A combination drug for relieving menopausal syndrome and a preparation method thereof

Abstract

The application discloses a combined medicine for relieving menopausal syndrome and a preparation method thereof, and belongs to the technical field of medicines.The combined medicine comprises the following components in mass fractions: dehydroepiandrosterone 5-50 mg, vitamin D3 0.01-0.25 mg, L-methyl folic acid 1-15 mg and magnesium glycinate 10-400 mg; and the preparation method comprises the following steps: uniformly mixing dehydroepiandrosterone, vitamin D3, L-methyl folic acid, magnesium glycinate, microcrystalline cellulose, stearic acid and silicon dioxide according to mass fractions to obtain the combined medicine for relieving menopausal syndrome.In the application, the four-component synergistically functions, realizes multi-target point synchronous conditioning of hormone balance, bone maintenance, nerve soothing and sleep aiding, cardiovascular protection and metabolism regulation, and breaks through the limitation that the existing single-product can only improve a single menopausal symptom.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a combination drug for relieving menopausal syndrome and its preparation method. Background Technology

[0002] Menopause is characterized by ovarian failure and a sharp decline in estrogen levels, leading to both acute and chronic health problems. Menopause brings complex endocrine and metabolic changes, including decreased estrogen, altered neurotransmitter balance, and an increased risk of osteoporosis, cardiovascular disease, mood disorders, and cognitive decline.

[0003] Common symptoms include: vasomotor symptoms: hot flashes, night sweats; reproductive symptoms: vaginal dryness, decreased libido, urinary tract changes; psychological symptoms: mood swings, anxiety, depression, sleep disorders; physical symptoms: weight gain, weight loss, hair loss, dry skin, joint pain; cognitive symptoms: memory loss (brain fog); long-term estrogen deficiency can also lead to accelerated bone loss (bone density loss of up to 20-25% within a few years), increasing the risk of osteoporosis and fractures; vascular diseases and metabolic disorders, such as heart disease, stroke, and diabetes.

[0004] Hormone replacement therapy (HRT) is effective for many menopausal symptoms and can prevent bone loss, but it carries well-known risks: increased risk of stroke, blood clots, breast and endometrial cancer, and cardiovascular events. Therefore, there is significant interest in safe, non-hormonal interventions. Current non-hormonal therapies (SSRIs / SNRIs for hot flashes, vaginal lubricants, phytoestrogens) often fail to provide complete symptom relief. Many women seek nutritional or “biohomogeneous” therapies to manage multi-system symptoms while avoiding the risks of HRT.

[0005] Existing treatments have significant shortcomings, and there is an urgent clinical need to develop a compound combination with excellent safety and synergistic effects on multiple targets to avoid the medication risks of hormone replacement therapy and comprehensively improve various menopausal complications from multiple dimensions including endocrine, skeletal, nervous, cardiovascular and metabolic aspects. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to overcome the shortcomings of the prior art and provide a combination drug and preparation method for relieving menopausal syndrome. In the present invention, the four components work synergistically to achieve simultaneous regulation of multiple targets such as hormone balance, bone health, calming and sleep aid, cardiovascular protection and metabolic regulation, breaking through the limitation of existing single products that can only improve a single menopausal symptom.

[0007] To achieve the above objectives, the present invention provides a synergistic nutritional combination drug for relieving menopausal syndrome, comprising the following components by weight: 5-50 mg dehydroepiandrosterone, 0.01-0.25 mg vitamin D3, 1-15 mg L-methylfolate, and 10-400 mg magnesium glycine.

[0008] This invention contains therapeutically effective amounts of dehydroepiandrosterone (DHEA), vitamin D3, L-methylfolate, and magnesium glycine. The four components work synergistically to specifically improve the core pathophysiological changes during menopause. DHEA, as a steroid hormone precursor, can restore some of the physiological activity of androgens and estrogens in the body; this component can maintain vaginal tissue health, improve sexual function, and also has an antidepressant effect in individuals with low DHEA levels. Vitamin D3 is a key substance for maintaining calcium balance and bone mineralization, and can also promote vaginal epithelial proliferation and participate in the regulation of immune and metabolic functions. L-methylfolate is a bioactive form of folic acid and an essential raw material for the synthesis of neurotransmitters such as serotonin, norepinephrine, and dopamine; supplementing with L-methylfolate can alleviate hot flashes and improve depressive mood by regulating hypothalamic pathways affected by estrogen. The glycine magnesium in this formula has excellent bioavailability, which can maintain normal neuromuscular physiological function, improve sleep quality, and soothe negative emotions; and when glycine magnesium is combined with vitamin D3, it can synergistically improve calcium absorption efficiency and strengthen bone strength.

