Traditional Chinese medicine composition for treating circadian rhythm disorder of Parkinson's disease and its preparation method and application

Abstract

The present invention belongs to the field of traditional Chinese medicine technology, and specifically relates to a traditional Chinese medicine composition for treating circadian rhythm disorders in Parkinson's disease, as well as its preparation method and application. The traditional Chinese medicine composition is made from the following raw materials in parts by weight: 3-10 parts of cinnamon twig, 15-30 parts of raw dragon bone, 15-30 parts of raw oyster, 10-15 parts of cooked rehmannia, 9-15 parts of wolfberry, 10-30 parts of parasitic loranthus, 9-30 parts of gastrodia elata, 10-30 parts of white peony root, 6-15 parts of bombyx batryticatus, 1-6 parts of scorpion, 1-6 parts of centipede, 9-15 parts of arisaema, and 3-10 parts of zedoaria. The present invention rationally combines the components to jointly exert the functions of harmonizing the nutrient and defensive systems, nourishing the liver and kidneys, and detoxifying and unblocking the meridians.

Description

Technical Field

[0001] The present invention belongs to the technical field of traditional Chinese medicine, and particularly relates to a traditional Chinese medicine composition for treating circadian rhythm disorder of Parkinson's disease, and a preparation method and application thereof. Background Art

[0002] Parkinson's disease (PD) is the second most common chronic neurodegenerative disorder. In addition to the typical motor symptoms of PD, including tremor, bradykinesia, rigidity, and abnormal posture and gait, non-motor symptoms such as cognitive impairment, depression, anxiety, and sleep disturbances may also appear before the onset of motor symptoms. Over 40 years of research, it has been gradually recognized that non-motor symptoms of Parkinson's disease are more clinically significant in assessing and predicting the progression and prognosis of Parkinson's disease than its typical motor manifestations. Studies have found that 80% of patients with RBD (rapid eye movement sleep behavior disorder) will progress to PD within 10 to 12 years; 67.5% of PD patients experience one or more gastrointestinal symptoms before the onset of motor symptoms, with constipation being a typical prodromal biomarker for PD; and PD patients with hyperhidrosis have higher motor impairment scores than those without hyperhidrosis. In addition, clinical studies have shown that among non-motor symptoms, RBD, constipation, and temperature regulation disorders are independent risk factors for postural instability / gait disorder (PIGD) in Parkinson's disease, and PD patients with PIGD as the dominant symptom generally have more severe clinical symptoms and faster disease progression.

[0003] Circadian rhythm is the most common biological rhythm in nature. It refers to the changes in the body's vital activities with a 24-hour cycle. For example, sleep and wakefulness, hormone secretion, body temperature, heart rate and blood pressure all have 24-hour periodic fluctuations. In recent years, the correlation between circadian rhythm and neurodegenerative diseases has attracted widespread attention and research from scholars. Many studies have found that although Parkinson's disease, Alzheimer's disease, Huntington's disease, etc. have specific clinical symptoms, they are often accompanied by circadian rhythm disorders. More and more clinical data show that circadian rhythm disorders are not only a common symptom of many neurodegenerative diseases, but may also be the main mechanism driving the progression of these diseases.

[0004] The complex and varied clinical manifestations of Parkinson's disease, such as altered rest-activity rhythms, disrupted sleep-wake cycles, body temperature rhythms, and gastrointestinal dysfunction, are closely linked to circadian rhythm disruption. Disruption of this circadian rhythm not only impairs the quality of life of Parkinson's patients but may also accelerate disease progression. Studies have shown that circadian rhythm disruption can lead to oxidative stress and neuroinflammatory responses that damage dopamine neurons, accelerating Parkinson's disease progression. Furthermore, circadian rhythm disruption itself affects the regulation of various physiological processes. For example, circadian rhythm disruption can induce neuroinflammation, impair protein homeostasis, and redox homeostasis, leading to pathological deposition of α-synuclein in the locus coeruleus, brainstem reticular formation, dorsolateral tegmental nucleus, and pedunculopontine nucleus. These degenerations can cause abnormalities in wake-sleep transitions, leading to RBD. Both the intestinal microbiome and colonic motility follow a circadian rhythm. Disruption of circadian rhythms can also lead to disturbances in the intestinal microbiome and abnormal colonic motility, leading to gastrointestinal symptoms. There is also extensive functional overlap between the neural circuits controlling body temperature regulation and the circadian system, particularly within the pons and medulla oblongata. Circadian rhythm disruption can induce abnormalities in temperature regulation, such as intolerance to cold and heat. Furthermore, some researchers have suggested that continued levodopa use during Parkinson's disease treatment may be a significant factor in exacerbating and driving central and peripheral circadian rhythm disruption in Parkinson's patients. Consequently, a growing body of research suggests that circadian rhythm disruption may occur early in Parkinson's disease and may contribute to the onset and progression of the disease. Circadian rhythm regulation is a crucial component of Parkinson's disease treatment, potentially enabling holistic regulation of Parkinson's disease. Clinical research supports this view. For example, bright light therapy (BLT), exogenous melatonin supplementation, and deep brain stimulation have been shown to improve not only the motor symptoms of Parkinson's disease but also associated non-motor symptoms such as RBD, gastrointestinal symptoms, excessive sweating, and mood. Therefore, pharmacological and non-pharmacological interventions targeting circadian rhythms may become a new strategy to delay the clinical progression of early PD.

