External gel emplastrum containing local anesthetic as well as preparation method and application of external gel emplastrum

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and relates to an external gel emplastrum containing local anesthetics as well as a preparation method and application of the external gel emplastrum. The gel emplastrum comprises a backing layer, an emplastrum body layer and an anti-sticking film from bottom to top, wherein the pasty fluid layer adopts organic water-retaining resin as a framework structure, and contains local anesthetics accounting for 1-20% of the weight of the pasty fluid layer. The external gel emplastrum containing the local anesthetic can have a higher transdermal release rate, and can improve the stability of a supply chain of the added part of neutralized polyacrylic acid.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations and relates to an external gel plaster containing a local anesthetic and a preparation method and application thereof. Background Art

[0002] Herpes zoster virus is a varicella-zoster virus, which usually lurks in sensory ganglia or autonomic nerves. When the body's immune function is low, the latent virus is activated and replicates in large quantities, spreading along the nervous system to the skin, causing symptoms of herpes zoster. Herpes zoster can be cured after proper treatment, but neuralgia after the healing of herpes is the most common complication after the treatment of herpes zoster virus. It can persist and recur again after a period of relief. Neuralgia can manifest in various forms such as burning, electric shock, knife cutting, needle-like or tearing, with no limit on the specific form. Sometimes even multiple forms of pain coexist, causing great pain to patients. Specifically, the site of pain is mainly unilateral chest, trigeminal nerve or neck (a few patients may experience bilateral pain), among which the chest has the highest probability of pain, about 50%, followed by the head, face, neck and waist, which can reach 20%. Generally speaking, the area of ​​the site of postherpetic neuralgia is usually larger than the area of ​​the herpes zoster itself. At present, the treatment goal of postherpetic neuralgia is to effectively control the pain as soon as possible, relieve the accompanying sleep and emotional disorders, and improve the quality of life. Existing domestic drugs for the treatment of postherpetic neuralgia include calcium channel modulators, tricyclic antidepressants and lidocaine topical gel patch preparations (drug concentration 5wt%), etc.

[0003] Lidocaine is a local anesthetic, also known as local anesthetic, which can block the occurrence and transmission of sensory nerve impulses in the local area where the drug is applied, so that the patient can temporarily cause the local pain of the drug-applied tissue to disappear while maintaining consciousness. When the local anesthetic effect of the drug is eliminated, the sensation of the drug-applied tissue will gradually return to normal. Because this reversible effect has little effect on the human body, cacao local anesthetics are often used clinically at home and abroad. Other cacao local anesthetics include bupivacaine, ropivacaine, etc. However, currently only lidocaine gel patch is used to treat postherpetic neuralgia.

[0004] Gel plaster, commonly known as cataplasm in the industry, is prepared by coating a backing with a variety of components such as drugs, suitable matrices, and water. Its manufacturing technology originated abroad, mainly from pharmaceutical companies in Japan and the United States. In recent years, some gel plaster products and related technologies have been successively introduced into China. Like traditional black plasters, gel plasters, which are also topical preparations, do not need to pass through the digestive tract, are not affected or damaged by food or gastric juice, and can avoid the irritation and damage caused by oral administration to the gastrointestinal mucosa and liver; the drug can be changed at any time, and the compliance of taking medicine is high; the drug components can be released continuously and stably. In addition, compared with traditional black plasters, gel plaster preparations have the following advantages including but not limited to: high water content, which can not only increase the swelling degree of the skin stratum corneum, but also improve the skin permeability of various drug components; the paste has an appropriate thickness and excellent affinity with the skin; the paste has little irritation to the skin and is not likely to cause local symptoms such as skin allergy at the application site. Due to the above advantages that gel plaster preparations do not have, they have been pursued by domestic pharmaceutical manufacturers in recent years. At present, there are already a variety of gel plaster preparation products in clinical use in China, such as flurbiprofen gel plaster, loxoprofen sodium gel plaster, lidocaine gel plaster, etc.

