Hydroxyl-alpha-sanshool gel plaster, preparation method thereof and application of hydroxyl-alpha-sanshool gel plaster in preparation of medicine for treating peripheral neuropathic pain

Abstract

The invention relates to the technical field of biological medicines, in particular to a hydroxyl-alpha-sanshool gel plaster, a preparation method thereof and application of the hydroxyl-alpha-sanshool gel plaster in preparation of a medicine for treating peripheral neuropathic pain. The preparation method specifically comprises the following steps: (1) mixing hydroxyl-alpha-sanshool with hydroxypropyl-beta-cyclodextrin for reaction, and removing a solvent to obtain a reactant; (2) filtering a reactant, and freeze-drying the reactant to obtain a hydroxyl-alpha-sanshool cyclodextrin inclusion compound; and (3) preparing the hydroxyl-alpha-sanshool cyclodextrin inclusion compound into the hydroxyl-alpha-sanshool gel plaster. The invention aims to construct a hydroxypropyl-beta-cyclodextrin inclusion compound system through a molecular inclusion technology so as to improve the water solubility of HAS and increase the stability of HAS. The prepared gel plaster is used for local treatment of peripheral nerve pathological pain, and aims to avoid loss caused by a first-pass effect, improve patient discomfort caused by frequent administration and reduce side effects caused by systemic administration.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedicine, and in particular to a hydroxy-α-sanshool gel patch, a preparation method thereof, and application thereof in preparing a medicine for treating peripheral neuropathic pain. Background Art

[0002] Chronic pain may affect one-fifth of the world's population. It leads to a long-term decline in patients' body function and a significant reduction in their quality of life. Chronic pain is divided into seven major categories: chronic primary pain, chronic cancer-related pain, chronic postoperative and post-traumatic pain, chronic secondary musculoskeletal pain, chronic secondary visceral pain, chronic neuropathic pain, and chronic secondary headache or maxillofacial pain. Among them, neuropathic pain is the most stubborn chronic pain, with a prevalence of 6.9% to 10% in the general population. The International Association for the Study of Pain (IASP) defines neuropathic pain as "pain caused by damage to or disease of the somatic sensory nervous system." Depending on the location of the onset, it can be further subdivided into central neuropathic pain and peripheral neuropathic pain (pNP), with pNP being more common clinically. According to ICD-11, pNP includes five conditions: trigeminal neuralgia, peripheral nerve injury, painful neuropathy, postherpetic neuralgia, and painful radiculopathy.

[0003] The most common clinical diagnostic tool for neuropathic pain is the DN4 scale, which assesses the patient's pain status through 10 questions. Treatment can also be determined based on the patient's description of pain (on a scale of 0-10, with 0 indicating no pain and 10 indicating maximum pain). Medication is currently the mainstay of treatment for pneumothorax neuralgia (pNP), requiring a personalized approach tailored to the patient's specific clinical circumstances and the drug's mechanism of action. The calcium channel modulators gabapentin and pregabalin are first-line treatments for almost all forms of pneumothorax neuralgia, while the sodium channel blockers carbamazepine and oxcarbazepine are first-line treatments for trigeminal neuralgia. The tricyclic antidepressant amitriptyline and the local anesthetic lidocaine are first-line treatments for postherpetic neuralgia. However, most of these medications are associated with side effects such as sedation and dizziness, and analyses have shown that their effectiveness is declining as clinical pharmacology data accumulate. This situation has driven the development of novel drugs, such as sodium channel NaV1.7 and NaV1.8 inhibitors, P2XR antagonists, and NMDA antagonists.

[0004] Zanthoxylum bungeanum (Zanthoxylum bungeanum Maxim.) and Zanthoxylum schinifolium Sieb. et Zucc. Due to its pungent flavor, Zanthoxylum bungeanum (Zanthoxylum bungeanum Maxim.) is often used in cooking, particularly in Sichuan cuisine. Zanthoxylum bungeanum contains a variety of bioactive compounds, including alkaloids, coumarins, lignans, and flavonoids. Alkaloids, represented by sanshool, are responsible for the pepper's numbing flavor. The sanshool family includes hydroxy-α-sanshool (HAS), hydroxy-β-sanshool, and hydroxy-γ-sanshool, with HAS being the most abundant. HAS exhibits multiple pharmacological activities, including anti-inflammatory, antioxidant, and neuroprotective properties. Most importantly, HAS is the primary anesthetic component in Zanthoxylum bungeanum and is commonly used for oral anesthesia and toothache treatment. Studies have shown that HAS not only induces numbness by inhibiting the diaphanous KCNK channel but also exerts analgesic effects on sodium channels, with the most profound inhibitory effect on the Nav1.7 channel. Therefore, HAS may be a promising therapeutic agent for neuropathic pain. However, HAS has extremely low solubility in water and is easily degraded under oxygen, high temperature and ultraviolet irradiation. Therefore, the preparation of HAS in a suitable dosage form is the focus of research for those skilled in the art. Summary of the Invention