[0005] Currently, clinical research lacks specific therapeutic agents and methods for the circadian rhythm disturbances of Parkinson's disease (PD). Many Western medications are associated with toxic side effects such as drug resistance, dependence, truncation, "on / off" phenomena, dyskinesias, and "wearing-off" phenomena, failing to meet the dual needs of PD patients for both efficacy and safety. In Traditional Chinese Medicine (TCM), Parkinson's disease is primarily categorized as a "tremor syndrome" due to its characteristic tremor. From the perspective of TCM, the tremor syndrome of Parkinson's disease is primarily a manifestation of the physiological decline of yin and yang in middle-aged and elderly people, linked to liver and kidney deficiency, and deficiency of essence and blood. This imbalance, primarily due to yin and blood deficiency, can lead to yin deficiency and yang hyperactivity, resulting in wind-like symptoms that circulate in the limbs. Many researchers have explored the clinical application of Traditional Chinese Medicine (TCM) to treat Parkinson's disease's non-motor symptoms associated with circadian rhythm disturbances. Clinical research has been conducted on Parkinson's disease with sleep disturbances, depression, constipation, and nocturia. Treatments employ methods such as promoting blood circulation and tranquilizing the mind, harmonizing the Shaoyang meridian, nourishing yin and moistening the intestines, and warming the kidneys and astringing the dampness. However, a TCM combination that effectively integrates these symptoms and systematically analyzes and explores these symptoms for the treatment of circadian rhythm disturbances in Parkinson's disease is currently lacking. Summary of the Invention

[0006] In view of the problems and shortcomings of the prior art, the present invention provides a traditional Chinese medicine composition for treating circadian rhythm disorder in Parkinson's disease.

[0007] To achieve the above object, the technical solution adopted by the present invention is:

[0008] The first object of the present invention is to provide a traditional Chinese medicine composition for treating circadian rhythm disorder in Parkinson's disease. The traditional Chinese medicine composition is prepared from the following raw materials in parts by weight: 3-10 parts of cinnamon twig, 15-30 parts of raw dragon bone, 15-30 parts of raw oyster, 10-15 parts of cooked rehmannia, 9-15 parts of wolfberry, 10-30 parts of mistletoe, 9-30 parts of gastrodia, 10-30 parts of white peony root, 6-15 parts of bombyx batryticatus, 1-6 parts of scorpion, 1-6 parts of centipede, 9-15 parts of arisaema, and 3-10 parts of zedoaria.

[0009] Preferably, the traditional Chinese medicine composition is made of the following raw medicines in parts by weight: 10 parts of cinnamon twig, 30 parts of raw dragon bone, 30 parts of raw oyster, 15 parts of cooked rehmannia, 12 parts of wolfberry, 15 parts of mistletoe, 9 parts of gastrodia, 15 parts of white peony root, 9 parts of bombyx batryticatus, 3 parts of scorpion, 3 parts of centipede, 15 parts of arisaema, and 9 parts of zedoaria.

[0010] The second object of the present invention is to provide a method for preparing the Chinese medicine composition, comprising the following steps:

[0011] Weigh cinnamon twig, raw dragon bone, raw oyster, cooked rehmannia, wolfberry, parasitic herb, gastrodia elata, white peony root, bombyx batryticatus, scorpion, centipede, arisaema, and zedoaria according to weight and set aside;

[0012] The weighed Chinese medicinal raw materials are mixed, water is added and boiled, and the decoction is collected to obtain the product.

[0013] Preferably, the specific operation process of decocting with water is: adding water equivalent to 6 to 8 times the amount of the medicinal material mixture, decocting 2 to 3 times, each time for 40 to 60 minutes.

[0014] The third object of the present invention is to provide a use of the traditional Chinese medicine composition in the preparation of a medicine for treating Parkinson's disease.

