Chinese medicine composition for treating menopausal syndrome

Abstract

This application discloses the use of a traditional Chinese medicine composition in the preparation of a medicament for treating menopausal syndrome. The traditional Chinese medicine composition is prepared from the following traditional Chinese medicinal materials in parts by weight: 22-26 parts of bull penis, 8-12 parts of cinnamon, 10-14 parts of alfalfa seeds, 8-12 parts of galangal, 10-14 parts of onion seeds, 8-12 parts of cloves, 10-14 parts of dandelion seeds, 8-12 parts of Sichuan pepper, 12-16 parts of carrot seeds, 38-46 parts of sesame seeds, 10-14 parts of melon seeds, 56-64 parts of almond kernels, and cucumber seeds. 10-14 parts, Asarum heterotropoides 8-12 parts, Allium tuberosum seed 10-14 parts, Limonium sibiricum 16-20 parts, Dill seed 10-14 parts, Tribulus terrestris 13-17 parts, Prunus armeniaca 36-44 parts, Mirabilis jalapa root 8-12 parts, Cottonseed 18-22 parts, Saussurea costus 10-14 parts, Ginger slices 10-14 parts, Nutmeg skin 8-12 parts, Pine nuts 46-54 parts, Arugula spp. seed 10-14 parts, Saffron 3-7 parts, Ironwood 8-12 parts, Piper longum 8-12 parts, Nutmeg 18-22 parts.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical technology, specifically relating to a traditional Chinese medicine composition for treating menopausal syndrome. Background Technology

[0002] Menopausal syndrome, also known as perimenopausal syndrome, refers to a group of symptoms primarily characterized by autonomic nervous system dysfunction and accompanied by neuropsychological symptoms, caused by fluctuations or decreases in sex hormones around the time of menopause. Clinical manifestations include menstrual irregularities, hot flashes, sweating, irritability, and depression, significantly impacting patients' quality of life. It is mainly due to the decline in ovarian reserve, leading to a continuous decrease in hormone secretion from the ovaries. With social progress and improved medical conditions, life expectancy in Chinese women has increased, resulting in a growing number of menopausal women. Currently, there are 220 million women aged 40-65. Standardized healthcare and treatment are becoming increasingly important, and are more conducive to providing comprehensive life-cycle management and improving the quality of life for menopausal women.

[0003] The occurrence of menopausal-related disorders is closely related to a decline in estrogen levels. Hormone therapy is highly targeted and convenient, making it the preferred treatment for hot flashes in Western medicine. However, hormone therapy is not suitable for all women. It carries the risk of blood clots and is not suitable for patients with a history of smoking, blood clots, or cardiovascular disease. Long-term use of hormone therapy increases the risk of breast cancer, endometrial cancer, and ovarian cancer.

[0004] Traditional Chinese medicine (TCM) is safe and effective in relieving menopausal symptoms, especially suitable for women who are unwilling to receive estrogen therapy or have contraindications to it. Patients with perimenopausal syndrome who do not respond well to estrogen therapy, such as hot flashes, insomnia, memory loss, lower back pain, urinary incontinence, vaginal dryness, and hypertension, show significant improvement after receiving TCM treatment to tonify the kidneys and replenish essence. For patients with blood stasis tendencies, adding TCM herbs that promote blood circulation and remove blood stasis can both prevent thrombosis and enhance efficacy. Furthermore, TCM can supplement hormones, promote ovulation, regulate the menstrual cycle, and provide multi-target regulation. Evidence-based studies show that TCM can significantly improve multi-system clinical symptoms in menopausal patients, improve their quality of life, and currently has no significant adverse reactions.

[0005] Uyghur medicine, widely practiced as part of traditional Chinese medicine, is also included in my country's drug standards. Luobufukebiru Pills are listed in the 1998 edition of the "Drug Standards of the Ministry of Health of the People's Republic of China - Uyghur Medicine Volume," and are derived from pre-Qing Dynasty Uyghur classical medical texts and registered preparations in Uyghur medical hospitals in Hotan region, with modifications and additions. It is mainly composed of thirty medicinal materials: bull penis, cinnamon, alfalfa seeds, galangal, onion seeds, cloves, dandelion seeds, Sichuan pepper, carrot seeds, sesame, melon seeds, almonds, cucumber seeds, asarum (spider spice, asarum), leek seeds, large-leaved blood-tonifying herb, dill seeds, tribulus terrestris, milk peach, four o'clock root (cornflower), cottonseed, costus root, ginger slices, nutmeg coat, white pine nuts, sesame seeds, saffron, ironwood, long pepper, and nutmeg. Luobufukebiru pills are mainly used for impotence, depression, spermatorrhea, premature ejaculation, physical weakness, emaciation, and neurasthenia. Clinical studies have shown that Luobufukebiru pills can improve semen quality in patients with oligospermia and asthenospermia, increase sex hormone levels, and reduce erectile dysfunction, with clear clinical effects. However, there are no reports on the effects of Luobufukebiru pills in treating menopausal syndrome (perimenopause syndrome). Summary of the Invention

[0006] In order to solve one of the above-mentioned technical problems, this application provides the use of the traditional Chinese medicine composition of this application in the preparation of a medicine for treating menopausal syndrome (perimenopause syndrome).

