Plaster containing anilinoprofen and composition

Abstract

The invention belongs to the technical field of medicines. The invention relates to a plaster, in particular to a plaster containing anilinoprofen and a composition. The invention provides an externally applied medicine containing anilinoprofen or a composition containing anilinoprofen and iguratimod. Pharmacodynamic studies show that the aniline-ibuprofen single-prescription plaster can treat osteoarthritis (OA) and rheumatoid arthritis (RA), can effectively inhibit arthrocele and volume increase, remarkably reduces the level of proinflammatory factors, and improves the pathological score of joint tissue. After the anilinoprofen and the iguratimod are combined for use, the curative effect is further enhanced, multiple indexes are obviously superior to those of a single drug group, and an obvious synergistic interaction effect is shown. The iguratimod and anilinoprofen compound preparation disclosed by the invention is developed in an external form such as a gel plaster for the first time, an external compound system of anilinoprofen and iguratimod is innovatively constructed, a safe, effective and convenient novel local treatment choice is provided for OA / RA patients, especially people with oral taboo or needing long-term treatment, and the iguratimod and anilinoprofen compound preparation has good clinical transformation potential and application value.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine. More particularly, it relates to a plaster containing anilofiban and an anilofiban-containing composition. BACKGROUND

[0002] Orthopedic inflammatory diseases such as osteoarthritis, rheumatoid arthritis, periarthritis of shoulder, tendonitis, tenosynovitis, peritenosynovitis, or lateral epicondylitis of humerus, etc., among which osteoarthritis (OA) and rheumatoid arthritis (RA) are clinically high-incidence chronic orthopedic diseases, characterized by progressive degeneration of articular cartilage and chronic inflammation of synovial membrane mediated by autoimmunity, often accompanied by joint swelling, pain aggravation, and dysfunction, and can cause disability in severe cases, significantly reducing the patient's quality of life and social participation ability. In addition, myalgia, as a common accompanying symptom in orthopedics, can be caused by compensatory muscle load imbalance of OA / RA and other joint lesions, often coexists with and aggravates joint inflammation, significantly affecting the patient's functional activity and quality of life.

[0003] At present, the first-line treatment of OA / RA still mainly focuses on early intervention, individualized plan, and combination of drugs and non-drugs, with the goal of controlling inflammation, relieving symptoms, and delaying joint destruction. There is currently no "best" single therapy, and a comprehensive plan needs to be developed according to the severity of the disease, complications, etc. Patients with severe symptoms often use oral non-steroidal anti-inflammatory drugs (NSAIDs) (such as ibuprofen, loxoprofen, etc.) or external application of traditional Chinese medicine plasters, but long-term use of oral drugs can easily cause gastrointestinal bleeding, liver and kidney toxicity, and cardiovascular risks, especially for elderly patients, patients with underlying diseases, or patients who need long-term management, which poses a significant obstacle to drug use. The degree of symptom relief of external application of traditional Chinese medicine plasters is limited, and can only provide short-term symptom relief.

[0004] In recent years, there have also been reports of the development of NSAIDs into external dosage forms, such as loxoprofen plasters, which have gradually become one of the preferred treatment strategies recommended by guidelines due to their local targeted drug delivery, low systemic exposure, and higher safety. However, the existing external preparations still have the problem of limited symptom relief and can only provide short-term symptom relief, especially for insufficient control of moderate to severe inflammation.

[0005] Therefore, there is an urgent need to develop a new type of external drug with high safety and better effect to meet the urgent need for local precise treatment of OA / RA in clinical practice. SUMMARY

[0006] This invention aims to overcome the shortcomings of the existing technology and explore more effective topical medications for orthopedic inflammatory diseases such as OA / RA. This invention develops topical patches containing aniline-profen and combinations of aniline-profen and alamod, which can significantly inhibit joint swelling, reduce pro-inflammatory factor levels, and improve histopathological damage, and are particularly suitable for OA / RA patients with oral contraindications or requiring long-term management.

[0007] The first objective of this invention is to provide the use of anilineprofen in the preparation of a medicament for treating orthopedic inflammatory diseases and related symptoms.

