A traditional Chinese medicine composition for treating insomnia, a preparation method thereof and application thereof

Abstract

This invention provides a traditional Chinese medicine composition for treating insomnia, its preparation method, and its application, belonging to the field of traditional Chinese medicine preparation technology. The composition includes the following raw materials: lavender, *Pteris vittata*, white peony root, *Houttuynia cordata*, licorice root, celery seed, fennel root bark, *Clerodendrum trichotomum* fruit, *Althaea rosea* seed, *Viola yedoensis*, rose petals, and red raisins; the composition also includes *Atractylodes macrocephala*, *Poria cocos*, *Ophiopogon japonicus*, lily bulb, and *Albizia julibrissin* bark. This invention also provides a preparation process for making tablets from the above raw materials through water extraction, volatile oil encapsulation, mixing and granulation, and compression. The resulting tablets are of stable quality, convenient to take, and suitable for treating insomnia, especially abnormal spleen fluid constitution (Saiwuda) insomnia, as well as accompanying symptoms such as depression, anxiety, and neurasthenia, showing significant clinical value and application prospects.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine preparation technology, specifically a traditional Chinese medicine composition for treating insomnia, its preparation method, and its application. Background Technology

[0002] Insomnia is a common sleep disorder, and long-term insomnia seriously affects patients' physical and mental health and quality of life. Modern medicine often uses sedative-hypnotic drugs for treatment, but these have problems such as strong dependence and obvious side effects. In the field of traditional medicine, Uyghur medicine (hereinafter referred to as "Uyghur medicine") has a unique theoretical understanding and rich clinical experience in treating insomnia. The "Four Humors Theory" of Uyghur medicine believes that human health depends on the balance of bile, blood, phlegm, and black bile (Sayuda). Among them, black bile, which is mainly produced and stored by the spleen, becomes abnormal when its quantity or properties are abnormal, forming abnormal black bile or abnormal spleen fluid. This abnormal "cold-dry" nature of the body fluid is considered by Uyghur medicine to be an important root cause of a series of complex and chronic diseases, including a specific type of intractable insomnia, namely abnormal spleen fluid (Sayuda) insomnia. Its core pathogenesis lies in the accumulation of abnormal black bile, which affects the normal nourishment and function of the brain and is often accompanied by emotional disorders such as depression and anxiety. In existing technologies, various traditional Chinese medicine (TCM) compound formulas have been applied to the treatment of insomnia. For example, the publicly available classic formula, Suanzaoren Tang, provides a composition with core medicinal materials such as jujube seed, poria cocos, anemarrhena rhizome or deer antler, epimedium, and prepared he shou wu, primarily focusing on improving sleep by nourishing blood, calming the mind, and tonifying the heart and kidneys. However, in practice, it has been found that such conventional approaches still have certain limitations for the specific and complex syndrome of abnormal spleen fluid (Saiwuda) insomnia as defined by Uyghur medicine theory. For example, its treatment approach is mostly based on the conventional TCM pathogenesis of heart-kidney disharmony and qi and blood deficiency, emphasizing nourishment and calming the mind, but it lacks targeted intervention for the abnormal black bile formation and accumulation caused by spleen dysfunction in Uyghur medicine theory, making it difficult to stop the continuous production of pathological products from the source.

[0003] Therefore, there is an urgent need for a more advantageous traditional Chinese medicine compound for the specific condition of abnormal spleen fluid (Saiwuda) insomnia. Summary of the Invention

[0004] In view of this, the purpose of the present invention is to provide a traditional Chinese medicine composition for treating insomnia, which, while treating insomnia, can comprehensively improve accompanying symptoms such as depression, anxiety, and neurasthenia in patients, and has high safety.

[0005] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a traditional Chinese medicine composition for treating insomnia, comprising the following raw materials in parts by weight: 1-12 parts lavender, 1-12 parts iron fern, 1-12 parts white peony root, 1-10 parts ox tongue grass, 1-10 parts licorice root, 1-10 parts celery seed, 1-10 parts fennel root bark, 7-20 parts clematis fruit, 1-10 parts hollyhock seed, 1-11 parts tianshan violet, 5-12 parts rose, and 8-18 parts red raisins.

[0006] Preferably, the traditional Chinese medicine composition further includes the following raw materials in parts by weight: 8-15 parts of Atractylodes macrocephala, 10-20 parts of Poria cocos, 10-18 parts of Ophiopogon japonicus, 10-18 parts of Lilium brownii, and 8-15 parts of Albizia julibrissin bark.

[0007] The present invention also provides a traditional Chinese medicine compound tablet for treating insomnia, the traditional Chinese medicine compound tablet comprising the aforementioned traditional Chinese medicine composition and pharmaceutically acceptable excipients.

[0008] The present invention also provides a method for preparing the aforementioned traditional Chinese medicine compound tablets, comprising the following steps: (1) Extract volatile oils from lavender and celery seeds to obtain volatile oils; encapsulate the volatile oils to obtain inclusion complexes; (2) Extract the remaining raw materials in the Chinese herbal composition with water, except for the raw material used to extract volatile oil, to obtain an aqueous extract; concentrate the aqueous extract and vacuum dry it to obtain a dry extract powder; (3) The inclusion complex, the dry powder and pharmaceutically acceptable excipients are mixed, granulated and tableted to obtain the traditional Chinese medicine compound tablet.

