution

[0118] Lidocaine and acyclovir were added to a solution of polydopamine nanoparticles with a particle size of 180 nm to make the concentration of polydopamine nanoparticles 80 mg / mL and the concentration of drugs 60 mg / mL, and the nanoparticles were fully dissolved and mixed. Polyvinylpyrrolidone with a molecular weight of 55 kDa was dissolved in ultrapure water to prepare a solution with a concentration of 300 mg / mL.

[0119] (2) Fabrication of microneedle array

[0120] 50 μL of drug-loaded polydopamine nanoparticle solution and 100 μL of polyvinylpyrrolidone solution were thoroughly mixed and then filled into a polystyrene mold (25 microcavities, microneedle array arranged in a 5×5 pattern) using a vacuum method. The vacuuming time was 20 min, and excess solution was scraped off and recovered. The mold containing the solution was placed in a 55℃ forced-air drying oven and dried for 1.5 h to form the needle tip. The resulting microneedle height H was 1000 μm, the bottom diameter D was 750 μm, and the spacing L between adjacent microneedles was 600 μm.

[0121] 2. Preparation of the backing layer

[0122] (1) Preparation of polyvinyl alcohol adhesive layer

[0123] Polyvinyl alcohol (molecular weight 31–50 kDa, degree of hydrolysis 87–89%), sodium carboxymethyl cellulose, and glycerol were dissolved in ultrapure water at mass-volume ratios of 72 mg / mL, 9 mg / mL, and 1.5 mg / mL, respectively, and stirred until completely dissolved and free of bubbles. This solution was then uniformly coated onto the substrate surface of the microneedle array to a height of 750 μm and dried at 25 °C for 8 h, allowing the microneedle array substrate to embed and fix within the polyvinyl alcohol adhesive layer.

[0124] (2) Preparation of ethyl cellulose waterproof layer

[0125] Ethyl cellulose was dissolved in anhydrous ethanol to prepare a solution with a concentration of 120 mg / mL. This solution was then uniformly coated onto the surface of the polyvinyl alcohol adhesive layer away from the microneedle array to a height of 750 μm and dried at 25 °C for 8 h.

[0126] 3. Demolding

[0127] The entire structure was demolded to obtain a multilayer dissolution microneedle patch.

[0128] In the microneedle patch prepared in this embodiment, the backing layer is square in shape with a side length of 10 mm.

[0129] The embodiments described above are only some, not all, of the embodiments of the present invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of the claimed invention, but merely to illustrate selected embodiments. The scope of protection of the present invention is determined by the scope claimed in the claims. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

Claims

1. A multilayer dissolving microneedle patch for the treatment of oral mucosal diseases, characterized in that, The device includes a microneedle array and a backing layer. The microneedle array consists of a plurality of microneedles. The tips of the microneedles are composed of drug-loaded polydopamine nanoparticles and polyvinylpyrrolidone. The backing layer includes a polyvinyl alcohol adhesive layer and an ethyl cellulose waterproof layer. The substrate of the microneedle array is fixed to one side of the polyvinyl alcohol adhesive layer, and the ethyl cellulose waterproof layer covers the other side of the polyvinyl alcohol adhesive layer.

2. The multilayer dissolving microneedle patch for treating oral mucosal diseases according to claim 1, characterized in that, The microneedle array consists of n 2 It consists of microneedles arranged in an n×n pattern, where n is 4 to 12.

3. The multilayer dissolving microneedle patch for treating oral mucosal diseases according to claim 1, characterized in that, The total height H of the microneedles is 400~1000 μm, the bottom diameter D is 180~750 μm, and the distance L between adjacent microneedles is 200~600 μm.

4. The multilayer dissolving microneedle patch for treating oral mucosal diseases according to claim 1, characterized in that, The thickness of both the polyvinyl alcohol adhesive layer and the ethyl cellulose waterproof layer is 400~750 μm, and the shape of the backing layer is circular or square, with the diameter of the circle or the side length of the square being 5~10 mm.

5. A multilayer dissolving microneedle patch for treating oral mucosal diseases according to claim 1, characterized in that, The drug is any one or more of triamcinolone acetonide, dexamethasone, recombinant human epidermal growth factor, watermelon frost, acyclovir, lidocaine, ibuprofen, fluconazole, rosmarinic acid, and prednisolone.

6. A multilayer dissolving microneedle patch for treating oral mucosal diseases according to claim 1, characterized in that, The polydopamine nanoparticles have a particle size of 10-180 nm; the polyvinylpyrrolidone has a molecular weight of 50-60 kDa.

7. A method for preparing a multilayer dissolving microneedle patch for treating oral mucosal diseases as described in any one of claims 1-6, characterized in that, Includes the following steps: Step 1) Mix the drug-loaded polydopamine nanoparticle solution and polyvinylpyrrolidone aqueous solution, fill the mold by centrifugation or vacuuming, and dry to form a microneedle array; Step 2) Aqueous solutions of polyvinyl alcohol, sodium carboxymethyl cellulose and glycerin are uniformly coated on the substrate surface of the microneedle array and dried to form a polyvinyl alcohol adhesion layer, so that the substrate of the microneedle array is embedded and fixed in the polyvinyl alcohol adhesion layer. Step 3) Apply the ethyl cellulose ethanol solution evenly to the surface of the polyvinyl alcohol adhesive layer away from the microneedle array, and dry to form an ethyl cellulose waterproof layer; Step 4) Demolding, thus obtaining the multilayer dissolving microneedle patch.

8. The preparation method according to claim 7, characterized in that, Step 1) The concentration of the drug is 10-100 mg / mL, the concentration of the polydopamine nanoparticles is 80-120 mg / mL, and the concentration of the polyvinylpyrrolidone is 200-350 mg / mL; Step 2) The concentration of the polyvinyl alcohol is 60-75 mg / mL, the concentration of the sodium carboxymethyl cellulose is 5-10 mg / mL, and the concentration of the glycerol is 10-15 mg / mL; Step 3) The concentration of the ethyl cellulose is 80-120 mg / mL.

9. The preparation method according to claim 7, characterized in that, Step 1) The centrifugation speed is 3000~5000 rpm, the time is 15~25 min, and the temperature is 4℃; the vacuuming time is 10~20 min; the drying temperature is 40~60℃ and the time is 0.5~2 h; Step 2) and Step 3) The drying temperature is 20~30℃ and the time is 5~8 h.

10. The use of the multilayer dissolving microneedle patch as described in any one of claims 1-6 in the preparation of a drug delivery system for treating oral mucosal diseases.

Images