Paste for warming kidney, activating meridians and relieving pain and preparation method thereof

Abstract

The preparation method comprises the following steps: mixing herba epimedii, fructus psoraleae, liquidambar formosana hance, rhizoma cibotii, radix clematidis, cassia twig and rhizoma corydalis, crushing, sieving, adding an ethanol aqueous solution, carrying out ultrasonic extraction, filtering, and collecting a first filtrate; adding water into the medicine residues for reflux extraction, filtering, collecting second filtrate, and mixing the first filtrate with the second filtrate to obtain an extracting solution; adding beta-cyclodextrin, mixing, stirring and heating, centrifuging and performing ultrafiltration, and collecting filtrate; concentrating under reduced pressure to obtain a concentrated solution, and adding sodium alginate, azone, glycyrrhizic acid, nano-zinc oxide and a calcium chloride solution to obtain transdermal gel; mixing the transdermal gel with a starch-based adhesive to obtain slurry, coating the surface of a non-woven fabric carrier with the slurry, and drying. The kidney-warming, meridian-activating and pain-relieving ointment has the advantages of strong pain relieving effect, long-acting slow release, low irritation and the like.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine plaster technology, and relates to a kidney-warming, meridian-clearing, and pain-relieving plaster and its preparation method. Background Technology

[0002] In TCM clinical practice, symptoms such as lower back and knee pain, weakness, and limited joint flexion and extension caused by kidney yang deficiency, cold-dampness obstruction, or meridian blockage are common. For these conditions, which are rooted in deficiency and cold and manifested by meridian blockage, internal administration of formulas to warm and tonify kidney yang and relieve pain is effective, but often has a relatively slow onset of action, and some people experience inconvenience or poor gastrointestinal tolerance. Traditional external therapies, such as ordinary plasters, medicated wines, or moxibustion, while providing convenience by acting directly on the local area, also face many limitations. Existing ordinary external plasters generally have low drug penetration efficiency, making it difficult to reach deep tissues to exert their warming and meridian-clearing effects; the reliance on skin penetration for absorption challenges the bioavailability of the active ingredients; conventional patches lack a sustained physical stimulation mechanism for enhanced efficacy, sometimes resulting in weak or unstable therapeutic effects; and some plasters have problems such as poor adhesion, easy allergic reactions, or overly irritating odors, affecting patient acceptance and compliance.

[0003] Therefore, an ideal plaster needs to have the characteristics of efficient penetration, deep warming, and powerful pain relief, while also being convenient and safe in dosage form. There is an urgent need in clinical practice and the market for a new type of topical preparation that can effectively solve the above pain points. Summary of the Invention

[0004] To address the shortcomings of existing technologies, the present invention aims to provide a kidney-warming and meridian-clearing analgesic plaster and its preparation method. The preparation method of the kidney-warming and meridian-clearing analgesic plaster provided by the present invention organically combines the effective components of traditional Chinese medicine with modern pharmaceutical technology, significantly improving the stability, transdermal efficiency and clinical applicability of the drug. The resulting kidney-warming and meridian-clearing analgesic plaster has the advantages of strong analgesia, long-lasting sustained release and low irritation.

[0005] To achieve this objective, the present invention adopts the following technical solution:

[0006] In a first aspect, the present invention provides a method for preparing a kidney-warming, meridian-clearing, and pain-relieving plaster, the method comprising:

[0007] (I) After mixing and pulverizing Epimedium, Psoralea corylifolia, Liquidambar formosana, Cibotium barometz, Clematis chinensis, Cinnamomum cassia and Corydalis yanhusuo to obtain a mixture of Chinese herbs, an ethanol aqueous solution is added to the mixture for ultrasonic extraction, and the first filtrate is collected after filtration. Water is added to the filtered residue for reflux extraction, and the second filtrate is collected after filtration. The first filtrate and the second filtrate are mixed to obtain an extract.

[0008] (II) Add β-cyclodextrin to the extract, mix, stir and heat, then centrifuge, take the supernatant for ultrafiltration, and collect the filtrate;

[0009] (III) The filtrate is concentrated under reduced pressure to obtain a concentrate; sodium alginate, azone, glycyrrhizic acid, nano zinc oxide and calcium chloride solution are added to the concentrate to obtain a transdermal gel;

[0010] (IV) The transdermal gel is mixed with a starch-based adhesive to obtain a slurry. The slurry is then coated onto the surface of a nonwoven fabric carrier and dried to obtain the warm kidney and blood circulation relieving ointment.

[0011] The preparation method of the kidney-warming and meridian-clearing analgesic plaster provided by this invention organically combines the effective components of traditional Chinese medicine with modern pharmaceutical technology, which significantly improves the stability, transdermal efficiency and clinical applicability of the drug. The resulting kidney-warming and meridian-clearing analgesic plaster has the advantages of strong analgesia, long-lasting sustained release and low irritation.

[0012] First, this invention selects Epimedium, Psoralea corylifolia, Liquidambar formosana, Cibotium barometz, Clematis chinensis, Cinnamomum cassia, and Corydalis yanhusuo as the main medicinal materials. Epimedium and Psoralea corylifolia are the main herbs for warming and tonifying kidney yang, and their effective components are flavonoids and coumarins such as icariin and psoralen. Liquidambar formosana, Cibotium barometz, and Clematis chinensis focus on unblocking the meridians and relieving numbness, and contain volatile oils, saponins, and polysaccharides. Cinnamomum cassia warms the meridians and unblocks the blood vessels, and its effective component is cinnamaldehyde. Corydalis yanhusuo invigorates blood and relieves pain, and its core analgesic component is alkaloids such as corydaline. In this invention, Epimedium, Psoralea corylifolia, Liquidambar formosana, Cibotium barometz, Clematis chinensis, Cinnamomum cassia, and Corydalis yanhusuo are mixed, pulverized, and sieved. Pulverization increases the specific surface area of ​​the medicinal materials and greatly destroys the cell wall structure, making it easier for the subsequent extraction solvent to penetrate into the medicinal materials and contact the effective components.

[0013] Epimedium and Psoralea corylifolia, as the main drugs for warming and tonifying kidney yang, have core active ingredients (such as flavonoid glycosides and coumarins) that are well soluble in ethanol aqueous solution. However, the collateral-clearing components (saponins and polysaccharides) of Liquidambar formosana, Cibotium barometz, and Clematis chinensis, as well as the analgesic alkaloids of Corydalis yanhusuo, require stepwise extraction with solvents of different polarities. For complex ingredient formulations, this invention adopts a two-step extraction method of ultrasonic extraction with ethanol aqueous solution and water extraction of the residue. First, ethanol aqueous solution is used as the extraction solvent, whose polarity can better dissolve the moderately polar components in the medicinal materials, such as flavonoid glycosides (epimedium glycoside), coumarins (psoralen), some alkaloids (corydaline), and saponins (Clematis chinensis and Liquidambar formosana). During ultrasonic extraction, the cavitation effect, microjets, and intense vibration energy of ultrasound are used to strongly destroy the cell walls and cell membranes of the medicinal materials, accelerate solvent penetration, and greatly improve the dissolution rate and efficiency of the active ingredients. At the same time, the local high temperature generated by ultrasound is also conducive to extraction. The first filtrate obtained by ultrasonic extraction is mainly rich in the above-mentioned moderately polar active ingredients. Subsequently, the residue after ethanol extraction was refluxed with water. Water, being the most polar, was primarily used to dissolve water-soluble components that ethanol could not fully extract, such as residual polysaccharides (Cibotium barometz, Clematis chinensis), proteins, amino acids, and some highly polar glycosides. The second filtrate obtained in this step was mainly rich in water-soluble components. By mixing the first and second filtrates, a comprehensive and efficient extraction of the effective components from moderate to high polarity in the formulated medicinal materials was achieved. The warming components in Epimedium and Psoralea corylifolia, the meridian-clearing components in Liquidambar formosana and Clematis chinensis, the analgesic components in Corydalis yanhusuo, and the warming and invigorating components in Cinnamomum cassia were extracted to the maximum extent through the two-step extraction process provided by this invention.

[0014] Subsequently, β-cyclodextrin was added to the extract, and the mixture was stirred and heated to complete the inclusion of the active ingredients. β-cyclodextrin is a molecule with a special cyclic hollow structure; its inner cavity is hydrophobic, and its outer wall is hydrophilic. Under heating and stirring conditions, many active ingredients with hydrophobic portions in the extract (such as volatile oil components like cinnamaldehyde, some alkaloids, and terpenoids) are included within the hydrophobic cavity of the β-cyclodextrin, forming inclusion complexes. Through β-cyclodextrin inclusion, on the one hand, photo- and heat-sensitive active ingredients in the extract are protected from damage, ensuring their stable content during subsequent vacuum concentration and storage, and reducing the loss of active ingredients. On the other hand, some originally poorly water-soluble, fat-soluble components show significantly improved water solubility after inclusion, which is beneficial for their uniform dispersion and stable existence in subsequent water-based transdermal gels, solving the problem of easy precipitation of oily components in traditional plasters. On the other hand, some medicinal ingredients have irritating odors or bitter tastes, which can be masked by encapsulation. At the same time, for some active ingredients that are irritating to the skin, encapsulation can slow down their release rate, which helps to reduce potential skin irritation and allergic reactions.

[0015] Subsequently, the filtrate is concentrated under reduced pressure, which removes most of the solvent (water and residual ethanol) at a lower temperature (avoiding high temperatures that could damage heat-sensitive components), resulting in a high-concentration concentrate and increasing the content of active ingredients per unit volume. Then, sodium alginate, azone, glycyrrhizic acid, nano-zinc oxide, and calcium chloride solution are added to the concentrate. Sodium alginate and calcium chloride solution are the main materials for gel formation. Sodium alginate is a natural polysaccharide; when it encounters calcium ions, the molecular chains cross-link through calcium ions to form a three-dimensional network hydrogel. This gel has good biocompatibility, water retention, and adhesion. As a carrier of the active ingredients, it can encapsulate the active ingredients in the concentrate within the gel network, achieving a sustained-release function.

[0016] Azone is a safe and highly effective transdermal penetration enhancer. Its main function is to disrupt the orderly arrangement of lipids in the stratum corneum, increasing lipid fluidity and thus temporarily and reversibly reducing the skin's barrier function. This promotes the penetration of water-soluble or lipophilic active ingredients into the stratum corneum. The addition of azone can significantly enhance the transdermal absorption rate and total transdermal volume of active ingredients, allowing the drug to be absorbed into the body more quickly and in greater quantities to exert its therapeutic effect. Glycyrrhizic acid has anti-inflammatory, anti-allergic, and skin-soothing effects. Its addition helps alleviate minor skin discomfort or inflammatory reactions, reduces skin irritation, and improves product safety and patient compliance. Nano-zinc oxide provides antibacterial protection and a physical barrier. Its nano-size allows for good dispersion in the gel, helping to maintain a healthy skin microenvironment at the application site and prevent minor infections.

