Skin external preparation for treating dysmenorrhea as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and provides a skin external preparation for treating dysmenorrhea and a preparation method and application thereof. According to the invention, folium artemisiae argyi, rhizoma cyperi, fructus evodiae, cortex cinnamomi, radix angelicae sinensis, radix astragali, radix paeoniae alba and the like are used as raw materials, and a transdermal preparation which takes effect quickly, is low in dosage, is higher in safety and is convenient to use is obtained through prescription optimization, extraction process, effective part screening and preparation research of the raw materials. The traditional Chinese medicine composition can significantly treat or relieve dysmenorrhea symptoms, and provides an effective, stable, safe and reliable solution for treating dysmenorrhea and other symptoms. According to the invention, the optimal alcohol extraction of the whole prescription is determined through research, different extraction treatments are not required to be carried out on different medicines, and it is found that the stability, applicability and effectiveness of the medicine can be remarkably improved by modifying oral administration into an external preparation, the process is simple, the cost is reduced, and the preparation is suitable for industrial expanded production.

Description

Technical Field

[0001] The invention belongs to the technical field of medical preparations and provides a skin external preparation for treating dysmenorrhea and a preparation method and application thereof. Background Art

[0002] Dysmenorrhea is accompanied by lower abdominal pain, heaviness, backache, or nausea, diarrhea, fatigue, headache, etc. Traditional Chinese medicine believes that the main cause of dysmenorrhea is closely related to organs such as the liver, kidneys, and spleen, and is caused by qi stagnation, blood stasis, cold and dampness stagnation, and qi and blood deficiency. Dysmenorrhea is one of the common gynecological symptoms and is clinically divided into two categories: primary dysmenorrhea and secondary dysmenorrhea.

[0003] At present, Western medicine clinical treatment methods for dysmenorrhea include nonsteroidal anti-inflammatory drugs, oral contraceptives and other hormone drugs and antipyretic analgesics, which can relieve dysmenorrhea symptoms to a certain extent. Although the effect of Western medicine in relieving pain in a timely manner is very obvious, the effect of pain relief is generally difficult to maintain, and it is easy to rebound and relapse. Long-term use will affect the gastrointestinal system and central nervous system, and may induce adverse reactions. Traditional Chinese medicine has great advantages in the treatment of dysmenorrhea. It has a history of thousands of years. Through traditional Chinese medicine methods such as traditional Chinese medicine, Chinese patent medicine, acupuncture, external application treatment, etc., the patient's body functions are regulated, so that the body can reach a state of "yin and yang harmony". Traditional Chinese medicine external treatment has gradually become one of the standard measures for the treatment of dysmenorrhea.

[0004] Chinese invention patent CN117919329A provides a preparation method and detection method of a warm palace patch, which mainly includes: taking wormwood (charcoal) and cinnamon, crushing them into fine powder, sieving, and standby; taking vinegar cyperus, processed evodia, angelica, chuanxiong, white peony root (fried with wine), rehmannia, roasted astragalus, and radix schizonepetae, breaking and soaking them in vegetable oil, refining the medicinal oil until it drips into beads, turning off the fire, cooling it slightly, removing the residue, and filtering; taking the medicinal oil and adding red lead to combine, removing fire poison and adding fine powder and turpentine to mix and stir, and tidal flat, that is, obtaining. The invention combines the formula of Ai Fu Nuan Gong Wan with the preparation method of black plaster to make a warm palace patch, but the preparation process of the method is cumbersome, and the obtained black plaster warm palace patch has problems of fire poison and allergy, which can cause itching, redness, swelling, and blistering.

[0005] Chinese invention patent CN105596633A discloses a Chinese medicine pill for treating menstrual disorders caused by blood deficiency and qi stagnation and a preparation method thereof, wherein the components and their mass ratios of the Chinese medicine pill are as follows: 5-15g of Artemisia argyi (charcoal), 5-18g of Salvia miltiorrhiza, 7.5-15g of Cyperus rotundus (vinegar-processed), 1.5-8g of Cinnamon twig, 2.5-10g of Evodia rutaecarpa (processed), 2.5-7.5g of Cinnamon bark, 7.5-15g of Angelica sinensis, 5-10g of Chuanxiong, 10-20g of White Peony Root (fried with wine), 12-30g of Rehmannia glutinosa, 15-25g of Astragalus membranaceus (honey-fried), 10-20g of Dipsacus asper, and an appropriate amount of honey. The drug provided by the invention has good efficacy and quick effect, and is a good Chinese medicine prescription for treating both the symptoms and the root causes, and is particularly suitable for clinical use. However, in practice, the disadvantage of pills is that they are inconvenient to use, causing a lot of trouble for the elderly, children and patients with swallowing difficulties; and this invention directly crushes the raw materials and mixes them with honey for medicine, resulting in too low concentration of effective active ingredients and low bioavailability of the drug, while also introducing ingredients harmful to the human body.

[0006] Aifu Nuan Gong Wan uses mugwort leaf (charcoal), cyperus rotundus (made with vinegar), evodia rutaecarpa (made), cinnamon bark, angelica, astragalus (roasted with honey), white peony root (fried with wine), rehmannia root, and chuanxiong as prescription ingredients. It was first approved in 2002. Mugwort leaf (charcoal): warms the meridians and uterus, dispels cold and relieves pain, and is one of the main drugs. Cyperus rotundus (made with vinegar): soothes the liver and relieves depression, regulates menstruation and relieves pain, and is one of the main drugs. Evodia rutaecarpa (made) and cinnamon bark: warms the meridians and dispels cold and dredges the meridians as auxiliary drugs. Angelica, chuanxiong, white peony root (fried with wine): activates blood circulation and removes blood stasis, nourishes blood and regulates menstruation. Rehmannia root, roasted astragalus root, and radix scutellariae: replenishes qi, nourishes yin and nourishes blood, and has the effects of regulating qi, replenishing blood, warming the uterus and regulating menstruation. The Chinese Pharmacopoeia stipulates that the preparation method of Aifu Nuan Gong Wan is to crush the ten Chinese medicines in the prescription into fine powder, sieve, add the prescribed amount of refined honey, and make large or small honey pills; usage and dosage: 9g each time, 2-3 times a day. Ai Fu Nuangong Pills have the disadvantages of large dosage and difficult storage. Summary of the invention

[0007] In order to solve the above technical problems, the present invention provides a skin external preparation for treating dysmenorrhea, a preparation method and its use in treating dysmenorrhea. Based on Zhuyu Xiaoyao Recipe, Xuanyu Tongjing Recipe and Aifu Nuangong Pill, the present invention first screens and proposes to prepare the prescription of Aifu Nuangong Pill into an external plaster preparation with higher safety, fast absorption and convenient administration. By optimizing the prescription and extraction process, as well as the preparation process, the original prescription of Artemisia argyi carbon is replaced with Artemisia argyi, aiming to accelerate the onset time, improve the efficacy and reduce the amount of medicine. The transdermal administration preparation can significantly treat or quickly relieve the symptoms of dysmenorrhea with less oral dosage, effectively regulate qi and blood, warm the meridians and dispel cold, promote qi and relieve pain, greatly expand the clinical value of the prescription and patient compliance, and the process of the present invention is simple, reduces the cost, and is suitable for industrial scale-up production.