[0005] The purpose of this invention is to provide a solution for HAS, which has limited its clinical application due to its poor water solubility and stability. We aim to construct a hydroxypropyl-β-cyclodextrin inclusion complex system through molecular inclusion technology to improve the water solubility and increase its stability of HAS. In addition, we further developed and prepared a gel patch for the local treatment of peripheral neuropathic pain, aiming to circumvent the losses caused by the first-pass effect, improve patient discomfort caused by frequent dosing, and reduce the side effects of systemic administration.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0007] The present invention provides a method for preparing a hydroxy-α-sanshool gel plaster, comprising the following steps:

[0008] (1) mixing hydroxy-α-sanshool and hydroxypropyl-β-cyclodextrin for reaction, removing the solvent, and obtaining a reactant;

[0009] (2) filtering the reactant obtained in step (1) and freeze-drying the reactant to obtain a hydroxy-α-sanshool cyclodextrin inclusion complex;

[0010] (3) mixing the hydroxy-α-sanshool cyclodextrin inclusion complex obtained in step (2), acrylamide, chitosan quaternary ammonium salt and water, and then adding N,N'-methylenebisacrylamide and ammonium persulfate to the mixture, and allowing it to stand to obtain a hydroxy-α-sanshool gel patch.

[0011] Preferably, the molar ratio of hydroxy-α-sanshool to hydroxypropyl-β-cyclodextrin in step (1) is 1:3-5.

[0012] Preferably, the reaction in step (1) is stirred under a nitrogen atmosphere in a dark place.

[0013] Preferably, the hydroxy-α-sanshool in step (1) is a hydroxy-α-sanshool solution; and the hydroxy-α-sanshool solution uses anhydrous ethanol as a solvent.

[0014] Preferably, the hydroxypropyl-β-cyclodextrin in step (1) is a hydroxypropyl-β-cyclodextrin solution; the hydroxypropyl-β-cyclodextrin solution uses water as a solvent.

[0015] Preferably, the filtration in step (2) is performed using a 0.22 μm syringe filter; and the freeze-drying temperature is -75 to -85°C.

[0016] Preferably, in step (3), the added mass ratio of the N,N'-methylenebisacrylamide is 0.8 to 1.2‰ of acrylamide; and the added mass ratio of the ammonium persulfate is 4 to 6‰ of acrylamide.

[0017] Preferably, the standing temperature in step (3) is 55-65° C. and the standing time is 25-35 minutes.

[0018] The present invention also provides a hydroxy-α-sanshool gel plaster prepared by the preparation method.

[0019] The present invention also provides the use of the hydroxy-α-sanshool gel plaster in preparing a medicine for treating peripheral neuropathic pain.

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] Although HAS has long been used as an anesthetic in oral surgery, its clinical application has been significantly limited over the past few decades due to its physicochemical properties. Here, we used HAS for the treatment of peripheral neuropathic pain through a "drug repositioning" strategy based on known pharmacological mechanisms and target properties. We systematically optimized key physicochemical parameters such as water solubility and stability, and achieved local delivery by changing the route of administration. This research and development approach, centered on molecular modification and delivery technology optimization, not only validates the diverse pharmacological potential of HAS but also embodies the modernization of classic drugs.

[0022] This invention uses molecular inclusion technology to construct a hydroxypropyl-β-cyclodextrin inclusion complex system to improve the water solubility and stability of HAS. Furthermore, we have further developed and prepared a gel patch for the local treatment of peripheral neuropathic pain, aiming to circumvent the damage caused by the first-pass effect, improve patient discomfort caused by frequent dosing, and reduce the side effects of systemic administration. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are merely embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the provided drawings without paying any creative work.

[0024] Figure 1 This is the hydrogen spectrum of HAS / HP-β-CD inclusion complex.

