Matrine hydrogel transdermal patch as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of transdermal medicinal preparations, and particularly relates to a matrine hydrogel transdermal patch as well as a preparation method and application thereof. The transdermal patch comprises a back lining layer, a medicine storage layer and a protective layer which are sequentially stacked, and the medicine storage layer is prepared from the following raw materials in parts by weight: 8-15 parts of sophocarpidine, 8-15 parts of a gel matrix, 3-6 parts of ethanol, 0.3-1.5 parts of a penetration enhancer, 3-10 parts of a humectant and the balance of a pH buffer solution, totaling 100 parts. The matrine transdermal patch is high in drug loading capacity, excellent in transdermal efficiency, lasting in slow release performance, good in biocompatibility, high in stability and comfortable to apply, and can be used for long-acting treatment of chronic hepatitis, non-alcoholic fatty liver diseases and tumor diseases.

Description

Technical Field

[0001] This invention belongs to the field of transdermal drug formulation technology, specifically relating to a matrine hydrogel transdermal patch, its preparation method, and its application. Background Technology

[0002] Matrine is a quinolone alkaloid extracted from the legumes *Sophora flavescens* and *Sophora alopecuroides*. It possesses multiple pharmacological activities, including anti-inflammatory, antibacterial, antiviral, antitumor, and immunomodulatory effects, and is widely used in the adjuvant treatment of chronic hepatitis, non-alcoholic fatty liver disease (NAFLD), and cancer. Currently, the main clinical dosage forms of matrine are injections, oral preparations, and topical ointments. Injections have a rapid onset of action but are inconvenient to use, cause significant pain, and pose a risk of infection. Oral preparations are susceptible to the first-pass effect in the liver, resulting in low bioavailability and potential gastrointestinal discomfort. Topical ointments suffer from short drug retention time, low transdermal efficiency, and short duration of action.

[0003] Matrine possesses a small molecular weight, low melting point, and suitable oil / water partition coefficient. These key characteristics not only determine its excellent transdermal absorption performance, but also allow matrine transdermal patches developed based on these characteristics to effectively avoid the influence of gastrointestinal physiological factors (such as pH fluctuations and enzyme degradation) on the drug, while bypassing the first-pass effect of the liver and not increasing the metabolic burden on the liver. Furthermore, transdermal patches enable slow, continuous, and stable drug release, significantly reducing the frequency of administration and thus effectively improving patient medication adherence. This makes it an effective and safe form of therapeutic drug suitable for long-term patient administration. However, existing matrine transdermal patches generally suffer from several bottlenecks, such as low drug loading, insufficient transdermal efficiency, high skin irritation, or complex manufacturing processes, which restrict their clinical application.

[0004] Chinese patent CN106031718A discloses a method for preparing a matrine transdermal agent, using chitosan oligosaccharide as the matrix material. The preparation process involves glacial acetic acid emulsification and glutaraldehyde chemical cross-linking. This process is not only cumbersome, but the glacial acetic acid and glutaraldehyde used may irritate the skin, posing a safety risk. Furthermore, this method focuses on film-forming technology and does not disclose how to improve the transdermal penetration efficiency of matrine. Chinese patent CN1772054A discloses a liver-softening patch and its preparation method, which combines *Cremastra appendiculata*, *Sophora tonkinensis*, *Bupleurum chinense*, *Angelica sinensis*, *Frog corydalis*, *Eupolyphaga sinensis*, and *Rheum palmatum*, physically mixed with cactus juice, and applied to liver diseases. This patch releases rapidly but is unstable, requiring patch replacement twice daily, and its complex compound composition easily leads to skin allergies or irritation. Summary of the Invention

[0005] To address the shortcomings of existing methods, this invention provides a matrine hydrogel transdermal patch, its preparation method, and its applications. This matrine transdermal patch exhibits high drug loading capacity, excellent transdermal efficiency, long-lasting sustained-release properties, good biocompatibility, and high stability. It is comfortable to apply and can be used for long-term treatment of chronic hepatitis, non-alcoholic fatty liver disease, and tumors.