[0008] In order to achieve the above object, the technical solution adopted by the present invention is as follows:

[0009] The invention provides a skin external preparation for treating dysmenorrhea. The medicinal ingredients of the traditional Chinese medicine composition are prepared from raw materials of wormwood leaf, cyperus rotundus, evodia rutaecarpa, cinnamon bark, angelica sinensis, ligusticum chuanxiong, white peony root, rehmannia root, astragalus and dipsacus.

[0010] The wormwood leaves include but are not limited to wormwood leaves and vinegar wormwood leaves.

[0011] The Cyperus rotundus includes but is not limited to Cyperus rotundus, vinegar-cured Cyperus rotundus, wine-cured Corydalis yanhusuo, four-processed Cyperus rotundus and Cyperus rotundus charcoal.

[0012] The Evodia rutaecarpa includes but is not limited to Evodia rutaecarpa, Evodia rutaecarpa or Evodia rutaecarpa sparsely pubescens.

[0013] The chuanxiong includes but is not limited to chuanxiong, wine-cooked chuanxiong, stir-fried chuanxiong and stir-fried chuanxiong with bran.

[0014] The angelica includes but is not limited to angelica, wine-fried angelica, and native fried angelica.

[0015] The astragalus includes but is not limited to astragalus and processed astragalus.

[0016] The white peony root includes but is not limited to white peony root, white peony root made with wine, white peony root with vinegar, and white peony root fried with earth.

[0017] The Rehmannia root includes but is not limited to raw Rehmannia root and cooked Rehmannia root.

[0018] The Dipsacus asper includes but is not limited to Dipsacus asper, Dipsacus asper with wine, and Dipsacus asper with salt.

[0019] Furthermore, the drug ingredients (raw materials) are mixed in the following proportions by mass: 6-11 parts of Artemisia argyi, 12-20 parts of Cyperus rotundus, 4-12 parts of Evodia rutaecarpa, 1-3 parts of Cinnamon bark, 6-15 parts of Angelica sinensis, 3-12 parts of Chuanxiong, 4-9 parts of White Peony Root, 1-5 parts of Rehmannia glutinosa, 4-8 parts of Astragalus, and 1-9 parts of Dipsacus asper. The external preparations include liniments, ointments, plasters, hot melt patches, tinctures, lotions, oils, emulsions, pastes, plasters, film coatings, gels, aerosols, and the like.

[0020] Further preferably, the raw materials are mixed in the following proportions by mass: 6 parts of Artemisia argyi, 12 parts of Cyperus rotundus, 4 parts of Evodia rutaecarpa, 1 part of Cinnamon bark, 6 parts of Angelica sinensis, 4 parts of Ligusticum chuanxiong, 4 parts of White Peony Root, 2 parts of Rehmannia glutinosa, 4 parts of Astragalus membranaceus, and 3 parts of Dipsacus asper.

[0021] Furthermore, the skin external preparation also includes a pharmaceutically acceptable carrier component.

[0022] The present invention also provides a method for preparing the skin external preparation for treating dysmenorrhea, the method comprising: adding ethanol to extract the raw materials of the Chinese medicine composition, concentrating the extract under reduced pressure to obtain an extract, and mixing the extract with a carrier to prepare the skin external preparation.

[0023] Furthermore, the material-liquid ratio of the raw material to ethanol is 1:6-10 (W / V).

[0024] Furthermore, the concentration of the ethanol is 30%-95%.

[0025] Furthermore, the relative density of the extract is 1.10-1.30.

[0026] Furthermore, the extraction times are 1-3 times, 1-3 hours per time.

[0027] Furthermore, the preparation method comprises: adding 6-10 times the volume of 30%-95% ethanol to the raw material of the Chinese medicine composition for extraction, extracting 1-3 times, 1-3 hours / time, and concentrating the extract under reduced pressure to an extract with a relative density of 1.10-1.30.

[0028] Furthermore, the extract is added with auxiliary materials to prepare the skin external preparation.

[0029] The present invention also provides a skin external plaster for treating dysmenorrhea, wherein the plaster comprises 40-70 parts of the above skin external preparation, 4-12 parts of soluble starch, 5-15 parts of sodium carboxymethyl cellulose, 2.5-8 parts of hexadecanol, 3-10 parts of lanolin, 8-20 parts of glycerol and 0.5-2 parts of azone in proportion by mass.

[0030] The present invention also provides a method for preparing the plaster, comprising the following steps:

[0031] Step 1: Take the prescribed amount of hexadecanol, lanolin, glycerin and azone, keep warm and melt them as a matrix for later use;

[0032] Step 2: adding the skin external preparation to the matrix of step 1, stirring and mixing, adding sodium carboxymethyl cellulose and soluble starch to mix, and obtaining an ointment;

[0033] Step 3: Apply the ointment evenly onto the pressure-sensitive adhesive patch and cover with an anti-adhesive film to obtain a dysmenorrhea patch.

[0034] The present invention also provides application of the skin external preparation in preparing a medicine for treating dysmenorrhea.

[0035] Furthermore, the drug is a drug for treating endometriosis, adenomyosis, irregular menstruation, dysmenorrhea and / or premenstrual tension syndrome.

[0036] Zhuyu Xiaoyaotie is derived from Xiaoyaosan and Wuzhuyutang. Xiaoyaosan prescription: wine angelica, wine white peony root, bupleurum, earth-fried atractylodes, roasted licorice, mint, ginger slices; Wuzhuyutang prescription: 3g each of angelica, cinnamon, evodia, peony bark, pinellia, ophiopogon, saposhnikovia, asarum, ligusticum, dried ginger, tuckahoe, costusroot, roasted licorice. Xiaoyaosan can dissipate qi stagnation and shake blood stagnation without hurting the vital energy; Wuzhuyutang is used to treat postmenstrual pain caused by wind and cold after the cells are not empty. Combining the two prescriptions, it is used to treat primary dysmenorrhea. The final prescription is: evodia, angelica, white peony root, moutan bark, bupleurum, cinnamon, ligusticum, tuckahoe, dried ginger, roasted licorice.