[0025] Figure 2 This is the FTIR spectrum of HAS / HP-β-CD inclusion complex.

[0026] Figure 3 Schematic diagram of the preparation of hydrogel.

[0027] Figure 4 FTIR spectrum of PAM-QCS hydrogel.

[0028] Figure 5 This is the surface morphology of PAM-QCS hydrogel.

[0029] Figure 6 is the swelling property of PAM-QCS hydrogel.

[0030] Figure 7 This is the tensile stress-strain curve of PAM-QCS hydrogel.

[0031] Figure 8 Adhesion of PAM-QCS hydrogel on finger joints.

[0032] Figure 9 Cytotoxicity to L929 cells.

[0033] Figure 10 Cytotoxicity to RSC96 cells.

[0034] Figure 11 are PWT values ​​at different time points.

[0035] Figure 12 H&E staining was used to evaluate the biological safety of the sanshool gel patch (100×). DETAILED DESCRIPTION

[0036] The technical solutions provided by the present invention are described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0037] Example 1

[0038] 1. Preparation and characterization of HAS / HP-β-CD inclusion complex

[0039] An inclusion complex of HAS (hydroxy-α-sanshool) and HP-β-CD (hydroxypropyl-β-cyclodextrin) with a molar ratio of 1:4 was prepared.

[0040] First, weigh an appropriate amount of HAS and dissolve it in anhydrous ethanol to prepare a stock solution, place it in a -20℃ refrigerator, and use it up within one month. Accurately weigh HP-β-CD according to a certain molar ratio (HAS: HP-β-CD = 1:4). Dissolve HP-β-CD in 15mL deionized water. Drop the HAS ethanol solution into the HP-β-CD aqueous solution and mix it on a magnetic stirrer under nitrogen protection and light protection. Place the reacted sample in a rotary evaporator to remove ethanol, and filter the mixed solution using a 0.22μm syringe filter. Freeze-dry the filtered liquid at -80℃ to obtain HAS / HP-β-CD inclusion complex powder.

[0041] Field emission scanning electron microscopy (SEM) was used to observe and image the surface morphology of pure HP-β-CD, HAS / HP-β-CD inclusion complex, and HAS-HP-β-CD physical mixture (simply mixing HAS solution and HP-β-CD solution without other treatment). The samples were first treated with gold by sputter coating, and then the morphology was observed under SEM.

[0042] About 5 mg of HAS, HP-β-CD and HAS / HP-β-CD inclusion complex were dissolved in appropriate solvents and added to NMR tubes, and 1H NMR experiments were performed using a 400M NMR spectrometer (AVANCE NEO 400, Bruker, Germany).

[0043] The formation of intermolecular hydrogen bonds between HAS and HP-β-CD was studied by Fourier transform infrared spectroscopy (FTIR). Pure HAS and HAS / HP-β-CD inclusion complex (containing equal amounts of HAS) were crushed and mixed with potassium bromide and pressed into thin films. FT-IR (NICOLET 5700, Nicolet, USA) was then used to analyze the hydrogen bonds between HAS and HP-β-CD at 400-4000 cm -1 The sample is analyzed within the range, and the scanning speed is 1cm -1 / s.

[0044] An appropriate amount of HAS / HP-β-CD was dissolved in ethanol solution and filtered through a 0.22 μm filter after ultrasonication for 15 minutes. The filtered solution was diluted to a certain concentration and the inclusion rate (%) was measured by HPLC at a wavelength of 269 nm and calculated according to the following formula.

[0045]

[0046] Pure HAS and a HAS / HP-β-CD inclusion complex (containing 1 mg HAS) at a molar ratio of 1:4 were dissolved in 1 mL of pure water. The solution was stirred thoroughly on a shaker and then filtered through a 0.22 μm syringe filter to remove the undissolved drug. The HAS content in the sample was determined by HPLC according to the above method.

[0047] 2. Preparation and characterization of transdermal gel patch

[0048] Acrylamide (AM) and chitosan quaternary ammonium salt (QCS) in a 3:1 mass ratio were added to 3 volumes of ultrapure water. Air bubbles were removed by ultrasonication, and then 1‰ (by mass) of N,N'-methylenebisacrylamide (MBA) and 5‰ (by mass) of ammonium persulfate were added. The mixture was allowed to stand at 60°C for 0.5 h to prepare a polyacrylamide-chitosan quaternary ammonium hydrogel (PAM-QCS). The drug-loaded hydrogel was prepared similarly: the inclusion complex was dispersed after mixing acrylamide and chitosan quaternary ammonium salt in a 1:3 volume ratio. The PAM-QCS@HAS / HP-β-CD gel patch was prepared using the same method as above.