[0015] Preferably, the drug is used to improve circadian rhythm disorder in Parkinson's disease, or

[0016] The drug is used to improve Parkinson's disease combined with sleep disorders, or

[0017] The drug is used to improve Parkinson's disease combined with gastrointestinal dysfunction, or

[0018] The medicine is used to improve Parkinson's disease combined with temperature regulation dysfunction.

[0019] The fourth object of the present invention is to provide a pharmaceutical preparation for treating circadian rhythm disorder in Parkinson's disease, which comprises the traditional Chinese medicine composition and pharmaceutically acceptable excipients.

[0020] Preferably, the pharmaceutical preparation is a granule, powder, capsule, tablet, mixture or oral solution.

[0021] Preferably, the preparation method of the granules comprises the following steps:

[0022] Weigh cassia twig, raw dragon bone, raw oyster, cooked rehmannia, wolfberry, parasitic herb, gastrodia elata, white peony root, bombyx batryticatus, scorpion, centipede, arisaema and zedoaria according to weight, mix, add water and boil, collect the decoction, filter, concentrate the filtrate to a relative density of 1.14-1.15 at 60-80° C., add auxiliary materials, dry, granulate and package to obtain the product.

[0023] Preferably, the auxiliary material is dextrin, and the mass ratio of the dextrin to the concentrated material is 1:12-32.

[0024] At present, traditional Chinese medicine treatment of circadian rhythm disorder in Parkinson's disease mostly targets a non-motor symptom such as sleep disorder, constipation, etc., and conducts syndrome differentiation and treatment on this basis, or adds or subtracts according to the symptoms, which cannot take into account the diversity and complexity of patients' non-motor symptoms. The present invention team believes that the etiology and pathogenesis of circadian rhythm disorder in Parkinson's disease are mainly due to the deficiency of Ying and Blood in the elderly, the disruption of Ying and Wei balance, and the disharmony between Ying and Wei. Combined with the Ying and Wei theory of TCM, Wei Qi has three circulation routes. One is to accompany Ying Qi and consolidate Ying Yin, the second is to spread throughout the body and control the outside, and the third is to circulate in the twelve meridians and five internal organs day and night to determine sleep and wakefulness. All three are directly or indirectly restricted by Ying Yin. When elderly people experience Ying Yin depletion and disharmony between Ying and Wei, they are unable to consolidate Ying Yin, resulting in frequent urination at night, constipation, and diarrhea. They are unable to protect the exterior, resulting in chills and heat intolerance, hot sweats, and restless sleep, with frequent wakings and difficulty falling asleep. Simultaneously, when Wei is strong but Ying is weak, they experience tremors in the hands and feet and unstable posture. Therefore, in addition to "nourishing the liver and kidneys, detoxifying and unblocking the meridians," the fundamental principle of Parkinson's disease treatment is to "harmonize Ying and Wei."

[0025] This prescription has the effects of harmonizing the Ying and Wei, nourishing the liver and kidneys, and detoxifying and unblocking the meridians. In the prescription, cinnamon twig and white peony root harmonize the Ying and Wei as the main herbs, while Rehmannia root, wolfberry fruit, and mulberry fruit replenish essence and blood and nourish the Ying Yin. Arisaema, scorpion, and centipede detoxify and clear the meridians, and promote the Wei Yang, all of which serve as the auxiliary herbs. Calcined dragon bone and calcined oyster are used to consolidate the Ying Yin, while Gastrodia elata and silkworm regulate and suppress the Wei Yang. The combination of these herbs not only nourishes the liver and kidneys, detoxifies and unblocks the meridians, but also plays a role in harmonizing the Ying and Wei. Research has shown that this prescription has the functions of harmonizing the Ying and Wei, nourishing the liver and kidneys, and unblocking the meridians and detoxifying. Its efficacy is not only reflected in the improvement of motor symptoms such as tremor, rigidity, bradykinesia, postural instability, and gait disorders, but can also effectively improve non-motor symptoms of PD such as sleep-wake cycle disorders, abnormal body temperature regulation, and gastrointestinal dysfunction.

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] The present invention rationally combines the various components and has a rigorous drug formulation to accurately identify the pathogenesis of Parkinson's disease's circadian rhythm disorder: disharmony between the Ying and Wei, liver and kidney deficiency, and toxic accumulation and obstruction of the meridians. Targeting these key pathological mechanisms, the drug works together to harmonize the Ying and Wei, nourish the liver and kidneys, and detoxify and dredge the meridians.

