Use of a traditional Chinese medicine composition or extract thereof in the preparation of a medicament for treating Parkinson's disease

Abstract

The application belongs to the technical field of medicine research, and particularly relates to application of a traditional Chinese medicine composition or extract thereof in preparation of a medicine for treating Parkinson's disease. The traditional Chinese medicine composition is composed of the following raw materials in parts by weight: 15-30 parts of schleichera integrifolia, 10-30 parts of lotus seed, 10-30 parts of lily, 9-30 parts of clematis, and 0.25-1 part of safflower. The application takes the imbalance of circadian rhythm as a breakthrough point, realizes overall regulation of'regulating rhythm with rhythm', and synchronously improves non-motor symptoms such as Parkinson's disease motor disorders, sleep, and autonomic nervous system. Through'regulating rhythm' instead of simple sedation / excitation, sleep is promoted at night while daytime sleepiness, cognitive decline and fall risk are avoided. The application can also reduce the damage of dopaminergic drugs to sleep structure, stabilize the sleep-wake cycle, improve treatment compliance and quality of life, open up a new technical path for comprehensive treatment of Parkinson's disease, and has no obvious adverse reactions, high safety, and is worthy of clinical popularization and application.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical research technology, specifically relating to the application of a traditional Chinese medicine composition or its extract in the preparation of a drug for treating Parkinson's disease. Background Technology

[0002] Parkinson's disease (PD) is the second most common chronic progressive neurodegenerative disease after Alzheimer's disease. Its incidence increases significantly with age, severely impacting patients' quality of life and imposing a heavy social and family burden. The clinical manifestations of PD are complex and diverse. In addition to motor symptoms such as tremor, rigidity, bradykinesia, postural instability, and gait disturbances, non-motor symptoms such as sleep disturbances, autonomic dysfunction, and mood and cognitive impairments are also widespread.

[0003] Recent studies have shown that while various motor and non-motor symptoms of Parkinson's disease (PD) affect multiple systems, they are highly concentrated in the common pathophysiological feature of circadian rhythm disruption over time. Common clinical manifestations include: significantly decreased daytime activity levels coupled with restless legs syndrome at night; excessive daytime sleepiness coupled with rapid eye movement sleep behavior disorder (REM sleep behavior disorder, RBD) at night; and low daytime core body temperature coupled with elevated nighttime blood pressure. These abnormalities do not exist in isolation but rather interact and overlap, forming a complex state of rhythm imbalance that further exacerbates the overall symptom burden in PD patients.

[0004] Currently, treatment strategies for Parkinson's disease (PD) accompanied by circadian rhythm disorders, both domestically and internationally, primarily focus on symptomatic intervention for sleep disturbances. Benzodiazepines are widely used as first-line drugs for nocturnal insomnia and Recurrent Bed rest disorder (RBD), mainly by enhancing GABAergic inhibition to alleviate nocturnal abnormal behaviors and difficulty falling asleep. However, existing treatments have the following technical limitations:

[0005] (1) The treatment approach is mainly based on symptomatic intervention, lacking overall regulation of the circadian rhythm imbalance. Current treatment options primarily target individual symptoms such as insomnia and REM sleep behavior disorder with medication, failing to address the core pathological aspect of circadian rhythm disruption through systematic regulation. Consequently, they are unable to simultaneously improve the various motor and non-motor symptoms in Parkinson's disease patients.

[0006] (2) Commonly used sedative-hypnotic drugs have significant risks of adverse reactions. While sedative-hypnotic drugs such as benzodiazepines can alleviate abnormal nighttime behavior and difficulty falling asleep, long-term use can easily cause daytime sleepiness, cognitive decline, decreased balance, and increased risk of falls. They are especially unsuitable for Parkinson's disease patients who require long-term medication management.

[0007] (3) Dopaminergic therapy may worsen circadian rhythm disorders. While improving motor symptoms, levodopa and other dopaminergic agents may increase central arousal levels, induce increased nocturnal awakenings, abnormal dreams, and disruption of sleep structure, leading to sleep fragmentation and even exacerbating REM sleep behavior disorder, creating a paradox of "symptom improvement - rhythm deterioration".

[0008] (4) Lack of treatment methods that balance safety and long-term regulatory effects Current treatments mostly focus on short-term symptom control, and there is a lack of a treatment plan that can safely and stably reconstruct the diurnal rhythm homeostasis of Parkinson's disease patients in the long term, thereby achieving synergistic improvement of multiple symptoms. Summary of the Invention

[0009] In view of the above technical problems, the present invention provides the application of a traditional Chinese medicine composition or its extract in the preparation of a drug for treating Parkinson's disease. Experimental verification shows that this traditional Chinese medicine composition can regulate and restore the homeostasis of the human circadian rhythm, fundamentally improving Parkinson's disease-related circadian rhythm disorders and alleviating motor symptoms.

[0010] The specific technical solution provided by this invention is as follows: This invention provides the application of a traditional Chinese medicine composition or its extract in the preparation of a drug for treating Parkinson's disease. The traditional Chinese medicine composition is composed of the following raw materials in parts by weight: 15-30 parts of Albizia bark, 10-30 parts of lotus seeds, 10-30 parts of lily bulb, 9-30 parts of Polygonum multiflorum stem, and 0.25-1 part of saffron.

[0011] As a preferred embodiment of the present invention, the traditional Chinese medicine composition comprises the following raw materials in parts by weight: 12-18 parts of Albizia bark, 12-18 parts of lotus seeds, 12-18 parts of lily bulbs, 15-30 parts of Polygonum multiflorum stem, and 0.5-1 part of saffron.

[0012] As a preferred embodiment of the present invention, the traditional Chinese medicine composition comprises the following raw materials in parts by weight: 15 parts of Albizia bark, 15 parts of lotus seeds, 15 parts of lily bulbs, 30 parts of Polygonum multiflorum, and 1 part of saffron.

[0013] In a preferred embodiment of the present invention, the extract is prepared according to the following steps: Weigh out the following ingredients according to their weight proportions: Albizia bark, lotus seeds, lily bulbs, Polygonum multiflorum vine, and saffron. Mix them together, add water, and decoct. Collect the decoction.

[0014] More preferably, the decoction involves adding water equivalent to 8 to 10 times the total weight of the medicinal materials, and decocting 2 to 3 times, each time for 0.5 to 1 hour.