[0009] When the dose of dehydroepiandrosterone (DHEA) is below 5 mg, insufficient supply of hormone precursors makes it difficult to alleviate menopausal endocrine-related discomforts such as hot flashes and vaginal dryness; it cannot inhibit bone loss to reduce the risk of osteoporosis; nor can it relieve negative emotions or improve cognition. Furthermore, it is difficult to coordinate with other components to regulate metabolism and cannot alleviate abdominal obesity. When the dose of DHEA exceeds 50 mg, it can cause excessive androgens in the body, leading to hirsutism, acne, increased risk of abnormal breast and endometrial hyperplasia, disruption of endocrine rhythms, exacerbation of insomnia, anxiety, and physical weakness, increased blood lipids, increased risk of thrombosis and worsening of obesity, and can also induce hair loss and menstrual disorders. Long-term high-dose use increases the metabolic burden on the liver. Dehydroepiandrosterone is abbreviated as DHEA.

[0010] Insufficient vitamin D3 intake can hinder calcium absorption and bone mineralization, easily leading to bone pain, cramps, and decreased bone density. It also fails to regulate central nervous system inflammation, improve negative emotions and shallow sleep, and exacerbate chronic systemic inflammation, joint pain, and weakness. Furthermore, it cannot work synergistically with folic acid to protect blood vessels, increasing the risk of cardiovascular and cerebrovascular diseases and reducing the body's immunity. Excessive vitamin D3 intake can easily cause accumulation and toxicity, leading to hypercalcemia and hypercalciuria. Calcium deposits in the kidneys and multiple soft tissues, damaging kidney function and exacerbating arteriosclerosis and joint stiffness. It can also cause headaches, irritability, and worsened insomnia, among other neuropsychiatric symptoms. In addition, it can disrupt the calcium-magnesium balance, counteracting the soothing effect of magnesium glycine, and worsening muscle spasms and insomnia.

[0011] Insufficient L-methylfolate intake can hinder one-carbon metabolism, leading to elevated homocysteine ​​levels and increasing the risk of cardiovascular and cognitive decline; it can also inhibit neurotransmitter synthesis, exacerbating mood disorders and forgetfulness; and interfere with hormone conversion, weakening its effect on improving menopausal reproductive discomfort. Furthermore, it cannot synergistically alleviate inflammation, fatigue, and metabolic abnormalities with vitamin D3 and magnesium. Excessive L-methylfolate intake can cause neurological excitation disorders, worsening palpitations, insomnia, and anxiety; irritate the gastrointestinal tract, causing various digestive discomforts; hinder zinc absorption; exacerbate skin and hair problems; and reduce immunity.

[0012] Insufficient magnesium glycinate can prevent the activation of sedative-sleep pathways and the antagonism of hot flash-related receptors, exacerbating hot flashes, insomnia, and muscle discomfort. It can also hinder calcium deposition, exacerbating bone pain and cramps, reducing insulin sensitivity, increasing cardiovascular risk, and causing muscle stiffness, migraines, and mood sensitivity. Excessive magnesium glycinate can easily cause diarrhea, abdominal pain, gastrointestinal irritation, and electrolyte loss. Excessive inhibition of neuromuscular function can lead to fatigue, drowsiness, and even muscle weakness and respiratory depression. It can also disrupt the calcium-magnesium balance, weakening the bone-protecting effect of vitamin D3, and inhibit cardiovascular function, causing low blood pressure and dizziness.