[0008] The second objective of this invention is to provide the use of the combination of anilineprofen and alamod in the preparation of a medicament for treating orthopedic inflammatory diseases and related symptoms.

[0009] The third objective of this invention is to provide a topical medication, such as a plaster, containing aniline profen or a combination of aniline profen and alamod.

[0010] The above-mentioned objective of this invention is achieved through the following technical solution: This invention, through extensive research and exploration, has for the first time demonstrated the value of topical anilineprofen in the treatment of orthopedic inflammatory diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA), as well as accompanying muscle pain symptoms. Animal model experiments showed that topical anilineprofen patches can significantly inhibit joint swelling, reduce pro-inflammatory factor levels, improve articular cartilage damage, and exhibit a clear analgesic effect on muscle pain. Furthermore, the combination of anilineprofen and alamod further demonstrated a significant synergistic effect, significantly outperforming monotherapy in both joint inflammation control and muscle pain relief.

[0011] Therefore, the present invention provides the following application solutions: This invention provides the use of anilineprofen in the preparation of medicaments for treating or improving orthopedic inflammatory diseases and related symptoms, including osteoarthritis, rheumatoid arthritis, frozen shoulder, tendinitis, tenosynovitis, peritendinitis, lateral epicondylitis of the humerus, or muscle pain.

[0012] This invention provides the use of a combination of anilineprofen and alamod in the preparation of a medicament for treating or improving orthopedic inflammatory diseases and related symptoms, including osteoarthritis, rheumatoid arthritis, frozen shoulder, tendinitis, tenosynovitis, peritendinitis, lateral epicondylitis of the humerus, or muscle pain.

[0013] Regarding specific effects, the above-mentioned aniline profen and the combination of aniline profen and alamod are suitable for anti-inflammatory and analgesic effects on the following diseases and symptoms: osteoarthritis, rheumatoid arthritis, frozen shoulder, tendinitis, tenosynovitis, peritendinitis, lateral epicondylitis of the humerus, or muscle pain.

[0014] As a specific implementation scheme, in the above application, the dosage form of the drug is a topical preparation.

[0015] Specifically, as an alternative implementation, the dosage form of the drug is a patch.

[0016] The present invention provides a pharmaceutical composition comprising anilineprofen and alamod.

[0017] As an alternative embodiment, the mass ratio of anilineprofen to aramid in the above composition is 1:(0.1~10).

[0018] As an alternative implementation, the mass ratio of anilineprofen to aramid in the above composition is (3~5):(3~5).

[0019] As an alternative implementation, the above composition contains aniline profen and alamod in a mass ratio of 1:1.

[0020] The present invention provides a medicine having anilineprofen, or a combination of anilineprofen and alamod as the active ingredient, and further comprising pharmaceutically acceptable excipients.

[0021] Optionally, the above-mentioned pharmaceutical excipients include any one or a combination of at least two of the following: carrier, diluent, excipient, filler, binder, wetting agent, emulsifier, cosolvent, surfactant or buffer.

[0022] The present invention provides a plaster comprising an active ingredient and excipients required for the plaster dosage form; the active ingredient contains aniline profen or a combination of aniline profen and alamod.

[0023] Specifically, as an alternative embodiment, the present invention provides a gel patch comprising a backing layer, a paste layer, and an anti-adhesive layer; the paste layer contains aniline profen, or contains a combination of aniline profen and alamod.

[0024] Optionally, the above-mentioned ointment layer also contains a transdermal absorption enhancer and a matrix.

[0025] Optionally, the transdermal absorption enhancer includes lauryl ketone transdermal absorption enhancers, fatty acid transdermal absorption enhancers, surfactant transdermal absorption enhancers, menthol, etc.

[0026] Optionally, the lauryl ketone transdermal absorption enhancer includes azones, etc.

[0027] Optionally, the fatty acid transdermal absorption enhancer includes oleic acid, linoleic acid, palmitic acid, or stearic acid, etc.

[0028] Optionally, the surfactant-based transdermal absorption enhancer includes polysorbate 80, sodium lauryl sulfate, lecithin, etc.

[0029] Preferably, the transdermal absorption enhancer may be further selected from at least one of menthol, lecithin, and polysorbate 80.