[0009] Preferably, the extraction method for the volatile oil is steam distillation.

[0010] Preferably, the inclusion agent used for inclusion is β-cyclodextrin or hydroxypropyl-β-cyclodextrin.

[0011] Preferably, the water extraction involves decocting 2-3 times, with each decoction consisting of 6-15 times the total amount of the medicinal materials, and each decoction lasting 1-2 hours.

[0012] Preferably, the vacuum drying temperature is 50-80℃ and the vacuum degree is -0.06MPa to -0.1MPa.

[0013] Preferably, the pharmaceutically acceptable excipients include fillers, disintegrants, and lubricants.

[0014] The present invention also provides the application of the aforementioned traditional Chinese medicine compound tablets in the preparation of a drug for treating abnormal spleen fluid-type insomnia.

[0015] Compared with the prior art, the present invention has the following advantages: (1) This invention integrates the Uyghur medical principle of "regulating abnormal spleen fluid quality" with the traditional Chinese medicine principle of "strengthening the spleen and nourishing blood, nourishing yin and moistening dryness, and soothing the liver and calming the mind." Pharmacodynamic test data show that, under the same dosage of raw herbs, the sleep-promoting and anti-anxiety and antidepressant effects of the preferred formulation of this invention are significantly better than those of the classic single herb Ziziphus jujuba seed, which only focuses on nourishing blood and calming the mind. This proves that by adding herbs such as Atractylodes macrocephala, Poria cocos, Ophiopogon japonicus, and Lilium brownii, it is possible to intervene in the generation of abnormal body fluids from the source and effectively improve the yin deficiency and dryness caused by its "cold-dry" characteristics, thus achieving both symptomatic and root-cause treatment and synergistic effect for the complex disease of abnormal spleen fluid quality (Saiwuda) insomnia.

[0016] (2) This invention not only targets the core symptoms of insomnia but also has a good effect on improving accompanying mood disorders. Results show that the preferred formulation of this invention is comparable to the antidepressant fluoxetine in improving behavioral despair and anhedonia in mice with chronic stress, and is significantly superior to the basic formulation and the jujube seed control. This confirms the liver-soothing and mood-regulating effects of herbs such as rose and albizia bark in the formulation, enabling this invention to comprehensively improve accompanying symptoms such as depression, anxiety, and neurasthenia while treating insomnia, thus broadening its applicability.

[0017] (3) This invention provides a clear tablet preparation process, ensuring the stability of the active ingredient and the uniformity of the formulation quality. Acute toxicity test results show that the maximum dosage of the preferred formulation of this invention (16.0 g crude drug / kg) is more than 5.3 times the effective dose (3.0 g crude drug / kg). At this dosage, no animal death or obvious toxic reaction was caused, indicating that it has great safety at the effective dose, providing a solid guarantee for the industrial production and safe clinical application of the product. Detailed Implementation