[0005] Among them, lidocaine gel plaster is mainly used for the treatment of postherpetic neuralgia. It was approved for marketing in the United States as a new dosage form in 1999 and is sold by American Ende Pharmaceutical Company. Since 2018, products of the same dosage form have been approved for marketing in China. Whether it is the lidocaine gel plaster already on the market abroad or the domestic products already on the market, the effective drug concentration is 5%, and each patch contains 700 mg of lidocaine.

[0006] However, according to the information of American Ende Pharmaceutical Company (see: CN1571656B, the use of lidocaine in the preparation of a transdermal patch for the treatment of non-neuropathic pain) and related patents (see: CN102018696B, a skin topical preparation containing lidocaine or its medicinal salt, applicant: Beijing Tide Pharmaceutical Co., Ltd.), about 95% of the lidocaine in the existing lidocaine gel plaster preparation products is not utilized, that is, only less than 5% of the lidocaine is transferred from the product to the skin. It can be seen that the transdermal release rate or bioavailability of lidocaine is very low. This not only causes ineffective waste of lidocaine gel plaster preparations, but also causes higher unnecessary treatment costs for patients and their families.

[0007] As one of the main parameter indicators of topical preparations, the transdermal release amount or release rate has a great impact on the efficacy of the product or the patient experience. According to investigations, about 95% of lidocaine that cannot be utilized by the human body in existing domestic and foreign gel plaster products is easily recycled. That is, about 665 mg of lidocaine per patch is discarded as waste and may even be utilized by others. Moreover, although lidocaine is not explicitly regulated by the state, it belongs to anesthetic drugs, and unrestricted circulation will cause immeasurable impacts. Therefore, for lidocaine gel plaster preparation manufacturers and R & D enterprises, they are also seeking a new method to improve the transdermal release rate or bioavailability of lidocaine.

[0008] When producing lidocaine gel plaster preparations at home and abroad, a variety of excipients are used, each playing a different role. For example, the excipients of the original research product of lidocaine gel plaster already on the market abroad include 15 components such as aluminum glycinate, disodium edetate, gelatin, glycerin, kaolin, methylparaben, polyacrylic acid, polyvinyl alcohol, propylene glycol, propylparaben, sodium carboxymethylcellulose, sodium polyacrylate, D-sorbitol, tartaric acid, and urea.

[0009] The skeleton cross-linked structure is the main structure of this type of preparation. Generally speaking, polyacrylic acid polymers, including sodium polyacrylate or partially neutralized polyacrylic acid, are commonly used as the skeleton structure of gel plasters. Among them, partially neutralized polyacrylic acid is more commonly used due to its dual physical and chemical properties of polyacrylic acid and polyacrylate.

[0010] Partially neutralized polyacrylic acid is a polymer of acrylic acid, and a part of its carboxyl groups is neutralized by alkaline substances. Currently, most of the partially neutralized polyacrylic acid used at home and abroad is produced by Japanese or American companies, with trade names such as VISCOMATE (specific models such as NP-600, NP-700, and NP-800). Generally speaking, the conventional dosage of such neutralized substances in gel plaster preparations can reach about 10%. In domestic and foreign patent literatures, when preparing lidocaine gel plaster preparations, Japanese-produced partially neutralized polyacrylic acid is also mostly used (see: CN102018696B, a skin topical preparation containing lidocaine or its medicinal salt, applicant: Beijing Tide Pharmaceutical Co., Ltd.; CN103608009B, a plaster containing lidocaine, applicant: Kissei Pharmaceutical Co., Ltd.; CN103930102B, a water-containing patch, applicant: Nipro Pharmaceutical Co., Ltd.). Currently, in the medicinal excipient registration system of the State Drug Administration, the partially neutralized polyacrylic acid products are mainly the NP series imported from Showa Denko K.K. and Toagosei Co., Ltd. in Japan. Among them, only the products of Showa Denko K.K. have been associated with preparations. Summary of the Invention

[0011] The primary objective of the present invention is to provide a topical gel patch containing a local anesthetic, which can have a higher transdermal release rate and can improve the supply chain stability problem of the partially neutralized polyacrylic acid added therein.