[0030] Optionally, the matrix includes at least one of glycerol, sodium polyacrylate, sodium carboxymethyl cellulose, carbomer, and gelatin.

[0031] As an alternative implementation, the above-mentioned gel patch contains the following ingredients by weight percentage: 0.5-2.0 wt% aniline-profen, 1.0-2.0 wt% menthol, 0.5-2.0 wt% polysorbate, 10-20 wt% glycerin, 4-8 wt% sodium polyacrylate, and 2-6 wt% sodium carboxymethyl cellulose.

[0032] The present invention has the following beneficial effects: This invention is the first to demonstrate the value of topical anilineprofen in the treatment of orthopedic inflammatory diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA). Pharmacodynamic studies of this invention show that anilineprofen monotherapy patches can treat osteoarthritis (OA) and rheumatoid arthritis (RA), effectively inhibiting joint swelling and volume increase, significantly reducing pro-inflammatory factor levels (IL-1β, IL-6, TNF-α), and improving joint histopathological scores; it has significant clinical value for the treatment of orthopedic inflammatory diseases such as OA / RA. Furthermore, the patch of this invention also shows good relief of accompanying muscle pain symptoms, expanding its application in comprehensive orthopedic pain management.

[0033] Further research revealed that the combination of anilineprofen and alamod showed more significant efficacy. The combined use of anilineprofen and alamod further enhanced the efficacy, with many indicators significantly better than the single-drug group, demonstrating a synergistic effect.

[0034] This invention provides a topical medication containing anilineprofen or a combination of anilineprofen and alamod. It is the first time that anilineprofen has been developed in a topical form such as a gel patch, and an innovative topical compound system of anilineprofen and alamod has been constructed. This provides a safe, effective and convenient new local treatment option for OA / RA patients, especially those who have oral contraindications or require long-term treatment, and has good clinical translation potential and application value. Attached Figure Description

[0035] Figure 1 The results show the comparison of the degree of knee joint swelling in rats from different treatment groups.

[0036] Figure 2 Results of knee joint swelling measurement in rats of each treatment group 12 days after administration.

[0037] Figure 3 The results show the serum IL-6 levels in rats from each treatment group.

[0038] Figure 4 The results show the serum IL-1β levels in rats from each treatment group.

[0039] Figure 5 The results show the serum TNF-α levels in rats from each treatment group.

[0040] Figure 6 The results show the paw volume measurements of rats in each treatment group.

[0041] Figure 7 The results of the Von Frey test for rats in each treatment group are shown. Detailed Implementation

[0042] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, but the embodiments do not limit the present invention in any way. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in this technical field.

[0043] Unless otherwise specified, all reagents and materials used in the following examples are commercially available.

[0044] Anilineprofen, CAS No.: 935886-64-9, has the following structural formula:

[0045] Ailamod, CAS No. 123663-49-0, has the following structural formula:

[0046] Papain and L-cysteine ​​mixture: 4% papain solution and 0.03 mol / L cysteine ​​solution are mixed at a ratio of 1:1.

[0047] 4% Papain Solution: Dissolve 4 g of papain powder in 100 mL of water.

[0048] Example 1 The plaster formula contains the following ingredients: 1 g aniline profen, 1.5 g menthol, 1 g polysorbate 80, 15 g glycerin, 6 g sodium polyacrylate, 4 g sodium carboxymethyl cellulose, and 100 mL purified water.

[0049] The preparation method of the plaster is as follows: (1) Preparation of phase A adhesive Weigh 70.0 mL of pure water into a beaker, slowly sprinkle sodium polyacrylate into it while stirring (200 rpm), and accelerate dissolution in a 40℃ water bath for 30 min to obtain phase A gel solution; (2) Preparation of phase B drug-containing solution Mix polysorbate 80 and menthol, stirring until completely dissolved; add the active drug aniline profen, stirring until completely dissolved and clear; slowly add glycerin, mix well, and obtain phase B drug-containing solution; (3) Preparation of viscous paste Sodium carboxymethyl cellulose was slowly added to 30 mL of purified water and stirred for 30 min to obtain a sodium carboxymethyl cellulose dispersion. The sodium carboxymethyl cellulose dispersion was added to phase A gel and stirred at medium speed (300 rpm) for 30 min to obtain a matrix gel. Then, phase B containing the drug was slowly added dropwise to the matrix gel (while stirring), stirred at 800 rpm for 20 min, and then vacuum degassed for 10-15 min to obtain a uniform, bubble-free, viscous paste.

