Traditional Chinese medicine patch for treating rheumatoid arthritis and preparation method thereof

Abstract

The invention relates to the field of pharmaceutical preparations, in particular to a traditional Chinese medicine patch for treating rheumatoid arthritis and a preparation method thereof. The traditional Chinese medicine patch contains a traditional Chinese medicine extract and a penetration enhancer; wherein the traditional Chinese medicine extract is obtained by extracting schizonepeta, divaricate saposhnikovia root, garden balsam stem and folium artemisiae argyi as raw materials, and the penetration enhancer is borneol. Schizonepeta and divaricate saposhnikovia root in the patch expel wind and remove cold to prevent invasion of exogenous evil, garden balsam stem introduces internal evil to permeate outside, folium artemisiae argyi warms channels and removes cold to stop pain, and the patch is prepared into a medicine transdermal absorption patch and directly acts on local parts to achieve the effects of relieving pain and improving joint functions. The medicine is definite in curative effect, low in cost, small in toxic and side effects, simple in process and preparation and suitable for batch industrial production.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical preparations, in particular to a traditional Chinese medicine patch for treating rheumatoid arthritis and a preparation method thereof. Background Art

[0002] Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects multiple joints throughout the body. It belongs to the category of "arthritis" in traditional Chinese medicine. At present, modern medicine has no effective cure for rheumatoid arthritis, but external treatment with traditional Chinese medicine has shown a good trend.

[0003] At present, there are three types of treatments for RA: physical therapy, surgery, and drug therapy. Most of them are aimed at controlling the production of inflammatory factors to relieve joint pain. In drug treatment, although Western medicine has certain curative effects, long-term use has great toxic side effects. In recent years, the research on the treatment of RA with traditional Chinese medicine has been extensive, and compared with Western medicine, its efficacy is reliable and safe. The theory of traditional Chinese medicine treatment of RA is mostly to dispel wind and dampness. There are three methods: acupuncture, massage, and traditional Chinese medicine treatment. The ingredients of traditional Chinese medicine are complex, and only some of the effective ingredients have been clinically confirmed. Therefore, the development of effective ingredients of traditional Chinese medicine is particularly important for the treatment of RA.

[0004] Schizonepeta, Saposhnikovia divaricata, Herba Artemisiae Argyi and Artemisiae Argyi are commonly used Chinese herbal medicines for the treatment of RA. They can be used alone or in combination. Among them, Schizonepeta and Saposhnikovia divaricata are a group of commonly used drug pairs in antipyretic drugs. The two are used together to enhance the wind-dispelling effect. They can be used to treat wind-cold-damp arthralgia, etc. Herba Artemisiae Argyi and Artemisiae Argyi also play a significant role in various prescriptions for the treatment of arthralgia. However, most of the medicines containing these Chinese herbal medicines are currently used orally. Although oral preparations are effective, the dosage is large and the bioavailability is low. Due to the long treatment cycle of RA, long-term medication is required. Long-term use has great toxic side effects and liver and kidney toxicity, which seriously affects the safety of patients' medication.

[0005] Compared with oral administration, transdermal administration avoids the first-pass effect of the liver and gastrointestinal absorption, improves medication safety and patient compliance, etc. This type of transdermal drug preparation plays a very important role in the treatment of rheumatoid arthritis and occupies a large proportion in the field of modern medicine.

[0006] Patches belong to transdermal drug delivery systems and are divided into reservoir type, adhesive dispersion type, and peripheral adhesive skeleton type. Among them, the pressure-sensitive adhesive dispersion type patch is the patch with the simplest preparation process and the lowest production cost. The pressure-sensitive adhesive layer not only plays the role of applying to the skin, but also plays the role of forming a drug reservoir and controlling drug release. Therefore, the pressure-sensitive adhesive dispersion type patch has been widely used. Patches can not only be applied and removed immediately, but also are easy to carry, and the safety factor has also been improved, providing new ideas and basis for the clinical treatment of RA. However, although pressure-sensitive adhesive dispersion patches have obvious advantages over traditional preparations, not all drugs are suitable for preparation. Only a few drugs can exert their efficacy through the skin, especially traditional Chinese medicines with complex ingredients, which need to be developed. Therefore, the release of drugs from the preparation is very important. It is necessary to find a suitable way to make it work. Summary of the invention

[0007] The purpose of the present invention is to provide a Chinese medicine patch for treating rheumatoid arthritis which has low cost, simple preparation process and high safety and a preparation method thereof.