[0007] One or more embodiments of this application provide the use of a traditional Chinese medicine composition in the preparation of a medicament for treating menopausal syndrome, wherein the traditional Chinese medicine composition is prepared from the following parts by weight of traditional Chinese medicinal materials:

[0008]

[0009] In one or more embodiments, the traditional Chinese medicine composition is prepared from the following parts by weight of traditional Chinese medicinal materials:

[0010]

[0011]

[0012] In one or more embodiments, the traditional Chinese medicine composition comprises the following parts by weight of powdered traditional Chinese medicinal materials:

[0013]

[0014] In one or more embodiments, the traditional Chinese medicine composition comprises the following parts by weight of powdered traditional Chinese medicinal materials:

[0015]

[0016] In one or more embodiments, the traditional Chinese medicine composition is prepared by the following method: pulverizing the medicinal materials other than saffron into fine powder; grinding saffron into a fine powder and mixing it with the fine powder; adding 550-650 parts by weight of refined honey, stirring well, making small honey pills, and drying them to obtain the final product.

[0017] In one or more embodiments, the traditional Chinese medicine composition is prepared as an oral formulation.

[0018] In one or more embodiments, the oral formulation is a pill.

[0019] In one or more embodiments, the pill is a small honey pill.

[0020] In one or more embodiments, the dosage form of the honey pill is 0.3g, 1.5g or 3g per pill.

[0021] In one or more embodiments, the menopausal syndrome is a liver and kidney yin deficiency type of menopausal syndrome.

[0022] In one or more embodiments, the clinical symptoms of the menopausal syndrome are selected from irritability, dizziness, tinnitus, hot flashes, sweating, mood swings, anxiety, forgetfulness, insomnia, edema, loss of appetite, loose stools, menstrual disorders, etc.

[0023] In one or more embodiments, the traditional Chinese medicine composition regulates serum estrogen levels.

[0024] In one or more embodiments, the traditional Chinese medicine composition reduces the risk of menopausal women developing tumors or cardiovascular diseases.

[0025] Bullwhip is the dried penis of the cattle Bos taurus domesticus Gmelin or Bos grunnienslinnaeusa.

[0026] Cinnamon is the dried bark of the cinnamon tree (Cinnamomum cassia Presl), a plant belonging to the Lauraceae family.

[0027] Alfalfa seeds are the dried, mature seeds of the legume plant Medicago sativa L.

[0028] Alpinia officinarum Hance is the dried rhizome of the ginger family plant Alpinia officinarum Hance.

[0029] Onion seeds are the dried, mature seeds of the onion plant (Allium cepa L.) belonging to the lily family.

[0030] Clove is the dried flower bud of Eugenia caryophyllata Thunb., a plant in the Myrtaceae family.

[0031] Turnip seeds are the dried, mature seeds of the Brassica rapa L. plant, belonging to the Brassicaceae family.

[0032] Sichuan pepper is the dried, mature pericarp of the plants Zanthoxylum schinifolium Sieb. et Zucc. or Zantho xylum bungeanum Maxim., both belonging to the Rutaceae family.

[0033] Carrot seeds are the dried, ripe fruit of the carrot plant (Daucus carota L.Var.Sativa DC.) belonging to the Apiaceae family.

[0034] Sesame is the dried, mature seed of Sesamum indicum L., belonging to the family Sesamaceae.

[0035] Melon seeds are the dried, mature seeds of the melon plant *Cucumis melo* L., belonging to the Cucurbitaceae family.

[0036] Almond kernels are the dried, mature seeds of the sweet almond (Amygdalus communis L.), a plant belonging to the Rosaceae family.

[0037] Cucumber seeds are the dried, mature seeds of the cucumber plant Cucumis sativus L., belonging to the Cucurbitaceae family.

[0038] Asarum, also known as spider spice or asarum, is the dried rhizome and root of Valeriana ajatamansi Jones, a plant in the Valerianaceae family.

[0039] Leek seeds are the dried, mature seeds of Allium tuberosum Rottl ex Spreng., a plant belonging to the Liliaceae family.

