Rapid surface anesthesia patch combining near-infrared photothermal effect and microneedle technology as well as preparation method and application of rapid surface anesthesia patch

Abstract

The invention discloses a rapid surface anesthesia patch combining a near-infrared photothermal effect and a microneedle technology and a preparation method and application of the rapid surface anesthesia patch. The rapid surface anesthesia patch comprises a backing layer and a microneedle body arranged on the backing layer, and the backing layer comprises a photo-thermal material, a microneedle framework material, an auxiliary molecular material and a solvent; the micro-needle body comprises an active component for anesthesia and a micro-needle framework material. The photo-thermal material MXene adopted by the micro-needle patch is only positioned on the backing layer of the micro-needle patch and does not directly penetrate into the skin; according to the structural design, MXene and a drug release area are ingeniously and physically isolated, the risk that non-drug components enter an organism is reduced to the maximum extent, the biological safety is improved while the drug effect is guaranteed, and the MXene sustained-release capsule has a wide clinical application prospect.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of microneedle, in particular to a rapid surface anesthesia patch combining near-infrared photothermal effect and microneedle technology, and a preparation method and application thereof. BACKGROUND

[0002] Surface anesthesia, as a common form of local anesthesia, is widely used in clinical practice in the fields of small surgical operations, plastic surgery, or pain management. Surface anesthesia works by allowing local drugs to penetrate the skin or mucosa, blocking nerve endings, and thus producing analgesia. It has the advantages of simple operation, rapid recovery, and is especially suitable for the elderly, children, and patients with systemic diseases.

[0003] Although surface anesthesia has a wide range of applications in the field of local anesthesia and has many advantages, such as simple operation and rapid recovery, the existing technology still has deficiencies and limitations in many aspects. The existence of these problems mainly affects the effect and scope of application of surface anesthesia. Specific problems include: (1) long onset time of anesthesia: Traditional surface anesthesia drugs usually need a long time to penetrate the skin or mucosa and produce anesthetic effect. The transdermal absorption of drugs is limited by the stratum corneum of the skin, which makes it difficult for drugs to quickly reach the target tissue, thereby affecting the onset speed of anesthesia. In medical scenarios that require rapid anesthesia, the long onset time of anesthetic drugs becomes an important limiting factor. Existing penetration enhancement techniques, such as electroosmosis or ultrasound, can improve drug absorption, but these methods are often complex and difficult to apply universally in clinical practice. (2) Difficulty in controlling the duration and depth of anesthetic effect: Current surface anesthesia drugs cannot accurately control the depth and duration of anesthesia in clinical use. Especially in some medical operations that require precise control of anesthesia depth, traditional drugs often cannot be adjusted flexibly, resulting in anesthesia effects that may be too shallow or too deep. This is mainly due to the relatively single release mechanism of existing anesthetic drugs, which lack adjustable delivery systems that can adjust the release rate and dosage of drugs in real time according to different clinical needs. (3) Limited transdermal absorption of drugs: The stratum corneum of the skin acts as a natural barrier to drug penetration, making it difficult for drugs, especially macromolecular drugs or hydrophilic drugs, to quickly and fully pass through the skin into the body. The molecular structure of the drug and the physiological characteristics of the skin barrier are the root causes of this problem. However, existing penetration enhancement methods often have complex operations, high costs, and low patient acceptance, making them difficult to be widely applied in clinical practice. SUMMARY

[0004] The technical problem to be solved by the present application is to provide a rapid surface anesthesia patch combining near-infrared photothermal effect and microneedle technology, and a preparation method and application thereof. By optimizing the material composition and structure of the microneedle, as well as the application of photothermal materials, rapid drug penetration and efficient local anesthetic effect are achieved to meet the clinical demand for rapid and effective surface anesthesia.

[0005] The technical problem to be solved by the present application is solved by the following technical solutions:

[0006] The first aspect of the present application provides a rapid surface anesthesia patch combining near-infrared photothermal effect and microneedle technology. The rapid surface anesthesia patch comprises a backing layer and a microneedle body disposed on the backing layer. The backing layer comprises a photothermal material, a microneedle skeleton material, an auxiliary molecular material, and a solvent. The microneedle body comprises an active ingredient for anesthesia and a microneedle skeleton material.