[0037] Xuanyu Tongjing Patch is derived from Xuanyu Tongjing Decoction, a prescription in Fu Qingzhu's Gynecology, used to treat abdominal pain before menstruation, pain for several days, and black blood clots during menstruation. The prescription is: white peony root, angelica root, moutan bark, stir-fried gardenia, white mustard seed, cyperus rotundus, bupleurum root, Sichuan turmeric, scutellaria baicalensis, and roasted licorice.

[0038] Aifu Nuan Gong Patch is derived from Aifu Nuan Gong Pills, which comes from Volume 26 of Renzhai Zhizhi Fuyi and is included in the Pharmacopoeia. It is used for irregular menstruation and dysmenorrhea caused by blood deficiency and qi stagnation, and coldness in the lower jiao. Symptoms include delayed menstruation, scanty menstruation, blood clots, lower abdominal pain, cold pain in the lower abdomen during menstruation and preference for heat, and soreness in the waist and knees. The prescription is: mugwort leaves, cyperus rotundus, evodia rutaecarpa, cinnamon bark, angelica, chuanxiong, white peony root, rehmannia root, astragalus, and radix dipsaci.

[0039] The beneficial effects achieved by the present invention are:

[0040] (1) The present invention screened and obtained a prescription suitable for external application to treat dysmenorrhea, and through the optimization of the preparation process, the extract of the drug in the prescription after being extracted by the preparation process of the present invention achieved significant results in dysmenorrhea tests and in vivo uterine contraction tests, and can significantly treat or relieve dysmenorrhea symptoms, effectively regulate qi and blood, warm the meridians and dispel cold, promote qi circulation and relieve pain, and has a smaller oral dose, a higher drug release rate and stronger targeting, and a faster onset time, which can provide an effective, stable, safe and reliable solution for treating symptoms such as dysmenorrhea.

[0041] (2) The present invention proposes for the first time to prepare a prescription into a skin external preparation with higher safety, faster absorption and convenient administration. The external Chinese medicine composition acts directly on the affected part without passing through the gastrointestinal tract, without the first-pass effect of the drug, and can be rapidly effective through transdermal absorption. In addition, the process of the present invention preferably extracts the whole prescription with alcohol, and there is no need to perform different extraction treatments for different medicinal flavors, which reduces the steps of operation, reduces the cost, and is simple in process, which is suitable for industrial scale-up production.

[0042] (3) The present invention prepares Ai Fu Nuangong Pills with a large dosage into an external preparation, and extracts the active substances in the medicinal materials through the process method of the present invention. When a considerable dose of active substances is used, the external administration method of the navel has a better effect on treating dysmenorrhea than oral administration. The precise external administration method of the navel can significantly reduce the dosage.

[0043] (4) The present invention also provides a skin external plaster for treating dysmenorrhea, wherein the plaster is formulated according to the mass ratio of: 40-70 parts of drug ingredients, 4-12 parts of soluble starch, 5-15 parts of sodium carboxymethylcellulose, 2.5-8 parts of hexadecanol, 3-10 parts of lanolin, 8-20 parts of glycerol, and 0.5-2 parts of azone. The effect of the prepared external plaster in treating dysmenorrhea is better than that of the alcohol-extracted concentrate, that is, the preparation process of the present invention can be beneficial to the transdermal and absorption of the active substance. In addition, compared with traditional black plasters, the problem of excessive heavy metal lead caused by the use of red lead is avoided. After being further prepared into an external preparation by the preparation process of the present invention, the applicability, stability and effectiveness of the preparation can be significantly improved. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 This is a picture showing uterine tension after injection of normal saline;

[0045] Figure 2 This is a picture showing the uterine tension after oxytocin injection;

[0046] Figure 3 This is a graph showing the uterine tension after injection of oxytocin followed by treatment with alcohol extract concentrate. DETAILED DESCRIPTION

[0047] The following non-limiting examples can enable those skilled in the art to more fully understand the present invention, but do not limit the present invention in any way. The following content is merely an exemplary description of the scope of the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, which should also fall within the scope of the present invention.

[0048] When the embodiments give numerical ranges, it should be understood that, unless otherwise specified in the present invention, both endpoints of each numerical range and any numerical value between the two endpoints can be selected. Unless otherwise defined, all technical and scientific terms used in the present invention have the same meanings as those generally understood by those of ordinary skill in the art to which the present invention belongs.

[0049] The present invention is further described below by way of specific examples. The various chemical reagents used in the examples of the present invention are obtained through conventional commercial channels unless otherwise specified. Products from different manufacturers have no significant effect on the effects.

[0050] Basic Example

[0051] The prescription of this embodiment is as follows:

[0052] Prescription 1: Evodia rutaecarpa 6g, Angelica sinensis 4.5g, White Peony Root 4.5g, Cortex Moutan 3g, Bupleurum 3g, Cinnamon 3g, Ligusticum chuanxiong 3g, Poria 3g, Dry Ginger 3g, Roasted Licorice 1.5g;

[0053] Prescription 2: White peony root 15g, Chinese angelica root 15g, red peony root 15g, stir-fried gardenia 9g, white mustard seed 6g, cyperus rotundus 3g, bupleurum 3g, Sichuan turmeric 3g, scutellaria 3g, roasted liquorice root 3g;

[0054] Prescription 3: Artemisia argyi 6g, Cyperus rotundus 12g, Evodia rutaecarpa 4g, Cinnamon bark 1g, Angelica sinensis 6g, Ligusticum chuanxiong 4g, White Peony 4g, Rehmannia glutinosa 2g, Astragalus membranaceus 4g, Dipsacus asper 3g.

[0055] The extraction processes of active ingredients are:

[0056] (1) Water extraction process of prescription 1-3: add 1 times the amount of water of all the medicinal ingredients and extract twice, 1 hour each time, and concentrate the extract under reduced pressure at 60°C to a relative density of 1.20 to obtain a water-extracted concentrate.

[0057] (2) Alcohol extraction process of prescription 1-3: add 30% ethanol in an amount equal to the total amount of all medicinal ingredients and extract once for 1 hour each time. Concentrate the extract under reduced pressure at 60°C to a relative density of 1.20 to obtain an alcohol extract concentrate.

[0058] Test Example 1 Animal Dysmenorrhea Test

[0059] (1) Experimental materials: SPF-grade ICR mice, female, 3-4 weeks old, 16.6-24.5 g, 88 mice; purchased from Guangdong Weitonglihua Laboratory Animal Technology Co., Ltd., Laboratory Animal Production License No.: SCXK (Yue) 2022-0063. Quarantine for 4 days.

