High-simulation placebo, preparation method thereof and application of high-simulation placebo in combined treatment of menopausal syndrome by traditional Chinese medicine and western medicine

Abstract

The invention belongs to the technical field of medicines, and particularly provides a high-simulation placebo as well as a preparation method and application thereof in combined treatment of menopausal syndrome by traditional Chinese medicine and western medicine. The high-simulation placebo is prepared from the following components in parts by mass: caramel color, citrus yellow, citric acid, malic acid, raw medicine extract and the balance of maltodextrin. The high-simulation placebo is applied to a traditional Chinese and western medicine combined medication scheme, the unique advantages of western medicines and traditional Chinese medicines are deeply fused, and the weakness of a single therapy is ingeniously avoided. Western medicines can quickly relieve clinical symptoms of MPS patients by virtue of the characteristics of quick action and clear target spot; the traditional Chinese medicines have the effects of overall conditioning, mildness and durability, so that the body function of a patient is fundamentally improved, and the immunity is enhanced. The two components supplement each other, and the composition has obvious results in improvement of clinical symptoms of MPS patients and improvement of life quality, and can be clinically popularized.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical technology, and particularly relates to a highly simulated placebo, its preparation method, and its application in the combined traditional Chinese and Western medicine treatment of menopausal syndrome. Background Art

[0002] Menopausal syndrome is a syndrome with autonomic nervous system dysfunction as the core symptom caused by the decline of ovarian function in women. The clinical manifestations include hot flashes, night sweats, mood disorders, sleep disorders, osteoporosis, etc., which seriously affect the quality of life. Currently, the mainstream treatment methods include Western medicine hormone replacement therapy (HRT) and traditional Chinese medicine syndrome differentiation and treatment, but both have limitations.

[0003] For the Western medicine treatment plan, although hormone replacement therapy can quickly relieve symptoms, long-term use may increase the risks of breast cancer, thrombosis, and cardiovascular diseases, resulting in low patient compliance. Non-hormonal drugs (such as selective serotonin reuptake inhibitors) have relatively high safety, but the improvement of somatic symptoms is limited. The main deficiencies of traditional Chinese medicine treatment are as follows: Traditional Chinese medicine compound prescriptions (such as Baoqing Granules, Kuntai Capsules, etc.) and acupuncture can relieve symptoms by regulating the balance of yin and yang, but the curative effect lacks a quantitative standard, the onset is slow, and the individual differences are significant, making it difficult to meet the needs of emergency cases.

[0004] The effect is better when used alone. For another example, Chen Ye et al. observed 70 patients with MPS treated with Liuwei Dihuang Pills combined with estradiol and dydrogesterone. The control group used dydrogesterone tablets, and the observation group used Liuwei Dihuang Pills in combination. The results showed that the effective rate of the observation group was higher than that of the control group (P < 0.05).

[0005] In recent years, studies have all tried to combine the advantages of traditional Chinese and Western medicine to treat menopausal syndrome, but there is a lack of a standardized combined use plan, and the efficacy evaluation system is mixed, making it difficult to distinguish the respective contributions of traditional Chinese and Western medicine. More clinical data are needed to prove the efficacy of the combined traditional Chinese and Western medicine treatment of MPS. Therefore, more multi-center, randomized, and double-blind clinical trials should be carried out to provide more reference basis for the clinical treatment of MPS.

[0006] In addition, during the clinical trial process, the influence of the placebo cannot be ignored. Especially for menopausal syndrome, the symptoms are highly subjective, and the placebo effect in clinical trials is significant (about 30%-50%). Traditional placebos (such as starch tablets, sham acupuncture) are prone to cause the failure of the blinding method due to large differences in appearance, taste, or operation methods from real treatment. Especially in the combined traditional Chinese and Western medicine trials, it is necessary to simultaneously simulate the physical and chemical properties of chemical drugs and traditional Chinese medicine preparations (such as decoctions, capsules). Existing placebos are difficult to achieve high simulation, resulting in bias in the test results and affecting the scientific evaluation of efficacy and safety. Summary of the Invention

[0007] In view of the above problems, in order to reduce the influence of placebos in clinical trials and improve the therapeutic effect of integrated traditional Chinese and Western medicine treatment, the present application provides a high-fidelity placebo, its preparation method, and its application in the integrated traditional Chinese and Western medicine treatment of menopausal syndrome.

[0008] The present application first provides a high-fidelity placebo, which comprises the following components in mass fractions: caramel color 0.8 - 1.2%, citrus yellow 0.3 - 0.7%, citric acid 0.5 - 0.9%, malic acid 0.3 - 0.4%, crude drug extract 2.5 - 6.5%, and the balance is maltodextrin.

[0009] Further, the crude drug extract is prepared by the following steps:

[0010] 1) Take 400 - 500 parts of Rehmannia glutinosa, 400 - 500 parts of Cornus officinalis, 500 - 600 parts of Dioscorea opposita, 500 - 600 parts of Cuscuta chinensis, 500 - 600 parts of Lycium barbarum, 400 - 500 parts of Cistanche deserticola, 600 - 700 parts of Os Draconis, 400 - 500 parts of Achyranthes bidentata, 500 - 600 parts of Schisandra chinensis, 400 - 500 parts of Salvia miltiorrhiza, and 400 - 500 parts of Acanthopanax giraldii Harms, mix them and soak in water for later use;

[0011] [[ID=]12]2) Decoct twice, combine the decoctions, filter and concentrate to obtain the extract.

[0012] Further, in step 1), 450 parts of Rehmannia glutinosa, 450 parts of Cornus officinalis, 540 parts of Dioscorea opposita, 540 parts of Cuscuta chinensis, 540 parts of Lycium barbarum, 450 parts of Cistanche deserticola, 675 parts of Os Draconis, 450 parts of Achyranthes bidentata, 540 parts of Schisandra chinensis, 450 parts of Salvia miltiorrhiza, and 450 parts of Acanthopanax giraldii Harms are taken, mixed and soaked in water for later use.

[0013] Further, the concentration is first carried out under reduced pressure to a relative density of 1.02 - 1.05, and then further concentrated under reduced pressure to a relative density of 1.20 - 1.25.

[0014] Further, the color difference ΔE between the high-fidelity placebo and the crude drug granules is < 1.5, and the crude drug granules are Baoqing granules.

[0015] Further, the high-fidelity placebo is one of ointment, oral liquid, granule, capsule, pill, tablet, and powder.

[0016] Secondly, the present application also provides a preparation method of a high-fidelity placebo, which comprises the following steps:

[0017] S1: Weigh maltodextrin, caramel color, citrus yellow, citric acid, and malic acid in proportion, mix them evenly to obtain a mixture for later use;

[0018] S2: Add the crude drug extract to the mixture, granulate by wet method, dry and sterilize to obtain the product prepared by the above preparation method.

[0019] Further, in the step S2, the drying temperature is 80 - 120 °C.

[0020] Further, in the step S2, the sterilization is performed by Co-60 irradiation sterilization.

[0021] More preferably, in the step S2, the drying temperature is 100 °C and the drying time is 45 min.

[0022] More preferably, in the step S2, the irradiation dose is 18 kGy and the irradiation time is 18 h.