[0013] If the dosage of any one of the four components—dehydroepiandrosterone (DHEA), vitamin D3, L-methylfolate, and magnesium glycine—is too low, the synergistic effect of the four components cannot be effectively exerted, resulting in the inability to simultaneously regulate menopausal complications in multiple systems. If the dosage of any one of the four components is too high, it will not only produce toxic side effects, but also disrupt the synergistic balance of the other three components, leading to a significant decrease in the overall conditioning effect and the superimposed multiple uncomfortable symptoms.

[0014] Dehydroepiandrosterone (DHEA) is a pro-hormone synthesized by the adrenal glands, and its levels decline sharply with age. It is a precursor to both estrogen and androgen. DHEA is converted to estrogen / testosterone in peripheral tissues. The benefits of DHEA supplementation during menopause include restoring hormonal balance by increasing downstream estrogen / testosterone levels in tissues; improving sexual function, vaginal atrophy, and libido; and improving mood, cognitive function, and bone density.

[0015] Vitamin D3, L-methylfolate, and magnesium glycine can all penetrate the blood-brain barrier and act on the brain's nerve and endocrine centers, working together to achieve multi-dimensional improvement effects.

[0016] Vitamin D3, after crossing the blood-brain barrier, upregulates serotonin synthesis in the brain, regulates central nervous system inflammation levels, and alleviates the depression, irritability, and mood swings caused by declining estrogen levels during menopause; it also reduces central nervous system inflammation and relieves persistent emotional distress. Vitamin D3, chemically known as cholecalciferol, is the active form of vitamin D and helps maintain calcium homeostasis, bone mineralization, immune function, and mood regulation. Vitamin D3 can upregulate osteocalcin, thereby maintaining bone density. Vitamin D3 deficiency is common after menopause and is associated with osteoporosis, depression, and cardiovascular disease. The benefits of vitamin D3 supplementation during menopause include maintaining bone density, reducing the risk of bone loss and fractures; regulating inflammation, improving menopausal joint pain and fatigue symptoms; and promoting serotonin synthesis, thus playing a role in stabilizing mood.

[0017] L-methylfolate is an active form of folic acid and needs to be supplemented postmenopausal due to its crucial role in homocysteine ​​regulation, DNA methylation, and neurotransmitter synthesis. L-methylfolate is a cofactor in norepinephrine / dopamine synthesis and can combat depression. Benefits of L-methylfolate supplementation during menopause include: postmenopausal women often experience elevated homocysteine ​​levels, a risk factor for cardiovascular disease, cognitive decline, and osteoporosis; L-methylfolate is superior to folic acid by bypassing the methylenetetrahydrofolate reductase gene polymorphism (which affects up to 60% of women and impairs folic acid metabolism); it promotes the synthesis of serotonin, dopamine, and norepinephrine, helping to alleviate depression and mood instability.

[0018] Magnesium glycinate is crucial for bone structure, glucose metabolism, muscle relaxation, and neurotransmitter regulation. Magnesium glycinate deficiency is common in older women, affecting approximately 30-40% of menopausal women and is associated with osteoporosis. As an N-methyl-D-aspartate receptor antagonist, magnesium glycinate can reduce the severity of hot flashes. It also supports the GABAergic and melatonin pathways, improving sleep and mood, and has a calming effect. Magnesium glycinate supplementation is beneficial during menopause, relieving migraines, mood swings, and muscle cramps; as a cofactor in calcium regulation and vitamin D metabolism, it supports bone health; and it reduces insomnia, fatigue, and restless legs, all common menopausal symptoms.

[0019] The combined use of dehydroepiandrosterone (DHEA), vitamin D3, L-methylfolate, and magnesium glycine can synergistically address menopausal-related hormonal imbalances, decreased bone density, mood disturbances, and metabolic disorders. Magnesium glycine, vitamin D3, and L-methylfolate work together to support neurotransmitter production, potentially improving mood; DHEA helps alleviate brain fog and memory decline. Vitamin D3 and magnesium glycine work together to promote calcium absorption and bone mineralization, reducing the risk of osteoporosis; L-methylfolate can lower homocysteine ​​levels, preventing cardiovascular disease. DHEA supplements can complement the effects of other nutrients by addressing hormonal imbalances. Dehydroepiandrosterone provides the raw materials for the synthesis of estrogen and testosterone, while magnesium glycine and L-methylfolate support adrenal and liver function, ensuring normal hormone metabolism. Vitamin D3 can reduce inflammation, and magnesium glycine can improve insulin sensitivity, which is crucial for preventing menopausal weight gain and metabolic syndrome.