[0008] To achieve the above purpose, the technical solution adopted by the present invention to solve the technical problem is:

[0009] A Chinese medicine patch for treating rheumatoid arthritis contains a Chinese medicine volatile oil extract and a penetration enhancer; wherein the Chinese medicine volatile oil extract is extracted from raw materials of schizonepeta, siler, radix polygoni lobatae and wormwood, and the penetration enhancer is borneol.

[0010] The extract is prepared by mixing schizonepeta, siler, radix polygoni lobatae and wormwood, adding water in an amount 10-14 times of the mixed weight, soaking in a water bath at 25-45° C. for 0.5-2 hours, and extracting with a volatile oil extractor for 3-5 hours.

[0011] The raw materials in the Chinese medicine extract are calculated by weight, including 1-3 parts of Schizonepeta, 1-3 parts of Saposhnikovia divaricata, 1-3 parts of Herba Polygoni Multiflori, and 1-3 parts of Artemisia argyi.

[0012] A preparation method of a Chinese medicine patch for treating rheumatoid arthritis comprises the following steps: weighing 1 portion of hot-melt pressure-sensitive adhesive into a mortar, placing the mixture in a temperature-adjustable electric heating sleeve, heating the mixture to 140-180°C until the mixture is melted, adding 1-5% of a penetration enhancer and 2-8% of a Chinese medicine extract (both by mass ratio, based on the total mass of the plaster), stirring the mixture evenly, and immediately applying the mixed adhesive solution on a release layer while the mixture is hot using a 0.2-0.9 mm frame coater, and then covering the mixture with a backing layer and cutting the mixture into suitable sizes to obtain the patch.

[0013] An application of the patch, which is application of the patch as a traditional Chinese medicine patch for treating rheumatoid arthritis.

[0014] The advantages of the present invention are:

[0015] The patch of the present invention is composed of a Chinese medicine volatile oil extract obtained by steam distillation and a penetration enhancer. Among the Chinese medicines, schizonepeta and siler are selected to dispel wind and cold and prevent invasion of external pathogens, and radix schizonepetae and rhizoma scutellariae are selected to introduce internal pathogens to penetrate externally, and argyi leaves are selected to warm the meridians and dispel cold to relieve pain. At the same time, the volatile oil extracts of the four Chinese medicinal materials are used as active ingredients to prepare a drug percutaneous absorption patch, which directly acts on the local area and plays the role of relieving pain and improving joint function. It has definite efficacy, low cost, small toxic and side effects, simple process and production, and is suitable for batch industrial production. DETAILED DESCRIPTION

[0016] The present invention will be further described below in conjunction with embodiments:

[0017] Example 1

[0018] The raw materials of a Chinese herbal volatile oil extract for treating rheumatoid arthritis include the following raw materials in parts by weight: 1 part of schizonepeta, 1 part of siler, 1 part of radix scutellariae, 1 part of herba schizonepetae and 1 part of argyi.

[0019] The extraction process is as follows: weigh 1 part of Schizonepeta, 1 part of Saposhnikovia, 1 part of Herba Polygoni Multiflori, and 1 part of Artemisia argyi, place them in a round-bottom flask, add 12 times the amount of water of the total amount of the Chinese medicinal materials, soak them in a water bath at 35°C for 1 hour, and extract them with a volatile oil extractor for 4 hours.

[0020] The preparation method of the Chinese medicine patch is as follows: weigh 1 part of hot-melt pressure-sensitive adhesive in a mortar, place it in a temperature-adjustable electric heating sleeve, heat it to 140-150° C. to melt, add 1% borneol and 5% Chinese medicine volatile oil extract, stir evenly, immediately use a 0.6 mm frame coater to coat the mixed adhesive solution on the anti-adhesive layer while hot, then cover it with a backing layer, and cut it into a suitable size to obtain the patch.

