A traditional Chinese medicine preparation for migraine and a preparation method and application thereof

Abstract

The application provides a traditional Chinese medicine preparation for migraine, and relates to the technical field of biological medicine. According to the theory of traditional Chinese medicine, under the guidance of the pathogenesis of hyperactivity of wind and yang, invasion of turbid evil and loss of nourishment of clear orifices, the traditional Chinese medicine preparation is prepared from the following components: Flos Panacis Majoris, Cortex Radicis Trichosanthis, Helianthus annuus L. leaf, Santalum album L., Itea yunnanensis root, Hemerocallis fulva and Zea mays L. The traditional Chinese medicine preparation has the functions of soothing liver and clearing heat, regulating qi and promoting blood circulation, and removing dampness and turbidity. Basic research proves that the traditional Chinese medicine preparation can significantly reduce the head scratching frequency of a migraine model rat, improve the pain threshold, and has a good regulatory effect on vasoactive substances and neurogenic inflammation related indexes. Clinical research also shows its unique advantages, can significantly reduce the frequency and duration of headache attacks, effectively relieve pain, and significantly improve the cerebral vascular function disorder, and no obvious adverse reactions are found during the medication. In conclusion, the application provides a safe and effective new scheme with Chinese characteristics and broad transformation prospects for the clinical treatment of migraine.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, specifically to a traditional Chinese medicine preparation for migraines, its preparation method, and its application. Background Technology

[0002] Migraine is a common and highly disabling neurological disorder. Its pathological basis lies in neurovascular dysfunction. Clinically, it is characterized by recurrent episodes of unilateral, moderate to severe throbbing headache, often accompanied by autonomic symptoms such as nausea, vomiting, and photophobia and phonophobia. The etiology of this disease is complex, the condition is protracted, and it presents with periodic attacks. Long-term recurrence not only severely reduces patients' quality of life but also often coexists with various mental and psychological disorders.

[0003] Currently, Western medicine lacks a radical cure for migraines, and clinical practice mainly focuses on symptomatic pain relief during the acute phase. Although oral anti-migraine medications can quickly control attacks, long-term use is often accompanied by adverse reactions such as drug dependence, reduced efficacy, and liver and kidney damage, and the condition is prone to recurrence and prolongation, making it difficult to achieve ideal long-term control.

[0004] In comparison, Traditional Chinese Medicine (TCM) demonstrates unique advantages in treating migraines, including high safety, stable efficacy, and low cost. Numerous clinical studies have confirmed that TCM intervention can significantly reduce the recurrence frequency of migraines, and is well-tolerated by patients. Therefore, in-depth exploration and systematic research into TCM formulas for migraines have significant clinical application value and translational significance for optimizing clinical treatment strategies and overcoming the limitations of existing Western medicine treatments. Summary of the Invention

[0005] (a) Technical problems to be solved

[0006] In view of the shortcomings of the prior art, the present invention provides a traditional Chinese medicine preparation for migraine, its preparation method and application.

[0007] (II) Technical Solution

[0008] To achieve the above objectives, the present invention provides the following technical solution:

[0009] On the one hand, this application provides a traditional Chinese medicine preparation for migraine, which is made from the following herbal raw materials in parts by weight: 1-18 parts of Panax notoginseng flower, 9-45 parts of Acanthopanax senticosus bark, 9-40 parts of sunflower leaf, 1-18 parts of sandalwood, 8-40 parts of white-backed leaf root, 1-20 parts of globe amaranth, and 10-40 parts of corn silk.

[0010] Specifically, the traditional Chinese medicine preparation is made from the following herbal raw materials in parts by weight: 3-10 parts of Panax notoginseng flower, 15-30 parts of Acanthopanax senticosus bark, 15-30 parts of sunflower leaf, 5-10 parts of sandalwood, 15-30 parts of white-backed leaf root, 5-10 parts of globe amaranth, and 12-30 parts of corn silk.

[0011] Specifically, the traditional Chinese medicine preparation is made from the following herbal raw materials in parts by weight: 6 parts of Panax notoginseng flower, 20 parts of Acanthopanax senticosus bark, 20 parts of sunflower leaf, 6 parts of sandalwood, 20 parts of white-backed leaf root, 8 parts of globe amaranth, and 15 parts of corn silk.