[0017] Finally, the transdermal gel is mixed with a starch-based adhesive to obtain a slurry, which is then coated onto the surface of a nonwoven fabric carrier and dried to form an ointment. The starch-based adhesive possesses excellent adhesion, film-forming properties, and biocompatibility. When mixed with the transdermal gel, it adjusts the viscosity of the slurry, improves film-forming properties, and makes it easier to evenly coat and form a film on the nonwoven fabric carrier. The nonwoven fabric, with its softness, breathability, and low allergenicity, serves as the backing layer for the plaster, ensuring skin comfort and breathability during application, reducing stuffiness and dampness, and minimizing skin irritation. Drying removes moisture from the slurry, allowing the coating layer to solidify and form a solid or semi-solid ointment layer attached to the nonwoven fabric. The dried ointment has a stable structure, facilitating storage, transportation, and use. During application, the plaster is applied to the affected area; moisture (sweat) on the skin surface rehydrates the gel layer, initiating drug release, and promoting transdermal absorption through the action of azone.

[0018] As a preferred technical solution of the present invention, in step (I), based on 100 parts by weight of the traditional Chinese medicine mixture, it includes the following components in parts by weight:

[0019]

[0020] The weight portions of Epimedium can be 19, 19.2, 19.4, 19.6, 19.8, 20, 20.2, 20.4, 20.6, 20.8, or 21 parts, and the weight portions of Psoralea can be 15, 15.2, 15.4, 15.6, 15.8, 16, 16.2, 16.4, or 16.6 parts. The weight portions of *Lulu Tong* can be 14, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, or 15 parts, and the weight portions of *Cibotium barometz* can be 10, 10.2, 10.4, 10.6, 10.8, 11, or 11.2 parts. The weight of Clematis chinensis can be 10, 10.2, 10.4, 10.6, 10.8, 11, 11.2, 11.4, 11.6, 11.8, or 12 parts; the weight of Cinnamomum cassia can be 10, 10.2, 10.4, 10.6, 10.8, 11, 11.2, 11.4, 11.6, 11.8, or 12 parts; and the weight of Corydalis yanhusuo can be 16, 16.2, 16.4, 16.6, 16.8, 17, 17.2, 17.4, 17.6, 17.8, or 18 parts, but is not limited to the listed values; other unlisted values ​​within this range also apply.

[0021] In some optional instances, the mesh size of the sieve used for crushing and sieving is 80 to 100 mesh, for example, 80 mesh, 82 mesh, 84 mesh, 86 mesh, 88 mesh, 90 mesh, 92 mesh, 94 mesh, 96 mesh, 98 mesh or 100 mesh, but is not limited to the listed values, and other unlisted values ​​within this range are also applicable.

[0022] In some optional instances, the mass ratio of the traditional Chinese medicine mixture to the aqueous ethanol solution is 1:(8-10), for example, it can be 1:8.0, 1:8.2, 1:8.4, 1:8.6, 1:8.8, 1:9.0, 1:9.2, 1:9.4, 1:9.6, 1:9.8 or 1:10.0, but is not limited to the listed values, other unlisted values ​​within this range are also applicable.

[0023] In some optional instances, the ultrasonic power of the ultrasonic extraction is 300 to 400 W, for example, 300 W, 310 W, 320 W, 330 W, 340 W, 350 W, 360 W, 370 W, 380 W, 390 W or 400 W, but is not limited to the listed values, and other unlisted values ​​within this range are also applicable.

[0024] In some optional instances, the ultrasonic extraction time is 20 to 30 minutes, for example, 20 minutes, 21 minutes, 22 minutes, 23 minutes, 24 minutes, 25 minutes, 26 minutes, 27 minutes, 28 minutes, 29 minutes or 30 minutes, but is not limited to the listed values, and other unlisted values ​​within this range are also applicable.

[0025] In some optional instances, the ultrasonic extraction temperature is 40–50°C, for example, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, or 50°C, but is not limited to the listed values; other unlisted values ​​within this range are also applicable.

[0026] In some alternative instances, the mass ratio of the dregs to water is 1:(5-6), for example, 1:5.0, 1:5.1, 1:5.2, 1:5.3, 1:5.4, 1:5.5, 1:5.6, 1:5.7, 1:5.8, 1:5.9 or 1:6.0, but is not limited to the listed values; other unlisted values ​​within this range are also applicable.

[0027] In some optional instances, the reflux extraction temperature is 70–80°C, for example, 70°C, 71°C, 72°C, 73°C, 74°C, 75°C, 76°C, 77°C, 78°C, 79°C, or 80°C, but is not limited to the listed values; other unlisted values ​​within this range are also applicable.

[0028] In some optional instances, the reflux extraction time is 1 to 2 hours, for example, 1.0h, 1.1h, 1.2h, 1.3h, 1.4h, 1.5h, 1.6h, 1.7h, 1.8h, 1.9h or 2.0h, but is not limited to the listed values; other unlisted values ​​within this range are also applicable.

[0029] As a preferred technical solution of the present invention, in step (II), the amount of β-cyclodextrin added is 3 to 4 wt% of the mass of the extract, for example, it can be 3.0 wt%, 3.1 wt%, 3.2 wt%, 3.3 wt%, 3.4 wt%, 3.5 wt%, 3.6 wt%, 3.7 wt%, 3.8 wt%, 3.9 wt%, or 4.0 wt%, but it is not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0030] This invention specifically limits the amount of β-cyclodextrin added to 3-4 wt% of the extract. Within this range, it can fully encapsulate the fat-soluble active ingredients (such as cinnamon twig volatile oil and corydalis alkaloids) in the extract, forming a stable inclusion complex.

[0031] When the amount of β-cyclodextrin added is less than 3 wt%, it is insufficient to completely encapsulate the fat-soluble active ingredients, and some free volatile oils or alkaloids are lost due to heat during subsequent vacuum concentration. In addition, unencapsulated irritating components (such as cinnamaldehyde) may come into direct contact with the skin, increasing the risk of allergies.

[0032] When the amount of β-cyclodextrin added exceeds 4 wt%, the excess β-cyclodextrin significantly increases the solution viscosity, leading to incomplete sedimentation of solid impurities during centrifugation, increased turbidity of the supernatant, and clogging of the ultrafiltration membrane used in subsequent ultrafiltration processes due to the viscous solution. Furthermore, residual β-cyclodextrin competes with sodium alginate for calcium ions in subsequent steps, interfering with gel network formation, resulting in insufficient transdermal gel structure strength and affecting drug sustained-release performance.

[0033] In some optional examples, after adding the β-cyclodextrin, the mixture is stirred at 55–65°C for 25–35 min, then allowed to stand for 2 h before centrifugation. The temperature can be 55°C, 56°C, 57°C, 58°C, 59°C, 60°C, 61°C, 62°C, 63°C, 64°C, or 65°C, and the time can be 25 min, 26 min, 27 min, 28 min, 29 min, 30 min, 31 min, 32 min, 33 min, 34 min, or 35 min, but is not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0034] In some optional instances, the centrifugation speed is 7000 to 8000 rpm, for example, 7000 rpm, 7100 rpm, 7200 rpm, 7300 rpm, 7400 rpm, 7500 rpm, 7600 rpm, 7700 rpm, 7800 rpm, 7900 rpm or 8000 rpm, but is not limited to the listed values, and other unlisted values ​​within this range are also applicable.

[0035] In some optional instances, the centrifugation time is 10 to 20 minutes, for example, 10 minutes, 11 minutes, 12 minutes, 13 minutes, 14 minutes, 15 minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes or 20 minutes, but is not limited to the listed values, and other unlisted values ​​within this range are also applicable.

[0036] In some optional instances, the ultrafiltration has a molecular weight cutoff of 5 to 15 kDa, for example, 5 kDa, 6 kDa, 7 kDa, 8 kDa, 9 kDa, 10 kDa, 11 kDa, 12 kDa, 13 kDa, 14 kDa or 15 kDa, but is not limited to the listed values; other unlisted values ​​within this range are also applicable.

[0037] As a preferred technical solution of the present invention, in step (III), the temperature of the filtrate concentration under reduced pressure is 40-50°C, for example, it can be 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C or 50°C, but it is not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0038] In some alternative instances, the pressure for vacuum concentration of the filtrate is -0.065 to -0.075 MPa, for example, -0.065 MPa, -0.066 MPa, -0.067 MPa, -0.068 MPa, -0.069 MPa, -0.07 MPa, -0.071 MPa, -0.072 MPa, -0.073 MPa, -0.074 MPa, or -0.075 MPa, but is not limited to the listed values; other unlisted values ​​within this range are also applicable.

[0039] In some optional instances, the filtrate is concentrated under reduced pressure to 20-30% of its original volume, for example, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30%, but is not limited to the listed values; other unlisted values ​​within this range are also applicable.

[0040] In some alternative examples, sodium alginate is added to the concentrate, stirred and dissolved at 50–60°C, and then cooled to room temperature. Subsequently, azone, glycyrrhizic acid, and nano zinc oxide are added, mixed thoroughly, and then calcium chloride solution is added dropwise. The temperature range may be 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, or 60°C, but is not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0041] In some optional instances, the amount of sodium alginate added is 3 to 4 wt% of the mass of the concentrate, for example, 3.0 wt%, 3.1 wt%, 3.2 wt%, 3.3 wt%, 3.4 wt%, 3.5 wt%, 3.6 wt%, 3.7 wt%, 3.8 wt%, 3.9 wt%, or 4.0 wt%, but is not limited to the listed values; other unlisted values ​​within this range are also applicable.

[0042] This invention specifically limits the amount of sodium alginate added to 3-4 wt% of the concentrate. Within this range, the sodium alginate molecular chains can form a sufficient but not excessively dense three-dimensional network when calcium ions crosslink. This network can effectively encapsulate drug components (especially β-cyclodextrin inclusion complexes) and provide a stable sustained-release carrier, while maintaining appropriate porosity to ensure smooth diffusion of azone-promoted drug molecules.

[0043] When the amount of sodium alginate added is less than 3 wt%, the number of sodium alginate molecules is insufficient, and the gel network formed after cross-linking with calcium ions is too sparse. This results in insufficient mechanical strength to effectively encapsulate the drug components, causing the β-cyclodextrin inclusion complex to be released prematurely during drying or application. Furthermore, an excessively thin gel layer reduces the adhesion durability of the patch to the skin, making it prone to falling off due to body activity. Simultaneously, the sparse gel network cannot constrain the nano-zinc oxide particles, leading to their aggregation and reduced antibacterial effect.

[0044] When the amount of sodium alginate added exceeds 4 wt%, the high concentration of sodium alginate will competitively absorb water when mixed with starch-based binders, leading to an increase in the viscosity of the slurry. This makes it prone to air bubbles or uneven thickness during the coating process, and the paste becomes more brittle and prone to cracking after drying. In addition, excessive sodium alginate will form an overly dense gel network structure, which on the one hand hinders the free movement of azone molecules, weakening their transdermal ability; on the other hand, the dense network structure will also excessively block drug release, making it difficult for the active ingredients to penetrate the gel layer and reach the skin.

[0045] In some alternative instances, the amount of azone added is 3 to 5 wt% of the concentrate mass, for example, 3.0 wt%, 3.2 wt%, 3.4 wt%, 3.6 wt%, 3.8 wt%, 4.0 wt%, 4.2 wt%, 4.4 wt%, 4.6 wt%, 4.8 wt%, or 5.0 wt%, but is not limited to the listed values; other unlisted values ​​within this range are also applicable.