[0021] Example 2

[0022] The Chinese herbal volatile oil extract raw material for treating rheumatoid arthritis comprises the following raw materials in parts by weight: 1 part of schizonepeta, 1 part of siler, 3 parts of radix polygoni lobatae, and 2 parts of wormwood.

[0023] The extraction process is as follows: weigh 1 part of Schizonepeta, 1 part of Saposhnikovia, 3 parts of Herba Polygoni Multiflori, and 2 parts of Artemisia argyi, place them in a round-bottom flask, add 14 times the amount of water of the total amount of the Chinese medicinal materials, soak them in a water bath at 45°C for 2 hours, and extract them with a volatile oil extractor for 5 hours.

[0024] The preparation method of the Chinese medicine patch is as follows: weigh 1 portion of hot-melt pressure-sensitive adhesive in a mortar, place it in a temperature-adjustable electric heating sleeve, heat it to 160-170°C to melt, add 3% borneol and 7% Chinese medicine volatile oil extract, stir evenly, immediately use a 0.9mm frame coater to coat the mixed adhesive solution on the anti-adhesive layer while it is hot, then cover it with a backing layer, and cut it into a suitable size to obtain the patch.

[0025] Example 3

[0026] The raw materials of a Chinese herbal volatile oil extract for treating rheumatoid arthritis include the following raw materials in parts by weight: 2 parts of schizonepeta, 3 parts of siler, 1 part of radix polygoni lobatae, and 2 parts of wormwood.

[0027] The extraction process is as follows: weigh 2 parts of Schizonepeta, 3 parts of Saposhnikovia, 1 part of Herba Polygoni Multiflori, and 2 parts of Artemisia argyi, place them in a round-bottom flask, add 10 times the amount of water of the total amount of the Chinese medicinal raw materials, soak them in a water bath at 35°C for 1 hour, and extract them with a volatile oil extractor for 3 hours.

[0028] The preparation method of the Chinese medicine patch is as follows: weigh 1 portion of hot-melt pressure-sensitive adhesive in a mortar, place it in a temperature-adjustable electric heating sleeve, heat it to 170-180°C to melt, add 5% borneol and 2% Chinese medicine volatile oil extract, stir evenly, immediately use a 0.7mm frame coater to coat the mixed adhesive solution on the anti-adhesive layer while it is hot, then cover it with a backing layer, and cut it into a suitable size to obtain the patch.

[0029] Example 4

[0030] The raw materials of a Chinese medicinal volatile oil extract for treating rheumatoid arthritis include the following raw materials in parts by weight: 2 parts of schizonepeta, 2 parts of siler, 2 parts of radix scutellariae, and 3 parts of wormwood.

[0031] The extraction process is as follows: weigh 2 parts of Schizonepeta, 2 parts of Saposhnikovia, 2 parts of Herba Polygoni Multiflori, and 3 parts of Artemisia argyi, place them in a round-bottom flask, add 10 times the amount of water of the total amount of the Chinese medicinal raw materials, soak in a water bath at 25°C for 0.5h, and extract with a volatile oil extractor for 5h.

[0032] The preparation method of the Chinese medicine patch is as follows: weigh 1 portion of hot-melt pressure-sensitive adhesive in a mortar, place it in a temperature-adjustable electric heating sleeve, heat it to 140-150° C. to melt, add 3% borneol and 5% Chinese medicine volatile oil extract, stir evenly, immediately use a 0.5 mm frame coater to coat the mixed adhesive solution on the anti-adhesive layer while it is hot, then cover it with a backing layer, and cut it into a suitable size to obtain the patch.

[0033] Comparative Example 1

[0034] The raw materials of a Chinese medicinal volatile oil extract for treating rheumatoid arthritis include the following raw materials in parts by weight: 2 parts of schizonepeta, 2 parts of siler, 2 parts of radix scutellariae, and 3 parts of wormwood.

[0035] The extraction process is as follows: weigh 2 parts of Schizonepeta, 2 parts of Saposhnikovia, 2 parts of Herba Polygoni Multiflori, and 3 parts of Artemisia argyi, place them in a round-bottom flask, add 10 times the amount of water of the total amount of the Chinese medicinal raw materials, soak in a water bath at 25°C for 0.5h, and extract with a volatile oil extractor for 5h.