[0018] This invention provides a traditional Chinese medicine composition for treating insomnia. The core ingredients of the composition preferably include the following raw materials in parts by weight: lavender 1-12 parts, *Pteris vittata* 1-12 parts, white peony root 1-12 parts, *Houttuynia cordata* 1-10 parts, licorice root 1-10 parts, celery seed 1-10 parts, fennel root bark 1-10 parts, *Clerodendrum trichotomum* fruit 7-20 parts, *Althaea rosea* seed 1-10 parts, *Viola yedoensis* 1-11 parts, rose 5-12 parts, and red raisins 8-18 parts; a preferred ratio is: lavender 5-10 parts, *Pteris vittata* 5-10 parts, white peony root 8-12 parts, *Houttuynia cordata* 4-8 parts, and licorice root 5 parts. -8 parts, celery seeds 4-8 parts, fennel root bark 4-8 ​​parts, clematis fruit 10-15 parts, hollyhock seeds 4-8 parts, tianshan violet 6-10 parts, rose petals 6-10 parts, red raisins 12-16 parts; the traditional Chinese medicine composition further preferably includes the following raw materials in parts by weight: lavender 1-12 parts, iron fern 1-12 parts, white peony root 1-12 parts, ox tongue grass 1-10 parts, licorice root 1-10 parts, celery seeds 1-10 parts, fennel root bark 1-10 parts, clematis fruit 7-20 parts, hollyhock seeds 1-10 parts, tianshan violet 1-11 parts, rose petals 5-12 parts, red raisins 8-18 parts. To further enhance the effects of strengthening the spleen, nourishing yin, and relieving depression, and targeting the core pathogenesis of insomnia due to abnormal spleen fluid quality (Saiwuda), the following ingredients can be added in additional weight proportions based on the aforementioned preferred range: 8-15 parts of Atractylodes macrocephala, 10-20 parts of Poria cocos, 10-18 parts of Ophiopogon japonicus, 10-18 parts of Lilium brownii, and 8-15 parts of Albizia julibrissin bark; a further preferred addition amount is: 10-14 parts of Atractylodes macrocephala, 15-18 parts of Poria cocos, 12-16 parts of Ophiopogon japonicus, 12-16 parts of Lilium brownii, and 10-14 parts of Albizia julibrissin bark. Based on extensive formulation screening and pharmacodynamic verification, this invention provides a specific formulation value (by weight) with outstanding effects: 6 parts lavender, 6 parts iron fern, 10 parts white peony root, 5 parts ox tongue grass, 6 parts licorice root, 5 parts celery seed, 5 parts fennel root bark, 12 parts *Polygonum multiflorum* fruit, 5 parts hollyhock seed, 8 parts *Viola yedoensis*, 8 parts rose, 15 parts red raisins, 12 parts *Atractylodes macrocephala*, 15 parts *Poria cocos*, 15 parts *Ophiopogon japonicus*, 15 parts lily bulb, and 12 parts *Albizia julibrissin* bark. This formula integrates the Uyghur medical theory of "regulating abnormal spleen fluids," achieving the effects of strengthening the spleen and soothing the liver, nourishing yin and blood, and calming the mind. The principal ingredient in the formula is *Polygonum multiflorum* fruit, a core drug in Uyghur medicine for clearing abnormal black bile (Saiwuda). It is warm in nature and specifically regulates abnormal body fluids, directly addressing the root pathogenesis of insomnia caused by abnormal spleen fluids. The assistant ingredients are white peony root, rose, and *Albizia julibrissin* bark. These three herbs work together as assistant herbs, helping the principal herb to regulate emotions, nourish blood, and calm the mind. White peony root nourishes blood and astringes yin, softens the liver and relieves spasms, treating yin deficiency and liver hyperactivity; rose flower is fragrant and promotes qi circulation, relieving depression and harmonizing blood; and albizia bark soothes the heart and calms the mind, relieving depression and eliminating irritability. These three herbs work synergistically to address the depression and anxiety often accompanying insomnia, jointly relieving liver stagnation and nourishing the mind. The adjuvant herbs are divided into three groups to treat concurrent symptoms.The first ingredient is Atractylodes macrocephala and Poria cocos, which together strengthen the spleen and stomach, promote the transformation and transportation of fluids, and prevent the generation of abnormal body fluids caused by spleen deficiency at its source. The second ingredient is Ophiopogon japonicus and Lilium brownii, which are sweet, cold, and moistening, nourishing the yin of the heart and lungs, clearing away vexation and restlessness, and addressing yin deficiency and dryness caused by abnormal black bile, resulting in dry mouth and palpitations. The third ingredient is lavender, Viola yedoensis, and Althaea rosea seeds; these three herbs are either aromatic and penetrating or clear heat and calm the mind, assisting the principal and assistant herbs in enhancing their sedative and hypnotic effects. The guiding herbs are licorice root, red raisins, and a group of characteristic Uyghur herbs including Pteris vittata, Achyranthes bidentata, celery seeds, and fennel root bark. Licorice root harmonizes the other herbs, tonifies qi and regulates the middle jiao. Red raisins are sweet and neutral, tonifying qi, nourishing blood and moistening dryness. The remaining characteristic Uyghur herbs each perform their specific functions, working together to regulate the balance of abnormal body fluids. The guiding herbs in the entire formula have both harmonizing and guiding abilities, ensuring that all herbs are in their proper place and work together for harmony. The formula is well-organized, with clear distinctions between the principal and assistant herbs. It combines the Uyghur medicine's "regulating abnormal body fluids" with the traditional Chinese medicine's "strengthening the spleen, nourishing yin, soothing the liver, and calming the mind," addressing both the symptoms and the root cause, thus creating an effective treatment for abnormal spleen fluid constitution (Saiwuda)-related insomnia.

[0019] The present invention also provides a traditional Chinese medicine compound tablet for treating insomnia, wherein the traditional Chinese medicine compound tablet preferably comprises the aforementioned traditional Chinese medicine composition and pharmaceutically acceptable excipients.

[0020] The present invention also provides a method for preparing the aforementioned traditional Chinese medicine compound tablets, wherein the preparation method preferably includes the following steps: (1) Extract volatile oils from lavender and celery seeds to obtain volatile oils; encapsulate the volatile oils to obtain inclusion complexes; (2) Extract the remaining raw materials in the Chinese herbal composition with water, except for the raw material used to extract volatile oil, to obtain an aqueous extract; concentrate the aqueous extract and vacuum dry it to obtain a dry extract powder; (3) The inclusion complex, the dry powder and pharmaceutically acceptable excipients are mixed, granulated and tableted to obtain the traditional Chinese medicine compound tablet.