[0012] On the other hand, this application provides the application of a traditional Chinese medicine preparation in the preparation of a drug for migraine, wherein the traditional Chinese medicine preparation is made from the above-mentioned parts by weight of Chinese herbal medicine as raw materials, supplemented with pharmaceutically acceptable excipients to produce any one of oral liquid, capsules, tablets, pills or granules.

[0013] Specifically, the preparation method of granules is as follows:

[0014] (1) Weigh each Chinese medicinal material according to the above weight proportions, wash them, and dry them at 50℃;

[0015] (2) Crush sandalwood into coarse powder, add 6-8 times the amount of water, soak for 1 hour, extract by steam distillation for 4-6 hours, collect sandalwood aromatic water, volatile oil and dregs, seal and refrigerate the volatile oil for later use, and keep the aromatic water and dregs for later use.

[0016] (3) Mix the dregs from step (2) with the remaining medicinal materials, add 8-10 times the amount of water, soak for 40 minutes, boil and decoct twice, each time for 1-2 hours, combine the two decoctions and filter to obtain the filtrate. Add the sandalwood aromatic water from step (2) to the filtrate and combine to obtain the total filtrate.

[0017] (4) The total filtrate obtained in step (3) is concentrated to a clear paste with a relative density of 1.10-1.15 (measured at 60℃) under the conditions of temperature 60-70℃ and vacuum of -0.06 to 0.08MPa;

[0018] (5) The clear extract obtained in step (4) is vacuum dried at 60~70℃ to obtain a dry extract powder. After being pulverized, it is passed through an 80-mesh sieve to obtain a dry extract powder.

[0019] (6) The sandalwood volatile oil collected in step (2) is mixed with β-cyclodextrin and an appropriate amount of purified water at a weight ratio of volatile oil to β-cyclodextrin of 1:6 to 1:10. The mixture is stirred and incorporated at a constant temperature of 40 to 50°C for 1 to 2 hours. It is then refrigerated at 2 to 6°C for 24 hours, filtered, and the precipitate is dried under reduced pressure below 50°C and pulverized to obtain the sandalwood volatile oil β-cyclodextrin inclusion complex.

[0020] (7) The dry extract powder obtained in step (5), the sandalwood volatile oil β-cyclodextrin inclusion complex obtained in step (6), and any one of the following excipients—dextrin, soluble starch, and sucrose powder—are mixed thoroughly in a mixer at a weight ratio of 1:1 to 1:3. 70% to 80% ethanol is added to form a soft mass, which is then granulated using a swaying granulator to obtain wet granules.

[0021] (8) Place the wet granules obtained in step (7) in a fluidized bed dryer or oven and dry them at 60℃~80℃ until the moisture content is less than 4.0%. After drying, granulate the granules through a 14~16 mesh sieve to remove fine powder and broken particles. Pack the granulated granules into 15g bags and seal them to obtain the traditional Chinese medicine granules of the present invention.

[0022] The pharmacological effects of various Chinese herbal raw materials in the traditional Chinese medicine preparation of this invention are as follows:

[0023] Panax notoginseng flower: The dried inflorescence of Panax notoginseng (Burk.) FHChen, a plant of the Araliaceae family. It has a sweet taste and cool properties, and enters the liver and kidney meridians. It has the effects of clearing heat and detoxifying, calming the liver and improving eyesight, and promoting the production of body fluids and quenching thirst. It can be used to treat dizziness, tinnitus, insomnia, hypertension, migraines, and acute pharyngitis.

[0024] Sanjiapi: The root or root bark of *Acanthopanax trifoliatus* (L.) Merr. [Zanthaxylum trifoliatum L.], a plant belonging to the genus *Acanthopanax* of the Araliaceae family. It tastes bitter and pungent, and is cool in nature; it enters the spleen and liver meridians. It has the effects of clearing heat and detoxifying, dispelling wind and dampness, and promoting blood circulation and relaxing muscles and tendons. It is commonly used for colds with fever, sore throat, headache, cough with chest pain, stomach pain, diarrhea, dysentery, hypochondriac pain, jaundice, urinary stones, leukorrhea, rheumatic pain, lower back and leg pain, muscle and bone contractures and numbness, fractures, mumps, mastitis, sores and boils, and snake and insect bites.