[0050] (4) Finished product A viscous paste is evenly coated onto a non-woven fabric (backing layer), with the wet paste thickness controlled at 1.0 mm. After curing at room temperature for 24 hours, a plaster is obtained.

[0051] Example 2 The plaster formula contains the following ingredients: 1 g aniline profen, 1 g alamod, 1.5 g menthol, 1 g polysorbate 80, 15 g glycerin, 6 g sodium polyacrylate, 4 g sodium carboxymethyl cellulose, and 100 mL purified water.

[0052] The preparation method is the same as in Example 1, except that the active drug anilineprofen in phase B is replaced with anilineprofen and alamod.

[0053] Example 3 The plaster formula contains the following ingredients: 1 g anilineprofen, 10 g alamol, 1.5 g menthol, 1 g polysorbate 80, 15 g glycerin, 6 g sodium polyacrylate, 4 g sodium carboxymethyl cellulose, and 100 mL purified water.

[0054] The preparation method is the same as in Example 1, except that the active drug anilineprofen in phase B is replaced with anilineprofen and alamod.

[0055] Example 4 The plaster formula contains the following ingredients: 10 g aniline profen, 1 g alamod, 1.5 g menthol, 1 g polysorbate 80, 15 g glycerin, 6 g sodium polyacrylate, 4 g sodium carboxymethyl cellulose, and 100 mL purified water.

[0056] The preparation method is the same as in Example 1, except that the active drug anilineprofen in phase B is replaced with anilineprofen and alamod.

[0057] Comparative Example 1 The plaster formula (blank matrix) contains the following ingredients: 1.5 g menthol, 1 g polysorbate 80, 15 g glycerin, 6 g sodium polyacrylate, 4 g sodium carboxymethyl cellulose, and 100 mL purified water.

[0058] The preparation method is the same as in Example 1, except that no active drug is added to phase B.

[0059] Comparative Example 2 The plaster formula contains the following ingredients: 1 g Ailamod, 1.5 g menthol, 1 g polysorbate 80, 15 g glycerin, 6 g sodium polyacrylate, 4 g sodium carboxymethyl cellulose, and 100 mL purified water.

[0060] The preparation method is the same as in Example 1, except that anilineprofen in phase B is replaced with alamod.

[0061] Comparative Example 3 The plaster formula contains the following ingredients: 1 g loxoprofen sodium, 1.5 g menthol, 1 g polysorbate 80, 15 g glycerin, 6 g sodium polyacrylate, 4 g sodium carboxymethyl cellulose, and 100 mL purified water.

[0062] The preparation method is the same as in Example 1, except that anilineprofen in phase B is replaced with loxoprofen sodium.

[0063] Comparative Example 4 The plaster formula contains the following ingredients: 1 g loxoprofen sodium, 1 g elamod, 1.5 g menthol, 1 g polysorbate 80, 15 g glycerin, 6 g sodium polyacrylate, 4 g sodium carboxymethyl cellulose, and 100 mL purified water.

[0064] The preparation method is the same as in Example 1, except that anilineprofen in phase B is replaced with loxoprofen sodium and alamod.

[0065] Example 5: Treatment Experiment of a Rat Model of Osteoarthritis (OA) I. Animal Grouping and Modeling After a week of acclimatization, SD rats were used for modeling. Rats were fasted for 12 hours prior to modeling (with free access to water). The right knee joint area was prepared and disinfected. A needle was inserted into the intercondylar fossa via the lateral patellar fossa (after touching the bone surface, the needle was slightly withdrawn). A mixture of papain and L-cysteine ​​(0.1 mL / kg) was injected via a microsyringe (100 μL). This injection was repeated on days 4 and 7 post-modeling to enhance the modeling effect. At week 4 post-modeling, joint swelling (diameter measured with calipers) and MRI were used to assess cartilage damage, meniscus degeneration, and joint effusion; rats exhibiting the same imaging / morphological changes were considered successfully modeled.