[0021] In this invention, to achieve efficient extraction and stable preservation of the volatile active ingredients in the prescription, the preferred specific operation of step (1) is as follows: Take the prescribed amount of lavender and celery seeds and put them together into the volatile oil extraction device. Extraction is carried out by steam distillation, with the amount of water added being 8-15 times the total amount of the medicinal materials. The mixture is heated to a gentle boil, and the distillation time is usually 4-6 hours until the amount of oil no longer increases significantly. The upper volatile oil is separated and collected, dehydrated with anhydrous sodium sulfate, and then sealed and refrigerated for later use to obtain a mixed volatile oil. To improve its stability, prevent it from escaping during production and storage, and mask unpleasant odors, the volatile oil needs to be encapsulated. The preferred inclusion method is as follows: The volatile oil obtained above is dispersed in a small amount of edible ethanol (such as 95% ethanol), and then slowly added dropwise to a saturated aqueous solution of β-cyclodextrin or hydroxypropyl-β-cyclodextrin while continuously stirring at 300-500 rpm. The ratio of volatile oil to cyclodextrin (mL / g) is controlled between 1:4 and 1:8. The inclusion process is carried out in a constant temperature water bath at 40-60℃, with continuous stirring for 2-3 hours to ensure complete inclusion. Subsequently, the inclusion solution is transferred to a 2-8℃ environment and allowed to stand for 12-24 hours to allow the inclusion compound to fully separate. Finally, it is filtered under reduced pressure, the filter cake is washed with a small amount of low-temperature purified water, dried to constant weight in a vacuum drying oven at 40-50℃, and pulverized through an 80-100 mesh sieve to obtain a free-flowing volatile oil cyclodextrin inclusion compound powder. This powder can be directly used in subsequent formulation mixing processes, ensuring the stability of the volatile component content and bioavailability in the final solid dosage form.

[0022] In this invention, after the extraction of volatile oils, the preferred specific step (2) is as follows: All remaining raw materials in the prescription, excluding the lavender and celery seeds already used for volatile oil extraction, including *Pteris vittata*, *Paeonia lactiflora*, *Houttuynia cordata*, licorice, fennel root bark, *Gnaphalium affine* fruit, *Althaea rosea* seeds, *Viola yedoensis*, rose petals, red raisins, and *Atractylodes macrocephala*, *Poria cocos*, *Ophiopogon japonicus*, lily bulb, and *Albizia julibrissin* bark added according to the preferred scheme, are combined. Drinking water, 8-12 times the total amount of the medicinal materials, is added and soaked for 25-30 minutes. Extraction is performed by decoction, usually 2-3 times, each decoction lasting 1-2 hours. The amount of water added the first time can be slightly more. All decoctions are combined and filtered while hot using a 100-200 mesh filter cloth or plate and frame filter to remove the dregs, yielding a clear aqueous extract. The aqueous extract was transferred to a vacuum concentration tank and concentrated under reduced pressure at 60-70°C and a vacuum degree of -0.08 MPa to -0.1 MPa to protect the heat-sensitive components. The relative density of the extract was closely monitored during concentration, typically concentrated to a viscous extract with a relative density of 1.10-1.25 (measured at 60°C). The viscous extract was then transferred to a vacuum drying oven, with the tray thickness controlled at 1-2 cm, and vacuum dried at 50-80°C and a vacuum degree maintained at -0.06 MPa to -0.1 MPa. In this invention, the low-temperature reduced-pressure environment efficiently removes moisture while minimizing the damage to the active pharmaceutical ingredients caused by high temperatures. After drying to a moisture content ≤5.0%, the material was removed, pulverized, and passed through an 80-120 mesh sieve to obtain a dry extract powder with uniform color and good flowability.

[0023] In this invention, the pharmaceutically acceptable excipients preferably include fillers, disintegrants, and lubricants. In the tablet preparation of this invention, the main function of the filler is to regulate the dosage volume for accurate dispensing and to improve the powder properties of the material. In this invention, the filler includes, but is not limited to, one or more combinations of microcrystalline cellulose, pregelatinized starch, lactose, and mannitol. For example, microcrystalline cellulose has both good compressibility and disintegration properties; pregelatinized starch provides both binding and disintegration effects; lactose and mannitol help improve taste and dissolution. Its dosage is typically 20%-70% of the total weight of the final tablet, and the specific proportion needs to be optimized and adjusted according to the drug loading and physical properties of the dry extract powder. The disintegrant ensures that the tablet rapidly disintegrates into fine particles or powder in the gastrointestinal fluid after administration, thereby promoting the dissolution and absorption of the drug components. Considering the high viscosity of the herbal extract in this invention, super-disintegrants are preferred, such as croscarmellose sodium, croscarmellose, and low-substituted hydroxypropyl cellulose. To achieve optimal disintegration, an "internal and external addition method" is often used: 50%-70% of the total disintegrant is mixed with the dry powder before granulation (internal addition) to distribute it within the granules; the remaining portion is mixed with the dried granules after granulation (external addition) to adhere to the granule surface. The lubricant's function is to reduce friction between granules and between granules and the die wall, preventing sticking and blockage during compression, and ensuring that tablet weight variation meets specifications. The lubricants used in this invention preferably include magnesium stearate, micronized silica gel, and talc. Among these, magnesium stearate is the most commonly used hydrophobic lubricant, while micronized silica gel has both good flow-aiding and anti-sticking properties. The lubricant is usually added in the final step, briefly mixed with the granules for 3-5 minutes, and the preferred dosage is 0.5%-2% of the total powder weight.