[0049] The prepared hydrogels were placed in phosphate-buffered saline (PBS, pH 7.4) at 37°C and weighed at 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 120, and 192 hours to plot swelling curves. The morphology of the PAM-QCS was observed and imaged using a scanning electron microscope (SEM). The AM, QCS, and PAM-QCS hydrogels were scanned and data collected using an FT-IR spectrophotometer. The rheological properties of the hydrogels were determined using a rheometer.

[0050] In addition, hydrogel extracts were prepared for subsequent experiments according to GB / T 16886.5-2017, "Biological Evaluation of Medical Devices - Part 5: In Vitro Cytotoxicity Tests." Nile Red / HP-β-CD inclusion complexes and PAM-QCS@Nile Red / HP-β-CD hydrogels were prepared using the same method described above for the HAS / HP-β-CD inclusion complex. After being immobilized with a special restraint device, equal amounts of Nile Red inclusion complex and hydrogel were topically applied to the backs of two groups of rats. At predetermined time points, rats were sacrificed, and the skin at the treated sites was harvested according to standard procedures. Fluorescence penetration depth was examined by fluorescence microscopy.

[0051] 3. Safety evaluation and analgesic activity study

[0052] (1) Cytotoxicity test

[0053] L929 mouse fibroblasts and RSC96 rat Schwann cells were cultured in a humidified environment of 37°C, 5% CO2, and 95% air using DMEM medium containing 10% fetal bovine serum and 1% double antibody, and the CCK-8 method was used to evaluate drug cytotoxicity. Cells growing in the logarithmic phase were seeded in a 96-well cell culture plate (100 μL per well, 3000 cells / well). When the cells grew to about 80%, the supernatant was discarded and 100 μL of different concentrations of HAS, HAS / HP-β-CD inclusion complex, and PAM-QCS hydrogel extract were added. The supernatant was discarded after culturing for 24 hours. Next, serum-free DMEM medium containing 10% CCK-8 was added to each well and cultured at 37°C for 30 minutes. The absorbance value was measured at 450 nm using a microplate reader, and the cell survival rate was calculated.

[0054] Cells in logarithmic phase growth were seeded onto 6-well cell culture plates. When the cells reached approximately 80% growth, the supernatant was discarded and 2 mL of HAS, HAS / HP-β-CD inclusion complex, and PAM-QCS hydrogel extract at varying concentrations were added. After 24 hours of incubation, the supernatant was discarded. A staining solution was prepared at a ratio of PBS:PI:AM = 1000:3:2, with 1 mL of dye added to each well. The plates were incubated at 37°C in the dark for 30 minutes, washed with PBS, and photographed under a fluorescence microscope.

[0055] (2) Analgesic activity studies

[0056] A rat sciatic nerve injury model was established. SNI rats were randomly divided into six groups: sham, SNI, SNI + HAS / HP-β-CD, SNI + PAM-QCS, SNI + PAM-QCS@HAS / HP-β-CD, and SNI + positive control group (n = 6 / group). In the sham group, the sciatic nerve and its branches were exposed as in the SNI procedure, but no further intervention was given. Like the SNI group, the sciatic nerve was treated with saline. The SNI + HAS / HP-β-CD group was treated with HAS / HP-β-CD inclusion complex in vitro, the SNI + PAM-QCS group was treated with a blank hydrogel, the SNI + PAM-QCS@HAS / HP-β-CD group was treated with PAM-QCS@HAS / HP-β-CD gel, and the SNI + positive control group was treated with lidocaine gel. Dosing was once daily for 14 days. The experiment began 7 days after the rats underwent acclimation training. Baseline PWT of each rat's hind paw was measured using a VonFery electronic analgesia before surgery. Seven days after modeling, the PWT of rats was measured to confirm the success of modeling and the drug was divided into groups for drug administration. The PWT of rats was measured on D1 (2 and 8 hours after drug administration), D3, D5, D7, D10, and D14 to evaluate the analgesic effect.

