A capsaicin electrode patch

Abstract

This invention discloses a capsaicin electrode pad, which is composed of, from top to bottom, an outer conductive backing layer, a middle absorbent gel patch, a middle insulating conductive backing layer, a capsaicin gel patch, and an anti-adhesive layer. The outer conductive backing layer and the middle insulating conductive backing layer are both films or sheets with conductive coatings. The middle absorbent gel patch, by weight, comprises: 3-10% of a first skeleton material, 10-18% of a humectant, 0.1-1% of a crosslinking agent, 1-5% of a cooling agent, and 66-85.9% of a solvent. The capsaicin gel patch, by weight, comprises: 0.1-5% capsaicin, 4.6-26% of a second skeleton material, 10-25% of a humectant, 0.1-1% of a crosslinking agent, and 43-85.2% of a solvent. The capsaicin electrode pad provided by this invention, through electroosmotic delivery, effectively inhibits pathological pain and simultaneously effectively adsorbs capsaicin residues on the skin.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, specifically to a capsaicin electrode sheet. Background Technology

[0002] Capsaicin is an alkaloid that does not cause drug dependence. 18 H 27 NO3 (trans-8-methyl-N-vanillyl-6-nonenamide) is a vanillamide alkaloid extracted from plants of the Capsicum genus. It has a pungent odor and is poorly soluble in water. Commercially available capsaicin mainly comes from two sources: one is synthesis through the reaction of vanillin with 7-methylene-5-en-1-carboxylic acid chloride, and the other is extraction and isolation from dried chili pepper fruits. Both have the same pharmacological activity. Clinically, capsaicin is mainly used for various superficial pain syndromes, such as postoperative neuromas and various painful neuropathy types—diabetic neuropathy and postherpetic neuralgia. Postherpetic neuralgia (PHN) is a persistent neuropathic pain, usually caused by improper or delayed treatment of herpes zoster (HZ). The pain is persistent or paroxysmal, described as electric shock-like or burning, and has a long course, often lasting more than one month.

[0003] The mechanism of action of capsaicin in treating various painful neuropathy is related to its ability to influence the release, synthesis, and storage of neuropeptide P on type C sensory neurons. Recent studies on the clinical application of capsaicin have also found that it plays a positive role in the treatment of cancer, obesity, and cardiovascular diseases. These effects are closely related to the activation of transient receptor potential vanilloid type 1 (TRPV1) receptors. Capsaicin is a potent TRPV1 agonist. Its mechanism of action involves stimulating the secretion of glucagon-like peptide-1 (GLP-1) in the intestine, improving blood glucose homeostasis; activating TRPV1 in hepatocytes, preventing hepatic steatosis and metabolic fatty liver; activating TRPV1 in vascular endothelial cells, promoting protein kinase A phosphorylation, increasing nitric oxide production, dilating blood vessels, and lowering blood pressure; activating TRPV1 in vascular smooth muscle cells, inhibiting foam cell formation, and reducing the formation of atherosclerotic plaques; and activating TRPV1 in cardiomyocytes, improving mitochondrial function, and antagonizing high-salt-induced myocardial hypertrophy.

[0004] Capsaicin belongs to Class II drugs in the Biopharmaceutics Classification System (BCS). It exhibits low solubility and high lipophilicity, a strong first-pass effect in the liver, and a short half-life (7.06 min in rats and 12.44 min in New Zealand rabbits). Furthermore, diabetic neuropathy and postherpetic neuralgia are both superficial conditions, making transdermal administration the primary route of delivery for capsaicin. Transdermal administration, which delivers drugs to a local area or within the body through the skin, avoids the first-pass effect in the enterohepatic system compared to conventional oral administration. This effectively reduces gastrointestinal side effects, maintains a constant blood concentration within the therapeutic window, avoids peak-and-trough phenomena caused by oral absorption, and reduces drug toxicity. It is also convenient and has high patient compliance. When the drug acts locally on a tissue, the local concentration is high and the systemic concentration is low, resulting in better efficacy and fewer side effects. However, the skin is the body's natural barrier, and most drugs cannot be directly absorbed through the skin, especially drugs with larger molecular weights and ionic properties. Furthermore, drugs need to be slowly absorbed through the skin with the help of stimulants, resulting in slow onset of action and less penetration, making it more difficult to achieve therapeutic effects.

[0005] Currently available capsaicin topical preparations in my country, such as creams and gels, have drawbacks such as short duration of action, uncertain dosage, poor transdermal absorption, the need for multiple applications per day, and easy staining of clothing. These low-dose capsaicin topical preparations mainly relieve local pain such as arthritis by promoting blood circulation through the warming effect caused by capsaicin.

[0006] In 2009, the United States approved the high-dose capsaicin transdermal patch (Qutenza) for marketing. Qutenza contains 8% capsaicin (640 μg / cm³). 2 Each patch contains a total of 179 mg / 280 cm 2Qutenza, a clinically prescribed medication for relieving neuropathic pain, is primarily used to treat neuropathic pain associated with postherpetic neuralgia (PHN) and diabetic peripheral neuropathy (DPN). It is listed in the United States Pharmacopeia 24th Edition (USP 24). The recommended dosage for PHN-related neuropathic pain is one application of four patches for 60 minutes at a time. For diabetic peripheral neuropathy-related neuropathic pain, the recommended dosage is one application of four patches to the foot for 30 minutes at a time. However, Qutenza is a high-dose medication that can be irritating to the skin, potentially causing local irritation. Patients may experience significant procedural pain and burning after use, and there are certain side effects. Pre-treatment with a local anesthetic is necessary to minimize discomfort associated with Qutenza application. After removing Qutenza, apply a cleansing gel generously to the treated area and leave it on for at least one minute. Wipe off the cleansing gel with a dry towel, then gently wash with mild soap and water and dry thoroughly.

[0007] Electroosmosis is a method of drug delivery in which ions or neutral molecules actively permeate biological barriers under the influence of an external electric field, and it is now widely used in transdermal drug delivery. The system consists of several parts, including a power source, electrodes, control circuitry, and electrode pads (containing a drug reservoir). Building upon the traditional passive transport of drugs, electroosmosis utilizes electroosmotic flow and electric field forces to shorten the time required for drug accumulation and layer-by-layer delivery within the skin. This allows for rapid drug delivery to subcutaneous tissues and into the bloodstream to produce therapeutic effects. It is particularly suitable for delivering large molecular weight drugs, ionic drugs, and small molecule peptides that cannot easily penetrate the skin's lipid bilayer. Summary of the Invention

[0008] In view of this, the present invention provides a capsaicin electrode sheet.

[0009] In a first aspect, the present invention provides a capsaicin electrode sheet, which is composed of, from top to bottom, an outer conductive backing layer, a middle absorbent gel patch, a middle insulating conductive backing layer, a capsaicin gel patch, and an anti-adhesive layer.

[0010] Wherein, the outer conductive backing layer and the middle insulating conductive backing layer are both films or sheets with conductive coatings.

[0011] The middle layer adsorbent gel patch comprises, by weight: 3-10% of the first skeleton material, 10-18% of the moisturizer, 0.1-1% of the crosslinking agent, 1-5% of the cooling agent, and 66-85.9% of the solvent.

[0012] The capsaicin gel patch comprises, by weight: 0.1-5% capsaicin, 4.6-26% secondary skeleton material, 10-25% humectant, 0.1-1% crosslinking agent, and 43-85.2% solvent.

[0013] A second aspect of this invention provides a method for preparing a capsaicin electrode sheet, the method comprising:

[0014] Preparation of the middle layer adsorption gel patch: Weigh the first skeleton material, cooling agent and crosslinking agent in the prescription amount and dissolve them in the moisturizer. Add solvent to fully swell, centrifuge to remove air bubbles, coat it on the conductive backing film, and dry it so that the open side of the gel surface is combined with the middle layer isolation conductive backing film and the middle layer isolation conductive backing film respectively, to obtain a middle layer adsorption gel patch that is sealed on both sides by the conductive backing layer.

[0015] Preparation of capsaicin gel patch: Weigh the prescribed amount of moisturizer, crosslinking agent and second skeleton material, dissolve them in solvent and mix evenly, then add the prescribed amount of capsaicin, stir thoroughly to dissolve and swell, centrifuge to remove air bubbles, coat it on the anti-adhesive layer, and dry it to obtain capsaicin gel patch.

[0016] The capsaicin electrode sheet is obtained by combining the medicated adhesive side of the dried capsaicin gel patch with the conductive backing film of the middle layer adsorption gel patch.

[0017] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0018] (1) The capsaicin electrode pad provided by the present invention is composed of, from top to bottom, an outer conductive backing layer, a middle absorbent gel patch, a middle insulating conductive backing layer, a capsaicin gel patch, and an anti-adhesive layer, wherein the capsaicin gel patch contains 0.1-5% capsaicin. Driven by an external electric field, the drug rapidly enters the skin, achieving the therapeutic effect achievable with a capsaicin dosage of 2%-5%, while requiring less time. Furthermore, it exhibits good therapeutic effects on arthritis and joint pain at a lower dosage of 0.1%-3%. Simultaneously, no prior anesthetic is required.

[0019] (2) During drug delivery, the capsaicin electrode pads can penetrate the skin more quickly than ordinary gels with the aid of electroosmotic infusion. After a period of drug administration, the electrode pads are removed from the affected area, and the middle insulating conductive backing layer and the capsaicin gel patch are peeled off together. The middle adsorption gel patch is then applied to the affected skin. Driven by the electric field, the cooling agent in the gel patch quickly enters the subcutaneous tissue, providing rapid relief from the burning sensation and temporary pain allergy caused by capsaicin. At the same time, the gel has an adsorption effect on capsaicin remaining on the skin surface. After use, the middle adsorption gel patch is peeled off, removing the capsaicin remaining on the skin surface. This invention improves the transdermal absorption efficiency of drugs while reducing drug side effects and improving comfort. Attached Figure Description

[0020] To more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0021] Figure 1 This is a flowchart illustrating the preparation process of capsaicin electrode sheets.

[0022] Figure 2 This is a schematic diagram of the drug delivery method for capsaicin electrode pads;

[0023] Figure 3 This is a graph showing the cumulative drug penetration time in vitro through skin compared to the examples and commercially available formulations.