[0028] The raw materials of the present invention have a wide source and a simple preparation method. Clinical data have verified that the prescription has a definite clinical efficacy without obvious adverse reactions and toxic side effects. It has a good application prospect and can promote the development of the integration of traditional Chinese and Western medicine in the treatment and scientific research of early and middle stage PD. DETAILED DESCRIPTION

[0029] Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiments are only used to illustrate the present invention and are not used in limiting the scope of the present invention.In addition, should be understood that after reading the content of the present invention record, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms fall equally within the scope limited by the application's appended claims.

[0030] The Chinese medicinal materials used in the present invention and their effects are as follows:

[0031] Cinnamon twig: Cinnamon twig extract can dilate blood vessels, improve blood circulation, and promote blood flow to the body's surface, thereby promoting sweating and heat dissipation. Cinnamaldehyde can promote gastrointestinal smooth muscle motility, enhance digestion, and have a choleretic effect. Cinnamon twig also has analgesic, anti-inflammatory, anti-allergic, increased coronary blood flow, improved cardiac function, sedative, anticonvulsant, and anti-tumor effects.

[0032] Raw dragon bone: Raw dragon bone extract has central inhibitory and skeletal muscle relaxant effects, can regulate the body's immune function, and also has sedative, hypnotic, anticonvulsant, blood coagulation promoting, and vascular permeability reducing effects.

[0033] Raw oysters: Raw oyster extracts have sedative, anticonvulsant, anti-epileptic, analgesic, anti-liver damage, immune-enhancing, anti-tumor, antioxidant, and anti-aging effects. Oyster polysaccharides have lipid-lowering, anti-coagulation, and anti-thrombotic effects.

[0034] Rehmannia glutinosa: The water decoction and alcohol extract of Rehmannia glutinosa have the effects of promoting hematopoiesis, improving immunity, anti-aging, and preventing osteoporosis.

[0035] Lycium barbarum: Lycium barbarum can significantly enhance the body's nonspecific immune function. Lycium barbarum polysaccharides can improve the phagocytic capacity of macrophages. Its decoction regulates both cellular and humoral immunity. Lycium barbarum also has antioxidant, anti-aging, lipid-lowering, blood sugar-lowering, anti-tumor, anti-mutagenic, and blood pressure-lowering properties.

[0036] Mistletoe: Mistletoe has anti-inflammatory, analgesic, lipid-lowering and blood pressure-lowering effects; its extract has a dilating effect on coronary arteries and can slow down the heart rate.

[0037] Gastrodia elata: Gastrodia elata extract has sedative and hypnotic effects, anticonvulsant effects, improves learning and memory, protects neurons, has anti-anxiety, anti-depression, lowers blood pressure, dilates blood vessels, protects myocardial cells, has anti-coagulation, anti-thrombosis, anti-platelet aggregation, anti-inflammatory, analgesic effects, and can also resist aging, antioxidant, anti-hypoxia, anti-radiation, protect the liver, protect the gastric mucosa, and stimulate the intestine.

[0038] White Peony Root: White Peony Root decoction has sedative, antidepressant, and gastrointestinal regulating effects. Both the decoction and total saponins have immune-regulating and anti-inflammatory effects. Paeoniflorin and white peony root extract have a strong antispasmodic effect.

[0039] Bombyx batryticatus: Bombyx batryticatus has sedative, hypnotic, anticonvulsant, anticoagulant, anti-tumor, and blood sugar lowering effects.

[0040] Scorpion: Scorpion has anti-epileptic, anticonvulsant, analgesic, anticoagulant, antithrombotic, and anti-tumor effects. In addition, this product also has antihypertensive and antibacterial effects.

[0041] Centipede: Centipede has anticonvulsant, anti-inflammatory, analgesic, anti-tumor, anti-myocardial ischemia, antibacterial, microcirculation improving, coagulation time prolonging, blood viscosity reducing and other effects.

[0042] Arisaema: Arisaema decoction has an expectorant effect, significant analgesic and sedative properties, and can significantly prolong the hypnotic effect of pentobarbital, creating a synergistic effect. Different varieties have a certain degree of anticonvulsant effect.

[0043] Curcuma: Curcuma extract can inhibit platelet aggregation, resist thrombosis, and improve hemorheology. It can also resist gastric ulcers and has hepatoprotective effects. In addition, this product also has anti-inflammatory and analgesic effects.

[0044] The present invention will be described below with reference to specific embodiments.