[0012] To achieve this objective, in a basic embodiment, the present invention provides a topical gel patch containing a local anesthetic. The gel patch includes a backing layer, a paste layer, and a mucosal barrier layer from bottom to top. Among them, the paste layer uses an organic water-retaining resin as the skeletal structure and contains 1-20% (preferably 3-8%) of the local anesthetic based on the weight of the paste layer.

[0013] In a preferred embodiment, the present invention provides a topical gel patch containing a local anesthetic, wherein the organic water-retaining resin, as a filler, accounts for 1-40% (preferably 1-20%) of the weight of the paste layer. The organic water-retaining resin is selected from one or more of starch graft copolymers, polyacrylic acid polymers, polyvinyl alcohol polymers, cellulose graft copolymers, and styrene copolymers. Preferably, it is one or more of polyvinyl ether-maleic anhydride copolymer, methoxyethylene-maleic anhydride copolymer, isobutene-maleic anhydride copolymer, gelatin, polyacrylic acid or its salt, and carbomer.

[0014] In a preferred embodiment, the present invention provides a topical gel patch containing a local anesthetic, wherein:

[0015] The starch graft copolymer is selected from one or more of starch graft acrylate, starch graft acrylamide, starch graft acrylic acid, starch graft acrylonitrile, and starch xanthate graft acrylate;

[0016] The polyacrylic acid polymers are selected from one or more of polyacrylic acid, polyacrylates, polyacrylates with polyolefins, acrylonitrile fiber and acrylate complexes, vinyl acetate-acrylic acid copolymers, and acrylic acid and allyl sucrose polymers (the above polyacrylates are high molecular products containing carboxyl groups obtained by polymerizing acrylic acid monomers, including partially neutralized products formed by neutralizing their carboxyl groups. The partially neutralized product refers to that part of the carboxyl groups in polyacrylic acid are neutralized by metals such as sodium, calcium, aluminum, or ammonium ions, etc., and sodium ions are preferred. Strictly speaking, polyacrylic acid or fully neutralized products can also be classified as partially neutralized products, with a neutralization rate of 0 or 100%. Those between 0-100% are partially neutralized products in the general sense. Generally, the mass percentage content of polyacrylic acid or its salt in the paste layer is 1-10%);

[0017] The polyvinyl alcohol polymers are selected from one or more of vinyl acetate-unsaturated acid copolymers, vinyl acetate-acrylic acid copolymers, polyvinyl alcohol acrylamide graft copolymers, and polyvinyl alcohol acetic anhydride cross-linked copolymers;

[0018] The cellulose graft copolymer is selected from one or more of cellulose graft acrylate, cellulose graft acrylonitrile, cellulose xanthate graft acrylate, and cellulose graft acrylamide;

[0019] The styrene copolymer is selected from one or more of styrene-butadiene-styrene copolymer, hydrogenated styrene-butadiene block copolymer, styrene-isoprene-styrene copolymer, and styrene-ethylene-propylene-styrene block copolymer.

[0020] In a preferred embodiment, the present invention provides an external gel plaster containing a local anesthetic, wherein the local anesthetic is selected from one or more of lidocaine, bupivacaine, tetracaine, dicaine, ropivacaine, procaine, and their pharmaceutically acceptable salts. The pharmaceutically acceptable salts are inorganic salts or organic salts, but inorganic salts are preferred. The inorganic salts include hydrochloride, hydrobromide, mesylate, citrate, tartrate, etc.

[0021] In a preferred embodiment, the present invention provides an external gel plaster containing a local anesthetic, wherein the paste layer further contains 0.05-0.4% by weight of clove oil and 0.05-0.2% by weight of peppermint oil. Clove oil and peppermint oil can increase the skin penetration rate of local anesthetics, such as lidocaine, by about 20% on average (the mechanism of increase is not yet clear and may be related to the interaction with other components or the promotion of changes in the structure of the skin stratum corneum).