[0015] More preferably, the collected decoction is concentrated to a relative density of 1.40 at 20°C and then dried.

[0016] As a preferred embodiment of the present invention, the traditional Chinese medicine composition or its extract is used to improve motor symptoms, non-motor symptoms and / or circadian rhythm disorders associated with Parkinson's disease.

[0017] More preferably, the motor symptoms include tremor, rigidity, bradykinesia, and / or postural and gait disorders; the non-motor symptoms include sleep disorders, anxiety, depression, and autonomic dysfunction; and the circadian rhythm disorders include sleep-wake rhythm disorders, cardiovascular circadian rhythm abnormalities, and / or melatonin secretion rhythm abnormalities.

[0018] The present invention also provides a medicament for treating Parkinson's disease, which is formulated by combining the aforementioned traditional Chinese medicine composition or its extract with pharmaceutically acceptable excipients, the medicament being used to improve Parkinson's disease-related motor symptoms, non-motor symptoms and / or circadian rhythm disorders.

[0019] In a preferred embodiment of the present invention, the extract is prepared according to the following steps: Weigh out the following ingredients according to their weight proportions: Albizia bark, lotus seeds, lily bulbs, Polygonum multiflorum vine, and saffron. Mix them together, add water and decoct. Collect the decoction, concentrate it to a relative density of 1.40 at 20°C, centrifuge, spray dry, and collect the dry extract. In a preferred embodiment of the present invention, the drug is an oral preparation.

[0020] More preferably, the drug is in the form of granules, capsules, tablets, or oral liquid.

[0021] More preferably, the granules are prepared by mixing the dry extract with sucrose and dextrin in a mass ratio of 1:3:1, using 70% ethanol as a wetting agent, and then granulating, drying, and straightening the mixture sequentially.

[0022] More preferably, the capsule is prepared by mixing the dry extract with micronized silica gel and α-galactose, using ethanol as a wetting agent, granulating, drying, sizing, and then filling into capsules.

[0023] More preferably, the tablets are prepared by mixing the dry extract with sucrose and dextrin, using ethanol as a wetting agent, and then sequentially granulating, drying, sizing, and compressing.

[0024] More preferably, the oral liquid is prepared by adding sucrose and flavoring to the supernatant after centrifugation, mixing, sterilizing, and filling.

[0025] The present invention also provides the use of the traditional Chinese medicine composition in the preparation of a medicament for the combined treatment of Parkinson's disease with levodopa.

[0026] In a preferred embodiment of the present invention, the traditional Chinese medicine composition is used to alleviate sleep structure disruption induced by dopaminergic drugs.

[0027] More preferably, the disruption of sleep structure includes at least one of increased nighttime awakenings, abnormal dreams, sleep fragmentation, or worsening of REM sleep behavior disorder.

[0028] This invention is based on the traditional Chinese medicine concept of "Yang stagnation—disruption of the Wei Yang's movement" as a key syndrome characteristic of Parkinson's disease's diurnal rhythm disorder. It proposes a treatment approach that restores the homeostasis of the body's Yin-Yang rhythm by regulating the physiological rhythm of Wei Yang's movement during the day and night. To this end, the herbal composition of this invention uses scientifically formulated nocturnal herbal plants with diurnal rhythmic movement characteristics. Utilizing the inherent diurnal rhythmic properties of these plants, it regulates and rebuilds the body's diurnal rhythm homeostasis, fundamentally improving the diurnal rhythm disorder associated with Parkinson's disease and alleviating motor symptoms. This invention uses a nocturnal herbal formula composed of saffron, albizia bark, lily bulb, polygonum multiflorum stem, and lotus seed to treat Parkinson's disease. All five herbs in this formula possess a rhythmic nature responsive to the night, enabling them to exert the effect of "restoring rhythm through rhythm." Among them, saffron, which invigorates blood and calms the mind, relieving yang stagnation, serves as the principal herb. Lily bulb clears the heart and calms the mind; Polygonum multiflorum nourishes blood and calms the mind; and Albizia julibrissin bark relieves depression and calms the mind—these three act as assistant herbs. This formula addresses rhythmic disorders caused by yin deficiency and excessive fire disturbing the mind, as well as those caused by insufficient qi and blood failing to nourish the mind. It can also be used for rhythmic disorders caused by emotional distress and liver stagnation disturbing the heart, embodying the treatment philosophy of combining symptom and syndrome differentiation. Lotus seed, with its sweet and astringent properties, acts as the guiding herb, relieving urgency and calming the mind, while also astringing the spirit, thus coordinating the effects of the other herbs to guide yang into yin and restore rhythm through rhythm.

[0029] The herbal composition of this invention addresses the imbalance of circadian rhythms, simultaneously improving motor disorders and non-motor symptoms such as sleep and autonomic nervous system dysfunction in Parkinson's disease with a single dose. Through "rhythm regulation" rather than simple sedation / excitation, it promotes sleep at night while avoiding daytime sleepiness, cognitive decline, and the risk of falls. Furthermore, it can reduce the damage to sleep structure caused by dopaminergic drugs, stabilize the sleep-wake cycle, improve treatment adherence and quality of life, opening up a new technical pathway for the comprehensive treatment of Parkinson's disease. Moreover, it has no significant adverse reactions, high safety, and is worthy of clinical promotion and application.

[0030] This invention demonstrates through clinical research that the herbal composition (Nyctinastic Herbal Decoction, NHD) of this invention has multidimensional positive therapeutic effects on Parkinson's disease (PD), and the efficacy gradually increases with the duration of treatment, with all aspects of the effect being significantly superior to the placebo group. NHD can effectively improve the overall symptoms of PD, including motor symptoms such as tremor and rigidity, as well as non-motor symptoms such as anxiety, depression, gastrointestinal and urinary dysfunction. At the same time, NHD has a significant regulatory effect on the circadian rhythm disorder in PD patients, improving sleep quality by reducing RBDQ-HK and PSQI scores and increasing PDSS scores. Polysomnography shows that it performs better in improving sleep efficiency and reducing sleep fragmentation. In addition, NHD can also regulate the cardiovascular circadian rhythm, increase the rate of nocturnal systolic blood pressure drop, and normalize the blood pressure curve; improve the circadian rhythm of salivary melatonin (SM), increase its median circadian secretion rhythm, and increase the amplitude of the circadian secretion rhythm.