[0057] After the D14 data measurement, the rats were sacrificed after blood was collected and samples were taken from the liver, heart, spleen, lung, kidney, spinal cord, and skin. Systemic toxicity was analyzed by preparing HE sections of the heart, liver, spleen, lung, kidney, and skin.

[0058] Results and Analysis

[0059] 1. Preparation and characterization of HAS / HP-β-CD inclusion complex

[0060] The prepared HAS / HP-β-CD inclusion complex is in the form of a yellow powder. The formation of inclusion complexes of HAS and HP-β-CD was further confirmed by examining the chemical shift changes of HAS and HP-β-CD. For example, the peak at 5.31 ppm in pure HAS shifted to 5.44 ppm in the HAS / HP-β-CD inclusion complex, indicating that HAS had formed an intermolecular bond with HP-β-CD ( Figure 1 FTIR spectra of HAS, HP-β-CD, HAS / HP-β-CD inclusion complex and their physical mixtures are shown in Figure 2. Figure 2 The FTIR spectrum of HAS provides a large number of fingerprint absorption peaks, and the characteristic absorption peaks of its amide structure are at 1670 cm-1 (C=O stretching vibration) and 1548 cm-1. -1 (NH bending + CN stretching). For HAS / HP-β-CD inclusion complex, the absorption peak is at 1550cm -1 、1668cm -1The results show that the HAS content in HP-β-CD was weakened, indicating that HAS was contained in HP-β-CD and formed intermolecular hydrogen bonds with HP-β-CD. According to HPLC data, the encapsulation efficiency of the HAS / HP-β-CD inclusion complex with a molar ratio of 1:4 was 90.33±1.21%, and the drug loading was 3.61±0.05% (n=3). The solubility of pure HAS was 2.62±0.06μg / mL, and the solubility of the HAS / HP-β-CD inclusion complex with a molar ratio of 1:4 was about 1mg / mL (meaning that 1mg of the inclusion complex drug was completely dissolved in a volume of 1mL), which greatly improved the solubility of HAS.

[0061] 2. Preparation and characterization of transdermal gel patch

[0062] PAM-QCS hydrogel was prepared by a one-step solution polymerization method. The formation mechanism of the hydrogel is as follows Figure 3 As shown. PAM and QCS have similar polarity and both contain a large number of amino groups. QCS can form a semi-interpenetrating cross-linked network with the PAM network through physical entanglement without forming chemical bonds. Therefore, the infrared spectrum of PAM-QCS hydrogel shows standard PAM hydrogel characteristic peaks, such as Figure 4 The morphology of the obtained hydrogel observed by scanning electron microscopy (SEM) showed a porous structure with a pore size of approximately 10 μm ( Figure 5 ). PAM-QCS hydrogel exhibits strong water absorption capacity, with an equilibrium swelling ratio of approximately 1800% ( Figure 6 ). The internal structure of the hydrogel was analyzed by rheological measurements ( Figure 7 ), with the increase of angular frequency (ω), the storage modulus (G') and loss modulus (G") of the hydrogel remain unchanged, and G' is much higher than G", which has good mechanical properties. The adhesive hydrogel can adhere firmly to the wound. Figure 8 As shown, when the hydrogel is placed on the finger joint, the hydrogel does not slide with the change of joint angle, showing good adhesion.

[0063] 3. Safety evaluation and analgesic activity study

[0064] As a transdermal hydrogel patch, biosafety is a prerequisite for its application in analgesia. CCK-8 results showed that the cell viability of the hydrogel-treated samples was higher than 90%, and double staining of live / dead cells with calcein-PI showed that almost no dead cells were observed after treatment, indicating that HAS, HAS / HP-β-CD inclusion complex and PAM-QCS hydrogel have good biocompatibility ( Figure 9 and Figure 10 ).

[0065] In order to explore the analgesic effect of HAS on peripheral neuropathic pain, a SNI rat model was established, and a preliminary experiment was conducted using HAS / HP-β-CD inclusion compound. Compared with before modeling (pre), the PWT values ​​of each group decreased significantly on the 7th day (mo) after modeling, and continued throughout the entire experimental process until the end of the experiment, when the PWT value of the model control group remained stable at around 20g. Compared with the model control group, there was no significant difference in the PWT values ​​of the positive control group and the HAS / HP-β-CD inclusion compound group before modeling (pre) and after modeling (mo). After administration, the PWT value of the HAS / HP-β-CD inclusion compound group increased significantly, reflecting that HAS has a good analgesic effect ( Figure 11 ).

