Oral ulcer temperature-sensitive shrinkage hydrogel patch and preparation method thereof

Abstract

The invention relates to an oral ulcer temperature-sensitive shrinkage hydrogel patch and a preparation method thereof, the patch comprises an adhesion layer, a bridging polymer layer and a functional layer, the patch transmits shrinkage force to drive an ulcer surface to shrink, and it is guaranteed that the patch plays a wound surface shrinkage role for a long time; the temperature-sensitive polymer material isopropylacrylamide in the functional layer of the dental ulcer patch can generate phase change at the oral temperature to cause spontaneous shrinkage of the gel patch, so that the ulcer surface is driven to shrink, and healing is promoted; the patch is mild in triggering deformation mode, the nano clay can improve the mechanical strength of the patch, the patch adapts to dynamic oral cavity mechanical environments in daily activities such as chewing and speech, and meanwhile the patch has a hemostatic effect; the oral ulcer temperature-sensitive shrinkage hydrogel patch is also prepared by constructing a macromolecular interpenetrating network, can be used as a physical barrier to isolate and protect a wound surface, and can shrink under the induction of a relatively high temperature in an oral cavity, so that mucous membranes around the ulcer are effectively pulled, the ulcer wound surface is closed, and ulcer healing is actively promoted.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedical polymer materials, and particularly relates to a thermosensitive shrinkable hydrogel patch for oral ulcers and a preparation method thereof. Background Art

[0002] Oral ulcer, commonly known as "aphtha", is a common oral mucosal ulcerative injury disease. The histopathological manifestation during the ulcer stage is that the ulcer surface is covered with fibrin exudate or necrotic tissue, the collagen fibers in the lamina propria are degenerated and damaged, and a large number of inflammatory cells infiltrate. Oral ulcers can occur at any age and in any season. When they occur, the pain is severe and the local burning pain is obvious, which affects eating and speech, and is prone to recurrence, seriously affecting people's normal life.

[0003] At present, the treatment of oral ulcers in clinical practice mainly focuses on local medication. The commonly used dosage forms include powders, sprays, mouthwashes, ointments, gels, lozenges, patches, etc. However, due to the special physiological environment of the oral cavity, daily activities such as saliva secretion, chewing, and speech make the oral cavity in a humid and highly dynamic environment, resulting in most dosage forms being difficult to stay at the ulcer site stably for a long time, greatly affecting the action time of the drug and the therapeutic effect is poor. Compared with other dosage forms, patches can make up for this shortcoming to a certain extent. Specifically, it can adhere to the mucosal surface and play a role in mechanically protecting the ulcer surface and delivering drugs. However, the current oral patch products on the market have problems such as weak adhesion in a wet environment, easy detachment and damage, which affect the treatment effect and the patient experience. Therefore, the development of technologies with strong wet adhesion and "actively" promoting the healing of oral ulcer wounds is of great significance for the clinical treatment of oral ulcers.

[0004] Chinese patent application with patent number CN103142562B discloses a sustained-release film for treating oral ulcers. The sustained-release film has a three-layer structure: the bottom layer is a sustained-release coating in contact with the ulcer surface; the top layer is a polyacrylic acid film with a protective effect; the middle layer is a drug-loading layer including a bacterial cellulose / drug-loading substance composite film. This sustained-release film has a large drug loading capacity and a long local action time, and can relieve pain, promote wound healing, and prevent wound infection. However, due to the humid physiological environment in the oral cavity, most film agents have low adhesion and short residence time in the oral cavity, and it is difficult to achieve a continuous effective effect at the ulcer site. Moreover, most current oral films contain hormonal drugs such as dexamethasone and dexamethasone acetate, and long-term use is likely to cause serious side effects, restricting their promotion and application.

[0005] The Chinese patent with the application number 202111140211.1 discloses the preparation and application of a wet-adhesive oral gel patch. Its bottom layer is a poly-N-acryloyl-2-glycine hydrogel, and the top layer is a gellan gum hydrogel modified with polymethacrylic anhydride, which can achieve drug controlled release and serve the purpose of treating oral ulcers. However, the drug it loads is still the hormonal drug dexamethasone. The mechanical strength of the bottom-layer hydrogel is relatively low, and in the oral environment with a pH of 6.6 - 7.1, the poly-N-acryloylglycine hydrogel has a high degree of water absorption and swelling, seriously affecting the mechanical properties and adhesion strength of the patch.

[0006] It can be seen that currently, the oral ulcer patches in clinical practice mainly deliver hormonal drugs for treatment, accompanied by a relatively high risk of side effects, and have weak wet adhesion ability and low mechanical strength, making it difficult to adapt to the humid and dynamically mechanically loaded environment in the oral cavity. Research shows that appropriate mechanical loading can promote the proliferation of undifferentiated cell populations, affect the biological behavior of fibroblasts, regulate extracellular matrix remodeling, and control the inflammatory response, thereby promoting wound contraction and healing. Summary of the Invention

[0007] In order to overcome the shortcomings of existing technical means, the purpose of the present invention is to provide an oral ulcer thermosensitive contractile hydrogel patch and its preparation method. The oral ulcer patch prepared by the process method of the present invention has a high wet adhesion strength with oral mucosa, can not only serve as a physical barrier to isolate and protect the wound surface, but also contract under the induction of the physiological temperature of oral mucosa or an external heat source, effectively pulling the mucosa around the ulcer and closing the ulcer wound surface, "actively" promoting ulcer healing; the patch of the present invention has strong adhesion, low swelling, and strong mechanical properties, and can promote the repair of oral ulcer wounds.

[0008] To achieve the above purpose, the present invention provides the following technical solutions:

[0009] An oral ulcer thermosensitive contractile hydrogel patch, comprising an adhesion layer, a bridging polymer layer, and a functional layer; wherein, the components of the adhesion layer include acrylic acid, polyvinyl alcohol, AAc-NHS, α-ketoglutaric acid, polyethylene glycol diacrylate, and deionized water;

[0010] The components of the bridging polymer layer include a 50wt% acrylamide solution, a 1.25wt% N,N'-methylenebisacrylamide solution, a 10wt% ammonium persulfate solution, tetramethylethylenediamine, and deionized water;

[0011] The components of the functional layer include isopropylacrylamide, N,N'-methylenebisacrylamide, nanoclay, sodium pyrophosphate, potassium persulfate, 2-hydroxy-2-methyl-1-phenyl-1-propanone, and deionized water.

[0012] The adhesion layer per portion contains 6.3 - 7.7 g of acrylic acid, 0.67 - 0.80 g of polyvinyl alcohol, 0.54 - 0.66 g of AAc-NHS at 27 - 33 mg / mL, 0.036 - 0.044 g of α-ketoglutaric acid, 9.0 - 11.0 μL of polyethylene glycol diacrylate, and 10.4 - 12.7 mL of deionized water.

[0013] The bridging polymer layer per portion contains 120.0 - 400.0 μL of 50 wt% acrylamide solution, 24 - 240 μL of 1.25 wt% N,N'-methylenebisacrylamide solution, 9.0 - 11.0 μL of 10 wt% ammonium persulfate solution, 0.9 - 1.1 μL of tetramethylethylenediamine, and 549.0 - 821.0 μL of deionized water.

[0014] The functional layer per portion contains 1.71 - 2.09 g of isopropylacrylamide, 0.09 - 0.11 g of N,N'-methylenebisacrylamide, 0.369 - 1.847 g of nanoclay, 0.0307 - 0.1538 g of sodium pyrophosphate, 0.054 - 0.066 g of potassium persulfate, 1.8 - 2.2 μL / mL of 2-hydroxy-2-methyl-1-phenyl-1-propanone, and 16.2 - 19.8 mL of deionized water.