[0024] Figure 4 Cumulative permeation-time curves for different current intensities;

[0025] Figure 5 A graph showing the cumulative skin penetration time of different drug concentrations;

[0026] Figure 6 Images of rat skin tissue sections before and after administration of capsaicin electrode pads. Detailed Implementation

[0027] The following embodiments further illustrate the present invention, but these embodiments are merely illustrative and not intended to limit the invention. Therefore, any simple modifications to the present invention based on the method described herein are within the scope of protection of the present invention. The present invention will be described in detail below with reference to the accompanying drawings and embodiments, making its objectives and effects more apparent.

[0028] This invention provides a capsaicin electrode sheet, characterized in that the capsaicin electrode sheet is composed of, from top to bottom, an outer conductive backing layer, a middle absorbent gel patch, a middle insulating conductive backing layer, a capsaicin gel patch, and an anti-adhesive layer.

[0029] Wherein, the outer conductive backing layer and the middle insulating conductive backing layer are both films or sheets with conductive coatings.

[0030] The middle layer adsorbent gel patch comprises, by weight: 3-10% of the first skeleton material, 10-18% of the moisturizer, 0.1-1% of the crosslinking agent, 1-5% of the cooling agent, and 66-85.9% of the solvent.

[0031] The capsaicin gel patch comprises, by weight: 0.1-5% capsaicin, 4.6-26% secondary skeleton material, 10-25% humectant, 0.1-1% crosslinking agent, and 43-85.2% solvent.

[0032] It should be noted that capsaicin is a neutral molecule, and its main permeation-enhancing mechanism is electroosmosis and current-induced changes in the structure of the biological barrier. Electroosmosis refers to the directional movement of solvent caused by the electromigration of ions across the membrane under an applied electric field, i.e., electroosmotic flow. Electroosmotic flow plays a dominant role in the transport of neutral molecules. Current-induced changes in the structure of the biological barrier refer to the reduction of the ordered arrangement of intercellular lipids in the stratum corneum by the action of the current.

[0033] Furthermore, the drug delivery process of the capsaicin electrode pad includes:

[0034] Remove the anti-adhesive layer and apply the capsaicin gel patch to the affected area. Adjust the current intensity of the electroosmosis device to 0.1~0.5mA / cm. 2 ;

[0035] 10-30 minutes after drug administration, remove the electrode pads from the affected area. Then, peel off the middle insulating conductive backing layer along with the capsaicin gel patch. Next, apply the middle absorbent gel patch to the affected skin, adjusting the electroosmotic current intensity to 0.1-0.5 mA / cm². 2 Remove the electrode after at least 30 minutes.

[0036] It should be noted that this invention, by adjusting the current intensity of electroosmotic induction, can achieve precise control of the drug delivery rate, reduce drug side effects in patients, and improve the safety of capsaicin electrode patches. Simultaneously, during drug delivery, the capsaicin electrode patches, aided by electroosmotic induction, can penetrate the skin more quickly than ordinary gels. After a period of drug administration, the electrode patch is removed from the affected area, and the middle insulating conductive backing layer and capsaicin gel patch are peeled off together. The middle absorbent gel patch is then applied to the affected skin. Driven by the electric field, the cooling agent in the gel patch quickly penetrates the subcutaneous tissue, rapidly alleviating the burning sensation and temporary pain allergy caused by capsaicin. Simultaneously, the gel has an adsorption effect on capsaicin residue on the skin surface; removing the middle absorbent gel patch after use removes any remaining capsaicin from the skin surface. This invention improves the transdermal absorption efficiency of drugs while reducing side effects and increasing comfort.

[0037] Furthermore, the first skeleton material in the middle layer adsorbent gel patch is selected from one or two of hydroxypropyl methylcellulose, carbomer, polyvinyl alcohol 350, and sodium alginate, mixed in any proportion.

[0038] Furthermore, the second skeleton material in the capsaicin gel patch includes a first component, a second component, and a third component: wherein the first component is sodium polyacrylate, the second component is gelatin, and the mass ratio of sodium polyacrylate to gelatin is 10:1-5:1; the third component is one of polyvinylpyrrolidone K90, ethyl cellulose, and polyvinyl alcohol 350; the mass ratio of the third component to the second component is 1:2.

[0039] Furthermore, the solvents in the middle layer adsorption gel patch and the capsaicin gel patch are both a mixture of ethanol and ultrapure water in a mass ratio of 2:5 to 1:4.

[0040] Furthermore, the moisturizers in the middle layer adsorbent gel patch and the capsaicin gel patch are both made of one or two of 1,2-propanediol and glycerin, mixed in any proportion.

[0041] Furthermore, the crosslinking agent in the middle layer adsorbent gel patch and the capsaicin gel patch is selected from aluminum hydroxyl and aluminum glycinate.

[0042] Furthermore, the capsaicin concentration in the capsaicin gel patch is 2-5%; the capsaicin is selected from one or more of capsaicin, dihydrocapsaicin, nordihydrocapsaicin, homodihydrocapsaicin, or homocapsaicin mixed in any proportion.

[0043] Furthermore, the cooling agent in the middle layer adsorbent gel patch is selected from one or two of menthol, menthol, and borneol, mixed in any proportion.

[0044] Furthermore, the anti-stick layer is a polyester film coated with dimethyl silicone oil.

[0045] Furthermore, the conductive backing film is a stretchable conductive film made by spraying carbon nanotubes (CNTs) and mechanically exfoliated graphene (MLG) onto a polydimethylsiloxane (PDMS) film.

[0046] This invention evaluates the feasibility and safety of the capsaicin electrode pad for transdermal drug penetration, therapeutic effect, and other aspects by studying its conductivity, adhesion, formability, in vitro skin penetration, pharmacokinetics, pharmacodynamics, and irritation / allergic reactions. The invention also provides a flowchart of the manufacturing process for the capsaicin electrode pad. Figure 1 It provides a method for administering capsaicin electrode tablets, such as... Figure 2 .

[0047] Example 1

[0048] This invention provides a blank gel formulation with good conductivity and its preparation method. Its purpose is to provide a blank electrode corresponding to the capsaicin electrode for energizing. It is a universal blank gel for all embodiments. The specific process is as follows: Weigh 3.5% polyvinylpyrrolidone, 10% glycerol, 0.12% ethylparaben, 0.08% triethanolamine, and 86.3% pH 6.2 citrate buffer according to the following weight ratio. Dissolve glycerol and ethylparaben in the citrate buffer and mix thoroughly. Then add polyvinylpyrrolidone and disperse evenly. Adjust the pH to 5.2 with triethanolamine. Centrifuge at 2000 rpm for 30 min to remove air bubbles to obtain the blank gel.

[0049] Example 2

[0050] Example 2 of this invention provides a method for preparing a middle-layer adsorption gel patch and a capsaicin gel patch, the specific process of which is as follows:

[0051] (1) Preparation of the middle layer adsorption gel patch: Weigh 0.15 g of the skeleton material hydroxypropyl methylcellulose, 0.15 g of carbomer, 0.1 g of the cooling agent menthol, and 0.01 g of the crosslinking agent aluminum hydroxyl, dissolve them in 1 g of glycerol, add 1.96 g of ethanol and 6.63 g of ultrapure water to swell for 24 h, and finally centrifuge at 2000~6000 rpm for 5~30 min to remove air bubbles, coat it on the conductive backing film, dry it at 50℃ for 4 hours, and combine the open side with the middle layer isolation conductive backing film to obtain a middle layer adsorption gel patch that is sealed on both sides by the conductive backing layer.

[0052] (2) Preparation of capsaicin gel patch: Weigh 2.39 g of ethanol and 6.13 g of ultrapure water, weigh 0.4 g of sodium polyacrylate, 0.04 g of gelatin, 0.02 g of polyvinyl alcohol-350, 1 g of glycerin moisturizer, and 0.01 g of aluminum hydroxyl crosslinking agent according to the prescription, dissolve them in the mixed solvent of ethanol and ultrapure water and mix evenly. Further dissolve 0.01 g of capsaicin according to the prescription in the above mixed solvent and swell for 24 h. Finally, centrifuge at 2000~6000 rpm for 5~30 min to remove air bubbles, coat it on the anti-adhesive layer, and dry it at 50℃ for 4 h to obtain capsaicin gel patch.

[0053] (3) The coated and dried capsaicin gel patch is combined with the middle conductive backing film of the middle adsorption gel patch to obtain capsaicin electrode sheet.

[0054] Comparative Example 2-1

[0055] The preparation process of Comparative Example 2-1 is the same as that of Example 2. When the proportion of capsaicin gel patch as skeleton material is less than 4.6%, the preparation formula and process are as follows:

[0056] (1) Preparation of the middle layer adsorption gel patch: Weigh 0.15 g of the skeleton material hydroxypropyl methylcellulose, 0.15 g of carbomer, 0.1 g of the cooling agent menthol, and 0.01 g of the crosslinking agent aluminum hydroxyl, dissolve them in 1 g of glycerol, add 1.96 g of ethanol and 6.63 g of ultrapure water to swell for 24 h, and finally centrifuge at 2000~6000 rpm for 5~30 min to remove air bubbles, coat it on the conductive backing film, dry it at 50℃ for 4 hours, and combine the open side with the middle layer isolation conductive backing film to obtain a middle layer adsorption gel patch that is sealed on both sides by the conductive backing layer.

[0057] (2) Preparation of capsaicin gel patch: Weigh 2.36 g of ethanol and 6.39 g of ultrapure water, weigh 0.2 g of sodium polyacrylate, 0.02 g of gelatin, 0.01 g of polyvinyl alcohol-350, 1 g of glycerin moisturizer, and 0.01 g of aluminum hydroxyl crosslinking agent according to the prescription, dissolve them in the mixed solvent of ethanol and ultrapure water and mix evenly. Further dissolve 0.01 g of capsaicin according to the prescription in the above mixed solvent and swell for 24 h. Finally, centrifuge at 2000~6000 rpm for 5~30 min to remove air bubbles, coat it on the anti-adhesive layer, and dry it at 50℃ for 4 h to obtain capsaicin gel patch.

[0058] (3) The coated and dried capsaicin gel patch is combined with the middle conductive backing film of the middle adsorption gel patch to obtain capsaicin electrode sheet.