[0066] 4. Biosafety Experiment of Sanshool Gel Patch

[0067] By visually observing the skin condition of the rats at the drug administration site, it was found that no allergic or redness or swelling occurred on the skin of the rats in each group. To further clarify whether pathological changes occurred in the heart, liver, spleen, lung, kidney and skin tissues, samples were collected from the rats 2 weeks after administration and H&E sections were prepared for observation. Figure 12 As shown, the results showed that no obvious pathological changes occurred in the heart, liver, spleen, lung, kidney and skin tissues of each group, indicating that the inclusion compound and the hydrogel carrier have good biosafety.

[0068] The present invention prepares HAS and HP-β-CD into HAS / HP-β-CD inclusion complex, which greatly increases its water solubility (more than 350 times). The increase in water solubility increases the possibility of clinical application of HAS. Polyacrylamide (PAM) hydrogel is a typical hydrogel with good biocompatibility, high water retention capacity, adjustability and low synthetic properties. It has important research value in many fields such as drug delivery, biosensing and wound healing. Chitosan quaternary ammonium salt (QCS) is a water-soluble chitosan derivative with broad-spectrum antibacterial activity, biological and mucosal adhesion and biocompatibility. It can also enhance the permeability of epithelial tissue and is widely used in the preparation of films, nanoparticles and hydrogels. Therefore, we prepared PAM-QCS hydrogel with synergistic advantages. Peripheral neuropathic pain is a common chronic pain with various pathogenesis, but the symptoms are usually limited to local nerves. SNI is a classic model for studying chronic peripheral nerve pain. In this study, we used the PWT value test to determine the analgesic activity of the drug by local administration.

[0069] In summary, this study prepared a well-water-soluble HAS / HP-β-CD inclusion complex, and successfully developed a PAM-QCS@HAS / HP-β-CD transdermal gel patch with analgesic activity using the multifunctional PAM-QCS hydrogel with good adhesion and biocompatibility as a carrier.

[0070] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A method for preparing a hydroxy-α-sanshool gel plaster, characterized in that: The steps include: (1) mixing hydroxy-α-sanshool and hydroxypropyl-β-cyclodextrin for reaction, removing the solvent, and obtaining a reactant; (2) filtering the reactant obtained in step (1) and freeze-drying the reactant to obtain a hydroxy-α-sanshool cyclodextrin inclusion complex; (3) mixing the hydroxy-α-sanshool cyclodextrin inclusion complex obtained in step (2), acrylamide, chitosan quaternary ammonium salt and water, and then adding N,N'-methylenebisacrylamide and ammonium persulfate to the mixture, and allowing it to stand to obtain a hydroxy-α-sanshool gel patch.

2. The preparation method according to claim 1, characterized in that The molar ratio of the hydroxy-α-sanshool to the hydroxypropyl-β-cyclodextrin in step (1) is 1:3-5.

3. The preparation method according to claim 1, characterized in that Step (1) is stirred to react under a nitrogen atmosphere in a dark place.

4. The preparation method according to claim 1, characterized in that The hydroxy-α-sanshool in step (1) is a hydroxy-α-sanshool solution; and the hydroxy-α-sanshool solution uses anhydrous ethanol as a solvent.

5. The preparation method according to claim 1, characterized in that The hydroxypropyl-β-cyclodextrin in step (1) is a hydroxypropyl-β-cyclodextrin solution; the hydroxypropyl-β-cyclodextrin solution uses water as a solvent.

6. The preparation method according to claim 1, characterized in that The filtration in step (2) is performed using a 0.22 μm syringe filter; the freeze-drying temperature is -75 to -85°C.

7. The preparation method according to claim 1, characterized in that In step (3), the addition mass ratio of the N,N'-methylenebisacrylamide is 0.8 to 1.2‰ of acrylamide; the addition mass ratio of the ammonium persulfate is 4 to 6‰ of acrylamide.

8. The preparation method according to claim 1, characterized in that The standing temperature in step (3) is 55-65° C. and the standing time is 25-35 minutes.

9. The hydroxy-α-sanshool gel patch prepared by the preparation method according to any one of claims 1 to 8.

10. Use of the hydroxy-α-sanshool gel patch according to claim 9 in the preparation of a medicament for treating peripheral neuropathic pain.

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