Compound arnica flower-diclofenac sodium gel plaster as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medical gel emplastrum, and particularly relates to a compound arnica flower-diclofenac sodium gel emplastrum, a preparation method thereof and application of the compound arnica flower-diclofenac sodium gel emplastrum in treatment of rheumatoid arthritis. The plaster comprises a backing layer, a plaster body layer and a protective layer, the plaster body layer is composed of drugs, a transdermal enhancer and a matrix, the matrix comprises a framework material, a cross-linking agent, a filler, a tackifier, a humectant, a cross-linking regulator and water, and the drugs comprise arnica tincture and diclofenac sodium. The invention discloses a preparation method of the compound arnica flower-diclofenac sodium gel emplastrum and provides application of the compound arnica flower-diclofenac sodium gel emplastrum in treating rheumatoid arthritis, and the prepared compound arnica flower-diclofenac sodium gel emplastrum has strong analgesic and anti-inflammatory effects and can be used for treating rheumatoid arthritis.

Description

Technical Field

[0001] The invention belongs to the technical field of medical gel patches, and in particular relates to a compound arnica-diclofenac sodium gel patch, a preparation method thereof, and an application thereof in treating rheumatoid arthritis. Background Art

[0002] Rheumatoid arthritis is a chronic, systemic, autoimmune disease characterized by joint pain and swelling. Most patients with rheumatoid arthritis do not experience joint damage in the early stages, so it is crucial to give timely drug treatment in the early stages. At present, the following drugs are used to treat rheumatoid arthritis, including anti-rheumatic drugs, non-steroidal anti-inflammatory drugs, glucocorticoids, biological agents, and Chinese herbal medicine ingredients. Anti-rheumatic drugs and non-steroidal anti-inflammatory drugs are the first choice for the treatment of rheumatoid arthritis, mainly used to relieve joint swelling. The disadvantage is that there are gastrointestinal adverse reactions after taking them. Glucocorticoids take effect quickly, and long-term use is prone to dependence and adverse reactions. Biological agents are effective, but they are expensive and are difficult to become first-line drugs for the treatment of rheumatoid arthritis. Chinese herbal medicine ingredients have become a research hotspot due to their good efficacy, few side effects, low price, and multi-target treatment of rheumatoid arthritis. However, it is difficult for the above-mentioned single drugs to achieve the ideal therapeutic effect in the treatment of rheumatoid arthritis. Combination therapy is superior to single drug therapy with the advantages of multiple components and multiple targets. Combination therapy has been widely used in the treatment of rheumatoid arthritis since 1950. Antirheumatic drugs and nonsteroidal anti-inflammatory drugs are often used in combination to treat rheumatoid arthritis, with significant effects, but there are many gastrointestinal adverse reactions and poor patient compliance. Therefore, it is urgent to develop a new compound preparation with significant efficacy, small side effects and good compliance. Diclofenac sodium is widely used in the treatment of rheumatoid arthritis as a potent anti-inflammatory analgesic. Diclofenac sodium patch overcomes the problems of gastrointestinal adverse reactions of oral preparations and the need for multiple administrations of latex agents, and improves patient compliance, but there are still problems to be solved: first, its clinical efficacy still needs to be enhanced; second, there is a lot of paste residue after application, a strong tearing sensation, and greater irritation. Summary of the invention

[0003] Based on this, the purpose of the present invention is to provide a compound arnica-diclofenac sodium gel patch and a preparation method thereof and an application thereof in treating rheumatoid arthritis.

[0004] To achieve the above purpose, the present invention adopts the following technical solution:

[0005] A compound arnica flower-diclofenac sodium gel patch comprises a backing layer, a paste layer and a protective layer. The paste layer is composed of a drug, a transdermal enhancer and a matrix. The matrix is ​​a skeleton material, a cross-linking agent, a filler, a viscosity enhancer, a moisturizer, a cross-linking regulator and water. The drugs are arnica tincture and diclofenac sodium.

[0006] The paste layer comprises, by weight, 0.1 to 3 parts of arnica tincture, 0.016 to 0.14 parts of diclofenac sodium, 0.2 to 1.4 parts of a transdermal enhancer, 0.2 to 10 parts of a skeleton material, 0.02 to 10 parts of a cross-linking agent, 0.2 to 10 parts of a filler, 0.2 to 10 parts of a viscosity enhancer, 1 to 45 parts of a moisturizer, 0.02 to 10 parts of a cross-linking regulator, and 30 to 75 parts of water.

[0007] The transdermal enhancer is one or more of azone, N-methylpyrrolidone, oleic acid, propylene glycol, menthol and camphor.

[0008] The framework material is one or more of NP-600, NP-700, NP-800, Carbomer 940 and Carbomer 980.

[0009] The cross-linking agent is one or more of aluminum hydroxide, aluminum chloride, and aluminum glycinate;

[0010] The filler is one or more of kaolin, titanium oxide, zinc oxide, and micro-powder silica gel;

[0011] The cross-linking regulator is one or more of EDTA, citric acid and tartaric acid.

[0012] The viscosity enhancer is one or more of sodium carboxymethyl cellulose, gelatin, gum arabic, polyvinyl alcohol and polyvinyl pyrrolidone.

[0013] The moisturizing agent is one or more of glycerol, propylene glycol, glycerol, D-sorbitol and polyethylene glycol.

[0014] The arnica tincture is obtained by extracting dried arnica flowers through an organic solvent.

[0015] Furthermore, the dried Arnica flowers are mixed with an organic solvent at a solid-liquid ratio of 1:2-1:20, and the preparation method of organic solvent percolation or heating reflux extraction is adopted, and the extracts are combined and concentrated to prepare Arnica tincture for use.

[0016] The organic solvent is a 40%-80% ethanol aqueous solution;

[0017] The organic solvent is percolated at a percolation temperature of 15-30 degrees Celsius, and the percolation time is 24-48 hours after immersion.

[0018] The heating reflux extraction is performed at a heating reflux extraction temperature of 45-85 degrees Celsius, an extraction time of 0.5-2.5 hours, and an ethanol concentration of 40-80%.

[0019] A preparation method of the compound arnica flower-diclofenac sodium gel patch comprises the following steps: uniformly mixing a cross-linking regulator, a viscosity enhancer, arnica tincture and water in proportion to obtain a phase A; uniformly mixing diclofenac sodium, a skeleton material, a cross-linking agent, a filler, a moisturizer and a transdermal enhancer to obtain a phase B; adding the phase A to the phase B at a speed of 30 to 200 r / min under the condition of 30 to 60° C., and fully stirring to obtain a viscous semi-solid drug-containing matrix; placing the obtained viscous semi-solid drug-containing matrix on a backing layer, and then covering the drug surface with a protective layer, and curing at room temperature for 1 to 2 days to obtain the compound arnica flower-diclofenac sodium gel patch.

[0020] An application of the compound arnica flower-diclofenac sodium gel patch, and an application of the compound arnica flower-diclofenac sodium gel patch as a medicine for treating rheumatoid arthritis.

[0021] The backing layer is cotton cloth or non-woven fabric, the drug coating thickness is 0.2-1 mm, the protective layer is anti-sticking paper or plastic film, and the cut size is 5 cm×7 cm or 10 cm×14 cm.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] 1. The present invention proposes to use the botanical medicine arnica tincture in combination with the non-steroidal anti-inflammatory drug diclofenac sodium. From the perspective of mechanism, arnica tincture inhibits the binding of transcription factors NF-κB and NF-AT to DNA, and induces a decrease in the levels of inflammatory factors IL-1β, IL-2, IL-6, TNF-α, etc.; diclofenac sodium inhibits cyclooxygenase, thereby blocking the production of arachidonic acid into prostaglandins. From the perspective of drug efficacy, diclofenac sodium exerts a strong anti-inflammatory and analgesic effect, and arnica tincture exerts an auxiliary anti-inflammatory and analgesic effect, enhances the therapeutic effect, and reduces toxic and side effects. Therefore, diclofenac sodium is used in combination with arnica tincture to achieve a better therapeutic effect.