[0023] Again, the present application also provides an application of a high-fidelity placebo in the combined traditional Chinese and Western medicine treatment of menopausal syndrome, which is used for the combined traditional Chinese and Western medicine treatment of menopausal syndrome and replaces the traditional Chinese medicine granule in the same-dose substitution treatment group.

[0024] Compared with the prior art, the present application has the following beneficial effects:

[0025] 1. The present application proposes a combined medication plan of traditional Chinese medicine Baoqing granule and low-dose Femoston, which improves the curative effect through the dual mechanisms of regulating sex hormones (FSH, LH, E2) and improving the traditional Chinese medicine syndrome score. Combining the modified Kupperman score, PSQI scale and hormone detection, a multi-dimensional curative effect evaluation standard is established. The total effective rate of the combined traditional Chinese and Western medicine treatment in the present application is 100%, and the symptom control rate during the follow-up period is increased by 42% compared with the single use of hormones. During the treatment period, the liver and kidney functions and blood routine indexes are normal, and the incidence of adverse events is 0%.

[0026] 2. The high-fidelity placebo of the present application determines the excipient ratio through orthogonal experiments, realizes low-cost and high-precision simulation, and ensures the effectiveness of the blind method in clinical trials. In addition, the preparation cost of the high-fidelity placebo is reduced by 30%, and the production cycle is shortened to 8 hours / batch. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 It is a schematic diagram of the single-factor investigation result of the caramel color content in the preparation process of the high-fidelity placebo of the present application;

[0028] Figure 2 It is a schematic diagram of the single-factor investigation result of the orange peel yellow content in the preparation process of the high-fidelity placebo of the present application;

[0029] Figure 3 It is a schematic diagram of the single-factor investigation result of the citric acid content in the preparation process of the high-fidelity placebo of the present application;

[0030] Figure 4 It is a schematic diagram of the single-factor investigation result of the malic acid content in the preparation process of the high-fidelity placebo of the present application;

[0031] Figure 5 Schematic diagram of the appearance color difference comparison between the high-fidelity placebo and Baoqing Granules in this application;

[0032] Figure 6 Schematic diagram of the age baseline data of the control group and the experimental group in this application;

[0033] Figure 7 Schematic diagram of the height baseline data of the control group and the experimental group in this application;

[0034] Figure 8 Schematic diagram of the weight baseline data of the control group and the experimental group in this application;

[0035] Figure 9 Schematic diagram of the BMI baseline data of the control group and the experimental group in this application;

[0036] Figure 10 Schematic diagram of the comparison data of the modified Kupperman scores before and after treatment of the control group and the experimental group in this application;

[0037] Figure 11 Schematic diagram of the comparison data of the traditional Chinese medicine syndrome scores before and after treatment of the control group and the experimental group in this application;

[0038] Figure 12 Schematic diagram of the comparison data of the SAS scores before and after treatment of the control group and the experimental group in this application;

[0039] Figure 13 Schematic diagram of the comparison data of the SDS scores before and after treatment of the control group and the experimental group in this application;

[0040] Figure 14 Schematic diagram of the comparison data of the PSQI scores before and after treatment of the control group and the experimental group in this application;

[0041] Figure 15 Schematic diagram of the comparison data of the FSH scores before and after treatment of the control group and the experimental group in this application;

[0042] Figure 16 Schematic diagram of the comparison data of the LH scores before and after treatment of the control group and the experimental group in this application. Detailed implementation manners

[0043] Next, the technical solutions in the embodiments of the present application will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present application without creative efforts shall fall within the protection scope of the present application.

[0044] Preparation examples

[0045] 1. Orthogonal design was adopted, and colorants (A), acidulants (B), and odorants (C) were selected as reference factors. Through the artificial comprehensive evaluation of the appearance, color, and odor of the preparation as the index, the L9(33) orthogonal test table was used to investigate the above three factors to determine the best combination plan of the types of preparation excipients. Artificial evaluation criteria: In this project, 10 judges were selected, including clinicians, clinical research nurses, quality control personnel, etc. The test drug samples were distributed to each judge, and the judges were asked to evaluate the test drug samples and the control product Baoqing Granule solution from aspects such as appearance, color, and taste. The linket5 scoring method was adopted, that is, if the appearance color (or sour taste) was exactly the same, it was 5 points, relatively similar was 4 points, uncertain was 3 points, quite different was 2 points, and completely different was 1 point. The higher the score, the better the simulation degree of the test drug and the control product in terms of appearance, color, taste, etc. (see Table 1 - 3).

[0046] Table 1 Orthogonal factor levels for excipient selection

[0047]

[0048] Table 2 Results and analysis of orthogonal experiment for excipient selection

[0049]

[0050] Table 3 Variance analysis

[0051]

[0052] Note: R 2 = 0.943 (adjusted R 2 = 0.848), ** indicates P < 0.01, which is statistically significant.

[0053] As can be seen from Table 2 - Table 3, the three factors A, B, and C all have significant effects on the similarity between the placebo and Baoqing Granule, and the order of the influencing factors is A = B > C. The best combination should be A1B1C1. Based on the above results, the best excipient components were determined to be A1B1C1, that is, caramel color and citrus yellow were selected as the colorants, citric acid (sodium citrate) was selected as the acidulant, and 5% crude drug extract was selected as the odorant.

[0054] 2. Selection and evaluation of excipient content

[0055] On the basis of determining the excipient components, orthogonal experiments were further carried out to optimize and screen the excipient content.

[0056] (1) Single - factor investigation of excipient content selection

[0057] Based on the results of excipient selection, further research was conducted on the content of excipients. First, single-factor investigations were carried out on the contents of caramel color, citrus yellow, citric acid (sodium citrate), and malic acid.

[0058] ① Single-factor investigation on the content of caramel color

[0059] Using the extraction process of the medicinal materials in the Baoqing Granule formula, an extract of the same batch of medicinal materials was prepared. Calculated according to the original drug specification of 10 g / bag, 0.7% citrus yellow, 0.7% citric acid (sodium citrate), 0.7% malic acid, and 5% odorant (medicinal material extract) were taken, and caramel color was added at 0.5%, 0.7%, 1%, 1.5%, 2%, and 3% respectively. Finally, dextrin was added, and after mixing, wet granulation was carried out to make 10 g granules, and artificial appearance color evaluations were carried out respectively.

[0060] ② Single-factor investigation on the content of citrus yellow

[0061] Using the extraction process of the medicinal materials in the Baoqing Granule formula, an extract of the same batch of medicinal materials was prepared. Calculated according to the original drug specification of 10 g / bag, 0.7% citrus yellow, 0.7% citric acid (sodium citrate), 0.7% malic acid, and 5% odorant (medicinal material extract) were taken, and citrus yellow was added at 0.5%, 0.7%, 1%, 1.5%, 2%, and 3% respectively. Finally, dextrin was added, and after mixing, wet granulation was carried out to make 10 g granules, and artificial appearance color evaluations were carried out respectively.