[0020] The combination drug for relieving menopausal syndrome also includes 20-270 mg of microcrystalline cellulose, 3.2-5.7 mg of stearic acid, and 1.8-4.1 mg of silica. Microcrystalline cellulose, stearic acid, and silica are used as excipients. Microcrystalline cellulose acts as a filler and disintegrant, improving powder formability; stearic acid acts as a lubricant, improving the flowability of the mixed powder; silica acts as a flow aid and anti-caking agent, inhibiting the agglomeration of raw materials by moisture absorption, ensuring the uniformity of multi-component mixing, and improving the stability of the formulation.

[0021] Preferably, the composition includes 105-220 mg of microcrystalline cellulose, 3.8-5.1 mg of stearic acid, and 2.3-3.5 mg of silicon dioxide. Within this range, the production process, formulation stability, absorption of active ingredients, and synergistic therapeutic effects of the formulation achieve a good overall technical effect.

[0022] Further preferred formulations include 170 mg of microcrystalline cellulose, 4.5 mg of stearic acid, and 2.9 mg of silica. This ratio achieves optimal technical results in terms of production process, storage stability, in vivo absorption, and synergistic therapeutic effects of the four components.

[0023] This invention also provides a method for preparing a combination drug to relieve menopausal syndrome, comprising the following steps: mixing dehydroepiandrosterone, vitamin D3, L-methylfolate, magnesium glycine, microcrystalline cellulose, stearic acid, and silicon dioxide in proportion to mass to obtain a combination drug to relieve menopausal syndrome; filling the obtained combination drug to relieve menopausal syndrome into a hollow capsule shell to prepare a capsule formulation. The capsule shell is made from plant-based capsules, preferably hydroxypropyl methylcellulose (HPMC).

[0024] The combination drug of the present invention can also be formulated into tablets, transdermal patches or oral suspensions.

[0025] Compared with the prior art, the beneficial effects of this invention are: This invention utilizes a synergistic effect of four components to achieve simultaneous multi-target conditioning of hormone balance, bone health, calming and sleep aid, cardiovascular protection, and metabolic regulation, overcoming the limitations of existing single-component products that can only improve a single menopausal symptom. This invention employs three active ingredients: vitamin D3, L-methylfolate, and magnesium glycine. All three can effectively penetrate the blood-brain barrier and act on the brain's neural and endocrine centers, exerting a synergistic effect from multiple dimensions. Furthermore, dehydroepiandrosterone (DHEA) is introduced, forming a synergistic quaternary composition with the aforementioned three ingredients. This synergistic effect of the four components can improve bone density and muscle function in menopausal women, alleviate vasomotor symptoms and vaginal discomfort, and stabilize mood and cognitive performance. This invention replaces traditional hormone therapy with safe and well-tolerated nutrients and hormone precursors, providing menopausal women with a comprehensive and systematic new approach to conditioning. Attached Figure Description

[0026] Figure 1 This is a comparison chart of Hamilton Depression Rating Scale (HAM-D) scores before and after using the combination drug prepared in Example 1.

[0027] Figure 2 This is a comparison chart of hip and neck bone mineral density scores before and after using the combination drug prepared in Example 1. Detailed Implementation

[0028] Example 1 is the preferred embodiment of the present invention. The present invention will be further described below with reference to specific embodiments and comparative examples.

[0029] The additives used in the embodiments and comparative examples of this invention are all commercially available, and the specific information is as follows: DHEA: Purchased from Purebulk Ltd. L-methylfolate: purchased from Merck Ltd.; Magnesium glycine: purchased from Purebulk Ltd.; Vitamin D3: Purchased from Purebulk Ltd.; Microcrystalline cellulose: purchased from Purebulk Ltd.; Stearic acid: purchased from Purebulk Ltd.; Silica: Purchased from Purebulk Ltd.

[0030] Table 1. Raw material formulations used in the examples. .