[0025] Sunflower leaves: The leaves of the sunflower (Helianthus annuus L.), a plant in the Asteraceae family. They have a bland, bitter taste and are neutral in nature; they enter the liver and stomach meridians. They have the effects of lowering blood pressure, treating malaria, and detoxifying. They are used for hypertension, malaria, and boils.

[0026] Sandalwood: The dried heartwood of the trunk of *Santalum album* L., a plant belonging to the genus *Santalum* in the family Santalaceae. It has a pungent taste and warm properties; it enters the spleen, stomach, heart, and lung meridians. It has the effects of regulating qi and warming the middle jiao, stimulating appetite and relieving pain. It is mainly used to treat cold stagnation of qi, chest discomfort, chest pain, abdominal pain, vomiting, and poor appetite.

[0027] White-backed Leaf Root: The root of *Mallotus apelta* (Lour.) Muell.-Arg., a plant belonging to the genus *Mallotus* in the family Euphorbiaceae. It has a slightly bitter and astringent taste, and is neutral in nature; it enters the liver and spleen meridians. It has the effects of clearing heat, removing dampness, astringing, and resolving blood stasis. It is mainly used to treat chronic hepatitis, enteritis, gonorrhea, leukorrhea, rectal prolapse, uterine prolapse, hepatosplenomegaly, and sprains and strains.

[0028] Globe amaranth: The inflorescence or whole plant of *Gomphrena globosa* L., a plant in the Amaranthaceae family. It has a sweet and slightly salty taste, and is neutral in nature; it enters the lung and liver meridians. It has the effects of relieving cough and asthma, clearing the liver and improving eyesight, and detoxifying. It is mainly used to treat cough, asthma, whooping cough, infantile night crying, red and swollen eyes, dizziness due to liver heat, headache, dysentery, and boils.

[0029] Corn silk: The dried style and stigma of *Zea mays* L., a plant belonging to the genus *Zea* of the Poaceae family. It is neutral in nature and sweet in taste; it enters the liver and kidney meridians. This product has the effects of promoting diuresis and reducing swelling, and relieving jaundice. It is mainly used to treat edema with scanty urine, damp-heat jaundice, and dizziness.

[0030] (III) Beneficial Effects

[0031] This formula uses Panax notoginseng flower and Acanthopanax senticosus bark as the principal herbs. Both herbs are sweet and cool in nature, and specifically enter the liver meridian. Recurrent and prolonged migraines inevitably lead to stagnation in the head's meridians. Liver fire scorches the blood vessels, resulting in throbbing pain. Panax notoginseng flower excels at clearing heat and reducing fire, calming the liver and improving eyesight, and clearing the head's orifices, directly addressing the core pathogenesis of throbbing headaches. Acanthopanax senticosus bark clears heat and detoxifies, dispels wind and dampness, and invigorates blood and relaxes muscles. Its heat-clearing power helps Panax notoginseng flower suppress liver fire, and its blood-invigorating and stasis-removing effects specifically clear obstructions in the meridians, relieving muscle tension, pulling pain, and numbness. Simultaneously, its wind-dispelling and dampness-removing properties guide the stagnant heat of the liver meridian downwards.

[0032] Sunflower leaves, sandalwood, and white-backed leaf root are used as assistant herbs. Sunflower leaves astringe the rising liver yang, suppressing the severe headache caused by the yang qi rushing to the top of the head, and help Panax notoginseng flower inhibit the upward rush of liver yang and blood stasis. White-backed leaf root clears heat and promotes diuresis. When combined with Acanthopanax senticosus root bark, it can enhance the ability to clear deep stagnation and blood stasis in the liver meridian, prevent the headache from becoming chronic, and also promote diuresis and eliminate turbidity, guiding the stagnant heat in the liver meridian downward. Moreover, its mild and astringent nature can gently restrain the floating liver yang, gently restraining the rampant and restless liver qi and deficiency fire, preventing the yang qi from attacking the head meridians without restraint, thereby reducing the hyperactivity of blood vessel pulsation. Sandalwood is aromatic and dispersing, and can promote qi and relieve pain. Firstly, it can promote qi circulation, helping Acanthopanax senticosus root bark and white-backed leaf root to enhance the effect of removing blood stasis and clearing the meridians, breaking the stagnant qi and quickly relieving the feeling of stuffiness in the head. Secondly, its pungent and warm nature can prevent the large group of cold and cooling drugs from stagnating qi. The combination of the two herbs works synergistically to clear the liver and subdue yang to address the root cause, and to invigorate blood circulation and unblock the meridians to address the symptoms, thus quickly relieving headaches.