[0007] Further, the photothermal material comprises one or more of the following: MXene, polydopamine, ferroferric oxide nanoparticles, black phosphorus, two-dimensional transition metal sulfide. Preferably, the photothermal material is selected from MXene.

[0008] In the present application, the photothermal material MXene is only located in the backing layer of the microneedle patch and does not directly penetrate the skin. This clever structural design physically isolates MXene from the drug release area, minimizing the risk of non-drug components entering the body, while ensuring drug efficacy and improving biological safety, which is superior to existing solutions that directly load photothermal materials on the needle tip or tissue-penetrating area.

[0009] Further, the microneedle skeleton material comprises one or more of the following: polyvinyl alcohol, hyaluronic acid or its sodium salt, polystyrene, acrylic resin, polycaprolactone, collagen, polylactic acid. Preferably, it is polyvinyl alcohol.

[0010] In the present application, the microneedle skeleton material is a high molecular material that can enhance the mechanical strength and toughness of the microneedle body, allowing the needle body to smoothly penetrate the skin; at the same time, the skeleton material can also make the backing layer have good flexibility. In a specific embodiment of the present application, the microneedle skeleton material is polyvinyl alcohol (PVA).

[0011] Further, the auxiliary molecular material comprises one or more of the following: sucrose, trehalose, mannitol. Preferably, it is sucrose.

[0012] In the present application, the auxiliary molecular material is a small molecular material, which makes the backing layer have good rigidity.

[0013] In the present application, the microneedle skeleton material and the auxiliary molecular material are used in combination, so that the backing layer has good flexibility and hardness, which can provide good support for the microneedle body during drug delivery, and can improve the adhesion of the backing layer and the skin, thereby achieving efficient delivery without increasing the number of needle bodies to deliver the required drug dosage for animal testing and clinical use.

[0014] Further, the active ingredient for anesthesia comprises one or more of the following: lidocaine, tetracaine, prilocaine. Preferably, lidocaine.

[0015] Further, the solvent comprises one or more of the following: ultrapure water, diglycol dimethyl ether, dioxane, N, N-dimethylacetamide, DMSO. Preferably, ultrapure water.

[0016] Further, the backing layer comprises MXene, polyvinyl alcohol, sucrose and ultrapure water. The microneedle needle body comprises lidocaine and polyvinyl alcohol.

[0017] In some embodiments, the protective agent is a small molecule protective agent, which has the effect of maintaining drug activity and promoting rapid dissolution of the needle body, thereby accelerating drug absorption.

[0018] Further, the protective agent is selected from at least one of the following: mannitol, glucose, sucrose, trehalose.

[0019] In some embodiments, when the amount of protective agent and / or microneedle skeleton material added in the microneedle needle body is 0, the drug loading capacity of the microneedle needle body can be increased and the mechanical strength required for penetration into the skin can be met. In addition, during long-term use of the microneedle patch, the risk of accumulation of protective agents and skeleton materials and biocompatibility problems can be reduced. At the same time, because there are many immune cells in the subcutaneous tissue, the use of high molecular weight skeleton materials can easily cause an immune response, so reducing the amount of high molecular weight skeleton material added can also improve the safety of the microneedle patch, thereby ensuring the safety of the human body.

[0020] Further, the mass ratio of polyvinyl alcohol, sucrose and ultrapure water in the backing layer is (7-9):(5-7):(14-16). Preferably, 8:6:15.

[0021] Further, the concentration of MXene in the backing layer is 0-200 μg / mL. Preferably, 50-200 μg / mL. More preferably, 100 μg / mL.

[0022] Further, the mass ratio of lidocaine and polyvinyl alcohol in the microneedle needle body is 0 / 4-2 / 1. Preferably, 1 / 4-2 / 1. More preferably, 1 / 4-3 / 4.

[0023] Further, the concentration of polyvinyl alcohol in the microneedle needle body is 20%-30%. Preferably, 25%.

[0024] Further, the rapid surface anesthesia patch is a multi-needle body array.

[0025] Further, the multi-needle body array is a (8-12) x (8-12) square array.

[0026] Furthermore, the distance between the tips of each microneedle in the rapid surface anesthesia patch is 450-550 μm, preferably 500 μm.

[0027] Furthermore, the microneedle body is a cone or a polygonal pyramid.