[0022] In a preferred embodiment, the present invention provides an external gel plaster containing a local anesthetic, wherein the paste layer further contains 0.1-40% (preferably 0.1-20%) by weight of a tackifier, 0.01-10% (preferably 0.01-4%) by weight of a crosslinking agent, 0.01%-10% (preferably 0.01-4%) by weight of a crosslinking regulator, 0.01-10% (preferably 0.01-5%) by weight of a transdermal absorption enhancer, 1-40% (preferably 1-30%) by weight of a humectant, 0.001-10% (preferably 0.01-5%) by weight of a preservative, 0.001-10% (preferably 0.01-5%) by weight of a pH regulator, and 20-70% (preferably 30-60%) by weight of water.

[0023] The above-mentioned tackifier has no special restrictions and can be selected from cellulose and its derivatives such as hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, etc., polymer synthetic materials such as methyl methacrylate-n-butyl acrylate copolymer, methyl acrylate-2-ethylhexyl acrylate copolymer, polyvinyl alcohol, polyvinylpyrrolidone, polybutene, polyisobutene, polybutenoic acid, etc., and one or more of gelatin, gum arabic, xanthan gum, guar gum, tragacanth gum, glycerol rosinate, terpene resin, dextrin palmitate, sodium alginate, carrageenan, alicyclic saturated hydrocarbon resin and other gum products. Polyvinyl alcohol, gelatin, and sodium carboxymethylcellulose are preferred.

[0024] The above-mentioned cross-linking agent causes cross-linking of the above-mentioned organic water-retaining resin filler, thereby gelifying the above-mentioned paste layer and forming a gel-like skeleton structure. As the above-mentioned cross-linking agent, there are no special restrictions, and calcium compounds such as calcium chloride, magnesium compounds such as magnesium chloride, sodium compounds such as sodium chloride, and aluminum compounds such as aluminum chloride can be cited. Among them, aluminum compounds with strong cross-linking effects are preferred. As the above-mentioned aluminum compounds, aluminum hydroxide, aluminum hydroxide gel, aluminum citrate, aluminum dihydroxyaminoacetate (also known as glycine aluminum), aluminum chloride, aluminum sulfate, synthetic aluminum silicate, aluminum acetate, potassium aluminum sulfate, aluminum stearate, etc. can be cited.

[0025] The above-mentioned cross-linking regulator has no special restrictions and can be selected from one or more of disodium edetate (ethylenediaminetetraacetic acid disodium), acetic acid, lactic acid, oxalic acid, citric acid, tartaric acid, citric acid, etc. Disodium edetate is preferred.

[0026] The above-mentioned transdermal absorption enhancer has no special restrictions, and absorption enhancers commonly used in conventional plaster agents can be selected, such as N-methylpyrrolidone, azone, crotamiton, polypropylene glycol, menthyl lactate, sorbitol, ethylene glycol, laurocapram, isopropyl myristate, diethyl adipate, sorbitan sesquioleate, castor oil, peppermint oil, sorbitan sesquioleate, polyethylene glycol monostearate, polyoxyalkylene sorbitan fatty acid ester, diisopropyl adipate, polyoxyethylene hydrogenated castor oil, polysorbate, etc. In addition, polyhydric alcohols such as menthol, propylene glycol, polyethylene glycol, 1,3-butanediol, 1,4-butanediol, maltitol, glycerol, and xylitol also have the effect of promoting transdermal penetration. One or more of the above-mentioned transdermal absorption enhancers can be selected, and menthol, isopropyl myristate, and azone are preferred.

[0027] The above-mentioned moisturizer has no special restrictions and can inhibit the evaporation of water from the paste layer to prevent the paste from drying. Specifically, one or more of maltitol, pyrrolidone carboxylic acid, sodium pyrrolidone carboxylate, sodium lactate, hyaluronic acid, sodium hyaluronic acid, urea, ethylene glycol, liquid paraffin, sorbitol solution, etc. can be cited. The above-mentioned polyhydric alcohols can also be used as moisturizers. Among them, glycerol, urea, and sorbitol solution are preferred.