[0036] The preparation method of the Chinese medicine patch is as follows: weigh 1 portion of hot-melt pressure-sensitive adhesive in a mortar, place it in a temperature-adjustable electric heating sleeve, heat it to 140-150° C. to melt, add 3% menthol and 5% Chinese medicine volatile oil extract, stir evenly, immediately use a 0.5 mm frame coater to coat the mixed adhesive solution on the anti-adhesive layer while hot, then cover it with a backing layer, and cut it into a suitable size to obtain the patch.

[0037] Comparative Example 2

[0038] The raw materials of a Chinese medicinal volatile oil extract for treating rheumatoid arthritis include the following raw materials in parts by weight: 2 parts of schizonepeta, 2 parts of siler, 2 parts of radix scutellariae, and 3 parts of wormwood.

[0039] The extraction process is as follows: weigh 2 parts of Schizonepeta, 2 parts of Saposhnikovia, 2 parts of Herba Polygoni Multiflori, and 3 parts of Artemisia argyi, place them in a round-bottom flask, add 10 times the amount of water of the total amount of the Chinese medicinal raw materials, soak in a water bath at 25°C for 0.5h, and extract with a volatile oil extractor for 5h.

[0040] The preparation method of the Chinese medicine patch is as follows: weigh 1 portion of hot-melt pressure-sensitive adhesive in a mortar, place it in a temperature-adjustable electric heating sleeve, heat it to 140-150° C. to melt, add 5% of Chinese medicine volatile oil extract, stir evenly, immediately use a 0.5 mm frame coater to coat the mixed adhesive liquid on the anti-adhesive layer while it is hot, then cover it with a backing layer, and cut it into a suitable size to obtain the patch.

[0041] Comparative Example 3

[0042] The Chinese medicinal raw material for treating rheumatoid arthritis comprises the following raw materials in parts by weight: 2 parts of schizonepeta, 2 parts of siler, 2 parts of radix sphenantheraefoliae, and 3 parts of wormwood.

[0043] The preparation method of the Chinese medicine patch is as follows: weigh 1 part of hot-melt pressure-sensitive adhesive into a mortar, place it in a temperature-adjustable electric heating sleeve, heat it to 140-150°C to melt, add 2 parts of raw materials, 2 parts of siler, 2 parts of schizonepeta tenuifolia, 2 parts of radix siler, 3 parts of artemisia argyi, stir evenly, immediately use a 0.5 mm frame coater to apply the mixed adhesive solution while hot on the anti-adhesive layer, then cover it with a backing layer, and cut it into suitable sizes to obtain the patch.

[0044] Comparative Example 4

[0045] The raw materials of a Chinese herbal volatile oil extract for treating rheumatoid arthritis include the following raw materials in parts by weight: 2 parts of schizonepeta and 2 parts of siler.

[0046] The extraction process is as follows: weigh 2 parts of Schizonepeta and 2 parts of Saposhnikovia, place them in a round-bottom flask, add water 10 times the total amount of the Chinese medicinal materials, soak them in a water bath at 25°C for 0.5h, and extract them with a volatile oil extractor for 5h.

[0047] The preparation method of the Chinese medicine patch is as follows: weigh 1 portion of hot-melt pressure-sensitive adhesive in a mortar, place it in a temperature-adjustable electric heating sleeve, heat it to 140-150° C. to melt, add 5% of Chinese medicine volatile oil extract, stir evenly, immediately use a 0.5 mm frame coater to coat the mixed adhesive liquid on the anti-adhesive layer while it is hot, then cover it with a backing layer, and cut it into a suitable size to obtain the patch.

[0048] Determination of the patches prepared in the above examples and comparative examples:

[0049] 1) Screening results of penetration enhancers

[0050] The patches prepared in Example 4, Comparative Examples 1 and 2 were tested, and the cumulative permeation per unit area Q 12 (μg / cm 2 ) size is: with permeation enhancer borneol > with permeation enhancer menthol > without permeation enhancer. The results are shown in Table 1.