[0028] In some implementations, the microneedle body needs to have a certain geometric shape in order to effectively pierce the skin. Therefore, the shape of the needle body includes, but is not limited to, cone, square pyramid, bullet, and polygonal star cone.

[0029] Furthermore, the height of the microneedle is 550-650 μm, preferably 600 μm.

[0030] Furthermore, the microneedle's base diameter is 300-400 μm, preferably 350 μm.

[0031] A second aspect of the present invention provides a method for preparing the rapid surface anesthesia patch described in the first aspect of the present invention, comprising the following steps:

[0032] (1) Preparation of needle solution: Lidocaine and polyvinyl alcohol are mixed and dissolved in a mass ratio of 0 / 4-2 / 1 to obtain needle solution;

[0033] (2) Preparation of backing layer solution: Polyvinyl alcohol, sucrose and ultrapure water are mixed and dissolved in a mass ratio of (7-9):(5-7):(14-16), and MXene is added to obtain the backing layer solution.

[0034] (3) Microneedle molding: The needle body solution and backing layer solution obtained in the above steps are placed in the microneedle mold to obtain a rapid surface anesthesia patch.

[0035] Further, in step (1), the polyvinyl alcohol is first dissolved in ultrapure water, and then lidocaine is added and mixed. The concentration of the polyvinyl alcohol is 20%-30%, preferably 25%. The mass ratio of lidocaine to polyvinyl alcohol is 1 / 4-2 / 1, preferably 1 / 4-3 / 4.

[0036] Further, in step (2), the mass ratio of polyvinyl alcohol, sucrose, and ultrapure water is 8:6:15. Further, the concentration of MXene is 0-200 μg / mL. Preferably, it is 50-200 μg / mL, more preferably 100 μg / mL.

[0037] Furthermore, in step (3), the needle solution is first placed in the microneedle mold under negative pressure to completely fill the needle part of the microneedle mold. The excess needle solution is then recovered, and negative pressure is applied again to fix the needle. Then, the backing layer solution is placed in the microneedle mold under negative pressure, dried, and demolded to obtain the rapid surface anesthesia patch.

[0038] Furthermore, the negative pressure time is 15 to 30 minutes, and the vacuum degree under the negative pressure condition is (-0.01 to -0.1) MPa.

[0039] In some implementations, after drying in step (3) is completed, the process also includes stopping the negative pressure, drying at normal pressure, vacuum drying, and demolding.

[0040] In some embodiments, the atmospheric pressure drying is carried out in an oven at a temperature of less than 40°C for a time of 6-9 hours.

[0041] In some embodiments, the vacuum drying is carried out in a vacuum drying oven, the drying temperature is less than 40°C, the vacuum degree is (-0.01 to -0.1) MPa, and the drying time is 18-25 h.

[0042] The third aspect of the present invention provides the use of the rapid surface anesthetic patch described in the first aspect of the present invention in the preparation of a medicament for local anesthesia.

[0043] Furthermore, the local anesthesia includes surface anesthesia used in minor surgical procedures, cosmetic surgery, or pain management.

[0044] The above-described technical solution of the present invention has the following beneficial effects:

[0045] (1) The photothermal material MXene used in this invention is located only in the backing layer of the microneedle patch and does not directly penetrate the skin. This structural design cleverly isolates MXene from the drug release area, minimizing the risk of non-drug components entering the body. It improves biosafety while ensuring efficacy, which is superior to the existing technology that directly loads the photothermal material onto the needle tip or penetrable tissue area.

[0046] (2) Compared with traditional surface anesthetics (such as lidocaine cream), this invention combines photothermal effect and triggers the rapid release of drugs in microneedle patches by external light, so as to achieve local anesthesia in a shorter time. This feature is especially suitable for skin plastic surgery and cosmetic treatments such as laser beauty, injection filling, photon skin rejuvenation, and microneedle mesotherapy. It can reduce patient waiting time, improve treatment efficiency and comfort, and has broad clinical application prospects. Attached Figure Description

[0047] The accompanying drawings, which are incorporated in and form part of this specification, illustrate embodiments of the invention and, together with their description, serve to explain the principles of the invention.

[0048] Figure 1 To prepare drug loading capacity for MNs single-piece microneedles in solutions with different proportions.

[0049] Figure 2 The images show the morphology and drug distribution of the microneedles under optical microscopy, scanning electron microscopy, and EDS.