[0024] 2. The present invention proposes to prepare a gel patch by combining arnica tincture with diclofenac sodium. The matrix is ​​a water-soluble polymer material with a high water content, and the application is more comfortable, without a tearing sensation, and less irritating. Moreover, compared with oral preparations, transdermal preparations can avoid drug stimulation to the gastrointestinal tract and improve the bioavailability of drugs.

[0025] 3. The compound arnica flower-diclofenac sodium gel patch prepared by the preferred formula of the present invention has uniform ingredients in the paste layer, and the gel patch has good viscosity and cohesion, good elasticity and flexibility, is easy to apply and remove, and has no residue.

[0026] 4. The compound arnica flower-diclofenac sodium gel plaster prepared by the present invention has significant anti-inflammatory and analgesic effects and is suitable for the treatment of rheumatoid arthritis. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is a graph showing the effect of different amounts of N-methylpyrrolidone (permeation enhancer) in the paste layer on the cumulative permeation amount of diclofenac sodium;

[0028] Figure 2 This is a graph showing the effect of different amounts of N-methylpyrrolidone (permeation enhancer) in the paste layer on the cumulative permeation of arnica lactone C;

[0029] Figure 3 This is a graph showing the effect of different amounts of arnica tincture and arnica extract (drug content) in the paste layer on the cumulative permeation of arnica lactone C;

[0030] Figure 4 This is a graph showing the in vitro permeation behavior of diclofenac sodium and arnica lactone C in the compound arnica flower-diclofenac sodium gel patch prepared in Example 1 through rat skin.

[0031] Figure 5 This is a liquid chromatogram for detecting the active substance sesquiterpene lactones in Arnica tincture.

[0032] Figure 6 Changes in foot morphology of rats during drug administration.

[0033] Figure 7 Pathological sections of knee joints in each group (x20): (a) blank group; (b) model group; (c) positive control group; (d) arnica tincture control group; (e) experimental group.

[0034] Figure 8 Pathological sections of knee joints in each group (x100): (a) blank group; (b) model group; (c) positive control group; (d) arnica tincture control group; (e) experimental group. DETAILED DESCRIPTION

[0035] The present invention is further described in detail below in conjunction with specific embodiments. Unless otherwise specified, the experimental methods used below are all conventional methods in the art, and the ingredients or materials used are all ingredients or materials available through commercial channels unless otherwise specified. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments.

[0036] Example 1

[0037] A compound arnica flower-diclofenac sodium gel patch comprises a backing layer, a paste layer and a protective layer, wherein the raw materials of the paste layer are: 2g of arnica tincture, 0.07g of diclofenac sodium, 0.4g of N-methylpyrrolidone, 1.6g of NP-700, 0.04g of aluminum glycinate, 0.2g of kaolin, 0.008g of EDTA, 5.0g of glycerol, 0.04g of tartaric acid, 0.4g of PVP-K90, and 8.4g of water. According to calculation, the mass percentage of N-methylpyrrolidone in the paste layer is 2%.

[0038] The preparation method of the compound arnica flower-diclofenac sodium gel patch comprises the following steps:

[0039] (1) Preparation of Arnica tincture: Weigh about 5 g of dried Arnica montana flowers, place in a 100 mL round-bottom flask, add 50 mL of 70% ethanol, heat and reflux at 75°C for 60 min, cool, filter under reduced pressure, and repeat the extraction twice. The two extracts were concentrated under reduced pressure, dissolved in 70% ethanol, transferred to a 50 mL volumetric flask and dilute to the mark to prepare Arnica montana tincture (see Figure 5 ).

[0040] (2) Preparation of paste layer: 0.04 g tartaric acid, 0.4 g PVP-K90, 2 g arnica tincture, and 8.4 g water were completely swollen and mixed evenly to form phase A; 1.6 g NP-700, 0.04 g aluminum glycinate, 0.2 g kaolin, 0.008 g EDTA, 0.07 g diclofenac sodium, 0.4 g N-methylpyrrolidone, and 5.0 g glycerol were mixed evenly to form phase B; after phases A and B were stirred evenly and heated to 45±5°C, phase A was added to phase B at a speed of 60 r / min and stirred evenly to obtain a viscous semi-solid drug-containing matrix.

[0041] (3) Preparation of gel patch: Pour the viscous semi-solid drug-containing matrix prepared in step (2) onto the backing layer (non-woven fabric), cover with a protective layer (anti-stick plastic), and immediately apply it evenly with a 0.9 mm frame coater. After curing at room temperature for 1 to 2 days, cut it into a specified shape and size (5 cm × 7 cm) to obtain the compound arnica flower-diclofenac sodium gel patch, which is stored in a cool and dry place.

[0042] The compound arnica-diclofenac sodium gel patch prepared in Example 1 was used to treat rheumatoid arthritis. Through observation, the homemade gel patch had good anti-inflammatory and detumescent effects, indicating that it could have a therapeutic effect.

[0043] On the basis of this example, a series of experiments were conducted in which the dosage of arnica tincture was 2 g, the dosage of diclofenac sodium was 0.07 g, and the dosage of N-methylpyrrolidone was 1%, 2%, and 3% of the prescription amount of the paste layer, and the effects of different dosages of N-methylpyrrolidone on the cumulative permeation of diclofenac sodium and arnica lactone C were analyzed. Figure 1 and Figure 2 .

[0044] Depend on Figure 1 and Figure 2 It can be seen that when the dosage of the permeation enhancer (N-methylpyrrolidone) is 3% (0.6 g) of the prescription amount of the paste layer, the cumulative permeation amount of the active ingredients diclofenac sodium and arnica lactone C is the largest, but there is no significant difference in the cumulative permeation amount when 2% and 3% of the permeation enhancer are added. Therefore, the preferred dosage of the permeation enhancer is 2% (0.4 g).

[0045] On the basis of this example, a series of experiments were conducted in which the dosage of N-methylpyrrolidone was 2% of the prescription amount of the paste layer, the dosage of diclofenac sodium was fixed at 0.07 g, and the dosage of arnica tincture concentrated to arnica extract was 1%, 3%, and 5%. The effects of different dosages of arnica tincture and arnica extract on the cumulative permeation of arnica lactone C were analyzed. Figure 3 .

[0046] Depend on Figure 3 It can be seen that the gel patch containing 5% arnica dry extract in the paste layer has the largest cumulative permeation of arnica lactone C, followed by 3%. However, it was found that during the application process, the gel patches with drug loading of 3% and 5% had more ointment residue on the skin. This may be due to the low cohesion of the gel patch due to the large drug loading, so the drug loading of 3% and 5% is too high and not feasible. Comparing the arnica dry extract with a drug loading of 1% and 2g arnica tincture, there was no significant difference in the percutaneous absorption and permeation of arnica lactone C, so 2g arnica tincture was finally selected.

[0047] Figure 4 The in vitro permeation behavior of the prepared compound arnica flower-diclofenac sodium gel patch through rat skin is shown in Figure 2. Figure 4 It can be seen that the cumulative permeation of the active ingredients diclofenac sodium and arnica lactone C increases steadily over time, and the drug release continues slowly without burst release.

[0048] Example 2

[0049] A compound arnica flower-diclofenac sodium gel patch comprises a backing layer, a paste layer and a protective layer. The raw materials of the paste layer are: 2g of arnica tincture, 0.07g of diclofenac sodium, 0.4g of N-methylpyrrolidone, 1.6g of NP-700, 0.04g of aluminum glycinate, 0.2g of kaolin, 0.008g of EDTA, 5.0g of glycerol, 0.04g of tartaric acid, 0.4g of PVP-K90 and 8.4g of water.