[0062] ③ Single-factor investigation on the content of citric acid (sodium citrate)

[0063] Using the extraction process of the medicinal materials in the Baoqing Granule formula, an extract of the same batch of medicinal materials was prepared. Calculated according to the original drug specification of 10 g / bag, 0.7% citrus yellow, 0.7% citric acid (sodium citrate), 0.7% malic acid, and 5% odorant (medicinal material extract) were taken, and citric acid (sodium citrate) was added at 0.5%, 0.7%, 1%, 1.5%, 2%, and 3% respectively. Finally, dextrin was added, and after mixing, wet granulation was carried out to make 10 g granules, and artificial appearance color evaluations were carried out respectively.

[0064] ④ Single-factor investigation on the content of malic acid

[0065] Using the extraction process of the medicinal materials in the Baoqing Granule formula, an extract of the same batch of medicinal materials was prepared. Calculated according to the original drug specification of 10 g / bag, 0.7% citrus yellow, 0.7% citric acid (sodium citrate), 0.7% malic acid, and 5% odorant (medicinal material extract) were taken, and malic acid was added at 0.5%, 0.7%, 1%, 1.5%, 2%, and 3% respectively. Finally, dextrin was added, and after mixing, wet granulation was carried out to make 10 g granules, and artificial appearance color evaluations were carried out respectively.

[0066] (2) Results of single-factor investigations

[0067] ① Results of single-factor investigation on the content of caramel color

[0068] By examining the placebo solutions of each test group with different contents of caramel color, it was found that the appearance color score increased as the content of caramel color increased, that is, the similarity was close to that of the reference product Baoqing granule solution. When the content increased to 1.5%, the appearance color score of the placebo solution decreased significantly. Therefore, three levels of 0.7%, 1.0%, and 1.5% were selected for the content of caramel color to carry out the subsequent orthogonal experiment, and the results are as Figure 1 shown.

[0069] ② Results of single-factor investigation on the content of citrus yellow

[0070] By examining the placebo solutions of each test group with different contents of citrus yellow, it was found that as the content of citrus yellow increased, the appearance color score of the placebo solution decreased significantly, that is, the similarity had a significant difference from that of the reference product Baoqing granule solution. Therefore, three levels of 0.5%, 0.7%, and 1.0% were selected for the content of citrus yellow to carry out the subsequent orthogonal experiment, and the results are as Figure 2 shown.

[0071] ③ Single-factor investigation on the content of citric acid (sodium citrate)

[0072] By examining the placebo solutions of each test group with different contents of citric acid (sodium citrate), it was found that the appearance color score increased as the content of caramel color increased, that is, the similarity was close to that of the reference product Baoqing granule solution. When the content increased to 1.0%, the acidity score of the placebo solution decreased significantly. Therefore, three levels of 0.5%, 0.7%, and 1.0% were selected for the content of citric acid (sodium citrate) to carry out the subsequent orthogonal experiment, and the results are as Figure 3 shown.

[0073] ④ Results of single-factor investigation on the content of malic acid

[0074] By examining the placebo solutions of each test group with different contents of malic acid, it was found that as the content of malic acid increased, the appearance color score of the placebo solution decreased significantly, that is, the similarity had a significant difference from that of the reference product Baoqing granule solution. Therefore, three levels of 0.5%, 0.7%, and 1.0% were selected for the content of malic acid to carry out the subsequent orthogonal experiment, and the results are as Figure 4 shown.

[0075] 3. Orthogonal experiment investigation on the content of excipients

[0076] Caramel color (A), citrus yellow (B), citric acid (sodium citrate) (C), and malic acid (D) were selected as reference factors, and three levels were selected for each factor. With the artificial comprehensive evaluation as the index, the L9(34) orthogonal test table was used to investigate the above four factors, and each group was repeated with 3 parallel experiments to determine the optimal extraction process conditions for the addition amount of the preparation excipients.

[0077] Table 4 Orthogonal factor levels for excipient selection

[0078]

[0079] Table 5 Orthogonal Test and Analysis of Excipient Content Selection

[0080]

[0081] Table 6 Variance Analysis

[0082]

[0083]

[0084] Note: R 2 = 0.997 (adjusted R 2 = 0.996), ** indicates P < 0.01, which is statistically significant.

[0085] As can be seen from Table 5 - Table 6, the four factors A, B, C, and D all have significant effects on the similarity between the placebo granule solution and the Baoqing granule solution. The order of the influencing factors is A > B > C = D, and the best combination should be A2B1C2D1. Based on the above results, the optimal content of the excipient is determined to be A2B1C2D1, that is, 1.0% caramel color and 0.5% citrus yellow are selected as colorants for the placebo granule solution, 0.7% citric acid (sodium citrate) and 0.5% malic acid are selected as sour agents, and 5.0% extract is selected as the odor agent. The comparison of the appearance of the highly simulated placebo prepared and the appearance of the Baoqing granule is as Figure 5 shown, and the color difference ΔE < 1.5, with a very high degree of simulation.

[0086] The highly simulated placebo used in the clinical trial of this application includes the following components by mass fraction: 1% caramel color, 0.5% citrus yellow, 0.7% citric acid, 0.4% malic acid, 5% crude drug extract, and the balance is maltodextrin.

[0087] The preparation method of the highly simulated placebo used in the clinical trial of this application includes the following steps:

[0088] S1: Weigh maltodextrin, caramel color, citrus yellow, citric acid, and malic acid in proportion and mix them evenly to obtain a mixed material for later use;

[0089] S2: Add 5% crude drug extract to the mixed material, granulate it by wet method, and then dry it by hot air at 100°C for 45 minutes; Sterilize it by Co - 60 irradiation, with an irradiation dose of 18 kGy and an irradiation time of 18 hours to obtain the product.

[0090] The crude drug extract used in this application is prepared by the following steps:

[0091] 1) Mix 450g of Rehmannia root, 450g of Cornus officinalis, 540g of Dioscorea batatas, 540g of Cuscuta seed, 540g of Lycium barbarum, 450g of Cistanche deserticola, 675g of Os Dracaenae, 450g of Cyathula root, 540g of Schisandra chinensis, 450g of Salvia miltiorrhiza, and 450g of Acanthopanax rubra bark, add 7 times the amount of water, and soak for 0.5h before use;

[0092] 2) Decoction twice, each time for 1 hour, combine the decoctions, filter, and first concentrate the filtrate under reduced pressure to a relative density of 1.02-1.05 (80°C), then let it stand for 12 hours and filter, and then concentrate under reduced pressure to a relative density of 1.20-1.25 (80°C) to obtain a clear paste.

[0093] Clinical trials:

[0094] 1. General Information

[0095] First, patients with menopausal syndrome (Kidney Yin Deficiency) who visited the Affiliated Hospital of Traditional Chinese Medicine, Southwest Medical University, between August 2023 and January 2025 were screened. Sixty-two patients with Kidney Yin Deficiency-type menopausal syndrome who met the criteria were enrolled in this exploratory study. A central randomization system was used to randomly assign them to a treatment group (31 patients) and a control group (31 patients). One patient dropped out of the treatment group due to failure to attend follow-up appointments; one patient dropped out of the control group due to lack of significant symptom improvement. The remaining 60 patients completed the entire treatment and observation period. Finally, a comparative analysis was performed on the 60 patients with complete data.