[0060] (2) Test substances: water extract concentrate and alcohol extract concentrate of prescriptions 1-3 prepared in Example 1, the water extract concentrate was administered orally (Group A), the water extract concentrate was applied externally to the navel (Group B), and the alcohol extract concentrate was applied externally to the navel (Group C).

[0061] (3) Construction of a dysmenorrhea mouse model: Mice were subcutaneously injected with estradiol benzoate (10 mg / kg) once a day for 10 consecutive days (to enhance the sensitivity of the uterus to oxytocin), with the injection dose on the 10th day being 20 mg / kg. One hour after the last injection of estradiol benzoate, oxytocin was injected intraperitoneally at 30 U / kg to prepare a mouse dysmenorrhea model.

[0062] (4) Dosage design and administration method: SPF-level ICR mice that passed the quarantine were taken, and their weights were measured. 88 mice with lighter weight were selected and randomly divided into 11 groups according to their weights, with 8 mice in each group. Three days before the injection of oxytocin, the oral group was given intragastric administration, and the topical group was given by navel application. The administration lasted for 3 days, and the last administration time was 30 minutes after the injection of estradiol benzoate. The day of the first administration was recorded as D1, the day before was recorded as D0, and so on. The groups and doses are shown in Table 1.

[0063] Table 1 Grouping and measurement table

[0064]

[0065]

[0066] (5) Index detection: D3, 30 min after drug administration, oxytocin was injected intraperitoneally, and the number of body twisting of the mice within 30 min was immediately observed and recorded, and the body twisting latency was calculated.

[0067] (6) Data processing:

[0068] The experimental measurement data were summarized in Excel, expressed as mean ± standard deviation, and analyzed using SPSS26.0. One-way analysis of variance was used for statistics. LSD test was used for inter-group comparison when variance was equal, and Dunnett's T3 test was used for inter-group comparison when variance was unequal. When the mean difference between the normal control group and the model control group was large, independent sample t test was used for inter-group comparison; P < 0.05 was considered statistically significant.

[0069] (7) Test results

[0070] Table 2 Effects on the number of writhing times and writhing latency of dysmenorrhea model mice

[0071]

[0072] Note: vs. model control group: *, P<0.05, **, P<0.01.

[0073] The latency period refers to the time when the first twisting of the body occurs. In theory, the longer the time, the better the effect. The experimental results show that all three prescriptions can significantly reduce the number of twisting and prolong the latency period of twisting.

[0074] Due to the limitation of the dosage of topical administration during the experiment, the dosage of topical administration is only 1 / 3 of that of oral administration, but topical administration has achieved better or equivalent analgesic effect than oral administration, indicating that the present invention is more suitable for external administration, and the possible reason is that the drug transdermal absorption is faster, the drug onset duration is long, and the concentration of the drug reaching the lesion is higher. In addition, compared with prescription 1, prescription 2 and prescription 3, whether it is water extract concentrate or alcohol extract concentrate, can significantly reduce the number of twisting times in the case of oral and external use, and the amount of crude drug in prescription 3 is only 61.5% of prescription 2, but the effect is equivalent, and there is a significant difference relative to the model control group, indicating that the oral liquid and navel external use of the alcohol extract and water extract concentrate of prescription 3 are better than prescription 2, that is, prescription 3 is better for the treatment of dysmenorrhea. Therefore, the present invention is further studied for the extraction process of the external preparation of prescription 3, but compared with positive drugs, the action intensity is not enough to solve clinical problems, and further in-depth research is required by extraction process, preparation process and administration method to solve clinical practical problems.

[0075] Example 1 Alcohol Extraction Concentrate

[0076] According to the total weight of the 3 medicinal ingredients in the prescription, 10 times the volume of 50% ethanol was added for extraction 3 times, 1 hour each time, and the extract was concentrated under reduced pressure to an extract with a relative density of 1.10, thereby obtaining the alcohol-extracted concentrated solution sample 1.

[0077] Example 2 Alcohol Extraction Concentrate

[0078] According to the total weight of the medicinal ingredients in prescription 3, 60% ethanol with a volume of 6 times was added for extraction twice, 2 hours each time, and the extract was concentrated under reduced pressure to an extract with a relative density of 1.20, thereby obtaining alcohol-extracted concentrated solution sample 2.

[0079] Example 3 Alcohol Extraction Concentrate

[0080] According to the total weight of the medicinal ingredients in prescription 3, 80% ethanol was added in an amount of 8 times the volume to extract twice, 3 hours each time, and the extract was concentrated under reduced pressure to an extract with a relative density of 1.30, thereby obtaining alcohol-extracted concentrated solution sample 3.

[0081] Example 4 Alcohol Extraction Concentrate

[0082] According to the total weight of the medicinal ingredients in prescription 3, 8 times the volume of 95% ethanol was added for extraction once, 2 hours per time, and the extract was concentrated under reduced pressure to an extract with a relative density of 1.20, thereby obtaining alcohol-extracted concentrated solution sample 4.

[0083] Comparative Example 1 Water Extract Concentrate

[0084] According to the total weight of the medicinal ingredients in the prescription 3, add 8 times the volume of water, extract twice for 1 hour each time, and concentrate the extract under reduced pressure at 60°C to obtain a concentrated paste with a relative density of 1.20, namely, the water-extracted concentrated solution sample 5.

[0085] Comparative Example 2 Volatile oil + alcohol extract concentrate

[0086] For prescription 3, add 6 times the volume of water to the volatile oil components of Artemisia argyi, Cyperus rotundus, Evodia rutaecarpa, Cinnamon bark, Chinese angelica and Chuanxiong, and distill for 5 hours, collect the volatile oil A and the distilled liquid B, add the remaining medicinal materials (Astragalus, White Peony, Rehmannia glutinosa, Dipsacus asper) to the residue after distillation, and add 8 times 80% ethanol to extract to obtain ethanol extract C, combine B and C, and concentrate under reduced pressure at 60°C to obtain a concentrated paste with a relative density of 1.30, add the volatile oil A and mix well to obtain the alcohol extract concentrated liquid sample 6.

[0087] Comparative Example 3 Volatile oil + water extraction and alcohol precipitation concentrate

[0088] According to the total weight of the ingredients in prescription 3, add 8 times the volume of water and distill for 5 hours, collect volatile oil A and distilled liquid B, add 8 times the volume of water to the residue after distillation and extract for 1 hour to obtain liquid C, combine B and C, and concentrate under reduced pressure at 60°C to obtain a concentrated solution, add ethanol to precipitate to an alcohol content of 60%, let stand overnight for 12 hours, separate the supernatant of the precipitate, and concentrate under reduced pressure to an appropriate amount to obtain a concentrated paste with a relative density of 1.1. Add volatile oil A to the concentrated paste and mix well to obtain the water-extracted alcohol-precipitated concentrated solution sample 7.