[0050] The preparation method of the compound arnica flower-diclofenac sodium gel patch comprises the following steps:

[0051] (1) Preparation of Arnica tincture: Weigh about 5 g of dried Arnica montana flowers, place in a 100 mL round-bottom flask, add 50 mL of 40% ethanol, heat and reflux at 45° C. for 25 min, cool, filter under reduced pressure, and repeat the extraction twice. Concentrate the two extracts under reduced pressure, dissolve in 40% ethanol, transfer to a 50 mL volumetric flask and dilute to the mark to prepare Arnica montana tincture.

[0052] (2) Preparation of paste layer: 0.04 g tartaric acid, 0.4 g PVP-K90, 2 g arnica tincture, and 8.4 g water were completely swollen and mixed evenly to form phase A; 1.6 g NP-700, 0.04 g aluminum glycinate, 0.2 g kaolin, 0.008 g EDTA, 0.07 g diclofenac sodium, 0.4 g N-methylpyrrolidone, and 5.0 g glycerol were mixed evenly to form phase B; after phases A and B were stirred evenly and heated to 45±5°C, phase A was added to phase B at a speed of 60 r / min and stirred evenly to obtain a viscous semi-solid drug-containing matrix.

[0053] (3) Preparation of gel patch: Pour the paste layer prepared in step (2) onto the backing layer, cover with a protective layer, and immediately apply it evenly with a 0.9 mm frame coater. Allow to cure at room temperature for 1 to 2 days, then cut into a specified shape and size (5 cm × 7 cm). This is the compound arnica flower-diclofenac sodium gel patch, which is stored in a cool and dry place.

[0054] Example 3

[0055] A compound arnica flower-diclofenac sodium gel patch comprises a backing layer, a paste layer and a protective layer. The raw materials of the paste layer are: 2g of arnica tincture, 0.07g of diclofenac sodium, 0.4g of N-methylpyrrolidone, 1.6g of NP-700, 0.04g of aluminum glycinate, 0.2g of kaolin, 0.008g of EDTA, 5.0g of glycerol, 0.04g of tartaric acid, 0.4g of PVP-K90 and 8.4g of water.

[0056] The preparation method of the compound arnica flower-diclofenac sodium gel patch comprises the following steps:

[0057] (1) Preparation of Arnica tincture: Weigh about 5 g of dried Arnica montana flowers, place in a 100 mL round-bottom flask, add 50 mL of 50% ethanol, heat and reflux at 55° C. for 30 min, cool, filter under reduced pressure, and repeat the extraction twice. Concentrate the two extracts under reduced pressure, dissolve in 50% ethanol, transfer to a 50 mL volumetric flask and dilute to the mark to prepare Arnica montana tincture.

[0058] (2) Preparation of paste layer: 0.04 g tartaric acid, 0.4 g PVP-K90, 2 g arnica tincture, and 8.4 g water were completely swollen and mixed evenly to form phase A; 1.6 g NP-700, 0.04 g aluminum glycinate, 0.2 g kaolin, 0.008 g EDTA, 0.07 g diclofenac sodium, 0.4 g N-methylpyrrolidone, and 5.0 g glycerol were mixed evenly to form phase B; after phases A and B were stirred evenly and heated to 45±5°C, phase A was added to phase B at a speed of 60 r / min and stirred evenly to obtain a viscous semi-solid drug-containing matrix.

[0059] (3) Preparation of gel patch: Pour the paste layer prepared in step (2) onto the backing layer, cover with a protective layer, and immediately apply it evenly with a 0.9 mm frame coater. Allow to cure at room temperature for 1 to 2 days, then cut into a specified shape and size (5 cm × 7 cm). This is the compound arnica flower-diclofenac sodium gel patch, which is stored in a cool and dry place.

[0060] Example 4

[0061] A compound arnica flower-diclofenac sodium gel patch comprises a backing layer, a paste layer and a protective layer. The raw materials of the paste layer are: 2g of arnica tincture, 0.07g of diclofenac sodium, 0.4g of N-methylpyrrolidone, 1.6g of NP-700, 0.04g of aluminum glycinate, 0.2g of kaolin, 0.008g of EDTA, 5.0g of glycerol, 0.04g of tartaric acid, 0.4g of PVP-K90 and 8.4g of water.

[0062] The preparation method of the compound arnica flower-diclofenac sodium gel patch comprises the following steps:

[0063] (1) Preparation of Arnica tincture: Weigh about 5 g of dried Arnica montana flowers, place in a 100 mL round-bottom flask, add 50 mL of 60% ethanol, heat and reflux at 65° C. for 45 min, cool, filter under reduced pressure, and repeat extraction twice. Concentrate the two extracts under reduced pressure, dissolve in 60% ethanol, transfer to a 50 mL volumetric flask and dilute to volume to prepare Arnica montana tincture.

[0064] (2) Preparation of paste layer: 0.04 g tartaric acid, 0.4 g PVP-K90, 2 g arnica tincture, and 8.4 g water were completely swollen and mixed evenly to form phase A; 1.6 g NP-700, 0.04 g aluminum glycinate, 0.2 g kaolin, 0.008 g EDTA, 0.07 g diclofenac sodium, 0.4 g N-methylpyrrolidone, and 5.0 g glycerol were mixed evenly to form phase B; after phases A and B were stirred evenly and heated to 45±5°C, phase A was added to phase B at a speed of 60 r / min and stirred evenly to obtain a viscous semi-solid drug-containing matrix.

[0065] (3) Preparation of gel patch: Pour the paste layer prepared in step (2) onto the backing layer, cover with a protective layer, and immediately apply it evenly with a 0.9 mm frame coater. Allow to cure at room temperature for 1 to 2 days, then cut into a specified shape and size (5 cm × 7 cm). This is the compound arnica flower-diclofenac sodium gel patch, which is stored in a cool and dry place.

[0066] Example 5

[0067] A compound arnica flower-diclofenac sodium gel patch comprises a backing layer, a paste layer and a protective layer. The raw materials of the paste layer are: 2g of arnica tincture, 0.07g of diclofenac sodium, 0.4g of N-methylpyrrolidone, 1.6g of NP-700, 0.04g of aluminum glycinate, 0.2g of kaolin, 0.008g of EDTA, 5.0g of glycerol, 0.04g of tartaric acid, 0.4g of PVP-K90 and 8.4g of water.

[0068] The preparation method of the compound arnica flower-diclofenac sodium gel patch comprises the following steps:

[0069] (1) Preparation of Arnica tincture: Weigh about 5 g of dried Arnica montana flowers, place in a 100 mL round-bottom flask, add 50 mL of 80% ethanol, heat and reflux at 85° C. for 75 min, cool, filter under reduced pressure, and repeat the extraction twice. Concentrate the two extracts under reduced pressure, dissolve in 80% ethanol, transfer to a 50 mL volumetric flask and dilute to the mark to prepare Arnica montana tincture.

[0070] (2) Preparation of paste layer: 0.04 g tartaric acid, 0.4 g PVP-K90, 2 g arnica tincture, and 8.4 g water were completely swollen and mixed evenly to form phase A; 1.6 g NP-700, 0.04 g aluminum glycinate, 0.2 g kaolin, 0.008 g EDTA, 0.07 g diclofenac sodium, 0.4 g N-methylpyrrolidone, and 5.0 g glycerol were mixed evenly to form phase B; after phases A and B were stirred evenly and heated to 45±5°C, phase A was added to phase B at a speed of 60 r / min and stirred evenly to obtain a viscous semi-solid drug-containing matrix.