[0015] 25 - 75% of the deionized water in the functional layer can be equivalently replaced by Kangfuxin solution (KFX).

[0016] The Young's modulus of the functional layer of the hydrogel patch is 45.67 - 105.9 kPa, the Young's modulus of the adhesion layer is 12.20 - 14.91 kPa, the tensile strength is greater than 100 kPa, and the fracture strain is greater than 700%.

[0017] The shear adhesion test of the adhesion layer of the hydrogel patch with pig skin shows that the adhesion strength is 103.8 ± 24.85 kPa in the dry state and 112.3 ± 5.61 kPa in the wet state; the shear adhesion test of the adhesion layer of the hydrogel patch with pig oral mucosa shows that the adhesion strength is 73.44 ± 8.68 kPa in the dry state and 94.87 ± 7.86 kPa in the wet state; the 180° peeling test of the adhesion layer of the hydrogel patch with pig skin shows that the adhesion strength is 393.8 ± 58.24 J m -2 , and 451.4 ± 121.6 J m in the wet state -2 ; the 180° peeling test of the adhesion layer of the hydrogel patch with pig oral mucosa shows that the adhesion strength is 431.4 ± 24.76 J m in the dry state -2 , and 212.5 ± 105.0 J m in the wet state -2 .

[0018] The thickness of the functional layer is 1 - 3 mm, the thickness of the bridging polymer layer is 100 - 200 μm, and the thickness of the adhesion layer is 216 - 264 μm.

[0019] A preparation method of a temperature-sensitive shrinkable hydrogel patch for oral ulcers, comprising the following steps:

[0020] Step 1: Take 1.71 - 2.09 g of isopropylacrylamide, 0.09 - 0.11 g of N,N'-methylenebisacrylamide, and 0.054 - 0.066 g of potassium persulfate and add them to a container containing 16.2 - 19.8 mL of deionized water. After adding a magnetic rotor, place it on a magnetic stirrer and stir at a speed of 500 - 1000 rpm at room temperature for 10 - 15 min until all substances are mixed evenly; then slowly add 0.369 - 1.847 g of nanoclay and 0.0307 - 0.1538 g of sodium pyrophosphate while stirring, and continue to stir at a speed of 500 - 1000 rpm at room temperature for 4 - 6 h until all substances are completely dissolved to obtain a precursor solution of the functional layer hydrogel;

[0021] Step 2: Take 3 - 5 mL of the precursor solution and place it in a centrifuge tube. Add 1.8 - 2.2 μL / mL of photoinitiator 1173, mix well, then ultrasonically disperse to remove air bubbles, and then inject 3 - 5 mL of the precursor solution into molds of different shapes and sizes. Cover the surface with a cover plate with a thickness of 1 - 2 mm to overflow the excess precursor solution, and place it in a UV crosslinker to crosslink for 900 - 1200 s to form the functional layer hydrogel of the temperature-sensitive shrinkable hydrogel patch;

[0022] Step 3: Take 6.3 - 7.7 g of acrylic acid and slowly add it to a container containing 10.4 - 12.7 mL of deionized water. After placing a magnetic rotor in the container, place it on a magnetic stirrer and stir at a speed of 400 - 600 rpm for 4 - 6 min. While stirring, sequentially and slowly add 0.67 - 0.80 g of polyvinyl alcohol and 0.036 - 0.044 g of α-ketoglutaric acid, and then add 9.0 - 11.0 μL of polyethylene glycol diacrylate and mix evenly; then add 0.54 - 0.66 g of AAc-NHS at 27 - 33 mg / mL, and use a vortex oscillator to assist its complete dissolution to obtain a precursor solution of the adhesion layer hydrogel;

[0023] Step 4: According to the required thickness of the adhesion layer, inject the precursor solution of the adhesion layer into different special glass molds, and then place it in a UV crosslinker to crosslink and cure into a gel to form the adhesion layer hydrogel of the temperature-sensitive shrinkable hydrogel patch;

[0024] Step 5: Take 120.0 - 400.0 μL of 50 wt% acrylamide solution, 24 - 240 μL of 1.25 wt% N,N'-methylenebisacrylamide solution, and 10.0 μL of 10 wt% ammonium persulfate solution. After degassing each solution under vacuum, add them to 549.0 - 821.0 μL of deionized water, then add 0.9 - 1.1 μL of tetramethylethylenediamine, mix well, and then coat one side surface of the functional layer hydrogel prepared in Step 2. After standing for crosslinking, a bridging polymer layer is formed.

[0025] Step 6: Finally, demold the adhesive layer hydrogel prepared in Step 4 and place it above the bridging polymer layer prepared in Step 5. Press evenly to make the functional layer, bridging polymer layer, and adhesive layer come into full contact to form the overall structure of the three-layer oral ulcer thermosensitive shrinking hydrogel patch.

[0026] In the said Step 2, the light source power of the ultraviolet crosslinker is 7.2 - 8.8 W, the wavelength is 229 - 279 nm, and the crosslinking time is 900 - 1200 s.

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] 1. The warm and humid dynamic environment in the oral cavity affects ulcer healing. In the present invention, a polymer interpenetrating network is constructed in the functional layer, bridging polymer layer, and adhesive layer of the hydrogel, that is: in the hydrogel functional layer, a chemical crosslinking network of PNIPAM (hydrogel) is formed by free radical polymerization, and nano-clay interacts with PNIPAM (hydrogel) through physical crosslinking such as hydrogen bonding and electrostatic interaction to form a physical network; the chemical crosslinking network of the hydrogel adhesive layer is formed by acrylic acid through free radical polymerization to form polyacrylic acid chains, and a three-dimensional network crosslinked by the diacrylate groups of polyethylene glycol diacrylate, and AA-NHS forms covalent bonds with other components; the physical crosslinking network is formed by polyvinyl alcohol through hydrogen bonding with the polyacrylic acid and polyethylene glycol diacrylate networks to form physical crosslinking; polyvinyl alcohol may also enhance the mechanical properties of the network through entanglement or intermolecular interaction; in the bridging polymer layer, acrylamide forms linear polymer chains by free radical polymerization, and N,N'-methylenebisacrylamide crosslinks these polymer chains to form a stable three-dimensional network. The oral ulcer thermosensitive shrinking hydrogel patch composed of the functional layer, bridging polymer layer, and adhesive layer can not only act as a physical barrier to isolate and protect the wound surface, but also shrink under the induction of a higher temperature in the oral cavity, effectively pulling the surrounding mucosa of the ulcer and closing the ulcer wound surface, "actively" promoting ulcer healing.

[0029] 2. The present invention achieves strong adhesion to the mucosa through the adhesion layer. The components of the adhesion layer include an interpenetrating network between covalently crosslinked polyacrylic acid, AAc-NHS, and physically crosslinked polyvinyl alcohol. The former is used for bioadhesion, while the physically crosslinked polyvinyl alcohol can be used to improve the mechanical properties of the adhesion layer. When the adhesive is applied to the tissue surface, the hydrophilic and hygroscopic AAc-NHS and polyvinyl alcohol absorb and dry the interfacial water of the wet tissue upon contact. Subsequently, the carboxyl groups and NHS ester groups in the AAc-NHS network promote the rapid and firm adhesion of the adhesion layer to the surface of the mucosal tissue through physical crosslinking of hydrogen bonds and covalent crosslinking of amide bonds, respectively, thereby achieving firm adhesion to the oral mucosal tissue in a humid environment.