[0028] There is no special limitation on the above-mentioned preservatives, and preservatives commonly used in conventional plaster agents can be selected, such as methyl paraben, ethyl paraben, propyl paraben, butyl paraben, benzoic acid, thymol, methyl nipagin, ethyl nipagin, etc.

[0029] There is no special limitation on the above-mentioned pH regulators, and acidic substances such as acetic acid, lactic acid, oxalic acid, tartaric acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, malic acid, citric acid, or basic substances such as sodium hydroxide, sodium bicarbonate, triethanolamine, diethanolamine, diisopropanolamine, etc. or one or more of their salts can be cited.

[0030] Based on the mass percentage of the paste layer, the water content in the gel plaster of the present invention is 20-70%, preferably 30-60%. When the water content exceeds 75%, the paste layer is likely to remain on the skin in a muddy state, which is not conducive to sticking, affects the use experience, and may even make the cooling and stimulating sensation of the plaster stronger due to increased evaporation of water, thus aggravating the pain of the skin; on the other hand, when the water content is less than 20%, the adhesiveness of the paste layer may be too strong and become hard, resulting in uneven coating during the preparation of the preparation and unable to obtain a good product. In addition, it is easy to leave the paste layer on the skin and cause irritation to the skin.

[0031] In a preferred embodiment, the present invention provides an external gel plaster containing a local anesthetic, wherein the material of the backing layer is selected from one or more of fabrics, plastic films, and papers.

[0032] The present invention has no particular limitation on the material of the backing layer, and materials commonly used as the backing of plaster agents can be used, such as fabrics, plastic films, papers, etc. Specifically, the materials include polyesters such as polyethylene, polypropylene, polybutene, ethylene-vinyl acetate copolymer, polyvinyl chloride, polyoxyethylene, polyurethane, polyethylene terephthalate, polybutylene terephthalate; polyamides such as nylon; celluloses such as non-woven fabrics, woven fabrics, rayon, and cotton fabrics. At least one of the materials of the above specific materials can be selected, and non-woven fabric is preferred. The pore size of the non-woven fabric can be controlled by the gram weight ratio (g / m 2 ) of the non-woven fabric, and preferably 30-180 g / m 2 . When the pore size of the non-woven fabric is less than the above lower limit, problems such as fiber breakage during peeling of the plaster, and the paste oozing out from the paste layer and sticking to the skin or clothes may occur; if the pore size of the non-woven fabric exceeds the above upper limit, the paste may become hard, resulting in poor follow-up feeling to the skin, and the paste oozing out from the pores and sticking to the clothes and other problems.

[0033] In a preferred embodiment, the present invention provides a topical gel patch containing a local anesthetic, wherein the material for preventing mucosal contact is selected from one or more of polyethylene, polypropylene, polybutene, polyisobutene, ethylene-vinyl acetate copolymer, ethylene-vinyl alcohol copolymer, polyvinyl chloride, polyoxyethylene, polyurethane, polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, nylon, polyacrylonitrile, cellulose or its derivatives, and aluminum foil.

[0034] The second object of the present invention is to provide a method for preparing the above-mentioned gel patch, so as to better prepare the above-mentioned gel patch. The obtained gel patch can have a higher transdermal release rate and can improve the stability of the supply chain of partially neutralized polyacrylic acid added therein.

[0035] To achieve this object, in a basic embodiment, the present invention provides a method for preparing the above-mentioned gel patch. The preparation method is to first prepare the paste layer, and then coat the backing layer and the anti-mucosal layer on the obtained paste layer.

[0036] The third object of the present invention is to provide the use of the above-mentioned gel patch for preparing a drug for treating or relieving neuralgia.

[0037] The beneficial effect of the present invention is that the topical gel patch containing a local anesthetic of the present invention can have a higher transdermal release rate and can improve the stability of the supply chain of partially neutralized polyacrylic acid added therein.