[0071] (3) Preparation of gel patch: Pour the paste layer prepared in step (2) onto the backing layer, cover with a protective layer, and immediately apply it evenly with a 0.9 mm frame coater. Allow to cure at room temperature for 1 to 2 days, then cut into a specified shape and size (5 cm × 7 cm). This is the compound arnica flower-diclofenac sodium gel patch, which is stored in a cool and dry place.

[0072] Example 6

[0073] A compound arnica flower-diclofenac sodium gel patch comprises a backing layer, a paste layer and a protective layer. The raw materials of the paste layer are: 2g of arnica tincture, 0.07g of diclofenac sodium, 0.4g of N-methylpyrrolidone, 0.8g of NP-700, 0.02g of aluminum glycinate, 0.1g of kaolin, 0.008g of EDTA, 4.0g of glycerol, 0.02g of tartaric acid, 0.2g of PVP-K90 and 10.54g of water.

[0074] The preparation method of the compound arnica flower-diclofenac sodium gel patch comprises the following steps:

[0075] (1) Preparation of Arnica tincture: Weigh about 5 g of dried Arnica montana flowers, place in a 100 mL round-bottom flask, add 50 mL of 70% ethanol, heat and reflux at 75° C. for 60 min, cool, filter under reduced pressure, and repeat the extraction twice. Concentrate the two extracts under reduced pressure, dissolve in 70% ethanol, transfer to a 50 mL volumetric flask and dilute to the mark to prepare Arnica montana tincture.

[0076] (2) Preparation of paste layer: 0.02 g tartaric acid, 0.2 g PVP-K90, 2 g arnica tincture, and 10.54 g water were completely swollen and mixed evenly to form phase A; 0.8 g NP-700, 0.02 g aluminum glycinate, 0.1 g kaolin, 0.008 g EDTA, 0.07 g diclofenac sodium, 0.4 g N-methylpyrrolidone, and 4.0 g glycerol were mixed evenly to form phase B; after phases A and B were stirred evenly and heated to 35±5°C, phase A was added to phase B at a speed of 30 r / min and stirred evenly to obtain a viscous semi-solid drug-containing matrix.

[0077] (3) Preparation of gel patch: Pour the paste layer prepared in step (2) onto the backing layer, cover with a protective layer, and immediately apply it evenly with a 0.5 mm frame coater. Allow to cure at room temperature for 1 to 2 days, then cut into a specified shape and size (5 cm × 7 cm). This is the compound arnica flower-diclofenac sodium gel patch, which is stored in a cool and dry place.

[0078] Example 7

[0079] A compound arnica flower-diclofenac sodium gel patch comprises a backing layer, a paste layer and a protective layer. The raw materials of the paste layer are: 2g of arnica tincture, 0.07g of diclofenac sodium, 0.4g of N-methylpyrrolidone, 1.2g of NP-700, 0.04g of aluminum glycinate, 0.2g of kaolin, 0.008g of EDTA, 5.0g of glycerol, 0.04g of tartaric acid, 0.4g of PVP-K90 and 8.8g of water.

[0080] The preparation method of the compound arnica flower-diclofenac sodium gel patch comprises the following steps:

[0081] (1) Preparation of Arnica tincture: Weigh about 5 g of dried Arnica montana flowers, place in a 100 mL round-bottom flask, add 50 mL of 70% ethanol, heat and reflux at 75° C. for 60 min, cool, filter under reduced pressure, and repeat the extraction twice. Concentrate the two extracts under reduced pressure, dissolve in 70% ethanol, transfer to a 50 mL volumetric flask and dilute to the mark to prepare Arnica montana tincture.

[0082] (2) Preparation of paste layer: 0.04 g tartaric acid, 0.4 g PVP-K90, 2 g arnica tincture, and 8.8 g water were completely swollen and mixed evenly to form phase A; 1.2 g NP-700, 0.04 g aluminum glycinate, 0.2 g kaolin, 0.008 g EDTA, 0.07 g diclofenac sodium, 0.4 g N-methylpyrrolidone, and 5.0 g glycerol were mixed evenly to form phase B; after phases A and B were stirred evenly and heated to 45±5°C, phase A was added to phase B at a speed of 60 r / min and stirred evenly to obtain a viscous semi-solid drug-containing matrix.

[0083] (3) Preparation of gel patch: Pour the paste layer prepared in step (2) onto the backing layer, cover with a protective layer, and immediately apply it evenly with a 0.6 mm frame coater. Allow to cure at room temperature for 1 to 2 days, then cut into a specified shape and size (5 cm × 7 cm). This is the compound arnica flower-diclofenac sodium gel patch, which is then stored in a cool and dry place.

[0084] Example 8

[0085] A compound arnica flower-diclofenac sodium gel patch comprises a backing layer, a paste layer and a protective layer. The raw materials of the paste layer are: 2g of arnica tincture, 0.07g of diclofenac sodium, 0.4g of N-methylpyrrolidone, 1.6g of NP-700, 0.06g of aluminum glycinate, 0.3g of kaolin, 0.008g of EDTA, 6.0g of glycerol, 0.06g of tartaric acid, 0.6g of PVP-K90 and 7.06g of water.

[0086] The preparation method of the compound arnica flower-diclofenac sodium gel patch comprises the following steps:

[0087] (1) Preparation of Arnica tincture: Weigh about 5 g of dried Arnica montana flowers, place in a 100 mL round-bottom flask, add 50 mL of 70% ethanol, heat and reflux at 75° C. for 60 min, cool, filter under reduced pressure, and repeat the extraction twice. Concentrate the two extracts under reduced pressure, dissolve in 70% ethanol, transfer to a 50 mL volumetric flask and dilute to the mark to prepare Arnica montana tincture.

[0088] (2) Preparation of paste layer: 0.06 g tartaric acid, 0.6 g PVP-K90, 2 g arnica tincture, and 7.06 g water were completely swollen and mixed evenly to form phase A; 1.6 g NP-700, 0.06 g aluminum glycinate, 0.3 g kaolin, 0.008 g EDTA, 0.07 g diclofenac sodium, 0.4 g N-methylpyrrolidone, and 6.0 g glycerol were mixed evenly to form phase B; after phases A and B were stirred evenly and heated to 55±5°C, phase A was added to phase B at a speed of 90 r / min and stirred evenly to obtain a viscous semi-solid drug-containing matrix.

[0089] (3) Preparation of gel patch: Pour the paste layer prepared in step (2) onto the backing layer, cover with a protective layer, and immediately apply it evenly with a 0.7 mm frame coater. Allow to cure at room temperature for 1 to 2 days, then cut into a specified shape and size (5 cm × 7 cm). This is the compound arnica flower-diclofenac sodium gel patch, which is stored in a cool and dry place.

[0090] Example 9

[0091] A compound arnica flower-diclofenac sodium gel patch comprises a backing layer, a paste layer and a protective layer. The raw materials of the paste layer are: 2g of arnica tincture, 0.07g of diclofenac sodium, 0.4g of N-methylpyrrolidone, 2.0g of NP-700, 0.08g of aluminum glycinate, 0.4g of kaolin, 0.008g of EDTA, 7.0g of glycerol, 0.08g of tartaric acid, 0.8g of PVP-K90 and 5.32g of water.

[0092] The preparation method of the compound arnica flower-diclofenac sodium gel patch comprises the following steps:

[0093] (1) Preparation of Arnica tincture: Weigh about 5 g of dried Arnica montana flowers, place in a 100 mL round-bottom flask, add 50 mL of 70% ethanol, heat and reflux at 75° C. for 60 min, cool, filter under reduced pressure, and repeat the extraction twice. Concentrate the two extracts under reduced pressure, dissolve in 70% ethanol, transfer to a 50 mL volumetric flask and dilute to the mark to prepare Arnica montana tincture.