[0045] Example 1

[0046] A traditional Chinese medicine composition for treating circadian rhythm disorder in Parkinson's disease is composed of the following raw materials: 10g of cinnamon twig, 30g of raw dragon bone, 30g of raw oyster, 15g of cooked rehmannia, 12g of wolfberry, 15g of mistletoe, 9g of gastrodia elata, 15g of white peony root, 9g of bombyx batryticatus, 3g of scorpion, 3g of centipede, 15g of arisaema, and 9g of zedoaria.

[0047] Example 2

[0048] A traditional Chinese medicine composition for treating circadian rhythm disorder in Parkinson's disease is composed of the following ingredients: 9g of cinnamon twig, 15g of raw dragon bone, 15g of raw oyster, 10g of cooked rehmannia, 9g of wolfberry, 10g of mistletoe, 12g of gastrodia, 30g of white peony root, 6g of bombyx batryticatus, 3g of scorpion, 3g of centipede, 10g of arisaema, and 10g of zedoaria.

[0049] Example 3

[0050] A traditional Chinese medicine composition for treating circadian rhythm disorder in Parkinson's disease is composed of the following ingredients: 6g of cinnamon twig, 30g of raw dragon bone, 30g of raw oyster, 12g of cooked rehmannia, 15g of wolfberry, 12g of parasitic plant, 10g of gastrodia elata, 15g of white peony root, 9g of bombyx batryticatus, 1g of scorpion, 1g of centipede, 9g of arisaema, and 9g of zedoaria.

[0051] Example 4

[0052] A traditional Chinese medicine composition for treating circadian rhythm disorder in Parkinson's disease is composed of the following ingredients: 10g of cinnamon twig, 20g of raw dragon bone, 20g of raw oyster, 10g of cooked rehmannia, 9g of wolfberry, 15g of parasitic plant, 9g of gastrodia elata, 20g of white peony root, 6g of bombyx batryticatus, 2g of scorpion, 2g of centipede, 12g of arisaema, and 10g of zedoaria.

[0053] Example 5

[0054] A traditional Chinese medicine composition for treating circadian rhythm disorder in Parkinson's disease is composed of the following ingredients: 3g of cinnamon twig, 15g of raw dragon bone, 15g of raw oyster, 10g of cooked rehmannia, 9g of wolfberry, 10g of mistletoe, 9g of gastrodia elata, 10g of white peony root, 6g of bombyx batryticatus, 1g of scorpion, 1g of centipede, 9g of arisaema, and 3g of zedoaria.

[0055] Example 6

[0056] A traditional Chinese medicine composition for treating circadian rhythm disorder in Parkinson's disease is composed of the following raw materials: 10g of cinnamon twig, 30g of raw dragon bone, 30g of raw oyster, 15g of cooked rehmannia, 15g of wolfberry, 30g of mistletoe, 30g of gastrodia elata, 15g of white peony root, 15g of bombyx batryticatus, 6g of scorpion, 6g of centipede, 15g of arisaema, and 10g of zedoaria.

[0057] The Chinese medicine compositions provided in Examples 1 to 6 above were prepared according to the following steps:

[0058] Weigh cinnamon twig, raw dragon bone, raw oyster, cooked rehmannia, wolfberry, parasitic herb, gastrodia elata, white peony root, bombyx batryticatus, scorpion, centipede, arisaema, and zedoaria, mix them, add water equivalent to 6 times the amount of the medicinal material mixture, decoct twice, each time for 60 minutes, and combine the decoctions to obtain the product.

[0059] Example 7

[0060] A Chinese medicine composition for treating circadian rhythm disorder in Parkinson's disease, which differs from Example 1 only in the preparation method, specifically:

[0061] Weigh cinnamon twig, raw dragon bone, raw oyster, cooked rehmannia, wolfberry, parasitic herb, gastrodia elata, white peony root, bombyx batryticatus, scorpion, centipede, arisaema, and zedoaria, mix them, add water equivalent to 8 times the amount of the medicinal material mixture, decoct 3 times, each time for 40 minutes, combine the decoctions, and obtain the product.

[0062] The Chinese medicine compositions provided in Examples 1 to 7 above can be taken directly as decoctions, or can be further prepared into pharmaceutical preparations such as granules, powders, capsules, tablets, mixtures, or oral solutions according to pharmaceutically acceptable methods. The preparation of pharmaceutical preparations will be described below using granules as an example.