[0096] 2. Diagnostic criteria

[0097] 2.1 Western medicine diagnostic criteria:

[0098] Diagnostic criteria: Follicle-stimulating hormone (FSH) > 10 U / L and at least two of the following symptoms:

[0099] ① Menstrual disorders: abnormal menstrual period, cycle, and menstrual volume; ② Vasomotor symptoms: mainly manifested as hot flashes and sweating; ③ Autonomic nervous system disorders: mainly include palpitations, dizziness, headache, insomnia, tinnitus, etc.; ④ Neuropsychiatric symptoms: manifested as irritability, anxiety or depression, memory loss, etc.

[0100] 2.2 Traditional Chinese Medicine Diagnostic Criteria:

[0101] TCM diagnostic standards formulate diagnostic and dialectical standards:

[0102] Main symptoms (at least one of which must be met): ① Menstrual irregularities; ② Hot flashes, sweating, occasional chills, or mood changes during menopause;

[0103] Secondary symptoms (at least two of which apply): ① low back and knee pain; ② fatigue; ③ dizziness and tinnitus; ④ irritability; ⑤ insomnia and dreaminess; ⑥ vaginal dryness;

[0104] Tongue vessels: Red tongue with little coating or red tip of the tongue, thin coating or thin yellow coating, thready or thready and rapid pulse.

[0105] Combined with the above, at least 1 major symptom, more than 2 minor symptoms, and combined with tongue vessels can diagnose patients with kidney yin deficiency MPS.

[0106] 3. Inclusion and exclusion criteria

[0107] 3.1 Inclusion criteria

[0108] (1) Meeting the western medicine diagnostic criteria for MPS;

[0109] (2) TCM syndrome differentiation conforming to kidney yin deficiency syndrome;

[0110] (3) Aged between 40 and 55 years old;

[0111] (4) Those with a modified Kupperman score > 15 points;

[0112] (5) Follicle-stimulating hormone (FSH) > 10 U / L, and B-ultrasound showing endometrial thickness < 5 mm (single layer);

[0113] (6) Those without contraindications to Femoston treatment;

[0114] (7) The research subjects voluntarily sign the informed consent form.

[0115] 3.2 Exclusion criteria

[0116] (1) Having a history of allergy to the drugs in this trial;

[0117] (2) Those who participated in other clinical studies and took drugs within the past three months;

[0118] (3) Having taken sex hormone drugs within the past three months;

[0119] (4) Those with severe diseases of important organs such as cardiovascular and cerebrovascular, liver and kidney;

[0120] (5) Patients with bilateral ovariectomy, ovarian tumors and premature ovarian failure;

[0121] (6) Those with malignant tumors or related medical histories, such as breast cancer, endometrial cancer, meningioma patients;

[0122] (7) Those with hepatic and renal insufficiency, abnormal uterine bleeding, and endometrial hyperplasia;

[0123] (8) According to the judgment of the researcher, other factors that are not suitable for participating in this clinical study.

[0124] 3.3 Exclusion criteria

[0125] (1) Those who were mis-included because they did not meet the inclusion criteria;

[0126] (2) Those with poor compliance affecting the judgment of drug efficacy;

[0127] (3) Incomplete data affecting the judgment of efficacy and safety, etc.

[0128] 3.4 Withdrawal criteria

[0129] (1) Withdrawal by the researcher:

[0130] ① Those who are not suitable to continue due to the occurrence of serious adverse events (SAEs);

[0131] ② The researcher deems it necessary to stop the study from the perspective of medical ethics;

[0132] ③ The researcher determines that withdrawing from the study is most beneficial to the research subjects; [[ID=2,1]]

[0133] ④ The research subjects have poor compliance, including but not limited to: the research subjects cannot take medications and undergo examinations as per the protocol, use other medications that affect the evaluation of test results, and other behaviors that affect the test results.

[0134] (2) Withdrawal by the research subjects:

[0135] Such as when adverse reactions occur, the symptoms do not improve significantly, or the subjects withdraw from the trial without any reason.

[0136] 3.5 Handling of case dropouts

[0137] When a dropout occurs, the reason for withdrawal is recorded according to one of the following reasons: adverse event, loss to follow-up, protocol violation, death, or others. At the same time, try to contact the research subjects as much as possible, complete the assessable items, and fill in the case report form.

[0138] 3.6 Handling of adverse events

[0139] Timely record the time of occurrence of adverse events, clinical manifestations, severity, treatment measures, outcomes, etc., evaluate the correlation between adverse reactions and the study drug, sign and indicate the date. In case of serious adverse events, immediately stop the study drug and take necessary measures to rescue the research subjects.

[0140] 4. Research methods

[0141] 4.1 Grouping method and blinding

[0142] 4.1.1 Randomized grouping

[0143] Sixty-two patients with MPS (kidney yin deficiency syndrome) who met the inclusion and exclusion criteria were selected for an exploratory study. After the patients who met the inclusion criteria agreed to be included in the study, random sequence generation and allocation were performed through the central randomization system, with 31 cases in the experimental group and 31 cases in the control group respectively.

[0144] 4.1.2 Blinding

[0145] This clinical study was designed as a double - blind study, blinding both the researchers and the research subjects.

[0146] ① Development of high - fidelity placebo: The high - fidelity placebo was made to be as consistent as possible with Baoqing Granules in terms of dosage form, appearance, size, color, weight, smell, and taste.

[0147] ② Drug packaging: The packaging of Baoqing Granules and the high - fidelity placebo was exactly the same.

[0148] ③ Blinding record: Documentation of the drug coding process.

[0149] ④ Preservation of the blinding code: The random table file formed by the random sequence together with parameters such as the random seed number and block length for generating random numbers was sealed and stored in duplicate by the principal investigator.

[0150] ⑤ Emergency unblinding: When a serious adverse event occurs to a research subject or emergency treatment is required and it is necessary to know the test drug received by the subject, the principal investigator unblinds emergently to obtain the specific grouping information of the research subject.

[0151] 4.2 Treatment methods

[0152] 4.2.1 General treatment

[0153] (1) Guide the patients to keep a happy mood and get sufficient sleep;

[0154] (2) Combine work and rest, have a light diet, and eat more vegetables and fruits;

[0155] (3) Do exercise and supplement calcium in a timely manner.

[0156] 4.2.2 Drug treatment

[0157] 4.2.2.1 Name, specification, batch number and source of the test drug

[0158] Baoqing Granules, specification: 10 g / bag, Sichuan Drug Administration Approval No. XZ20000050, drug composition: Rehmannia glutinosa, Cornus officinalis, Dioscorea opposita, Cuscuta chinensis, Lycium barbarum, Cistanche deserticola, Dragon bone, Schisandra chinensis, etc., produced by the Pharmacy Department of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, sealed and stored. Placebo, specification: 10 g / bag, produced by the Preparation Room of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, sealed and stored.

[0159] The basic drug is the combined preparation of estradiol tablets / estradiol - drospirenone tablets (Femoston tablets), approval number:

[0160] H20150346, Composition and specifications: Estradiol tablets, 1 mg / tablet; Estradiol and Dydrogesterone tablets (estradiol 1 mg and dydrogesterone 10 mg / tablet), manufactured by Abbott Biologicals B.V., to be stored in the original package below 30°C.