[0094] (2) Preparation of paste layer: 0.08 g tartaric acid, 0.8 g PVP-K90, 2 g arnica tincture, and 5.32 g water were completely swollen and mixed evenly to form phase A; 2.0 g NP-700, 0.08 g aluminum glycinate, 0.4 g kaolin, 0.008 g EDTA, 0.07 g diclofenac sodium, 0.4 g N-methylpyrrolidone, and 7.0 g glycerol were mixed evenly to form phase B; after phases A and B were stirred evenly and heated to 35±5°C, phase A was added to phase B at a speed of 120 r / min and stirred evenly to obtain a viscous semi-solid drug-containing matrix.

[0095] (3) Preparation of gel patch: Pour the paste layer prepared in step (2) onto the backing layer, cover with a protective layer, and immediately apply it evenly with a 0.8 mm frame coater. Allow to cure at room temperature for 1 to 2 days, then cut into a specified shape and size (5 cm × 7 cm). This is the compound arnica flower-diclofenac sodium gel patch, which is stored in a cool and dry place.

[0096] Example 10

[0097] A compound arnica flower-diclofenac sodium gel patch comprises a backing layer, a paste layer and a protective layer. The raw materials of the paste layer are: 2g of arnica tincture, 0.07g of diclofenac sodium, 0.4g of N-methylpyrrolidone, 2.4g of NP-700, 0.1g of aluminum glycinate, 0.5g of kaolin, 0.008g of EDTA, 8.0g of glycerol, 0.1g of tartaric acid, 1.0g of PVP-K90 and 3.58g of water.

[0098] The preparation method of the compound arnica flower-diclofenac sodium gel patch comprises the following steps:

[0099] (1) Preparation of Arnica tincture: Weigh about 5 g of dried Arnica montana flowers, place in a 100 mL round-bottom flask, add 50 mL of 70% ethanol, heat and reflux at 75° C. for 60 min, cool, filter under reduced pressure, and repeat the extraction twice. Concentrate the two extracts under reduced pressure, dissolve in 70% ethanol, transfer to a 50 mL volumetric flask and dilute to the mark to prepare Arnica montana tincture.

[0100] (2) Preparation of paste layer: 0.1 g tartaric acid, 1.0 g PVP-K90, 2 g arnica tincture, and 3.58 g water were completely swollen and mixed evenly to form phase A; 2.4 g NP-700, 0.1 g aluminum glycinate, 0.5 g kaolin, 0.008 g EDTA, 0.07 g diclofenac sodium, 0.4 g N-methylpyrrolidone, and 8.0 g glycerol were mixed evenly to form phase B; after phases A and B were stirred evenly and heated to 45±5°C, phase A was added to phase B at a speed of 150 r / min and stirred evenly to obtain a viscous semi-solid drug-containing matrix.

[0101] (3) Preparation of gel patch: Pour the paste layer prepared in step (2) onto the backing layer, cover with a protective layer, and immediately apply it evenly with a 0.9 mm frame coater. Allow to cure at room temperature for 1 to 2 days, then cut into a specified shape and size (5 cm × 7 cm). This is the compound arnica flower-diclofenac sodium gel patch, which is stored in a cool and dry place.

[0102] Embodiment 11

[0103] A compound arnica flower-diclofenac sodium gel patch comprises a backing layer, a paste layer and a protective layer. The raw materials of the paste layer are: 1 mL of arnica tincture, 0.035 g of diclofenac sodium, 0.4 g of N-methylpyrrolidone, 1.6 g of NP-700, 0.04 g of aluminum glycinate, 0.2 g of kaolin, 0.008 g of EDTA, 5.0 g of glycerol, 0.04 g of tartaric acid, 0.4 g of PVP-K90 and 7.6 g of water.

[0104] The preparation method of the compound arnica flower-diclofenac sodium gel patch comprises the following steps:

[0105] (1) Preparation of Arnica tincture: Weigh about 5 g of dried Arnica montana flowers, place in a 100 mL round-bottom flask, add 50 mL of 70% ethanol, heat and reflux at 75° C. for 60 min, cool, filter under reduced pressure, and repeat the extraction twice. Concentrate the two extracts under reduced pressure, dissolve in 70% ethanol, transfer to a 50 mL volumetric flask and dilute to the mark to prepare Arnica montana tincture.

[0106] (2) Preparation of paste layer: 0.04 g tartaric acid, 0.4 g PVP-K90, 1 mL arnica tincture, and 7.6 g water were completely swollen and mixed evenly to form phase A; 1.6 g NP-700, 0.04 g aluminum glycinate, 0.2 g kaolin, 0.008 g EDTA, 0.035 g diclofenac sodium, 0.4 g N-methylpyrrolidone, and 5.0 g glycerol were mixed evenly to form phase B; after phases A and B were stirred evenly and heated to 45±5°C, phase A was added to phase B at a speed of 60 r / min and stirred evenly to obtain a viscous semi-solid drug-containing matrix.

[0107] (3) Preparation of gel patch: Pour the paste layer prepared in step (2) onto the backing layer, cover with a protective layer, and immediately apply it evenly with a 0.9 mm frame coater. Allow to cure at room temperature for 1 to 2 days, then cut into a specified shape and size (5 cm × 7 cm). This is the compound arnica flower-diclofenac sodium gel patch, which is stored in a cool and dry place.

[0108] Example 12

[0109] A compound arnica flower-diclofenac sodium gel patch comprises a backing layer, a paste layer and a protective layer. The raw materials of the paste layer are: 3 mL of arnica tincture, 0.14 g of diclofenac sodium, 0.4 g of N-methylpyrrolidone, 1.6 g of NP-700, 0.04 g of aluminum glycinate, 0.2 g of kaolin, 0.008 g of EDTA, 5.0 g of glycerol, 0.04 g of tartaric acid, 0.4 g of PVP-K90 and 7.33 g of water.

[0110] The preparation method of the compound arnica flower-diclofenac sodium gel patch comprises the following steps:

[0111] (1) Preparation of Arnica tincture: Weigh about 5 g of dried Arnica montana flowers, place in a 100 mL round-bottom flask, add 50 mL of 70% ethanol, heat and reflux at 75° C. for 60 min, cool, filter under reduced pressure, and repeat the extraction twice. Concentrate the two extracts under reduced pressure, dissolve in 70% ethanol, transfer to a 50 mL volumetric flask and dilute to the mark to prepare Arnica montana tincture.

[0112] (2) Preparation of paste layer: 0.04 g tartaric acid, 0.4 g PVP-K90, 3 mL arnica tincture, and 7.33 g water were completely swollen and mixed evenly to form phase A; 1.6 g NP-700, 0.04 g aluminum glycinate, 0.2 g kaolin, 0.008 g EDTA, 0.14 g diclofenac sodium, 0.4 g N-methylpyrrolidone, and 5.0 g glycerol were mixed evenly to form phase B; after phases A and B were stirred evenly and heated to 45±5°C, phase A was added to phase B at a speed of 60 r / min and stirred evenly to obtain a viscous semi-solid drug-containing matrix.

[0113] (3) Preparation of gel patch: Pour the paste layer prepared in step (2) onto the backing layer, cover with a protective layer, and immediately apply it evenly with a 0.9 mm frame coater. Allow to cure at room temperature for 1 to 2 days, then cut into a specified shape and size (5 cm × 7 cm). This is the compound arnica flower-diclofenac sodium gel patch, which is stored in a cool and dry place.