[0059] Comparative Example 2-2

[0060] The preparation process for Comparative Example 2-2 is the same as that for Example 2. When the crosslinking agent content of the capsaicin gel patch is less than 0.1%, the preparation formula and process are as follows:

[0061] (1) Preparation of the middle layer adsorption gel patch: Weigh 0.15 g of the skeleton material hydroxypropyl methylcellulose, 0.15 g of carbomer, 0.1 g of the cooling agent menthol, and 0.01 g of the crosslinking agent aluminum hydroxyl, dissolve them in 1 g of glycerol, add 1.96 g of ethanol and 6.63 g of ultrapure water to swell for 24 h, and finally centrifuge at 2000~6000 rpm for 5~30 min to remove air bubbles, coat it on the conductive backing film, dry it at 50℃ for 4 hours, and combine the open side with the middle layer isolation conductive backing film to obtain a middle layer adsorption gel patch that is sealed on both sides by the conductive backing layer.

[0062] (2) Preparation of capsaicin gel patch: Weigh 2.32 g of ethanol and 6.205 g of ultrapure water, weigh 0.4 g of sodium polyacrylate, 0.04 g of gelatin, 0.02 g of polyvinyl alcohol-350, 1 g of glycerin moisturizer, and 0.005 g of aluminum hydroxyl crosslinking agent according to the prescription, dissolve them in the mixed solvent of ethanol and ultrapure water and mix evenly. Further dissolve 0.01 g of capsaicin according to the prescription in the above mixed solvent and swell for 24 h. Finally, centrifuge at 2000~6000 rpm for 5~30 min to remove air bubbles, coat it on the anti-adhesive layer, and dry it at 50℃ for 4 h to obtain capsaicin gel patch.

[0063] (3) The coated and dried capsaicin gel patch is combined with the middle conductive backing film of the middle adsorption gel patch to obtain capsaicin electrode sheet.

[0064] Comparative Examples 2-3

[0065] The preparation process for Comparative Examples 2-3 is the same as that for Example 2. When the proportion of capsaicin gel patch as a moisturizer is less than 10%, the preparation formula and process are as follows:

[0066] (1) Preparation of the middle layer adsorption gel patch: Weigh 0.15 g of the skeleton material hydroxypropyl methylcellulose, 0.15 g of carbomer, 0.1 g of the cooling agent menthol, and 0.01 g of the crosslinking agent aluminum hydroxyl, dissolve them in 1 g of glycerol, add 1.96 g of ethanol and 6.63 g of ultrapure water to swell for 24 h, and finally centrifuge at 2000~6000 rpm for 5~30 min to remove air bubbles, coat it on the conductive backing film, dry it at 50℃ for 4 hours, and combine the open side with the middle layer isolation conductive backing film to obtain a middle layer adsorption gel patch that is sealed on both sides by the conductive backing layer.

[0067] (2) Preparation of capsaicin gel patch: Weigh 2.42 g of ethanol and 6.60 g of ultrapure water, weigh 0.4 g of sodium polyacrylate, 0.04 g of gelatin, 0.02 g of polyvinyl alcohol-350, 0.5 g of glycerin humectant and 0.01 g of aluminum hydroxyl crosslinking agent, dissolve them in the mixed solvent of ethanol and ultrapure water and mix evenly. Further dissolve 0.01 g of capsaicin in the above mixed solvent and swell for 24 h. Finally, centrifuge at 2000~6000 rpm for 5~30 min to remove air bubbles, coat it on the anti-adhesive layer, and dry it at 50℃ for 4 h to obtain capsaicin gel patch.

[0068] (3) The coated and dried capsaicin gel patch is combined with the middle conductive backing film of the middle adsorption gel patch to obtain capsaicin electrode sheet.

[0069] Example 3

[0070] Example 3 of this invention provides a method for preparing a middle-layer adsorption gel patch and a capsaicin gel patch, the specific process of which is as follows:

[0071] (1) Preparation of the middle layer adsorption gel patch: Weigh 0.5 g of the skeleton material hydroxypropyl methylcellulose, 0.5 g of polyvinyl alcohol-350, 0.5 g of the cooling agent camphor, and 0.1 g of the crosslinking agent aluminum glycinate, dissolve them in 0.9 g of glycerol and 0.9 g of 1,2-propanediol, add 1.8 g of ethanol and 4.8 g of ultrapure water to swell for 24 h, and finally centrifuge at 2000~6000 rpm for 5~30 min to remove air bubbles, coat it on the conductive backing film, dry it at 50℃ for 4 hours, and combine the open side with the middle layer isolation conductive backing film to obtain a middle layer adsorption gel patch that is sealed on both sides by the conductive backing layer.

[0072] (2) Preparation of capsaicin gel patch: Weigh 1.2 g of ethanol and 3.1 g of ultrapure water, weigh 2 g of sodium polyacrylate, 0.4 g of gelatin, 0.2 g of polyvinyl alcohol-350, 1.25 g of glycerin, 1.25 g of 1,2-propanediol, and 0.1 g of aluminum glycinate as the crosslinking agent according to the prescription, dissolve them in the mixed solvent of ethanol and ultrapure water and mix evenly. Further dissolve 0.5 g of capsaicin according to the prescription in the above mixed solvent and swell for 24 h. Finally, centrifuge at 2000~6000 rpm for 5~30 min to remove air bubbles, coat it on the anti-adhesive layer, and dry it at 50℃ for 4 h to obtain capsaicin gel patch.

[0073] (3) The coated and dried capsaicin gel patch is combined with the middle conductive backing film of the middle adsorption gel patch to obtain capsaicin electrode sheet.

[0074] Comparative Example 3-1

[0075] Comparative Example 3-1 was prepared using the same process as Example 3, with the following formulation when the proportion of the skeleton material in the capsaicin gel patch was 28.5%:

[0076] (1) Preparation of the middle layer adsorption gel patch: Weigh 0.5 g of the skeleton material hydroxypropyl methylcellulose, 0.5 g of polyvinyl alcohol-350, 0.5 g of the cooling agent camphor, and 0.1 g of the crosslinking agent aluminum glycinate, dissolve them in 0.9 g of glycerol and 0.9 g of 1,2-propanediol, add 1.8 g of ethanol and 4.8 g of ultrapure water to swell for 24 h, and finally centrifuge at 2000~6000 rpm for 5~30 min to remove air bubbles, coat it on the conductive backing film, dry it at 50℃ for 3 hours, and combine the open side with the middle layer isolation conductive backing film to obtain a middle layer adsorption gel patch that is sealed on both sides by the conductive backing layer.

[0077] (2) Preparation of capsaicin gel patch: Weigh 1.2 g of ethanol and 2.45 g of ultrapure water, weigh 2.5 g of sodium polyacrylate, 0.5 g of gelatin, 0.25 g of polyvinyl alcohol-350, 1.25 g of glycerin, 1.25 g of 1,2-propanediol, and 0.1 g of aluminum glycinate as crosslinking agent according to the prescription, dissolve them in a mixed solvent of ethanol and ultrapure water and mix evenly. Further dissolve 0.5 g of capsaicin according to the prescription in the above mixed solvent and swell for 24 h. Finally, centrifuge at 2000~6000 rpm for 5~30 min to remove air bubbles, coat it on the anti-adhesive layer, and dry it at 50℃ for 3 h to obtain capsaicin gel patch.

[0078] (3) The coated and dried capsaicin gel patch is combined with the middle conductive backing film of the middle adsorption gel patch to obtain capsaicin electrode sheet.

[0079] Comparative Example 3-2

[0080] Comparative Example 3-2 was prepared using the same process as Example 3, with the following formulation when the cross-linking agent in the capsaicin gel patch accounted for 2% of the total content:

[0081] (1) Preparation of the middle layer adsorption gel patch: Weigh 0.5 g of the skeleton material hydroxypropyl methylcellulose, 0.5 g of polyvinyl alcohol-350, 0.5 g of the cooling agent camphor, and 0.1 g of the crosslinking agent aluminum glycinate, dissolve them in 0.9 g of glycerol and 0.9 g of 1,2-propanediol, add 1.8 g of ethanol and 4.8 g of ultrapure water to swell for 24 h, and finally centrifuge at 2000~6000 rpm for 5~30 min to remove air bubbles, coat it on the conductive backing film, dry it at 50℃ for 3 hours, and combine the open side with the middle layer isolation conductive backing film to obtain a middle layer adsorption gel patch that is sealed on both sides by the conductive backing layer.

[0082] (2) Preparation of capsaicin gel patch: Weigh 1.2g of ethanol and 3.0g of ultrapure water; weigh the prescribed amount of skeleton material sodium polyacrylate 2g, gelatin 0.4g, polyvinyl alcohol-350 0.2g, moisturizing agent glycerin 1.25g, 1,2-propanediol 1.25g, crosslinking agent aluminum glycinate 0.2g, dissolve them in the mixed solvent of ethanol and ultrapure water and mix evenly. Further dissolve the prescribed amount of capsaicin 0.5g in the above mixed solvent and swell for 24h. Finally, centrifuge at 2000~6000 rpm for 5~30min to remove air bubbles, coat it on the anti-adhesive layer, and dry it at 50℃ for 3h to obtain capsaicin gel patch.

[0083] (3) The coated and dried capsaicin gel patch is combined with the middle conductive backing film of the middle adsorption gel patch to obtain capsaicin electrode sheet.

[0084] Comparative Example 3-3

[0085] Comparative Example 3-3 was prepared using the same process as Example 3, with the following formulation when the capsaicin gel patch contained 28% moisturizer:

[0086] (1) Preparation of the middle layer adsorption gel patch: Weigh 0.5 g of the skeleton material hydroxypropyl methylcellulose, 0.5 g of polyvinyl alcohol-350, 0.5 g of the cooling agent camphor, and 0.1 g of the crosslinking agent aluminum glycinate, dissolve them in 0.9 g of glycerol and 0.9 g of 1,2-propanediol, add 1.8 g of ethanol and 4.8 g of ultrapure water to swell for 24 h, and finally centrifuge at 2000~6000 rpm for 5~30 min to remove air bubbles, coat it on the conductive backing film, dry it at 50℃ for 3 hours, and combine the open side with the middle layer isolation conductive backing film to obtain a middle layer adsorption gel patch that is sealed on both sides by the conductive backing layer.