[0046] In some alternative examples, the amount of glycyrrhizic acid added is 0.2 to 0.3 wt% of the mass of the concentrate, for example, 0.2 wt%, 0.21 wt%, 0.22 wt%, 0.23 wt%, 0.24 wt%, 0.25 wt%, 0.26 wt%, 0.27 wt%, 0.28 wt%, 0.29 wt%, or 0.3 wt%, but is not limited to the listed values; other unlisted values ​​within this range are also applicable.

[0047] In some optional instances, the amount of nano zinc oxide added is 0.8 to 1.2 wt% of the mass of the concentrate, for example, 0.8 wt%, 0.85 wt%, 0.9 wt%, 0.95 wt%, 1 wt%, 1.05 wt%, 1.1 wt%, 1.15 wt%, or 1.2 wt%, but is not limited to the listed values; other unlisted values ​​within this range are also applicable.

[0048] This invention specifically limits the amount of nano zinc oxide added to 0.8–1.2 wt% of the concentrated solution. The effects of nano zinc oxide are as follows: Firstly, its surface zinc ions form weak coordination bonds with the carboxyl groups in the gel, enhancing the stability of the gel network structure and preventing excessive swelling of the patch due to sweat penetration during use. Secondly, an appropriate amount of nano zinc oxide forms a physical barrier, effectively blocking the degradation of photosensitive components (such as psoralen and icariin) by ultraviolet rays. Thirdly, the antibacterial activity of nano zinc oxide complements the anti-inflammatory effect of glycyrrhizic acid, jointly maintaining the skin microenvironment at the application site.

[0049] When the amount of nano-zinc oxide added is less than 0.8 wt%, the ultraviolet shielding effect is insufficient, which will accelerate the decomposition of photosensitive components and reduce the duration of efficacy. In addition, the antibacterial ability is weakened, leading to bacterial growth after 24 hours of application and increasing the risk of skin infection. At the same time, too few nano-zinc oxide particles are insufficient to form an effective physical barrier, resulting in a decrease in the transdermal gel's ability to resist sweat erosion, and the patch is prone to falling off the skin due to excessive moisture absorption.

[0050] When the amount of nano-zinc oxide added exceeds 1.2 wt%, the excess nano-zinc oxide particles will aggregate in the transdermal gel, forming micron-sized aggregates that block the pores of the gel network and hinder the diffusion of drug molecules into the skin. Furthermore, high concentrations of nano-zinc oxide significantly increase the solution viscosity, interfering with the uniform cross-linking of calcium ions and sodium alginate, and affecting the gel network structure.

[0051] In some alternative examples, the calcium chloride solution has a mass fraction of 1 to 3 wt%, for example, 1.0 wt%, 1.2 wt%, 1.4 wt%, 1.6 wt%, 1.8 wt%, 2.0 wt%, 2.2 wt%, 2.4 wt%, 2.6 wt%, 2.8 wt%, or 3.0 wt%, but is not limited to the listed values; other unlisted values ​​within this range are also applicable.

[0052] In some alternative examples, the molar ratio of sodium alginate to calcium ions in the calcium chloride solution is 1:(0.8 to 1.2), for example, it can be 1:0.8, 1:0.85, 1:0.9, 1:0.95, 1:1.0, 1:1.05, 1:1.1, 1:1.15 or 1:1.2, but is not limited to the listed values, other unlisted values ​​within this range are also applicable.

[0053] As a preferred technical solution of the present invention, in step (IV), the mass ratio of the transdermal gel to the starch-based adhesive is 1:(1.8 to 2.2), for example, it can be 1:1.8, 1:1.85, 1:1.9, 1:1.95, 1:2.0, 1:2.05, 1:2.1, 1:2.15 or 1:2.2, but it is not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0054] This invention specifically defines the mass ratio of transdermal gel to starch-based adhesive as 1:(1.8–2.2). Within this range, the oxidized starch carboxyl groups in the starch-based adhesive form moderate cross-links with the sodium alginate gel network through hydrogen bonds. This enhances the cohesive force of the slurry, preventing it from flowing during application, while also maintaining gel pores to ensure smooth diffusion of the azone penetration enhancer and drug components into the skin. Simultaneously, the nano-silica in the starch-based adhesive fills the gaps in the gel network, improving the toughness of the dried paste and the adhesion to the non-woven fabric, preventing the patch from curling or falling off due to limb movement during application.

[0055] When the amount of starch-based binder added is below the lower limit defined in this invention, the slurry exhibits high viscoelasticity due to the excessively high proportion of transdermal gel. This can easily lead to stringing or uneven thickness during application, and the paste becomes too brittle after drying, leaving fragments upon removal. Furthermore, insufficient starch-based binder cannot adequately encapsulate the gel particles, resulting in the sodium alginate-calcium gel network being exposed on the surface. Upon application, this network will swell and release the drug too quickly upon contact with sweat, failing to maintain the required sustained release for more than 12 hours.

[0056] When the amount of starch-based adhesive added exceeds the upper limit of the range defined in this invention, the excess starch molecules will form a dense barrier. On the one hand, this will block the gel pores and hinder the migration of drug molecules to the skin; on the other hand, the hydroxyl groups on the starch chain will form hydrogen bonds with azone, weakening its transdermal ability.

[0057] In some optional examples, the coating thickness of the slurry on the surface of the nonwoven carrier is 0.13 to 0.18 mm, for example, 0.13 mm, 0.135 mm, 0.14 mm, 0.145 mm, 0.15 mm, 0.155 mm, 0.16 mm, 0.165 mm, 0.17 mm, 0.175 mm or 0.18 mm, but is not limited to the listed values, and other unlisted values ​​within this range are also applicable.

[0058] In some alternative instances, the drying temperature is 40–50°C, for example, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, or 50°C, but is not limited to the listed values; other unlisted values ​​within this range are also applicable.

[0059] In some optional instances, the drying time is 0.5 to 1 hour, for example, it can be 0.5 hours, 0.55 hours, 0.6 hours, 0.65 hours, 0.7 hours, 0.75 hours, 0.8 hours, 0.85 hours, 0.9 hours, 0.95 hours or 1 hour, but is not limited to the listed values, other unlisted values ​​within this range are also applicable.

[0060] As a preferred embodiment of the present invention, the starch-based adhesive is obtained by spray drying a mixture of modified starch and nano-silica. The modified starch is obtained by sequentially treating corn starch with hydrogen peroxide oxidation, silane coupling agent, and magnesium stearate.

[0061] In some optional examples, the starch-based adhesive is specifically prepared by the following method:

[0062] (1) Disperse corn starch in deionized water to obtain a starch solution, add ferrous sulfate catalyst and hydrogen peroxide solution to the starch solution, mix, stir and heat to react to obtain an oxidized starch solution;

[0063] (2) Add silane coupling agent and magnesium stearate to the oxidized starch solution, add citric acid solution to adjust the pH, then mix, stir and heat to react, centrifuge after the reaction is completed and collect the precipitate;

[0064] (3) The precipitate is mixed with nano-silica and then spray-dried, pulverized and sieved to obtain the starch-based adhesive.

[0065] When the starch-based adhesive prepared in this invention is mixed with the transdermal gel, the oxidized starch carboxyl groups in the starch-based adhesive form a hydrogen bond network with the sodium alginate molecular chains, enhancing the interfacial bonding force and preventing phase separation during slurry application. The hydrophobic modified layer of the starch-based adhesive itself can regulate the water absorption rate, ensuring the long-lasting adhesion of the patch in a sweaty environment (maintaining it for more than 12 hours) while preventing excessive swelling and compression of the transdermal gel, which would affect drug release.

[0066] First, under the catalysis of ferrous sulfate, hydrogen peroxide releases hydroxyl radicals (·OH), which selectively attack the primary hydroxyl group at the C6 position of the glucose unit in corn starch, oxidizing it to an aldehyde group and further oxidizing it to a carboxyl group (-COOH). This starch oxidation reduces the starch molecular weight, improves its dispersibility, and prevents clumping during subsequent mixing with the transdermal gel. Furthermore, the introduced carboxyl group provides reaction sites for silane coupling, and simultaneously forms hydrogen bond crosslinking points during subsequent mixing with sodium alginate gel.

[0067] Subsequently, the added silane coupling agent (such as KH550) hydrolyzes to silanol (Si-OH) in a weakly acidic environment (pH = 4.8–5.2). This silanol condenses with the hydroxyl groups of oxidized starch to form Si-OC covalent bonds, while the long organic chains of the silane align directionally on the starch surface, constructing a hydrophobic layer. Simultaneously added magnesium stearate plays two roles: firstly, magnesium ions coordinate with the carboxyl groups of oxidized starch, enhancing cohesion; secondly, long stearic acid chains insert into the gaps between the silane hydrophobic layer, forming a dynamic lubrication network. The silane coupling agent and magnesium stearate work synergistically, endowing the starch-based adhesive with excellent moisture regulation capabilities. The hydrophobic layer formed by silane grafting prevents excessive moisture penetration, and the coordination bonds between magnesium ions and carboxyl groups maintain structural rigidity, ensuring that the adhesive plaster swells slowly rather than disintegrates rapidly in a humid environment.

[0068] The addition of nano-silica achieves a mechanical enhancement effect. Its abundant silanol groups (Si-OH) on the surface form a dense hydrogen bond network with the residual hydroxyl groups of oxidized starch. Nano-silica is uniformly filled in the gaps between starch molecular chains, producing a physical cross-linking effect. On the one hand, it improves the tensile strength of starch-based adhesives, making the dried paste more resistant to the stress generated by limb activities. On the other hand, it locks in some free water through surface adsorption, reducing the degree of swelling of the patch in sweat.

[0069] As a preferred technical solution of the present invention, in step (1), the mass fraction of corn starch in the starch solution is 10-12 wt%, for example, it can be 10 wt%, 10.2 wt%, 10.4 wt%, 10.6 wt%, 10.8 wt%, 11 wt%, 11.2 wt%, 11.4 wt%, 11.6 wt%, 11.8 wt%, or 12 wt%, but it is not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0070] In some alternative examples, the amount of ferrous sulfate catalyst added is 0.5 to 1.5 wt% of the mass of corn starch in the starch solution, for example, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1.0 wt%, 1.1 wt%, 1.2 wt%, 1.3 wt%, 1.4 wt%, or 1.5 wt%, but is not limited to the listed values; other unlisted values ​​within this range are also applicable.

[0071] In some alternative examples, the hydrogen peroxide solution has a mass fraction of 5 to 7 wt%, for example, 5.0 wt%, 5.2 wt%, 5.4 wt%, 5.6 wt%, 5.8 wt%, 6.0 wt%, 6.2 wt%, 6.4 wt%, 6.6 wt%, 6.8 wt%, or 7.0 wt%, but is not limited to the listed values; other unlisted values ​​within this range are also applicable.

[0072] In some alternative examples, the amount of hydrogen peroxide solution added is 8 to 12 wt% of the mass of corn starch in the starch solution, for example, 8.0 wt%, 8.5 wt%, 9.0 wt%, 9.5 wt%, 10.0 wt%, 10.5 wt%, 11.0 wt%, 11.5 wt%, or 12.0 wt%, but is not limited to the listed values; other unlisted values ​​within this range are also applicable.