[0006] To achieve the above objectives, the present invention adopts the following technical solution: A matrine hydrogel transdermal patch includes a backing layer, a drug storage layer, and a protective layer stacked sequentially. The drug storage layer is made of the following raw materials in parts by weight: 8-15 parts matrine, 8-15 parts gel matrix, 3-6 parts ethanol, 0.3-1.5 parts penetration enhancer, 3-10 parts humectant, and pH buffer to 100 parts.

[0007] Preferably, the penetration enhancer is one or more of azone, oleyl alcohol, propylene glycol lauryl ester, lecithin, diethylene glycol monoethyl ether, isopropyl myristate, menthol, and propylene glycol.

[0008] Preferably, the penetration enhancer is azone and menthol in a weight ratio of 1-5:1.

[0009] Preferably, the gel matrix is ​​a composite hydrogel composed of polyamide elastomer TPAE and polyacrylic acid PAA.

[0010] Preferably, the composite hydrogel contains silver nanoparticles, the weight of which is 0.05-0.2% of the total weight of the gel matrix.

[0011] Preferably, the moisturizer is one or more of glycerin, 1,3-butanediol, trehalose, and hyaluronic acid.

[0012] Preferably, the pH buffer solution is one or more of the following: carbonate buffer solution, citrate buffer solution, phosphate buffer solution, and acetate buffer solution.

[0013] Preferably, the backing layer is made of polyethylene, polypropylene, or polyurethane; the protective layer is one or more of polyethylene film, polypropylene film, polyethylene terephthalate film, polystyrene film, aluminum film, foamed polyethylene film, and foamed polypropylene film.

[0014] A method for preparing a matrine hydrogel transdermal patch includes the following steps: S1. Add ethanol, humectant, and penetration enhancer to the pH buffer solution in sequence, shake to mix, add matrine and stir until completely dissolved to form a uniformly dispersed drug-loaded solution. S2. Immerse the gel matrix in the drug loading solution described in step S1 to swell, thereby obtaining a drug storage layer; S3. The drug storage layer described in step S2 is evenly coated onto the backing layer, a protective layer is covered on the surface of the drug storage layer, and it is cut into a preset size to obtain the matrine hydrogel transdermal patch.

[0015] The application of the above-mentioned matrine hydrogel transdermal patch in the preparation of drugs for treating chronic hepatitis, non-alcoholic fatty liver disease, or tumors.

[0016] The positive and beneficial effects of this invention are: 1. Achieving efficient drug delivery and long-lasting sustained release This invention uses a polyamide elastomer and a polyacrylic acid (TPAE / PAA) dual-network interpenetrating hydrogel as the core matrix. Its abundant amide bonds and carboxyl groups form multiple hydrogen bonds with matrine molecules. Combined with the three-dimensional porous structure of the hydrogel, it achieves high capacity loading and firm binding of matrine. This interaction ensures that the drug can be continuously and stably released for at least 48 hours without affecting the drug activity, maintaining a stable blood drug concentration and laying the foundation for long-acting treatment.

[0017] 2. High transdermal efficiency The penetration enhancer of this invention is one or more of azone, oleyl alcohol, propylene glycol laurate, lecithin, diethylene glycol monoethyl ether, isopropyl myristate, menthol, and propylene glycol, preferably azone and menthol. Through different mechanisms of action, it synergistically alters the lipid structure of the stratum corneum of the skin, significantly reduces transdermal barrier resistance, and ensures that the drug can penetrate efficiently and enter the systemic circulation.

[0018] 3. Excellent biocompatibility and comfort Firstly, transdermal drug delivery is non-invasive, avoiding injection pain and the first-pass effect of the liver; Secondly, polyamide elastomer hydrogels themselves have excellent biocompatibility and a mild matrix; Third, the optional addition of nano-silver particles to the gel matrix can effectively inhibit the growth of microorganisms at the patch-skin interface and prevent secondary infections, thereby replacing chemical antibacterial agents (such as phenylmercuric nitrate) that may cause irritation or allergies in traditional formulations. Fourth, the addition of low-concentration penetration enhancers and moisturizers ensures the penetration enhancement effect while greatly reducing skin irritation, dryness, or burning sensation caused by single high-concentration penetration enhancers, making long-term application comfortable.