[0038] In the topical gel patch containing a local anesthetic of the present invention, an organic water-retaining resin is used to replace partially neutralized polyacrylic acid. Compared with commercially available products, it has better adhesiveness and transdermal effect (the skin penetration rate is increased by more than 20%), thereby achieving better therapeutic effects, more meeting the medication needs of patients, and having a better use feeling. Description of the Drawings

[0039] Figure 1 It is a view of the appearance of the gel patch prepared in Example 1.

[0040] Figure 2 They are the transdermal curves (penetration amount) measured for the samples of the examples and the comparative examples respectively.

[0041] Figure 3 They are the transdermal curves (increase rate) measured for the samples of the examples and the comparative examples respectively. Detailed Embodiments

[0042] The following further illustrates the specific embodiments of the present invention in conjunction with examples and drawings.

[0043] Examples 1-4

[0044] Mix the prescription amount of the main drug ingredient lidocaine with the prescription amount of propylene glycol, and record it as the main drug solution; use one-fourth of the prescription amount of glycerin to stir and mix the prescription amounts of clove oil and peppermint oil evenly, and record it as Component A; disperse or dissolve the prescription amounts of water-retaining resin fillers (after crushing and sieving), tartaric acid, gelatin, carbomer, polyvinyl alcohol, sorbitol, and urea evenly with partial purified water, and record it as Component B; disperse the prescription amounts of sodium alginate, kaolin, glyceryl aluminum hydroxide, disodium edetate, methylparaben, and propylparaben evenly in the remaining glycerin, and record it as Component C; stir Components A and C in a stirring kettle 2 times, each time for 5 minutes. After it becomes a paste-like state, add the main drug solution and stir for another 5 minutes; then add Component B to the stirring kettle and knead for 5 minutes until the paste is uniform; transfer the whole paste to a coater equipped with pre-prepared non-woven fabric and anti-mucosal membrane (polypropylene film), and perform coating and cutting to obtain the preparation.

[0045] The prescriptions and dosages (mass percentage of the paste layer) of the examples are shown in Table 1.

[0046] Table 1 Example formula table

[0047]

[0048]

[0049] Representative examples of the gel plaster prepared in the examples are as Figure 1 shown.

[0050] Comparative Examples 1-6:

[0051] The prescriptions and dosages (mass percentage of the paste layer) of the comparative examples are shown in Table 2. The preparation method of the comparative examples is the same as that of the examples.

[0052] Table 2 Comparative example formula table

[0053]

[0054]

[0055] Determination of the Adhesion Force of Plasters

[0056] Take the above Examples 1-4, Comparative Examples 1-6, and commercial products (Endo Pharmaceuticals Inc, USA), respectively peel off the anti-mucosal membrane, place them on an inclined plate, and measure the adhesion force according to the first method of the plaster adhesion force measurement method (General Chapter 0952, Fourth Part, Chinese Pharmacopoeia 2020 Edition). The larger the ball number adhered, the stronger the adhesion force. Repeat the measurement 3 times, and take the average value as an integer for the result.

[0057] The test results are shown in Table 3. From the results, it can be seen that the adhesion forces of Examples 1-4 and Comparative Examples 1-4 are good, similar to or better than those of the commercial products, and on average, they can adhere to balls numbered 26 to 27. Although the adhesion forces of Comparative Examples 5-6 are similar to those of the commercial products, they are lower compared to Examples 1-4 and Comparative Examples 1-4. For the differences among them, it may be due to the too high content of oil-soluble components, resulting in a decrease in the skin adhesion force of the products of Comparative Examples 5-6, thus reducing the adhesion force.

[0058] Table 3 Adhesion Force Measurement Results

[0059]

[0060]

[0061] From the adhesion force measurement results, it can be seen that compared with the commercial products, the adhesion forces of each example are higher and more in line with the medication habits of domestic patients; while the comparative examples have slightly higher or similar adhesion forces. Through comprehensive analysis, although they are oil-soluble components, adding a certain proportion of clove oil and peppermint oil helps to improve the adhesion force.