[0087] (2) Preparation of capsaicin gel patch: Weigh 1.2g of ethanol and 2.9g of ultrapure water, weigh 2g of sodium polyacrylate, 0.2g of gelatin, 0.1g of polyvinyl alcohol-350, 1.5g of glycerin (moisturizing agent), 1.5g of 1,2-propanediol, and 0.1g of aluminum glycinate (crosslinking agent) of the prescribed amount of skeleton material, dissolve them in the mixed solvent of ethanol and ultrapure water and mix evenly. Further dissolve 0.5g of capsaicin (prescribed amount) in the above mixed solvent and swell for 24 h. Finally, centrifuge at 2000~6000 rpm for 5~30 min to remove air bubbles, coat it on the anti-adhesive layer, and dry it at 50℃ for 3 h to obtain capsaicin gel patch.

[0088] (3) The coated and dried capsaicin gel patch is combined with the middle conductive backing film of the middle adsorption gel patch to obtain capsaicin electrode sheet.

[0089] Example 4

[0090] Example 4 provides a method for preparing a middle-layer adsorption gel patch and a capsaicin gel patch, the specific process of which is as follows:

[0091] (1) Preparation of the middle layer adsorption gel patch: Weigh 0.5 g of the skeleton material sodium alginate, 0.1 g of the cooling agent menthol, and 0.1 g of the cross-linking agent aluminum glycinate, dissolve them in 1.4 g of glycerol, add 2.1 g of ethanol and 5.8 g of ultrapure water to swell for 24 h, and finally centrifuge at 2000~6000 rpm for 5~30 min to remove air bubbles, coat it on the conductive backing film, dry it at 50℃ for 4 hours, and combine the open side with the middle layer isolation conductive backing film to obtain a middle layer adsorption gel patch that is sealed on both sides by the conductive backing layer.

[0092] (2) Preparation of capsaicin gel patch: Weigh 1.75 g of ethanol and 4.75 g of ultrapure water, weigh 1 g of sodium polyacrylate, 0.1 g of gelatin, 0.05 g of polyvinyl alcohol-350, 1 g of glycerin, 1 g of 1,2-propanediol, and 0.05 g of aluminum hydroxyl crosslinking agent, dissolve them in a mixed solvent of ethanol and ultrapure water and mix evenly. Further dissolve 0.3 g of capsaicin in the above mixed solvent and swell for 24 h. Finally, centrifuge at 2000~6000 rpm for 5~30 min to remove air bubbles, coat it on the anti-adhesive layer, and dry it at 50℃ for 4 h to obtain capsaicin gel patch.

[0093] (3) The coated and dried capsaicin gel patch is combined with the middle conductive backing film of the middle adsorption gel patch to obtain capsaicin electrode sheet.

[0094] Comparative Example 4-1

[0095] The difference between Comparative Example 4-1 and Example 4 is that the middle-layer adsorption gel patch and the capsaicin gel patch are prepared separately and not combined into a multilayer structure. They are administered separately during application. The preparation formula and process are as follows:

[0096] (1) Preparation of the middle layer adsorption gel patch: Weigh 0.5 g of the skeleton material sodium alginate, 0.1 g of the cooling agent menthol, and 0.1 g of the cross-linking agent aluminum glycinate, dissolve them in 1.4 g of glycerol, add 2.1 g of ethanol and 5.8 g of ultrapure water to swell for 24 h, and finally centrifuge at 2000~6000 rpm for 5~30 min to remove air bubbles, coat it on the conductive backing film, dry it at 50℃ for 4 hours, and then combine the open surface with the anti-adhesive layer for later use.

[0097] (2) Preparation of capsaicin gel patch: Weigh 1.75 g of ethanol and 4.75 g of ultrapure water, weigh 1 g of sodium polyacrylate, 0.1 g of gelatin, 0.05 g of polyvinyl alcohol-350, 1 g of glycerin (moisturizer), 1 g of 1,2-propanediol, and 0.05 g of aluminum hydroxyl crosslinking agent (crosslinking agent) in the mixed solvent of ethanol and ultrapure water and mix evenly. Further dissolve 0.3 g of capsaicin (prescription amount) in the above mixed solvent and swell for 24 h. Finally, centrifuge at 2000~6000 rpm for 5~30 min to remove air bubbles, coat it on the bottom conductive backing film, dry it at 50℃ for 4 hours, and then combine the open surface with the anti-adhesive layer to obtain capsaicin gel patch.

[0098] Administration method: Remove the anti-adhesive layer, apply the capsaicin gel patch to the affected area, and adjust the electroosmotic current intensity to 0.1~0.5 mA / cm². 2Thirty minutes after drug administration, the capsaicin gel patch was removed, and then a middle-layer absorbent gel patch with the anti-adhesive layer removed was applied to the same site. The electroosmotic current intensity was adjusted to 0.1~0.5 mA / cm. 2 Remove the patch after 30 minutes.

[0099] Comparative Example 4-2

[0100] The difference between Comparative Example 4-2 and Example 4 is that there is no conductive backing film between the middle layer adsorption gel patch and the capsaicin gel patch in the preparation process. The preparation formula and process are as follows:

[0101] (1) Preparation of the middle layer adsorption gel patch: Weigh 0.5 g of the skeleton material sodium alginate, 0.1 g of the cooling agent menthol, and 0.1 g of the crosslinking agent aluminum glycinate, dissolve them in 1.4 g of glycerol, add 2.1 g of ethanol and 5.8 g of ultrapure water to swell for 24 h, and finally centrifuge at 2000~6000 rpm for 5~30 min to remove air bubbles, coat it on the conductive backing film, and dry it at 50℃ for 4 hours before composite.

[0102] (2) Preparation of capsaicin gel patch: Weigh 1.75 g of ethanol and 4.75 g of ultrapure water, weigh 1 g of sodium polyacrylate, 0.1 g of gelatin, 0.05 g of polyvinyl alcohol-350, 1 g of glycerin, 1 g of 1,2-propanediol, and 0.05 g of aluminum hydroxyl crosslinking agent, dissolve them in a mixed solvent of ethanol and ultrapure water and mix evenly. Further dissolve 0.3 g of capsaicin in the above mixed solvent and swell for 24 h. Finally, centrifuge at 2000~6000 rpm for 5~30 min to remove air bubbles, coat it on the anti-adhesive layer, and dry it at 50℃ for 4 h to obtain capsaicin gel patch.

[0103] (3) The capsaicin gel patch surface coated and dried is combined with the open surface of the middle layer adsorption gel patch to obtain capsaicin electrode sheet.

[0104] Example 5

[0105] Example 5 provides a method for preparing a mid-layer adsorption gel patch and a capsaicin gel patch for pharmacodynamic experiments. The specific process is as follows:

[0106] (1) Preparation of the middle layer adsorption gel patch: Weigh 0.4 g of the skeleton material hydroxypropyl cellulose, 0.4 g of polyvinyl alcohol-350, 0.1 g of the cooling agent menthol, and 0.1 g of the crosslinking agent aluminum hydroxyl, dissolve them in 1.5 g of glycerol, add 1.8 g of ethanol and 5.7 g of ultrapure water to swell for 24 h, and finally centrifuge at 2000~6000 rpm for 5~30 min to remove air bubbles, coat it on the conductive backing film, dry it at 50℃ for 4 hours, and combine the open side with the middle layer isolation conductive backing film to obtain a middle layer adsorption gel patch that is sealed on both sides by the conductive backing layer.

[0107] (2) Preparation of capsaicin gel patch: Weigh 1.9 g of ethanol and 4.37 g of ultrapure water, weigh 1.2 g of sodium polyacrylate, 0.12 g of gelatin, 0.06 g of polyvinyl alcohol-350, 1 g of glycerin (moisturizer), 1 g of 1,2-propanediol, and 0.05 g of aluminum hydroxyl crosslinking agent (prescription amount), dissolve them in a mixed solvent of ethanol and ultrapure water and mix evenly. Further dissolve 0.3 g of capsaicin (prescription amount) in the above mixed solvent and swell for 24 h. Finally, centrifuge at 2000~6000 rpm for 5~30 min to remove air bubbles, coat it on the anti-adhesive layer, and dry it at 50℃ for 4 h to obtain capsaicin gel patch.

[0108] (3) The coated and dried capsaicin gel patch is combined with the middle conductive backing film of the middle adsorption gel patch to obtain capsaicin electrode sheet.

[0109] This invention investigates the effects of the formulation components and their content on the properties of capsaicin electrode pads, such as conductivity, adhesion, and formability, to obtain capsaicin electrode pads with excellent performance that meet usage requirements. Through studies on the in vitro skin penetration, pharmacokinetics, pharmacodynamics, and irritation / allergic reactions of the capsaicin electrode pads, the feasibility and safety of the therapeutic effects provided by this invention are evaluated. Specific evaluation methods and results are as follows:

[0110] Evaluation of the molding properties, electrical conductivity, and adhesive properties of each embodiment and comparative formulation

[0111] The formulation formability described in this invention mainly focuses on the layering effect, gel properties, and color of the drug-loaded gel layer of the capsaicin electrode sheet, with appearance as the primary evaluation criterion. Conductivity refers to connecting both ends of the capsaicin electrode sheet to the positive and negative electrodes of a medical power supply device, turning on the power, and testing the current in the circuit with an ammeter. A higher current reading (mA) indicates stronger conductivity of the formulation. Additionally, referring to the adhesion determination method in General Chapter 0952 of the 2020 edition of the Chinese Pharmacopoeia, the initial tack and holding power of the middle layer adsorbent gel patch and the capsaicin gel patch in the capsaicin electrode sheet were tested. Initial tack indicates the electrode sheet's ability to adhere to the skin when in light, rapid contact; holding power indicates the electrode sheet's ability to resist creep damage caused by persistent shear forces.