[0019] 4. Good stability and compliance The polyamide elastomer and polyacrylic acid double-network interpenetrating hydrogel of this invention have abundant amide bonds and carboxyl groups, which form stable hydrogen bonds with matrine molecules, enhancing the physicochemical stability of matrine in the formulation. A single application can provide continuous treatment for up to 48 hours. Compared with traditional dosage forms (such as ointments) or short-acting patches that require multiple daily administrations, this significantly reduces the frequency of administration and greatly improves the convenience of long-term treatment and medication adherence for patients. Attached Figure Description

[0020] Figure 1 This is a schematic diagram of the structure of the matrine transdermal patch of the present invention; Figure 2 This is a graph showing the cumulative permeation of the drug storage layer over 48 hours as a function of time in Example 1. Figure 3 This is a graph showing the change in total impurity content of the transdermal patches used in the examples and comparative examples during accelerated testing. Figure 4 This is a bar chart showing the effect of different concentrations of extract from the drug storage layer on the viability of L929 cells in Example 1. Figure 5 Photographs showing the antibacterial effect of the drug storage layer in Examples 1 and 4; Figure 6 This figure shows the effect of the matrine transdermal patch of the present invention on blood lipids and liver fat accumulation in a mouse model of non-alcoholic fatty liver disease. Detailed Implementation

[0021] The present invention will be further described below with reference to some specific embodiments.

[0022] Example 1 A matrine transdermal patch, with its layered structure (see...). Figure 1 The composition of the raw materials is as follows: Backing layer: polyurethane film; Drug storage layer (total mass 100g): matrine 10g, TPAE / PAA hydrogel matrix 12g, ethanol 5g, azone 0.6g, menthol 0.2g, glycerol 6g, PBS buffer 66.2g; Protective layer: polyethylene film.

[0023] The preparation method of TPAE / PAA hydrogel matrix is ​​the same as that in patent number CN120173177A, and mainly includes the following steps: (1) In a high-temperature and high-pressure polymerization reactor, 233.92g hexamethylenediamine, 368.02g adipic acid, and 879.56g polyetheramine ED-2003 (amino-terminated polyethylene oxide-propylene oxide copolymer, molecular weight 2000) were added. Sodium hypophosphite was used as a catalyst, and the amount of sodium hypophosphite was 0.1% of the total weight of caprolactam, adipic acid, and polyetheramine. 50mL of deionized water was added, and carbon dioxide gas was replaced three times. The mixture was kept under pressure at 1.5MPa and heated to 240℃ for 2h. After that, the gas was slowly released to atmospheric pressure and vacuumed for 2h to obtain TPAE prepolymer. (2) Dissolve 5g of TPAE prepolymer in 8mL of deionized water, add 0.648g of crosslinking agent glycerol triglycidyl ether, stir evenly and vacuum defoaming, then inject into a mold and react at 70℃ for 5h to obtain TPAE gel. (3) Dissolve 2.75 mL of acrylic acid in 6.05 mL of deionized water, add 1.2 mL of polyethylene glycol diacrylate solution with a concentration of 20 mg / mL (polyethylene glycol diacrylate molecular weight is 600) and 0.0224 g of photoinitiator Irgacure 2959, mix well, and then pass high-purity nitrogen gas for 20 min to remove oxygen to obtain polymer solution; (4) The TPAE gel obtained in step (2) was immersed in the deoxygenated polymer solution in step (3) for 10 min. The weight ratio of TPAE gel to polymer solution was 1:7. Then it was placed in a mold and the reaction was initiated by ultraviolet light for 4 h to obtain the TPAE / PAA hydrogel matrix. The preparation of the above-mentioned matrine transdermal patch includes the following steps: S1. Pretreatment: Add ethanol, glycerol, menthol and azone to PBS buffer in sequence, shake to mix, add matrine and stir at 37°C for 10 min until completely dissolved to form a uniformly dispersed drug-loaded solution. S2. Drug loading: The TPAE / PAA hydrogel matrix is ​​immersed in the above drug loading solution and swells for 10 min to obtain the drug storage layer; S3. Molding: The drug storage layer is evenly coated on the polyurethane backing layer with a thickness of 500μm. A polyethylene film is then covered on the surface of the drug storage layer and cut into 10cm×15cm patches to obtain the final product.