[0030] 3. Since there is no primary amine group in the structure of isopropylacrylamide, it cannot achieve a firm bond with the adhesive on its own. Acrylamide and isopropylacrylamide have similar chemical structures and the structure contains a primary amine group. The present invention uses an acrylamide hydrogel precursor solution as a bridging polymer. One side penetrates therein by virtue of a chemical structure similar to that of isopropylacrylamide, and the other side forms a covalent bond with the adhesion layer through the primary amine group in the structure to achieve covalent binding, which can improve the tissue adhesion performance of the functional layer and tightly connect the functional layer and the adhesion layer as an overall thermosensitive shrinking hydrogel patch.

[0031] 4. The functional layer of the present invention contains a thermosensitive polymer material, isopropylacrylamide, which can undergo a phase change at oral temperature, causing the gel patch to spontaneously shrink, and is anti-swelling in a humid environment at 37°C; alginate produces firm adhesion of the patch to the oral mucosa through covalent bonding, thereby driving the contraction of the mucosa around the ulcer, promoting the closure of the ulcer wound macroscopically, and microscopically affecting the biological behaviors of cells such as fibroblasts in the wound surface through a series of mechanical signal transduction pathways, regulating the wound closure process of hemostasis, inflammation, proliferation, and remodeling.

[0032] 5. The adhesion layer of the present invention is acrylic acid, polyvinyl alcohol, polyethylene glycol diacrylate, and α-ketoglutaric acid, which firmly adheres the functional layer to the oral mucosa, transmits the contraction force to drive the contraction of the ulcer surface, and ensures that the patch plays a role in contracting the wound surface for a long time.

[0033] In summary, the oral ulcer gel patch prepared by the present invention has excellent adhesion to the oral mucosa. It can not only serve as a physical barrier to isolate and protect the wound surface, but also contract under the induction of the physiological temperature of the oral mucosa, effectively pulling the mucosa around the ulcer and closing the ulcer wound, "actively" promoting ulcer healing. Brief Description of the Drawings

[0034] Figure 1 It is a photograph of the thermosensitive shrinking hydrogel patch for oral ulcers.

[0035] Figure 2Photograph of the functional layer of the thermosensitive contractile hydrogel patch for oral ulcers, where Figure 2 (a) is the precursor solution of the functional layer hydrogel, Figure 2 (b) is the solidified functional layer hydrogel.

[0036] Figure 3 Scanning electron micrograph of the functional layer of the thermosensitive contractile hydrogel patch for oral ulcers.

[0037] Figure 4 Photograph of the functional layer of the thermosensitive contractile hydrogel patch for oral ulcers loaded with Kangfuxin Liquid, where Figure 4 (a) is the functional layer hydrogel loaded with Kangfuxin Liquid, Figure 4 (b) is the solidified functional layer hydrogel loaded with Kangfuxin Liquid.

[0038] Figure 5 Scanning electron micrograph of the functional layer of the thermosensitive contractile hydrogel patch for oral ulcers loaded with Kangfuxin Liquid.

[0039] Figure 6 Release curve of Kangfuxin Liquid from the functional layer of the thermosensitive contractile hydrogel patch for oral ulcers loaded with Kangfuxin Liquid, where Figure 6 (a) is the standard curve of Kangfuxin Liquid, Figure 6 (b) is the release curve of Kangfuxin Liquid from the functional layer hydrogel loaded with Kangfuxin Liquid.

[0040] Figure 7 Test result graph of the adhesion strength of the adhesive layer of the thermosensitive contractile hydrogel patch for oral ulcers, where Figure 7 (a) is the adhesion strength to pig skin in the dry state, Figure 7 (b) is the adhesion strength to pig skin in the wet state, Figure 7 (c) is the adhesion strength to porcine oral mucosa in the dry state, Figure 7 (d) is the adhesion strength to porcine oral mucosa in the wet state.

[0041] Figure 8 Test result of the tensile test of the adhesive layer of the thermosensitive contractile hydrogel patch for oral ulcers, where Figure 8 (a) is the photograph of the tensile test of the adhesive layer, Figure 8 (b) is the stress-strain curve obtained from the tensile test of the adhesive layer.

[0042] Figure 9 Test result graph of the thermosensitive contraction test of the thermosensitive contractile hydrogel patch for oral ulcers adhered to the wound surface of rat buccal mucosa, where Figure 9 (a) is the photograph of the gel and the wound surface at different time points when the thermosensitive contractile hydrogel patch for oral ulcers is applied to the wound surface of rat buccal mucosa, Figure 9(b) Quantitative analysis results of the contraction test of the temperature-sensitive contractile hydrogel patch for oral ulcers applied to the buccal mucosa wound of rats.

[0043] Figure 10 For the therapeutic effect of the temperature-sensitive contractile hydrogel patch for oral ulcers applied to oral ulcers in rats, among which, Figure 10 (a) Photos of the buccal mucosa ulcers of rats in the control group, "Yike Tie" group, temperature-sensitive contractile hydrogel patch group, and temperature-sensitive contractile hydrogel patch loaded with Kangfuxin solution at 0, 2, 4, and 6 days. Figure 10 (b) Quantitative analysis results of the area of the buccal mucosa ulcers in rats. Specific implementation manners

[0044] Next, the technical solutions of the present invention will be clearly and completely described in conjunction with the embodiments, but these embodiments do not limit the present invention.

[0045] Example 1

[0046] A preparation method of a temperature-sensitive contractile hydrogel patch for oral ulcers:

[0047] 1) Weigh 1.95 g of isopropylacrylamide, 0.1 g of N,N'-methylenebisacrylamide, and 0.06 g of potassium persulfate and add them to a beaker containing 17.5 mL of deionized water. After adding a magnetic rotor, place it on a magnetic stirrer and stir at a speed of 750 rpm at room temperature for 12.5 min until the substances are mixed evenly. Then, slowly add 0.9235 g of nanoclay and 0.0769 g of sodium pyrophosphate while stirring, and continue to stir under the same conditions for 5 h until all substances are completely dissolved to obtain a precursor solution of the functional layer hydrogel.

[0048] 2) Take 4 mL of the precursor solution and place it in a centrifuge tube. Add 8 μL of photoinitiator 1173 thereto, mix it using a vortex oscillator, then ultrasonically disperse to remove air bubbles. Then, inject a certain amount of the precursor solution into polymethyl methacrylate (PMMA) molds of different shapes and sizes, cover the surface with a PMMA plate with a thickness of 1.5 mm to make the excess precursor solution overflow, and place it in a UV crosslinker for crosslinking for 1200 s. The light source power of the UV crosslinker is 7.2 W and the wavelength is 229 nm to form the functional layer hydrogel of the temperature-sensitive contractile hydrogel patch.

[0049] 3) Weigh 7 g of acrylic acid and add it to a beaker containing 11.55 mL of deionized water while slowly stirring with a glass rod. Place a rotor in the beaker and then place it on a magnetic stirrer and stir at a speed of 500 rpm for 5 min. Then, while stirring, slowly add 0.735 g of polyvinyl alcohol and 0.04 g of α-ketoglutaric acid in sequence, and then add 10 μL of polyethylene glycol diacrylate and mix evenly. Then add 570 mg of AAc-NHS, and use a vortex oscillator to assist in its complete dissolution to obtain the precursor solution of the adhesive layer hydrogel;

[0050] 4) According to the required thickness of the adhesive layer, inject the precursor solution of the adhesive layer into different special glass molds, and then place them in a UV cross-linking instrument for cross-linking and curing to form the adhesive layer hydrogel of the thermosensitive shrinking hydrogel patch;

[0051] 5) Take 120 μL of 50 wt% acrylamide solution, 48 μL of 1.25 wt% N,N-methylenebisacrylamide solution, and 10 μL of 10 wt% ammonium persulfate solution. After degassing each solution under vacuum, add them to a centrifuge tube containing 821 μL of deionized water, then add 1 μL of tetramethylethylenediamine, mix well, and then coat it on one side surface of the functional layer hydrogel prepared in step 2), and let it stand for cross-linking to form a bridging polymer layer;

[0052] 6) Finally, demold the adhesive layer hydrogel prepared in step 4) and place it above the bridging polymer layer prepared in step 5), and press evenly to make the functional layer, bridging polymer layer and adhesive layer fully contact to form the overall structure of the three-layer oral ulcer thermosensitive shrinking hydrogel patch.