[0063] Example 8

[0064] A granule for treating circadian rhythm disorder in Parkinson's disease is prepared according to the following steps:

[0065] According to Example 1, cinnamon twig, raw dragon bone, raw oyster, cooked rehmannia, wolfberry, parasitic herb, gastrodia elata, white peony root, silkworm, scorpion, centipede, arisaema, and zedoaria were weighed and mixed, and water equivalent to 6 times the amount of the medicinal material mixture was added. The mixture was decocted twice, each time for 60 minutes. The decoctions were combined, filtered, and the filtrate was concentrated to a relative density of 1.15 at 80° C.; dextrin was diluted with pure water and filtered, and then mixed evenly with the clear paste, and spray-dried to obtain a dry paste powder, wherein the mass ratio of the clear paste to the dextrin was 12:1; the dry paste powder was granulated and packaged to obtain a granular powder.

[0066] Example 9

[0067] A granule for treating circadian rhythm disorder in Parkinson's disease is prepared according to the following steps:

[0068] According to Example 1, cinnamon twig, raw dragon bone, raw oyster, cooked rehmannia, wolfberry, parasitic herb, gastrodia elata, white peony root, silkworm, scorpion, centipede, arisaema, and zedoaria were weighed and mixed, and water equivalent to 6 times the amount of the medicinal material mixture was added. The mixture was decocted twice, each time for 60 minutes. The decoctions were combined, filtered, and the filtrate was concentrated to a relative density of 1.14 at 60° C.; dextrin was diluted with pure water and filtered, and then uniformly mixed with the clear paste and spray-dried to obtain a dry paste powder, wherein the mass ratio of the clear paste to dextrin was 32:1; the dry paste powder was granulated and packaged to obtain a granular powder.

[0069] Since the therapeutic effects of the Chinese medicine compositions or Chinese medicine preparations provided in Examples 1 to 9 are substantially the same, only Example 1 is used as an example to illustrate the effects below.

[0070] clinical trials

[0071] 1. Materials and Methods

[0072] 1. Research subjects

[0073] This trial used a randomized, double-blind, placebo-controlled parallel method, followed the Declaration of Helsinki and the Consolidated Standards of Reporting Trials (CONSORT), and selected 420 patients with early and middle stage PD who were outpatients or inpatients of the Department of Neurology, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine and were willing to follow the treatment method. Among them, 245 patients were in the treatment group and 175 patients were in the control group.

[0074] 2. Inclusion criteria:

[0075] ①Age 30 to 80 years old, regardless of gender;

[0076] ② Meet the diagnostic criteria for idiopathic Parkinson's disease revised by the Movement Disorder Society (MDS) in 2015;

[0077] ③Hoehn-Yahr stage ≤3;

[0078] ④ Rapid Eye Movement Behavior Disorder Questionnaire (RBDQ-HK) of the Chinese University of Hong Kong ≥ 17 points;

[0079] ⑤At least one of the following symptoms: fear of cold or heat; constipation or diarrhea;

[0080] ⑥ For subjects who have been receiving anti-Parkinson's treatment (levodopa preparations, dopamine receptor agonists, monoamine oxidase inhibitors, catechol-O-methyltransferase inhibitors, anticholinergic drugs, etc.), the dosage of anti-Parkinson's drugs is required to be relatively stable for at least 3 months before this clinical trial, and there is no clear plan to change the existing treatment plan in the next 3 months;

[0081] ⑦ Participate voluntarily and sign the informed consent form.

[0082] 3. Exclusion criteria:

[0083] ①Patients with Parkinson's disease syndrome or Parkinson's disease plus syndrome;

[0084] ② Active depression or psychosis and / or treatment with antidepressant or antipsychotic drugs;

[0085] ③ Severe sequelae of stroke and diseases of other systems such as heart, lung, liver, and kidney;

[0086] ④ History of drug abuse or alcoholism;

[0087] ⑤ Patients who are participating in other clinical studies or have participated in other clinical studies within the previous 30 days.

[0088] 4. Medication regimen

[0089] Both the Chinese medicine group and the control group received basic Western medicine treatment (dobaserazide tablets, 0.25g (levodopa 200mg, benserazide 50mg), three times a day, 0.5 tablets each time, orally), and the dosage of anti-Parkinson's drugs was required to be relatively stable for at least 3 months before this clinical trial.

[0090] Traditional Chinese medicine group: Traditional Chinese medicine composition provided in Example 1 of the present invention + Western medicine basic treatment group;

[0091] Control group: Traditional Chinese medicine placebo + basic Western medicine treatment group. The control group was given a traditional Chinese medicine placebo. The traditional Chinese medicine placebo was prepared according to the method of Example 1, and the concentration of the traditional Chinese medicine used was 1 / 20 of the concentration of the traditional Chinese medicine composition provided in Example 1. The appearance and smell of the medicine were consistent with the study drug.