[0033] The formula uses globe amaranth and corn silk as adjuvants. Globe amaranth clears the liver and improves eyesight, and is good at relieving symptoms such as eye socket swelling and pain that accompany migraine attacks; corn silk promotes diuresis and reduces swelling, eliminates dampness and clears jaundice, and can remove the turbid yin and dampness in the liver from the lower burner, giving the pathogens an outlet and preventing the turbid pathogens from rushing up to the head and orifices again.

[0034] The seven herbs work synergistically to soothe the liver, clear heat, regulate qi and blood circulation, and eliminate dampness and turbidity. This formula is not simply a collection of various analgesic herbs, but rather closely addresses the four major pathological factors of "wind, fire, blood stasis, and dampness," establishing a comprehensive treatment network that treats both the root cause and symptoms of the condition.

[0035] This study, through comparative analysis of different traditional Chinese medicine (TCM) formulations, demonstrated that replacing the principal herb or removing the assistant herb significantly weakens the control effect on core biochemical indicators of migraine. From a pharmacodynamic perspective, this fully demonstrates the irreplaceable and rational nature of the original prescription's herbal combinations, highlighting the holistic view of synergistic effects in TCM compound formulations. Based on this, clinical research further validated the outstanding efficacy of this preparation. It significantly outperformed the control group in reducing the frequency and duration of headache attacks, improving accompanying symptoms, and optimizing intracranial blood flow velocity, with a much lower incidence of adverse reactions, demonstrating a significant safety advantage. In summary, this TCM preparation possesses both clear pharmacological compatibility and definite clinical efficacy, effectively improving cerebral hemodynamics while exhibiting high safety and tolerability, demonstrating good clinical translation and application promotion value. Attached Figure Description

[0036] Figure 1 The effects of each drug administration group on the number of head scratches (A), periorbital pain threshold (B), hind paw mechanical pain threshold (C), and neurogenic indicators of vasoactive agents in plasma and brain tissue in migraine rats (D) were compared with the control group. 1 P<0.05, 2 P<0.01; compared with the traditional Chinese medicine preparation group, 3 P<0.05, 4 P<0.01. Detailed Implementation

[0037] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0038] Example 1

[0039] A traditional Chinese medicine preparation for migraines is made from the following ingredients in parts by weight: 1 part Panax notoginseng flower, 9 parts Acanthopanax senticosus bark, 9 parts sunflower leaf, 1 part sandalwood, 8 parts white-backed leaf root, 1 part globe amaranth, and 10 parts corn silk.

[0040] Example 2

[0041] The difference between this embodiment and Embodiment 1 is that the traditional Chinese medicine preparation is made from the following raw materials in parts by weight: 18 parts of Panax notoginseng flower, 45 parts of Acanthopanax senticosus bark, 40 parts of sunflower leaf, 18 parts of sandalwood, 40 parts of white-backed leaf root, 20 parts of globe amaranth, and 40 parts of corn silk.

[0042] Example 3

[0043] The difference between this embodiment and Embodiment 1 is that the traditional Chinese medicine preparation is made from the following raw materials in parts by weight: 3 parts of Panax notoginseng flower, 15 parts of Acanthopanax senticosus bark, 15 parts of sunflower leaf, 5 parts of sandalwood, 15 parts of white-backed leaf root, 5 parts of globe amaranth, and 12 parts of corn silk.

[0044] Example 4

[0045] The difference between this embodiment and Embodiment 1 is that the traditional Chinese medicine preparation is made from the following raw materials in parts by weight: 10 parts of Panax notoginseng flower, 30 parts of Acanthopanax senticosus bark, 30 parts of sunflower leaf, 10 parts of sandalwood, 30 parts of white-backed leaf root, 10 parts of globe amaranth, and 30 parts of corn silk.