[0050] Figure 3 The mechanical properties of the microneedles are characterized.

[0051] Figure 4 The photothermal response and thermal cycling stability of microneedle patches under different MXene concentrations and different 808nm near-infrared excitation conditions were studied.

[0052] Figure 5 This shows the recovery status of the microneedle insertion marks.

[0053] Figure 6 The skin response of rats under different near-infrared light irradiation times.

[0054] Figure 7 This study investigated the permeation-enhancing effect of microneedle patches on gelatin and isolated pigskin.

[0055] Figure 8 Transdermal diffusion of microneedle patches in rats and Franz diffusion cells.

[0056] Figure 9 Behavioral tests for mechanical pain.

[0057] Figure 10 Behavioral tests for heat-related pain. Detailed Implementation

[0058] Various exemplary embodiments of the present invention will now be described in detail with reference to the accompanying drawings. It should be noted that, unless otherwise specifically stated, the relative arrangement, numerical expressions, and values ​​of the components and steps set forth in these embodiments do not limit the scope of the invention.

[0059] Unless otherwise specified, the experimental methods used in the following examples are conventional methods, and the materials and reagents used are commercially available. Unless otherwise specified, the equipment used in the experiments is well known to those skilled in the art.

[0060] Example 1: Preparation and Characterization of Near-Infrared Photothermal Microneedle Patches

[0061] Experimental materials:

[0062] Sucrose and PVA (9-10 kDa) were purchased from Sigma-Aldrich (MO, USA), lidocaine hydrochloride (Lido) was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd., and the molds for MXene and PDMS microneedles (10*10, 600 μm high, 350 μm bottom diameter, 500 μm spacing) were provided by the Microneedle Laboratory of Beijing University of Chemical Technology.

[0063] Experimental methods:

[0064] (1) Preparation of microneedles: The photothermal responsive microneedle system prepared in this study mainly consists of two parts: a PVA needle body loaded with Lido and a photothermal responsive backing layer loaded with MXene. First, a 25% (w / v) PVA solution was prepared by dissolving PVA in ultrapure water. Then, according to different Lido:PVA mass ratios (0 / 4, 1 / 4, 1 / 2, 3 / 4, 1 / 1, 2 / 1, respectively), Lido was added to the PVA solution to prepare a Lido / PVA mixed solution, which was used to form the PVA needle body. Next, the photothermal responsive backing layer was prepared by mixing and dissolving PVA, sucrose, and ultrapure water at a mass ratio of 8:6:15, and adding different concentrations of MXene (0-200 μg / mL). The photothermal responsive backing layer prepared in this way can generate a thermal effect under specific light conditions, thereby realizing the photothermal responsive function of the microneedle system.

[0065] 50 μL of 25% Lido / PVA solution was evenly applied to the pinhole area of ​​the microneedle PDMS mold. A vacuum was applied under the PDMS mold for 15 minutes to ensure complete filling of the microneedle mold with the Lido / PVA solution. Excess solution was then removed, and any remaining residue was wiped away with a wet tool. Next, a vacuum was applied for another 20 minutes to completely draw the filled Lido / PVA solution into the needle body, and any water in the solution was removed to prevent drug diffusion into the backing layer. Finally, 100 μL of MXene / PVA solution was coated onto the PDMS mold, and the mold was kept under vacuum for 30 minutes to prepare the photothermal responsive backing layer. The mold was then dried overnight, demolded, and stored in a vacuum drying oven for later use.

[0066] (2) Determination of drug loading in microneedles: Lido PBS standard solutions of different concentrations were prepared, and the prepared Lido / PVA microneedles (excluding MXene) of different concentrations were immersed in the PBS solution until they were completely dissolved. The final drug loading in the finished microneedles was then determined using high-performance liquid chromatography (254 nm, peak position 12.6 min).

[0067] (3) Morphological characterization of microneedles: The prepared microneedles were observed and their morphology was recorded under an optical microscope to analyze the microneedle height and the integrity of the needle tip array. The distribution of the drug in the needle body was simulated by doping with Rhodamine B dye. At the same time, the surface morphology of the microneedles was observed with higher precision by scanning electron microscopy, and the distribution and content of the drug were analyzed by energy dispersive X-ray spectroscopy (EDS).