[0051] Table 1 Effect of penetration enhancers on cumulative permeation per unit area of ​​the patch in 12 hours

[0052]

[0053] 2) Volatile oil penetration-enhancing effect

[0054] The patches prepared in Example 4 and Comparative Example 3 were tested, and the cumulative permeation per unit area Q 12 (μg / cm 2 ) size is: volatile oil prepared patch>raw material prepared patch. The results are shown in Table 2.

[0055] Table 2 Effect of volatile oil on cumulative permeation per unit area of ​​patch in 12 hours

[0056]

[0057] 3) The penetration-enhancing effects of 4 traditional Chinese medicines

[0058] The patches prepared in Example 4 and Comparative Example 4 were tested, and the cumulative permeation per unit area Q 12 (μg / cm 2 ) size: 4 kinds of Chinese medicines prepared patch> Schizonepeta radix and Saposhnikovia prepared patch. The results are shown in Table 3.

[0059] Table 3 Results of cumulative permeation per unit area of ​​the patch for 12 hours

[0060]

[0061] 4) Pharmacodynamic evaluation

[0062] The acetic acid writhing analgesic model in mice and the paw swelling anti-inflammatory model in rats were established to evaluate the anti-inflammatory and analgesic effects of traditional Chinese medicine patches for the treatment of rheumatoid arthritis.

[0063] The test drugs in the following examples were all prepared according to the method of Example 4, except that the content of the volatile oils was different when mixed to prepare low-dose or high-dose test drugs.

[0064] Acetic acid writhing analgesia test in mice

[0065] Twenty-four male SD mice were randomly divided into four groups, each with six mice, as follows: blank control group (no medication); negative control group (blank patch without medication, 6 cm 2 ); low-dose test group (2% volatile oil patch, 6cm 2 ); high-dose test group (8% volatile oil patch, 6cm 2 ). 24 hours before the experiment, the mouse abdomen was carefully depilated and placed in an environment of about 22°C. The temperature was kept constant during the entire experiment to prevent the temperature from affecting the mouse's writhing reaction time. Before administration, the mouse abdominal skin was disinfected and a homemade volatile oil patch was applied. The patch was removed after 6 hours. 0.2 ml of 1% GAA solution (v / v) was injected into the mouse's peritoneum. The number of writhing times W within 20 minutes was recorded. The pain inhibition rate PIR% was calculated using the following formula to evaluate the analgesic effect. Wc and Wt are the average number of writhing times in the blank group and the test drug group, respectively.

[0066]

[0067] Experimental results: When PIR% is greater than 50%, it can be said that the preparation has analgesic effect. Compared with the blank control group, the PIR% of the negative control group was 32.27%, which is lower than 50%, and the time for writhing to occur was 3.50min, indicating that borneol alone has a certain analgesic effect and can prolong the time for mice to writhe to a certain extent, but it did not reach an effective pain inhibition rate; the PIR% of the high and low test groups were 86.19% and 73.32% respectively, both greater than 50%, and there was no significant difference between the two groups (p>0.05), and the time for writhing to occur was 6.00min. Therefore, the experimental results show that the Chinese medicine volatile oil patch has a good analgesic effect.

[0068] Rat foot swelling test

[0069] Thirty SD rats were weighed and randomly divided into 5 groups, each with 6 rats, as follows: blank control group; model group; negative control group (blank patch without drug); high-dose test drug group (8% volatile oil patch, 20 cm 2 ); low-dose test group (2% volatile oil patch, 20cm 2 ), except the blank control group, the other four groups were treated with modeling.

[0070] Modeling method: Rats were anesthetized with ether anesthesia (higher survival rate), and the skin of the hind feet of the rats was disinfected. Then, 0.1 ml of CFA was injected into the left and right hind foot pads of each rat, and the needle was gently pressed by hand to ensure that all CFA was injected into the foot pad without overflow. The modeling was completed. After modeling, the circumference of the toes of the hind feet of the rats was measured once a day, and the swelling degree S was calculated using the following formula, where Vn and Vt are the circumference of the toes before and after the injection of CFA, respectively.