[0062] User Experience

[0063] Take 1 patch each of the above Examples 1-4, Comparative Examples 1-6 and the commercial product (Endo Pharmaceuticals Inc, USA), and distribute them to 10 healthy adults respectively. They can be applied to the limbs or the lower back, and the usage feelings are counted after 24 hours (grading standard: comfortable, no irritation; general; uncomfortable, irritating).

[0064] No significant differences were found between the commercial product and Examples 1-4 and Comparative Examples 1-6. This result shows that the products of the present invention have a good usage experience.

[0065] Transdermal Absorption Test

[0066] Take the above Examples 1-4, and Comparative Examples 1-6 and the commercial product (Endo Pharmaceuticals Inc, USA) as comparative examples. Take pig ear skin, with its dermal side as the receiving layer side, and cut it into 7 cm 2Porcine ear skin was loaded into a Franz diffusion cell, and warm water at 32 °C circulated outside the diffusion cell. Each sample was cut into circular patches with a diameter of 19 mm, and the patches were attached to the stratum corneum layer of the porcine skin. A phosphate buffer solution with a pH of 7.4 was used as the transdermal medium. The volume of the receiving cell was 18 ml, the set temperature was 32 °C, and the stirring speed was 500 revolutions per minute. Samples were collected from the receiving side every 2 hours until 12 hours, 18 ml was taken each time, and then isothermal blank receiving solution was added. There were 6 parallel samples in each group. The concentration (μg / ml) of lidocaine in the receiving solution was determined by high performance liquid chromatography, and finally the permeation amount of lidocaine in each test patch (the permeation amount of lidocaine in the test patch (μg / cm 2 ) = [drug concentration (μg / ml) × volume (ml)] / patch area (cm 2 )) was calculated, as well as the permeation amount increase rate relative to the commercial product (permeation amount increase rate (%) = (permeation amount of lidocaine in the test patch - permeation amount of lidocaine in the commercial product) / permeation amount of lidocaine in the commercial product × 100%).

[0067] The test results are shown in Figure 2 and Figure 3 , and the specific data are shown in Table 4 and Table 5.

[0068] Table 4 Average cumulative permeation amount (μg / cm 2 )

[0069]

[0070] Table 5 Average cumulative permeation amount increase rate (%)

[0071]

[0072]

[0073] From these results, it can be seen that compared with the comparative examples and the commercial product, lidocaine in Examples 1-4 had higher skin permeation amounts and permeation rates. Although the skin permeation amounts and permeation rates of lidocaine at different time points in different examples were different, compared with the commercial product and the comparative examples, the skin permeation amounts and permeation rates of Examples 1-4 increased by about 10 - 30%, with an average increase of about 20%.

[0074] On the other hand, compared with commercial products, the changes in skin permeation amount and permeation rate of each comparative example were not very obvious, such as Comparative Examples 3 and 4. The inventors believe that adding clove oil and peppermint oil to the formulation may have some synergistic effects with each other or with other components, thereby improving the skin permeation performance of lidocaine, but the specific mechanism of action cannot be determined. Moreover, the effect of adding clove oil and peppermint oil to the formulation to improve skin permeation performance is also related to a certain addition ratio range. For example, in Comparative Examples 5 and 6, adding excessive clove oil and peppermint oil does not bring corresponding benefits to promoting the transdermal absorption of lidocaine with the increase in content.

[0075] Based on comprehensive analysis, adding a certain proportion of clove oil and peppermint oil to the paste helps to improve the skin permeability of lidocaine.

[0076] Industrial Applicability

[0077] From the perspective of industrial development, as described above, adding an organic water-retaining resin to replace the conventional materials in the product of the present invention can improve the innovation ability and product competitiveness of the product; adding a certain proportion of clove oil and peppermint oil to the product can improve the skin permeability of lidocaine, making the product have better curative effects and a better experience for patients.