[0068] (4) Mechanical property characterization of microneedles: To ensure that the microneedles have sufficient mechanical properties to penetrate the skin, we evaluated the mechanical properties of prepared Lido / PVA microneedles of different concentrations to assess the balance between drug loading and mechanical properties. Microneedle patches were fixed to the displacement axis of a force gauge, and the mechanical displacement curve was recorded at a speed of 10 mm / min. The number of penetration layers and depth were observed by inserting the microneedles into a simulated skin sealing film with a fixed force. Ex vivo pig skin was dried, and a Rhodamine B-loaded microneedle patch was inserted to observe the penetration rate and the penetration depth was observed by lateral incision. Furthermore, optical coherence tomography (OCT) was used to observe the real-time penetration of microneedles in rat skin.

[0069] (5) Evaluation of the photothermal performance of microneedles: Microneedles loaded with different concentrations of MXene were placed under different power 808nm laser excitation, and real-time temperature changes were recorded by a thermal imaging camera. The correlation between photothermal conversion capacity and concentration and power was compared, and photothermal stability was observed through multiple cycles.

[0070] (6) Safety evaluation of microneedles: In order to safely apply microneedles to humans, the recovery of needle marks and the appropriate photothermal temperature were investigated. Specifically, microneedles were inserted into the skin of hair-removed rats, and the puncture marks formed at different times were observed to evaluate the recovery of microneedle insertion. Microneedle patches were attached to the skin of rats' backs and then irradiated at different temperatures (40-70℃) for different times. After a period of time, the state of the corresponding positions on the rats' backs was observed.

[0071] Example 2: In vitro drug diffusion enhancement study

[0072] To compare the photothermal effect on drug penetration, Rhodamine B was used for assisted observation. Microneedles were applied to isolated pig skin, gelatin blocks, and live rats. Drug diffusion under different conditions was observed using an optical microscope and a small animal in vivo imaging system. Furthermore, using a Franz cell diffusion cell, the receiving fluid at different time points was collected to determine the Lido concentration, thereby evaluating the transdermal diffusion of Lido.

[0073] Example 3: In vivo experiment of photothermal microneedle patch for rapid surface anesthesia

[0074] Six-week-old healthy SPF-grade male rats, obtained from Beijing SPAF Biotechnology Co., Ltd., were housed in a standard environment with humidity of 40-60% and temperature of 22±2℃. The rats had free access to food and water and were exposed to 12 hours of light daily. This experimental protocol was approved by the Laboratory Animal Welfare and Ethics Committee of Peking Union Medical College Hospital, Chinese Academy of Medical Sciences (Approval No.: XHDW-2024-126). The rats were divided into six groups (n=6 per group): control group, foot incision surgery group, foot incision lidocaine cream group (Lido / Cream), foot incision blank MN patch group (MNs), foot incision lidocaine-loaded microneedle patch group (Lido@MNs), and foot incision lidocaine-loaded photothermal microneedle patch group (Lido / MXene@MNs).

[0075] This study used a plantar laceration model to observe postoperative pain. Rats were anesthetized by intraperitoneal injection of 1% sodium pentobarbital and inhalation of isoflurane. After disinfection, a 1cm longitudinal incision was made 0.5cm from the proximal edge of the heel. The incision penetrated the skin, fascia, and muscle, while preserving the muscle origins and insertions at both ends. After hemostasis, the incision was sutured with 4-0 nylon sutures, and a small amount of antibiotic ointment was applied to the wound. Control group rats received anesthesia, disinfection, and antibiotic treatment, but did not undergo any surgery. After the surgery, the rats were returned to their original cages. Appropriate treatment measures were administered to rats in each group 24 days after the model was established.

[0076] Postoperative pain behavior testing: Pain behavior testing was conducted at specific time points, including one day before surgery and at designated postoperative time points (baseline, 5, 10, 20, 30, 45, 60, 90, and 120 min), to evaluate the onset speed and duration of analgesia for different anesthesia measures. Mechanical pain sensitivity was evaluated using von Frey filaments. Rats were acclimatized to the testing environment for 30 min before each test phase. A series of calibrated filaments with different bending forces (1.0, 1.4, 2.0, 4.0, 6.0, 8.0, 10.0, and 15.0 g) were sequentially applied to the area near the plantar incision. These filaments were applied sequentially from under the cage through the mesh bottom to the plantar skin of the planned surgical area. Each time a von Frey filament was applied, the filament was bent and held for 2 to 3 seconds, and the rats were observed for withdrawal responses (such as foot retraction, licking, etc.). A rapid foot retraction response in response to the stimulus was marked as a positive reaction. It is important to distinguish whether this withdrawal response is caused by the stimulus or by physical activity. A positive response is recorded as X when three out of five consecutive stimuli produce a positive response; otherwise, it is recorded as O. If there is no response when the response decreases to the previous level of pressure, the pressure is increased to the next level. This process is repeated (six rounds in total), and the pressure value corresponding to the last fiber used (i.e., the pressure value marked X) is recorded to calculate the mechanical stimulus withdrawal response threshold.