[0031] Animal experiments have demonstrated that the combined use of NHD and levodopa significantly enhances the motor and balance abilities of mice with PD and circadian rhythm disorders (prolonged rotarod dwell time, increased adaptable rotation speed, shortened pole turning latency, and accelerated descent time). Long-term spontaneous activity monitoring shows an increase in total activity and restoration of the "nocturnal" circadian rhythm. Mechanistically, the combined use of NHD and levodopa significantly increases the expression of 5-HT in the mouse gut, the dorsal raphe nucleus microregion, and DA in the striatum microregion, with NHD showing a better regulatory effect on the 5-HT system than levodopa alone. Furthermore, NHD can regulate the levels of 5-HT-related receptors, increasing the levels of 5-HT3 in the gut and 5-HT1A in the midbrain while decreasing the levels of 5-HT1B receptors, and also promotes the expression of the PER, CLOCK, and BMAL1 circadian rhythm genes in the mouse hypothalamus.

[0032] The advantages of this invention are: (1) Starting from the key pathological mechanism of circadian rhythm imbalance, we can simultaneously improve the motor symptoms and non-motor symptoms such as sleep disorders and autonomic dysfunction in Parkinson's disease patients. (2) Avoid the side effects of simple sedation or stimulation, improve the quality of nighttime sleep without aggravating daytime sleepiness, cognitive decline and risk of falls; (3) Reduce the adverse effects of dopaminergic drugs on sleep structure, improve the stability of the sleep-wake cycle through rhythm regulation, and improve overall treatment compliance and quality of life; (4) Provide a safe, effective and suitable traditional Chinese medicine treatment plan for long-term use, realize the overall regulation of Parkinson's disease by using the traditional Chinese medicine formula for treating nocturnal diseases to restore the law, and provide a new technical path for the comprehensive treatment of Parkinson's disease. Attached Figure Description

[0033] Figure 1 This is a comparison of sleep profile parameters before and after treatment in two groups. A: Total bed rest time, total sleep time; B: Sleep latency, sleep efficiency; C: Number of micro-awakenings, micro-awakening index; T-T0: Before treatment in the treatment group; T-T3: After 12 weeks of treatment in the treatment group; P-T0: Before treatment in the placebo group; P-T3: After treatment in the placebo group; Before treatment vs. after treatment: *: P<0.05; Treatment vs. Placebo: #: P<0.05.

[0034] Figure 2 This is a comparison of the percentage of sleep stages before and after treatment in the two groups. T-T0: before treatment in the treatment group; T-T3: after 12 weeks of treatment in the treatment group; P-T0: before treatment in the placebo group; P-T3: after treatment in the placebo group; before treatment vs. after treatment: *: P<0.05, **: P<0.01.

[0035] Figure 3 This is a comparison of REM activity, density, and intensity before and after treatment in two groups. A: REM activity; B: REM density and intensity; T-T0: before treatment in the treatment group; T-T3: after 12 weeks of treatment in the treatment group; P-T0: before treatment in the placebo group; P-T3: after treatment in the placebo group; Before treatment vs. after treatment: *: P<0.05, **: P<0.01.

[0036] Figure 4 This is a graph showing the total diurnal and circadian melatonin secretion in saliva before and after treatment. T0: before treatment; T3: 12 weeks of treatment; Treatment vs Placebo: ###: P < 0.001; Before treatment vs After treatment: **: P < 0.01, ****: P < 0.0001.

[0037] Figure 5 These are cosine curves of salivary melatonin secretion. A: Cosine curves of salivary melatonin in the two groups before treatment; B: Cosine curves of salivary melatonin in the two groups after treatment; C: Cosine curves of salivary melatonin in the treatment group before and after treatment; D: Cosine curves of salivary melatonin in the placebo group before and after treatment; T0: Before treatment; T3: 12 weeks of treatment.

[0038] Figure 6 This is a comparison of daytime and nighttime systolic and diastolic blood pressure before and after treatment in two groups. T-T0: before treatment in the treatment group; T-T3: after 12 weeks of treatment in the treatment group; P-P0: before treatment in the placebo group; P-P3: after treatment in the treatment group; Treatment vsPlacebo: #: P<0.05, ##: P<0.01.

[0039] Figure 7This is a comparison of the coefficient of variation of blood pressure before and after treatment in the two groups. T-T0: before treatment in the treatment group; T-T3: after 12 weeks of treatment in the treatment group; P-P0: before treatment in the placebo group; P-P3: after treatment in the treatment group; Treatment vs Placebo: #: P<0.05, ##: P<0.01.

[0040] Figure 8 This is a comparison of the rate of decrease in nocturnal systolic blood pressure and the difference between the two groups before and after treatment. A: Rate of decrease in nocturnal systolic blood pressure; B: Difference in rate of decrease in nocturnal systolic blood pressure; Before treatment vs. after treatment: **: P < 0.01; Treatment vs. Placebo: #: P < 0.05, ##: P < 0.01.

[0041] Figure 9 This study investigated the efficacy of NHD on rotarod and pole-climbing behaviors in Parkinson's disease (PD) mice with circadian rhythm disorders. In both rotarod and pole-climbing experiments, the CRSD+PD group showed reduced time spent on the rotarod and a shorter adaptive rotarod speed, while the latency for automatic turning and the time to descend to the bottom of the pole were prolonged. NHD intervention effectively improved motor impairment in both rotarod and pole-climbing experiments, with superior efficacy compared to the L-Dopa group alone, suggesting that NHD has an ameliorative effect on motor symptoms in PD mice with circadian rhythm disorders. (A) Rotarod dwell time; (B) Adaptable rotarod speed; (C) Pole turning time; (D) Time to descend to the bottom of the pole; vs CRSD+PD; *: P < 0.05, **: P < 0.01, ***: P < 0.001, ****: P < 0.0001.

[0042] Figure 10 This refers to the distance of spontaneous activity during the light-dark cycle in mice after drug intervention. The effect of NHD on spontaneous activity in mice with Parkinson's disease and circadian rhythm disorder (CRSD+PD) was evaluated. After CRSD+PD modeling, the spontaneous activity distance of mice decreased significantly, but the decrease was mainly observed in the dark cycle; the light cycle distance increased compared to the control group. The total activity distance of mice after NHD intervention was prolonged compared to the initial modeling, showing a synchronous increase in the light-dark cycle. Compared to LDopa intervention alone, NHD had a more significant effect on prolonging the nighttime activity distance. A: Total distance of photo-dark cycle activity; B: Total distance of dark cycle activity; C: Total distance of photo-dark cycle activity; *: P < 0.05, ****: P < 0.0001; BM: Before modeling; AM: After modeling (CRSD+MPTP); AT: After treatment; vs CRSD+PD: *: P < 0.05, **: P < 0.01, ***: P < 0.001, ****: P < 0.0001; vs L-Dopa; ###: P < 0.001; ####: P < 0.0001.