[0046] Example 5

[0047] The difference between this embodiment and Embodiment 1 is that the traditional Chinese medicine preparation is made from the following raw materials in parts by weight: 10 parts of Panax notoginseng flower, 30 parts of Acanthopanax senticosus bark, 30 parts of sunflower leaf, 10 parts of sandalwood, 30 parts of white-backed leaf root, 12 parts of globe amaranth, and 25 parts of corn silk.

[0048] Example 6

[0049] The difference between this embodiment and Embodiment 1 is that the traditional Chinese medicine preparation is made from the following raw materials in parts by weight: 16 parts of Panax notoginseng flower, 42 parts of Acanthopanax senticosus bark, 38 parts of sunflower leaf, 16 parts of sandalwood, 38 parts of white-backed leaf root, 18 parts of globe amaranth, and 38 parts of corn silk.

[0050] Example 7

[0051] The difference between this embodiment and Embodiment 1 is that the traditional Chinese medicine preparation is made from the following raw materials in parts by weight: 14 parts of Panax notoginseng flower, 38 parts of Acanthopanax senticosus bark, 35 parts of sunflower leaf, 13 parts of sandalwood, 35 parts of white-backed leaf root, 15 parts of globe amaranth, and 35 parts of corn silk.

[0052] Example 8

[0053] The difference between this embodiment and Embodiment 1 is that the traditional Chinese medicine preparation is made from the following raw materials in parts by weight: 8 parts of Panax notoginseng flower, 25 parts of Acanthopanax senticosus bark, 25 parts of sunflower leaf, 3 parts of sandalwood, 25 parts of white-backed leaf root, 3 parts of globe amaranth, and 20 parts of corn silk.

[0054] Example 9

[0055] The difference between this embodiment and Embodiment 1 is that the traditional Chinese medicine preparation is made from the following raw materials in parts by weight: 6 parts of Panax notoginseng flower, 20 parts of Acanthopanax senticosus bark, 20 parts of sunflower leaf, 6 parts of sandalwood, 20 parts of white-backed leaf root, 8 parts of globe amaranth, and 15 parts of corn silk.

[0056] Comparative Example 1

[0057] The difference between this embodiment and Embodiment 1 is that the traditional Chinese medicine preparation is made from the following raw materials in parts by weight: 6 parts chrysanthemum, 20 parts Acanthopanax senticosus root bark, 20 parts sunflower leaves, 6 parts sandalwood, 20 parts white-backed leaf root, 8 parts globe amaranth, and 15 parts corn silk.

[0058] Comparative Example 2

[0059] The difference between this embodiment and Embodiment 1 is that the traditional Chinese medicine preparation is made from the following raw materials in parts by weight: 6 parts of Panax notoginseng flower, 20 parts of Spatholobus suberectus, 20 parts of sunflower leaf, 6 parts of sandalwood, 20 parts of white-backed leaf root, 8 parts of globe amaranth, and 15 parts of corn silk.

[0060] Comparative Example 3

[0061] The difference between this embodiment and Embodiment 1 is that the traditional Chinese medicine preparation is made from the following raw materials in parts by weight: 6 parts of Panax notoginseng flower, 20 parts of Acanthopanax senticosus bark, 20 parts of sunflower leaf, 20 parts of white-backed leaf root, 8 parts of Gomphrena globosa, and 15 parts of corn silk.

[0062] Examples 1-9 and Comparative Examples 1-3 were all prepared according to the following preparation method:

[0063] (1) Weigh each Chinese medicinal material according to the above weight proportions, wash them, and dry them at 50℃;

[0064] (2) Crush sandalwood into coarse powder, add 8 times the amount of water, soak for 1 hour, extract by steam distillation for 5 hours, collect sandalwood aromatic water, volatile oil and dregs, seal and refrigerate the volatile oil for later use, and keep the aromatic water and dregs for later use.

[0065] (3) Mix the dregs from step (2) with the remaining medicinal materials, add 10 times the amount of water, soak for 40 minutes, boil and decoct twice, each time for 1.5 hours, combine the two decoctions and filter to obtain the filtrate. Add the sandalwood aromatic water from step (2) to the filtrate and combine to obtain the total filtrate.