[0024] The present invention also provides the application of the aforementioned traditional Chinese medicine compound tablets in the preparation of a drug for treating abnormal spleen fluid-type insomnia.

[0025] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0026] Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods. Unless otherwise specified, the experimental materials used in the following embodiments are commercially available products.

[0027] Example 1 A traditional Chinese medicine compound tablet for treating insomnia includes the following ingredients: 80g lavender, 80g iron fern, 80g white peony root, 60g ox tongue grass, 60g licorice root, 60g celery seed, 60g fennel root bark, 150g clematis fruit, 60g hollyhock seed, 80g Tian Shan violet, 100g rose petals, and 150g red raisins.

[0028] Excipients: 150g microcrystalline cellulose, 100g pregelatinized starch; sodium croscarmellose, totaling 50g, added internally and externally: 30g mixed with dry extract powder and other excipients before granulation (internal addition), 20g mixed with dried granules after granulation (external addition); 8g magnesium stearate.

[0029] The preparation method of the above-mentioned traditional Chinese medicine compound tablets includes the following steps: (1) Extraction and inclusion of volatile oil: Take the prescribed amount of lavender and celery seeds, add 10 times the amount of water, steam distill for 4 hours, and collect the volatile oil. Disperse the volatile oil with a small amount of anhydrous ethanol, and slowly add it to 8 times the amount (based on the weight of β-cyclodextrin by the volume of volatile oil) of β-cyclodextrin saturated aqueous solution. Stir and include at 50°C for 2 hours, refrigerate at 4°C overnight, filter, vacuum dry the filter cake at 40°C, pulverize and pass through a 100-mesh sieve to obtain inclusion complex A.

[0030] (2) Water extraction and concentration drying: The distilled residue was combined with the remaining ingredients in the prescription (fern, white peony root, ox tongue grass, licorice, fennel root bark, clematis fruit, hollyhock seed, violet, rose, and red raisins), and decocted twice with 10 times the amount of water, 1.5 hours each time. The decoctions were combined and filtered. The filtrate was concentrated under reduced pressure at 65°C to a thick paste with a relative density of 1.15 (60°C). The thick paste was spray-dried (inlet air temperature 175°C, outlet air temperature 90°C) to obtain dry paste powder B.

[0031] (3) Granulation and tableting: Mix the dry extract powder B, inclusion complex A, and internal excipients (150g microcrystalline cellulose, 100g pregelatinized starch, and 30g croscarmellose sodium) evenly, prepare a soft mass with 85% ethanol, granulate through a 20-mesh sieve, dry at 60℃, and granulate through an 18-mesh sieve. Add 20g of external croscarmellose sodium and 8g of magnesium stearate, mix well, and compress into tablets to obtain tablet C1. Each tablet weighs approximately 0.45g.

[0032] Example 2 A traditional Chinese medicine compound tablet for treating insomnia includes the following ingredients: 60g lavender, 60g iron fern, 120g white peony root, 50g ox tongue grass, 60g licorice root, 50g celery seed, 50g fennel root bark, 150g clematis fruit, 50g hollyhock seed, 80g Tian Shan violet, 80g rose, 150g red raisins, 120g atractylodes macrocephala, 150g poria cocos, 150g ophiopogon japonicus, 150g lily bulb, and 120g albizia bark.

[0033] Excipients: 180g microcrystalline cellulose, 80g lactose; low-substituted hydroxypropyl cellulose (25g internally, 15g externally); 10g micronized silica gel, 6g magnesium stearate.

[0034] The preparation method of the above-mentioned traditional Chinese medicine compound tablets includes the following steps: (1) Extraction and inclusion of volatile oil: Take the prescribed amount of lavender and celery seeds, add 12 times the amount of water, steam distill for 5 hours, and collect the volatile oil. Use hydroxypropyl-β-cyclodextrin for inclusion (oil:HP-β-CD=1:6), the method is the same as in Example 1, to obtain inclusion compound D.

[0035] (2) Water extraction and concentration drying: The distilled residue was combined with the remaining raw materials (iron fern, white peony root, ox tongue grass, licorice, fennel root bark, clematis fruit, hollyhock seed, violet, rose, red raisins, atractylodes macrocephala, poria cocos, ophiopogon japonicus, lily bulb, albizia bark), and decocted three times with 12 times the amount of water (1.5 hours the first time, and 1 hour each for the second and third times). The decoctions were combined and filtered. The filtrate was concentrated under reduced pressure at 60℃ to a relative density of 1.10 (60℃), transferred to a vacuum drying oven, and vacuum dried at 65℃ and -0.08MPa until the moisture content was ≤5%. The dried extract powder E was obtained by pulverizing.

[0036] (3) Granulation and tableting: Mix the dry extract powder E, inclusion complex D and internal excipients, granulate, dry and granulate, then add external excipients and mix and compress to obtain tablet C2. The tablet weight is about 0.55g.