[0043] Figure 11 This is a long-term spontaneous activity experiment using light-dark cycle activity trend graphs and cosine curves after drug intervention. The 24-hour activity trend graph and cosine curve were used to evaluate the rhythmicity of light-dark cycle activity in mice. After CRSD+PD modeling, the light-dark cycle activity trend in mice tended to flatten, and the rhythmicity of the cosine curve disappeared. NHD combined with LDopa intervention, compared to LDopa alone, effectively restored the light-dark cycle activity rhythm in mice, suggesting that NHD, in addition to improving the activity capacity of PD mice, also helps to improve the diurnal rhythm in mice. A: Diurnal activity trend graph of the control group; B: Light-dark cycle activity trend graph (left) and light-dark cycle activity cosine curve graph (right) of the PD+CRSD group; C: Light-dark cycle activity trend graph (left) and light-dark cycle activity cosine curve graph (right) of the NHD group; D: Light-dark cycle activity trend graph (left) and light-dark cycle activity cosine curve graph (right) of the LDopa group; BM: Before modeling; AM: After modeling (CRSD+MPTP); vs PD-BM; AT: After Treatment; vs AM: *: P < 0.05, **: P < 0.01, ***: P < 0.001, ****: P < 0.0001.

[0044] Figure 12 This is a MALDI-MS imaging image of 5-HT neurotransmitter expression in the DRN microregion. A: Schematic diagram of HE staining in the DRN brain region; B: Control group; C: PD group; D: CRSD+PD group; E: NHD group; F: LDopa group; The data are presented in rainbow color scale (reflecting ion intensity) for optimal visualization, with a lateral resolution of 80 micrometers.

[0045] Figure 13 This is a MALDI-MS image of 5-HT neurotransmitter expression in the colonic microregion. The control group showed abundant 5-HT expression in the DRN and colonic microregion. After modeling, both the PD group and the CRSD+PD group showed a significant decrease in 5-HT expression in the DRN and colonic microregion. However, compared to the PD group, the decrease was more pronounced in the CRSD+PD group, with almost no 5-HT expression in the DRN brain region. Combined intervention with NHD and levodopa effectively reversed this effect, and NHD had a more significant impact on the 5-HT system compared to levodopa alone. A: Control group; B: PD group; C: CRSD+PD group; D: NHD group; E: LDopa group; Data are presented in rainbow color scales (reflecting ion intensity) for optimal visualization, with a lateral resolution of 80 micrometers.

[0046] Figure 14This is a MALDI-MS imaging image of dopamine (DA) neurotransmitter expression in the CCu microregion. The Control group showed abundant DA expression in the CCu microregion. MPTP-induced DA disruption reduced DA expression in the CCu microregion, while circadian rhythm disruption further accelerated DA depletion. Combined intervention with NHD and levodopa showed better DA recovery compared to levodopa alone. A: Schematic diagram of HE staining in the CCu brain region; B: Control group; C: PD group; D: CRSD+PD group; E: NHD group; F: LDopa group; Data are presented in a rainbow color scale (reflecting ion intensity) for optimal visualization, with a lateral resolution of 80 micrometers.

[0047] Figure 15 The data represent the relative expression levels of 5-HT and DA neurotransmitters in the brain-gut microregions. A: 5-HT expression in the dorsal raphe nucleus microregion; B: 5-HT expression in the colonic microregion; C: DA expression in the striatum. Data are presented as mean intensity from MALDI-MS imaging; *: P < 0.05, **: P < 0.01, ***: P < 0.001; ****: P < 0.0001.

[0048] Figure 16 This refers to the expression of 5-HT-related receptors in the midbrain. 5-HT1A is associated with sleep promotion, while 5-HT2A and 5-HT1B are associated with wakefulness promotion; their activation levels participate in the regulation of circadian rhythms. Western blotting results showed that, compared to the PD group alone, CRSD exacerbated the decrease in 5-HT1A expression and the increase in 5-HT1B expression, while NHD increased 5-HT1A and decreased 5-HT1B levels, showing better effects than L-dopa intervention alone. However, there was no significant difference in 5-HT2A expression across all groups. A: Western blotting; B: Relative expression levels of corresponding receptor proteins; vs CRSD+PD, *: P < 0.05, **: P < 0.01, ***: P < 0.001.

[0049] Figure 17 This refers to the expression of colonic 5-HT3A receptors. 5-HT3 receptors distributed in the intestinal 5-HT system are important carriers for the gut to influence central 5-HT receptor expression via the vagus nerve. Studies have found that the decrease in 5-HT3 receptors is not significant in the simple PD model, but after combining it with CRSD modeling, the expression of 5-HT3A receptors is significantly decreased. NHD intervention has a reversing effect on its expression. A: Western blotting; B: Relative expression level of corresponding receptor protein; vs CRSD+PD, *: P < 0.05, **: P < 0.01, ****: P < 0.0001.

[0050] Figure 18This refers to the expression of hypothalamic Bmal1, Clock, and Per1 genes related to circadian rhythms. Both the CRSD+PD and PD groups showed a certain degree of decrease in Bmal1, Clock, and Per1 circadian rhythm-related genes, but the CRSD+PD group exhibited more severe circadian rhythm disruption and a more significant decrease in gene expression. NHD+L-Dopa upregulated the expression of related genes, with a more pronounced effect on Bmal1 and Per1 genes compared to L-Dopa alone. A: Bmal1 gene expression; B: Clock gene expression; C: Per1 gene; vs CRSD+PD, *: P < 0.05, **: P < 0.01, ****: P < 0.0001; vs L-Dopa, #: P < 0.05. Detailed Implementation

[0051] Before further describing specific embodiments of the present invention, it should be understood that the scope of protection of the present invention is not limited to the specific embodiments described below; it should also be understood that the terminology used in the embodiments of the present invention is for describing specific embodiments and not for limiting the scope of protection of the present invention. Test methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the respective manufacturers.