[0089] Comparative Example 4 Volatile oil + water extraction and alcohol precipitation concentrate

[0090] According to the total weight of the 3 medicinal ingredients in the prescription, add 8 times the volume of water and distill for 5 hours, collect the volatile oil A and the distilled liquid B, add 6 times the volume of water to the distilled residue and distill for 1 hour to obtain the distilled liquid C, combine B and C, and concentrate under reduced pressure at 60°C to obtain a concentrated solution, add ethanol to precipitate to an alcohol content of 40%, let it stand for 12 hours overnight, separate the alcohol precipitate supernatant, and concentrate under reduced pressure to an appropriate amount to obtain a concentrated paste with a relative density of 1.30. Add the volatile oil A to the concentrated paste and mix well to obtain the water-extracted alcohol-precipitated concentrated solution sample 8.

[0091] Test Example 2 Animal Dysmenorrhea Test

[0092] (1) Experimental materials: SPF-grade ICR mice, female, 3-4 weeks old, 16.6-24.5 g, 80 mice; purchased from Guangdong Weitonglihua Laboratory Animal Technology Co., Ltd., Laboratory Animal Production License No.: SCXK (Yue) 2022-0063. Quarantine for 4 days.

[0093] (2) Test substances: Samples 1-3 of Examples 1-3, Sample 5 of Control Example 1, Sample 7 of Control Example 3; Positive drugs: Ibuprofen (Shandong Xinhua Pharmaceutical Co., Ltd.); 0.9% sodium chloride injection (Shandong Hualu Pharmaceutical Co., Ltd.).

[0094] (3) Construction of a dysmenorrhea mouse model: Mice were subcutaneously injected with estradiol benzoate (10 mg / kg) once a day for 10 consecutive days (to enhance the sensitivity of the uterus to oxytocin), with the injection dose on the 10th day being 20 mg / kg. One hour after the last injection of estradiol benzoate, oxytocin was injected intraperitoneally at 30 U / kg to prepare a mouse dysmenorrhea model.

[0095] (4) Dosage design and administration method: SPF-level ICR mice that passed the quarantine were taken, and their weights were measured. 80 mice with lighter weight were selected and randomly divided into 10 groups according to their weights, with 8 mice in each group. Three days before the injection of oxytocin, the oral group was given intragastric administration, and the topical group was given by navel application. The administration lasted for 3 days, and the last administration time was 30 minutes after the injection of estradiol benzoate. The day of the first administration was recorded as D1, the day before was recorded as D0, and so on. The groups and doses are shown in Table 3.

[0096] Table 3 Grouping and dosage table

[0097]

[0098]

[0099] (5) Index detection:

[0100] D3, 30 minutes after administration, oxytocin was injected intraperitoneally, and the number of body twisting of the mice within 30 minutes was immediately observed and recorded, and the body twisting latency was calculated.

[0101] Torsion inhibition rate (%) = (number of torsion in the model control group - number of torsion in the experimental group) / (number of torsion in the model control group) × 100%.

[0102] (6) Data processing:

[0103] The experimental measurement data were summarized in Excel, expressed as mean ± standard deviation, and analyzed using SPSS26.0. One-way analysis of variance was used for statistics. LSD test was used for inter-group comparison when variance was equal, and Dunnett's T3 test was used for inter-group comparison when variance was unequal. When the mean difference between the normal control group and the model control group was large, independent sample t test was used for inter-group comparison; P < 0.05 was considered statistically significant.

[0104] (7) Test results

[0105] Table 4 Effects on the number of writhing times and writhing latency of dysmenorrhea model mice

[0106]

[0107] Note: vs. model control group: *, P<0.05, **, P<0.01.

[0108] The test results show that the water extract concentrate, volatile oil + water extract concentrate, and alcohol extract concentrate can reduce the number of twisting times in the case of oral and external use, indicating that it has a significant effect on the treatment of dysmenorrhea. However, the effect of the alcohol extract concentrate of Examples 1-3 is better than that of the water extract concentrate and volatile oil + water extract concentrate of Control Examples 1-3. In addition, after alcohol extraction, Examples 1-3 have better dysmenorrhea treatment effects compared to the navel external use of the basic embodiment prescription 3-C group, and a better analgesic effect than oral administration is achieved with a smaller external dosage, and in order to improve the applicability of the patient when using it, the stability, applicability and effectiveness of the active substance are improved. The present invention continues to study the preparation of the alcohol extract concentrate into an external preparation, in order to further solve the problem of the present invention for the treatment of dysmenorrhea.

[0109] Test Example 3 In vivo uterine contraction test

[0110] (1) Experimental materials: 88 female SPF SD rats, 6-9 weeks old, 174.1-241.5 g; purchased from Guangdong Weitonglihua Experimental Animal Technology Co., Ltd., with the experimental animal production license number: SCXK (Yue) 2022-0063. Animals were quarantined for 3 days.

[0111] (2) Test substances: Samples 1-4 of Examples 1-4, Samples 5-8 of Comparative Examples 1-4. Positive drug: Yangxue Tiaojing Paste (Tianjin Darentang Jingwanhong Pharmaceutical Co., Ltd.).

[0112] (3) In vivo uterine modeling: 4 days before the experiment, estradiol benzoate was intraperitoneally injected (ip) for 4 consecutive days at doses of 4, 2, 2, and 4 mg / kg, respectively. The next day, anesthesia was performed, an incision of about 1 cm was made in the lower abdomen, the abdominal cavity was opened, and a 4-0 suture was used to tie the uterus, suture the wound, and connect the suture to the tension transducer. After the uterine contraction stabilized for 10 minutes, the drug was started. After the drug was administered, 0.1 ml of 20% oxytocin was immediately dripped through the wound (except for the normal control group), and the dosage was 0.2 U / mouse, and the model was established.

[0113] (5) Dosage design and administration method:

[0114] The animals that passed the quarantine were randomly divided into 11 groups according to their weight, with 8 animals in each group. After the modeling and uterine tension test were ready, the uterus contracted stably for 10 minutes, and the drug was applied to the navel. The drug application area was 3.14cm 2 / mouse, the normal control group and the model control group were given 0.1g of blank excipient / mouse. The grouping and dosage information are shown in Table 5.