[0024] Example 2 The matrine transdermal patch in this embodiment is basically the same as that in Example 1, except that the formulation of the drug storage layer is changed as follows: Drug storage layer (total mass 100g): matrine 8g, TPAE / PAA hydrogel matrix 10g, ethanol 4g, azone 0.45g, menthol 0.15g, propylene glycol 0.2g, glycerol 3g, carbonate buffer 74.2g.

[0025] The preparation of the above-mentioned matrine transdermal patch includes the following steps: S1. Pretreatment: Add ethanol, glycerol, menthol, azone and propylene glycol to PBS buffer in sequence, shake to mix, add matrine and stir at 37°C for 10 min until completely dissolved to form a uniformly dispersed drug-loaded solution. S2. Drug loading: The TPAE / PAA hydrogel matrix is ​​immersed in the above drug loading solution and swells for 10 min to obtain the drug storage layer; S3. Molding: The drug storage layer is evenly coated on the polyurethane backing layer with a thickness of 500μm. A polyethylene film is then covered on the surface of the drug storage layer and cut into 10cm×15cm patches to obtain the final product.

[0026] Example 3 The matrine transdermal patch in this embodiment is basically the same as that in Example 1, except that the formulation of the drug storage layer is changed as follows: Drug storage layer (total mass 100g): matrine 15g, TPAE / PAA hydrogel matrix 12g, ethanol 6g, azone 0.9g, menthol 0.3g, glycerol 9g, PBS buffer 56.8g.

[0027] Example 4 The matrine transdermal patch in this embodiment is basically the same as that in Example 1, except that the formulation of the drug storage layer is changed as follows: Drug storage layer (total mass 100g): matrine 10g, TPAE / PAA hydrogel matrix containing silver nanoparticles (TPAE / PAA-Ag) 12g, ethanol 5g, azone 0.6g, menthol 0.2g, glycerol 6g, PBS buffer 66.2g; The preparation method of TPAE / PAA-Ag hydrogel is the same as that in patent number CN120173177A, and mainly includes the following steps: (1) In a high-temperature and high-pressure polymerization reactor, 233.92g hexamethylenediamine, 368.02g adipic acid, and 879.56g polyetheramine ED-2003 (amino-terminated polyethylene oxide-propylene oxide copolymer, molecular weight 2000) were added. Sodium hypophosphite was used as a catalyst, and the amount of sodium hypophosphite was 0.1% of the total weight of caprolactam, adipic acid, and polyetheramine. 50mL of deionized water was added, and carbon dioxide gas was replaced three times. The mixture was kept under pressure at 1.5MPa and heated to 240℃ for 2h. After that, the gas was slowly released to atmospheric pressure and vacuumed for 2h to obtain TPAE prepolymer. (2) Dissolve 5g of TPAE prepolymer in 8mL of deionized water, add 0.648g of crosslinking agent glycerol triglycidyl ether, stir evenly and vacuum defoaming, then inject into a mold and react at 70℃ for 5h to obtain TPAE gel. (3) Dissolve 2.75 mL of acrylic acid in 6.05 mL of deionized water, add 1.2 mL of polyethylene glycol diacrylate solution with a concentration of 20 mg / mL (polyethylene glycol diacrylate molecular weight is 600), 0.0224 g of photoinitiator Irgacure 2959 and 0.0035 g of silver nitrate, mix well, and then pass high-purity nitrogen gas for 20 min to remove oxygen to obtain polymer solution; (4) The TPAE gel obtained in step (2) was immersed in the deoxygenated polymer solution in step (3) for 10 min. The weight ratio of TPAE gel to polymer solution was 1:7. Then it was placed in a mold and the reaction was initiated by ultraviolet light for 4 h to obtain TPAE / PAA-Ag hydrogel matrix. The preparation of the above-mentioned matrine transdermal patch includes the following steps: S1. Pretreatment: Add ethanol, glycerol, menthol and azone to PBS buffer in sequence, shake to mix, add matrine and stir at 37°C for 10 min until completely dissolved to form a uniformly dispersed drug-loaded solution. S2, Drug loading: The TPAE / PAA-Ag hydrogel matrix is ​​immersed in the above drug loading solution and swells for 10 min to obtain the drug storage layer; S3. Molding: The drug storage layer is evenly coated on the polyurethane backing layer with a thickness of 500μm. A polyethylene film is then covered on the surface of the drug storage layer and cut into 10cm×15cm patches to obtain the final product.