[0066] (4) The total filtrate obtained in step (3) is concentrated to a clear paste with a relative density of 1.10-1.15 (measured at 60℃) under the conditions of temperature 60-70℃ and vacuum of -0.06 to 0.08MPa;

[0067] (5) The clear extract obtained in step (4) is vacuum dried at 60~70℃ to obtain a dry extract powder. After being pulverized, it is passed through an 80-mesh sieve to obtain a dry extract powder.

[0068] (6) The sandalwood volatile oil collected in step (2) is mixed with β-cyclodextrin and an appropriate amount of purified water at a weight ratio of 1:8. The mixture is stirred and incorporated at a constant temperature of 40~50℃ for 1.5 hours, then refrigerated at 2~6℃ for 24 hours. The mixture is filtered, and the precipitate is dried under reduced pressure below 50℃ and pulverized to obtain the sandalwood volatile oil β-cyclodextrin inclusion complex.

[0069] (7) The dry extract powder obtained in step (5) and the sandalwood volatile oil β-cyclodextrin inclusion complex obtained in step (6) are placed in a mixer and thoroughly mixed at a weight ratio of 1:2 between the dry extract powder and the sucrose powder. 75% ethanol is added to form a soft mass, which is then granulated by a swaying granulator to obtain wet granules.

[0070] (8) Place the wet granules obtained in step (7) in a fluidized bed dryer or oven and dry them at 60℃~80℃ until the moisture content is less than 4.0%. After drying, granulate the granules through a 14~16 mesh sieve to remove fine powder and broken particles. Pack the granulated granules into 15g bags and seal them to obtain the traditional Chinese medicine granules of the present invention.

[0071] Experiment 1

[0072] 1.1 Laboratory Animals

[0073] Sixty-four male SD rats were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0074] 1.2 Experimental Drugs

[0075] Traditional Chinese medicine preparation: 6g of Panax notoginseng flower, 20g of Acanthopanax senticosus root bark, 20g of sunflower leaf, 6g of sandalwood, 20g of white-backed leaf root, 8g of globe amaranth, and 15g of corn silk.

[0076] Comparative Example 1: Chrysanthemum 6g, Acanthopanax senticosus 20g, sunflower leaf 20g, sandalwood 6g, white-backed leaf root 20g, globe amaranth 8g, corn silk 15g.

[0077] Comparative Example 2: 6g of Panax notoginseng flower, 20g of Spatholobus suberectus, 20g of sunflower leaf, 6g of sandalwood, 20g of white-backed leaf root, 8g of globe amaranth, and 15g of corn silk.

[0078] Comparative Example 3: 6g of Panax notoginseng flower, 20g of Acanthopanax senticosus bark, 20g of sunflower leaf, 20g of white-backed leaf root, 8g of globe amaranth, and 15g of corn silk.

[0079] (1) Weigh each Chinese medicinal material according to the above weight proportions, wash them, and dry them at 50℃;

[0080] (2) Crush sandalwood into coarse powder, add 8 times the amount of water, soak for 1 hour, extract by steam distillation for 5 hours, collect sandalwood aromatic water, volatile oil and dregs, seal and refrigerate the volatile oil for later use, and keep the aromatic water and dregs for later use (this step can be omitted if there is no sandalwood in the formula).

[0081] (3) Mix the dregs from step (2) with the remaining medicinal materials, add 10 times the amount of water, soak for 40 minutes, boil and decoct twice, each time for 1.5 hours, combine the two decoctions and filter to obtain the filtrate. Add the sandalwood aromatic water from step (2) to the filtrate and combine to obtain the total filtrate.

[0082] (4) The total filtrate obtained in step (3) is concentrated to a clear paste with a relative density of 1.10-1.15 (measured at 60℃) under the conditions of temperature 60-70℃ and vacuum of -0.06 to 0.08MPa;

[0083] (5) Mix the clear paste obtained in step (4) with the volatile oil obtained in step (1) to obtain a traditional Chinese medicine mixture (i.e. containing 1.4g / ml of raw herbs).

[0084] Zolmitriptan Tablets: Hangzhou Conba Pharmaceutical Co., Ltd.

[0085] Qingnao Zhitong Capsules: Jilin Aodong Taonan Pharmaceutical Co., Ltd.

[0086] 1.2 Animal modeling and grouping

[0087] Except for the control group which received physiological saline, each group was given intraperitoneal injection of nitroglycerin solution at 10 mg / kg on days 1, 3, 5, 7, and 9 to establish an animal model of chronic migraine.