[0073] This invention specifically limits the amount of hydrogen peroxide solution added to 8-12 wt% of the corn starch in the starch solution. Within this range, the starch molecular chains can be precisely cleaved and an appropriate amount of carboxyl groups introduced. On the one hand, this moderately reduces the molecular weight of the starch, improves its water dispersibility, and ensures uniform reaction with the silane coupling agent. On the other hand, the appropriate amount of carboxyl groups forms hydrogen bonds with the sodium alginate gel, enhancing the bonding strength between the transdermal gel and the starch-based adhesive. Simultaneously, the appropriate degree of oxidation maintains the film-forming ability of the starch and avoids excessive chain cleavage that could reduce the mechanical properties of the starch-based adhesive.

[0074] When the amount of hydrogen peroxide solution added is less than 8 wt%, the oxidation of starch is insufficient, and the high molecular weight of starch results in poor water dispersibility of the starch-based adhesive. This leads to clumping when mixed with transdermal gel, and particles appear during the coating process. Furthermore, insufficiently opened starch molecules can affect the grafting of silane coupling agents, resulting in an incomplete hydrophobic layer construction of the starch-based adhesive. This causes the plaster to absorb water and swell significantly when exposed to sweat, reducing its adhesion.

[0075] When the amount of hydrogen peroxide solution added exceeds 12 wt%, excessive oxidation causes starch molecules to degrade excessively into small molecular fragments. Although water solubility increases, film-forming properties are significantly reduced, resulting in a brittle film layer after drying that cannot withstand the stress of limb bending and thus breaks. In addition, excessive oxidation leads to the formation of a large number of carboxyl groups. When mixed with transdermal gel, the excess carboxyl groups combine with calcium ions, competing for cross-linking sites of sodium alginate, resulting in a loose gel network structure and premature drug release.

[0076] In some optional instances, the mixing and heating temperature is 40 to 50°C, for example, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C or 50°C, but is not limited to the listed values, and other unlisted values ​​within this range are also applicable.

[0077] In some optional instances, the mixing and heating time is 1.5 to 2.5 hours, for example, 1.5 hours, 1.6 hours, 1.7 hours, 1.8 hours, 1.9 hours, 2.0 hours, 2.1 hours, 2.2 hours, 2.3 hours, 2.4 hours, or 2.5 hours, but is not limited to the listed values; other unlisted values ​​within this range are also applicable.

[0078] As a preferred technical solution of the present invention, in step (2), the amount of silane coupling agent added is 0.3 to 0.8 wt% of the mass of the oxidized starch solution, for example, it can be 0.3 wt%, 0.35 wt%, 0.4 wt%, 0.45 wt%, 0.5 wt%, 0.55 wt%, 0.6 wt%, 0.65 wt%, 0.7 wt%, 0.75 wt%, or 0.8 wt%, but it is not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0079] In some alternative examples, the amount of magnesium stearate added is 0.5 to 1 wt% of the mass of the oxidized starch solution, for example, 0.5 wt%, 0.55 wt%, 0.6 wt%, 0.65 wt%, 0.7 wt%, 0.75 wt%, 0.8 wt%, 0.85 wt%, 0.9 wt%, 0.95 wt%, or 1 wt%, but is not limited to the listed values; other unlisted values ​​within this range are also applicable.

[0080] The present invention specifically limits the amount of magnesium stearate added to 0.5 to 1 wt% of the mass of the oxidized starch solution. Within this range, magnesium ions form coordination bonds with the carboxyl groups of oxidized starch, enhancing the intermolecular cohesive force; long-chain fatty acids are embedded in the gaps between starch molecules, exerting a dynamic lubrication effect, so that the slurry has suitable fluidity when coated, ensuring uniform spreading on the nonwoven fabric while avoiding excessive flow.

[0081] When the amount of magnesium stearate added is less than 0.5 wt%, the cohesive force of the slurry is too strong during coating, making it difficult to spread evenly through the coating equipment, resulting in poor uniformity of the thickness of the dried paste. In addition, too low an amount of magnesium stearate leads to a lack of fatty acid chain buffer, which significantly increases the brittleness of the starch-based adhesive, making the paste easy to break and leave residue on the skin surface when it is peeled off.

[0082] When the amount of magnesium stearate exceeds 1 wt%, the excess magnesium ions compete with sodium alginate for calcium ions, interfering with the cross-linking density of the gel network and accelerating drug release. Furthermore, the fatty acid chains deposited on the surface form a dense hydrophobic film at the interface between the patch and the skin, hindering the penetration of azone penetration enhancers and drug components into the skin.

[0083] In some alternative instances, the citric acid solution is added dropwise to adjust the pH of the mixed solution to 4.8–5.2, for example, 4.8, 4.85, 4.9, 4.95, 5.0, 5.05, 5.1, 5.15, or 5.2, but not limited to the listed values; other unlisted values ​​within this range are also applicable.

[0084] In some optional instances, the citric acid solution has a mass fraction of 5 to 10 wt%, for example, 5.0 wt%, 5.5 wt%, 6 wt%, 6.5 wt%, 7 wt%, 7.5 wt%, 8 wt%, 8.5 wt%, 9 wt%, 9.5 wt%, or 10 wt%, but is not limited to the listed values; other unlisted values ​​within this range are also applicable.

[0085] In some optional instances, the mixing and heating temperature is 60 to 70°C, for example, 60°C, 61°C, 62°C, 63°C, 64°C, 65°C, 66°C, 67°C, 68°C, 69°C or 70°C, but is not limited to the listed values, and other unlisted values ​​within this range are also applicable.

[0086] In some optional instances, the mixing and heating time is 1 to 2 hours, for example, 1.0h, 1.1h, 1.2h, 1.3h, 1.4h, 1.5h, 1.6h, 1.7h, 1.8h, 1.9h or 2.0h, but is not limited to the listed values; other unlisted values ​​within this range are also applicable.

[0087] In some optional instances, the centrifugation speed is 3000 to 4000 rpm, for example, 3000 rpm, 3100 rpm, 3200 rpm, 3300 rpm, 3400 rpm, 3500 rpm, 3600 rpm, 3700 rpm, 3800 rpm, 3900 rpm or 4000 rpm, but is not limited to the listed values, and other unlisted values ​​within this range are also applicable.

[0088] In some optional instances, the centrifugation time is 8 to 12 minutes, for example, 8.0 minutes, 8.5 minutes, 9.0 minutes, 9.5 minutes, 10.0 minutes, 10.5 minutes, 11.0 minutes, 11.5 minutes, or 12.0 minutes, but is not limited to the listed values; other unlisted values ​​within this range are also applicable.

[0089] As a preferred technical solution of the present invention, in step (3), the mass ratio of the precipitate to the nano-silica is 100:(2-3), for example, it can be 100:2.0, 100:2.1, 100:2.2, 100:2.3, 100:2.4, 100:2.5, 100:2.6, 100:2.7, 100:2.8, 100:2.9 or 100:3.0, but it is not limited to the listed values. Other unlisted values ​​within this range are also applicable.

[0090] This invention specifically limits the mass ratio of precipitate to nano-silica to 100:(2-3). Within this range, nano-silica, with its huge specific surface area, forms a dense hydrogen bond network with oxidized starch molecules. On the one hand, nano-silica uniformly fills the gaps between starch molecular chains, improving the tensile strength of starch-based adhesives through physical cross-linking, enabling the dried paste to withstand the stress generated by limb activity. On the other hand, the silanol groups on the surface of nano-silica adsorb free water molecules, reducing the swelling rate of the patch in a sweat environment and maintaining a lasting bond with the nonwoven fabric.

[0091] When the amount of nano-silica added is below the lower limit of the range defined in this invention, the tensile strength of the dried paste decreases, making it prone to breakage upon removal. Furthermore, insufficient nano-silica absorption causes the paste to swell too rapidly in humid environments, leading to detachment of the paste layer from the non-woven fabric carrier.

[0092] When the amount of nano-silica added exceeds the upper limit of the range defined in this invention, the excess nano-silica agglomerates in the starch matrix to form micron-sized aggregates, which not only lose their mechanical reinforcing effect, but also become stress concentration points, increasing the brittleness of the paste after drying.

[0093] In some optional instances, the inlet temperature of the spray dryer is 105–115°C, for example, 105°C, 106°C, 107°C, 108°C, 109°C, 110°C, 111°C, 112°C, 113°C, 114°C, or 115°C, but is not limited to the listed values; other unlisted values ​​within this range are also applicable.

[0094] In some optional instances, the outlet temperature of the spray dryer is 50–60°C, for example, 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, or 60°C, but is not limited to the listed values; other unlisted values ​​within this range are also applicable.

[0095] In some optional instances, the sieve mesh size of the pulverized material is 120 to 150 mesh, for example, 120 mesh, 125 mesh, 130 mesh, 135 mesh, 140 mesh, 145 mesh or 150 mesh, but is not limited to the listed values, and other unlisted values ​​within this range are also applicable.

[0096] Secondly, the present invention provides a kidney-warming, meridian-clearing, and pain-relieving ointment prepared using the preparation method described in the first aspect.

[0097] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0098] The preparation method of the kidney-warming and meridian-clearing analgesic plaster provided by this invention organically combines the effective components of traditional Chinese medicine with modern pharmaceutical technology, which significantly improves the stability, transdermal efficiency and clinical applicability of the drug. The resulting kidney-warming and meridian-clearing analgesic plaster has the advantages of strong analgesia, long-lasting sustained release and low irritation. Attached Figure Description

[0099] Figure 1 The following is a flowchart of the preparation process of the kidney-warming, meridian-clearing, and pain-relieving plaster provided in Examples 1-19 of this invention;

[0100] Figure 2 These are photographs of mouse skin in the negative control group, positive control group, and drug administration group (Example 1) during the sensitization test.

[0101] Figure 3 Microscopic images of mouse ear cell tissues in the control group (blank matrix) and the drug-treated group (Example 1) during the anti-inflammatory effect test. Detailed Implementation

[0102] The technical solutions of the present invention will be described in detail below with reference to specific embodiments and accompanying drawings. The embodiments described herein are specific implementations of the present invention, used to illustrate the concept of the present invention; these descriptions are explanatory and exemplary, and should not be construed as limiting the implementation methods or the scope of protection of the present invention. In addition to the embodiments described herein, those skilled in the art can employ other obvious technical solutions based on the content disclosed in the claims and specification of this application. These technical solutions include those that make any obvious substitutions and modifications to the embodiments described herein.

[0103] Example 1

[0104] This embodiment provides a method for preparing a kidney-warming, meridian-clearing, and pain-relieving plaster, such as... Figure 1 As shown, the preparation method specifically includes the following steps:

[0105] (1) Mix 19 parts of Epimedium, 17 parts of Psoralea corylifolia, 14 parts of Liquidambar formosana, 11 parts of Cibotium barometz, 10 parts of Clematis chinensis, 12 parts of Cinnamomum cassia and 17 parts of Corydalis yanhusuo, pulverize them and pass them through an 80-mesh sieve to obtain a mixture of Chinese medicines.

[0106] Add an ethanol-water solution (volume ratio of anhydrous ethanol to deionized water is 6:4) to the Chinese herbal medicine mixture. The mass ratio of the Chinese herbal medicine mixture to the ethanol-water solution is 1:8. After mixing evenly, perform ultrasonic extraction for 30 minutes at an ultrasonic power of 300W and a heating temperature of 40℃. Collect the first filtrate after filtration.