[0031] Example 1 The preparation method in this embodiment adopts the following steps: Dehydroepiandrosterone, vitamin D3, L-methylfolate, magnesium glycine, microcrystalline cellulose, stearic acid, and silicon dioxide were mixed evenly in the specified mass proportions to obtain a combination drug for relieving menopausal syndrome. The obtained combination drug for relieving menopausal syndrome was filled into a hollow capsule shell to prepare a capsule formulation. The capsule shell was made of hydroxypropyl methylcellulose.

[0032] Example 2 The preparation method in this embodiment adopts the following steps: Dehydroepiandrosterone, vitamin D3, L-methylfolate, magnesium glycine, microcrystalline cellulose, stearic acid, and silicon dioxide were mixed evenly in the specified mass proportions to obtain a combination drug for relieving menopausal syndrome. The obtained combination drug for relieving menopausal syndrome was filled into a hollow capsule shell to prepare a capsule formulation. The capsule shell was made of hydroxypropyl methylcellulose.

[0033] Example 3 The preparation method in this embodiment adopts the following steps: Dehydroepiandrosterone, vitamin D3, L-methylfolate, magnesium glycine, microcrystalline cellulose, stearic acid, and silicon dioxide were mixed evenly in the specified mass proportions to obtain a combination drug for relieving menopausal syndrome. The obtained combination drug for relieving menopausal syndrome was filled into a hollow capsule shell to prepare a capsule formulation. The capsule shell was made of hydroxypropyl methylcellulose.

[0034] Example 4 The preparation method in this embodiment adopts the following steps: Dehydroepiandrosterone, vitamin D3, L-methylfolate, magnesium glycine, microcrystalline cellulose, stearic acid, and silicon dioxide were mixed evenly in the specified mass proportions to obtain a combination drug for relieving menopausal syndrome. The obtained combination drug for relieving menopausal syndrome was filled into a hollow capsule shell to prepare a capsule formulation. The capsule shell was made of hydroxypropyl methylcellulose.

[0035] Example 5 The preparation method in this embodiment adopts the following steps: Dehydroepiandrosterone, vitamin D3, L-methylfolate, magnesium glycine, microcrystalline cellulose, stearic acid, and silicon dioxide were mixed evenly in the specified mass proportions to obtain a combination drug for relieving menopausal syndrome. The obtained combination drug for relieving menopausal syndrome was filled into a hollow capsule shell to prepare a capsule formulation. The capsule shell was made of hydroxypropyl methylcellulose.

[0036] Comparative Example 1 The preparation method of the combination drug for relieving menopausal syndrome described in this comparative example is the same as that in Example 1, except that 3 mg DHEA, 0.8 mg L-methylfolate, 8 mg glycine magnesium and 0.005 mg vitamin D3 are added.

[0037] Comparative Example 2 The preparation method of the combination drug for relieving menopausal syndrome described in this comparative example is the same as that in Example 1, except that 55mg DHEA, 18mg L-methylfolate, 550mg magnesium glycine and 0.3mg vitamin D3 all exceed the upper limit of the present invention.

[0038] Comparative Example 3 The preparation method of the combination drug for relieving menopausal syndrome described in this comparative example is the same as that in Example 1, except that DHEA is not added.

[0039] Comparative Example 4 The preparation method of the combination drug for relieving menopausal syndrome described in this comparative example is the same as that in Example 1, except that L-methylfolic acid is replaced with folic acid.

[0040] Comparative Example 5 The preparation method of the combination drug for relieving menopausal syndrome described in this comparative example is the same as that in Example 1, except that vitamin D3 is replaced with vitamin D1.

[0041] Comparative Example 6 The preparation method of the combination drug for relieving menopausal syndrome described in this comparative example is the same as that in Example 1, except that magnesium glycine is replaced with magnesium oxide.

[0042] Performance testing The performance of the combined drugs prepared in Examples 1-5 and Comparative Examples 1-6 was tested. Specific test results are shown in [link to test results]. Figures 1-2 See Tables 2-5.

[0043] Subjects: This invention selected 198 postmenopausal women (50-60 years old) who underwent neurological evaluations at the Lagrange Neurology Department between January 2014 and December 2024. The 198 subjects were divided into 11 groups: Examples 1-5 and Comparative Examples 1-6, with 18 subjects in each group. Menopause was defined as the cessation of menstruation for 12 consecutive months without other biological or physiological causes. Subjects took one capsule daily at 9:00 PM.