[0088] Control group rats (C): 1 hour before the modeling operation on the same day, they were given the same volume of physiological saline by gavage for a total of 9 days.

[0089] Model group rats (M): One hour before the modeling operation on the same day, they were given the same volume of physiological saline by gavage, for a total of 9 days, once a day;

[0090] Traditional Chinese medicine preparation group (Z): The drug of Example 9 was administered 1 hour before the modeling operation on the same day, and was administered by gavage at a dose of 10g / kg for a total of 9 days, once a day;

[0091] Comparative Example 1 (D1): The drug of Comparative Example 1 was administered 1 hour before the modeling operation on the same day, at a dose of 10g / kg by gavage, for a total of 9 days, once a day.

[0092] Comparative Example 2 (D2): The drug of Comparative Example 2 was administered 1 hour before the modeling operation on the same day, at a dose of 10g / kg by gavage, for a total of 9 days, once a day.

[0093] Comparative Example 3 (D3): The drug of Comparative Example 3 was administered 1 hour before the modeling operation on the same day, at a dose of 10g / kg by gavage, for a total of 9 days, once a day.

[0094] Zolmitriptan group (T): 0.25 mg / kg zolmitriptan tablets were administered by gavage 1 hour before the modeling procedure on the same day, for a total of 9 days, once a day;

[0095] Qingnao Zhitong Capsules (Q): Administer 1.4g / kg of Qingnao Zhitong Capsules by gavage 1 hour before the modeling operation on the same day, for a total of 9 days, once a day;

[0096] 1.3 Detection Indicators

[0097] (1) The number of times rats scratched their heads was counted at two time points: 30-60 min and 90-120 min after the last administration of nitroglycerin.

[0098] (2) The pain sensitivity of rats was tested around the eyes and on the soles of their hind feet using Von Frey fibers. The bending force of the fibers that could produce a 50% positive response (such as the withdrawal reflex) was determined using standardized procedures such as the "up-down" method. This was used to quantitatively assess the pain threshold of the animals.

[0099] (3) The NO content in rat plasma and brain tissue was detected, and the contents of CGRP, β-EP and 5-HT in rat brain tissue were detected by enzyme-linked immunosorbent assay.

[0100] 1.4 Statistical Analysis

[0101] All experimental data were analyzed using GraphPad Prism 10.0 statistical software, and one-way ANOVA was used for comparisons between groups. A p-value < 0.05 was considered statistically significant, and a p-value < 0.01 was considered extremely statistically significant.

[0102] 1.5 Test Results

[0103] 1.5.1 Effects of different drugs on the number of head scratches in model rats at different time points

[0104] The results showed that the number of head shakings in the control group (C) remained low in both observation periods; while the number of head shakings in the model group (M) increased significantly, especially reaching a high level 30-60 minutes after nitroglycerin injection. Although there was a decline from 90-120 minutes, which is a physiological trend of relief, it was still much higher than that in the control group, indicating that the migraine model was successfully established. Compared with other treatment groups, this traditional Chinese medicine preparation (Z) significantly reduced the number of head shakings in rats in both detection periods, and the reduction was significant. Its inhibitory effect was better than that of Qingnao Zhitong granules and other modified or replaced formulas. Compared with the zolmitriptan group, the traditional Chinese medicine preparation was comparable to the zolmitriptan group in the 30-60 minute period. It is worth noting that in the 90-120 minute period, the traditional Chinese medicine preparation group still showed significant efficacy and was better than the zolmitriptan group.

[0105] 1.5.2 Effects of various drugs on pain sensitivity in model rats

[0106] According to Von Frey fiber analysis, the pain threshold of the model group rats was significantly lower than that of the blank group rats, indicating that the animals' pain sensitivity was increased; while the intervention of this traditional Chinese medicine preparation can effectively increase the pain threshold of the model mice, suggesting that it has the effect of relieving pain.

[0107] 1.5.3 Effects of each drug group on vasoactivity and corresponding neurogenic indicators in migraine rats

[0108] In a nitroglycerin (NTG)-induced migraine model in rats, NTG acts as an exogenous nitric oxide (NO) donor, releasing NO in vivo and binding to its corresponding receptors, promoting vasodilation of vascular smooth muscle and inducing abnormal cerebral vasodilation. The results of this experiment showed that the NO levels in the plasma and brain tissue of the model group rats were significantly higher than those in the control group, a result consistent with the pathological characteristics of abnormal cerebral vasodilation during a migraine attack.