[0066] A control group (without modeling) was also set up.

[0067] II. Dosing Regimen After successful modeling, the participants were randomly divided into the following groups and given medication: (1) Control group: Unmodeled rats were treated with the patch (blank matrix) of Comparative Example 1. (2) Model group: The patch of Comparative Example 1 (blank matrix) was applied. (3) Aniline profen group (FB): Apply the patch of Example 1; (4) Elamode group (IGU): The patch of Comparative Example 2 was applied; (5) Anilineprofen and elamod combined group (FB+IGU): Apply the patch of Example 2; (6) Loxoprofen group: Apply the patch of comparison example 3; (7) Lox + IGU combination group: the patch of comparison ratio 4 was applied.

[0068] The administration method was as follows: cut the plaster into pieces of 1 cm × 2 cm size, apply them to the right knee joint of the rat, and change them once a day for 12 consecutive days.

[0069] III. Morphological Evaluation of the Knee Joint Before administration (0 days) and on days 4, 8, and 12, the diameter of the right knee joint was measured using calipers to assess the degree of swelling.

[0070] IV. Detection of inflammatory factor levels in rat serum Twenty-four hours after the last administration, blood was collected by saphenous vein puncture in the saphenous vein area (hind limb). After being placed at room temperature and separated into layers, the blood was centrifuged at 4000 r / min for 10 min, and the serum was collected (stored at -20℃). The serum levels of IL-1β, IL-6, and TNF-α were detected using an ELISA kit (Beyotime).

[0071] V. Histopathological Analysis of Joints After euthanizing the rats, the right knee joint tissue was harvested, decalcified with 10% EDTA for 60 days, then dehydrated in a gradient manner, embedded in paraffin, and sectioned (4 μm). The sections were stained with HE and Safranin O-Fix Green. The semi-quantitative assessment of cartilage degeneration was performed according to the Mankin scoring system.

[0072] VI. Experimental Results (1) Improvement of joint swelling The results of the comparison of the degree of knee joint swelling in rats in each treatment group are as follows: Figure 1 and Figure 2 As shown, the results indicate that: Compared with the control group, the model group showed significant joint swelling.

[0073] Compared with the model group, the degree of swelling was reduced in all drug-treated groups, with the FB+IGU group showing the most significant relief.

[0074] Furthermore, comparisons of the FB group, IGU group, and FB+IGU group showed that the combination of anilineprofen and alamoside exhibited a significant synergistic effect.

[0075] (2) Serum inflammatory factor levels The effects of each treatment group on serum inflammatory factor levels are as follows: Figure 3 , Figure 4 , Figure 5 As shown in Table 1, the results indicate that: Compared with the control group, the serum levels of inflammatory factors IL-1β, IL-6, and TNF-α in the model group were significantly increased. P <0.05).

[0076] Compared with the model group, the serum inflammatory factor levels in the FB monotherapy group were significantly reduced, and the serum inflammatory factor levels in the FB+IGU group were even more significantly reduced.

[0077] The IGU monotherapy group and the Lox+IGU combination group also showed a certain degree of downregulation of some inflammatory factors, but the effect was not as good as the FB+IGU group and the FB group.

[0078] Table 1. Results of serum inflammatory factor levels in rats of each group

[0079] Note: Different lowercase letters in the table indicate significant differences. P <0.05) (3) Joint histopathological score The results of the effects of each treatment group on the pathological morphology of the knee joint tissue are shown in Table 2. The results indicate that: Compared with the control group, the Mankin score of the model group was significantly higher; Compared with the model group, the scores of all drug-treated groups decreased significantly, with the FB+IGU group showing the most significant decrease and the lowest score, indicating the strongest chondrogenic protective effect.

[0080] Table 2. Histopathological scores of the knee joints of rats in each group

[0081] Note: Different lowercase letters in the table indicate significant differences. P <0.05) Example 6 Evaluation of a rat model of rheumatoid arthritis (RA) I. Animal grouping and model construction After 1 week of acclimatization, SD rats were used to establish the rat model.