[0112] The performance evaluation of the various embodiments and comparative examples of the present invention is shown in Table 1 below. As can be observed from Table 1, the test results are as follows: The mid-layer adsorption gel patch and capsaicin gel patch prepared in the above embodiments both showed good applicability for electroosmotic delivery. Comparative Examples 2-1 and 2-2, due to insufficient skeleton material or cross-linking agent, could not provide enough cross-linking sites to form adhesion with the skin substrate, resulting in low adhesion strength. The gel patches were prone to falling off and could not form a gel sheet with strong cohesion. At the same time, the gel patches were too flexible and extensible, making it difficult to fix them to the skin during use. Comparative Example 2-3, due to the small amount of moisturizer, affected the diffusion of the drug in the gel network. Insufficient moisturizer made it difficult to exert this effect, resulting in a slow drug release rate. In contrast, Comparative Examples 3-1 and 3-2, due to excessive amounts of matrix material or cross-linking agent, resulted in an overly dense gel network structure and excessively strong cohesion, leading to a hard and brittle gel patch that was uncomfortable to use and prone to breakage or detachment. Similarly, the overly dense network structure restricted drug diffusion within the gel patch, resulting in slow drug release and failure to reach effective therapeutic concentrations. Comparative Example 3-3, due to excessive amounts of moisturizer, caused the gel patch surface to become wet, even oozing water droplets, affecting its appearance and user experience. Furthermore, the gel patch under these conditions excessively adhered to the skin, making it difficult to remove after use and causing skin strain. Overall, the examples demonstrated similar or better performance than the comparative examples in terms of conductivity, adhesion, and moldability, particularly exhibiting superior adhesion. This is because the examples had more suitable material selection and processing ratios than the comparative examples, resulting in formulations with higher conductivity, adhesion, and moldability, as well as good moldability. The content of matrix material and cross-linking agent also significantly affects conductivity; appropriate materials and contents are necessary for good conductivity, which is beneficial for drug penetration.

[0113] Table 1. Conductivity and Adhesion of the Formulations in Each Example and Comparative Example

[0114]

[0115] Evaluation of skin penetration of each embodiment and comparative formulation in isolated rats

[0116] The transdermal drug permeation was evaluated using an isolated skin permeation test conducted in the Valia-Chien dual-chamber permeation tank, as described in the examples and comparative studies. Hairless skin from the back of an isolated rat was fixed to the permeation tank with the epidermis facing outwards, and a 1cm capsaicin electrode was placed on top. 2 The drug was applied to the epidermis. 4 mL of physiological saline containing 40% polyethylene glycol 400 was added to the osmosis chamber as the receiving solution. One electrode of the electroosmotic apparatus was connected to the capsaicin electrode, and the other electrode was inserted into the osmosis chamber. The electroosmotic apparatus was then turned on, maintaining a constant current intensity. Under constant temperature and stirring at 32℃, 1 mL of the receiving solution was collected at 0, 5, 10, 20, and 30 min, and an equal amount of blank receiving solution was added. The osmosis test samples were filtered through a 0.22µm disposable syringe filter and analyzed by liquid chromatography. The drug concentration in the osmosis solution was determined by HPLC. The cumulative osmosis volume Q was plotted against time t at different times to calculate the skin osmosis volume and / or skin osmosis rate.

[0117] Table 2 shows the transdermal penetration results for each embodiment and comparative example. A comparison of the ex vivo skin penetration of this patented formulation and imported capsaicin patch formulation is also available. Figure 3 .

[0118] Formula for calculating cumulative infiltration per unit area:

[0119]

[0120] Note: Q n C represents the cumulative transdermal permeability per unit area at the nth sampling point. n Vn represents the drug concentration measured at the nth sampling point; V0 represents the volume of the receiving chamber; Cn represents the concentration of the drug at the nth sampling point. i V represents the drug concentration measured at the i-th sampling point; V is the sampling volume; and A is the effective permeation area. In this experiment, V0 = 5.5 ml, and A = 0.71 cm². 2 V = 1 mL.

[0121] Table 2. Evaluation of in vitro skin permeability of formulations in each example and comparative example.

[0122]

[0123] The experimental results show that the positive electrode drug reservoir gels prepared in the above examples all exhibit good iontophoresis suitability. After passing through a 0.3 mA / cm² electrode, the gels showed good iontophoresis performance. 2 Under the current-induced permeation-enhancing effect, all showed significant permeation-enhancing effects. Furthermore, by comparing the effects of various formulations and imported preparations on iontophoresis in the comparative examples, the following conclusions can be drawn.

[0124] First, the conductivity of the formulation ensures effective current conduction, which is crucial for the electroosmotic delivery process. However, the advantage of conductivity can only be fully realized when there is good adhesion between the gel and the skin. As can be seen from Example 3 and Comparative Example 3-3, although both have the same conductivity (15 mA), Comparative Example 3-3 has poorer adhesion (initial tack of 10, holding power at 8 min), resulting in a significant reduction in its ex vivo skin penetration results, from 65.37 μg / cm² to 43.13 μg / cm². This indicates that good adhesion is essential for improving drug penetration efficiency.

[0125] Furthermore, the formability of a gel not only affects its physical stability but also the uniformity of drug release. For example, Example 2 exhibited excellent formability (clearly distinguishable layers, transparent hydrogel sheet), and its ex vivo skin penetration (1.82 μg / cm²) and intradermal drug retention (10.75 μg / cm²) were superior to Comparative Example 2-1 (1.47 μg / cm² and 7.01 μg / cm²), reflecting the importance of formability in promoting effective penetration. A well-formable gel layer can more effectively support current conduction and uniform drug distribution, thereby working in conjunction with conductivity and adhesion to improve skin penetration efficiency.

[0126] The difference in cumulative penetration amount between Example 4 and Comparative Example 4-1 over 30 minutes was small, while the mixed gel patch of Comparative Example 4-2 delivered much less drug than the other two groups. This phenomenon may be related to the competitive penetration of the cooling agent and capsaicin through the skin.

[0127] Therefore, the effects of conductivity, adhesion, and formability on the permeability of ex vivo skin are not isolated factors; the influence of each component in the formulation will significantly affect the interaction and balance among these three factors. Furthermore, the use of formulations with different drug loadings based on varying medication requirements also needs careful consideration.

[0128] Comparing the iontophoresis formulation and the commercially available non-iontophoresis formulation Qutenza, it can be seen that Qutenza (a commercially available non-iontophoresis formulation) has a certain skin penetration (21.72 μg / cm²) and intradermal drug retention (92.52 μg / cm²). However, its efficiency is lower compared to the optimized electroosmotic formulation as shown in the examples. Figure 3 In these examples, electroosmotic delivery formulations with significantly lower drug loadings than Qutenza (Examples 4 and 5) achieved higher and faster penetration with lower drug loadings in a shorter time. These results indicate that electroosmotic delivery formulations, through the action of electric current, promote drug movement in the skin, thereby increasing penetration and intradermal drug retention. Commercially available non-electroosmotic delivery formulations lack this promoting effect of electrodynamic force, and therefore are generally less efficient than specially designed electroosmotic delivery formulations.

[0129] Experiment on the effect of current intensity on the electroosmotic delivery rate of capsaicin

[0130] The capsaicin electrode pads prepared in Example 5 were used in an in vitro rat skin permeation experiment. The rats were divided into six groups, with the output current intensities of the electroosmosis apparatus being 0, 0.10, 0.20, 0.30, 0.40, and 0.50 mA·cm⁻¹, respectively. -2 Samples were taken at 0, 5, 10, 20 and 30 min after administration, and analyzed by liquid chromatography. The drug concentration in the samples was calculated, and the osmotic kinetics of capsaicin under different current intensities were investigated.

[0131] Based on the capsaicin concentration values ​​measured at different time points, the cumulative permeation per unit area Q at each time point was calculated. The cumulative permeation per unit area was measured at various current intensities, and then a graph was plotted against time t against the cumulative permeation per unit area Q to obtain the capsaicin permeation kinetic curves under different current intensities. The results are as follows: Figure 4 As shown in Table 3 below, regression analysis was performed on the linear portion of the permeability kinetic curve to calculate the steady-state permeability rate Jss for each experimental group, as well as the corresponding permeability enhancement factor ER.

[0132] Table 3 Steady-state permeation rate and permeation enhancement factor under different current intensities

[0133]

[0134] The results above show that the steady-state permeation rates differed significantly among the different current intensity groups (P < 0.05). When the current intensity increased from 0.10 mA / cm², the steady-state permeation rate also showed significant differences. 2 Gradually increase to 0.50 mA / cm 2 At this point, the steady-state permeation rate increased with increasing current intensity, from 0.25 µg / cm²·min to 2.28 µg / cm²·min, indicating a significant permeation-enhancing effect of current on capsaicin. Furthermore, as the current increased, it was observed that the permeation-enhancing effect of current intensity initially increased and then gradually decreased. Therefore, when the current was 0.1–0.5 mA / cm²·min... 2 This can be used as the drug delivery current. If the current intensity exceeds 0.5 mA / cm... 2 This will intensify the patient's electric shock sensation, making it difficult to administer medication.

[0135] Experiment on the effect of drug concentration on the rate of capsaicin electroosmotic delivery

[0136] Based on the formulation and preparation process of the capsaicin gel patch in Example 3, the total amount of capsaicin was adjusted so that the drug content in each group was 10%, 30%, 50%, 70%, 90%, and 100% of that in Example 3, i.e., the feed amounts were 142.8, 428.6, 714.3, 1000, 1285.7, and 1428.5 µg, respectively. An in vitro guinea pig skin permeation experiment was conducted, and the output current intensity of the electroosmotic device was adjusted and maintained at 0.3 mA·cm⁻¹. -2 Samples were taken at 0, 5, 10, 20 and 30 min after drug administration, and analyzed by liquid chromatography. The drug concentration in the samples was calculated, and the osmotic kinetics of capsaicin at different drug concentrations were investigated.

[0137] Based on the capsaicin concentration values ​​measured at different time points, the cumulative permeability Q per unit area at each time point was calculated. The cumulative permeability at each drug concentration was measured, and then a graph was plotted against time t against the cumulative permeability Q to obtain the capsaicin osmotic kinetic curves at different drug concentrations. The results are as follows: Figure 5 As shown in Table 4 below, regression analysis was performed on the linear portion of the permeability kinetics curve to calculate the steady-state permeability rate Jss for each experimental group, as well as the corresponding permeability enhancement factor ER.

[0138] Table 4 Steady-state permeation rate and permeation enhancement factor at different drug concentrations

[0139]

[0140] The experimental results showed that capsaicin and steady-state permeation rate had a non-linear relationship. When the concentration was less than 0.35% (before 70% of that in Example 3), the steady-state permeation rate increased with increasing concentration. When the concentration was in the range of 0.35-0.5%, the increase in steady-state permeation rate slowed down and was no longer proportional. Student t-test analysis using Excel showed that there were no significant differences between Jss (0.7%), Jss (0.9%), and Jss (1.0%) (P>0.05).