[0053] The overall structure of the thermosensitive shrinking hydrogel patch of the present invention is as Figure 1 shown, where 1 is the functional layer, 2 is the bridging polymer layer, and 3 is the adhesive layer. The functional layer and the adhesive layer are firmly combined. When external forces are applied parallel or perpendicular to the bonding interface direction respectively, a certain resistance can be felt, and the main body structure of the functional layer hydrogel is damaged while the two have not been debonded, indicating that the functional layer hydrogel and the adhesive layer are tightly combined through the bridging polymer layer hydrogel. (To clearly show and distinguish the structures of the functional layer, bridging polymer layer and adhesive layer, the thickness of each layer of hydrogel is prepared to be 2 mm, and a red dye is added to the precursor solution of the adhesive hydrogel.)

[0054] The precursor solution of the functional layer hydrogel prepared in the present invention is a light yellow clear liquid as Figure 2 (a) shown, and a jelly-like functional layer hydrogel can be prepared after UV cross-linking as Figure 2 (b) shown.

[0055] The precursor solution of the functional layer hydrogel loaded with Kangfuxin Liquid prepared in the present invention is a dark brown clear liquid as Figure 4As shown in (a), a jelly-like functional layer hydrogel loaded with Kangfuxin Liquid can be prepared after ultraviolet cross-linking, as Figure 4 shown in (b), and the hydrogel is brown.

[0056] Under a scanning electron microscope, the surface morphologies of the functional layer hydrogel and the functional layer hydrogel loaded with Kangfuxin Liquid of the present invention were observed, and it can be seen that both have a porous network structure. The pores of the functional layer hydrogel are larger and the surface structure is relatively loose, as Figure 3 shown. After loading Kangfuxin Liquid, the pores of the hydrogel decrease and the surface structure is relatively dense, as Figure 5 shown.

[0057] Example 2

[0058] A preparation method of a thermosensitive shrinking hydrogel patch for oral ulcers:

[0059] 1) Weigh 1.71 g of isopropylacrylamide, 0.09 g of N,N'-methylenebisacrylamide, and 0.054 g of potassium persulfate, add them to a beaker containing 16.2 mL of deionized water, add a magnetic rotor, and place it on a magnetic stirrer to stir at a speed of 500 rpm for 10 min at room temperature until the substances are mixed evenly. Then, while stirring, slowly add 0.369 g of nanoclay and 0.0307 g of sodium pyrophosphate, and continue to stir under the same conditions for 4 h until all substances are completely dissolved to obtain a precursor solution of the functional layer hydrogel;

[0060] 2) Take 3 mL of the precursor solution and place it in a centrifuge tube. Add 6 μL of photoinitiator 1173, mix it evenly using a vortex oscillator, then ultrasonically disperse to remove air bubbles. Then, inject a certain amount of the precursor solution into polymethyl methacrylate (PMMA) molds of different shapes and sizes, cover the surface with a 1-mm-thick PMMA plate to make the excess precursor solution overflow, and place it in an ultraviolet cross-linker for cross-linking for 900 s. The light source power of the ultraviolet cross-linker is 7.8 W and the wavelength is 259 nm to form the functional layer hydrogel of the thermosensitive shrinking hydrogel patch;

[0061] 3) Weigh 6.3 g of acrylic acid and add it to a beaker containing 11.55 mL of deionized water while slowly stirring with a glass rod. Place a rotor in the beaker and place it on a magnetic stirrer to stir at a speed of 500 rpm for 5 min. Then, while stirring, sequentially and slowly add 0.7376 g of polyvinyl alcohol and 0.04 g of α-ketoglutaric acid, and then add 10 μL of polyethylene glycol diacrylate and mix evenly. Then add 360 mg of AAc-NHS, and use a vortex oscillator to assist its complete dissolution to obtain a precursor solution of the adhesion layer hydrogel;

[0062] 4) According to the required thickness of the adhesion layer, inject the adhesion layer precursor solution into different special glass molds, and then place them in a UV cross-linking instrument for cross-linking and curing into a gel to form the adhesion layer hydrogel of the temperature-sensitive shrinkable hydrogel patch;

[0063] 5) Measure 260 μL of 50 wt% acrylamide solution, 132 μL of 1.25 wt% N,N'-methylenebisacrylamide solution, and 10 μL of 10 wt% ammonium persulfate solution. After degassing each solution under vacuum, add them to a centrifuge tube containing 685 μL of deionized water, then add 1 μL of tetramethylethylenediamine, mix well, and then coat one side surface of the functional layer hydrogel prepared in step 2). After standing for cross-linking, form a bridging polymer layer;

[0064] 6) Finally, demold the adhesion layer hydrogel prepared in step 4) and place it above the bridging polymer layer prepared in step 5). Press evenly to make the functional layer, bridging polymer layer, and adhesion layer come into full contact to form the overall structure of the three-layer oral ulcer temperature-sensitive shrinkable hydrogel patch.

[0065] Example 3

[0066] A preparation method of an oral ulcer temperature-sensitive shrinkable hydrogel patch:

[0067] 1) Weigh 2.09 g of isopropylacrylamide, 0.11 g of N,N'-methylenebisacrylamide, and 0.066 g of potassium persulfate, add them to a beaker containing 19.8 mL of deionized water, add a magnetic rotor, and place it on a magnetic stirrer to stir at a speed of 1000 rpm at room temperature for 15 min until all substances are mixed evenly. Then, while stirring, slowly add 1.847 g of nanoclay and 0.1538 g of sodium pyrophosphate, and continue to stir under the same conditions for 6 h until all substances are completely dissolved to obtain the functional layer hydrogel precursor solution;

[0068] 2) Take 5 mL of the precursor solution and place it in a centrifuge tube. Add 10 μL of photoinitiator 1173, mix well using a vortex oscillator, then ultrasonically disperse to remove bubbles. Then, inject a certain amount of the precursor solution into polymethyl methacrylate (PMMA) molds of different shapes and sizes, cover the surface with a 1 mm thick PMMA plate to overflow the excess precursor solution, and place it in a UV cross-linking instrument for cross-linking for 1200 s. The light source power of the UV cross-linking instrument is 8.8 W, and the wavelength is 279 nm to form the functional layer hydrogel of the temperature-sensitive shrinkable hydrogel patch;

[0069] 3) Weigh 7.7 g of acrylic acid and add it to a beaker containing 12.7 mL of deionized water while slowly stirring with a glass rod. Place a rotor in the beaker and stir it on a magnetic stirrer at a speed of 600 rpm for 6 min. Then, while stirring, slowly add 0.8 g of polyvinyl alcohol and 0.044 g of α-ketoglutaric acid in sequence, and then add 11 μL of polyethylene glycol diacrylate and mix evenly. Then add 673.2 mg of AAc-NHS, and use a vortex oscillator to assist in its complete dissolution to obtain the precursor solution of the adhesive layer hydrogel;

[0070] 4) According to the required thickness of the adhesive layer, inject the precursor solution of the adhesive layer into different special glass molds, and then place them in a UV cross-linking instrument for cross-linking and curing to form the adhesive layer hydrogel of the thermosensitive shrinkable hydrogel patch;

[0071] 5) Take 400 μL of 50 wt% acrylamide solution, 240 μL of 1.25 wt% N,N'-methylenebisacrylamide solution, and 10 μL of 10 wt% ammonium persulfate solution. After degassing each solution under vacuum, add them to a centrifuge tube containing 821 μL of deionized water, then add 1.1 μL of tetramethylethylenediamine, mix well, and then coat one side surface of the functional layer hydrogel prepared in step 2), and let it stand for cross-linking to form a bridging polymer layer;

[0072] 6) Finally, demold the adhesive layer hydrogel prepared in step 4) and place it above the bridging polymer layer prepared in step 5), and press evenly to make the functional layer, bridging polymer layer and adhesive layer fully contact to form the overall structure of the three layers of the oral ulcer thermosensitive shrinkable hydrogel patch.