[0040] Limonium gmelinii (willd.) O.ktze, a plant in the Plumbaginaceae family, is a rhizome of this herb.

[0041] Dill seeds are the dried, ripe fruits of the dill plant (Anethum graveolens L.) belonging to the Apiaceae family.

[0042] Tribulus terrestris L., a plant belonging to the family Zygophyllaceae, is the dried, mature fruit of the plant.

[0043] Milk peach is the endosperm of the mature seed of the palm tree Cocos nucifera L.

[0044] Four o'clock root, also known as European cornflower, is the dried root and rhizome of the plant Centaurea behen L., belonging to the Asteraceae family.

[0045] Cottonseeds are the seeds of the Malvaceae plants *Gossypium herbaceum* L., *Gossypium hirsutum* L., *Gossypium barbadense* L., and *Gossypium arboreum* L.

[0046] Costus root is the dried root of Aucklandia lappa Decne., a plant in the Asteraceae family.

[0047] Ginger slices are the dried rhizomes of Zingiber officinale Rosc., a plant in the ginger family.

[0048] Nutmeg aril is the dried aril of the nutmeg plant (Myristica fragrans Houtt.) belonging to the Myristaceae family.

[0049] White pine nuts are the seeds of the Tibetan white pine (Pinus gerardiana Wall.), a plant belonging to the Pinaceae family.

[0050] Arugula seeds are the dried, mature seeds of the cruciferous plant *Eurca sativa* Mill.

[0051] Saffron is the dried stigma of Crocus sativus L., a plant in the Iridaceae family.

[0052] Ironwood refers to the dried flower buds of Mesua ferrea L., a plant belonging to the Clusiaceae family.

[0053] Piper longum is the dried, nearly mature or mature fruit spike of Piper longum L., a plant in the Piperaceae family.

[0054] Nutmeg is the dried seed kernel of Myristica fragrans Houtt., a plant in the Myristaceae family.

[0055] In one or more embodiments, the traditional Chinese medicine composition of this application can alleviate clinical symptoms, especially hot flashes, five-center heat (palms, soles, and chest), lower back pain, irritability, insomnia, and itchy skin. Its efficacy gradually increases with prolonged use. The improvement of menopausal syndrome clinical symptoms by the traditional Chinese medicine composition of this application is related to the regulation of serum estrogen levels. Regarding hormone supplementation, unlike chemical drugs such as tibolone that directly target hormone levels, the traditional Chinese medicine composition of this application better reflects the traditional Chinese medicine characteristic of "treating both the symptoms and the root cause," which is also the advantage of this composition. The traditional Chinese medicine composition of this application not only reduces the risk of tumors or cardiovascular diseases in menopausal women but also provides good complementary treatment for patients with tumors or cardiovascular diseases. Attached Figure Description

[0056] Figure 1 This paper illustrates a comparison of the efficacy of the traditional Chinese medicine composition of this application on sex hormones in menopausal patients before and after interventional treatment, wherein... Figure 1 A indicates a significant reduction in the levels of sex hormones FSH and LH in menopausal patients. Figure 1 B indicates an increase in E2 levels in menopausal patients.

[0057] Figure 2 This paper presents a comparison of the efficacy of the traditional Chinese medicine composition of this application on clinical symptom indicators in menopausal patients before and after interventional treatment. Figure 2 A indicates a significant improvement in the Kupperman index during menopause in the treatment group. Figure 2 B indicates a significant improvement in the liver and kidney yin deficiency index in the treatment group.

[0058] Figure 3 The correlation analysis between the course of treatment and the efficacy of the traditional Chinese medicine composition of this application is shown.

[0059] Figure 4 This shows a comparison of the differences in menopausal syndrome, sex hormones, and efficacy before and after treatment between the control group and the treatment group. Figure 4 A represents the comparison of FSH effectiveness. Figure 4 B represents the comparison of LH effectiveness. Figure 4 C represents the comparison of E2 efficiency. Figure 4 D represents the Koopman index for efficiency comparison. Figure 4 E represents the comparison of the effectiveness of the liver and kidney yin deficiency index. Figure 4 F represents the FSH difference. Figure 4 G represents LH difference. Figure 4 H represents the E2 difference. Figure 4 I represents the Koopman index difference. Figure 4 J represents the difference in the liver and kidney yin deficiency index.

[0060] Figure 5The ovarian and uterine indices of rats in the model group, the low-, medium-, and high-dose groups of the traditional Chinese medicine composition of this application, the menopause relief group, and the estradiol valerate group are shown. This indicates that compared with the model group, the tissue coefficients of rats in the low-, medium-, and high-dose groups of the traditional Chinese medicine composition of this application, the menopause relief group, and the estradiol valerate group are improved.