[0077] In addition, the SH-1000 foot heat meter (Shanghai Vox) was used to assess thermal pain sensitivity. During the experiment, rats were placed in a 79cm×40cm×6.5cm testing platform. Invisible infrared light was emitted to the rat's foot to generate heat. When the rat felt thermal pain and exhibited a paw withdrawal response, displacement was observed, and the latency of paw licking was recorded. The cutoff time was usually set to 30 seconds to prevent tissue damage.

[0078] Experimental results:

[0079] (1) Preparation and characterization of near-infrared photothermal microneedle patches

[0080] 1.1 Determination of drug loading of microneedles: Without considering the impact on the mechanical properties of the microneedles, Lido / PVA ratios ranging from 0 / 4 to 2 / 1 can be used to form needles with drug loading capacities from 69ug to 643ug, all of which meet the requirements for local anesthetic dosage. Figure 1 ).

[0081] 1.2 Morphological Characterization of Microneedles: The prepared microneedle patches are at the micrometer level, with the entire patch being about the size of a coin. The microneedle array structure is complete, with no missing tips, and the height of the microneedles in the entire array is approximately 600 μm. Scanning electron microscopy images show that the microneedle surface is smooth, with no drug crystallization and no obvious boundary phenomena, indicating that the drug and PVA matrix material are uniformly dispersed. Energy dispersive X-ray spectroscopy (EDS) analysis shows that the characteristic element Cl of Lido is mainly distributed in the 1 / 2-3 / 4 position of the needle body, which can avoid incomplete insertion due to skin elasticity and contraction, ensuring efficient drug delivery after insertion. Figure 2 ).

[0082] 1.3 Mechanical Properties Characterization of Microneedles: To maximize drug loading while ensuring the microneedle patch meets basic mechanical performance requirements for skin penetration, we investigated the relationship between mechanical properties and microneedles prepared with different ratios. The mechanical displacement graph shows that the mechanical properties of the microneedles gradually decrease with increasing Lido content. Simultaneously, in the heatmap of seal film penetration rate simulating skin penetration, microneedles with ratios of 0 / 4 to 3 / 4 could essentially penetrate three layers of seal film, while the penetration rate significantly decreased in ratios of 1 / 1 to 2 / 1. Fluorescence images from pigskin penetration experiments also verified this conclusion; the penetration rates of the 1 / 1 and 2 / 1 groups decreased significantly, and lateral section images showed a clear difference in penetration depth. The main reason for this phenomenon is that with increasing Lido content, the main components of the microneedle tip become Lido and PVA, and the high molecular chain structure of PVA has excellent mechanical properties, effectively improving the mechanical strength of the microneedle. However, the increased Lido content leads to a lack of sufficient intermolecular interactions, making the microneedles more susceptible to structural damage under external forces, thus resulting in a decrease in mechanical properties. Figure 3 ).

[0083] 1.4 Evaluation of the Photothermal Performance of Microneedles: To verify the thermal response performance of MXene integrated into microneedle patches, we systematically tested its thermal response capability under different conditions. Experimental results show that the thermal response performance of the microneedle patches gradually increases with the increase of MXene concentration. In samples with different MXene concentrations, the microneedle patches can achieve a temperature increase of 0-5℃ under 808nm laser irradiation, and the temperature increase is positively correlated with the laser power, without obvious abrupt change. This indicates that MXene in the microneedle patches can stably respond to laser irradiation and has relatively linear thermal response characteristics. In addition, after five rounds of cyclic testing, the prepared microneedle patches exhibit excellent thermal stability during the thermal response process, maintaining a stable temperature response without significant performance degradation. This result further demonstrates the excellent performance and good thermal stability of MXene as a photothermal material in microneedle systems, indicating its potential for long service life and reusability in practical applications. Figure 4 ).