[0037] Example 3 A traditional Chinese medicine compound tablet for treating insomnia includes the following ingredients: 100g lavender, 100g iron fern, 150g white peony root, 35g ox tongue grass, 100g licorice root, 35g celery seed, 35g fennel root bark, 180g clematis fruit, 35g hollyhock seed, 110g Tian Shan violet, 120g rose, 180g red raisins, 150g atractylodes macrocephala, 200g poria cocos, 180g ophiopogon japonicus, 180g lily bulb, and 150g albizia bark.

[0038] Excipients: Mannitol 120g, microcrystalline cellulose 100g; crospovidone (PVPP XL-10) 50g (all added); magnesium stearate 10g.

[0039] The preparation method of the above-mentioned traditional Chinese medicine compound tablets: (1) Extraction and inclusion of volatile oil: Take the prescribed amount of lavender and celery seeds, add 10 times the amount of water, steam distill for 6 hours, and collect the volatile oil. Include the volatile oil with hydroxypropyl-β-cyclodextrin (oil:HP-β-CD=1:8, w / w), the method is the same as in Example 2, to obtain inclusion compound G.

[0040] (2) Water extraction and concentration drying: The distilled residue was combined with the remaining raw materials (iron fern, white peony root, ox tongue grass, licorice, fennel root bark, clematis fruit, hollyhock seed, violet, rose, red raisins, atractylodes macrocephala, poria cocos, ophiopogon japonicus, lily bulb, albizia bark), and decocted three times with 8 times the amount of water, each time for 1 hour. The decoctions were combined and filtered. The filtrate was concentrated under reduced pressure at 70℃ to a thick paste with a relative density of 1.25 (60℃). The thick paste was placed in a vacuum drying oven and vacuum dried at 80℃ and -0.06MPa until the moisture content was ≤5%. The paste was then pulverized through an 80-mesh sieve to obtain dry paste powder H.

[0041] (3) Granulation and tableting: Direct compression of powder is used. Dry extract powder H, inclusion complex G, mannitol, and microcrystalline cellulose are mixed evenly and passed through a 60-mesh sieve twice. Then crospovidone and magnesium stearate are added and mixed evenly. Direct compression is then performed to obtain tablet C3. Each tablet weighs approximately 0.65g.

[0042] Example 4: The therapeutic effect of the traditional Chinese medicine compound tablets of the present invention on a mouse insomnia model. 1. Experimental materials: (1) Experimental animals: 8-10 week old male ICR mice with a weight of 18-22g were selected.

[0043] (2) Test samples: Tablet C1 prepared in Example 1, Tablet C2 prepared in Example 2, and Tablet C3 prepared in Example 3. Positive control drug: Diazepam tablets. Control group drug: Ziziphus jujuba seed, a classic sedative Chinese medicine, prepared by decoction of Ziziphus jujuba seed alone (prepared according to the method of the 2020 edition of the Chinese Pharmacopoeia and concentrated to the equivalent of 1.0 g / mL of crude drug).

[0044] 2. Experimental Methods: (1) Grouping and administration: After 3 days of acclimatization, mice were randomly divided into 7 groups (n=10): normal control group, model control group, diazepam group (2mg / kg), jujube seed group (3.0g crude drug / kg), C1 group (3.0g crude drug / kg), C2 group (3.0g crude drug / kg), and C3 group (3.0g crude drug / kg).

[0045] (2) Modeling and drug administration: Except for the normal control group, mice in the other groups were intraperitoneally injected with p-chlorophenylalanine (PCPA) suspension (350 mg / kg) once a day for 2 consecutive days to establish an insomnia model. On the day of modeling, the drug was administered by gavage once a day for 7 consecutive days. The normal control group and the model control group were given the same volume of distilled water.

[0046] (3) Index detection: One hour after the last administration, all mice were injected intraperitoneally with a subthreshold dose of sodium pentobarbital (35 mg / kg). The sleep rate (the righting reflex disappeared for more than 1 minute) and sleep latency of the mice were immediately observed and recorded within 15 minutes.

[0047] 3. Results and Analysis Table 1. Therapeutic effects of each group on mouse insomnia model

[0048] Note: Compared with the model control group, P<0.05, P<0.01 As shown in Table 1, at the same dosage of crude drug (3.0 g / kg), the basic formula (C1) of this invention has a comparable sleep-inducing effect to the classic single herb, Ziziphus jujuba seed. However, the sleep-inducing effects (sleep onset rate and sleep latency) of formulas C2 and C3, obtained by adding herbs to the basic formula, are significantly better than Ziziphus jujuba seed and the basic formula (C1), and there is no statistically significant difference compared with the effect of diazepam. These results, at the same dosage baseline, strongly demonstrate the synergistic effect of the compound formulation of this invention, and its sedative-hypnotic effect is superior to that of classic single sedative drugs.

[0049] Example 5 1. Experimental Materials (1) Experimental animals: ICR male mice, 8-10 weeks old, weighing 20-24g.