[0061] Figure 6 The model group, the low, medium and high dose groups of the traditional Chinese medicine composition of this application, the menopause relief group and the estradiol valerate group of rats are shown. It is shown that the estradiol level of rats in the traditional Chinese medicine composition group of this application is significantly reduced, and the effect is comparable to that of estradiol valerate and menopause relief tablets.

[0062] Figure 7 The results of HE staining of the ovaries of rats in the model group, the low, medium and high dose groups of the traditional Chinese medicine composition of this application, the menopause relief group and the estradiol valerate group are shown, indicating the pathological effects of the traditional Chinese medicine composition of this application on the ovaries.

[0063] Figure 8 The results of HE staining of the uterus of rats in the model group, the low, medium and high dose groups of the traditional Chinese medicine composition of this application, the menopause relief group and the estradiol valerate group are shown, indicating the effect of the traditional Chinese medicine composition of this application on uterine pathology. Detailed Implementation

[0064] The following embodiments are used to illustrate the technical solutions of this application in detail, but are not intended to limit the scope of this application.

[0065] Example 1

[0066] 1. Materials

[0067] 1.1 Drugs and Reagents: Estradiol Valerate Tablets (Bayer AG, Germany, J20171038, Batch No. 654A); Menopause Tablets (Jiangxi Sanghai Pharmaceutical, National Drug Approval Number Z20073293, Batch No. 220715); Luobufu Kebi Ri Pills (Hotan Uygur Pharmaceutical Co., Ltd., National Drug Approval Number Z65020142, Batch No. 20211013); Rat Estradiol (E2) ELISA Kit (Wuhan Yilairuit Biotechnology Co., Ltd., Catalog No. E-OSEL-R0001); Penicillin Sodium for Injection: North China Pharmaceutical Co., Ltd., Specification: 800,000 units / vial.

[0068] 1.2 Experimental instruments: Multifunctional microplate reader (TECAN, Switzerland); Miniature centrifuge (Mio, Hangzhou); DM3000 microscope (Leica).

[0069] 2. Preparation process of Luobufukebiru pill

[0070]

[0071] Take the above-mentioned weights of ox penis, cinnamon, alfalfa seeds, galangal, onion seeds, cloves, turnip seeds, Sichuan pepper, carrot seeds, sesame seeds, melon seeds, almonds, cucumber seeds, asarum (spider spice, asarum), leek seeds, large-leaved blood-tonifying herb, dill seeds, tribulus terrestris, milk peach, four o'clock root (cornflower), cottonseed, costus root, ginger slices, nutmeg coat, white pine nuts, sesame seeds, saffron, ironwood, long pepper, and nutmeg—thirty kinds of medicinal materials. Except for saffron, the remaining twenty-nine ingredients, including ox penis, are pulverized into a fine powder. Grind the saffron into a fine powder, mix it with the above-mentioned fine powder, add 550-650g of refined honey, stir well, make small honey pills, and dry them to obtain the traditional Chinese medicine composition of this application.

[0072] 3. Clinical efficacy trial design for menopausal syndrome

[0073] 3.1 Criteria for inclusion, exclusion, rejection, withdrawal, and termination

[0074] 3.1.1 Inclusion: Participants who met the following diagnostic criteria were included in the clinical study.

[0075] 3.1.1.1 Modern Medical Diagnostic Criteria

[0076] (1) Female, 41-60 years old;

[0077] (2) Irregular menstrual cycles in the past 12 months indicate perimenopause or cessation of menstruation for at least 3 months;

[0078] (3) Hot flashes, with a KMI score of 15 or higher (moderate to severe menopausal symptoms with hot flashes).

[0079] 3.1.1.2 Traditional Chinese Medicine Diagnostic Criteria

[0080] According to the "Standards of Traditional Chinese Medicine of the People's Republic of China" for liver and kidney yin deficiency before and after menstruation (menopausal syndrome).

[0081] (1) Main symptoms: hot flashes and sweating.

[0082] (2) Secondary diseases: five-center heat, irritability, restlessness, depression, dry mouth, constipation, irregular menstruation, amenorrhea, red tongue, little coating, and thready and rapid pulse.

[0083] If two or more of the above main symptoms are present, a diagnosis of menopausal syndrome due to liver and kidney yin deficiency can be made.

[0084] 3.1.2 Exclusion

[0085] (1) Age not between 41 and 60 years old.

[0086] (2) Allergic constitution or drug allergy.

[0087] (3) Pregnant women or suspected pregnant women.