[0107] Add water to the filtered residue, with a mass ratio of residue to water of 1:5. After mixing evenly, reflux extraction is carried out at a heating temperature of 70°C for 2 hours. After filtration, the second filtrate is collected. The first filtrate and the second filtrate are mixed to obtain the extract.

[0108] (2) Add β-cyclodextrin to the extract obtained in step (1). The amount of β-cyclodextrin added is 3wt% of the mass of the extract. Mix and stir at 55℃ for 35 min, then let stand for 2 h, centrifuge at 7000 rpm for 20 min, and use an ultrafiltration membrane with a molecular weight cutoff of 5 kDa to ultrafilter the supernatant after centrifugation and collect the filtrate.

[0109] (3) The filtrate obtained in step (2) was concentrated under reduced pressure to 30% of its original volume at a temperature of 40℃ and a pressure of -0.065MPa to obtain a concentrated solution;

[0110] Sodium alginate was added to the concentrate at a concentration of 3 wt% of the concentrate mass. The solution was stirred and dissolved at 50°C. After complete dissolution, the solution temperature was allowed to drop to room temperature. Then, azone, glycyrrhizic acid, and nano zinc oxide were added, with azone at a concentration of 3 wt%, glycyrrhizic acid at a concentration of 0.2 wt%, and nano zinc oxide at a concentration of 0.8 wt%. After thorough mixing, a 1 wt% calcium chloride solution was added dropwise. The molar ratio of calcium ions in the sodium alginate solution to calcium chloride solution was 1:0.8. After thorough mixing, a transdermal gel was obtained.

[0111] (4) Disperse corn starch in deionized water to obtain a starch solution with a mass fraction of 10 wt%. Add ferrous sulfate catalyst and hydrogen peroxide solution with a mass fraction of 5 wt% to the starch solution. The amount of ferrous sulfate catalyst added is 0.5 wt% of the mass of corn starch, and the amount of hydrogen peroxide solution added is 8 wt% of the mass of corn starch. Then mix and heat at a heating temperature of 40°C for 2.5 h to obtain an oxidized starch solution.

[0112] Silane coupling agent KH550 and magnesium stearate were added to an oxidized starch solution. The amount of silane coupling agent KH550 added was 0.3 wt% of the mass of the oxidized starch solution, and the amount of magnesium stearate added was 0.5 wt% of the mass of the oxidized starch solution. After mixing evenly, a mixed solution was obtained. A 5 wt% citric acid solution was added dropwise to the mixed solution to adjust its pH value to 5.2. Then, the mixture was stirred and heated at 60°C for 2 hours to allow the reaction to occur. After the reaction was completed, the mixture was centrifuged at 3000 rpm for 12 minutes, and the precipitate was collected.

[0113] The precipitate was mixed with nano-silica at a mass ratio of 100:2 and then spray-dried. The inlet temperature of the spray dryer was 105℃ and the outlet temperature was 50℃. Finally, the starch-based adhesive was obtained by crushing the mixture through a 120-mesh sieve.

[0114] (5) The transdermal gel obtained in step (3) and the starch-based adhesive obtained in step (4) are mixed at a mass ratio of 1:1.8 to obtain a slurry. The slurry is coated on the surface of a non-woven fabric carrier with a coating thickness of 0.13 mm and dried at 40°C for 1 h to obtain the warm kidney and unblock meridian analgesic ointment.

[0115] Example 2

[0116] This embodiment provides a method for preparing a kidney-warming, meridian-clearing, and pain-relieving plaster, such as... Figure 1 As shown, the preparation method specifically includes the following steps:

[0117] (1) Mix 19 parts of Epimedium, 16 parts of Psoralea corylifolia, 14 parts of Liquidambar formosana, 12 parts of Cibotium barometz, 11 parts of Clematis chinensis, 12 parts of Cinnamomum cassia and 16 parts of Corydalis yanhusuo, pulverize them and pass them through an 85-mesh sieve to obtain a mixture of Chinese medicines.

[0118] Add an ethanol-water solution (volume ratio of anhydrous ethanol to deionized water is 6:4) to the Chinese herbal medicine mixture. The mass ratio of the Chinese herbal medicine mixture to the ethanol-water solution is 1:8.5. After mixing evenly, perform ultrasonic extraction for 28 minutes at an ultrasonic power of 320W and a heating temperature of 42℃. Collect the first filtrate after filtration.

[0119] Add water to the filtered residue at a mass ratio of 1:5.2. After mixing evenly, reflux extract at 72°C for 1.8 hours. Collect the second filtrate after filtration. Mix the first and second filtrates to obtain the extract.

[0120] (2) Add β-cyclodextrin to the extract obtained in step (1). The amount of β-cyclodextrin added is 3.2 wt% of the mass of the extract. Mix and stir at 58°C for 32 min, then let stand for 2 h, centrifuge at 7200 rpm for 18 min, and use an ultrafiltration membrane with a molecular weight cutoff of 8 kDa to ultrafilter the supernatant after centrifugation and collect the filtrate.

[0121] (3) The filtrate obtained in step (2) was concentrated under reduced pressure to 28% of its original volume at a temperature of 42℃ and a pressure of -0.068MPa to obtain a concentrated solution;

[0122] Sodium alginate was added to the concentrate at a concentration of 3.2 wt% of the concentrate mass. The solution was stirred and dissolved at 52°C. After complete dissolution, the solution temperature was allowed to drop to room temperature. Then, azone, glycyrrhizic acid, and nano zinc oxide were added, with azone at a concentration of 3.5 wt%, glycyrrhizic acid at a concentration of 0.22 wt%, and nano zinc oxide at a concentration of 0.9 wt%. After thorough mixing, a 1.5 wt% calcium chloride solution was added dropwise. The molar ratio of calcium ions in the sodium alginate solution to calcium chloride solution was 1:0.9. After thorough mixing, a transdermal gel was obtained.

[0123] (4) Disperse corn starch in deionized water to obtain a starch solution with a mass fraction of 10.5 wt%. Add ferrous sulfate catalyst and hydrogen peroxide solution with a mass fraction of 5.5 wt% to the starch solution. The amount of ferrous sulfate catalyst added is 0.8 wt% of the mass of corn starch, and the amount of hydrogen peroxide solution added is 9 wt% of the mass of corn starch. Then mix and heat at a heating temperature of 42°C for 2.2 h to obtain an oxidized starch solution.

[0124] Silane coupling agent KH550 and magnesium stearate were added to an oxidized starch solution. The amount of silane coupling agent KH550 added was 0.4 wt% of the mass of the oxidized starch solution, and the amount of magnesium stearate added was 0.6 wt% of the mass of the oxidized starch solution. After mixing evenly, a mixed solution was obtained. A 6 wt% citric acid solution was added dropwise to the mixed solution to adjust its pH value to 5.1. Then, the mixture was stirred and heated at 62°C for 1.8 h to allow the reaction to occur. After the reaction was completed, the mixture was centrifuged at 3200 rpm for 11 min, and the precipitate was collected.

[0125] The precipitate was mixed with nano-silica at a mass ratio of 100:2.2 and then spray-dried. The inlet temperature of the spray dryer was 108℃ and the outlet temperature was 52℃. Finally, the starch-based adhesive was obtained after being pulverized and passed through a 130-mesh sieve.

[0126] (5) The transdermal gel obtained in step (3) and the starch-based adhesive obtained in step (4) are mixed at a mass ratio of 1:1.9 to obtain a slurry. The slurry is coated on the surface of a non-woven fabric carrier with a coating thickness of 0.14 mm and dried at 42°C for 0.8 h to obtain the warm kidney and unblock meridian analgesia plaster.

[0127] Example 3

[0128] This embodiment provides a method for preparing a kidney-warming, meridian-clearing, and pain-relieving plaster, such as... Figure 1 As shown, the preparation method specifically includes the following steps:

[0129] (1) Mix 20 parts of Epimedium, 16 parts of Psoralea corylifolia, 14 parts of Liquidambar formosana, 11 parts of Cibotium barometz, 12 parts of Clematis chinensis, 10 parts of Cinnamomum cassia and 17 parts of Corydalis yanhusuo, pulverize them and pass them through a 90-mesh sieve to obtain a mixture of Chinese medicines.

[0130] Add an ethanol-water solution (volume ratio of anhydrous ethanol to deionized water is 6:4) to the Chinese herbal medicine mixture. The mass ratio of the Chinese herbal medicine mixture to the ethanol-water solution is 1:9. After mixing evenly, perform ultrasonic extraction for 25 minutes at an ultrasonic power of 350W and a heating temperature of 45℃. Collect the first filtrate after filtration.

[0131] Add water to the filtered residue at a mass ratio of 1:5.5. After mixing evenly, reflux extract at 75°C for 1.5 hours. Collect the second filtrate after filtration. Mix the first and second filtrates to obtain the extract.

[0132] (2) Add β-cyclodextrin to the extract obtained in step (1). The amount of β-cyclodextrin added is 3.5 wt% of the mass of the extract. Mix and stir at 60°C for 30 min, then let stand for 2 h, centrifuge at 7500 rpm for 15 min, and use an ultrafiltration membrane with a molecular weight cutoff of 10 kDa to ultrafilter the supernatant after centrifugation and collect the filtrate.

[0133] (3) The filtrate obtained in step (2) was concentrated under reduced pressure to 25% of its original volume at a temperature of 45℃ and a pressure of -0.07MPa to obtain a concentrated solution;

[0134] Sodium alginate was added to the concentrate at a concentration of 3.5 wt% of the concentrate mass. The solution was stirred and dissolved at 55°C. After complete dissolution, the solution temperature was allowed to drop to room temperature. Then, azone, glycyrrhizic acid, and nano zinc oxide were added, with azone at a concentration of 4 wt% of the concentrate mass, glycyrrhizic acid at a concentration of 0.25 wt% of the concentrate mass, and nano zinc oxide at a concentration of 1 wt% of the concentrate mass. After thorough mixing, a 2 wt% calcium chloride solution was added dropwise, with the molar ratio of calcium ions in the sodium alginate solution to calcium chloride solution being 1:1. After thorough mixing, a transdermal gel was obtained.

[0135] (4) Disperse corn starch in deionized water to obtain a starch solution with a mass fraction of 11 wt%. Add ferrous sulfate catalyst and hydrogen peroxide solution with a mass fraction of 6 wt% to the starch solution. The amount of ferrous sulfate catalyst added is 1 wt% of the mass of corn starch, and the amount of hydrogen peroxide solution added is 10 wt% of the mass of corn starch. Then mix and stir at a heating temperature of 45°C for 2 hours to obtain an oxidized starch solution.

[0136] Silane coupling agent KH550 and magnesium stearate were added to an oxidized starch solution. The amount of silane coupling agent KH550 added was 0.5 wt% of the mass of the oxidized starch solution, and the amount of magnesium stearate added was 0.7 wt% of the mass of the oxidized starch solution. After mixing evenly, a mixed solution was obtained. A 7 wt% citric acid solution was added dropwise to the mixed solution to adjust its pH value to 5. Then, the mixture was stirred and heated at 65°C for 1.5 h to allow the reaction to occur. After the reaction was completed, the mixture was centrifuged at 3500 rpm for 10 min, and the precipitate was collected.

[0137] The precipitate was mixed with nano-silica at a mass ratio of 100:2.5 and then spray-dried. The inlet temperature of the spray dryer was 110℃ and the outlet temperature was 55℃. Finally, the starch-based adhesive was obtained by crushing the mixture through a 140-mesh sieve.