[0073] Example 4

[0074] This example provides a preparation method of a thermosensitive shrinkable hydrogel patch loaded with Xin Kangfu Ye and its characteristics of releasing Xin Kangfu Ye:

[0075] Replace 50% or 100% of the water in the functional layer of the thermosensitive shrinkable hydrogel patch in Examples 1, 2, and 3 with Xin Kangfu Ye, and the remaining steps are the same as before, then the thermosensitive shrinkable hydrogel 50% KFX-PNC or 100% KFX-PNC loaded with Xin Kangfu Ye can be prepared.

[0076] Drug release test: The drug-loaded hydrogels prepared by mixing 1 mL of 50% KFX-PNC and 1 mL of 100% KFX-PNC hydrogel precursor solution were respectively immersed in beakers containing 20 mL of PBS solution (37 °C, 180 rpm). Every 10 minutes within 0 - 2 h, 1 mL of the solution was taken and transferred to a 1.5 mL centrifuge tube, and replaced with an equal volume of fresh PBS solution. The absorbance of KFX released from the KFX standard solution diluted with PBS at different concentrations and the KFX-PNC hydrogel was measured at 222 nm using a microplate spectrophotometer, and the KFX standard curve and drug release curve were plotted as Figure 6 shown. The 100% KFX-PNC hydrogel can release more than 90% of KFX within 1 h, and the KFX release ratio of the 50% KFX-PNC hydrogel is slightly higher than the former.

[0077] Example 5

[0078] This example provides the adhesion performance test of the adhesion layer of the thermosensitive shrinkable hydrogel patch:

[0079] 1) Lap shear test: The prepared mechanically loaded hydrogel was bonded to pig skin of the same size, and the overlapping area of the two was a square with a length of 10 mm and a width of 10 mm. A scalpel, hemostatic forceps, and tissue forceps were used to separate the samples of porcine gingival mucosa and buccal mucosa (0.5 cm × 2 cm), and they were glued to a polyethylene terephthalate (PET) film of the same size with cyanoacrylate glue. An adhesive hydrogel with dimensions of 0.5 cm × 2 cm × 1 mm was prepared and glued to a PET film of the same size with cyanoacrylate glue. The bonding strengths of the two were tested in both wet and dry states. Before the wet state test, PBS solution (200 μL) was evenly applied to the surface of the porcine oral mucosa. Before the dry state test, the surface water was blotted dry with absorbent paper. Then the gel was adhered to the oral mucosa to reach an overlapping area of about 0.5 cm × 0.5 cm, pressed for 15 s, and immediately tested with a microcomputer tensile tester after standing for 30 min. The separation speed was set at 10 mm / min, and the separation force values of the two were recorded. According to the output force and displacement curve, the adhesion strength was calculated using the formula F max / area. The sample preparation and test method for the adhesion strength test of the commercial glue and porcine oral mucosa were the same as above. The lap shear test method for pig skin was the same as that for mucosa.

[0080] 2) 180° peel test: Use a scalpel in combination with hemostatic forceps and tissue forceps to separate and prepare porcine gingival mucosa and buccal mucosa samples (1 cm x 2 cm), and use cyanoacrylate glue to stick them to a PET film of the same size. Prepare an adhesion layer hydrogel with dimensions of 1 cm x 2 cm x 1 mm, and use cyanoacrylate glue to stick it to the surface of a PET film of the same size. Test the adhesion strength of both in wet and dry states. Before the wet state test, evenly apply PBS solution (200 μL) to the surface of the porcine gingival mucosa. Before the dry state test, dry the surface moisture with absorbent paper. Then adhere the gel to the porcine oral mucosa to achieve an overlapping area of approximately 1 cm x 1 cm, and place a PET film with a width of 1 cm at the end to separate the mucosa from the gel, which serves as the part connected to the fixture during testing. After pressing for 15 s and placing for 30 min, immediately use a microcomputer tensile testing machine to test the sample at a constant separation speed of 10 mm / min, record the force value at the plateau period, and use the formula F peel / width to calculate the interfacial adhesion strength, i.e., the interfacial toughness, between the adhesion layer and the tissue. The sample preparation and testing methods for the adhesion strength test of commercial glue and porcine oral mucosa are the same as above. The 180° peel test method for porcine skin is the same as that for mucosa.

[0081] The results of the lap shear test are as Figure 7 shown. In dry and wet states, the shear adhesion strength between the adhesion layer and porcine skin is similar. In the dry state, it is 103.8 ± 24.85 kPa, and in the wet state, it is 112.3 ± 5.61 kPa. The average adhesion strength in the wet state slightly increases, but the difference is not statistically significant, indicating that external water has no significant effect on the shear adhesion strength between the adhesion layer and porcine skin. The shear adhesion strength between the adhesion layer and porcine oral mucosa is slightly lower than that of the skin. In the dry state, it is 73.44 ± 8.68 kPa, and in the wet state, it is 94.87 ± 7.86 kPa. However, the shear adhesion strength in the wet environment increases by approximately 21.43 kPa on average compared to the dry state (*p < 0.05), and the difference is statistically significant. The shear adhesion strength with porcine skin is 249.2 ± 64.17 kPa in the dry state and 132.2 ± 17.18 kPa in the wet state. Interfacial water significantly reduces its adhesion strength. Although its shear adhesion strength with porcine skin in the dry state is significantly higher than that of the adhesive layer (*p < 0.05), their adhesion strengths are similar in the wet state (p > 0.05); 3M TM Vetbond TM The shear adhesion strength with porcine oral mucosa is 431.4 ± 24.76 kPa in the dry state and 106.7 ± 5.69 kPa in the wet state. Although its shear adhesion strength with porcine skin in the dry state is significantly higher than that of the adhesive layer (**p < 0.01), their adhesion strengths are similar in the wet state (p > 0.05).