[0028] Comparative Example 1: No penetration enhancer The matrine transdermal patch in this embodiment is basically the same as that in Example 1, except that the formulation of the drug storage layer is changed as follows: Drug storage layer (total mass 100g): matrine 10g, TPAE / PAA hydrogel matrix 12g, ethanol 5g, glycerol 6g, PBS buffer 67g; Comparative Example 2: Single penetration enhancer (azone) The matrine transdermal patch in this embodiment is basically the same as that in Example 1, except that the formulation of the drug storage layer is changed as follows: Drug storage layer (total mass 100g): matrine 10g, TPAE / PAA hydrogel matrix 12g, ethanol 5g, azone 0.8g, glycerol 6g, PBS buffer 66.2g; Comparative Example 3: Compound Penetration Enhancer (with varying proportions) The matrine transdermal patch in this embodiment is basically the same as that in Example 1, except that the formulation of the drug storage layer is changed as follows: Drug storage layer (total mass 100g): matrine 10g, TPAE / PAA hydrogel matrix 12g, ethanol 5g, azone 0.2g, menthol 0.6g, glycerol 6g, PBS buffer 66.2g; the mass ratio of azone to menthol is 1:3.

[0029] Comparative Example 4: No moisturizer group The matrine transdermal patch in this embodiment is basically the same as that in Example 1, except that the formulation of the drug storage layer is changed as follows: Drug storage layer (total mass 100g): matrine 10g, TPAE / PAA hydrogel matrix 12g, ethanol 5g, azone 0.6g, menthol 0.2g, PBS buffer 72.2g; Comparative Example 5: Gel matrix content is too low The matrine transdermal patch in this embodiment is basically the same as that in Example 1, except that the formulation of the drug storage layer is changed as follows: Drug storage layer (total mass 100g): matrine 10g, TPAE / PAA hydrogel matrix 8g, ethanol 5g, azone 0.6g, menthol 0.2g, glycerol 10g, PBS buffer 66.2g; Comparative Example 6: The gel matrix is ​​sodium carboxymethyl cellulose. The matrine transdermal patch in this embodiment is basically the same as that in Example 1, except that: Drug storage layer (total mass 100g): matrine 10g, sodium carboxymethyl cellulose 7g, ethanol 5g, azone 0.6g, menthol 0.2g, glycerol 6g, PBS buffer 71.2g; The preparation method is as follows: (1) Preparation of phase A: Dissolve matrine in a mixture of 30g PBS buffer and ethanol, stir until completely dissolved, then add menthol, azone and glycerol in sequence, and stir until homogeneous; (2) Preparation of phase B: Sodium carboxymethyl cellulose was fully swollen in 30g PBS buffer to form a gel matrix; (3) Mixing: Under low speed stirring, slowly add phase A to phase B to avoid introducing too many air bubbles, add the remaining PBS buffer, and continue stirring until a homogeneous viscous gel is formed; (4) Coating and molding: The obtained gel is coated on the polyurethane backing layer with a thickness of 500μm, and a polyethylene film is covered on the surface of the drug storage layer. The gel is then cut into 10cm×15cm patches.