[0084] 1.5 Safety evaluation of microneedles

[0085] Recovery of microneedle insertion marks: Microneedle patches loaded with Rhodamine B were inserted into the skin of rats' backs. After removal, the insertion marks were observed at different times. It was found that the microneedle insertion marks almost completely disappeared within 2 hours, and there were no signs of inflammation such as redness and swelling. Figure 5 ).

[0086] To verify the safety of photothermal treatment at different temperatures, we investigated the effects of microneedle treatment for different durations at different temperatures. Considering patient patience and tolerability, a treatment time of less than 2 minutes was deemed appropriate. It was observed that no significant reaction was observed on the rat's back skin at 40 and 50°C, but as the temperature increased, obvious white or yellow edema appeared on the rat's back, indicating a burn reaction and inflammation. Based on this, we selected 50°C as the temperature for subsequent permeation enhancement experiments. Figure 6 ).

[0087] (2) In vitro drug diffusion promotion studies

[0088] To investigate the permeation-enhancing effect of photothermal stimulation, a selected microneedle patch (100ug 0.5w) was inserted into simulated skin gelatin and excised pig skin. After NIR excitation at 50°C for two minutes, it was observed that the diffusion of simulated drug pigments in the photothermally stimulated microneedle patch was more pronounced. Figure 7 ).

[0089] To further verify the permeation-enhancing effect of photothermal stimulation, the drug was injected into rats for observation, yielding similar results to those described above. It was clearly observed that NIR+ stimulation promoted drug diffusion. To quantitatively analyze this result, we simulated the transdermal diffusion of Lido in vitro using a Franz diffusion cell, finding that NIR stimulation significantly increased the transdermal diffusion rate of Lido. Furthermore, in vivo imaging revealed that photothermal stimulation accelerated the absorption of the loaded drug. Figure 8 ).

[0090] (3) In vivo experiments of photothermal microneedle patches for rapid surface anesthesia

[0091] 3.1 Changes in the mechanical withdrawal threshold of rats after different treatments: This study systematically evaluated the analgesic effects of different lidocaine delivery systems based on a rat plantar tomy model of postoperative pain. The mechanical withdrawal threshold (PWT) of each treatment group at different time points was detected using the von Frey filament method to clarify the onset and duration of analgesia. The results showed that the PWT value of rats in the postoperative model group (Surgery group) was significantly reduced, exhibiting significant mechanical pain sensitivity. Compared with traditional lidocaine cream (Lido / Cream) and ordinary microneedle patches (Lido@MNs), the lidocaine-loaded MXene photothermal microneedle patch (Lido / MXene@MNs) significantly increased the mechanical pain threshold within 5 minutes after administration, demonstrating a faster onset and stronger analgesic effect. At multiple time points including 5, 10, 20, and 30 minutes, the PWT of the Lido / MXene@MNs group was significantly higher than that of other groups (p<0.001), indicating that this photothermal microneedle system can achieve rapid drug penetration and analgesia in a short time, and reach a mechanical threshold close to that of normal rats within 30 minutes, which is significantly better than non-photothermal microneedle patches and commercially available lidocaine cream. Figure 9 ).

[0092] 3.2 Changes in the threshold of foot withdrawal response to thermal stimulation in rats after different treatments: The photothermal microneedle patch (Lido / MXene@MNs) of this invention exhibits rapid onset (within 5 minutes) and significantly prolonged foot withdrawal latency (PWL) analgesic effects in terms of thermal pain behavior, and the analgesic effect lasts for a longer period, still showing statistically significant differences at 60 minutes, demonstrating good potential for clinical translation. Figure 10 ).

[0093] Although the present invention has been disclosed above with reference to embodiments, it is not intended to limit the present invention. Any person skilled in the art can make various different choices and modifications without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention is defined by the claims and their equivalents.

Claims

1. A rapid surface anesthesia patch combining near-infrared photothermal effect and microneedle technology, characterized in that, The rapid surface anesthesia patch includes a backing layer and microneedles placed on the backing layer; the backing layer includes a photothermal material, a microneedle matrix material, an auxiliary molecular material, and a solvent; the microneedles include an active ingredient for anesthesia and a microneedle matrix material.