[0082] The results of the 180° peel test are as Figure 7 shown. The mean interfacial toughness between the adhesive layer and porcine skin is similar in both dry and wet states, being 393.8 ± 58.24 J / m in the dry state -2 and 451.4 ± 121.6 J / m in the wet state -2 . The interfacial toughness slightly increases in the wet state but the difference is not statistically significant, indicating that external water has no significant effect on the interfacial toughness between the adhesive layer and porcine skin. The interfacial toughness between the adhesive layer and porcine oral mucosa is higher than that with skin in the dry state and lower in the wet state, being 431.4 ± 24.76 J / m in the dry state -2 and 212.5 ± 105.0 J / m in the wet state -2 . Compared with the interfacial toughness of buccal oral mucosa in dry and wet environments, it decreases by approximately 219 J / m on average in the dry state -2 (*p < 0.05), and the difference is statistically significant, indicating that it has good shear adhesion strength with oral mucosa in a wet environment, can resist lateral shear forces generated by friction from liquids, food, etc. and adhere firmly to the mucosa. The decrease in interfacial toughness in the wet state is beneficial for its non-invasive peeling from the mucosal surface, laying a foundation for its application in the moist oral environment to promote oral mucosal wound healing. The interfacial toughness with porcine skin is 249.2 ± 46.21 J / m in the dry state -2 and 155.2 ± 73.00 J / m in the wet state -2 . The presence of interfacial water greatly reduces its interfacial toughness with porcine skin. Although its interfacial toughness with porcine skin is significantly higher than that of the adhesive layer in the dry state (*p < 0.05), the interfacial toughness between the adhesive layer and porcine skin is significantly higher than that of the commercial glue in the wet state (*p < 0.05); 3M TM Vetbond TM The interfacial toughness with porcine oral mucosa is 105.6 ± 40.16 J / m in the dry state -2 and 125.3 ± 6.18 J / m in the wet state -2 . The effect of interfacial water on its interfacial toughness is relatively small. Although its interfacial toughness with porcine oral mucosa is significantly higher than that of the adhesive layer in the dry state (***p < 0.001), the interfacial toughness between the adhesive layer and porcine oral mucosa is significantly higher than that of the commercial glue in the wet state (*p < 0.05).

[0083] Mechanical property tests were carried out on the adhesive layer of the temperature-sensitive shrinkable hydrogel patch:

[0084] Prepare dumbbell-shaped tensile test samples (dumbbell length 12 mm, width 5 mm, thickness 2 mm), fix both ends to the fixtures respectively, and conduct tensile tests using a microcomputer tensile testing machine. From the initial state until the sample breaks, the tensile speed is 10 mm / min, and draw the stress-strain curve as Figure 8 shown. Calculate the Young's modulus in the strain range of 0% - 10%. The tensile test results show that the average Young's modulus of the adhesive is 13.55 kPa, the tensile strength is greater than 100 kPa, and the fracture strain is greater than 700%, which is beneficial for its application in the dynamic oral environment.

[0085] The process and results of the thermosensitive shrinkable hydrogel patch adhesion to the buccal mucosa wound surface of Sprague-Dawley rats:

[0086] After anesthetizing 2 rats by intraperitoneal injection of 0.3 mL / 100 g of 10% chloral hydrate solution and fixing the head and limbs, disinfect the surgical area with 0.5% iodophor. Use a circular tissue biopsy punch with a diameter of 2 mm and a low-speed grinding machine to construct a circular full-thickness defect with a diameter of 2 mm on the bilateral buccal mucosa. Prepare a cylindrical thermosensitive shrinkable hydrogel patch with a diameter of 5 mm and a thickness of 1 mm, attach it to the surface of the bilateral buccal mucosa defects of the rats, and take pictures immediately. After 20 minutes, open the rat's mouth and take pictures of the hydrogel and the wound surface again as Figure 9 shown. Use Image J software to calculate and analyze the areas of the PNC hydrogel and the wound surface in the pictures, and calculate the shrinkage rates of the hydrogel and the wound surface as Figure 9 shown.

[0087] The application of the thermosensitive shrinkable hydrogel patch in the treatment of traumatic oral ulcers of the buccal mucosa of Sprague-Dawley rats:

[0088] 1) Establishment of the rat buccal mucosa oral ulcer model

[0089] After anesthetizing by intraperitoneal injection of 0.3 mL / 100 g of 10% chloral hydrate and fixing the limbs, use a ligature wire with a diameter of 0.25 mm to twist two strands into a twist shape to fix the upper teeth to assist in fixing the rat's head. Use an oral opener bent from a stainless steel wire with a diameter of 0.8 mm to assist in opening the mouth. Disinfect the surgical area with 0.5% iodophor. Use a circular tissue biopsy punch with a diameter of 2 mm and a grinding machine to create bilateral buccal mucosa defects, and symmetrically construct circular full-thickness mucosal defect wounds with a diameter of 2 mm on the left and right. Randomly divide all rats into four groups: thermosensitive shrinkable hydrogel patch (PNC) group, thermosensitive shrinkable hydrogel patch loaded with Kangfuxin solution (PNC + KFX) group, dexamethasone acetate oral patch ("Yiketie") group, and control group (Control), with 9 rats in each group.

[0090] 2) Treatment process

[0091] Hemostasis was achieved, the wound surface was rinsed with normal saline and then wiped clean, and the mucosal condition was photographed and recorded. In the experimental group, thermosensitive contractile hydrogel patches with a diameter of 8 mm and a thickness of 1 mm, thermosensitive contractile hydrogel patches loaded with Kangfuxin solution, and "Yike Tie" were adhered to the wound surface (try to keep the wound surface in the center of the patch). The control group was not treated. All animals were allowed to drink and eat freely during the experimental observation period. On the 3rd, 5th, and 7th days, the animals were euthanized, buccal mucosal photographs were taken and the mucosal conditions were recorded. A full-thickness tissue of the mucosa around the ulcer was excised using a 5-mm diameter tissue punch in combination with a scalpel, taking care to protect the buccal mucosa. The excised buccal mucosal tissues were immediately fixed in 4% paraformaldehyde for 24 h to prevent tissue deformation after being removed from the body. By calculating the ulcer area and comparing it with the ulcer area on the 0th day, the closure rate of the ulcer wound surface was calculated using the formula (wound area 0 –wound area x ) / wound area 0 ×100%, where wound area 0 represents the initial wound surface area, and wound area x represents the wound surface area on the day of treatment.

[0092] It can be seen that the wound healing conditions of each group are as Figure 10 shown. The appearance of the buccal mucosa in the PNC group was closest to normal, and the ulcer area was significantly reduced compared with the control group. Fresh oral mucosal tissue growth could be found. Especially on the 2nd day, the thermosensitive contractile hydrogel patch was more effective in ulcer closure. This may be because the PNC hydrogel undergoes a phase change and contraction in the warm oral environment, driving the contraction of the mucosa around the underlying ulcer, which can promote the contraction and closure of the ulcer wound surface, thus accelerating ulcer healing. The quantitative analysis results of the ulcer area showed that the ulcer area in the thermosensitive contractile hydrogel patch group was significantly reduced compared with the control group on the 2nd and 4th days.

Claims

1. A thermosensitive shrinkage hydrogel patch for oral ulcer, characterized in that: It includes an adhesive layer, a bridging polymer layer and a functional layer; wherein the adhesive layer comprises acrylic acid, polyvinyl alcohol, AAc-NHS, α-ketoglutaric acid, polyethylene glycol diacrylate and deionized water; The composition of the bridging polymer layer includes 50 wt % acrylamide solution, 1.25 wt % N,N-methylenebisacrylamide solution, 10 wt % ammonium persulfate solution, tetramethylethylenediamine and deionized water; The functional layer comprises isopropyl acrylamide, N,N'-methylenebisacrylamide, nano clay, sodium pyrophosphate, potassium persulfate, 2-hydroxy-2-methyl-1-phenyl-1-propanone and deionized water.

2. A thermosensitive shrinkage hydrogel patch for oral ulcers as claimed in claim 1, characterized in that: Each of the adhesive layers contains 6.3-7.7 g acrylic acid, 0.67-0.80 g polyvinyl alcohol, 27-33 mg / mL 0.54-0.66 g AAc-NHS, 0.036-0.044 g α-ketoglutaric acid, 9.0-11.0 μL polyethylene glycol diacrylate, and 10.4-12.7 mL deionized water.