[0115] Table 5 Grouping and dosage information

[0116]

[0117]

[0118] (6) Detection indicators

[0119] Each group used BL-420F biofunction experimental system to analyze the average uterine tension 10 minutes before administration and 30, 60, and 90 minutes after administration, and calculated the average tension change rate. Figure 1-Figure 3 shown.

[0120] Average tension change rate (%) = (average tension at this time point - average tension before oxytocin administration) / (average tension before oxytocin administration) × 100%

[0121] (7) Data processing

[0122] The experimental measurement data were summarized in Excel and expressed as mean ± standard deviation. SPSS26.0 was used for analysis. The normal control group and the model control group were compared with the independent sample T test, and the model control group and the other groups were compared with one-way analysis of variance. P<0.05 was considered statistically significant.

[0123] (8) Test results

[0124] Table 6 Effects on the average tension of the in vivo uterine contraction model ( Unit: g)

[0125]

[0126] Note: Model control group vs normal control group: ##, P<0.01; vs model control group: *, P<0.05, **, P<0.01.

[0127] Table 7 Effects on the average tension change rate of the in vivo uterine contraction model ( unit:%)

[0128]

[0129] Note: Model control group vs normal control group: ##, P<0.01; vs model control group: *, P<0.05, **, P<0.01.

[0130] The results in Tables 6-7 show that the samples of Examples 1-4 and Control Examples 1-4 can improve the average uterine tension change rate to a certain extent compared with the normal control group, have the effect of relieving uterine spasm, and have a good therapeutic effect on dysmenorrhea. The degree of change of the average uterine tension in Examples 1-4 is better than that in Control Examples 1-4. Compared with the model control group, Examples 1-4 have achieved significant improvement effects, which are equivalent to the inhibitory effect of the positive control group.

[0131] The tension change rate of Example 1-4 group 10 minutes after administration was significantly reduced, that is, the administration of oxytocin at the same time as the administration of the drug can significantly inhibit the strong uterine contraction induced by oxytocin within 10 minutes, and the average tension change rate is close to 50% at 90 minutes, indicating that the onset time of Example 1-4 is within 10 minutes, and the pharmacological effect can be maintained for at least 90 minutes.

[0132] Depend on Figure 1-Figure 3 It can be seen that after the injection of saline, the uterus basically had no contraction, and the contraction strength value was at the horizontal line; after the injection of oxytocin, the uterus began to contract significantly, and the maximum contraction strength value reached 6g, while Figure 3 It can be seen that after the alcohol extract concentrate of sample 3 was injected at 350 seconds, the amplitude of uterine contraction was significantly reduced and gradually became gentle, indicating that the alcohol extract concentrate of the present invention has the effect of relieving uterine spasm in a short period of time and has a significant therapeutic effect on dysmenorrhea.

[0133] Example 5 Screening study of external preparation technology

[0134] In this example, the alcohol-extracted concentrated sample 1 prepared in Example 1 is used as the active ingredient to prepare a dysmenorrhea plaster, and the prescription is as follows:

[0135] Table 8 Prescription of Dysmenorrhea Plaster

[0136]

[0137] Note: “ / ” means no addition.

[0138] The processes for preparing the dysmenorrhea plasters of each prescription are respectively:

[0139] Prescription 1:

[0140] Step 1 Take 15g lanolin and 5g glycerin, melt them at 55°C as a matrix, and set aside;

[0141] Step 2: Take 60 g of the alcohol-extracted concentrated sample 1 of Example 1 and add it to the matrix, stir and mix, add 10 g of sodium carboxymethyl cellulose and 25 g of kaolin and mix to obtain an ointment;

[0142] Step 3: evenly apply the ointment onto the pressure-sensitive adhesive patch and cover it with an anti-adhesive film to obtain a dysmenorrhea patch 1.

[0143] Prescription 2:

[0144] Step 1 Take 5 g of hexadecanol and melt it at 55°C as a matrix for later use;

[0145] Step 2: Take 60 g of the alcohol-extracted concentrated sample 1 of Example 1 and add it to the matrix, stir and mix, add 7 g of purified water, 25 g of soluble starch, and 8 g of methyl cellulose to obtain an ointment;

[0146] Step 3: evenly apply the ointment onto the pressure-sensitive adhesive patch and cover it with an anti-adhesive film to obtain a dysmenorrhea patch 2.

[0147] Prescription 3:

[0148] Step 1: Take 4g glycerol, 1g azone, and 10g hexadecanol, and melt them at 55°C as a matrix for later use;

[0149] Step 2: Take 60 g of the alcohol-extracted concentrated sample 1 of Example 1 and add it to the matrix, stir and mix, add 10 g of soluble starch and 15 g of sodium carboxymethyl cellulose and mix to obtain an ointment;

[0150] Step 3: evenly apply the ointment onto the pressure-sensitive adhesive patch and cover it with an anti-adhesive film to obtain a dysmenorrhea patch 3.

[0151] Prescription 4:

[0152] Step 1: Take 7g lanolin, 10g glycerol and 1g azone, melt them at 55°C as a matrix, and set aside;

[0153] Step 2 Take 60g of the alcohol-extracted concentrated sample 1 of Example 1 and add it to the matrix, stir and mix, add 10g of kaolin, 12g of methylcellulose, and 10g of sodium carboxymethylcellulose to mix, and obtain an ointment;

[0154] Step 3: evenly apply the ointment onto the pressure-sensitive adhesive patch and cover it with an anti-adhesive film to obtain a dysmenorrhea patch 4.

[0155] Prescription 5:

[0156] Step 1 Take 15g lanolin, 6g glycerin and 5g hexadecanol, melt them at 55°C as a matrix, and set aside;

[0157] Step 2: Take 60 g of the alcohol-extracted concentrated sample 1 of Example 1 and add it to the matrix, stir and mix, add 9 g of methyl cellulose and 6 g of kaolin to obtain an ointment;

[0158] Step 3: evenly apply the ointment onto the pressure-sensitive adhesive patch and cover it with an anti-adhesive film to obtain a dysmenorrhea patch 5.

[0159] Prescription 6:

[0160] Step 1: Take 6g lanolin, 3g hexadecanol, 15g glycerol and 1g azone, melt them at 55°C as a matrix, and set aside;

[0161] Step 2: Take 60 g of the alcohol-extracted concentrated sample 1 of Example 1 and add it to the matrix, stir and mix, add 9 g of carboxymethyl cellulose and 6 g of soluble starch and mix to obtain an ointment;

[0162] Step 3: evenly apply the ointment onto the pressure-sensitive adhesive patch and cover it with an anti-adhesive film to obtain a dysmenorrhea patch 6.