[0044] Table 2 shows the improvement in vasomotor symptoms and reproductive function in Examples 1-5 and Comparative Examples 1-6 after 12 weeks of treatment. Regarding the improvement in vasomotor symptoms The p-value is calculated using a single-sample proportion test: , ; Two-sided P=2[1-Φ(|Z|)]; n=18 for each group; .

[0045] Table 3 shows the depression assessments of Examples 1-5 and Comparative Examples 1-6 after 12 weeks of treatment. The HAM-D scores were assessed using paired t-tests, with n=18 for each group. Let dᵢ = pre-treatment score - post-treatment score, then the mean difference is... ; In Table 3, "Standard Deviation" refers to the standard deviation of the difference before and after treatment. Standard deviation of the difference , ; From degree d f =n-1, two-sided P=2[1-F t (|t|)]; .

[0046] Table 4 shows the hip and neck bone mineral density scores of menopausal women obtained from bone mineral density scans in Examples 1-5 and Comparative Examples 1-6. The standard deviation in Table 4 is calculated based on the sample standard deviation: ; The 95% confidence interval is: ; For each group, n=18, t(0.975,17)≈2.110; .

[0047] Table 5 shows the detailed test results of three subjects treated with the combination drug prepared in Example 1. .

[0048] The mean difference in hip and neck bone mineral density scores (post-treatment - pre-treatment) in Example 1 was 0.047 g / cm². An approximate t-test was performed based on the summary statistics in Table 4, with p = 0.085 (two-sided); hip and neck bone mineral density showed an increasing trend after treatment.

[0049] The mean difference in hip and neck bone mineral density scores (post-treatment - pre-treatment) in Example 2 was 0.038 g / cm². An approximate t-test was performed based on the summary statistics in Table 4, with p = 0.138 (two-sided); hip and neck bone mineral density showed an increasing trend after treatment.

[0050] The mean difference in hip and neck bone mineral density scores (post-treatment - pre-treatment) in Example 3 was 0.053 g / cm². An approximate t-test was performed based on the summary statistics in Table 4, with p = 0.045 (two-sided); the post-treatment hip and neck bone mineral density was significantly higher than the pre-treatment score.

[0051] The mean difference in hip and neck bone mineral density scores (post-treatment - pre-treatment) in Example 4 was 0.063 g / cm². An approximate t-test was performed based on the summary statistics in Table 4, with p = 0.022 (two-sided); the post-treatment hip and neck bone mineral density was significantly higher than the pre-treatment score.

[0052] The mean difference in hip and neck bone mineral density scores (post-treatment - pre-treatment) in Example 5 was 0.062 g / cm². An approximate t-test was performed based on the summary statistics in Table 4, with p = 0.025 (two-sided); the post-treatment hip and neck bone mineral density was significantly higher than the pre-treatment score.

[0053] The mean difference in hip and neck bone mineral density scores for Comparative Example 1 (post-treatment - pre-treatment) was -0.003 g / cm². An approximate t-test based on the summary statistics in Table 4 yielded p = 0.906 (two-sided); the difference was not statistically significant; no clear improvement in bone mineral density was observed.

[0054] The mean difference in hip and neck bone mineral density scores (post-treatment - pre-treatment) for Comparative Example 2 was 0.008 g / cm². An approximate t-test based on the summary statistics in Table 4 yielded a p-value of 0.768 (two-sided), indicating no statistically significant difference; no clear improvement in bone mineral density was observed.

[0055] The mean difference in hip and neck bone mineral density scores (post-treatment - pre-treatment) for Comparative Example 3 was 0.008 g / cm². An approximate t-test was performed based on the summary statistics in Table 4, with p = 0.754 (two-sided), indicating no statistically significant difference; post-treatment bone mineral density did not significantly improve compared to pre-treatment levels.

[0056] The mean difference in hip and neck bone mineral density scores (post-treatment - pre-treatment) for Comparative Example 4 was 0.013 g / cm². An approximate t-test was performed based on the summary statistics in Table 4, with p = 0.621 (two-sided), indicating no statistically significant difference; post-treatment bone mineral density did not significantly improve compared to pre-treatment levels.