3. A thermosensitive shrinkage hydrogel patch for oral ulcers as claimed in claim 1, characterized in that: Each of the bridging polymer layers contains 120.0-400.0 μL of 50 wt% acrylamide solution, 24-240 μL of 1.25 wt% N,N-methylenebisacrylamide solution, 9.0-11.0 μL of 10 wt% ammonium persulfate solution, 0.9-1.1 μL of tetramethylethylenediamine, and 549.0-821.0 μL of deionized water.

4. A thermosensitive shrinkage hydrogel patch for oral ulcers as claimed in claim 1, characterized in that: Each functional layer contains 1.71-2.09 g of isopropyl acrylamide, 0.09-0.11 g of N,N'-methylenebisacrylamide, 0.369-1.847 g of nano clay, 0.0307-0.1538 g of sodium pyrophosphate, 0.054-0.066 g of potassium persulfate, 1.8-2.2 μL / mL of 2-hydroxy-2-methyl-1-phenyl-1-propanone, and 16.2-19.8 mL of deionized water.

5. The oral ulcer thermosensitive shrinkage hydrogel patch according to claim 1 or 4, characterized in that: 25-75% of the deionized water in the functional layer can be replaced by an equal amount of Kangfuxin (KFX).

6. The oral ulcer thermosensitive shrinkage hydrogel patch according to claim 1, characterized in that: The Young's modulus of the functional layer of the hydrogel patch is 45.67-105.9 kPa, the Young's modulus of the adhesive layer is 12.20-14.91 kPa, the tensile strength is greater than 100 kPa, and the fracture strain is greater than 700%.

7. The oral ulcer thermosensitive shrinkage hydrogel patch according to claim 1 or 2, characterized in that: The hydrogel patch adhesive layer was subjected to a shear adhesion test with pig skin, and the obtained adhesion strength was 103.8±24.85 kPa in a dry state and 112.3±5.61 kPa in a wet state. The hydrogel patch adhesive layer was subjected to a shear adhesion test with pig oral mucosa, and the obtained adhesion strength was 73.44±8.68 kPa in a dry state and 94.87±7.86 kPa in a wet state. The hydrogel patch adhesive layer was subjected to a 180° peel test with pig skin, and the obtained adhesion strength was 393.8±58.24 J m -2 , 451.4±121.6 J m in wet state -2 The hydrogel patch adhesive layer was subjected to a 180° peel test with the pig oral mucosa, and the obtained adhesive strength in the dry state was 431.4±24.76 J m -2 , 212.5±105.0J m in wet state -2 .

8. The oral ulcer thermosensitive shrinkage hydrogel patch according to claim 1 or 4, characterized in that: The thickness of the functional layer is 1-3 mm, the thickness of the bridging polymer layer is 100-200 μm, and the thickness of the adhesion layer is 216-264 μm.

9. A method for preparing a thermosensitive shrinkage hydrogel patch for oral ulcer, characterized in that: The following steps are involved: Step 1, 1.71-2.09g isopropyl acrylamide, 0.09-0.11g N,N'-methylenebisacrylamide, 0.054-0.066g potassium persulfate are added to a container containing 16.2-19.8mL deionized water, a magnetic rotor is added, and the mixture is placed on a magnetic stirrer and stirred at a speed of 500-1000rpm at room temperature for 10-15min until all substances are evenly mixed; then 0.369-1.847g nanoclay and 0.0307-0.1538g sodium pyrophosphate are slowly added while stirring, and stirring is continued at a speed of 500-1000rpm at room temperature for 4h-6h until all substances are completely dissolved, to obtain a functional layer hydrogel precursor solution; Step 2, taking 3-5 mL of the precursor solution and placing it in a centrifuge tube, adding 1.8-2.2 μL / mL of the photoinitiator 1173 thereto, mixing, and then ultrasonically dispersing to remove bubbles, and then injecting 3-5 mL of the precursor solution into molds of different shapes and sizes, covering the surface with a cover plate with a thickness of 1-2 mm to allow excess precursor solution to overflow, and placing it in a UV crosslinker for crosslinking for 900-1200 seconds to form a functional layer hydrogel of the thermosensitive shrinkage hydrogel patch; Step 3, take 6.3-7.7 g of acrylic acid, add it to a container containing 10.4-12.7 mL of deionized water while slowly stirring, put a magnetic rotor in the container and place it on a magnetic stirrer and stir at a speed of 400-600 rpm for 4-6 minutes, slowly add 0.67-0.80 g of polyvinyl alcohol and 0.036-0.044 g of α-ketoglutaric acid in sequence while stirring, and then add 9.0-11.0 μL of polyethylene glycol diacrylate, and mix them evenly; then add 0.54-0.66 g of AAc-NHS at 27-33 mg / mL, use a vortex oscillator to assist in its complete dissolution to obtain an adhesion layer hydrogel precursor solution; Step 4, according to the required thickness of the adhesive layer, the adhesive layer precursor solution is injected into different special glass molds, and then placed in a UV cross-linking instrument to cross-link and solidify into a gel to form an adhesive layer hydrogel of the thermosensitive shrinkage hydrogel patch; Step 5, taking 120.0-400.0 μL of 50 wt% acrylamide solution, 24-240 μL of 1.25 wt% N,N-methylenebisacrylamide solution, and 10.0 μL of 10 wt% ammonium persulfate solution, adding each solution to 549.0-821.0 μL of deionized water after removing bubbles in vacuum, and then adding 0.9-1.1 μL of tetramethylethylenediamine, mixing well, and then applying it to one side surface of the functional layer hydrogel prepared in step 2, and forming a bridging polymer layer after standing and cross-linking; Step 6. Finally, demold the adhesive layer hydrogel prepared in step 4 and place it on top of the bridging polymer layer prepared in step 5. Press evenly to make the functional layer, the bridging polymer layer and the adhesive layer fully contact to form a three-layer overall structure of the oral ulcer thermosensitive shrinkage hydrogel patch.

10. The method for preparing a thermosensitive shrinkage hydrogel patch for oral ulcer according to claim 9, characterized in that: In step 2, the light source power of the UV cross-linking instrument is 7.2-8.8W, the wavelength is 229-279nm, and the cross-linking time is 900-1200s.