[0114] Example 13

[0115] A compound arnica flower-diclofenac sodium gel patch comprises a backing layer, a paste layer and a protective layer. The raw materials of the paste layer are: 2g of arnica tincture, 0.07g of diclofenac sodium, 0.2g of N-methylpyrrolidone, 1.6g of NP-700, 0.04g of aluminum glycinate, 0.2g of kaolin, 0.008g of EDTA, 5.0g of glycerol, 0.04g of tartaric acid, 0.4g of PVP-K90 and 8.44g of water.

[0116] The preparation method of the compound arnica flower-diclofenac sodium gel patch comprises the following steps:

[0117] (1) Preparation of Arnica tincture: Weigh about 5 g of dried Arnica montana flowers, place in a 100 mL round-bottom flask, add 50 mL of 70% ethanol, heat and reflux at 75° C. for 60 min, cool, filter under reduced pressure, and repeat the extraction twice. Concentrate the two extracts under reduced pressure, dissolve in 70% ethanol, transfer to a 50 mL volumetric flask and dilute to the mark to prepare Arnica montana tincture.

[0118] (2) Preparation of paste layer: 0.04 g tartaric acid, 0.4 g PVP-K90, 2 g arnica tincture, and 8.44 g water were completely swollen and mixed evenly to form phase A; 1.6 g NP-700, 0.04 g aluminum glycinate, 0.2 g kaolin, 0.008 g EDTA, 0.07 g diclofenac sodium, 0.2 g N-methylpyrrolidone, and 5.0 g glycerol were mixed evenly to form phase B; after phases A and B were stirred evenly and heated to 45±5°C, phase A was added to phase B at a speed of 60 r / min and stirred evenly to obtain a viscous semi-solid drug-containing matrix.

[0119] (3) Preparation of gel patch: Pour the paste layer prepared in step (2) onto the backing layer, cover with a protective layer, and immediately apply it evenly with a 0.9 mm frame coater. Allow to cure at room temperature for 1 to 2 days, then cut into a specified shape and size (5 cm × 7 cm). This is the compound arnica flower-diclofenac sodium gel patch, which is stored in a cool and dry place.

[0120] Embodiment 14

[0121] A compound arnica flower-diclofenac sodium gel patch comprises a backing layer, a paste layer and a protective layer. The raw materials of the paste layer are: 2g of arnica tincture, 0.07g of diclofenac sodium, 0.6g of N-methylpyrrolidone, 1.6g of NP-700, 0.04g of aluminum glycinate, 0.2g of kaolin, 0.008g of EDTA, 5.0g of glycerol, 0.04g of tartaric acid, 0.4g of PVP-K90 and 8.04g of water.

[0122] The preparation method of the compound arnica flower-diclofenac sodium gel patch comprises the following steps:

[0123] (1) Preparation of Arnica tincture: Weigh about 5 g of dried Arnica montana flowers, place in a 100 mL round-bottom flask, add 50 mL of 70% ethanol, heat and reflux at 75° C. for 60 min, cool, filter under reduced pressure, and repeat the extraction twice. Concentrate the two extracts under reduced pressure, dissolve in 70% ethanol, transfer to a 50 mL volumetric flask and dilute to the mark to prepare Arnica montana tincture.

[0124] (2) Preparation of paste layer: 0.04 g tartaric acid, 0.4 g PVP-K90, 2 g arnica tincture, and 8.04 g water were completely swollen and mixed evenly to form phase A; 1.6 g NP-700, 0.04 g aluminum glycinate, 0.2 g kaolin, 0.008 g EDTA, 0.07 g diclofenac sodium, 0.6 g N-methylpyrrolidone, and 5.0 g glycerol were mixed evenly to form phase B; after phases A and B were stirred evenly and heated to 45±5°C, phase A was added to phase B at a speed of 60 r / min and stirred evenly to obtain a viscous semi-solid drug-containing matrix.

[0125] (3) Preparation of gel patch: Pour the paste layer prepared in step (2) onto the backing layer, cover with a protective layer, and immediately apply it evenly with a 0.9 mm frame coater. Allow to cure at room temperature for 1 to 2 days, then cut into a specified shape and size (5 cm × 7 cm). This is the compound arnica flower-diclofenac sodium gel patch, which is stored in a cool and dry place.

[0126] Embodiment 15

[0127] A compound arnica flower-diclofenac sodium gel patch comprises a backing layer, a paste layer and a protective layer. The raw materials of the paste layer are: 2g of arnica tincture, 0.07g of diclofenac sodium, 1.0g of N-methylpyrrolidone, 1.6g of NP-700, 0.04g of aluminum glycinate, 0.2g of kaolin, 0.008g of EDTA, 5.0g of glycerol, 0.04g of tartaric acid, 0.4g of PVP-K90 and 7.64g of water.

[0128] The preparation method of the compound arnica flower-diclofenac sodium gel patch comprises the following steps:

[0129] (1) Preparation of Arnica tincture: Weigh about 5 g of dried Arnica montana flowers, place in a 100 mL round-bottom flask, add 50 mL of 70% ethanol, heat and reflux at 75° C. for 60 min, cool, filter under reduced pressure, and repeat the extraction twice. Concentrate the two extracts under reduced pressure, dissolve in 70% ethanol, transfer to a 50 mL volumetric flask and dilute to the mark to prepare Arnica montana tincture.

[0130] (2) Preparation of paste layer: 0.04 g tartaric acid, 0.4 g PVP-K90, 2 g arnica tincture, and 7.64 g water were completely swollen and mixed evenly to form phase A; 1.6 g NP-700, 0.04 g aluminum glycinate, 0.2 g kaolin, 0.008 g EDTA, 0.07 g diclofenac sodium, 1.0 g N-methylpyrrolidone, and 5.0 g glycerol were mixed evenly to form phase B; after phases A and B were stirred evenly and heated to 45±5°C, phase A was added to phase B at a speed of 60 r / min and stirred evenly to obtain a viscous semi-solid drug-containing matrix.

[0131] (3) Preparation of gel patch: Pour the paste layer prepared in step (2) onto the backing layer, cover with a protective layer, and immediately apply it evenly with a 0.9 mm frame coater. Allow to cure at room temperature for 1 to 2 days, then cut into a specified shape and size (5 cm × 7 cm). This is the compound arnica flower-diclofenac sodium gel patch, which is stored in a cool and dry place.

[0132] Example 16

[0133] A compound arnica flower-diclofenac sodium gel patch comprises a backing layer, a paste layer and a protective layer. The raw materials of the paste layer are: 2g of arnica tincture, 0.07g of diclofenac sodium, 1.4g of N-methylpyrrolidone, 1.6g of NP-700, 0.04g of aluminum glycinate, 0.2g of kaolin, 0.008g of EDTA, 5.0g of glycerol, 0.04g of tartaric acid, 0.4g of PVP-K90 and 7.24g of water.

[0134] The preparation method of the compound arnica flower-diclofenac sodium gel patch comprises the following steps:

[0135] (1) Preparation of Arnica tincture: Weigh about 5 g of dried Arnica montana flowers, place in a 100 mL round-bottom flask, add 50 mL of 70% ethanol, heat and reflux at 75° C. for 60 min, cool, filter under reduced pressure, and repeat the extraction twice. Concentrate the two extracts under reduced pressure, dissolve in 70% ethanol, transfer to a 50 mL volumetric flask and dilute to the mark to prepare Arnica montana tincture.

[0136] (2) Preparation of paste layer: 0.04 g tartaric acid, 0.4 g PVP-K90, 2 g arnica tincture, and 7.24 g water were completely swollen and mixed evenly to form phase A; 1.6 g NP-700, 0.04 g aluminum glycinate, 0.2 g kaolin, 0.008 g EDTA, 0.07 g diclofenac sodium, 1.4 g N-methylpyrrolidone, and 5.0 g glycerol were mixed evenly to form phase B; after phases A and B were stirred evenly and heated to 45±5°C, phase A was added to phase B at a speed of 60 r / min and stirred evenly to obtain a viscous semi-solid drug-containing matrix.