[0052] When numerical ranges are given in the embodiments, it should be understood that, unless otherwise stated in the present invention, both endpoints of each numerical range and any value between the two endpoints may be selected. Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. In addition to the specific methods, apparatus, and materials used in the embodiments, based on the knowledge of the prior art possessed by one of ordinary skill in the art and the description of this invention, any prior art methods, apparatus, and materials similar to or equivalent to those described, apparatus, and materials in the embodiments of this invention may be used to implement the present invention.

[0053] Unless otherwise stated, the experimental methods, detection methods and preparation methods disclosed in this invention all adopt conventional techniques in this technical field.

[0054] Given that existing Parkinson's disease treatments mainly focus on symptomatic interventions for motor symptoms or single sleep disorders, and lack holistic regulation methods targeting the key pathological link of circadian rhythm disorder in Parkinson's disease, and that long-term medication can easily lead to problems such as sleep structure disruption, daytime sleepiness, and cognitive decline, this invention aims to provide a safe, effective, and long-term applicable traditional Chinese medicine composition based on the core pathogenesis of "rhythm imbalance" for the treatment of Parkinson's disease and its associated circadian rhythm disorder.

[0055] The inventors had previously conducted systematic theoretical and clinical research on chronic insomnia, proposing and demonstrating that nocturnal herbal medicines can improve insomnia symptoms by regulating the body's diurnal rhythm disorder, achieving good clinical efficacy. Building on this, the inventors further expanded the theory of combining the properties of traditional Chinese medicine with rhythmic biology, applying nocturnal herbal medicines to the treatment of Parkinson's disease. They discovered that these herbal medicines can regulate the body's diurnal rhythm homeostasis by utilizing their inherent diurnal movement rhythm characteristics, simultaneously improving the diurnal rhythm disorder and related motor symptoms in Parkinson's disease patients through a "rhythm-to-rhythm" approach. The traditional Chinese medicine composition provided by this invention consists of the following raw materials by weight: 15-30 parts Albizia bark, 10-30 parts lotus seeds, 10-30 parts lily bulbs, 9-30 parts Polygonum multiflorum stem, and 0.25-1 part saffron.

[0056] The specific preparation of the extract of the traditional Chinese medicine composition is as follows: Weigh all the medicinal materials according to the ratio, add water equivalent to 8 to 10 times the total weight of the medicinal materials, decoct 2 to 3 times, each time for 0.5 to 1 hour, combine the decoction extracts, filter, concentrate, and obtain the extract.

[0057] Animal experiments and clinical studies have verified that the above-mentioned herbal formulas containing nocturnal plant extracts have a definite therapeutic effect on improving sleep-wake rhythm, motor function and overall symptoms, and have a good safety profile.

[0058] The raw materials used in the following examples—Albizia bark, lotus seeds, lily bulbs, Polygonum multiflorum stem, and saffron—all comply with the relevant provisions of the Chinese Pharmacopoeia 2020 edition, Volume I, under the respective medicinal materials section. Each medicinal material underwent cleaning, cutting, processing, and pulverizing. Before being added to the Pharmacopoeia, each material was identified to ensure that its actual appearance matched its name, and its quality met the national Pharmacopoeia standards (specific identification methods for medicinal materials were implemented according to the Pharmacopoeia standards).

[0059] The traditional Chinese medicine formulas used in the following experimental examples were prepared according to the following steps: Weigh out 150 g of Albizia bark, 150 g of lotus seeds, 150 g of lily bulbs, 300 g of Polygonum multiflorum stem, and 10 g of saffron. For the first decoction, add 7.5 L of water, bring to a boil over high heat, then simmer over low heat for 1 hour. Filter to obtain the first decoction. For the second decoction, add 6.0 L of water again, bring to a boil over high heat, then simmer over low heat for 30 minutes. Filter to obtain the second decoction. Combine the two decoction extracts, filter, and concentrate to a relative density of 1.40 at 20°C. Centrifuge at 3000 rpm for 10 minutes, collect the supernatant, and spray dry at 60°C to obtain a dry extract.

[0060] The dry extract obtained above is pulverized, and then mixed with sucrose and dextrin (mass ratio 1:3:1). Using 70% ethanol as a wetting agent, the mixture is granulated, dried, and sized to obtain granules. Alternatively, the dry extract obtained above is pulverized, and an appropriate amount of micronized silica gel and α-galactose are added and mixed. Using ethanol as a wetting agent, the mixture is granulated, dried, sized, and encapsulated to obtain capsules. Alternatively, the dry extract obtained above is pulverized, and an appropriate amount of sucrose and dextrin are added and mixed. Using ethanol as a wetting agent, the mixture is granulated, dried, sized, and compressed to obtain tablets. Alternatively, an appropriate amount of sucrose and flavoring are added to the concentrated liquid after centrifugation above, and the mixture is sterilized and filled to obtain an oral liquid.

[0061] Experimental Example 1 Clinical study of nocturnal herbal formula for treating Parkinson's disease with circadian rhythm disorder 1. Clinical Data 1.1 Research Subjects Sixty participants in the early to mid-stages of PD were selected from those who visited the outpatient or inpatient department of the Department of Neurology at Longhua Hospital affiliated with Shanghai University of Traditional Chinese Medicine between 2022 and 2024 and were willing to follow the treatment methods.

[0062] 1.2 Diagnostic criteria According to the "Diagnostic Criteria for Parkinson's Disease" established by the Movement Disorders and Parkinson's Disease Group of the Neurology Branch of the Chinese Medical Association in 2006: 1) Reduced motor function: The speed of initiating voluntary movements is slow. As the disease progresses, the speed and amplitude of repetitive movements decrease. 2) At least one of the following characteristics must be present: ① Muscle rigidity; ② Resting tremor 4-6 Hz; ③ Postural instability (not caused by primary visual, vestibular, cerebellar, or proprioceptive dysfunction);

[0063] 1.3 Inclusion Criteria 1) Age 30-80, gender not limited; 2) Meets the diagnostic criteria for primary Parkinson's disease as revised by the Movement Disorder Society (MDS) in 2015; 3) Hoehn Yahr stages ≤ 3 stages; 4) The Chinese University of Hong Kong Rapid Eye Movement Sleep Behavior Disorder Scale (RBDQ-HK) score is ≥17; 5) At least one of the following symptoms is present: sensitivity to cold or heat; constipation or diarrhea; 6) For subjects who have already received anti-Parkinson's disease treatment (levodopa preparations, dopamine receptor agonists, monoamine oxidase inhibitors, catechol-O-methyltransferase inhibitors, anticholinergic drugs, etc.), the dosage of the anti-Parkinson's disease drug must have been relatively stable for at least 3 months prior to this clinical trial, and there must be no clear plan to change the existing treatment regimen in the next 3 months. 7) Participation is voluntary, and informed consent must be signed.