11. A method for preparing a thermosensitive shrinkage hydrogel patch for oral ulcer, characterized in that: The following steps are involved: 1) Weigh 1.95 g of isopropyl acrylamide, 0.1 g of N,N'-methylenebisacrylamide, and 0.06 g of potassium persulfate into a beaker containing 17.5 mL of deionized water, add a magnetic rotor, place on a magnetic stirrer, and stir at 750 rpm for 12.5 min at room temperature until all substances are evenly mixed, then slowly add 0.9235 g of nanoclay and 0.0769 g of sodium pyrophosphate while stirring, and continue stirring under the same conditions for 5 h until all substances are completely dissolved, to obtain a functional layer hydrogel precursor solution; 2) 4 mL of the precursor solution was placed in a centrifuge tube, 8 μL of the photoinitiator 1173 was added thereto, and the mixture was mixed using a vortex oscillator, and then ultrasonically dispersed to remove bubbles. A certain amount of the precursor solution was then injected into polymethyl methacrylate (PMMA) molds of different shapes and sizes, and a 1.5 mm thick PMMA plate was placed on the surface to allow excess precursor solution to overflow. The molds were then placed in an ultraviolet crosslinker for crosslinking for 1200 s. The light source power of the ultraviolet crosslinker was 7.2 W and the wavelength was 229 nm, to form a functional layer hydrogel of the thermosensitive shrinkage hydrogel patch; 3) Weigh 7 g of acrylic acid and add it to a beaker containing 11.55 mL of deionized water while slowly stirring with a glass rod. Place a rotor in the beaker and place it on a magnetic stirrer and stir at 500 rpm for 5 min. Then, slowly add 0.735 g of polyvinyl alcohol and 0.04 g of α-ketoglutaric acid in sequence while stirring. Then, add 10 μL of polyethylene glycol diacrylate and mix well. Then, add 570 mg of AAc-NHS and use a vortex oscillator to assist in complete dissolution to obtain an adhesion layer hydrogel precursor solution. 4) According to the required thickness of the adhesive layer, the adhesive layer precursor solution is injected into different special glass molds, and then placed in a UV cross-linking instrument to cross-link and solidify into a gel to form an adhesive layer hydrogel of the thermosensitive shrinkage hydrogel patch; 5) adding 120 μL of 50 wt% acrylamide solution, 48 μL of 1.25 wt% N,N-methylenebisacrylamide solution, and 10 μL of 10 wt% ammonium persulfate solution to a centrifuge tube containing 821 μL of deionized water after vacuum degassing, and then adding 1 μL of tetramethylethylenediamine, mixing well, and then coating the solution on one side of the functional layer hydrogel prepared in step 2), and forming a bridging polymer layer after standing and cross-linking; 6) Finally, the adhesive layer hydrogel prepared in step 4) is demolded and placed on top of the bridging polymer layer prepared in step 5), and evenly pressed to make the functional layer, the bridging polymer layer and the adhesive layer fully contact to form a three-layer overall structure of the oral ulcer thermosensitive shrinkage hydrogel patch.

12. A method for preparing a thermosensitive shrinkage hydrogel patch for oral ulcer, characterized in that: The following steps are involved: 1) Weigh 1.71 g of isopropyl acrylamide, 0.09 g of N,N'-methylenebisacrylamide, and 0.054 g of potassium persulfate into a beaker containing 16.2 mL of deionized water, add a magnetic rotor, place on a magnetic stirrer and stir at 500 rpm for 10 min at room temperature until all substances are evenly mixed, then slowly add 0.369 g of nanoclay and 0.0307 g of sodium pyrophosphate while stirring, continue stirring under the same conditions for 4 h until all substances are completely dissolved, to obtain a functional layer hydrogel precursor solution; 2) 3 mL of the precursor solution was placed in a centrifuge tube, 6 μL of the photoinitiator 1173 was added thereto, and the mixture was mixed using a vortex oscillator, and then ultrasonically dispersed to remove bubbles. A certain amount of the precursor solution was then injected into polymethyl methacrylate (PMMA) molds of different shapes and sizes, and a 1 mm thick PMMA plate was placed on the surface to allow excess precursor solution to overflow. The molds were then placed in an ultraviolet crosslinker for crosslinking for 900 s. The light source power of the ultraviolet crosslinker was 7.8 W and the wavelength was 259 nm, to form a functional layer hydrogel of the thermosensitive shrinkage hydrogel patch; 3) Weigh 6.3 g of acrylic acid and add it to a beaker containing 11.55 mL of deionized water while slowly stirring with a glass rod. Place a rotor in the beaker and place it on a magnetic stirrer and stir at 500 rpm for 5 min. Then, slowly add 0.7376 g of polyvinyl alcohol and 0.04 g of α-ketoglutaric acid in sequence while stirring. Then, add 10 μL of polyethylene glycol diacrylate and mix well. Then, add 360 mg of AAc-NHS and use a vortex oscillator to assist in complete dissolution to obtain an adhesion layer hydrogel precursor solution. 4) According to the required thickness of the adhesive layer, the adhesive layer precursor solution is injected into different special glass molds, and then placed in a UV cross-linking instrument to cross-link and solidify into a gel to form an adhesive layer hydrogel of the thermosensitive shrinkage hydrogel patch; 5) adding 260 μL of 50 wt% acrylamide solution, 132 μL of 1.25 wt% N,N-methylenebisacrylamide solution, and 10 μL of 10 wt% ammonium persulfate solution to a centrifuge tube containing 685 μL of deionized water after vacuum degassing, and then adding 1 μL of tetramethylethylenediamine, mixing well, and then coating the solution on one side of the functional layer hydrogel prepared in step 2), and forming a bridging polymer layer after standing and cross-linking; 6) Finally, the adhesive layer hydrogel prepared in step 4) is demolded and placed on top of the bridging polymer layer prepared in step 5), and evenly pressed to make the functional layer, the bridging polymer layer and the adhesive layer fully contact to form a three-layer overall structure of the oral ulcer thermosensitive shrinkage hydrogel patch.

13. A method for preparing a thermosensitive shrinkage hydrogel patch for oral ulcer, characterized in that: The following steps are involved: 1) Weigh 2.09 g of isopropyl acrylamide, 0.11 g of N,N'-methylenebisacrylamide, and 0.066 g of potassium persulfate into a beaker containing 19.8 mL of deionized water, add a magnetic rotor, place on a magnetic stirrer and stir at 1000 rpm for 15 min at room temperature until all substances are evenly mixed, then slowly add 1.847 g of nanoclay and 0.1538 g of sodium pyrophosphate while stirring, continue stirring under the same conditions for 6 h until all substances are completely dissolved, to obtain a functional layer hydrogel precursor solution; 2) 5 mL of the precursor solution was placed in a centrifuge tube, 10 μL of the photoinitiator 1173 was added thereto, the mixture was mixed using a vortex oscillator, and then the bubbles were removed by ultrasonic dispersion. A certain amount of the precursor solution was then injected into polymethyl methacrylate (PMMA) molds of different shapes and sizes, and a 1 mm thick PMMA plate was placed on the surface to allow excess precursor solution to overflow. The molds were then placed in an ultraviolet crosslinker for crosslinking for 1200 s. The light source power of the ultraviolet crosslinker was 8.8 W, the wavelength was 279 nm, and the crosslinking time was 900 to 1200 s to form a functional layer hydrogel of the thermosensitive shrinkage hydrogel patch. 3) Weigh 7.7 g of acrylic acid and add it to a beaker containing 12.7 mL of deionized water while slowly stirring with a glass rod. Place a rotor in the beaker and place it on a magnetic stirrer and stir at 600 rpm for 6 min. Then, slowly add 0.8 g of polyvinyl alcohol and 0.044 g of α-ketoglutaric acid in sequence while stirring. Then, add 11 μL of polyethylene glycol diacrylate and mix well. Then, add 673.2 mg of AAc-NHS and use a vortex oscillator to assist in complete dissolution to obtain an adhesion layer hydrogel precursor solution. 4) According to the required thickness of the adhesive layer, the adhesive layer precursor solution is injected into different special glass molds, and then placed in a UV cross-linking instrument to cross-link and solidify into a gel to form an adhesive layer hydrogel of the thermosensitive shrinkage hydrogel patch; 5) 400 μL of 50 wt% acrylamide solution, 240 μL of 1.25 wt% N,N-methylenebisacrylamide solution, and 10 μL of 10 wt% ammonium persulfate solution were added to a centrifuge tube containing 821 μL of deionized water after vacuum degassing, and then 1.1 μL of tetramethylethylenediamine was added, mixed thoroughly, and then coated on one side of the functional layer hydrogel prepared in step 2), and allowed to stand for cross-linking to form a bridging polymer layer; 6) Finally, the adhesive layer hydrogel prepared in step 4) is demolded and placed on top of the bridging polymer layer prepared in step 5), and evenly pressed to make the functional layer, the bridging polymer layer and the adhesive layer fully contact to form a three-layer overall structure of the oral ulcer thermosensitive shrinkage hydrogel patch.

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