[0078] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalent technologies, the present invention is also intended to include these modifications and variations. The above embodiments or implementation manners are only illustrative examples of the present invention, and the present invention can also be implemented in other specific ways or other specific forms without departing from the gist or essential features of the present invention. Therefore, the described implementation manners should be regarded as illustrative rather than restrictive in any aspect. The scope of the present invention shall be defined by the appended claims, and any changes equivalent to the intention and scope of the claims shall also be included within the scope of the present invention.

Claims

1. An external gel plaster containing a local anesthetic, characterized in that: The gel plaster described above comprises a backing layer, a paste layer and a mucosal barrier layer from bottom to top; wherein, the paste layer uses an organic water-retaining resin as a framework structure and contains 1-20% by weight of a local anesthetic based on the weight of the paste layer.

2. The hydrogel patch according to claim 1, wherein: The organic water-retaining resin described above is used as a filler and accounts for 1-40% by weight of the paste layer; the organic water-retaining resin is selected from one or more of starch graft copolymers, polyacrylic acid polymers, polyvinyl alcohol polymers, cellulose graft copolymers or styrene copolymers.

3. The gel plaster according to claim 2, wherein: The starch graft copolymer is selected from one or more of starch graft acrylate, starch graft acrylamide, starch graft acrylic acid, starch graft acrylonitrile, starch xanthate graft acrylate; The polyacrylic acid polymer is selected from one or more of polyacrylic acid, polyacrylate, polyacrylate plus polyolefin, acrylonitrile fiber and acrylate complex, vinyl acetate acrylate copolymer, acrylic acid and allyl sucrose polymer; The polyvinyl alcohol polymer is selected from one or more of vinyl acetate unsaturated acid copolymer, vinyl acetate acrylate copolymer, polyvinyl alcohol acrylamide graft copolymer, polyvinyl alcohol acetic anhydride crosslinked copolymer; The cellulose graft copolymer is selected from one or more of cellulose graft acrylate, cellulose graft acrylonitrile, cellulose xanthate graft acrylate, cellulose graft acrylamide; The styrene copolymer is selected from one or more of styrene-butadiene-styrene copolymer, hydrogenated styrene-butadiene block copolymer, styrene-isoprene-styrene copolymer, styrene-ethylene-propylene-styrene block copolymer; 4. The hydrogel patch according to claim 1, wherein: The local anesthetic is selected from one or more of lidocaine, bupivacaine, tetracaine, dicaine, ropivacaine, procaine and their pharmaceutically acceptable salts.

5. The hydrogel patch according to claim 1, wherein: The paste layer further contains 0.05-0.4% by weight of clove oil and 0.05-0.2% by weight of peppermint oil.

6. The hydrogel patch according to claim 1, wherein: The paste layer further contains 0.1-40% by weight of a tackifier, 0.01-10% by weight of a crosslinking agent, 0.01%-10% by weight of a crosslinking regulator, 0.01-10% by weight of a transdermal absorption enhancer, 1-40% by weight of a humectant, 0.001-10% by weight of a preservative, 0.001-10% by weight of a pH regulator, and 20-70% by weight of water.

7. The hydrogel patch according to claim 1, wherein: The material of the backing layer is selected from one or more of fabric, plastic film, paper.

8. The hydrogel patch according to claim 1, wherein: The material of the mucosal barrier layer is selected from one or more of polyethylene, polypropylene, polybutene, polyisobutene, ethylene-vinyl acetate copolymer, ethylene-vinyl alcohol copolymer, polyvinyl chloride, polyoxyethylene, polyurethane, polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, nylon, polyacrylonitrile, cellulose or its derivatives, aluminum foil.

9. A method for preparing the hydrogel patch according to any one of claims 1-8, characterized in that: The preparation method is to first prepare the paste layer, and then coat the backing layer and the mucosal barrier layer on the obtained paste layer.

10. Use of the hydrogel patch according to any one of claims 1-8 for the preparation of a medicament for treating or alleviating neuralgia.

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