[0092] The trial drug was taken twice daily, one packet each time, with warm water in the morning and evening after meals, for 12 weeks. The trial drug was manufactured by Sichuan New Green Pharmaceutical Technology Development Co., Ltd. and supervised by Longhua Hospital, affiliated with Shanghai University of Traditional Chinese Medicine.

[0093] 5. Observation indicators

[0094] (1) Safety indicators:

[0095] Adverse reactions are dynamically monitored through blood routine, liver and kidney function, electrolytes, CRP, and myocardial enzyme spectrum.

[0096] (2) Efficacy indicators:

[0097] 1) Overall evaluation indicators of Parkinson's disease

[0098] The modified Hoehn-Yahr scale assesses the overall severity of Parkinson's disease. The Unified Parkinson's Disease Rating Scale (UPDRS), the SCOPA-AUT (Scale for Autonomic Function), the Hamilton Anxiety Rating Scale (HAMA), the Hamilton Depression Rating Scale (HAMD), and the Parkinson's Disease Quality of Life Questionnaire (PDQ-39) assess motor symptoms and non-motor symptoms (excluding sleep disturbances), respectively, in Parkinson's patients and can be used to assess the overall condition of Parkinson's patients.

[0099] 2) Circadian Rhythm Evaluation Indicators for Parkinson's Disease

[0100] ① Sleep-wake rhythm:

[0101] RBDQ-HK: a 13-item questionnaire with lifetime and recent 1-year subscales covering dream-related and behavioral factors in RBD;

[0102] Parkinson's Disease Sleep Scale (PDSS): This assesses the impact of nighttime symptoms on sleep in PD patients. Each item is scored from 0 to 10, with lower scores indicating more severe symptoms.

[0103] Sleep diary: A sleep diary is an important indicator of a patient's subjective sleep-wake state. Recorded daily for 14 days (at least 7 days) on weekdays, school days, and free days, the diary includes information about the day of the week, including bedtime, sleep onset, wake-up time, and rise time, as well as other behavioral information, such as medication use, caffeine or alcohol consumption, naps, or exercise.

[0104] 2. Results

[0105] During the study, 10 patients dropped out of the treatment group and 12 patients dropped out of the control group. Finally, 235 patients were included in the treatment group and 163 patients were included in the control group.

[0106] 1. UPDRS score before and after treatment

[0107] The results are shown in Table 1.

[0108] Table 1 Improvement of UPDRS scores before and after treatment

[0109]

[0110]

[0111] 2. SCOPA-AUT score before and after treatment

[0112] The results are shown in Table 2.

[0113] Table 2 Improvement of SCOPA-AUT scores before and after treatment

[0114]

[0115] 3. PDSS scores before and after treatment

[0116] The results are shown in Table 3.

[0117] Table 3 Improvement of PDSS scores before and after treatment

[0118]

[0119] 4. HAMA & HAMD scores before and after treatment

[0120] The results are shown in Table 4.

[0121] Table 4 Improvement of HAMA & HAMD scores before and after treatment

[0122]

[0123]

[0124] 5. PDQ scores before and after treatment

[0125] The results are shown in Table 5.

[0126] Table 5 Improvement of PDQ scores before and after treatment

[0127]

[0128] 6. Changes in sleep latency before and after treatment

[0129] The results are shown in Table 6.

[0130] Table 6 Changes in sleep latency before and after treatment [cases (%)]

[0131]

[0132] Note: A: 10-30 minutes, B: 30-60 minutes, C: 1-2 hours, D: more than 2 hours

[0133] 7. Changes in sleep duration before and after treatment

[0134] The results are shown in Table 7.

[0135] Table 7 Changes in sleep duration before and after treatment [cases (%)]

[0136]

[0137] Note: A: 7-8 hours, B: 6-7 hours, C: 5-6 hours, D: 3-5 hours, E: <3 hours

[0138] 8. Changes in sleep maintenance before and after treatment

[0139] The results are shown in Table 8.

[0140] Table 8 Changes in sleep maintenance before and after treatment [cases (%)]

[0141]

[0142]

[0143] 9. Changes in daytime function before and after treatment

[0144] The results are shown in Table 9.

[0145] Table 9 Changes in daytime function before and after treatment [cases (%)]

[0146]

[0147] Note: A: Feeling very good, B: Feeling relatively good, C: Feeling acceptable, D: Feeling not good, E: Feeling very bad 10. RBDQ-HK scores before and after treatment

[0148] The results are shown in Table 10.