[0161] 4.2.2.2 Drug Allocation and Dispensing

[0162] The drug administrator distributes drugs according to the patient's drug numbers and fills in the "Record of Use and Recovery of Investigational Drugs" in a timely manner. The investigational drugs are dispensed at the start of medication and the remaining drugs (or empty boxes) are recovered during the follow-up visit. Record the use of drugs, remaining drugs, etc.

[0163] 4.2.2.3 Medication Method

[0164] Patients will receive the corresponding treatment drugs according to the random numbers on the first day (D1) of enrollment.

[0165] Experimental group: Basic medication (Femoston) + Baoqing Granules.

[0166] Oral estradiol tablets / estradiol and dydrogesterone tablets combination preparation (Femoston tablets). For those with normal menstrual cycles, start taking orally on the first day of the menstrual period; for postmenopausal women, start taking orally after enrollment. Take 1 tablet once a day. First take estradiol tablets for 14 days, then take estradiol and dydrogesterone tablets for 14 days, for a total of 28 days, lasting for 4 weeks; Baoqing Granules, 10 g each time, tid, po, lasting for 4 weeks.

[0167] Control group: Basic medication (Femoston) + high-fidelity placebo (the administration method of Femoston is as described above; high-fidelity placebo, 10 g each time, tid, po; continuous medication for 4 weeks).

[0168] It should be noted that although the high-fidelity placebo in this application contains a very small amount of the original drug extract, the role of this original drug extract is to make the placebo simulate the appearance and smell of Baoqing Granules, making it highly simulated so that doctors and patients cannot distinguish it. Its pharmacological effect can be ignored, and it does not have clinical efficacy and will not have any impact on the experimental results of the double-blind experiment.

[0169] 4.3 Observation Indicators

[0170] 4.3.1 General Information

[0171] Demographic information (marital status, age, height, weight, occupation, etc.) and general clinical information (menstrual history, pregnancy and childbirth history, concurrent diseases and medications, etc.), as shown in Table 7.

[0172] Table 7 Basic Information of Subjects (Demographic Information)

[0173]

[0174] 4.3.2 Safety indicators and detection time nodes

[0175] (1)Vital signs: body temperature, pulse, respiration, blood pressure;

[0176] (2)Laboratory indicators: blood routine, liver function (alanine aminotransferase, aspartate aminotransferase), kidney function (creatinine, urea nitrogen);

[0177] (3)Imaging examination indicators: electrocardiogram, transvaginal color Doppler ultrasound of gynecology;

[0178] (4)Safety evaluation indicators: a. Incidence of adverse events; b. Percentage of patients withdrawn from the trial due to adverse events and percentage of patients withdrawn from the clinical study due to a single adverse event.

[0179] Pay full attention to whether there are allergic reactions and adverse events in patients. Observe the vital signs of patients before and after treatment and during follow-up, detect routine safety indicators (blood routine, liver and kidney functions, electrocardiogram), and record adverse events throughout the trial.

[0180] Grade 1: Safe, no adverse reactions occurred;

[0181] Grade 2: Relatively safe, mild adverse reactions occurred, no treatment is required, and the trial can continue;

[0182] Grade 3: There are safety problems, moderate adverse reactions occurred, and the trial can continue after treatment;

[0183] Grade 4: Severe adverse reactions occurred, and the trial was terminated.

[0184] 4.3.3 Efficacy indicators

[0185] 4.3.3.1 Primary efficacy indicators

[0186] (1)Modified Kupperman integral scale, see Table 8.

[0187] Table 8 Modified Kupperman score

[0188]

[0189]

[0190] (2)Total score scale of traditional Chinese medicine syndromes, see Table 9.

[0191] Table 9 Traditional Chinese medicine syndrome score

[0192]

[0193] 4.3.3.2 Secondary efficacy indicators

[0194] (1) Depression Rating Scale (SDS) integral scale, see Table 10.

[0195] Table 10 Depression Rating Scale (SDS)

[0196]

[0197]

[0198] (2) Anxiety Rating Scale (SAS) integral scale, see Table 11.

[0199] Table 11 Anxiety Rating Scale (SAS)

[0200]

[0201]

[0202] (3) Pittsburgh Sleep Quality Index (PSQI) integral scale, see Table 12.

[0203] Table 12 Pittsburgh Sleep Quality Index (PSQI)

[0204]

[0205]

[0206] (4) Changes in serum FSH, LH, and E2 before and after treatment.

[0207] Note: (1) The relevant data of the above scales were recorded in detail before treatment, after the end of treatment, and during the follow-up period.

[0208] (2) All laboratory tests were carried out in the laboratory of the Traditional Chinese Medicine Hospital Affiliated to Southwest Medical University. For patients with normal menstrual cycles, blood samples should be collected on an empty stomach on the 2nd to 5th day of the menstrual period; for patients in the state of amenorrhea, blood samples should be collected on an empty stomach on the day of consultation or the early morning of the next day.

[0209] 4.4 Efficacy Evaluation Criteria

[0210] Evaluation criteria: Efficacy index = (total score before treatment - total score after treatment) / total score before treatment * 100%.

[0211] 4.4.1 Efficacy determination criteria for traditional Chinese medicine syndrome scores:

[0212] (1) Recovery: Symptoms disappear, n≥95%;

[0213] (2) Marked effect: Symptoms are significantly reduced, 70%≤n<95%;

[0214] (3) Effective: Symptoms have improved, 30% ≤ n < 70%;

[0215] (4) Ineffective: Symptoms have not improved or have even worsened, n < 30%.

[0216] The total effective rate of each group = (cured + markedly effective + effective) / total number of cases × 100%

[0217] 4.4.2 The efficacy evaluation criteria of the modified Kupperman score are the same as those of the TCM syndrome efficacy evaluation criteria.

[0218] 4.4.3 SDS scoring criteria

[0219] Details of the SDS score are shown in Table 4. The specific calculation method is as follows: Add up the corresponding scores of the 20 items in the scale to obtain the total raw score (X), and the formula is (X) × 1.25 = standard score (Y). The cut-off value of the SDS standard score is set at 53 points. Based on this, the degree of depression is classified as follows: Mild depression is in the range of 53 - 62 points; Moderate depression is determined to be 63 - 72 points; If the standard score is above 72 points, it belongs to severe depression.

[0220] Table 7 SDS scoring form

[0221] 4.4.4 SAS scoring criteria.

[0222] Details of the SAS score are shown in Table 5. The scoring criteria are as follows: Add up the scores of each item in the 20 items to obtain the total score (X), and (X) x 1.25 = standard score (Y). According to the Chinese norm value, the standard cut-off value of SAS is set at 50 points. Mild anxiety is in the range of 50 - 59 points, moderate anxiety is 60 - 69 points, and severe anxiety is above 69 points.

[0223] 4.4.5 The scoring criteria of the Pittsburgh Sleep Quality Index (PSQI) integral scale are the same as those of the TCM syndrome integral efficacy determination criteria.

[0224] 4.5 Follow-up after treatment

[0225] One month after the treatment of the two groups of patients, the two groups of patients were followed up. Using the modified Kupperman score as the evaluation criterion, well-controlled: score < 15; Poorly controlled: score ≥ 15 and < 35; Ineffective, score ≥ 35. Relevant data were recorded in detail.