2. The rapid surface anesthesia patch according to claim 1, characterized in that, The photothermal material includes one or more of the following: MXene, polydopamine, iron oxide nanoparticles, black phosphorus, and two-dimensional transition metal sulfides. The microneedle matrix material includes one or more of the following: polyvinyl alcohol, hyaluronic acid or its sodium salt, polystyrene, acrylic resin, polycaprolactone, collagen, and polylactic acid; The auxiliary molecular material includes one or more of the following: sucrose, trehalose, and mannitol; The active ingredient used for anesthesia includes one or more of the following: lidocaine, tetracaine, and prilocaine; The solvent includes one or more of the following: ultrapure water, diethylene glycol dimethyl ether, dioxane, N,N-dimethylacetamide, and DMSO.

3. The rapid surface anesthesia patch according to claim 2, characterized in that, The photothermal material of the backing layer is MXene, the microneedle matrix material is polyvinyl alcohol, the auxiliary molecular material is sucrose, and the solvent is ultrapure water; the active ingredient for anesthesia of the microneedle body is lidocaine, and the microneedle matrix material is polyvinyl alcohol.

4. The rapid surface anesthesia patch according to claim 3, characterized in that, The mass ratio of polyvinyl alcohol, sucrose, and ultrapure water in the backing layer is (7-9):(5-7):(14-16); preferably 8:6:15; the concentration of MXene in the backing layer is 0-200 μg / mL; preferably 50-200 μg / mL; more preferably 100 μg / mL.

5. The rapid surface anesthesia patch according to claim 3, characterized in that, The mass ratio of lidocaine to polyvinyl alcohol in the microneedle body is 0 / 4-2 / 1, preferably 1 / 4-2 / 1, and more preferably 1 / 4-3 / 4; the concentration of polyvinyl alcohol in the microneedle body is 20%-30%, preferably 25%.

6. The rapid topical anesthesia patch according to any one of claims 1-5, characterized in that, The rapid surface anesthesia patch is a multi-needle array; The multi-needle array is an (8-12)×(8-12) square array; The distance between the tips of each microneedle in the rapid surface anesthesia patch is 450-550 μm; preferably 500 μm. The microneedle body is a cone or a polygonal pyramid; The height of the microneedle is 550-650 μm; preferably 600 μm. The microneedle has a base diameter of 300-400 μm; preferably 350 μm.

7. A method for preparing a rapid surface anesthesia patch according to any one of claims 1-5, characterized in that, The preparation method includes the following steps: (1) Preparation of needle solution: Lidocaine and polyvinyl alcohol are mixed and dissolved in a mass ratio of 0 / 4-2 / 1 to obtain needle solution; (2) Preparation of backing layer solution: Polyvinyl alcohol, sucrose and ultrapure water are mixed and dissolved in a mass ratio of (7-9):(5-7):(14-16), and MXene is added to obtain the backing layer solution. (3) Microneedle molding: The needle body solution obtained in step (1) and the backing layer solution obtained in step (2) are placed in the microneedle mold to obtain a rapid surface anesthesia patch.

8. The preparation method according to claim 7, characterized in that, In step (1), the polyvinyl alcohol is first dissolved in ultrapure water, and then lidocaine is added and mixed; wherein the concentration of the polyvinyl alcohol is 20%-30%, preferably 25%; the mass ratio of lidocaine to polyvinyl alcohol is 1 / 4-2 / 1, preferably 1 / 4-3 / 4. In step (2), the mass ratio of polyvinyl alcohol, sucrose and ultrapure water is 8:6:15; the concentration of MXene is 0-200 μg / mL, preferably 50-200 μg / mL, and more preferably 100 μg / mL.

9. The preparation method according to claim 7, characterized in that, In step (3), the needle solution is first placed in the microneedle mold under negative pressure to completely fill the needle part of the microneedle mold. The excess needle solution is then recovered, and negative pressure is applied again to fix the needle. Then, the backing layer solution is placed in the microneedle mold under negative pressure, dried, and demolded to obtain the rapid surface anesthesia patch. The negative pressure time is 15 to 30 minutes.

10. The use of the rapid surface anesthetic patch according to any one of claims 1-6 in the preparation of a medicament for local anesthesia, characterized in that, The local anesthesia includes surface anesthesia used in minor surgical procedures, cosmetic surgery, or pain management.

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