[0064] 1.4 Exclusion Criteria 1) Patients with Parkinson's syndrome or Parkinson's plus syndrome; 2) Active depression or psychosis and / or treatment with antidepressants or antipsychotics; 3) Severe sequelae of stroke and diseases of other systems such as the heart, lungs, liver, and kidneys; 4) History of drug abuse or alcoholism; 5) Patients who are currently participating in other clinical studies or who have participated in other clinical studies within the past 30 days.

[0065] 2. Research Plan This study included 60 patients with early to mid-stage Parkinson's disease and circadian rhythm disorders. It was a randomized, double-blind, placebo-controlled trial, with 30 patients in the treatment group and 30 in the placebo group. The treatment group received Nyctinastic Herbal Decoction (NHD) (administered as granules prepared above), while the control group received a placebo of NHD (prepared at 1 / 20th the concentration of NHD, with added excipients). The treatment course was 12 weeks. Changes in sleep-wake rhythms (RBDQ-HK, PDSS, PSQI, and PSG), circadian rhythms of salivary melatonin secretion, cardiovascular circadian rhythm changes in 24-hour ambulatory blood pressure, and overall Parkinson's disease status (UPDRS and SCOPA-AUT) were observed before and after treatment in both groups to clarify the clinical efficacy of NHD in patients with Parkinson's disease and circadian rhythm disorders. During the study, 2 patients dropped out of the treatment group and 3 patients dropped out of the placebo group. The final treatment group included 28 people, and the placebo group included 27 people.

[0066] The preparation process of the placebo of the traditional Chinese medicine formula for nocturnal emission is as follows: Weigh out 150 g of Albizia bark, 150 g of lotus seeds, 150 g of lily bulbs, 300 g of Polygonum multiflorum stem, and 10 g of saffron. For the first decoction, add 7.5 L of water, bring to a boil over high heat, then simmer over low heat for 1 hour. Filter to obtain the first decoction. For the second decoction, add 6.0 L of water again, bring to a boil over high heat, then simmer over low heat for 30 minutes. Filter to obtain the second decoction. Combine the two decoctions, filter, dilute by 1 / 20, and then concentrate to a relative density of 1.40 at 20℃. Centrifuge at 3000 r / min for 10 min, collect the supernatant, and spray dry at 60℃ to obtain a dry extract. Pulverize the obtained dry extract, mix it with sucrose and dextrin (mass ratio 1:3:1), use 70% ethanol as a wetting agent, granulate, dry, and granulate to obtain granules of the herbal formula for treating night-related ailments.

[0067] 3. Research Results The study results found (Tables 1-3 and...) Figures 1-8 Nocturnal herbal formulas can improve various aspects of Parkinson's disease (PD) patients with circadian rhythm disorders. NHD has a significant regulatory effect on circadian rhythm disorders in PD patients, effectively improving sleep quality by reducing RBDQ-HK scores, increasing PDSS scores, and reducing PSQI scores. Polysomnography shows that it is superior to the placebo group in improving sleep efficiency and reducing sleep fragmentation. Regarding cardiovascular circadian rhythms, NHD can increase the rate of nocturnal systolic blood pressure decline and regulate the blood pressure curve towards normal. Simultaneously, in regulating the circadian rhythm of salivary melatonin (SM), it can increase the median circadian rhythm of SM secretion and increase the amplitude of the circadian rhythm of SM secretion. Furthermore, NHD has a positive effect on improving overall PD symptoms, including motor symptoms and autonomic nervous system symptoms, and is significantly superior to the placebo group.

[0068] Table 1. Comparison of RBDQ-HK, PDSS, and PSQI scores before and after treatment in the two groups (points). ) Note: RBDQ-HK, Rapid Eye Movement Sleep Behavior Disorder Scale of the Chinese University of Hong Kong; PDSS, Parkinson's Disease Sleep Scale; PSQI, Pittsburgh Sleep Quality Index. a) Compared with before treatment, P < 0.05; b) Compared with the control group after treatment, P < 0.05.

[0069] Table 2 Comparison of blood pressure rhythm patterns between the treatment group and the placebo group Table 3. Comparison of UPDRS and SCOPA-AUT scores before and after treatment in the two groups (points). ) Note: UPDRS, Unified Parkinson's Disease Rating Scale; SCOPA-AUT, Autonomic Nervous System Assessment Scale. a) Compared with before treatment, P < 0.05; b) Compared with the control group after treatment, P < 0.05;

[0070] Experimental Example 2 Efficacy study of nocturnal Chinese medicine formula in treating mice with Parkinson's disease and circadian rhythm disorder 1. Experimental Methods 1.1 Pole Climbing Experiment The pole climbing experiment mainly evaluates a mouse's motor coordination and balance by observing its ability to climb down a pole.

[0071] The climbing device consists of a climbing pole and a base. The base provides good stability. The climbing pole is 5mm in diameter and 55cm high, and is wrapped in gauze to prevent the mice from slipping. The climbing device is placed in the rearing cage, and the cage is lined with bedding material to cover the base of the climbing device.

[0072] Adaptation training: Mice were placed at different locations on a pole to learn how to turn around on the pole and descend smoothly, and how to correctly use their paws and noses to maintain balance and descend. Training was conducted three times a day for seven consecutive days prior to the formal experiment.

[0073] Formal Experiment: In the formal experiment, mice were placed head-up on top of a pole. Normal mice would naturally orient themselves downwards and descend the pole continuously to the ground, returning to their cage. The latency of the animal's automatic orientation and the total time required to descend to the bottom of the pole were recorded.

[0074] Mice with Parkinson's disease have impaired motor coordination, and their latency and the total time required to descend to the bottom of the pole are usually significantly prolonged.

[0075] 1.2 Rotating Rod Experiment The rotarod test is mainly used to evaluate a mouse's coordination, balance and motor skills by observing its balance ability in a rotarod.

[0076] The rotating rod device has a diameter of 3cm and a length of 6cm. The rotation speed can be adjusted from 0 to 100 r / min.