[0030] Application Trial 1. In vitro transdermal test A modified Franz diffusion cell was used, with treated mouse abdominal skin as a barrier, to test the drug storage layers in Examples 1-4 and Comparative Examples 1-6. The receiving solution was pH 7.4 PBS buffer, and the temperature was 37±0.5℃. Samples were taken at 2h, 4h, 6h, 8h, 10h, 12h, 24h, 30h, 36h, and 48h. The concentration of matrine was determined by HPLC, and the cumulative permeation of drug per unit area (Q, mg / cm²) was calculated according to the following formula. 2 ): Where V is the total volume of the receiving liquid, and C n and C i V represents the drug concentration (mg / mL) measured at the nth and ith sampling points, respectively. i S is the sampling volume, and S is the effective diffusion area (cm²). 2 ).

[0031] Plot an in vitro transdermal permeation curve with time t on the x-axis and the cumulative drug permeation per unit area Q on the y-axis. The slope of the straight line portion of the curve is the steady-state transdermal rate J (mg / cm²). 2 / h).

[0032] Table 1. In vitro transdermal parameters of each embodiment and comparative example (n=6, ±SD) As shown in Table 1, the cumulative penetration amount and steady-state transdermal rate of Examples 1-4 were superior to those of the comparative examples over 48 hours. In Comparative Example 1, without a penetration enhancer, matrine was almost unable to penetrate the skin effectively, highlighting the necessity of adding a penetration enhancer. Comparative Examples 2 and 3, by changing the type and formulation of the penetration enhancer, further demonstrated the crucial influence of the choice and formulation on transdermal efficiency. They clearly confirmed that the optimal combination of azone and menthol (weight ratio 1-5:1) as a penetration enhancer significantly improved the cumulative penetration amount and steady-state transdermal rate of matrine per unit area, exhibiting a significant synergistic effect during the penetration enhancement process. Comparative Example 4, lacking a moisturizer, suffered from reduced patch stability, resulting in a decrease in both cumulative penetration amount and steady-state transdermal rate over 48 hours. This confirms the importance of moisturizers in improving the stability of matrine transdermal patches. Comparative Example 5 reduced the amount of gel matrix used, and Comparative Example 6 changed the gel matrix. The cumulative penetration amount and transdermal rate of both were significantly reduced compared with Example 1. This shows that the preferred gel matrix and its amount of use in this invention can more effectively improve the cumulative penetration amount and transdermal rate of the drug and improve the drug utilization rate.

[0033] Example 2 changed the type of penetration enhancer, and the cumulative penetration amount and transdermal rate decreased slightly. The preferred penetration enhancer of the present invention is a combination of azone and menthol (the weight ratio of the two is 1-5:1). Example 3, as a high drug loading group, showed the highest absolute penetration amount and penetration rate, which fully demonstrates that the gel system of the present invention has both excellent drug loading performance and efficient drug release ability. Example 4 introduced silver nanoparticles into the gel matrix to increase antibacterial properties. Compared with Example 1, there was no significant difference in cumulative penetration amount and transdermal rate, indicating that the silver nanoparticles do not affect the transdermal performance of the patch.

[0034] Figure 2The graph shows the cumulative permeation of matrine in the drug storage layer of Example 1 of the present invention over 48 hours. The release process was stable throughout the 48 hours without any stage fluctuations, demonstrating good sustained-release characteristics.

[0035] In summary, the matrine transdermal patch of the present invention has excellent skin penetration ability, can efficiently break through the skin barrier, and significantly improve the transdermal efficiency of the drug, thus having good application value.

[0036] 2. Stability test After packaging the matrine transdermal patches of Examples 1-4 and Comparative Examples 1, 2, 3, and 6, they were placed at a temperature of 40 ± 2°C and a relative humidity of 75% ± 5% for 6 months. Samples were taken at the end of the 1st, 2nd, 3rd, and 6th months of the test period, and the total impurity content was determined by high performance liquid chromatography (General Chapter 0512) according to the Chinese Pharmacopoeia. The results are as follows. Figure 3 As shown.