[0082] The specific modeling method is as follows: After preparing and disinfecting the skin of the left hind limb region of the rats, and anesthetizing the rats, 0.2 mL of complete Freund's adjuvant was injected subcutaneously into the left hind limb to induce inflammation. The foot volume was monitored daily after injection. The RA model was considered successfully established when the swelling of the left hind limb of the primary side and the right hind limb of the secondary side tended to stabilize and showed no significant difference.

[0083] A control group (control) without modeling was also set up.

[0084] II. Dosing Regimen After successful modeling, the participants were randomly divided into the following groups and given medication: (1) Control group: Unmodeled rats were treated with the patch (blank matrix) of Comparative Example 1. (2) Model group: The patch of Comparative Example 1 (blank matrix) was applied. (3) Aniline profen group (FB): Apply the patch of Example 1; (4) Elamode group (IGU): The patch of Comparative Example 2 was applied; (5) Anilineprofen and elamod combined group (FB+IGU): Apply the patch of Example 2; (6) Loxoprofen group: Apply the patch of comparison example 3; (7) Lox + IGU combination group: the patch of comparison ratio 4 was applied.

[0085] The administration method was as follows: cut the plaster into 1 cm × 2 cm pieces, apply them to the skin preparation area of ​​the rat, and change them once a day for 12 consecutive days.

[0086] III. Arthritis Index (AI) Score Before administration (Day 0) and on Day 12 (Day 12), the severity of joint lesions was assessed using a 5-point joint scoring system, and the arthritis index was calculated. The arthritis index scoring criteria are shown in Table 3.

[0087] Table 3 Arthritis Index Scoring Criteria

[0088] IV. Measurement of plantar volume Before administration (Day 0) and on Day 12 after administration (Day 12), the paw volume of the left hind limb of rats was measured using a paw volume measuring instrument. The specific method was as follows: the joint of the left hind limb of the rat was marked with a marker, the rat was straightened and placed into the measuring cup of the paw volume measuring instrument, and the paw volume was measured and recorded.

[0089] V. Experimental Results (1) Changes in the arthritis index The results of the arthritis index measurement are shown in Table 4. The results indicate that after 12 days of drug administration, the arthritis index in the model group remained at a high level (3.83). However, the arthritis indices in the FB group, IGU group, and FB+IGU group all decreased significantly. P <0.05), among which the FB+IGU group showed the most significant improvement, significantly better than the single-drug group and the Lox group.

[0090] Table 4. Results of arthritis index measurement in rats of each group.

[0091] Note: Different lowercase letters in the table indicate significant differences. P <0.05) (2) Changes in plantar volume The results of paw volume measurements for each group of rats are shown in Table 5 and Figure 6 As shown, the results indicated that the paw volume of the model group rats was significantly increased, indicating that the inflammation continued to progress; while the paw volume of the FB group, IGU group and FB+IGU group was significantly reduced, with the FB+IGU group being significantly better than the other treatment groups.

[0092] In summary, the combined patch of anilineprofen and alamod showed significant synergistic anti-inflammatory and anti-swelling effects in the RA rat model, and its efficacy was significantly better than that of each single drug group and traditional NSAIDs (loxoprofen).

[0093] Table 5. Results of paw volume measurement in rats of each group

[0094] Note: Different lowercase letters in the table indicate significant differences. P <0.05) Example 7 1. Plaster 1: A combination of aniline profen and elamod (FB+IGU-1): The formula contains the following ingredients: 1 g anilineprofen, 1 g alamod, 1 g azone, 1 g lecithin, 13 g glycerin, 6 g sodium polyacrylate, 4 g sodium carboxymethyl cellulose, and 100 mL purified water.

[0095] The preparation method of the plaster is as follows: (1) Preparation of phase A adhesive Weigh 70.0 mL of pure water into a beaker, slowly sprinkle sodium polyacrylate into it while stirring (200 rpm), and accelerate dissolution in a 40℃ water bath for 30 min to obtain phase A gel solution; (2) Preparation of phase B drug-containing solution Mix lecithin and azone, stirring until completely dissolved; add the active drugs anilineprofen and alamod, stirring until completely dissolved and clear; slowly add glycerin, mix well, and obtain phase B drug-containing solution; (3) Preparation of viscous paste Sodium carboxymethyl cellulose was slowly added to 30 mL of purified water and stirred for 30 min to obtain a sodium carboxymethyl cellulose dispersion. The sodium carboxymethyl cellulose dispersion was added to phase A gel and stirred at medium speed (300 rpm) for 30 min to obtain a matrix gel. Then, phase B containing the drug was slowly added dropwise to the matrix gel (while stirring), stirred at 800 rpm for 20 min, and then vacuum degassed for 10-15 min to obtain a uniform, bubble-free, viscous paste.