[0077] Adaptation training: Place the mouse on a rotisserie bar, facing away from the direction of rotation, and allow it to adapt to a speed of 4 rpm for 1-2 minutes. After adapting to the initial speed, gradually increase the rotisserie speed by 10 rpm every 2 minutes until it reaches 30 rpm, and maintain this speed for 6 minutes. If the animal falls off the rotisserie bar, it should be returned to its cage to rest for 15 minutes before continuing training. Before the formal experiment, train continuously for 7 days, twice a day.

[0078] Formal experiment: Mice were placed one by one on a rotating rod, facing away from the direction of rotation. The rod was started and, after adaptation at 4 rpm, the speed was increased from 4 rpm to 30 rpm within 6 minutes. The mice's movement was observed, including the time spent on the rod and the speed they could adapt to.

[0079] Mice with Parkinson's disease have impaired motor coordination and balance, resulting in shorter dwell times and a reduced range of rotation speeds.

[0080] 1.3 Long-term spontaneous activity experiment The long-term spontaneous activity experiment mainly evaluates the activity rhythm and motor ability of mice by observing their activity over a 24-hour period.

[0081] Environmental setting: Place the spontaneous activity box in a standard soundproof box, and control the environmental conditions inside the box: the temperature is maintained at (22 ± 2) °C, the humidity is kept at (60 ± 5)%, and the noise level is controlled below 70 dB to ensure the stability and low interference of the experimental environment. Use a time control switch to achieve the day-night cycle. Set the light cycle for the normal group as 7:00 - 19:00, the dark cycle as 19:00 - 7:00, and the illuminance is about 100 lux; set the circadian rhythm disorder group as the full dark cycle of 0:00 - 24:00. Put an appropriate amount of bedding in the standard soundproof box. To simulate the social characteristics of mice, place 5 mice in each activity box, and let them eat and drink freely.

[0082] Data collection: Use an industrial infrared camera to record the activities of mice for 24 hours. This camera has the characteristics of high sensitivity and low interference, and can accurately capture the activity trajectories of each mouse under light and dark conditions. The EthoVision XT software calculates the activity distance and trajectory of mice based on the collected data.

[0083] The activity of normal mice can show obvious circadian rhythm, that is, the activity decreases during the light cycle and increases during the dark cycle. Mice with circadian rhythm disorder can show obvious rhythm disorders and lack obvious differences between light and dark cycles. Due to their movement disorders, the activity of Parkinson's disease mice will decrease in both light and dark cycles.

[0084] 2. Experimental animals 50 SPF-grade male C57BL / 6 mice, 10 weeks old, weighing (20 ± 2) g, were purchased from Shanghai Jiesijie Experimental Animal Co., Ltd., with the license SYXK (Shanghai) 2020 - 0042. They were housed in the SPF-grade animal room of the I期 Animal Center of Shanghai Institute of Materia Medica, Chinese Academy of Sciences, at a constant temperature of (22 ± 2) °C and a constant humidity of (60 ± 5)%. The 12-hour artificial light-dark cycle was used to achieve the day-night cycle (light cycle 7:00 - 19:00, dark cycle 19:00 - 7:00, illuminance ≈ 100 lux), and the animals were allowed to move, eat, and drink freely. All animal experiments carried out have been approved by the Experimental Animal Welfare and Ethics Committee of Shanghai Institute of Materia Medica, Chinese Academy of Sciences (approval number: 2024 - 04 - LY - 29).

[0085] 3. Animal grouping After 7 days of adaptive feeding with free access to food and water. After the adaptation period, conduct the training of the pole climbing experiment and the rotarod experiment for 7 consecutive days. In the pole climbing experiment, train 3 times a day, and in the rotarod experiment, train 2 times a day. Select 25 mice with similar activity abilities and randomly divide them into a blank control group (Control group), a Parkinson's disease model group (PD group), a Parkinson's disease circadian rhythm disorder group (CRSD + PD group), a positive drug intervention group (L-Dopa group, levodopa), and a nocturnal traditional Chinese medicine formula combined with positive drug intervention group (NHD group), with 5 mice in each group.

[0086] 4. Modeling Mice in each group were placed in a spontaneous activity box with a timer switch regulating the day-night cycle. The Control and PD groups were placed in a 12hL / 12hD environment (photocycle 7:00-19:00, dark cycle 19:00-7:00, illuminance ≈100 lux). The CRSD+PD, L-Dopa, and NHD groups were placed in a 24h dark environment for 50 days to simulate the circadian rhythm disorder in the prodromal phase of Parkinson's disease. The disappearance of the nocturnal circadian rhythm fluctuation in mice indicated successful modeling.

[0087] On day 51, the PD group, CRSD+PD group, L-Dopa group, and NHD group were intraperitoneally injected with MPTP (8 mg / kg) once daily for 28 consecutive days to establish a Parkinson's disease model. The control group received the same dose of solvent as a control. On day 77, the mouse pole climbing test and rotarod test were performed. When the mouse swayed or paused during the pole climbing process, and the time spent on the rotarod decreased, it indicated that the model was successfully established.

[0088] 5. Administration of medication Prophylactic administration was used. On day 1 of MPTP modeling, the NHD group was given a traditional Chinese medicine composition (1.95 g / kg based on dry extract) by gavage at 10:00 a.m. On day 78, after successful PD modeling, both the NHD group and the L-Dopa group were given L-Dopa (levodopa, 10 mg / kg) by intraperitoneal injection at 10:00 a.m. for 18 days.

[0089] 6. Observation Indicators Long-term spontaneous activity data were collected on days 49, 77, and 94 (12:00 am) and recorded continuously for 3 days. Pole climbing and rotarod experiments were performed 30 minutes after drug administration on days 50, 78, and 95.

[0090] 6.1 Athletic Ability Indicators The motor abilities of mice were evaluated by the latency of spontaneous turning and the total time required to descend to the bottom of the pole in the pole climbing experiment, the dwell time on the rotunda bar, the latency from being placed on the rotunda bar to falling, the adaptable rotation speed, and the total activity distance in the long-term spontaneous activity experiment.

[0091] 6.2 Circadian Rhythm Indicators The diurnal rhythm of mice was evaluated by the trend of their activity distance per unit time in long-term spontaneous activity experiments.