[0050] (2) Test samples: Tablet C1 prepared in Example 1, Tablet C2 prepared in Example 2, and Tablet C3 prepared in Example 3. Positive control drug: Fluoxetine. Control group drug: Ziziphus jujuba seed, a classic sedative Chinese medicine, prepared by decoction of Ziziphus jujuba seed alone (prepared according to the method of the 2020 edition of the Chinese Pharmacopoeia and concentrated to the equivalent of 1.0 g / mL of crude drug).

[0051] 2. Experimental Methods (1) Animal grouping and modeling: After 3 days of acclimatization, mice were randomly divided into 7 groups (n=10): normal control group, CUMS model group, fluoxetine group (10mg / kg), jujube seed group (3.0g crude drug / kg), C1 group (3.0g crude drug / kg), C2 group (3.0g crude drug / kg), and C3 group (3.0g crude drug / kg). The chronic unpredictable mild stress (CUMS) program was used to model depression and anxiety for 21 consecutive days. The mice were administered the medication by gavage once a day during the modeling period.

[0052] (2) Behavioral tests: conducted on days 22-24 of modeling.

[0053] ① Sugar water preference experiment (SPT): After adaptation, the consumption of sucrose water and pure water was measured within 24 hours, and the sugar water preference rate was calculated.

[0054] ② Forced swimming test (FST): The mouse was placed in a cylindrical water tank and swam for 6 minutes. The cumulative immobility time in the last 4 minutes was recorded.

[0055] 3. Results and Analysis Table 2. Effects of each group on the behavior of anxiety and depression model mice

[0056] Note: Compared with the normal group, ##P<0.01; compared with the model group, P<0.05, P<0.01.

[0057] As shown in Table 2, under the same dosage of raw herbs, the basic formula (C1) of this invention and Ziziphus jujuba seed have similar effects in combating behavioral despair. However, in terms of comprehensively improving anhedonia and mood, the traditional Chinese medicine compound formulas C2 and C3 of this invention exhibit comprehensive and significant advantages, with effects significantly superior to Ziziphus jujuba seed and the basic formula (C1), and comparable to fluoxetine. This confirms, under comparable dosage conditions, that the traditional Chinese medicine compound formulas of this invention have superior comprehensive mood regulation capabilities, highlighting their compatibility advantage in addressing abnormal spleen fluid insomnia often accompanied by mood disorders.

[0058] Example 6: Acute toxicity test of the traditional Chinese medicine compound tablets of the present invention This embodiment aims to evaluate the acute toxicity of the traditional Chinese medicine compound tablet (C2) prepared in Example 2 of the present invention after a single dose, and to determine its maximum tolerated dose (MTD), so as to provide experimental evidence for the safety of clinical use. The clinically intended dose of this preparation is approximately 6.0 grams per day for adults based on the amount of raw medicinal material (i.e., approximately 0.1 g of raw medicinal material / kg for an adult weighing 60 kg).

[0059] 1. Test materials and test drugs: The traditional Chinese medicine compound tablet C2 prepared in Example 2 was ground into fine powder before use and prepared into a suspension of the required concentration with 0.5% sodium carboxymethyl cellulose (CMC-Na) aqueous solution.

[0060] 2. Experimental animals: SPF-grade Kunming mice, half male and half female, weighing 18-22g. Animals were acclimatized for 3 days.

[0061] 3. Test Methods (1) Preliminary test Ten healthy mice, half male and half female, were selected for a preliminary experiment. The drug was administered via single gavage, with the dosage gradually increased. The animals' toxic reactions and mortality were observed initially to determine the dosage range for the formal experiment. The preliminary experiment showed no mortality at the maximum administered concentration (0.4 g crude drug / mL) and maximum gavage volume (0.4 mL / 10 g body weight), therefore, a maximum dose experiment was conducted.

[0062] (2) Maximum dose test ① Animal grouping and administration: Forty healthy mice, half male and half female, were randomly divided into two groups: a control group and an administration group, with 20 mice in each group (10 male and 10 female).

[0063] ② Dosing regimen: In the treatment group: C2 suspension was administered, with a single oral dose of 16.0 g crude drug / kg body weight (equivalent to approximately 160 times the clinically intended dose). Patients were fasting for 12 hours prior to administration, but water intake was permitted.

[0064] Control group: Administered an equal volume of 0.5% CMC-Na solution.

[0065] ③ Observation and Recording: General observation: Observe the animal continuously for 14 days after administration, focusing on the animal's reaction within 4 hours after administration, and then observe 1-2 times a day. Record changes in the animal's general behavior, activity, fur, eyes, ears, nose, oral secretions, respiration, feces, etc., as well as poisoning symptoms, onset time, severity, duration, and recovery status.

[0066] Body weight and food intake: The animals were weighed and their food intake was recorded before administration (day 0) and on days 1, 3, 7 and 14 after administration.

[0067] Gross anatomy and organ coefficient: At the end of the observation period (day 15), all surviving animals were euthanized, and the major organs (heart, liver, spleen, lungs, kidneys, brain, thymus, adrenal glands, and gonads) were weighed and the organ coefficient (organ weight / body weight × 100%) was calculated.