[0141] Test on the adsorption capacity of capsaicin in the middle layer gel

[0142] To compare the adsorption capacity of the intermediate gel for capsaicin, the capsaicin gel patch prepared according to the preparation method in Example 5 was used as the drug delivery layer. After the drug delivery layer alone delivered the drug for 30 minutes, the intermediate gel patch prepared according to the methods in Examples 2-4 was further applied, and the amount of capsaicin residue on the skin surface was measured after 30 minutes of electroosmotic infusion. The results are shown in Table 5.

[0143] According to the results in the table, compared with the skin after capsaicin administration without the application of the middle layer gel patch, the middle layer adsorption gel patch has a significant adsorption effect on capsaicin. Under the conditions given in Example 3, it can adsorb more than 45%, and the adsorption rate is as high as 80%. This can effectively avoid the long-term irritation of the patient's skin by capsaicin residue on the skin surface after administration.

[0144] Table 5. Test of capsaicin adsorption capacity of the middle layer gel patch

[0145]

[0146] Influence of the cooling effect of the middle layer adsorption gel

[0147] The capsaicin electrode sheet prepared in Example 4, as well as Comparative Examples 4-1 and 4-2, were administered to rats for 30 minutes. The analgesic effect of the middle layer adsorption gel after capsaicin administration was then investigated.

[0148] In constructing a rat model of burning pain to evaluate the efficacy of analgesics, baseline data were first collected from healthy 6-8 week old rats, and they were acclimatized to the experimental environment. Next, a single capsaicin gel patch (containing 0.86 mg of capsaicin) from Example 4 was administered via iontophoresis as the model group to induce skin-induced burning pain behavior. After 30 minutes of iontophoresis, the drug was withdrawn, and the rats were immediately observed. The number of writhing movements within the first 30 minutes after drug withdrawal was recorded as a quantitative indicator of the capsaicin burning intensity.

[0149] Example 4 and Comparative Examples 4-1 and 4-2 were prepared according to... Figure 2 The administration method for capsaicin electrode patches involved attaching the positive electrode, coated with a drug-loaded gel, to the back of the rat, and attaching the electrode coated with a negative electrode containing an electrolyte reservoir gel to the abdomen of the rat. The rat was then placed in a stainless steel rat restraint. The transdermal electroosmotic drug delivery system was activated, and the required current intensity was adjusted and maintained according to the prescribed administration protocol for each gel patch. The control group received no drug administration; after 30 minutes of iontophoresis, the electrode patches and related electroosmotic devices were removed, and writhing movements during the first 30 minutes were recorded. In the other groups, rats were tested by administering the drug at a 5cm depth at the abdominal injection site according to each protocol. 2 The drug was removed after 30 minutes, and the electrode pads and related electroosmotic infusion equipment were taken off. The number of rat writhing movements was observed and recorded within 30 minutes to examine the analgesic effect of the preparation.

[0150] The experimental results are shown in Table 6 below. In rats, Example 4 showed significantly stronger analgesic effects than the other two groups. Compared to the split structure, the cooling agent in the integrated structure's middle-layer absorbent gel patch can accumulate in a section of the middle conductive backing layer under the influence of electric current. When this layer is peeled off, the cooling agent accumulated on one side can quickly penetrate the skin to achieve an analgesic effect. In contrast, the layered gel patch requires a longer administration time to allow sufficient cooling agent to penetrate. This study demonstrates that the secondary pain response caused by capsaicin accumulation on the skin surface can be reduced with the assistance of the middle-layer absorbent gel patch.

[0151] The above embodiments are only used to illustrate the design concept and features of the present invention, and their purpose is to enable those skilled in the art to understand the content of the present invention and implement it accordingly. The protection scope of the present invention is not limited to the above embodiments. Therefore, all equivalent changes or modifications made based on the principles and design ideas disclosed in the present invention are within the protection scope of the present invention.

[0152] Table 6. Effects of electrode structure on penetration into isolated skin and analgesic effect of the middle adsorbed gel layer.

[0153]

[0154] Pharmacokinetic studies

[0155] LC-MS detection of drug concentrations in skin, subcutaneous tissue, and serum: Detection conditions: a. Column: Agilent Zorbax SB-C18 (2.1 × 150 mm, µm); b. LC conditions: Mobile phase: Acetonitrile:water:formic acid (70:30:0.1, v / v / v), column temperature: 25 ℃, injection volume: 20 µL, flow rate: 0.25 mL / min; c. Mass spectrometry conditions: Electrospray ionization (ESI) source; positive ion resolution mode; multiple reaction monitoring (MRM); ion spray voltage: 4200 V; drying gas temperature: 400 ℃; drying gas flow rate: 9 L / min; nebulizer gas pressure: 276 kPa. Capsaicin [M+H] + : 306.2 → m / z 137.3; Glibenclamide m / z 494.0 → m / z 369.1; Dihydrocapsaicin [M+H] + 308.2 → m / z 137.3.

[0156] Using the high-dose 8% capsaicin transdermal patch (Qutenza) marketed in the United States as a control, the pharmacokinetic study of the capsaicin electrode pads in the example was conducted after administration to rats through the skin to examine the drug concentration in the skin and blood of rats after administration.

[0157] Animal species and number: 36 SD rats, weighing 200-250g, with their abdominal hair shaved off and water provided at regular intervals daily. 24 rats were selected for plasma drug concentration assay and the other 12 rats were selected for intradermal drug concentration assay.

[0158] Experimental Design: This experiment consisted of four groups: a control group (Qutenza patch group) and experimental groups (low, medium, and high concentrations of capsaicin electrode pads). The control group dose was calculated based on the commercially available patch dosage of 179 mg / 50g, equivalent to 0.6 mg / rat based on body surface area. The experimental groups (low concentration) received 50% of the commercially available dose, i.e., 0.3 mg / rat; the experimental groups (medium concentration) received the same dose, i.e., 0.6 mg / rat; and the experimental groups (high concentration) received 150% of the commercially available dose, i.e., 0.9 mg / rat.

[0159] Sample preparation: Take 100 µL of plasma sample and add it to a 1.5 mL centrifuge tube. Add 10 μL of internal standard solution and 200 μL of acetonitrile, vortex for 1 min, centrifuge at 12000 rpm for 10 min, and collect 100 µL of the supernatant for analysis. Take skin tissue and add 300 µL of physiological saline. Homogenize the tissue using a homogenizer at 7000 r / min. Take the homogenized sample, centrifuge at 12000 rpm for 10 min, collect 100 µL of the supernatant, add 10 µL of internal standard working solution, vortex for 1 min to mix thoroughly, centrifuge, and then inject for analysis.

[0160] Plasma pharmacokinetic assay methods:

[0161] The plasma pharmacokinetic test method is as follows: Qutenza was used as the control group. In Example 5, the capsaicin electrode patches were administered in low-dose (0.3 mg), medium-dose (0.6 mg), and high-dose (0.9 mg) groups according to the designed dosage. After removing the anti-adhesion film, the patches were applied to the hairless skin of the abdomen. The experimental groups were connected to an iontophoresis device, and the current was controlled at 0.4 mA / cm². 2 Drug administration was performed over a 30-minute iontophoresis period. Blood samples were collected from the orbital region of six rats in each group at 0 h before administration and at 15, 30 (withdrawal), 60, 120, and 240 min after administration. Blood samples were collected in heparin-containing centrifuge tubes and centrifuged at 2500 rpm for 20 minutes. Plasma was collected and stored at -20°C for subsequent analysis. Intradermal and plasma drug concentrations were determined using liquid chromatography-mass spectrometry (LC-MS / MS). Plasma drug concentration results are shown in Table 7, and skin drug concentration results are shown in Table 8.

[0162] Table 7. Plasma drug concentrations after in vivo administration of capsaicin electrode pads.

[0163]

[0164] This invention aims to investigate the transdermal absorption of different drug doses under electroosmotic conditions. The study design included four groups: a control group, a low-dose group, a medium-dose group, and a high-dose group. Blood drug concentrations were compared. The results showed that the blood drug concentrations in the experimental groups were significantly higher than those in the control group. The low-dose group showed a significantly higher drug concentration at 15 minutes than the control group at 30 minutes, indicating that the capsaicin electrode pads of this patent can achieve faster and higher drug concentrations even at lower doses. Furthermore, the blood drug concentration in the experimental groups decreased very slowly after drug withdrawal at 30 minutes, possibly due to the large amount of drug accumulated in the skin after rapid penetration and slow absorption after withdrawal.

[0165] Intradermal pharmacokinetic test method:

[0166] The intradermal pharmacokinetic test method is as follows: Qutenza was used as the control group. Capsaicin electrode patches from Example 5 were used as low-dose experimental groups (0.3 mg / animal), medium-dose experimental groups (0.6 mg / animal), and high-dose experimental groups (0.9 mg / animal), respectively. The designed dosage was administered. After removing the anti-adhesion film, the patches were applied to the hairless skin of the abdomen. The experimental groups were connected to an iontophoresis device, with the current controlled at 0.4 mA / cm². 2 Drug administration. One rat from each group was taken at 10 min, 30 min, and 60 min (drug withdrawal) after drug administration. The patch was removed, and the skin surface was cleaned with 75% ethanol to remove the drug. The treated skin area was then removed and stored at -20°C for analysis. Drug concentration in the skin was detected by liquid chromatography-mass spectrometry (LC-MS / MS), and the results are shown in Table 8.

[0167] Table 8. In vivo skin drug concentration after capsaicin electrode tablet administration.

[0168]

[0169] Intradermal drug concentrations in the control group and three experimental groups with different doses were measured at different time points to assess the effects of different formulations and doses on the distribution of drug concentrations in the skin. The following is an analysis based on the given data: Time-dependent changes: In all groups, intradermal drug concentrations increased with increasing time, particularly within 30 minutes, indicating continued drug accumulation in the skin tissue.

[0170] At 10 minutes, the intradermal concentration of the self-made low-dose formulation was 59.6 ng / mL, while that of the imported control formulation was 23.66 ng / mL. This indicates that the capsaicin electrode tablets can rapidly achieve high concentrations in the skin even at lower doses. Furthermore, this result demonstrates that the drug, administered via electroosmosis, can achieve a higher concentration in 10 minutes than the commercially available formulation after 60 minutes of application. This means that the self-made formulation can reach effective concentrations in the skin more quickly under electroosmotic conditions, which is particularly important for treatments requiring rapid symptom relief. The drug also accumulates and remains in the skin for a longer period after administration, indicating faster and stronger skin penetration and local retention properties. Additionally, the transdermal penetration of the self-made capsaicin electrode tablet formulation is correlated with the positive dose.