[0138] (5) The transdermal gel obtained in step (3) and the starch-based adhesive obtained in step (4) are mixed at a mass ratio of 1:2 to obtain a slurry. The slurry is coated on the surface of a non-woven fabric carrier with a coating thickness of 0.15 mm and dried at 45°C for 0.7 h to obtain the warm kidney and unblock meridian analgesia plaster.

[0139] Example 4

[0140] This embodiment provides a method for preparing a kidney-warming, meridian-clearing, and pain-relieving plaster, such as... Figure 1 As shown, the preparation method specifically includes the following steps:

[0141] (1) Mix 20 parts of Epimedium, 15 parts of Psoralea corylifolia, 15 parts of Liquidambar formosana, 11 parts of Cibotium barometz, 11 parts of Clematis chinensis, 10 parts of Cinnamomum cassia and 18 parts of Corydalis yanhusuo, pulverize them and pass them through a 95-mesh sieve to obtain a mixture of Chinese medicines.

[0142] Add an ethanol-water solution (volume ratio of anhydrous ethanol to deionized water of 6:4) to the Chinese herbal medicine mixture. The mass ratio of the Chinese herbal medicine mixture to the ethanol-water solution is 1:9.5. After mixing evenly, perform ultrasonic extraction for 22 minutes at an ultrasonic power of 380W and a heating temperature of 48℃. Collect the first filtrate after filtration.

[0143] Add water to the filtered residue at a mass ratio of 1:5.8. After mixing evenly, reflux extract at 78°C for 1.2 hours. Collect the second filtrate after filtration. Mix the first and second filtrates to obtain the extract.

[0144] (2) Add β-cyclodextrin to the extract obtained in step (1). The amount of β-cyclodextrin added is 3.8 wt% of the mass of the extract. Mix and stir at 62°C for 28 min, then let stand for 2 h, centrifuge at 7800 rpm for 12 min, and use an ultrafiltration membrane with a molecular weight cutoff of 12 kDa to ultrafilter the supernatant after centrifugation and collect the filtrate.

[0145] (3) The filtrate obtained in step (2) was concentrated under reduced pressure to 22% of its original volume at a temperature of 48℃ and a pressure of -0.072MPa to obtain a concentrated solution;

[0146] Sodium alginate was added to the concentrate at a concentration of 3.8 wt% of the concentrate mass. The solution was stirred and dissolved at 58 °C. After complete dissolution, the solution temperature was allowed to drop to room temperature. Then, azone, glycyrrhizic acid, and nano zinc oxide were added, with azone at a concentration of 4.5 wt%, glycyrrhizic acid at a concentration of 0.28 wt%, and nano zinc oxide at a concentration of 1.1 wt%. After thorough mixing, a 2.5 wt% calcium chloride solution was added dropwise. The molar ratio of calcium ions in the sodium alginate solution to calcium chloride solution was 1:1.1. After thorough mixing, a transdermal gel was obtained.

[0147] (4) Disperse corn starch in deionized water to obtain a starch solution with a mass fraction of 11.5 wt%. Add ferrous sulfate catalyst and hydrogen peroxide solution with a mass fraction of 6.5 wt% to the starch solution. The amount of ferrous sulfate catalyst added is 1.2 wt% of the mass of corn starch, and the amount of hydrogen peroxide solution added is 11 wt% of the mass of corn starch. Then mix and heat at a heating temperature of 48°C for 1.8 h to obtain an oxidized starch solution.

[0148] Silane coupling agent KH550 and magnesium stearate were added to an oxidized starch solution. The amount of silane coupling agent KH550 added was 0.6 wt% of the mass of the oxidized starch solution, and the amount of magnesium stearate added was 0.8 wt% of the mass of the oxidized starch solution. After mixing evenly, a mixed solution was obtained. An 8 wt% citric acid solution was added dropwise to the mixed solution to adjust its pH value to 4.9. Then, the mixture was stirred and heated at 68°C for 1.2 h to allow the reaction to occur. After the reaction was completed, the mixture was centrifuged at 3800 rpm for 9 min, and the precipitate was collected.

[0149] The precipitate was mixed with nano-silica at a mass ratio of 100:2.8 and then spray-dried. The inlet temperature of the spray dryer was 112℃ and the outlet temperature was 58℃. Finally, the starch-based adhesive was obtained after being crushed and passed through a 140-mesh sieve.

[0150] (5) The transdermal gel obtained in step (3) and the starch-based adhesive obtained in step (4) are mixed at a mass ratio of 1:2.1 to obtain a slurry. The slurry is coated on the surface of a non-woven fabric carrier with a coating thickness of 0.16 mm and dried at 48°C for 0.6 h to obtain the warm kidney and unblock meridian analgesia plaster.

[0151] Example 5

[0152] This embodiment provides a method for preparing a kidney-warming, meridian-clearing, and pain-relieving plaster, such as... Figure 1 As shown, the preparation method specifically includes the following steps:

[0153] (1) Mix 21 parts of Epimedium, 15 parts of Psoralea corylifolia, 15 parts of Liquidambar formosana, 10 parts of Cibotium barometz, 12 parts of Clematis chinensis, 11 parts of Cinnamomum cassia and 16 parts of Corydalis yanhusuo, pulverize them and pass them through a 100-mesh sieve to obtain a mixture of Chinese medicines.

[0154] Add an ethanol-water solution (volume ratio of anhydrous ethanol to deionized water is 6:4) to the Chinese herbal medicine mixture. The mass ratio of the Chinese herbal medicine mixture to the ethanol-water solution is 1:10. After mixing evenly, perform ultrasonic extraction for 20 minutes at an ultrasonic power of 400W and a heating temperature of 50℃. Collect the first filtrate after filtration.

[0155] Add water to the filtered residue, with a mass ratio of residue to water of 1:6. After mixing evenly, reflux extraction is performed at a heating temperature of 80°C for 1 hour. After filtration, the second filtrate is collected. The first filtrate and the second filtrate are mixed to obtain the extract.

[0156] (2) Add β-cyclodextrin to the extract obtained in step (1). The amount of β-cyclodextrin added is 4wt% of the mass of the extract. Mix and stir at 65℃ for 25 min, then let stand for 2 h, centrifuge at 8000 rpm for 10 min, and use an ultrafiltration membrane with a molecular weight cutoff of 15 kDa to ultrafilter the supernatant after centrifugation and collect the filtrate.

[0157] (3) The filtrate obtained in step (2) was concentrated under reduced pressure to 20% of its original volume at a temperature of 50℃ and a pressure of -0.075MPa to obtain a concentrated solution;

[0158] Sodium alginate was added to the concentrate at a concentration of 4 wt% of the concentrate mass. The solution was stirred and dissolved at 60°C. After complete dissolution, the solution temperature was allowed to drop to room temperature. Then, azone, glycyrrhizic acid, and nano zinc oxide were added, with azone at a concentration of 5 wt%, glycyrrhizic acid at a concentration of 0.3 wt%, and nano zinc oxide at a concentration of 1.2 wt%. After thorough mixing, a 3 wt% calcium chloride solution was added dropwise. The molar ratio of calcium ions in the sodium alginate solution to calcium chloride solution was 1:1.2. After thorough mixing, a transdermal gel was obtained.

[0159] (4) Disperse corn starch in deionized water to obtain a starch solution with a mass fraction of 12 wt%. Add ferrous sulfate catalyst and hydrogen peroxide solution with a mass fraction of 7 wt% to the starch solution. The amount of ferrous sulfate catalyst added is 1.5 wt% of the mass of corn starch, and the amount of hydrogen peroxide solution added is 12 wt% of the mass of corn starch. Then mix and heat at 50°C for 1.5 h to obtain an oxidized starch solution.

[0160] Silane coupling agent KH550 and magnesium stearate were added to an oxidized starch solution. The amount of silane coupling agent KH550 added was 0.8 wt% of the mass of the oxidized starch solution, and the amount of magnesium stearate added was 1 wt% of the mass of the oxidized starch solution. After mixing evenly, a mixed solution was obtained. A 10 wt% citric acid solution was added dropwise to the mixed solution to adjust its pH value to 4.8. Then, the mixture was stirred and heated at 70°C for 1 h to allow the reaction to occur. After the reaction was completed, the mixture was centrifuged at 4000 rpm for 8 min, and the precipitate was collected.

[0161] The precipitate was mixed with nano-silica at a mass ratio of 100:3 and then spray-dried. The inlet temperature of the spray dryer was 115℃ and the outlet temperature was 60℃. Finally, the starch-based adhesive was obtained by crushing the mixture through a 150-mesh sieve.

[0162] (5) The transdermal gel obtained in step (3) and the starch-based adhesive obtained in step (4) are mixed at a mass ratio of 1:2.2 to obtain a slurry. The slurry is coated on the surface of a non-woven fabric carrier with a coating thickness of 0.18 mm and dried at 50°C for 0.5 h to obtain the warm kidney and unblock meridian analgesia plaster.

[0163] Example 6

[0164] This embodiment provides a method for preparing a kidney-warming, meridian-clearing, and pain-relieving plaster. The difference from Embodiment 1 is that in step (2), the amount of β-cyclodextrin added is adjusted to 1 wt% of the mass of the extract. Other operating steps and process parameters are exactly the same as in Embodiment 1.

[0165] Example 7

[0166] This embodiment provides a method for preparing a kidney-warming, meridian-clearing, and pain-relieving plaster. The difference from Embodiment 1 is that in step (2), the amount of β-cyclodextrin added is adjusted to 6 wt% of the mass of the extract. Other operating steps and process parameters are exactly the same as in Embodiment 1.

[0167] Example 8

[0168] This embodiment provides a method for preparing a kidney-warming, meridian-clearing, and pain-relieving plaster. The difference from Embodiment 1 is that in step (3), the amount of sodium alginate added is adjusted to 1 wt% of the concentrated liquid mass. Other operating steps and process parameters are exactly the same as in Embodiment 1.

[0169] Example 9

[0170] This embodiment provides a method for preparing a kidney-warming, meridian-clearing, and pain-relieving plaster. The difference from Embodiment 1 is that in step (3), the amount of sodium alginate added is adjusted to 6 wt% of the concentrated liquid mass. Other operating steps and process parameters are exactly the same as in Embodiment 1.

[0171] Example 10

[0172] This embodiment provides a method for preparing a kidney-warming, meridian-clearing, and pain-relieving plaster. The difference from Embodiment 1 is that in step (3), the amount of nano zinc oxide added is adjusted to 0.2 wt% of the mass of the concentrated solution. Other operating steps and process parameters are exactly the same as in Embodiment 1.

[0173] Example 11

[0174] This embodiment provides a method for preparing a kidney-warming, meridian-clearing, and pain-relieving plaster. The difference from Embodiment 1 is that in step (3), the amount of nano zinc oxide added is adjusted to 1.5 wt% of the mass of the concentrated liquid. Other operating steps and process parameters are exactly the same as in Embodiment 1.

[0175] Example 12

[0176] This embodiment provides a method for preparing a kidney-warming, meridian-clearing, and pain-relieving plaster. The difference from Embodiment 1 is that in step (4), the amount of hydrogen peroxide solution added is adjusted to 5 wt% of the mass of corn starch in the starch solution. Other operating steps and process parameters are exactly the same as in Embodiment 1.