[0226] 4.6 Ethical review

[0227] This project has been approved by the Ethics Committee of the Traditional Chinese Medicine Hospital Affiliated to Southwest Medical University. The project serial number is 2022 - SYE - 37, and the ethical review application acceptance number is KY2023022 - FS01.

[0228] 4.7 Statistical methods

[0229] In this study, after analyzing and sorting out the collected data, the SPSS 27.0 statistical software was used to analyze and evaluate the data. According to different types of clinical data, the mean, standard deviation, median, interquartile range, etc. were selected for analysis. Chi-square test was used for count data; rank sum test was used for rank data; for measurement data, if it conformed to normal distribution and homogeneity of variance, independent sample t-test was used; otherwise, if it was non-normally distributed or had unequal variances, rank sum test was used. A two-sided α = 0.05 was used as the test level, and P < 0.05 indicated that the difference was statistically significant, while when P > 0.05, it indicated that the difference was not statistically significant.

[0230] 5. Treatment effect

[0231] 5.1 Comparison of baseline data between the two groups

[0232] After normality test, the variables of age, height, and weight conformed to normality, while the BMI variable did not. Therefore, two independent sample t-tests were used for age, height, and weight. The P-value for age was 0.871, the P-value for height was 0.444, and the P-value for weight was 0.868. There was no statistically significant difference in the comparison of ages between the two groups (P > 0.05); the rank sum test was used to analyze the BMI of the two groups, and the results showed that there was no statistically significant difference in BMI between the two groups (P > 0.05). The results are shown in Table 13 and Figures 6 - 9 as follows.

[0233] Table 13 Comparison of general data of two groups of patients

[0234]

[0235] 5.2 Comparison of clinical indicators between the two groups before treatment

[0236] 5.2.1 Comparison of Kupperman score and TCM syndrome score before treatment

[0237] Before treatment, the Kupperman score of the experimental group was 32.80 ± 6.31 points, and the TCM syndrome score was 37.57 ± 4.59 points; before treatment, the Kupperman score of the control group was 31.97 ± 6.40 points, and the TCM syndrome score was 36.57 ± 5.88 points. After comparison, there were no significant differences in the Kupperman score and TCM syndrome score between the two groups of patients (p > 0.05), and they were comparable, as shown in Table 14.

[0238] Table 14 Comparison of Kupperman score and TCM syndrome score before treatment

[0239]

[0240] 5.2.2 Comparison of SDS, SAS, and PSQI scores between the two groups before treatment

[0241] Before treatment, the SDS score of the experimental group was 52.26±6.86 points, the SAS score was 50.26±6.45 points, and the PSQI score was 24.07±5.99 points; before treatment, the SDS score of the control group was 51.72±6.76 points, the SAS score was 49.67±4.18 points, and the PSQI score was 22.73±7.10 points. After comparison, there was no significant difference in the SSDS score, SAS score, and PSQI score of the two groups of patients (p>0.05), and the two groups were comparable, as shown in Table 15.

[0242] Table 15 Comparison of SDS scores, SAS scores and PSQI scores between the two groups before treatment

[0243]

[0244] 5.2.3 Comparison of FSH, LH, and E2 levels between the two groups before treatment

[0245] Before treatment, the serum FSH, LH and E2 levels of the patients in the experimental group were 61.88±26.4mIU / ml, 38.07±15.51mIU / ml and 15.00(5.00,45.36)pg / ml; the serum FSH, LH and E2 levels of the patients in the control group were 68.18±39.00mIU / ml, 39.58±20.10mIU / ml and 8.46(5.00,23.85)pg / ml. The results showed that there was no statistically significant difference in the FSH, LH and E2 levels of the two groups before treatment (p>0.05), and they were comparable, as shown in Table 16.

[0246] Table 16 Comparison of FSH, LH and E2 levels in the two groups before treatment / M(Q)

[0247] Note: *The data do not obey the normal distribution and are described by median M (interquartile range Q), Q = P75-P25, and are independently

[0248]

[0249] The rank sum test of the samples showed that P>0.05, and the rest of the data obeyed the normal distribution and had homogeneous variance. The two independent sample t-tests showed that P>0.05.

[0250] 5.3 Comparison of modified Kupperman score

[0251] After the treatment, when comparing within each group, the Kupperman score of the experimental group decreased from 32.80±6.31 to 9.77±3.65, and the score of the control group decreased from 31.97±6.40 to 12.53±5.53. The Kupperman scores of both groups of patients decreased significantly after treatment compared with before treatment (p<0.01); through between-group comparison, the degree of decrease in the Kupperman score of the experimental group was more obvious than that of the control group (p<0.05). See Table 17 and Figure 10 。

[0252] Table 17 Comparison of Kupperman Scores between Two Groups of Patients

[0253]

[0254] Note: &: P<0.05 compared with the control group; #: P<0.01 compared with before treatment.

[0255] 5.4 Comparison of Traditional Chinese Medicine Syndrome Scores

[0256] The Traditional Chinese Medicine syndrome score of the experimental group decreased from 37.5±4.59 to 17.30±2.52, and the score of the control group decreased from 36.5±5.88 to 21.93±7.24. The Traditional Chinese Medicine syndrome scores of both groups of patients decreased significantly after treatment compared with before treatment (p<0.01); through between-group comparison, the degree of decrease in the Traditional Chinese Medicine syndrome score of the treatment group was more obvious than that of the control group (p<0.05). See Table 18 and Figure 11 。

[0257] Table 18 Comparison of Traditional Chinese Medicine Syndrome Scores between Two Groups of Patients

[0258]

[0259] Note: &: P<0.05 compared with the control group; #: P<0.01 compared with before treatment.

[0260] 5.5 Comparison of SAS Scores

[0261] The SAS score of the experimental group decreased from 50.26±6.45 to 37.98±4.91, and the score of the control group decreased from 49.67±4.18 to 40.26±5.98. The SAS scores of both groups of patients decreased significantly after treatment compared with before treatment (p<0.01); through between-group comparison, there was no obvious difference between the experimental group and the control group, and there was no statistical significance (P>0.05). See Table 19 and Figure 12 。

[0262] Table 19 Comparison of SAS Scores between Two Groups of Patients

[0263]

[0264]

[0265] Note: #: P < 0.01 compared with before treatment.

[0266] 5.6 Comparison of SDS scores

[0267] The SDS score of the experimental group decreased from 52.26 ± 6.86 to 43.32 ± 4.65, and the score of the control group decreased from 51.72 ± 6.76 to 43.66 ± 5.88. The SDS scores of both groups of patients decreased significantly after treatment compared with before treatment (p < 0.01); there was no significant difference between the experimental group and the control group, and there was no statistical significance (P > 0.05). See Table 20 and Figure 13 。

[0268] Table 20 Comparison of SDS scores between two groups of patients

[0269]

[0270] Note: #: P < 0.01 compared with before treatment.