[0088] (4) Received hormone replacement therapy in the past 6 weeks; received other medications or health supplements to improve menopausal symptoms in the past month; received psychoanalysis and psychological counseling in the past week; or took medication to relieve cerebral vasospasm in the past month.

[0089] (5) Cervical cytology results are CIN II, CIN III or other abnormalities in cervical examination in the past 6 months (excluding inflammation).

[0090] (6) Patients with serious primary diseases such as cardiovascular and cerebrovascular diseases, liver diseases, kidney diseases, hematopoietic system diseases, autoimmune diseases, and mental illnesses.

[0091] (7) Those who do not meet the inclusion criteria or do not use medication as required.

[0092] 3.1.3 Rejection Criteria

[0093] If, after enrollment, a participant is found to be ineligible for inclusion or to be using prohibited drugs as specified in the protocol, thus violating the clinical trial protocol, they should be eliminated.

[0094] 3.1.4 Exit Criteria

[0095] Participants who meet the inclusion criteria may opt out voluntarily, or researchers may deem it necessary for a participant to opt out.

[0096] 3.1.5 Termination Conditions

[0097] After registration, participants may experience drug-related complications, or researchers may believe that these complications may be related to the experimental drug. Therefore, participants need to terminate their registration.

[0098] 3.2 Research Design

[0099] Following initial screening, a total of 176 women were selected for the study. Of these, 114 patients had follow-up data (66 in the treatment group and 48 in the control group). The study was conducted in three phases.

[0100] 3.2.1 First Stage – Pre-intervention

[0101] During this phase, a baseline survey was conducted. Baseline data on basic information, routine biochemical tests, hormone status, perimenopausal and postmenopausal symptoms, and past medical history were collected using a pre-test questionnaire.

[0102] The tools and techniques used to collect necessary data and implement interventions include a consent form, questionnaires, and interview plans to gather general information and past medical history. Clinical parameters assessed include perimenopausal and postmenopausal symptoms. Routine blood and urine biochemical tests are performed, including standard blood tests, urinalysis, liver function tests, kidney function tests, and electrocardiogram. Serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) are measured to increase hormone levels.

[0103] The Kopperman Index is a numerically transformed index that covers 11 menopausal symptoms. These symptoms include hot flashes, paresthesia, insomnia, depression, mood swings, dizziness, fatigue, joint or muscle pain, headache, palpitations, and tingling sensations on the skin. The list of symptoms assessed was slightly modified based on a pre-test. Paresthesia and intermittent sweating were considered hot flash symptoms because most respondents considered them similar. The symptoms assessed by the Kopperman Index were based on participant-reported prevalence. Each symptom on the Kopperman Index was rated on a scale of 0 to 3, representing no, mild, moderate, or noticeable discomfort. The Kopperman Index was calculated by weighting hot flashes (×4), paresthesia (×2), insomnia (×2), depression (×2), and all other symptoms (×1). Specific scores are shown in Table 1. Therefore, the highest potential score was 51, and the lowest was 0. A total Kupperman index of 35 or higher is considered severe; a total Kupperman index between 20 and 38 is considered moderate; and a total Kupperman index between 15 and 21 is considered mild.

[0104] Table 1. Koopman Index Scoring Criteria

[0105] Hot flashes 4 None, Mild, Moderate, Obvious abnormal sensation 2 None, Mild, Moderate, Obvious Insomnia 2 None, Mild, Moderate, Obvious Depression 2 None, Mild, Moderate, Obvious Emotional fluctuations 1 None, Mild, Moderate, Obvious dizziness 1 None, mild, moderate, obvious fatigue 1 None, Mild, Moderate, Obvious Joint pain or muscle pain 1 None, Mild, Moderate, Obvious Headache 1 None, Mild, Moderate, Obvious Heart palpitations 1 None, Mild, Moderate, Obvious Skin ant crawling sensation 1 None, Mild, Moderate, Obvious

[0106] *0 = None; 1 = Mild; 2 = Moderate; 3 = Significant. Numerical conversion = Factor * Severity.

[0107] Menopausal Index (total): Severe =>35; Moderate =20-28; Mild =15-21.