[0057] The mean difference in hip and neck bone mineral density scores for Comparative Example 5 (post-treatment - pre-treatment) was -0.001 g / cm². An approximate t-test based on the summary statistics in Table 4 yielded a p-value of 0.970 (two-sided), indicating no statistically significant difference; no clear improvement in bone mineral density was observed.

[0058] For Comparative Example 6, the mean difference in hip and neck bone mineral density scores (post-treatment - pre-treatment) was 0.006 g / cm². An approximate t-test was performed based on the summary statistics in Table 4, with p = 0.827 (two-sided), indicating no statistically significant difference; post-treatment bone mineral density did not significantly improve compared to pre-treatment levels.

[0059] Subject 186 showed overall good treatment efficacy with no serious adverse events. After 12 weeks of treatment, subject 186 reported a decrease in hot flashes and HAM-D score, and an increase in femoral neck bone mineral density. Subject 143 also showed overall good treatment efficacy with no serious adverse events. After 12 weeks of treatment, subject 143 reported a decrease in hot flashes and HAM-D score, and an increase in femoral neck bone mineral density. Subject 117 also showed overall good treatment efficacy with no serious adverse events. After 12 weeks of treatment, subject 117 reported a decrease in hot flashes and HAM-D score, and an increase in femoral neck bone mineral density.

[0060] Depend on Figure 1 As can be seen, the Hamilton Depression Rating Scale (HAM-D) score decreased after treatment, indicating that the depressive symptoms of the subjects improved after treatment with the combination drug prepared in Example 1. Figure 2 It can be seen that after treatment with the combination drug prepared in Example 1, the subjects' hip and neck bone mineral density generally showed an increasing trend. In summary, the combination drug of the present invention, through the synergistic effect of its four components, can effectively improve menopausal-related bone mineral density loss, depressive mood, and hot flashes, achieving simultaneous regulation of multiple targets such as hormone balance, bone health, and mood regulation, breaking through the limitation of existing single-component products that can only improve a single symptom.

[0061] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention in any other way. Any person skilled in the art may make changes or modifications to the above-disclosed technical content to create equivalent embodiments. However, any simple modifications, equivalent changes, and modifications made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the protection scope of the present invention.

Claims

1. A combination drug for relieving menopausal syndrome, characterized in that, It comprises the following components by mass: 5–50 mg dehydroepiandrosterone, 0.01–0.25 mg vitamin D3, 1–15 mg L-methylfolate, and 10–400 mg magnesium glycine.

2. The combination drug for relieving menopausal syndrome according to claim 1, characterized in that, By weight, it comprises the following components: 10–40 mg dehydroepiandrosterone, 0.02–0.08 mg vitamin D3, 4–12 mg L-methylfolate, and 100–300 mg magnesium glycine.

3. The combination drug for relieving menopausal syndrome according to claim 1, characterized in that, By weight, it comprises the following components: 25 mg dehydroepiandrosterone, 0.05 mg vitamin D3, 7.5 mg L-methylfolate, and 200 mg magnesium glycine.

4. A combination drug for relieving menopausal syndrome according to claim 1, characterized in that: It also includes 20-270 mg of microcrystalline cellulose, 3.2-5.7 mg of stearic acid, and 1.8-4.1 mg of silicon dioxide.

5. A combination drug for relieving menopausal syndrome according to claim 1, characterized in that: It also includes 105-220 mg of microcrystalline cellulose, 3.8-5.1 mg of stearic acid, and 2.3-3.5 mg of silicon dioxide.

6. A combination drug for relieving menopausal syndrome according to claim 1, characterized in that: It also includes 170 mg of microcrystalline cellulose, 4.5 mg of stearic acid, and 2.9 mg of silicon dioxide.

7. A method for preparing a combination drug for relieving menopausal syndrome according to any one of claims 1 to 6, characterized in that: Dehydroepiandrosterone, vitamin D3, L-methylfolate, magnesium glycine, microcrystalline cellulose, stearic acid, and silicon dioxide were mixed evenly according to their mass proportions to obtain a combination drug for relieving menopausal syndrome.

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