[0071]

[0072] The arthritis index scoring standard is: 0 points, no redness and swelling; 1 point, mild redness and swelling of the toe joints and the soles of the feet; 2 points, redness and swelling of the ankle joints; 3 points, severe redness and swelling of the paws and the soles of the feet. This standard is used to evaluate the degree of limb lesions in rats, and the points are accumulated to calculate the arthritis index.

[0073] Experimental results: Compared with the blank control group, the other groups showed obvious redness and swelling on the first day after inflammation (p<0.001), and the toes began to swell. On the second day of inflammation, the swelling became more obvious, with obvious swelling in the entire paw, ankle joint and other parts. There was no significant difference in the swelling between the left and right feet of the rats (p>0.05), indicating that the model was successfully established and medication could be started.

[0074] Before administration, the measurement points of the hind feet of each rat were marked, and the circumference of the toes was measured at the marked points each time. Then the patch was applied to the sterilized abdominal skin of the rat, and the patch was wrapped tightly with gauze to prevent the patch from falling off. The patch was replaced every 24 hours. The circumference of the toes of the hind feet of the rats on the 5th, 7th and 11th days of modeling was measured according to the marked lines, and the swelling was calculated using the formula. The results showed that after administration, there was still a significant difference between the blank control group and the model group (p<0.001), indicating that the model was stable and feasible, and the experiment could continue; compared with the model group, there was no significant difference between the negative control group (p>0.05), indicating that the matrix in the patch had no obvious anti-inflammatory effect; compared with the model group, there were significant differences between the high and low dose groups of the test drug, indicating that the homemade volatile oil patch had a significant anti-inflammatory effect, and the swelling of the left and right hind feet of the rats was compared, and the result was no significant difference (p>0.05), indicating that the volatile oil patch had an anti-inflammatory effect on both hind feet of the rats.

[0075] The results of rat arthritis index scoring showed that, except for the blank group, the arthritis index of the bilateral hind feet of rats in the other groups gradually increased; after administration, there was no significant difference between the model group and the negative control group (p>0.05), which further indicated that the matrix in the patch had no anti-inflammatory effect; compared with the model group, the high and low doses of the test drug showed different degrees of differences, indicating that the homemade volatile oil patch had a certain improvement effect on the lesions caused by arthritis, and there was no significant difference in the relief of inflammation in the bilateral hind foot joints of rats (p>0.05).

Claims

1. A Chinese medicine patch for treating rheumatoid arthritis, characterized in that: The Chinese medicine patch contains Chinese medicine extracts and penetration enhancers; wherein the Chinese medicine extracts are extracted from Schizonepeta, Saposhnikovia divaricata, Radix Polygoni Multiflori and Artemisia argyi as raw materials, and the penetration enhancer is borneol.

2. The Chinese medicine patch for treating rheumatoid arthritis according to claim 1, characterized in that: The extract is prepared by mixing schizonepeta, siler, radix polygoni lobatae and wormwood, adding water in an amount 10-14 times of the mixed weight, soaking in a water bath at 25-45° C. for 0.5-2 hours, and extracting with a volatile oil extractor for 3-5 hours.

3. The Chinese medicine patch for treating rheumatoid arthritis according to claim 1 or 2, characterized in that: The raw materials in the Chinese medicine extract are calculated by weight, including 1-3 parts of Schizonepeta, 1-3 parts of Saposhnikovia divaricata, 1-3 parts of Herba Polygoni Multiflori, and 1-3 parts of Artemisia argyi.

4. A method for preparing the Chinese medicine patch for treating rheumatoid arthritis according to claim 1, characterized in that: Weigh the hot-melt pressure-sensitive adhesive in a mortar, place it in a temperature-adjustable electric heating sleeve, heat it to 140-180°C until it melts, add 1-5% of a penetration enhancer and 2-8% of a Chinese medicine extract (all by mass ratio, based on the total mass of the plaster), stir evenly, and immediately use a 0.2-0.9mm frame coater to apply the mixed adhesive while hot on the anti-sticking layer, then cover it with a backing layer, and cut it into appropriate sizes.

5. An application of the patch according to claim 1, characterized in that: The patch is used as a traditional Chinese medicine patch for treating rheumatoid arthritis.

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