[0171] Compared to commercially available Qutenza patches, capsaicin electrode pad formulations exhibit significant advantages in intradermal drug concentration. These include higher intradermal drug concentrations, faster drug release rates, superior skin penetration and local retention properties, and sustained drug release. These characteristics make the self-made formulations superior to commercially available formulations in terms of therapeutic efficacy, dosage flexibility, and rapid onset of action.

[0172] Pharmacodynamic studies in rat models of arthritis

[0173] Healthy male Wistar rats, weighing between 200 and 250 grams, were used in this study. These rats were randomly assigned to five different groups: a normal control group, a model group, a commercially available gel patch group, and an electroosmotic gel patch group (low current, high current). All animals underwent an acclimatization period of at least one week before the experiment and were housed under standardized environmental conditions, including a 12-hour light cycle and free access to food and water.

[0174] The pharmacodynamic model was induced by intra-articular injection of complete Freund's adjuvant. The specific method was as follows: after disinfecting the right hind limb knee joint with alcohol, a single injection of 50 μL of complete Freund's adjuvant (CFA, concentration 1 mg / mL) was administered. To ensure successful establishment of arthritis, drug treatment was initiated on day 3 post-injection.

[0175] The normal group consisted of rats that were not injected with complete Freund's adjuvant, i.e., were normally fed.

[0176] In the model group, rats received a single injection of 50 μL of complete Freund's adjuvant into the joint cavity;

[0177] Commercially available gel patch group: Rats were injected with 50 μL of complete Freund's adjuvant into the joint cavity once. On the 3rd day after administration, after swelling was observed, the circumference of the joint was measured at the time point of 0 h. A commercially available gel patch was applied to the right hind limb joint of the rats and fixed with adhesive tape. Qutenza (8%) was administered at a dose of 0.6 mg / rat for 7 consecutive days.

[0178] Iontophoresis gel patch group (low current group): Rats were injected once with 50 μL of complete Freund's adjuvant into the joint cavity. Swelling was observed on day 3 post-administration, and the joint circumference was measured at 0 h. Hair was removed from the rats' backs, and the iontophoresis transdermal drug delivery system gel (3%) prepared in Example 5 was administered at a dose of 0.6 mg / rat. The negative electrode reservoir electrolyte gel was applied to the shaved area on the rat's back. The small positive electrode, conductive backing membrane, middle adsorption gel patch, and capsaicin gel patch were sequentially applied to the right hind limb joint of the rat, and secured with adhesive tape. The rat was then connected to an iontophoresis transdermal device for electro-permeation for 30 min at a current density of 0.2 mA / cm². 2 For 7 consecutive days;

[0179] Electroosmotic gel patch group (high current group): Rats were injected once with 50 μL of complete Freund's adjuvant into the joint cavity. Swelling was observed on day 3 post-administration, and the joint circumference was measured at 0 h. Hair was removed from the rats' backs, and the iontophoresis transdermal drug delivery system gel prepared in Example 5 was administered at a dose of 0.6 mg / rat. The negative electrode reservoir electrolyte gel was applied to the shaved area on the rat's back. The small positive electrode, conductive backing membrane, middle layer adsorption gel patch, and capsaicin gel patch were sequentially applied to the right hind limb joint of the rat, and secured with adhesive tape. The rat was then connected to an iontophoresis transdermal device for electro-permeation for 30 min at a current density of 0.4 mA / cm². 2 For 7 consecutive days;

[0180] Electroosmotic gel patch group (low-dose group): Rats were injected once with 50 μL of complete Freund's adjuvant into the joint cavity. Swelling was observed on day 3 post-administration, and the joint circumference was measured at 0 h. Hair was removed from the rats' backs, and they were given the iontophoresis transdermal drug delivery system gel prepared in Example 2 (0.1%) at a dose of 0.02 mg / rat. The negative electrode reservoir electrolyte gel was applied to the shaved area on the rat's back. The small positive electrode, conductive backing membrane, middle adsorption gel patch, and capsaicin gel patch were sequentially applied to the right hind limb joint of the rat, and secured with adhesive tape. The rat was then connected to an iontophoresis transdermal device for electro-permeation for 30 min at a current density of 0.4 mA / cm². 2 For 7 consecutive days;

[0181] On day 7, rats in each group were anesthetized and euthanized by dislocation. The circumference of the right hind knee of the rats was measured, and samples such as blood, articular cartilage, and periarticular bone were collected to detect changes in the levels of tumor necrosis factor α and interleukin-6.

[0182] The experimental results are shown in Table 9. In this study, by comparing the pharmacodynamic parameters of the normal group, the model group, the commercially available gel patch group, and the iontophoresis gel patch group (low current, high current, and low dose) in a rat model of arthritis, we can gain a deeper understanding of the effects of different treatment strategies on arthritis. Pharmacodynamic parameters included the degree of swelling in the right hind limb, the concentrations of tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6). TNF-α is a pro-inflammatory cytokine, and its level is elevated in RA patients, which is positively correlated with RA disease activity. IL-6 is an important pro-inflammatory cytokine, and its levels are elevated in both serum and synovial fluid of RA patients, which is closely related to disease activity.

[0183] Compared with the experimental group, the average swelling degree of the commercially available formulation group was 3, which was significantly lower than that of the model group (6, P<0.01), but higher than that of the low-current and high-current groups (both 2). This indicates that the commercially available formulation can alleviate arthritis symptoms, but the iontophoresis gel patch (whether low-current or high-current) is more effective. Tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6): The levels of TNF-α and IL-6 in the commercially available gel patch group were significantly lower than those in the model group (P<0.01), indicating a certain inhibitory effect on the inflammatory response. However, the levels of TNF-α and IL-6 in the low-current and high-current groups were even lower, indicating that the electroosmotic gel patch is more effective in inhibiting inflammatory factors. Furthermore, when administering a low dose at a high current, significant differences in swelling degree, TNF-α, and IL-6 were observed compared to the model group, indicating that at a low dose (0.1%), the capsaicin electrode pad designed in this patent can effectively alleviate arthritis symptoms.

[0184] Comparison between the low-current and high-current groups: Both groups showed a 2 in swelling, but the high-current group had lower levels of TNF-α and IL-17 (P<0.05), indicating that increasing the current intensity can further enhance the anti-inflammatory effect of the iontophoresis gel patch. The data show that commercially available gel patches can effectively reduce inflammatory symptoms in arthritic rats, but the electroosmotic gel patch (both low and high current) is more effective in reducing swelling and lowering key inflammatory factors. This may be because electroosmosis improves local drug penetration and absorption, thereby enhancing efficacy. Furthermore, the high-current group showed better results than the low-current group, indicating that increasing the current intensity within a certain range can improve therapeutic effects.

[0185] Table 9. Effect of capsaicin electroosmotic delivery system on the coefficients of arthritic rats (n=6)

[0186]

[0187] Compared with the normal group, * indicates P<0.05, ** indicates P<0.01;

[0188] Compared with the model group, # This indicates that P < 0.05. ## This indicates that P < 0.01;

[0189] Compared with commercially available formulations, ^ This indicates that P < 0.05. ^^ This indicates that P < 0.01.

[0190] Skin irritation test of capsaicin electrode pads for iontophoresis

[0191] Hair was removed from both sides of the backs of six rats, with a hair removal area of ​​approximately 9 cm². 2 Capsaicin was administered daily via electroosmotic delivery using an electrode pad on the left side of the rat's back. Skin tissue sections from the administration site were collected before administration and 24 hours after administration for observation, to examine any differences in the tissue sections. (See attached image.) Figure 6 , Figure 6 (A) in the image is a skin tissue section from the drug administration site before drug administration. Figure 6 (B) is a skin tissue section at the administration site 24 h after drug withdrawal. The results show that no inflammation was observed in the skin at the administration site of the rats 24 h after drug withdrawal, and the skin condition was consistent with that before drug administration. It can be seen that the capsaicin electrode sheet protected by this patent application has no significant irritation to the skin.

[0192] Pharmacodynamic studies in rats with neuralgia

[0193] 1. Test method:

[0194] The hind paw withdrawal threshold (PWT) in rats is an important metric for determining the mechanical pain threshold in rats. This experiment used a dynamic plantar stimulator to determine the hind paw withdrawal threshold in rats. After adaptive training, the dynamic plantar stimulator was used to stimulate the middle of the right hind paw of the rat, with gradually increasing force. A positive response was indicated by the rat lifting its hind paw, avoiding the stimulus, or licking its hind paw.

[0195] During the experiment, rats were placed individually in a separate space separated by a plastic partition, with a 5 mm × 5 mm open mesh at the bottom of the cage. When the rats' olfactory responses disappeared, a probe wire was aimed at the middle of the right hind paw and a hand-operated switch was applied. Once the probe wire touched the bottom of the rat's right paw, a vertically upward force was applied, and the force was stopped when the rat showed a positive response.

[0196] Healthy male SD rats, weighing between 200 and 250 grams, were used in this study. These rats were randomly assigned to five different groups: a normal group, a model group, a commercially available gel patch group, and an iontophoresis gel patch group (low current, high current). All animals underwent an acclimatization period of at least one week before the experiment and were housed under standardized environmental conditions, including a 12-hour light cycle and free access to food and water.

[0197] The pharmacodynamic model was established by locally injuring the cutaneous nerves on one side of the rat's back. The specific method is as follows: First, the rat was general anesthetized using an appropriate anesthetic (such as isoflurane) to ensure the animal did not experience pain during the procedure. A suitable surgical area was selected on one side of the rat's back. The surgical site was disinfected with iodine, and then a small incision was made in the skin of the rat's back using sterile surgical instruments and techniques to expose the underlying nerve. A suitable peripheral nerve (such as the innervation area of ​​a spinal nerve) was selected and gently injured, for example, by gentle compression or ligation. After nerve injury, the skin incision was carefully sutured. After the surgery, the rat was placed in a warm, clean environment to promote recovery. The animal's recovery was monitored to ensure no infection or other complications occurred.