[0149] Table 10 Improvement of RBDQ-HK scores before and after treatment

[0150]

[0151] The above results show that the addition of the Chinese medicine composition provided by the present invention to Western medicine treatment can effectively shorten sleep latency, prolong sleep duration, reduce the number of nocturnal awakenings, improve daytime function, regulate non-motor symptoms such as gastrointestinal dysfunction and body temperature regulation dysfunction, and effectively improve Parkinson's disease circadian rhythm disorder, and the therapeutic effect is better than that of the control group. At the same time, there is also varying degrees of improvement in motor symptoms. It can be seen that the efficacy of the Chinese medicine composition in improving Parkinson's disease circadian rhythm disorder presents multiple levels and angles, and there are no obvious adverse reactions, high safety, and worthy of clinical promotion and application.

[0152] It should be noted that when the claims of the present invention involve numerical ranges, it should be understood that the two endpoints of each numerical range and any numerical value between the two endpoints can be selected. In order to avoid redundancy, the present invention describes preferred embodiments.

[0153] Although the preferred embodiments of the present invention have been described, those skilled in the art may make additional changes and modifications to these embodiments once they have learned the basic creative concept. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments and all changes and modifications that fall within the scope of the present invention.

[0154] Obviously, those skilled in the art may make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if such changes and modifications fall within the scope of the claims and their equivalents, the present invention is intended to include such changes and modifications.

Claims

1. A Chinese medicine composition for treating circadian rhythm disorder in Parkinson's disease, characterized in that: The traditional Chinese medicine composition is prepared from the following raw medicines in parts by weight: 3-10 parts of cassia twig, 15-30 parts of raw dragon bone, 15-30 parts of raw oyster, 10-15 parts of cooked rehmannia, 9-15 parts of wolfberry, 10-30 parts of mistletoe, 9-30 parts of gastrodia, 10-30 parts of white peony root, 6-15 parts of bombyx batryticatus, 1-6 parts of scorpion, 1-6 parts of centipede, 9-15 parts of arisaema, and 3-10 parts of zedoaria.

2. The Chinese medicine composition according to claim 1, characterized in that The invention is prepared from the following raw medicines in parts by weight: 10 parts of cassia twig, 30 parts of raw dragon bone, 30 parts of raw oyster, 15 parts of cooked rehmannia, 12 parts of wolfberry, 15 parts of mistletoe, 9 parts of gastrodia, 15 parts of white peony root, 9 parts of bombyx batryticatus, 3 parts of scorpion, 3 parts of centipede, 15 parts of arisaema and 9 parts of zedoaria.

3. A method for preparing the Chinese medicine composition according to claim 1, characterized in that: The following steps are involved: Weigh cinnamon twig, raw dragon bone, raw oyster, cooked rehmannia, wolfberry, parasitic herb, gastrodia elata, white peony root, bombyx batryticatus, scorpion, centipede, arisaema, and zedoaria according to weight and set aside; The weighed Chinese medicinal raw materials are mixed, water is added and boiled, and the decoction is collected to obtain the product.

4. The preparation method according to claim 3, characterized in that The specific operation process of decocting with water is as follows: adding water equivalent to 6 to 8 times the amount of the medicinal material mixture, decocting 2 to 3 times, each time for 40 to 60 minutes.

5. Use of the traditional Chinese medicine composition according to claim 1 in preparing a medicine for treating Parkinson's disease.

6. The use according to claim 5, characterized in that The drug is used to improve circadian rhythm disorder in Parkinson's disease, or The drug is used to improve Parkinson's disease combined with sleep disorders, or The drug is used to improve Parkinson's disease combined with gastrointestinal dysfunction, or The medicine is used to improve Parkinson's disease combined with temperature regulation dysfunction.

7. A pharmaceutical preparation for treating circadian rhythm disorder in Parkinson's disease, characterized in that: The invention comprises the traditional Chinese medicine composition according to claim 1 and pharmaceutically acceptable excipients.

8. The pharmaceutical preparation according to claim 7, characterized in that The pharmaceutical preparation is in the form of granules, powders, capsules, tablets, mixtures or oral solutions.

9. The pharmaceutical preparation according to claim 8, characterized in that The preparation method of the granules comprises the following steps: Weigh cassia twig, raw dragon bone, raw oyster, cooked rehmannia, wolfberry, parasitic herb, gastrodia elata, white peony root, bombyx batryticatus, scorpion, centipede, arisaema and zedoaria according to weight, mix, add water and boil, collect the decoction, filter, concentrate the filtrate to a relative density of 1.14-1.15 at 60-80° C., add auxiliary materials, dry, granulate and package to obtain the product.

10. The pharmaceutical preparation according to claim 9, characterized in that The auxiliary material is dextrin, and the mass ratio of the dextrin to the concentrated material is 1:12-32.

Images