[0096] (4) Finished product A viscous paste is evenly coated onto a non-woven fabric (backing layer), with the wet paste thickness controlled at 1.0 mm. After curing at room temperature for 24 hours, a plaster is obtained.

[0097] 2. Plaster 2: Two groups of combined use of anilineprofen and elastin (FB+IGU-2): The formula contains the following ingredients: 0.6 g anilineprofen, 1 g alamod, 1 g azone, 1 g lecithin, 13 g glycerin, 6 g sodium polyacrylate, 4 g sodium carboxymethyl cellulose, and 100 mL purified water.

[0098] The preparation method is the same as 1. 3. Plaster 3: Aniline profen combined with elastin in 3 groups (FB+IGU-3): The formula contains the following ingredients: 1 g anilineprofen, 0.6 g alamod, 1 g azone, 1 g lecithin, 13 g glycerin, 6 g sodium polyacrylate, 4 g sodium carboxymethyl cellulose, and 100 mL purified water.

[0099] The preparation method is the same as 1.

[0100] 4. Plaster 4: Aniline Profen Group (FB): The formula contains the following ingredients: 1 g aniline-profen, 1 g azone, 1 g lecithin, 13 g glycerin, 6 g sodium polyacrylate, 4 g sodium carboxymethyl cellulose, and 100 mL purified water.

[0101] The preparation method is the same as 1.

[0102] 5. Plaster 5: Elamod Group (IGU): The formula contains the following ingredients: 1 g Alamod, 1 g azone, 1 g lecithin, 13 g glycerin, 6 g sodium polyacrylate, 4 g sodium carboxymethyl cellulose, and 100 mL purified water.

[0103] The preparation method is the same as 1.

[0104] 6. Patches 6: Loxoprofen group: The formula contains the following ingredients: 1 g loxoprofen, 1 g azone, 1 g lecithin, 13 g glycerin, 6 g sodium polyacrylate, 4 g sodium carboxymethyl cellulose, and 100 mL purified water.

[0105] The preparation method is the same as 1.

[0106] 7. Plaster 7: Lox + IGU combination of loxoprofen and elamod: The formula contains the following ingredients: 1 g loxoprofen, 1 g elamod, 1 g azone, 1 g lecithin, 13 g glycerin, 6 g sodium polyacrylate, 4 g sodium carboxymethyl cellulose, and 100 mL purified water.

[0107] The preparation method is the same as 1.

[0108] Example 8 Evaluation of a rat model of inflammatory pain I. Animal grouping and model construction After 1 week of acclimatization, SD rats were used to establish the rat model.

[0109] The specific modeling method is as follows: After preparing and disinfecting the left hind limb area of ​​rats, and anesthetizing them, 100 μL of Complete Freund's Adjuvant (CFA) was subcutaneously injected into the palmar surface of the left hind paw to establish a chronic inflammatory pain model. A control group (not using the model) was also established. Two to four hours after injection, obvious signs of local inflammation (such as reddish-purple swelling) were observed at the injection site. Further analysis using the Von Frey test revealed a significant decrease in paw retraction pressure; rats with this characteristic were considered successfully modeled and used for subsequent experiments.