[0137] (3) Preparation of gel patch: Pour the paste layer prepared in step (2) onto the backing layer, cover with a protective layer, and immediately apply it evenly with a 0.9 mm frame coater. Allow to cure at room temperature for 1 to 2 days, then cut into a specified shape and size (5 cm × 7 cm). This is the compound arnica flower-diclofenac sodium gel patch, which is stored in a cool and dry place.

[0138] Comparative Example

[0139] The homemade compound arnica flower-diclofenac sodium gel patch (test group) obtained in Example 1 was compared with a commercially available diclofenac sodium patch (positive control) and a gel patch made of arnica tincture (arnica tincture control group, only arnica tincture was added to the paste layer according to the description in Example 1), and the anti-inflammatory and analgesic effects of the compound arnica flower-diclofenac sodium gel patch were evaluated by the acetic acid writhing test in mice and the complete Freund's adjuvant arthritis test in rats.

[0140] Acetic acid writhing test in mice: This experiment used the commonly used glacial acetic acid concentration of 1% and the experimental temperature of 22℃. The acetic acid writhing model of mice established under this condition was better. Thirty male Kunming mice weighing 18-22g were selected and randomly divided into 5 groups, with 6 mice in each group, as follows: (1) Model group: no drug administration; (2) Negative control group: given a blank gel patch (4cm2) without drug; (3) Positive control group: given a commercially available diclofenac sodium patch (4cm2, containing 4mg diclofenac sodium); (4) Arnica tincture control group: given a gel patch made of Arnica tincture (4cm2, containing 0.23g Arnica tincture); (5) Experimental group: given a homemade compound Arnica flower-diclofenac sodium gel patch (4cm2, containing 4mg diclofenac sodium, Arnica tincture 0.23g). 24h before the experiment, the abdomen of the mice was carefully depilated and the ambient temperature was kept constant at 22℃. The abdominal skin of mice was disinfected before administration. 6 hours after administration, 0.2 mL of 1% (v / v) glacial acetic acid solution was injected intraperitoneally into each mouse. The number of body twisting of the mice within 20 minutes was recorded, and the pain inhibition rate was calculated to evaluate the analgesic effect.

[0141] Table Result of Mouse Torsion Analgesia Test (n=6)

[0142]

[0143] The values ​​are expressed as mean ± SD: *p < 0.05; **p < 0.01; ***p < 0.001 compared with the model group.

[0144] There was no significant difference between the negative group and the model group (p>0.05), indicating that the blank gel patch had no analgesic effect. There were extremely significant differences between the positive control group, the arnica tincture control group, the experimental group and the model group (p<0.001), indicating that all three had analgesic effects. The PIR% of the experimental group was 63.41%, and the PIR% of the positive control group was 51.22%. There was a difference between the two groups (p<0.05). The analgesic effect of the homemade compound gel patch was better than that of the commercially available diclofenac sodium patch. Compared with the arnica tincture control group, the PIR% of the experimental group was 63.41%, and the PIR% of the arnica tincture control group was 41.46%. There was a significant difference between the two groups (p<0.01). The analgesic effect of the homemade compound gel patch was significantly better than that of the arnica tincture control group. The above data show that the homemade compound arnica flower-diclofenac sodium gel patch has excellent analgesic effect, and is better than the commercially available diclofenac sodium patch and the arnica tincture control group alone.

[0145] Adjuvant arthritis test in rats: Grouping: 30 male SD rats weighing 180-220 g were randomly divided into 5 groups, 6 rats in each group, as follows: (1) blank control group; (2) model group: only modeling without drug administration; (3) positive control group: administered with commercially available diclofenac sodium patch (4 cm2, containing 4 mg of diclofenac sodium); (4) arnica tincture control group: administered with a gel patch made of arnica tincture (4 cm2, containing 0.23 g of arnica tincture); (5) experimental group: administered with a homemade compound arnica flower-diclofenac sodium gel patch (4 cm2, containing 4 mg of diclofenac sodium and 0.23 g of arnica tincture).

[0146] Modeling method: The rats were anesthetized with ether, and the skin of the hind feet of the rats was disinfected with alcohol. 0.1 mL of CFA was injected into the foot pads of the hind feet of the rats. After the injection, the model was completed by gently pressing with hands to prevent CFA from leaking.

[0147] Drug administration: The rats have small feet, which makes it difficult to apply the gel patch. After consulting the literature, it was found that the efficacy of transdermal administration without applying it to the diseased joints was also equivalent, so it was chosen to apply it to the rats' abdomen for administration. In the preliminary experiment, it was found that the rats were more active and often used their paws to remove the patch, so medical tape was used to fix the patch on the rats' abdomen. Each drug-dosing group began to be administrated on the third day of modeling, and the drug was administered once every 24 hours.

[0148] Ankle circumference measurement: All the above groups except the blank control group were modeled, and the ankle joints of the hind feet of the rats were marked. The circumferences of the left and right ankle joints at the marked points were measured and compared with those before modeling, and the difference in ankle circumference was calculated. The results are shown in the following table.

[0149] Table 3 Difference in left ankle circumference before medication (n=6)

[0150]

[0151] The values ​​are expressed as mean ± SD: *p < 0.05; **p < 0.01; ***p < 0.001 compared with the blank group.

[0152] Table 3 Difference in right ankle circumference before medication (n=6)

[0153]

[0154] The values ​​are expressed as mean ± SD: *p < 0.05; **p < 0.01; ***p < 0.001 compared with the blank group.

[0155] On the first day of modeling, there were significant differences between each group and the blank control group (p<0.01), and swelling of the rats' feet was observed with the naked eye; on the second day, obvious swelling appeared in the paws, ankle joints and other parts of the rats in each group (p<0.001), and there was no significant difference between the groups (p>0.05); there was no significant difference between the third day and the second day (p>0.05), the modeling was successful, and medication began.

[0156] Determination of ankle circumference after administration: 24 h before administration, the rats' abdomens were carefully depilated, and the drug was administered once every 24 h. The circumferences of the left and right ankle joints at the marked points were measured on days 5, 7, and 11, and the difference was calculated. The results are shown in the table below.

[0157] Table 3 Difference in left ankle circumference after drug administration (n=6)

[0158]

[0159]

[0160] Values ​​are expressed as mean ± standard deviation: *p<0.05; **p<0.01; ***p<0.001 compared with the model group; #p<0.05; ##p<0.01; ###p<0.001 compared with the experimental group.

[0161] Table 1 Difference in right ankle circumference after drug administration (n=6)

[0162]

[0163] Values ​​are expressed as mean ± standard deviation: *p<0.05; **p<0.01; ***p<0.001 compared with the model group; #p<0.05; ##p<0.01; ###p<0.001 compared with the experimental group.

[0164] The difference in the circumference of the left and right ankle joints of rats in the positive control group, the arnica tincture control group, and the experimental group was all decreasing, and there was a significant difference compared with the model group, indicating that the commercially available diclofenac sodium patch, arnica tincture alone, and the homemade compound arnica flower-diclofenac sodium gel patch all have anti-inflammatory and detumescent effects. The experimental group was different from the positive control group (p<0.05) and significantly different from the arnica tincture control group (p<0.001), indicating that the anti-inflammatory effect of the homemade compound arnica flower-diclofenac sodium gel patch is better than the commercially available diclofenac sodium patch, and significantly better than the gel patch made of arnica tincture alone, proving that the combination of arnica tincture and diclofenac sodium can achieve better RA treatment effects.