[0037] Depend on Figure 3 It can be seen that the matrine transdermal patches of Examples 1-4 of this invention exhibit stable impurity formation rates under high temperature and high humidity conditions, fully demonstrating the excellent overall stability of the formulation. Comparative Example 1 had no penetration enhancer, while Comparative Examples 2 and 3 changed the type and formulation of the penetration enhancer; the stability of each comparative example was not as good as the examples, indicating that the introduction of penetration enhancers and appropriate formulation ratios can improve the stability of transdermal formulations. Comparative Example 6 changed the gel matrix, and impurities gradually increased over time, indicating that TPAE / PAA hydrogel can improve the stability of the matrine transdermal patch.

[0038] In summary, the matrine transdermal patch prepared by this invention can maintain good stability under harsh conditions of high temperature and high humidity, and the quality of the transdermal patch is highly controllable, giving it outstanding application advantages.

[0039] 3. Biocompatibility 0.1g of the drug storage layer from Example 1 was immersed in 10mL of complete cell culture medium and shaken on a shaker at 37°C for 24 hours. The extract was then filtered. L929 mouse fibroblasts were seeded into 96-well plates and treated for 24 hours with fresh complete culture medium containing 10%, 20%, 30%, 40%, 50%, and 60% (v / v) concentrations of the extract, respectively. Cell viability was then assessed using the CCK-8 assay, with fresh complete culture medium without the extract serving as a control. The results are as follows: Figure 4 As shown.

[0040] Depend on Figure 4 It can be seen that after 24 hours of treatment with extracts of various concentrations, the cell viability was not significantly different from that of the control group (>95%). The results show that the transdermal patch of the present invention has good in vitro biocompatibility, which fully demonstrates its high safety in future applications.

[0041] 4. Antibacterial test The drug storage layers from Examples 1 and 4 were placed in centrifuge tubes and co-cultured with *E. coli* at 37°C for 2 hours. The centrifuge tubes were then rinsed with PBS buffer, and 10 μL of the rinse solution was spread onto a solid culture medium and incubated at 37°C for 16 hours. A control group without the added drug storage layer was used. Relevant photographs were taken, and the results are as follows: Figure 5 As shown.

[0042] Depend on Figure 5 It can be seen that, compared with the control group, the number of colonies corresponding to the drug storage layers in Examples 1 and 4 was significantly reduced. Among them, the number of colonies in Example 1 was significantly reduced due to the antibacterial properties of matrine itself, thus meeting the antibacterial requirements. The number of colonies corresponding to the drug storage layer in Example 4 was the lowest. This indicates that the introduction of nano-silver particles can further enhance the antibacterial properties of the transdermal patch.

[0043] Experimental results verify that the matrine transdermal patch of the present invention has good antibacterial ability, without the need to add additional irritating antibacterial agents, and can avoid folliculitis, contact dermatitis and other diseases caused by bacterial proliferation in the local moist environment of patch-skin contact, thus having higher safety.

[0044] 5. In vivo pharmacodynamic experiments Eight-week-old male C57BL / 6J mice were provided by Liaoning Changsheng Biotechnology Co., Ltd. All mice were housed under constant temperature (23±2℃) and humidity (55±15%) conditions, with a 12-hour light-dark cycle per day, and had free access to water and either a standard diet or a high-fat diet (D12492, 60% fat) for 16 weeks to establish a non-alcoholic fatty liver disease model. Mice fed a standard diet served as the normal diet group (NC) and acted as a blank control. Mice fed a high-fat diet were randomly divided into three groups: a high-fat diet group (HF), a matrine gavage group (PO), and a matrine transdermal patch group (Mat@TPAE / PAA), with six mice in each group. The intervention and treatment process was as follows: The NC and HF groups received no treatment and were fed a standard diet and a high-fat diet, respectively. The Mat@TPAE / PAA group was fed a high-fat diet and simultaneously received a matrine transdermal patch (prepared according to the drug storage layer ratio in Example 1, with a drug storage layer of 10mg and matrine content of 1mg, and a patch size of 1.5cm × 1.5cm), applied once daily to the skin on the back of the mice. The PO group was fed a high-fat diet and simultaneously received an equal dose of matrine saline solution by gavage for 8 weeks. Serum and liver tissue were collected for medical analysis, and the results were as follows: Figure 6 As shown.