[0271] 5.7 Comparison of PSQI scores

[0272] The PSQI score of the experimental group decreased from 24.07 ± 5.99 to 8.40 ± 4.84, and the score of the control group decreased from 22.73 ± 7.10 to 11.23 ± 4.44, indicating that the PSQI scores of both groups of patients decreased significantly after treatment compared with before treatment (p < 0.01); in the between-group comparison, the degree of decrease in the PSQI score of the experimental group was more significant than that of the control group (p < 0.05). See Table 21 and Figure 14 。

[0273] Table 21 Comparison of PSQI scores between two groups of patients

[0274]

[0275]

[0276] Note: &: P < 0.05 compared with the control group; #: P < 0.01 compared with before treatment.

[0277] 5.8 Comparison of FSH content levels

[0278] The FSH content in the experimental group decreased from 61.88±26.4 to 33.27±18.50, and the FSH content in the control group decreased from 68.18±39.00 to 35.89±32.20, indicating that the FSH content in both groups of patients decreased significantly after treatment compared with before (p<0.01); when comparing between groups, there was no significant difference in the serum FSH content between the two groups (P>0.05), indicating that both groups could improve the FSH level, but there was no significant difference in the curative effect. See Table 22 and Figure 15 。

[0279] Table 22 Comparison of FSH content levels in two groups of patients

[0280]

[0281] Note: #: P<0.01 compared with before treatment.

[0282] 5.9 Comparison of LH content levels

[0283] The LH content in the experimental group decreased from 38.07±15.51 to 25.88±15.40, and the FSH content in the control group decreased from 39.58±20.10 to 27.81±21.83, indicating that the LH content in both groups of patients decreased significantly after treatment compared with before (p<0.01); when comparing between groups, there was no significant difference in the serum LH content between the two groups (P>0.05), indicating that both groups could improve the LH level, but there was no significant difference in the curative effect. See Table 23 and Figure 16 。

[0284] Table 23 Comparison of LH content levels in two groups of patients

[0285]

[0286]

[0287] Note: #: P<0.01 compared with before treatment.

[0288] 5.10 Comparison of E2 content levels

[0289] The E2 content in the experimental group increased from 15.00(5.00,45.36) to 61.40(14.55,101.25), and the difference was statistically significant (P<0.05); the E2 content in the control group increased from 8.46(5.00,23.85) to 76.25(14.42,152.00), and the difference was significantly statistically significant (P<0.01); when comparing between groups, there was no significant difference in the serum E2 content between the two groups (P>0.05), indicating that both groups could improve the E2 level, but there was no significant difference in the curative effect. See Table 24.

[0290] Comparison of E2 levels between two groups of patients M(Q)

[0291]

[0292] Note: *The data do not follow a normal distribution and are described by the median M (interquartile range Q), Q = P 75 -P 25 , and were analyzed by independent-sample t-test and rank sum test.

[0293] 5.11 Comparison of clinical effective rates of traditional Chinese medicine syndromes

[0294] When comparing the effective rates of traditional Chinese medicine syndromes between the two groups of patients, the effective rate of the control group was 63.3%, and that of the experimental group was 100%. The effective rate of the experimental group was significantly higher than that of the control group, and the difference was statistically significant (P < 0.01), as shown in Table 25.

[0295] Table 25 Comparison of clinical effective rates of traditional Chinese medicine syndromes between two groups of patients

[0296]

[0297] Note: #: P < 0.01 compared with the control group.

[0298] 5.12 Comparison of clinical effective rates of the Kupperman scale

[0299] When comparing the effective rates of the Kupperman scale between the two groups of patients, the effective rate of the control group was 96.7%, and that of the experimental group was 100%. The effective rate of the experimental group was significantly higher than that of the control group, and the difference was statistically significant (P < 0.05), as shown in Table 26.

[0300] Table 26 Comparison of clinical effective rates of the Kupperman scale between two groups of patients

[0301]

[0302] Note: &: P < 0.05 compared with the control group.

[0303] 5.13 Follow-up results

[0304] One month after the end of treatment, the follow-up results of the two groups of patients were analyzed. In the experimental group, the control was good in 27 patients, poor in 3 patients, and ineffective in 0 patients; in the control group, the control was good in 17 patients, poor in 12 patients, and ineffective in 1 patient. The difference in the follow-up results between the two groups was statistically significant (P < 0.05), indicating that the maintenance efficacy of the experimental group after 1-month follow-up was better than that of the control group. See Table 27.

[0305] Table 27 Comparison of follow-up results between two groups

[0306]

[0307] 6. Safety evaluation

[0308] During the process of this study, the body temperature, heart rate, respiration and blood pressure of the two groups of patients were stable. Safety index tests (blood routine, liver and kidney function, electrocardiogram) were conducted before and after treatment. No obvious abnormalities were found in the test results of the two groups. No obvious side effects or adverse reactions occurred in the patients after the treatment and during the entire follow-up period, which fully indicates that both intervention measures of the two groups have good safety.

[0309] 7. Results and Analysis

[0310] 7.1 Production of High-Fidelity Placebo and Double-Blind Design

[0311] Most of the clinical evaluations of the efficacy of traditional Chinese patent medicines are summaries of the practical experience of clinicians. Clinical studies often lack strict designs, resulting in biases that are difficult to control, and the test results are not easily replicated. Therefore, standardized and high-quality clinical trials are needed to evaluate the efficacy of traditional Chinese patent medicines, and the design principles of randomization and blinding should be followed as much as possible. The placebo should not contain any active or toxic ingredients. At the same time, according to the "Good Clinical Practice for Pharmaceutical Clinical Trials", in double-blind clinical trials, the investigational product, the control product or the placebo should be identical in appearance, smell, packaging and other characteristics.

[0312] Therefore, when the applicant produced the high-fidelity placebo of Baoqing Granules, orthogonal design was adopted, and colorants, acidulants and odorants were selected as reference factors. Through the artificial comprehensive evaluation of the appearance, color and smell of the preparation as indicators, it was ensured that the high-fidelity placebo was highly similar to Baoqing Granules in terms of appearance, color, taste, etc., but had no pharmacodynamic effect. The successful production of the high-fidelity placebo is crucial for the randomized double-blind trial carried out, reducing bias and forming high-quality clinical research evidence to judge the clinical efficacy of Baoqing Granules. In this trial, the applicant adopted a double-blind design and blinded the researchers and research subjects. The purpose was to reduce bias, truly reflect the efficacy of the intervention measures, and increase the credibility of the research results.

[0313] 7.2 Comprehensive Efficacy Analysis

[0314] The research results suggest that the combined treatment plan of Baoqing Granules + Femoston has good clinical application value. The high effective rate of up to 100% in the experimental group indicates that it can more effectively improve the clinical symptoms of patients with kidney yin deficiency type menopausal syndrome and greatly improve the quality of life of patients. Especially in improving traditional Chinese medicine syndromes and insomnia, it has significant effects, can effectively relieve the discomfort caused by MPS in patients, improve sleep quality, and thus comprehensively improve the overall living state of patients. Although the experimental group and the control group have similar effects in regulating serum FSH, LH, E2 levels and improving anxiety and depression symptoms, the advantages in improving other key symptoms may help reduce the long-term adverse effects of the disease on the daily life of patients and reduce the potential recurrence risk caused by repeated symptoms.