[0108] The Liver and Kidney Yin Deficiency Index is a numerical conversion index that covers 13 menopausal symptoms. These symptoms include hot flashes, excessive sweating, five-center heat (palms, soles, and chest), irritability, restless sleep, depression, dry mouth, constipation, irregular menstruation, amenorrhea, red tongue, thin coating, and thready, rapid pulse. Each symptom associated with the Liver and Kidney Yin Deficiency Index is scored from 0 to 3 (none, mild, moderate, or severe) (except for tongue, coating, and pulse, which are scored from 0 to 1 (none, mild)). To calculate the Liver and Kidney Yin Deficiency Index, hot flashes and sweating (×3), five-center heat (×2), lower back and knee pain or heel pain (×2), dizziness and tinnitus (×2), and other symptoms (×1) are used. Specific scores are shown in Table 2. Therefore, the highest potential score is 51 points, and the lowest is 0 points. A total Liver and Kidney Yin Deficiency Index ≥32 is considered severe; a total Liver and Kidney Yin Deficiency Index between 17 and 32 is moderate; and a total Liver and Kidney Yin Deficiency Index less than 17 is mild. To observe the efficacy of the herbal composition of this application in treating menopausal syndrome from the perspectives of modern medicine and traditional Chinese medicine, this study used the Cooperman index and the liver and kidney yin deficiency index.

[0109] Table 2. Scoring criteria for liver and kidney yin deficiency index

[0110] Hot flashes and sweating 3 None, Mild, Moderate, Obvious Five-center heat 2 None, Mild, Moderate, Obvious Lower back and knee pain or heel pain 2 None, mild, moderate, obvious Dizziness and tinnitus 2 None, mild, moderate, obvious Heart palpitations 1 None, Mild, Moderate, Obvious irritability 1 None, Mild, Moderate, Obvious restless sleep 1 None, mild, moderate, obvious Dry mouth 1 None, Mild, Moderate, Obvious vaginal dryness 1 None, Mild, Moderate, Obvious itching 1 None, mild, moderate, obvious Red tongue 1 None, slight moss 1 None, slight The pulse is thin and rapid. 1 None, slight

[0111] *0 = None; 1 = Mild; 2 = Moderate; 3 = Significant. Numerical conversion = Factor * Severity.

[0112] Liver and kidney yin deficiency index (total): severe >32; moderate = 17-32; mild <=16.

[0113] 3.2.2 Second Phase - Intervention

[0114] The experimental group received the herbal composition of this application orally, with warm water after meals (10 tablets twice daily). The control group received tiberon (2.5 mg once daily) orally with warm water after meals. At the start of the study, there were a total of 175 participants in both groups (127 in the experimental group and 48 in the control group). At this stage, 61 participants in the experimental group withdrew from the intervention. The study continued with 114 participants.

[0115] 3.2.3 Third Stage - Post-Intervention

[0116] During the intervention, the same techniques were used in both the experimental and control groups to collect clinical data and biochemical index levels, including menopausal symptoms (menopausal Kupperman index and liver and kidney yin deficiency index), routine biochemical and hormone tests. These data were collected to evaluate the safety and efficacy of the traditional Chinese medicine composition of this application in treating female menopausal syndrome.

[0117] 3.3 Clinical efficacy criteria

[0118] The clinical efficacy of the treatment group and the control group was evaluated based on sex hormone levels, clinical liver and kidney yin deficiency scores, and other relevant data after treatment. Clinical remission rate = (pre-treatment score - post-treatment score) / pre-treatment score × 100%. Cure: Clinical remission rate > 80%; Marked improvement: Clinical remission rate 50%-80%; Effective: Clinical remission rate 30%-49%; Ineffective: Clinical remission rate < 30%. (Total effective rate = Number of cured cases + Number of markedly effective cases + Number of effective cases) / Total number of cases × 100%)

[0119] 4. Experimental design for rats with menopausal syndrome

[0120] 4.1 Laboratory Animals

[0121] SPF-grade female SD rats, 10-12 months old, weighing 300-320g, were provided by the Experimental Animal Center of Xinjiang Medical University. They were housed at a temperature of (22±1)℃ and a relative humidity of 50%-60%, with free access to food and water, and following a natural 12h / 12h diurnal cycle. The entire experimental process followed the relevant regulations of the Experimental Animal Ethics Committee of the Xinjiang Institute of Materia Medica.

[0122] 4.2 Modeling and Drug Administration

[0123] After one week of acclimatization feeding, 10-12 month old SD rats were randomly divided into 6 groups of 6 rats each using a random number table (model group, low, medium, and high dose groups of the traditional Chinese medicine composition of this application, menopause relief tablet group, and estradiol valerate tablet group). Vaginal smears were performed on each rat once daily for 5 consecutive days. The model was considered successful if no estrus response was observed. Dosage was designed according to the equivalent dose conversion factor between humans and animals. For the estradiol valerate group, the dose was prepared as a suspension of 14.17 mg / kg using distilled water; for the menopause relief tablet group, the dose was prepared as a suspension of 0.49 g / kg using distilled water; for the low, medium, and high dose groups of the traditional Chinese medicine composition of this application, the doses were 0.63 g / kg, 0.78 g / kg, and 0.94 g / kg suspensions, respectively; and for the model group, an equal volume of distilled water was administered. Administered once daily for 30 days.