[0177] Example 13

[0178] This embodiment provides a method for preparing a kidney-warming, meridian-clearing, and pain-relieving plaster. The difference from Embodiment 1 is that in step (4), the amount of hydrogen peroxide solution added is adjusted to 15 wt% of the mass of corn starch in the starch solution. Other operating steps and process parameters are exactly the same as in Embodiment 1.

[0179] Example 14

[0180] This embodiment provides a method for preparing a kidney-warming, meridian-clearing, and pain-relieving plaster. The difference from Embodiment 1 is that in step (4), the amount of magnesium stearate added is adjusted to 0.1 wt% of the mass of the oxidized starch solution. Other operating steps and process parameters are exactly the same as in Embodiment 1.

[0181] Example 15

[0182] This embodiment provides a method for preparing a kidney-warming, meridian-clearing, and pain-relieving plaster. The difference from Embodiment 1 is that in step (4), the amount of magnesium stearate added is adjusted to 1.5 wt% of the mass of the oxidized starch solution. Other operating steps and process parameters are exactly the same as in Embodiment 1.

[0183] Example 16

[0184] This embodiment provides a method for preparing a kidney-warming, meridian-clearing, and pain-relieving plaster. The difference from Embodiment 1 is that in step (4), the mass ratio of the precipitate to nano-silica is adjusted to 100:1. Other operating steps and process parameters are exactly the same as in Embodiment 1.

[0185] Example 17

[0186] This embodiment provides a method for preparing a kidney-warming, meridian-clearing, and pain-relieving plaster. The difference from Embodiment 1 is that in step (4), the mass ratio of the precipitate to nano-silica is adjusted to 100:5. Other operating steps and process parameters are exactly the same as in Embodiment 1.

[0187] Example 18

[0188] This embodiment provides a method for preparing a kidney-warming, meridian-clearing, and pain-relieving plaster. The difference from Embodiment 1 is that in step (5), the mass ratio of transdermal gel to starch-based adhesive is adjusted to 1:1.5. Other operation steps and process parameters are exactly the same as in Embodiment 1.

[0189] Example 19

[0190] This embodiment provides a method for preparing a kidney-warming, meridian-clearing, and pain-relieving plaster. The difference from Embodiment 1 is that in step (5), the mass ratio of transdermal gel to starch-based adhesive is adjusted to 1:2.5. Other operation steps and process parameters are exactly the same as in Embodiment 1.

[0191] The properties of the kidney-warming, meridian-clearing, and pain-relieving plasters prepared in Examples 1-19 were tested. The specific test steps are as follows:

[0192] (1) Cumulative permeation and transdermal rate over 24 hours

[0193] The vertical diffusion cell method was used, with isolated abdominal skin of SD rats as the permeability barrier. The cumulative permeation of the active ingredients (tetracycline and icariin) in the receptor fluid was quantitatively measured, and the cumulative permeation and transdermal rate over 24 hours were calculated to evaluate the transdermal efficiency and sustained-release characteristics of the analgesic ointment. The specific test steps are as follows:

[0194] (1.1) Healthy SD rats (200±20g) were anesthetized and euthanized. The hair on the abdomen was shaved off, the full-thickness skin was peeled off, the subcutaneous fat tissue was removed, and the rats were rinsed repeatedly with physiological saline and stored at -20℃ (thawed before use and soaked in phosphate buffer solution of pH=7.4 for 30min).

[0195] (1.2) Measure 900 mL of physiological saline and 100 mL of polysorbate 80, mix them to prepare a receptor solution containing 0.5% (v / v) polysorbate 80, filter it through a 0.22 μm microporous membrane for sterilization, and set it aside for later use;

[0196] The slurry (transdermal gel + starch-based binder) prepared in the example was uniformly coated on the surface of a dialysis membrane (molecular cutoff 12kDa), and after drying, a circular drug-loaded dialysis membrane with a diameter of 1.5cm was formed for later use.

[0197] (1.3) The pretreated rat skin was fixed in a vertical diffusion chamber (effective diffusion area of ​​1.77 cm²). 2 Between the supply chamber and the receiving chamber, the stratum corneum of the skin faces the supply chamber, 5 mL of preheated acceptor fluid (37±0.5℃) is injected into the receiving chamber, air bubbles are removed, and the magnetic stirring speed is kept constant at 600 rpm.

[0198] Place the drug-loaded dialysis membrane in the supply chamber and ensure it is in close contact with the skin. Seal the top of the chamber with a sealing film to prevent evaporation. This point is recorded as the zero point of time (t = 0h). At t = 0.5h, 2h, 4h, 8h, 12h, and 24h, extract the recipient fluid from the outlet of the receiving chamber (0.5mL each time), and immediately replenish with an equal amount of preheated blank recipient fluid. After sampling, quickly reset the receiving chamber.

[0199] (1.4) The received solution was filtered through a 0.45 μm filter membrane and the concentrations of corydaline (detection wavelength 280 nm) and icariin (270 nm) were determined by high performance liquid chromatography (HPLC). The chromatographic conditions were: C18 column (4.6 × 150 mm, 5 μm), mobile phase acetonitrile-0.1% phosphoric acid water (35:65), flow rate 1.0 mL / min, and column temperature 30 °C.

[0200] The cumulative permeability (Q, μg / cm³) is calculated using the following formula. 2 ):

[0201]

[0202] Among them, C n V represents the measured concentrations (μg / mL) of corydaline and icariin in the receptor fluid during the nth sampling, V is the initial volume of the receptor pool (mL), and C is the measured concentration (μg / mL). i V represents the measured concentrations (μg / mL) of fumaricin and icariin in the recipient fluid at each sampling time. i A represents the volume of the receptor fluid sampled each time (mL), and A represents the effective diffusion area of ​​the diffusion cell (cm²). 2 ).

[0203] Plotting Q against time t, the slope of the linear regression during the steady-state phase (4–24 h) represents the transdermal transdermal rate (μg / cm). 2 / h).

[0204] (2) Analgesic inhibition rate

[0205] Based on the mouse hot plate test model, the analgesic efficiency was quantified by measuring the degree to which the plaster increased the pain threshold of heat stimulation on the mouse paw. The experiment included a matrix group and a drug administration group. The plaster used in the matrix group contained only starch-based adhesive and no transdermal gel; the plaster used in the drug administration group was the paste portion (transdermal gel + starch-based adhesive) of the Wen Shen Tong Luo Zhi Tong plaster prepared in the embodiments of this invention. Ten ICR mice (20±2g) were used in each group and were acclimatized in a constant temperature and humidity environment (25℃, 55%RH) for 3 days before the test.

[0206] Mice were placed on a preheated metal hot plate (20×20cm) at 55±0.5℃. A timer was started, and the first reaction time (s) when the mice exhibited licking their hind paws or jumping behavior was recorded. This time was defined as the baseline pain threshold. Individuals with reaction times less than 5s or greater than 30s were excluded to ensure consistent pain sensitivity among the mice. Each mouse was measured twice (10 min apart), and the average value was taken as the baseline pain threshold (T0).

[0207] The plaster was applied to the shaved skin of the hind limbs of mice and secured with an elastic mesh to prevent it from falling off. The plaster in the matrix group contained only starch-based adhesive and no transdermal gel, while the plaster in the treatment group was the paste portion (transdermal gel + starch-based adhesive) of the kidney-warming, meridian-clearing, and pain-relieving plaster prepared in the previous example. Two hours after application, the mice were placed back on a hot plate, and the pain threshold response time (T0) was recorded. t If the reaction time exceeds 60 seconds (to avoid tissue damage), immediately remove the hot plate and record it as 60 seconds.

[0208] The pain threshold elevation value (ΔT) is calculated using the following formula:

[0209] ΔT=T t -T0.

[0210] The analgesic inhibition rate (%) is calculated using the following formula:

[0211] Analgesia inhibition rate (%) = [(ΔT)] 给药组 -ΔT 基质组 ) / ΔT 基质组 ×100%.

[0212] (3) Sensitization rate

[0213] Healthy white guinea pigs (weighing 300±20g) were used as a model to simulate the sensitization risk of human contact with the plaster. Three groups were set up: a negative control group (saline plaster application), a positive control group (0.1% dinitrochlorophenylacetone solution), and a treatment group (the plaster prepared in the previous example). Each group consisted of 10 guinea pigs, half male and half female. The white guinea pigs were acclimatized for 7 days in an environment with a temperature of 22±2℃ and humidity of 50±10%. The hair on their backs (3×3cm area) was shaved 24 hours before the experiment.

[0214] In the center of the shaved area of ​​the guinea pig, 0.1 mL of Freund's complete adjuvant (FCA) was injected subcutaneously to enhance the immune response. 24 h later, a 2 cm diameter circular filter paper was soaked in the test substance and covered the injection site. The negative control group used filter paper moistened with physiological saline, and the positive control group used filter paper moistened with 0.1% dinitrochlorophenylacetone solution. The treatment group used the ointment prepared in the example (0.1 g of slurry (containing transdermal gel and starch-based binder) + 0.05 mL of physiological saline mixed). After covering the filter paper soaked in the test substance with gauze, it was sealed and fixed with non-sensitive adhesive tape for 48 h. Then the dressing was removed. After 48 h, the skin condition of the dressing area was observed and graded. Grade 0 was no erythema / edema, Grade 1 was scattered erythema, Grade 2 was confluent erythema with mild edema, and Grade 3 was severe erythema with significant edema or ulceration. A score ≥ Grade 1 was considered a positive sensitization.

[0215] The sensitization rate (%) is calculated using the following formula:

[0216] Sensitization rate (%) = (Number of animals with positive sensitization / Total number of animals in the group) × 100%.

[0217] Figure 2 The images show actual photos of mouse skin in the negative control group (physiological saline patch), the positive control group (0.1% dinitrochlorophenylacetone solution), and the treatment group (the ointment of the Wenshen Tongluo Zhitong ointment prepared in Example 1 of this invention). The comparison shows that the mice in the negative control group and the treatment group did not show obvious erythema and edema, while the mice in the positive control group showed a lot of erythema and mild edema.

[0218] (4) Average peel force

[0219] The analgesic plaster (2.5cm×10cm) was applied to the surface of a stainless steel plate and pressed back and forth three times with a pressure roller (2kg). The plate was then equilibrated at 25℃ and 65%RH for 24 hours. Subsequently, it was peeled off at a speed of 300mm / min at 180°. The peeling curve was recorded, and the average peeling force (N / cm) was the mean value of the stable segment of the peeling force curve.

[0220] (5) Anti-inflammatory effect

[0221] 0.2 mL of croton oil was thoroughly mixed with 2.0 mL of pyridine and 7.8 mL of anhydrous diethyl ether to obtain croton oil irritant, which was stored in a brown reagent bottle and kept at 4°C for later use.

[0222] Select healthy male mice weighing 20-22g. After the mice are securely fixed, apply 30μL of croton oil stimulant to the inner side of the left and right ears respectively, and wait 24 hours after application.

[0223] Blank matrix (i.e., the starch-based adhesive prepared in Example 1 of this invention, 0.1g starch-based adhesive + 0.05mL physiological saline) and analgesic ointment prepared in this embodiment of the invention (0.1g slurry (containing transdermal gel and starch-based adhesive) + 0.05mL physiological saline) were applied to the inner sides of the left and right ears respectively. The ointment was repeatedly and evenly applied to the mouse auricles until it was completely absorbed. Each dose was 0.05g, and the treatment lasted for 7 consecutive days.