[0092] 7. Results turn out( Figures 9-11The combination of a nocturnal herbal formula (NHD) and levodopa (L-DOPA) effectively prolonged the dwell time in rotarod tests in Parkinson's disease (PD) mice with circadian rhythm disorders, increased the adaptable rotation speed, shortened the spontaneous turning latency in pole climbing tests, and accelerated the descent time to the bottom, effectively improving motor function and balance in PD. In long-term spontaneous activity, NHD not only increased the total activity level and improved motor function in mice but also regulated the circadian rhythm, restoring the nocturnal rhythm. While L-DOPA alone improved motor function in PD, its effect on circadian rhythm was not significant.

[0093] Experimental Example 3 Mechanism study of nocturnal herbal formula in treating Parkinson's disease with circadian rhythm disorder in mice 1. Experimental Methods 1.1 Animal handling and sample collection Following the efficacy trials, mechanistic studies were conducted. On day 95, after completing the pole climbing and rotarod experiments, two mice from each group were placed in induction boxes, anesthetized with isoflurane gas, and perfused via the portal vein with PBS. The whole brain and colonic segment were quickly harvested, with the colonic segment rolled into a "Swiss roll" and embedded in 2% sodium carboxymethyl cellulose (CMC-Na). The embedding boxes were placed in isopentane / dry ice, and after the embedding agent had completely solidified, the embedding boxes were removed and stored at -80°C for subsequent spatial metabolomics detection. The remaining three mice were euthanized by cervical dislocation, and the colonic segment and midbrain tissue were quickly separated, weighed, flash-frozen in liquid nitrogen, and stored at -80°C for subsequent Western blotting and RT-PCR detection.

[0094] 1.2 Spatial Metabolomics Detection and Analysis The spatial metabolomics detection in this experiment was performed by Shanghai Zhenyi Biotechnology Co., Ltd. Brain and small intestinal tissue samples were first embedded in CMC and then frozen at -20℃. Target brain region slices were collected, vacuum dried, and labeled for localization. The slices were then coated with matrix according to predetermined parameters. Mass spectrometry imaging was then performed to acquire raw data from the positive mode scan. Finally, the raw data was imported into SCiLS™Lab 2024 software, and after baseline subtraction, peak alignment, and other processing, the spatial response intensity data of metabolites were obtained.

[0095] 1.3 Immunoblot Detection and Analysis Immunoblot assays were performed using midbrain and colon tissue samples. Protein samples were extracted by washing, grinding, lysis, and centrifugation, followed by SDS-PAGE electrophoresis. After the PVDF membrane was assembled using a transfer clamp, it was blocked at room temperature. The membrane bands were then incubated overnight with primary antibody at 4°C and incubated at room temperature with secondary antibody. The protein band images were obtained by chemiluminescence imaging, and finally, the gray values ​​of the bands were quantitatively analyzed using ImageJ software.

[0096] 1.4 Real-Time PCR Detection and Analysis Real-Time PCR detection first involves cryogenically pulverizing tissue samples, followed by lysis, centrifugation, precipitation, and washing to extract RNA. The RNA concentration and quality are then measured using a spectrophotometer. RNA is then reverse transcribed into cDNA according to a specific system. After measuring the cDNA concentration, an RT-qPCR reaction system is prepared based on the designed primers. Finally, the expression fold of the target gene in the experimental group relative to the control group is determined by calculating ΔCt and ΔΔCt values ​​and using the formula 2^-ΔΔCt.

[0097] 2. Results turn out( Figures 12-18 The combined intervention of a nocturnal herbal formula (NHD) and levodopa (L-DOPA) effectively increased the expression of 5-HT in the gut and dorsal raphe nucleus microregions, as well as the expression of DA in the striatal microregions. Compared with L-DOPA alone, NHD had a more significant effect on the 5-HT system. Western blotting and RT-PCR results further suggested that NHD could increase the levels of 5-HT3 receptors in the gut and 5-HT1A receptors in the midbrain, decrease the level of 5-HT1B receptors, and promote the expression of hypothalamic circadian rhythm genes PER, CLOCK, and BMAL1. These mechanisms of action may be related to the circadian rhythm regulation mediated by the gut-brain 5-HT system.

[0098] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. The use of a traditional Chinese medicine composition or its extract in the preparation of a medicament for treating Parkinson's disease, characterized in that, The traditional Chinese medicine composition consists of the following raw materials in parts by weight: 15-30 parts of Albizia bark, 10-30 parts of lotus seeds, 10-30 parts of lily bulbs, 9-30 parts of Polygonum multiflorum stem, and 0.25-1 part of saffron.

2. The application according to claim 1, characterized in that, The extract was prepared according to the following steps: Weigh out the following ingredients according to their weight proportions: Albizia bark, lotus seeds, lily bulbs, Polygonum multiflorum vine, and saffron. Mix them together, add water, and decoct. Collect the decoction.

3. The application according to claim 2, characterized in that, The decoction involves adding water equivalent to 8 to 10 times the total weight of the medicinal materials, and decocting 2 to 3 times, each time for 0.5 to 1 hour.

4. The application according to claim 1, characterized in that, The traditional Chinese medicine composition or its extract is used to improve motor symptoms, non-motor symptoms and / or circadian rhythm disorders associated with Parkinson's disease.

5. The application according to claim 4, characterized in that, The motor symptoms include tremor, rigidity, bradykinesia, and / or postural and gait disturbances; the non-motor symptoms include sleep disorders, anxiety, depression, and autonomic dysfunction; the circadian rhythm disturbances include sleep-wake rhythm disturbances, cardiovascular circadian rhythm abnormalities, and / or melatonin secretion rhythm abnormalities.

6. A drug for treating Parkinson's disease, characterized in that, It is formulated by combining the traditional Chinese medicine composition of claim 1 or its extract with pharmaceutically acceptable excipients, and the drug is used to improve motor symptoms, non-motor symptoms and / or circadian rhythm disorders associated with Parkinson's disease.

7. The drug according to claim 6, characterized in that, The drug is an oral preparation.

8. The medicament according to claim 7, characterized in that, The drug is in the form of granules, capsules, tablets, or oral liquid.

9. The use of the traditional Chinese medicine composition of claim 1 in the preparation of a medicament for the combined treatment of Parkinson's disease with levodopa.

10. The application according to claim 9, characterized in that, The traditional Chinese medicine composition is used to alleviate dopaminergic drug-induced sleep structure disruption, which includes at least one of increased nighttime awakenings, abnormal dreams, sleep fragmentation, or worsening REM sleep behavior disorder.

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