[0124] 4.3 Sample Preparation

[0125] Rats in each group were fasted for 12 hours after the last administration of the drug, anesthetized by intraperitoneal injection of sodium pentobarbital, and 5 mL of blood was collected from the abdominal aorta. The blood was allowed to stand at room temperature for 2 hours, then centrifuged at 3000 rpm for 15 minutes at 4°C to separate the serum, which was then stored at -20°C. The uterus, hypothalamus, and ovaries of the rats were harvested, rinsed with physiological saline, and the surface moisture was blotted dry with filter paper. The wet weight was accurately measured using an electronic balance, and the tissue index was calculated using the formula: wet tissue weight / rat body weight. A portion of the tissue was fixed in 4% paraformaldehyde, and the other portion was stored in liquid nitrogen for subsequent experiments.

[0126] 4.4 Observation Indicators and Measurement Methods

[0127] 4.4.1 Detection of serum E2 levels in rats using ELISA

[0128] The level of E2 in rat serum was detected using a commercially available kit, and the detection and analysis were performed according to the kit instructions.

[0129] 4.4.2 HE staining for histopathological observation

[0130] Tissue samples were excised from each group of rats and fixed with 4% paraformaldehyde. The fixed tissues were dehydrated and then embedded in paraffin to make paraffin blocks. The blocks were then sectioned using a microtome with a thickness of about 5 μm. The sections were stained with hematoxylin and eosin, mounted, and the pathological changes of the tissue sections were observed under a microscope.

[0131] 5. Experimental Results

[0132] 5.1 Results Evaluation

[0133] 5.1.1 Comparison of the efficacy of the traditional Chinese medicine composition of this application before and after treatment of menopausal patients

[0134] Before intervention, the average FSH level in the treatment group was 111.51±38.37 mIU / ml (range 55.36–200 mIU / ml), the average LH level was 41.47±14.25 mIU / ml (range 17.32–86.19 mIU / ml), and the average E2 level was 21.23±7.55 Pg / ml (range 5–43.14 Pg / ml). After intervention, the average FSH level was 93.59±34.66 mIU / ml (range 36.96–200 mIU / ml), the average LH level was 39.89±14.86 mIU / ml (range 13.46–86.19 mIU / ml), and the average E2 level was 23.79±12.48 Pg / ml (range 5–85 Pg / ml). Figure 1 As shown, the traditional Chinese medicine composition of this application can significantly reduce the levels of sex hormones FSH and LH in menopausal patients and increase the level of E2 in menopausal patients.

[0135] Regarding clinical symptoms, before intervention, the mean Kopperman index in the treatment group was 31.37±8.22 (range 15-49), and the mean liver and kidney yin deficiency index was 31.11±6.87 (range 15-44). After intervention, the mean Kopperman index was 17.93±9.11 (range 3-38), and the mean liver and kidney yin deficiency index was 17.43±8.85 (range 3-39). Figure 2 As shown, the traditional Chinese medicine composition of this application can significantly improve the menopausal Cooperman index and liver and kidney yin deficiency index, and alleviate the severity of clinical symptoms in menopausal patients.

[0136] Table 3. Improvement of sex hormones and clinical symptoms before and after treatment with the traditional Chinese medicine composition of this application.

[0137] cure 0 0 6 1 1 Effective 0 0 3 23 25 efficient 9 8 4 30 30 invalid 57 58 53 12 10 Overall efficiency 13.6％ 12.1％ 24.5％ 81.8％ 84.8％

[0138] As shown in Table 3, the improvement rates of FSH, LH, and E2 in the treatment group were 13.6%, 12.1%, and 24.5%, respectively, and the relief rates of the Cooperman index and the liver and kidney yin deficiency index were 81.8% and 84.8%, respectively. The results indicate that postmenopausal symptoms (including the Cooperman index and the liver and kidney yin deficiency index) were significantly improved in women treated with the traditional Chinese medicine composition of this application.

[0139] 5.1.2 Correlation analysis of the treatment course and efficacy of the traditional Chinese medicine composition of this application

[0140] To evaluate whether the efficacy of the traditional Chinese medicine composition described in this application for treating menopausal patients is related to the duration of treatment, this study analyzed the correlation between the improvement level of sex hormones, the severity of symptoms, and the duration of treatment in the treatment group. Figure 3 As shown, the results indicate that the improvement levels of FSH, LH, and E2 are positively correlated with the duration of treatment, and the improvement levels of the Cooperman index and the liver and kidney yin deficiency index are also positively correlated with the duration of treatment.