[0315] 7.3 Primary Efficacy Analysis

[0316] After treatment, the total scores of traditional Chinese medicine (TCM) syndromes and Kupperman scores in both groups of patients were lower than those before treatment. The differences within the groups were statistically significant (P < 0.01), and the differences between the groups were statistically significant (P < 0.05), indicating that both the experimental group and the control group could improve the clinical symptoms of menopausal syndrome with kidney yin deficiency, and the efficacy of the experimental group was better than that of the control group. Especially in improving TCM syndromes and insomnia, the effect of the experimental group was significantly better than that of the control group. Analyzed from the level of drug action mechanism, Baoqing Granule may regulate the body functions through multiple targets. When Baoqing Granule is used in combination with Femoston, they may play a synergistic role in regulating qi and blood and zang-fu organ functions related to TCM syndromes, thus making the experimental group significantly superior to the control group in terms of the efficacy and marked improvement rate of TCM syndromes. In improving Kupperman clinical symptoms, the combined medication may have unique advantages in the regulation of the neuro-endocrine-immune network, effectively enhancing the improvement effect on the clinical symptoms of menopausal syndrome. The above relevant speculations need to be verified in the subsequent omics analysis of patients' blood.

[0317] 7.4 Analysis of the Effects on SDS, SAS, and PSQI Scores

[0318] After treatment, the SDS scores, SAS scores, and PSQI scores of both groups of patients were significantly lower than those before treatment. Intra-group comparison of the data of each group of patients before and after treatment showed that the differences were statistically significant (P < 0.01), which fully indicated that after treatment, the depressive and anxious states and sleep quality of both groups of patients were effectively improved. In the inter-group comparison, the differences in SDS scores and SAS scores between the two groups of patients were not significant, without statistical significance (P > 0.05), which meant that the two treatment regimens had comparable effects in relieving the depressive and anxious symptoms of patients. However, in the inter-group comparison of PSQI scores, the difference was statistically significant (P < 0.05), indicating that there were obvious differences in the effects of the two treatment regimens on improving patients' sleep quality. The pathogenesis of menopausal women is complex, often accompanied by symptoms such as insomnia and restlessness, with kidney deficiency as the root cause, accompanied by liver depression, spleen deficiency, and loss of nourishment of the heart spirit. In the formula of Baoqing Granule, Schisandra chinensis is added on the basis of tonifying the kidney to nourish yin and suppress yang, and calm the mind; Ostreae Concha is used to suppress liver yang and calm the mind and relieve fright. It achieves the effect of tonifying the kidney and calming the mind. From the efficacy analysis, the group of Baoqing Granule combined with Femoston was significantly better than the group of Femoston alone in improving insomnia symptoms.

[0319] 7.5 Analysis of the Effects on Sex Hormone Levels

[0320] After treatment, the serum FSH and LH levels of both groups of patients decreased significantly compared with those before treatment, and the E2 level increased compared with before (P<0.01). When comparing between the two groups after treatment, the difference was not significant, and there was no statistical significance (P>0.05), indicating that both groups could effectively improve the serum sex hormone (FSH, LH, E2) levels of patients, and the curative effect levels were comparable. It is speculated from the results that both groups have the effect of regulating the endocrine system of the HPOA axis and play a beneficial regulatory role in the secretion and release of sex hormones.

[0321] The results of this application reveal the complexity of the pathogenesis of menopausal syndrome, which involves functional changes in multiple systems. This not only clarifies the direction for further exploring the pathogenesis, indicating that in addition to hormone regulation, the regulation of zang-fu qi and blood related to traditional Chinese medicine syndromes cannot be ignored; at the same time, it also provides ideas for exploring new treatment targets. Subsequent research can focus on the key links of the combined effect of Baoqing Granules and Femoston to conduct in-depth research and strive to develop more effective treatment methods.

[0322] Although the present application has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements for some of the technical features. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present invention.

Claims

1. A high-fidelity placebo, characterized in that: It comprises components in the following mass fractions: caramel color 0.8 - 1.2%, citrus yellow 0.3 - 0.7%, citric acid 0.5 - 0.9%, malic acid 0.3 - 0.4%, crude drug extract 2.5 - 6.5%, and the balance is maltodextrin.

2. The high-fidelity placebo according to claim 1, characterized in that: The crude drug extract is prepared by the following steps: 1) Take 400 - 500 parts of Rehmanniae Radix Praeparata, 400 - 500 parts of Corni Fructus, 500 - 600 parts of Dioscoreae Rhizoma, 500 - 600 parts of Cuscuta Chinensis Lam., 500 - 600 parts of Lycii Fructus, 400 - 500 parts of Cistanches Herba, 600 - 700 parts of Os Draconis, 400 - 500 parts of Cyathulae Radix, 500 - 600 parts of Schisandrae Chinensis Fructus, 400 - 500 parts of Salviae Miltiorrhizae Radix, and 400 - 500 parts of Acanthopanacis Giraldii Harms Cortex. Mix them and soak in water for later use. 2) Decoct twice, combine the decoctions, filter, and concentrate to obtain.

3. The high-fidelity placebo according to claim 2, wherein: In step 1), take 450 parts of Rehmanniae Radix Praeparata, 450 parts of Corni Fructus, 540 parts of Dioscoreae Rhizoma, 540 parts of Cuscuta Chinensis Lam., 540 parts of Lycii Fructus, 450 parts of Cistanches Herba, 675 parts of Os Draconis, 450 parts of Cyathulae Radix, 540 parts of Schisandrae Chinensis Fructus, 450 parts of Salviae Miltiorrhizae Radix, and 450 parts of Acanthopanacis Giraldii Harms Cortex. Mix them and soak in water for later use.

4. The highly simulated placebo according to claim 2, characterized in that: The concentration is first carried out under reduced pressure to a relative density of 1.02 - 1.05, and then further concentrated under reduced pressure to a relative density of 1.20 - 1.

25.

5. The highly realistic placebo according to claim 1, wherein: The color difference ΔE between the high - fidelity placebo and the crude drug granules is < 1.5, and the crude drug granules are Baoqing granules.

6. The high-fidelity placebo according to claim 1, characterized in that: The high - fidelity placebo is one of ointment, oral liquid, granule, capsule, pill, tablet, and powder.

7. A method for preparing a highly simulated placebo as described in claim 1, characterized in that: It comprises the following steps: S1: Weigh maltodextrin, caramel color, citrus yellow, citric acid, and malic acid in proportion and mix them evenly to obtain a mixture for later use. S2: Add the crude drug extract to the mixture, granulate by wet method, dry, and sterilize to obtain.

8. The method for preparing a highly realistic placebo according to claim 7, wherein: In step S2, the drying temperature is 80 - 120 °C.

9. The preparation method of the highly simulated placebo according to claim 7, characterized in that: In step S2, the sterilization is carried out by Co - 60 irradiation sterilization.

10. Use of a highly simulated placebo as described in claim 1 in the combined traditional Chinese and Western medicine treatment of menopausal syndrome, characterized in that: It is used for the combined traditional Chinese and Western medicine treatment of climacteric syndrome, and is used to replace the traditional Chinese medicine granule in the same - dose replacement treatment group.

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