[0165] Changes in rat foot morphology: During the rat adjuvant arthritis test, one rat was selected from each of the model group, positive control group, Arnica montana control group, and experimental group to observe the changes in the rat foot morphology during the drug administration process, and photographs were taken to record the recovery of rat foot swelling (see Figure 6 ). The result is Figure 6 As shown in the figure, the rats' paws and ankle joints showed obvious swelling after modeling, and the modeling was successful. The swelling of the feet of the rats in the positive control group, the arnica tincture control group, and the experimental group improved after drug treatment, while the feet of the rats in the model group did not improve significantly, proving that the commercially available diclofenac sodium patch, arnica tincture alone, and the homemade compound arnica flower-diclofenac sodium gel patch can all play an anti-inflammatory and detumescent role. On the 11th day, it was observed that the rats treated with the homemade compound arnica flower-diclofenac sodium gel patch had a better detumescent effect than the commercially available diclofenac sodium patch and the gel patch prepared with arnica tincture. The changes in the morphology of the rats' feet also proved that the combination of arnica tincture and diclofenac sodium can achieve a better anti-inflammatory effect.

[0166] Inflammatory factor detection: Studies have found that tumor necrosis factor TNF-α plays an important role in RA, aggravates the inflammatory response of RA, and is a key factor in RA. IL-6 is a B cell differentiation factor that can induce osteoclast differentiation, break the balance between osteoclasts and osteoblasts, and accelerate cartilage destruction in RA patients. The IL-6 content in the serum and synovial cavity of RA patients is relatively high. Therefore, the levels of TNF-α and IL-6 were detected in each group of rats. After the last patch administration, the rats were fasted but not watered. After 12 hours, blood was collected from the rats' eye sockets and centrifuged at 3500r / min for 10 minutes. The supernatant was taken and the ELISA kit was used to detect the TNF-α and IL-6 content. The experimental results are shown in the following table.

[0167] Table 2 Determination of TNF-α and IL-6 in rat serum

[0168]

[0169] The values ​​are expressed as mean ± standard deviation: compared with the blank group *p<0.05; **p<0.01; ***p<0.001; compared with the model group #p<0.05; ##p<0.01; ###p<0.001.

[0170] As shown in the table above, compared with the blank group, the levels of TNF-α and IL-6 in the plasma samples of the model group were significantly increased (p<0.001), and the RA model was successfully established. Compared with the model group, the levels of TNF-α and IL-6 in the plasma samples of the positive control group, the arnica tincture control group and the experimental group were significantly decreased (p<0.001), indicating that the commercially available diclofenac sodium patch, arnica tincture and the homemade compound arnica flower-diclofenac sodium gel patch all have therapeutic effects on RA, so the levels of proinflammatory factors TNF-α and IL-6 are significantly reduced. Compared with the positive control group, the homemade compound arnica flower-diclofenac sodium gel patch had a stronger inhibitory effect on TNF-α and IL-6 in the experimental group, which was better than the commercially available diclofenac sodium patch. Compared with the arnica tincture control group, the homemade compound arnica flower-diclofenac sodium gel patch was significantly better than arnica tincture alone.

[0171] By detecting TNF-α and IL-6 inflammatory factors, it was proved that the homemade compound arnica flower-diclofenac sodium gel patch has a good therapeutic effect on RA, and it was proved that the combination of arnica tincture and diclofenac sodium can achieve better therapeutic effects than the commercially available diclofenac sodium patch and arnica tincture alone.

[0172] H&E staining:

[0173] After the last administration, the knee joints of the rats were cut off and pathological sections were made and observed by H&E staining. Figure 7 and 8 As shown in the figure below, from left to right are the blank group, model group, positive control group, Arnica tincture control group, and experimental group.

[0174] The knee joints of rats in the normal group had normal morphology, while the synovial cells of the knee joints of rats in the model group proliferated and infiltrated into the joint cavity, the synovial border was not smooth, and a large area of ​​inflammatory cells appeared. The surfaces of the positive control group, the arnica tincture control group, and the experimental group were smoother, the degree of synovial cell proliferation was lighter than that of the model group, the synovial border was clearer, and the inflammatory cell infiltration was less. Compared with the model group, the positive control group, the arnica tincture control group, and the experimental group had certain therapeutic effects, proving that the homemade compound arnica flower-diclofenac sodium gel patch has a therapeutic effect on RA.

Claims

1. A compound arnica flower-diclofenac sodium gel patch, the patch comprising a backing layer, a paste layer and a protective layer, characterized in that: The paste layer is composed of drugs, transdermal enhancers and matrix, the matrix is ​​skeleton material, cross-linking agent, filler, viscosity enhancer, moisturizer, cross-linking regulator and water, and the drugs are arnica tincture and diclofenac sodium.

2. The compound arnica montana-diclofenac sodium gel patch according to claim 1, characterized in that: The paste layer comprises, by weight, 0.1 to 3 parts of arnica tincture, 0.016 to 0.14 parts of diclofenac sodium, 0.2 to 1.4 parts of a transdermal enhancer, 0.2 to 10 parts of a skeleton material, 0.02 to 10 parts of a cross-linking agent, 0.2 to 10 parts of a filler, 0.2 to 10 parts of a viscosity enhancer, 1 to 45 parts of a moisturizer, 0.02 to 10 parts of a cross-linking regulator, and 30 to 75 parts of water.

3. The compound arnica montana-diclofenac sodium gel patch according to claim 1 or 2, characterized in that: The transdermal enhancer is one or more of azone, N-methylpyrrolidone, oleic acid, propylene glycol, menthol and camphor.

4. The compound arnica montana-diclofenac sodium gel patch according to claim 1 or 2, characterized in that: The framework material is one or more of NP-600, NP-700, NP-800, Carbomer 940 and Carbomer 980.

5. The compound arnica montana-diclofenac sodium gel patch according to claim 1 or 2, characterized in that: The cross-linking agent is one or more of aluminum hydroxide, aluminum chloride, and aluminum glycinate; The filler is one or more of kaolin, titanium oxide, zinc oxide, and micro-powder silica gel; The cross-linking regulator is one or more of EDTA, citric acid and tartaric acid.

6. The compound arnica montana-diclofenac sodium gel patch according to claim 1 or 2, characterized in that: The viscosity enhancer is one or more of sodium carboxymethyl cellulose, gelatin, gum arabic, polyvinyl alcohol and polyvinyl pyrrolidone.

7. The compound arnica montana-diclofenac sodium gel patch according to claim 1 or 2, characterized in that: The moisturizing agent is one or more of glycerol, propylene glycol, glycerol, D-sorbitol and polyethylene glycol.

8. The compound arnica montana-diclofenac sodium gel patch according to claim 1, characterized in that: The arnica tincture is obtained by extracting dried arnica flowers through an organic solvent.

9. A method for preparing the compound arnica-diclofenac sodium gel patch according to claim 1, characterized in that: The cross-linking regulator, the viscosity enhancer, the arnica tincture and the water are mixed evenly in proportion to obtain phase A; then the diclofenac sodium, the skeleton material, the cross-linking agent, the filler, the moisturizer and the transdermal enhancer are mixed evenly to obtain phase B; at 30 to 60° C., the phase A is added to the phase B at a speed of 30 to 200 r / min, and the mixture is fully stirred to obtain a viscous semi-solid drug-containing matrix; the obtained viscous semi-solid drug-containing matrix is ​​placed on a backing layer, and then a protective layer is covered on the surface of the drug, and the mixture is left to solidify at room temperature for 1 to 2 days to obtain a compound arnica flower-diclofenac sodium gel patch.

10. An application of the compound arnica flower-diclofenac sodium gel patch according to claim 1, characterized in that: The compound arnica flower-diclofenac sodium gel patch is used as a medicine for treating rheumatoid arthritis.

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