[0141] 5.1.3 Comparison of therapeutic effects between the experimental group and the control group

[0142] In the treatment group, the median FSH level after intervention in matched patients was 77.21 mIU / ml (IQR, 72.14, 99.45 mIU / ml); the median LH level was 38.44±12.99 mIU / ml (range 13.46–58.9 mIU / ml); and the median E2 level was 20 pg / ml (poor, 11.98, 24.11 pg / ml), implying a Cooperman index of 17.33±7.08 (range 7–27), indicating a liver and kidney yin deficiency index of 16.92±7.35 (range 8–27). In the control group, the median FSH level after intervention was 54.06 mIU / ml (IQR, 49.62, 76.12 mIU / ml); the median LH level was 27.1±9.99 mIU / ml (range 5.09-43.23 mIU / ml); the median E2 level was 20 pg / ml (IQR 20, 20.25 pg / ml); the mean Couberman index was 13.25±7.42 (range 4-30); and the mean liver and kidney yin deficiency index was 37.50±5.86 years (range 6-32). Comparing the differences in efficacy before and after treatment, the traditional Chinese medicine composition of this application showed comparable efficacy to tibolone in treating menopausal syndrome sex hormone levels, especially in improving FSH, LH, Couberman index, and liver and kidney yin deficiency index. The results are shown in […]. Figure 4 .

[0143] 5.1.4 Effect of the traditional Chinese medicine composition of this application on the tissue coefficient of rats with perimenopausal syndrome

[0144] like Figure 5 As shown, compared with the model group, the tissue coefficients of rats in the low, medium and high dose groups of the traditional Chinese medicine composition of this application, the menopause relief group and the estradiol valerate group were improved, indicating that the drug did indeed play a therapeutic role.

[0145] 5.1.5 Effect of the traditional Chinese medicine composition of this application on estradiol levels

[0146] Compared with the model group, the estradiol level in rats in the group treated with the traditional Chinese medicine composition of this application was significantly reduced, with effects comparable to estradiol valerate and menopausal analgesia tablets. This indicates that the drug can effectively control hormonal changes during menopause (see [link to relevant documentation]). Figure 6 ).

[0147] 5.1.6 Effects of the Traditional Chinese Medicine Composition of this Application on Ovarian Pathology

[0148] In the model group rats, most ovarian follicles were underdeveloped or non-developing, with reduced blood vessels, and fewer follicles and corpora lutea. After drug intervention, the development of ovarian follicles in all treatment groups improved, with an increase in the number of follicles at each stage, the appearance of primordial or mature follicles, an increase in the granulosa cell layer in the ovary, a more compact arrangement, increased blood vessels, and an increase in the number of follicles and corpora lutea (see...). Figure 7 ).

[0149] 5.1.7 Effects of the Traditional Chinese Medicine Composition of this Application on the Uterus

[0150] Under an optical microscope, the morphology of the rat uterus was observed. In the model group, the endometrium was thinner, with fewer glands and capillaries, and smaller glandular lumens. After drug intervention, the endometrium of rats in all treatment groups was significantly thickened, and the number of glands and capillaries was significantly increased (see...). Figure 8 ).

Claims

1. Use of a traditional Chinese medicine composition in the preparation of a medicament for treating menopausal syndrome in women, wherein the traditional Chinese medicine composition is prepared from the following traditional Chinese medicinal materials in parts by weight:

2. The use as described in claim 1, wherein the traditional Chinese medicine composition is prepared from the following parts by weight of traditional Chinese medicinal materials:

3. The use as described in claim 1, wherein the traditional Chinese medicine composition comprises the following parts by weight of powdered traditional Chinese medicinal materials:

4. The use as described in claim 3, wherein the traditional Chinese medicine composition comprises the following parts by weight of powdered traditional Chinese medicinal materials:

5. The use according to any one of claims 1-4, wherein the traditional Chinese medicine composition is prepared by the following method: pulverizing the remaining medicinal materials except saffron into fine powder; grinding saffron into fine powder and mixing it with the fine powder; adding 550-650 parts by weight of refined honey, stirring well, making small honey pills, and drying to obtain the final product.

6. The use according to any one of claims 1-4, wherein the traditional Chinese medicine composition is prepared into an oral formulation.

7. The use as described in claim 6, wherein the oral formulation is a pill.

8. The use as described in claim 7, wherein the pill is a small honey pill.

9. The use as described in claim 8, wherein the dosage form of the small honey pill is 0.3g, 1.5g or 3g per pill.

10. The use as described in claim 1, wherein the menopausal syndrome is a type of menopausal syndrome caused by liver and kidney yin deficiency.

Images