[0224] Seven days later, mouse ears were collected, fixed in 4% paraformaldehyde for 24 hours, embedded in dehydrated paraffin using standard methods, stained with hematoxylin and eosin (HE), and then observed under an optical microscope.

[0225] like Figure 3 As shown in the comparison, under an optical microscope, a large number of inflammatory cells infiltrated the inner side of the left ear (blank matrix), with vasodilation, blood cell aggregation, and bleeding. In contrast, the inner side of the right ear (with the analgesic ointment) showed a significant reduction in inflammatory cells, decreased vasodilation, and appropriate relief from bleeding.

[0226] The test results are shown in Table 1.

[0227] Table 1

[0228]

[0229]

[0230] The test data from Examples 1, 6, and 7 show that the main function of β-cyclodextrin is to encapsulate lipid-soluble active ingredients, improving stability and water solubility. When the amount added is too low (Example 6), the encapsulation of active ingredients is insufficient, leading to the loss of heat-sensitive substances and exposure of irritating substances, thereby significantly reducing transdermal efficiency and analgesic effect, while increasing the risk of sensitization. When the amount added is too high (Example 7), the solution viscosity increases significantly, not only clogging the ultrafiltration membrane and affecting impurity removal, but also interfering with the formation of the sodium alginate gel network, hindering drug release, resulting in a decrease in the penetration of active ingredients and analgesic inhibition rate. At the same time, residual unencapsulated active ingredients can also cause skin discomfort and increase the sensitization rate.

[0231] The test data from Examples 1, 8, and 9 show that sodium alginate is the core component in forming the sustained-release gel network. When the amount added is too low (Example 8), the gel structure is sparse and cannot effectively encapsulate the drug, resulting in excessively rapid initial release, easy leakage of components that irritate the skin, increased sensitization rate, and reduced penetration and analgesic effect due to drug loss. When the amount added is too high (Example 9), the gel network is too dense, severely hindering the diffusion of drug molecules, reducing the transdermal rate and cumulative penetration, and weakening the analgesic effect.

[0232] The test data from Examples 1, 10, and 11 show that nano-zinc oxide provides UV protection and antibacterial effects, and enhances gel stability. When the amount added is too low (Example 10), the photosensitizing components (such as icariin) are easily degraded by UV radiation, leading to a decrease in the effective concentration of the drug, reduced antibacterial ability, increased risk of skin infection, decreased penetration and analgesic inhibition rate, and increased sensitization rate. When the amount added is too high (Example 11), the nano-zinc oxide agglomerates, forming aggregates that not only hinder drug release but also form local irritants, exacerbating skin allergies and increasing the sensitization rate.

[0233] The test data from Examples 1, 12, and 13 show that when hydrogen peroxide is used to oxidize starch and introduce carboxyl groups, insufficient oxidation (Example 12) leads to poor starch dispersibility, causing it to easily clump when mixed with transdermal gel, reducing slurry uniformity, weakening adhesion to the nonwoven fabric carrier, and significantly decreasing peel strength. When the amount added is too high (Example 13), starch is excessively degraded into small molecules, losing its film-forming ability. This not only reduces peel strength but also indirectly affects the stability of the drug carrier, decreasing penetration and analgesic effect, and increasing sensitization rate.

[0234] The test data from Examples 1, 14, and 15 show that magnesium stearate plays a role in lubrication and enhancing cohesion. When the amount added is too low (Example 14), the viscosity of the slurry is too high, resulting in uneven coating. After drying, the paste becomes more brittle and prone to breakage during peeling, leading to a decrease in peeling force. When the amount added is too high (Example 15), excessive magnesium ions compete with calcium ion crosslinking sites, interfering with the sodium alginate gel network, reducing the drug release rate. Moreover, it forms a hydrophobic film on the surface, hindering the transdermal absorption of the active ingredient, resulting in poor penetration and analgesic effect.

[0235] The test data from Examples 1, 16, and 17 show that nano-silica enhances the mechanical properties and water absorption capacity of the starch-based adhesive. When the amount added is too low (Example 16), the nano-silica is insufficiently filled, resulting in weak tensile strength, decreased peel strength, poor moisture control, and easy swelling and detachment of the paste. When the amount added is too high (Example 17), the nano-silica agglomerates, creating stress concentration points that make the paste brittle and prone to breakage during peeling. Simultaneously, the agglomerates block pores, hindering drug diffusion, leading to a decrease in penetration and transdermal rate, and an increase in sensitization rate due to agglomerate stimulation.

[0236] The test data from Examples 1, 18, and 19 show that the starch-based binder regulates the viscosity of the slurry and drug release. When the amount added is too low (Example 18), the slurry has excessive viscoelasticity, resulting in uneven coating thickness, rapid initial release, and insufficient adhesion, leading to a decrease in peel strength. When the amount added is too high (Example 19), excessive starch molecules form a dense barrier, hindering drug release and significantly reducing the transdermal rate and cumulative penetration. In addition, the hygroscopic swelling of starch also affects the adhesion between the paste and the nonwoven fabric carrier.

[0237] The applicant declares that the above description is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Those skilled in the art should understand that any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention fall within the protection and disclosure scope of the present invention.

Claims

1. A method for preparing a kidney-warming, meridian-clearing, and pain-relieving plaster, characterized in that, The preparation method includes: (I) After mixing and pulverizing Epimedium, Psoralea corylifolia, Liquidambar formosana, Cibotium barometz, Clematis chinensis, Cinnamomum cassia and Corydalis yanhusuo to obtain a mixture of Chinese herbs, an ethanol aqueous solution is added to the mixture for ultrasonic extraction, and the first filtrate is collected after filtration. Water is added to the filtered residue for reflux extraction, and the second filtrate is collected after filtration. The first filtrate and the second filtrate are mixed to obtain an extract. (II) Add β-cyclodextrin to the extract, mix, stir and heat, then centrifuge, take the supernatant for ultrafiltration, and collect the filtrate; (III) The filtrate is concentrated under reduced pressure to obtain a concentrate; sodium alginate, azone, glycyrrhizic acid, nano zinc oxide and calcium chloride solution are added to the concentrate to obtain a transdermal gel; (IV) The transdermal gel is mixed with a starch-based adhesive to obtain a slurry. The slurry is then coated onto the surface of a nonwoven fabric carrier and dried to obtain the warm kidney and blood circulation relieving ointment.

2. The preparation method according to claim 1, characterized in that, In step (I), based on 100 parts by weight of the traditional Chinese medicine mixture, it includes the following components in parts by weight: The sieve mesh size for pulverizing and sieving is 80-100 mesh; The mass ratio of the traditional Chinese medicine mixture to the ethanol aqueous solution is 1:(8-10); The ultrasonic power of the ultrasonic extraction is 300-400W; The ultrasonic extraction time is 20-30 min; The ultrasonic extraction temperature is 40–50°C. The mass ratio of the medicinal residue to water is 1:(5-6); The reflux extraction temperature is 70–80°C; The reflux extraction time is 1 to 2 hours.

3. The preparation method according to claim 1, characterized in that, In step (II), the amount of β-cyclodextrin added is 3 to 4 wt% of the mass of the extract; After adding the β-cyclodextrin, mix and stir at 55-65°C for 25-35 min, then let stand for 2 h and centrifuge. The centrifuge speed is 7000-8000 rpm; The centrifugation time is 10–20 min; The ultrafiltration has a molecular weight cutoff of 5–15 kDa.

4. The preparation method according to claim 1, characterized in that, In step (III), the temperature for vacuum concentration of the filtrate is 40–50°C; The pressure for vacuum concentration of the filtrate is -0.065 to -0.075 MPa; The filtrate is concentrated under reduced pressure to 20-30% of its original volume; Sodium alginate was added to the concentrate and stirred at 50-60°C until dissolved. The solution was then cooled to room temperature. Subsequently, azone, glycyrrhizic acid and nano zinc oxide were added and mixed evenly. Calcium chloride solution was then added dropwise. The amount of sodium alginate added is 3-4 wt% of the mass of the concentrate; The amount of azone added is 3-5 wt% of the mass of the concentrate; The amount of glycyrrhizic acid added is 0.2 to 0.3 wt% of the mass of the concentrate; The amount of nano zinc oxide added is 0.8 to 1.2 wt% of the mass of the concentrate; The calcium chloride solution has a mass fraction of 1–3 wt%. The molar ratio of sodium alginate to calcium ions in the calcium chloride solution is 1:(0.8-1.2).

5. The preparation method according to claim 1, characterized in that, In step (IV), the mass ratio of the transdermal gel to the starch-based adhesive is 1:(1.8-2.2); The coating thickness of the slurry on the surface of the nonwoven carrier is 0.13 to 0.18 mm; The drying temperature is 40–50°C; The drying time is 0.5 to 1 hour.

6. The preparation method according to claim 1, characterized in that, The starch-based adhesive is obtained by spray drying a mixture of modified starch and nano-silica. The modified starch is obtained by sequentially treating corn starch with hydrogen peroxide oxidation, silane coupling agent, and magnesium stearate. The starch-based adhesive is prepared using the following method: (1) Disperse corn starch in deionized water to obtain a starch solution, add ferrous sulfate catalyst and hydrogen peroxide solution to the starch solution, mix, stir and heat to react to obtain an oxidized starch solution; (2) Add silane coupling agent and magnesium stearate to the oxidized starch solution, add citric acid solution to adjust the pH, then mix, stir and heat to react, centrifuge after the reaction is completed and collect the precipitate; (3) The precipitate is mixed with nano-silica and then spray-dried, pulverized and sieved to obtain the starch-based adhesive.

7. The preparation method according to claim 6, characterized in that, In step (1), the mass fraction of corn starch in the starch solution is 10-12 wt%. The amount of ferrous sulfate catalyst added is 0.5 to 1.5 wt% of the mass of corn starch in the starch solution; The hydrogen peroxide aqueous solution has a mass fraction of 5-7 wt%. The amount of hydrogen peroxide solution added is 8-12 wt% of the mass of corn starch in the starch solution; The temperature for mixing and heating is 40–50°C; The mixing and heating time is 1.5 to 2.5 hours.

8. The preparation method according to claim 6, characterized in that, In step (2), the amount of the silane coupling agent added is 0.3 to 0.8 wt% of the mass of the oxidized starch solution; The amount of magnesium stearate added is 0.5 to 1 wt% of the mass of the oxidized starch solution; The citric acid solution was added dropwise to adjust the pH of the mixed solution to 4.8–5.2; The citric acid solution has a mass fraction of 5-10 wt%. The mixing and heating temperature is 60–70°C; The mixing and heating time is 1 to 2 hours; The centrifuge speed is 3000-4000 rpm; The centrifugation time is 8 to 12 minutes.

9. The preparation method according to claim 6, characterized in that, In step (3), the mass ratio of the precipitate to the nano-silica is 100:(2-3); The inlet temperature of the spray dryer is 105–115°C; The outlet temperature of the spray dryer is 50-60°C; The sieve used for crushing and sieving has a mesh size of 120 to 150.

10. A kidney-warming, meridian-clearing, and pain-relieving ointment prepared by the preparation method according to any one of claims 1 to 9.

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