[0198] Drug treatment was initiated on the 7th day post-surgery, after the neuralgia symptoms had stabilized. Prior to treatment, all rats underwent an acclimatization period of at least one week, during which they were housed in a standardized environment, including constant temperature and humidity, and a 12-hour light cycle.

[0199] In the normal group, only surgical incisions were made, but the nerves of the rats were not damaged.

[0200] In the model group, surgical incisions were made, and the nerves of the rats were damaged.

[0201] Commercially available gel patch group: Surgical incisions were made in rats, and nerve damage was induced. The circumference of the joint was measured at 0 h after a stable neuropathic response was observed on day 7. A commercially available gel patch was applied to the surgical site and secured with adhesive tape. Qutenza (8%) was administered at a dose of 0.6 mg / rat over 90 min. The patch was removed after administration, and the pulse weight (PWT) of the rats was measured at 0 h before administration and at 2, 4, 6, 8, 10, 24, and 32 h after administration.

[0202] Electroosmotic gel patch group (low current group): Rats were injected once with 50 μL of complete Freund's adjuvant into the joint cavity. Swelling was observed on day 3 post-administration, and the joint circumference was measured at 0 h. Hair was removed from the back and abdomen of the rats. The rats were then administered the iontophoresis transdermal drug delivery system gel prepared in Example 5 (3%) at a dose of 0.6 mg / rat. The negative electrode reservoir electrolyte gel was applied to the shaved area on the rat's abdomen. Small positive and side electrodes, a conductive backing membrane, a middle layer adsorbent gel patch, and a capsaicin gel patch were sequentially applied to the surgical site and secured with adhesive tape. The rats were then connected to an iontophoresis transdermal device for electro-permeation for 30 min at a current density of 0.2 mA / cm². 2 PWT in rats was measured at 0 h before administration and at 2, 4, 6, 8, 10, 24 and 32 h after administration.

[0203] Electroosmotic gel patch group (high current group): Rats were injected once with 50 μL of complete Freund's adjuvant into the joint cavity. Swelling was observed on day 3 post-administration, and the joint circumference was measured at 0 h. Hair was removed from the back of the rats, and they were given the iontophoresis transdermal drug delivery system gel prepared in Example 5 (3%) at a dose of 0.6 mg / rat. The negative electrode reservoir electrolyte gel was applied to the hairless area on the rat's abdomen. Small positive and side electrodes, a conductive backing membrane, a middle layer adsorbent gel patch, and a capsaicin gel patch were sequentially applied to the surgical site and secured with adhesive tape. The iontophoresis device was connected for 30 min of electro-permeation at a current density of 0.4 mA / cm². 2 PWT in rats was measured at 0 h before administration and at 2, 4, 6, 8, 10, 24 and 32 h after administration.

[0204] The PWT measurement method is as follows: During the experiment, in a quiet environment with a room temperature of about 20℃, the hind paw retraction threshold of the rat was measured using a dynamic plantar pain meter (recorded from the start of stimulation of the middle of the right hind paw sole of the rat until the rat showed a positive response).

[0205] In this study, the changes in pain withdrawal threshold (PWT) in a rat model of neuralgia were compared among the normal group, model group, commercially available gel patch group, low-current electroosmotic gel patch group, and high-current electroosmotic gel patch group. PWT refers to the threshold at which an animal responds to pain stimuli, and its value reflects the degree of pain sensitivity. In the control group (normal rats), the PWT value remained relatively stable throughout the observation period, indicating that rats have a high response threshold to pain stimuli under normal conditions. In contrast, in the model group, the PWT value decreased significantly over time, especially after 10 hours and 32 hours, when the PWT value dropped to 4.63 seconds and 3.87 seconds, respectively, significantly lower than that of the control group. This indicates that the PHN model was successfully established and led to increased pain sensitivity.

[0206] The commercially available gel patch group showed slightly lower PWT values ​​than the control group throughout the experiment, but significantly higher values ​​than the model group, especially at later observation points (e.g., after 32 hours). This indicates that the commercially available gel patch can alleviate pain sensitivity in PHN rats to some extent. The electroosmotic gel patch group showed higher PWT values ​​than the model group under both low and high current conditions, indicating that this treatment method is effective in reducing pain sensitivity in PHN rats. In particular, the high-current group showed PWT values ​​close to or equal to the control group throughout the experiment, indicating a smaller impact on pain perception. This suggests that high-current electroosmotic gel patches are more effective in reducing pain sensitivity induced by PHN.

[0207] Overall, both commercially available gel patches and electroosmotic gel patches (regardless of low or high current) reduced pain sensitivity in PHN rats. However, electroosmotic gel patches, especially the high-current group, were more effective in increasing PWT values, i.e., reducing pain sensitivity. These results suggest that electroosmotic gel patches may be a superior strategy for treating neuropathic pain.

[0208] Table 10 Effects of capsaicin electrode pads on PWT in rats with neuralgia (n=5)

[0209]

[0210] Note: Compared with the control group, * indicates P<0.05, ** indicates P<0.01.

[0211] In summary, the capsaicin electrode pad provided by this invention is a novel electroosmotic transdermal drug delivery system suitable for treating arthritis and neuralgia. This system utilizes an optimized gel carrier and current-enhanced permeation technology to achieve highly efficient transdermal drug penetration, exhibiting significant analgesic effects. The formulation consists of a three-layer structure: a backing, a neutral intermediate gel layer, and a capsaicin gel patch. The conductive backing ensures the passage of current. The electrode pad of this invention also employs a design including an intermediate absorbent gel patch and an intermediate insulating conductive backing layer. After the capsaicin gel patch is removed from the skin, the intermediate absorbent gel patch is applied. Under the drive of the electric field, the cooling agent in the gel patch quickly enters the subcutaneous tissue, rapidly alleviating the burning sensation and temporary pain caused by capsaicin. Simultaneously, the gel adsorbs capsaicin residue on the skin surface. Removing the intermediate absorbent gel patch after use removes any remaining capsaicin from the skin surface. Furthermore, current intensity is also a key parameter affecting drug delivery. This invention allows for control of drug release rate and accumulation by adjusting the current intensity, enabling sufficient drug penetration into the skin to achieve therapeutic effects within 10-30 minutes. Compared to ordinary gel patches, this system significantly improves drug penetration rate, absorption, and tolerability. The efficacy of this system has been verified in animal model experiments for anti-inflammatory and analgesic effects.

[0212] The above embodiments are only used to illustrate the design concept and features of the present invention, and the scope of protection of the present invention is not limited to the above embodiments. Therefore, all equivalent changes or modifications made based on the principles and design ideas disclosed in the present invention are within the scope of protection of the present invention.

Claims

1. A capsaicin electrode sheet, characterized in that, The capsaicin electrode sheet is composed of, from top to bottom, an outer conductive backing layer, a middle absorbent gel patch, a middle insulating conductive backing layer, a capsaicin gel patch, and an anti-sticking layer. Wherein, the outer conductive backing layer and the middle insulating conductive backing layer are both films or sheets with conductive coatings. The middle layer adsorbent gel patch comprises, by weight: 3-10% of the first skeleton material, 10-18% of the moisturizer, 0.1-1% of the crosslinking agent, 1-5% of the cooling agent, and 66-85.9% of the solvent; The capsaicin gel patch comprises, by weight: 0.1-5% capsaicin, 4.6-26% secondary skeleton material, 10-25% humectant, 0.1-1% crosslinking agent, and 43-85.2% solvent; The first skeleton material in the middle layer adsorption gel patch is selected from one or two of hydroxypropyl methylcellulose, carbomer, polyvinyl alcohol 350, and sodium alginate, mixed in any proportion. The second skeleton material in the capsaicin gel patch includes a first component, a second component, and a third component: wherein the first component is sodium polyacrylate, the second component is gelatin, and the mass ratio of sodium polyacrylate to gelatin is 10:1-5:1; the third component is polyvinyl alcohol 350, and the mass ratio of the third component to the second component is 1:2; The moisturizers in the middle layer adsorption gel patch and the capsaicin gel patch are one or two of 1,2-propanediol and glycerin, mixed in any proportion. The cross-linking agent in the middle layer adsorption gel patch and the capsaicin gel patch is aluminum hydroxyl.

2. The capsaicin electrode sheet according to claim 1, characterized in that, The solvents in the middle layer adsorption gel patch and the capsaicin gel patch are both mixtures of ethanol and ultrapure water in a mass ratio of 2:5 to 1:

4.

3. The capsaicin electrode sheet according to claim 1, characterized in that, The capsaicin concentration in the capsaicin gel patch is 2-5%.

4. The capsaicin electrode sheet according to claim 1, characterized in that, The cooling agent in the middle layer adsorbent gel patch is one or two of menthol and borneol mixed in any proportion.

5. The capsaicin electrode sheet according to claim 1, characterized in that, The anti-stick layer is a polyester film coated with dimethyl silicone oil; the conductive backing layer is a stretchable conductive film made by spraying and depositing carbon nanotubes and mechanically exfoliated graphene onto a polydimethylsiloxane film.

6. The capsaicin electrode sheet according to claim 1, characterized in that, The drug delivery process of the capsaicin electrode pad includes: Remove the protective layer, apply the capsaicin gel patch to the affected area, and adjust the current intensity of the electroosmosis device to 0.1~0.5 mA / cm². 2 ; 10-30 minutes after drug administration, remove the electrode pads from the affected area. Then, peel off the middle insulating conductive backing layer along with the capsaicin gel patch. Next, apply the middle absorbent gel patch to the affected skin, adjusting the electroosmotic current intensity to 0.1-0.5 mA / cm². 2 Remove the electrode after at least 30 minutes.

7. A method for preparing a capsaicin electrode sheet according to any one of claims 1-6, characterized in that, The preparation method includes: Weigh out the prescribed amount of the first skeleton material, cooling agent and crosslinking agent, dissolve them in the humectant, add solvent to fully swell, centrifuge to remove air bubbles, coat them on the outer conductive backing layer, and dry them to make the open surface of the gel surface composite with the middle insulating conductive backing layer. Weigh out the prescribed amount of moisturizer, crosslinking agent and second skeleton material, dissolve them in solvent and mix evenly, then add the prescribed amount of capsaicin, stir thoroughly to dissolve and swell, centrifuge to remove air bubbles, coat it on the non-stick layer and dry. The capsaicin electrode sheet is obtained by bonding the dried capsaicin gel-coated adhesive side to the middle insulating conductive backing layer.

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