[0163] Prescription 7:

[0164] Step 1: Take 10g lanolin, 2.5g hexadecanol, 20g glycerol, and 0.5g azone, and melt them at 55°C as a matrix for later use;

[0165] Step 2: Take 40 g of the alcohol-extracted concentrated sample 1 of Example 1 and add it to the matrix, stir and mix, add 15 g of carboxymethyl cellulose and 12 g of soluble starch and mix to obtain an ointment;

[0166] Step 3: evenly apply the ointment onto the pressure-sensitive adhesive patch and cover it with an anti-adhesive film to obtain a dysmenorrhea patch 7.

[0167] Prescription 8:

[0168] Step 1: Take 3g lanolin, 8g hexadecanol, 8g glycerol and 2g azone, melt them at 55°C as a matrix, and set aside;

[0169] Step 2: Take 70 g of the alcohol-extracted concentrated sample 1 of Example 1 and add it to the matrix, stir and mix, add 5 g of carboxymethyl cellulose and 4 g of soluble starch and mix to obtain an ointment;

[0170] Step 3: evenly apply the ointment onto the pressure-sensitive adhesive patch and cover it with an anti-adhesive film to obtain a dysmenorrhea patch 8.

[0171] Prescription 9:

[0172] The uterus warming patch was prepared according to the process of Example 1 of patent CN117919329A.

[0173] Test Example 4: Animal Dysmenorrhea Test of Dysmenorrhea Plaster

[0174] (1) Test materials: Same as in Test Example 2.

[0175] (2) Test substances: Dysmenorrhea patches 1-8 and uterine warming patches prepared in Example 5.

[0176] (3) Construction of dysmenorrhea mouse model: Same as Experimental Example 2.

[0177] (4) Dosage design and administration method: Same as in Experimental Example 2. Grouping and dosage are shown in Table 9.

[0178] Table 9 Grouping and dosage table

[0179]

[0180] (5) Index detection and data processing: Same as Experimental Example 2.

[0181] (6) Test results

[0182] Table 10 Effects on the number of writhing times and writhing latency of dysmenorrhea model mice

[0183]

[0184] Note: vs. model control group: *, P<0.05, **, P<0.01.

[0185] The test results showed that both the dysmenorrhea patch 1-8 and the warm uterus patch could reduce the number of twisting, indicating that they had significant effects on the treatment of dysmenorrhea. However, the twisting inhibition effect of the dysmenorrhea patch 6-8 was better than that of the dysmenorrhea patches prepared by other prescriptions, and the effect of the warm uterus patch was the worst.

[0186] The dysmenorrhea patch of the present invention optimizes and selects auxiliary materials such as soluble starch, sodium carboxymethylcellulose, hexadecanol, lanolin, glycerin and azone. After these auxiliary materials are combined with the drug extract of the present invention, the dysmenorrhea patch of the present invention can better exert its medicinal effect, promote the transdermal penetration and absorption of active substances, and significantly improve the applicability and effectiveness of the preparation.

[0187] Test Example 5 Stability Test of Dysmenorrhea Plaster

[0188] (1) Test materials: Dysmenorrhea patches 1-8 prepared in Example 5.

[0189] (2) Test method: Accelerated stability test According to the 2020 edition of the "Chinese Pharmacopoeia" Part IV 9001 Stability Test Guidelines for Active Pharmaceutical Ingredients and Preparations, the samples are placed at a temperature of 40℃±2℃ and a relative humidity of 75%±5% for 6 months, and samples are taken for testing at the 1st, 3rd and 6th month.

[0190] (3) Dosage design, administration method, index detection and data processing are the same as those in Experimental Example 4.

[0191] (4) The test results are shown in Table 11.

[0192] Table 11 Effects of accelerated stability on the number of writhing times and writhing latency in dysmenorrhea model mice

[0193]

[0194] Note: vs group 1: *, P < 0.05, **, P < 0.01.

[0195] The accelerated stability results are shown in Table 11. Dysmenorrhea patches 6-8 still have an inhibition rate greater than 50% after 6 months of acceleration, which is significantly higher than that of dysmenorrhea patches 1-5, indicating that the dysmenorrhea patches of the present invention have optimized the selection of auxiliary materials such as soluble starch, sodium carboxymethyl cellulose, hexadecanol, lanolin, glycerol, and azone. After these auxiliary materials are combined with the drug extract of the present invention, not only can the transdermal and absorption of the active drug be improved, but also the stability and pharmacodynamic activity of the dysmenorrhea patch preparation of the present invention can be significantly improved.

[0196] Test Example 6 Clinical Trial Case

[0197] Case selection criteria:

[0198] 1. The diagnostic criteria are formulated in accordance with the "Guidelines for Clinical Research on New Traditional Chinese Medicines for the Treatment of Dysmenorrhea".

[0199] 1. TCM diagnostic criteria

[0200] Women who experience periodic lower abdominal pain during menstruation or before and after menstruation (within 1 week) as the main symptom, accompanied by other discomforts that affect their work and life can be diagnosed with dysmenorrhea.

[0201] (II) TCM Syndrome Differentiation

[0202] Compared with modern medicine's understanding of the mechanism of disease occurrence from an anatomical perspective, traditional Chinese medicine believes that the root cause of dysmenorrhea is the circulation of "qi and blood" in the internal organs. If the qi and blood of the internal organs are not flowing smoothly, pain may occur due to "blockage"; if the qi and blood of the internal organs are insufficient and cannot nourish the uterus, pain may occur due to local "insufficiency". The former is real dysmenorrhea, and the latter is virtual dysmenorrhea. Real dysmenorrhea can be caused by factors such as cold stagnation, qi stagnation, and dampness obstruction, while virtual dysmenorrhea is caused by physical deficiency, acquired malnutrition, and loss of qi and blood due to heavy menstrual flow, surgery, etc.

[0203] 1. Qi stagnation and blood stasis syndrome: abdominal distension and pain before or during menstruation that refuses to be pressed, scanty menstrual blood, irregular menstruation, dark purple blood with clots, temporary relief of pain under the clots, breast distension and pain before menstruation, chest tightness and discomfort, dark purple tongue or with petechiae, and stringy pulse.

[0204] 2. Cold-dampness stagnation syndrome: cold pain in the lower abdomen before or during menstruation, pain relieved by heat, scanty menstruation in late period, dark menstrual blood with clots or like black bean sweat, fear of cold, cold hands and feet, heavy vaginal discharge, white or greasy tongue coating, and stringy or deep and tight pulse.