[0045] Depend on Figure 6It was found that, compared with the HF group, the serum triglyceride (TG) and total cholesterol (TC) levels in mice in the PO group and Mat@TPAE / PAA group were significantly reduced. Oil Red O staining of liver tissue showed that the area and degree of hepatic steatosis in the Mat@TPAE / PAA group were significantly reduced compared with the HF group, and the effect was comparable to that in the PO group. This indicates that the matrine transdermal patch of the present invention can effectively deliver matrine into the systemic circulation through the skin and exert a pharmacological effect in the treatment of non-alcoholic fatty liver disease.

[0046] In summary, the matrine transdermal patch of this invention integrates the advantages of high-efficiency drug loading, long-acting sustained release, strong transdermal effect, low irritation, and high stability, solving many bottlenecks in the existing technology and providing an innovative, safe, and effective solution for the clinical administration of matrine. At the same time, it provides more options for the long-term treatment of chronic hepatitis, non-alcoholic fatty liver disease, and tumors.

[0047] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Any other modifications or equivalent substitutions made by those skilled in the art to the technical solutions of the present invention, as long as they do not depart from the spirit and scope of the technical solutions of the present invention, should be covered within the scope of the claims of the present invention.

Claims

1. A matrine hydrogel transdermal patch, characterized in that, It comprises a backing layer, a drug storage layer, and a protective layer stacked in sequence. The drug storage layer is made of the following raw materials in parts by weight: 8-15 parts matrine, 8-15 parts gel matrix, 3-6 parts ethanol, 0.3-1.5 parts penetration enhancer, 3-10 parts humectant, and pH buffer to 100 parts.

2. The matrine hydrogel transdermal patch according to claim 1, characterized in that, The penetration enhancer is one or more of azone, oleyl alcohol, propylene glycol lauryl ester, lecithin, diethylene glycol monoethyl ether, isopropyl myristate, menthol, and propylene glycol.

3. The matrine hydrogel transdermal patch according to claim 2, characterized in that, The penetration enhancer is azone and menthol, with a weight ratio of 1-5:

1.

4. The matrine hydrogel transdermal patch according to claim 1, characterized in that, The gel matrix is ​​a composite hydrogel composed of polyamide elastomer TPAE and polyacrylic acid PAA.

5. The matrine hydrogel transdermal patch according to claim 4, characterized in that, The composite hydrogel contains silver nanoparticles, the weight of which is 0.05-0.2% of the total weight of the gel matrix.

6. The matrine hydrogel transdermal patch according to claim 1, characterized in that, The moisturizer is one or more of glycerin, 1,3-butanediol, trehalose, and hyaluronic acid.

7. The matrine hydrogel transdermal patch according to claim 1, characterized in that, The pH buffer solution is one or more of the following: carbonate buffer solution, citrate buffer solution, phosphate buffer solution, and acetate buffer solution.

8. The matrine hydrogel transdermal patch according to claim 1, characterized in that, The backing layer is made of polyethylene, polypropylene, or polyurethane; the protective layer is one or more of the following: polyethylene film, polypropylene film, polyethylene terephthalate film, polystyrene film, aluminum film, foamed polyethylene film, and foamed polypropylene film.

9. A method for preparing the matrine hydrogel transdermal patch according to any one of claims 1 to 8, characterized in that, Includes the following steps: S1. Add ethanol, humectant, and penetration enhancer to the pH buffer solution in sequence, shake to mix, add matrine and stir until completely dissolved to form a uniformly dispersed drug-loaded solution. S2. Immerse the gel matrix in the drug loading solution described in step S1 to swell, thereby obtaining a drug storage layer; S3. The drug storage layer described in step S2 is evenly coated onto the backing layer, a protective layer is covered on the surface of the drug storage layer, and it is cut into a preset size to obtain the matrine hydrogel transdermal patch.

10. The use of the matrine hydrogel transdermal patch according to any one of claims 1 to 8 in the preparation of a drug for treating chronic hepatitis, non-alcoholic fatty liver disease, or tumor diseases.

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