[0068] 4. Test Results (1) General observation and survival status All mice in the treatment group survived after a single oral gavage dose of 16.0 g crude drug / kg, with no deaths observed during the observation period. Within 2-4 hours after administration, some mice exhibited a transient decrease in spontaneous activity and curling up, gradually returning to normal after approximately 6 hours. No obvious symptoms of poisoning such as convulsions, tremors, salivation, dyspnea, or diarrhea were observed. Mice in the control group exhibited normal behavior and activity.

[0069] (2) Changes in body weight and food intake Throughout the 14-day observation period, mice in both the control and treatment groups remained in good condition, with continuous weight gain and normal food intake. The weight change trends of the two groups were largely consistent, with no statistically significant differences in average weight and weight gain at any time point (P>0.05). Specific data are shown in Table 3. Both groups of mice maintained continuous weight gain throughout the observation period, with normal food intake. The weight gain trends of the treatment and control groups were consistent during the same period, with no statistically significant differences in weight or cumulative weight gain at any time point (P>0.05).

[0070] Table 3. Effects of the tablets in Example 2 on mouse body weight changes ( ±SD, n=20, unit: g)

[0071] (3) Gross anatomy and organ coefficients At the end of the observation period, dissections were performed on the animals. No obvious abnormalities were found in the color, shape, or size of the major organs (heart, liver, spleen, lungs, kidneys, etc.) in either group. The results of the major organ coefficient measurements are shown in Table 4. Statistical analysis showed no statistically significant differences in the organ coefficients between the treatment group and the control group (P>0.05).

[0072] Table 4. Effects of the tablets in Example 2 on the coefficients of major organs in mice ( ±SD, n=20)

[0073] In summary, the maximum dose of the compound herbal tablet (C2) of Example 2 of this invention administered to mice via single gavage was 16.0 g crude drug / kg body weight. This dose did not cause animal death, nor were any acute poisoning symptoms, weight gain inhibition, or organ coefficient abnormalities observed that were of significant toxicological importance. Based on the pharmacodynamic results of Example 4, the effective dose of this preparation in treating insomnia model mice was 3.0 g crude drug / kg. The ratio of the maximum dose (16.0 g crude drug / kg) to the effective dose, as determined in the acute toxicity test, was greater than 5.3. These results preliminarily indicate that the compound herbal tablet (C2) of Example 2 of this invention has a large safety window at the effective dose and low acute toxicity, providing important safety experimental evidence for further long-term toxicity studies and clinical safe use.

[0074] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A traditional Chinese medicine composition for treating insomnia, characterized in that, The ingredients include the following parts by weight: lavender 1-12 parts, fern 1-12 parts, white peony 1-12 parts, ox tongue grass 1-10 parts, licorice 1-10 parts, celery seed 1-10 parts, fennel root bark 1-10 parts, clematis fruit 7-20 parts, hollyhock seed 1-10 parts, violet tianshanensis 1-11 parts, rose petals 5-12 parts, and red raisins 8-18 parts.

2. The traditional Chinese medicine composition according to claim 1, characterized in that, The traditional Chinese medicine composition also includes the following raw materials in parts by weight: 8-15 parts of Atractylodes macrocephala, 10-20 parts of Poria cocos, 10-18 parts of Ophiopogon japonicus, 10-18 parts of Lilium brownii, and 8-15 parts of Albizia julibrissin bark.

3. A traditional Chinese medicine compound tablet for treating insomnia, characterized in that, The traditional Chinese medicine compound tablets comprise the traditional Chinese medicine composition as described in claim 1 or 2 and pharmaceutically acceptable excipients.

4. The method for preparing the traditional Chinese medicine compound tablets according to claim 3, characterized in that, Includes the following steps: (1) Extract volatile oils from lavender and celery seeds to obtain volatile oils; encapsulate the volatile oils to obtain inclusion complexes; (2) Extract the remaining raw materials in the traditional Chinese medicine composition according to claim 1 or 2 with water, except for the raw material used to extract volatile oil, to obtain an aqueous extract; The aqueous extract was concentrated and vacuum dried to obtain a dry extract powder; (3) The inclusion complex, the dry powder and pharmaceutically acceptable excipients are mixed, granulated and tableted to obtain the traditional Chinese medicine compound tablet.

5. The preparation method according to claim 4, characterized in that, The volatile oil is extracted by steam distillation.

6. The preparation method according to claim 4, characterized in that, The inclusion agent used in the inclusion process is β-cyclodextrin or hydroxypropyl-β-cyclodextrin.

7. The preparation method according to claim 4, characterized in that, The water extraction involves decocting 2-3 times, with each decoction consisting of 6-15 times the total amount of the medicinal materials, and each decoction lasting 1-2 hours.

8. The preparation method according to claim 4, characterized in that, The vacuum drying temperature is 50-80℃, and the vacuum degree is -0.06MPa to -0.1MPa.

9. The preparation method according to claim 4, characterized in that, Pharmaceutically acceptable excipients include fillers, disintegrants, and lubricants.

10. The use of the traditional Chinese medicine composition according to claim 1 or 2, or the traditional Chinese medicine compound tablet according to claim 3, in the preparation of a drug for treating abnormal spleen fluid-type insomnia.

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