[0205] 3. Western medicine diagnostic criteria

[0206] Primary dysmenorrhea refers to the condition in which no obvious organic lesions in the reproductive organs are found through gynecological examination. It often occurs in adolescent girls or young women who have not given birth 2-3 years after the onset of menstruation.

[0207] 2. Criteria for inclusion of cases:

[0208] Patients who meet the diagnostic criteria for dysmenorrhea and who, according to TCM syndrome differentiation, have poor and insufficient circulation of "Qi and blood" in the zangqi, and who have not used / taken other medicines for treatment or have used / taken other medicines for treatment that have been ineffective.

[0209] 3. Exclusion criteria:

[0210] Patients who meet the diagnostic criteria for dysmenorrhea but have secondary dysmenorrhea, have obvious organic lesions in the genitals, have pelvic inflammatory disease, uterine fibroids, endometrial displacement, etc. after gynecological examination, B-ultrasound, laparoscopy and other technical examinations, or do not meet the above two TCM syndrome types, have serious primary diseases such as cardiovascular, liver, kidney and hematopoietic systems, mental illness, may be allergic to this drug, do not meet the inclusion criteria, do not use the drug as prescribed, cannot judge the efficacy or have incomplete data, etc., which affect the judgment of efficacy or safety.

[0211] Treatment case results:

[0212] (1) Hu, female, 20 years old, from Guangzhou, had obvious abdominal pain and a feeling of abdominal heaviness during menstruation, and was easily nervous and anxious. When the patient had dysmenorrhea symptoms during menstruation, she began to apply the dysmenorrhea plaster 6 to the area 1.5 inches below the navel (3 inches below the navel Shenxue, Guanyuan acupoint in the lower abdomen), which had a significant effect in relieving pain. After applying it for 1-2 days during menstruation, the patient's dysmenorrhea, lower abdominal and lumbar pain were significantly relieved, without a feeling of heaviness, discomfort, and no allergic symptoms such as itching, redness, and swelling.

[0213] (2) Zhang, female, 35 years old, from Hunan, had unbearable pain in the lower abdomen during menstruation, fear of cold, palpitations, shortness of breath, sweating, and pale complexion. The patient began to apply the gel patch of Dysmenorrhea Patch 7 3 days before the onset of menstruation, and applied it to the area 1.5 inches below the navel (3 inches below the navel Shenxue, Guanyuan acupoint in the lower abdomen). It had a significant effect in relieving pain, and the pain was relieved quickly. After applying it throughout the menstrual period, the pain and soreness before the second month's period were significantly relieved, and there were no allergic reactions such as itching, redness, and swelling.

[0214] (3) Gao, 42 years old, from Dongguan, had dysmenorrhea for 5 years, with a menstrual cycle of 28-32 days, heavy and dark blood flow, blood clots, severe dysmenorrhea, back pain and fatigue, and a wiry pulse. He began to apply the dysmenorrhea patch 6 3 days before the onset of menstruation, applied to the area 1.5 inches below the navel (3 inches below the navel Shenxue, Guanyuan acupoint on the lower abdomen). One menstrual period was one course of treatment. After 3 courses of treatment, the dysmenorrhea symptoms were alleviated, the blood flow was medium and dark, there were fewer blood clots, and the menstruation tended to be normal. After 6 courses of treatment, the symptoms disappeared and there has been no recurrence so far. There was no allergic reaction such as itching, redness, and swelling.

[0215] The above is only a preferred embodiment of the present invention, and does not limit the present invention in any form. Although the present invention has been disclosed as a preferred embodiment, it is not used to limit the present invention. Any technician familiar with this patent can make some changes or modify the technical contents suggested above into equivalent embodiments without departing from the scope of the technical solution of the present invention. However, any simple modification, equivalent change and modification made to the above embodiments according to the technical essence of the present invention without departing from the content of the technical solution of the present invention still fall within the scope of the solution of the present invention.

Claims

1. A skin external preparation for treating dysmenorrhea, characterized in that: The drug ingredients of the skin external preparation are mixed in the following proportions by mass: 6-11 parts of Artemisia argyi, 12-20 parts of Cyperus rotundus, 4-12 parts of Evodia rutaecarpa, 1-3 parts of cinnamon bark, 6-15 parts of Angelica sinensis, 3-12 parts of Ligusticum chuanxiong, 4-9 parts of White Peony Root, 1-5 parts of Rehmannia glutinosa, 4-8 parts of Astragalus membranaceus, and 1-9 parts of Dipsacus asper. The external preparation includes liniment, ointment, plaster, hot melt patch, tincture, lotion, oil, emulsion, paste, plaster, film coating, gel, and aerosol.

2. The skin external preparation according to claim 1, characterized in that The skin external preparation also includes pharmaceutically acceptable auxiliary materials.

3. The method for preparing the external skin preparation for treating dysmenorrhea according to claim 1 or 2, characterized in that: The preparation method comprises: adding the drug component material into ethanol for extraction, and concentrating the extract under reduced pressure to obtain an extract.

4. The preparation method according to claim 3, characterized in that: The material-liquid ratio of the raw material to ethanol is 1:6-10 (W / V); the concentration of the ethanol is 50%-95%; and the relative density of the extract is 1.10-1.

30.

5. The preparation method according to claim 3, characterized in that: The skin external patch also includes medically acceptable auxiliary materials, and the extract is combined with the auxiliary materials to prepare an external preparation.

6. A skin external plaster for treating dysmenorrhea, characterized in that: The patch comprises the following proportions by mass: 40-70 parts of the skin external preparation according to claim 1 or 2, 4-12 parts of soluble starch, 5-15 parts of sodium carboxymethylcellulose, 2.5-8 parts of hexadecanol, 3-10 parts of lanolin, 8-20 parts of glycerol, and 0.5-2 parts of azone.

7. The method for preparing the patch according to claim 6, characterized in that: The following steps are involved: Step 1: Take the prescribed amount of hexadecanol, lanolin, glycerin and azone, keep warm and melt them as a matrix for later use; Step 2: Add the skin external preparation of claim 1 or 2 to the matrix of step 1, stir and mix, add sodium carboxymethyl cellulose and soluble starch to mix, and obtain an ointment; Step 3: Apply the ointment evenly onto the pressure-sensitive adhesive patch and cover with an anti-adhesive film to obtain a dysmenorrhea patch.

8. Use of the skin external preparation according to claim 1 or 2, or the skin external preparation prepared by the preparation method according to any one of claims 3 to 5, or the plaster according to claim 6 in the preparation of a drug for treating dysmenorrhea.

9. The use according to claim 8, characterized in that: The medicine is a medicine for treating endometriosis, adenomyosis, irregular menstruation, dysmenorrhea and / or premenstrual tension syndrome.

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