[0110] II. Dosing Regimen After successful modeling, the participants were randomly divided into the following groups and given medication: (1) Control group: Unmodeled rats were covered with a blank matrix patch (the blank matrix consisted of 1 g azone, 1 g lecithin, 13 g glycerin, 6 g sodium polyacrylate, 4 g sodium carboxymethyl cellulose, and 100 mL pure water). (2) Model group: Model rats, with blank matrix patches applied (blank matrix: 1 g azone, 1 g lecithin, 13 g glycerin, 6 g sodium polyacrylate, 4 g sodium carboxymethyl cellulose, 100 mL pure water); (3) Group 1 of combined use of anilineprofen and aramod (FB+IGU-1): model rats, with patch 1 of Example 7 applied; (4) Two groups of combined use of anilineprofen and aramod (FB+IGU-2): model rats, with patch 2 of Example 7 applied; (5) Three groups of combined use of anilineprofen and aramod (FB+IGU-3): model rats, with patch 3 of Example 7 applied; (6) Aniline profen group (FB): Model rats, with patch 4 from Example 7 applied; (7) Elamode group (IGU): model rats, with patch 5 from Example 7 applied; (8) Loxoprofen group: model rats, with patch 6 from Example 7 applied; (9) Lox + IGU combination group: model rats, with patch 7 in Example 7 applied.

[0111] The administration method was as follows: cut the plaster into 1 cm × 2 cm pieces, apply them to the skin preparation area of ​​the rat, and change them once a day for 5 consecutive days.

[0112] III. Von Frey Test Twenty-four hours after drug administration, rats in different treatment groups were placed individually in transparent test cages with wire mesh bottoms and allowed to acclimatize for 30 minutes to reduce stress. A von Frey fiber (initial force 2.0 g) was applied vertically to the central area of ​​the left hind paw sole for 5–6 seconds. A positive response was recorded as paw retraction, paw lifting, or paw licking. The next test was then conducted with a lower force fiber (1.4 g); if no positive response was observed, the force was increased to a higher level (e.g., 4.0 g). The number of positive responses occurring out of every five stimuli was recorded, with the maximum stimulus intensity set at 15.0 g. The 50% mechanical threshold was calculated using the Dixon up-and-down method.

[0113] IV. Experimental Results The results of the Von Frey test in each group of rats are shown in Table 6. The results showed that compared with the control group, the mechanical threshold of 50% in the model group was reduced by about 90%, confirming the successful establishment of the inflammatory pain model. All single-drug treatment groups (FB, IGU, Lox) had certain analgesic effects, with the aniline profen (FB) group showing the best effect. The combined treatment of FB and IGU was significantly better than the corresponding single-drug groups (P<0.05), with the FB+IGU-1 group showing the most significant improvement, suggesting that the combination of aniline profen and elastomodil has a synergistic analgesic effect; the combination of loxoprofen and elastomodil did not show a significant synergistic effect, indicating that the synergistic effect is drug-specific.

[0114] Table 6. Results of Von Frey assay in rats of each group.

[0115] Note: Different lowercase letters in the table indicate significant differences. P <0.05) The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. The use of anilineprofen in the preparation of medicaments for the treatment or improvement of orthopedic inflammatory diseases and related symptoms, including osteoarthritis, rheumatoid arthritis, frozen shoulder, tendinitis, tenosynovitis, peritendinitis, lateral epicondylitis of the humerus, or myalgia.

2. The use of the combination of anilineprofen and alamod in the preparation of a medicament for the treatment or improvement of orthopedic inflammatory diseases and related symptoms, including osteoarthritis, rheumatoid arthritis, frozen shoulder, tendinitis, tenosynovitis, peritendinitis, lateral epicondylitis of the humerus, or myalgia.

3. The application according to claim 1 or 2, characterized in that, The drug is a topical preparation.

4. The application according to claim 3, characterized in that, The drug is in the form of a plaster.

5. A pharmaceutical composition, characterized in that, It contains aniline profen and aramod.

6. The composition according to claim 5, characterized in that, The mass ratio of anilineprofen to aramod is 1:(0.1~10).

7. A drug, characterized in that, The composition of claim 5 or 6 is the active ingredient, and also includes pharmaceutically acceptable excipients.

8. A plaster, characterized in that, Includes active ingredients and excipients required for the plaster formulation; the active ingredient contains aniline profen or the composition according to any one of claims 5-6.

9. A gel patch, characterized in that, It includes a backing layer, a paste layer, and an anti-sticking layer; the paste layer contains aniline profen or the composition of any one of claims 5-6.

10. The gel patch according to claim 9, characterized in that, The ointment layer also contains transdermal absorption enhancers and a matrix.

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