[0109] In the comparison of drug interventions, the whole-formula traditional Chinese medicine preparation effectively inhibited the abnormal increase of the aforementioned NO index, significantly reducing its level and bringing it much closer to that of the blank group. In contrast, the inhibitory effect of the fractional formulations (replacing the principal drug or removing the assistant drug) on ​​NO was significantly weakened, with a much smaller decrease than that of the whole-formula group, indicating that the absence of the core medicinal ingredients greatly weakens the vasodilatory inhibitory effect of this compound. Furthermore, the whole-formula traditional Chinese medicine preparation also effectively increased the level of β-EP, a key neurotransmitter in the body's analgesic system, with better results than the fractional formulations and comparable to that of the zolmitriptan group.

[0110] Regarding neurogenic inflammation and neurotransmitter regulation, calcitonin gene-related peptide (CGRP), as an important vasodilatory active substance, shows a significantly elevated concentration in the external jugular vein during migraine attacks. Clinically, CGRP receptor antagonists can effectively relieve headaches and restore CGRP levels. This study also confirmed that the CGRP content in the brain tissue of the model group rats was significantly higher than that in the control group. After drug intervention, all groups showed varying degrees of reduction, with the all-formula group and the zolmitriptan group showing the most ideal reduction. Meanwhile, 5-HT, as a key mediator between receptors and target cells, is a crucial factor in the pathogenesis of migraines due to its decreased content. The serum 5-HT level in the model rats was significantly reduced. After drug intervention, the all-formula group and the zolmitriptan group showed significant increases and restoration of 5-HT levels, with better results than the other groups.

[0111] In summary, through multi-dimensional and multi-indicator pharmacodynamic verification, this study confirms that this traditional Chinese medicine preparation can effectively intervene in the pathological process of migraine through multiple targets and pathways, demonstrating the advantage of overall synergistic effect.

[0112] 1.6 Discussion

[0113] This experiment compared different Chinese herbal formulas, and the results showed that changing the principal herb or removing the assistant herb resulted in poor control of several core migraine indicators. From a biochemical pharmacodynamic perspective, this fully demonstrated the irreplaceable nature of the original prescription's herbs and the rationality of the compatibility, proving the holistic view of the synergistic effect of this Chinese herbal preparation.

[0114] By comparing the efficacy of Qingnao Zhitong Capsules and Zolmitriptan Tablets, the results showed that this traditional Chinese medicine preparation was significantly better than Qingnao Zhitong Capsules in treating migraines, and comparable to Zolmitriptan Tablets, and even better than Zolmitriptan Tablets in some aspects. However, the traditional Chinese medicine preparation showed unique advantages due to its good safety and lack of obvious side effects.

[0115] Experiment 2

[0116] 1.1 General Information

[0117] Eighty-one migraine patients admitted to our hospital between March 2024 and February 2026 were randomly divided into a study group and a control group. The control group consisted of 41 patients (14 males and 27 females), aged 18-54 years, with a mean age of (41.27±8.6) years and a mean disease duration of (7.44±2.80) years. The study group consisted of 40 patients (18 males and 22 females), aged 19-65 years, with a mean age of (40.53±9.8) years and a mean disease duration of (6.78±3.10) years. Comparison of general characteristics between the two groups showed no significant difference (P>0.05).

[0118] Inclusion criteria: ① Both groups of patients were clinically diagnosed with migraines; ② The patients experienced at least two episodes per month; ③ The patients were informed and signed informed consent forms.

[0119] Exclusion criteria: ① Patients with other types of headaches ② Pregnant or lactating women ③ Patients with other comorbidities ④ Patients with poor treatment adherence

[0120] 1.2 Methods

[0121] Both groups of patients discontinued their headache medications before enrollment. The control group received Zheng Tian Wan (China Resources Sanjiu, National Drug Approval Number: Z44020711), taken 6 grams three times a day after meals. The study group received this traditional Chinese medicine preparation (corresponding to the granules prepared in Example 9, with each weight portion calculated as 1g), one sachet three times a day. Both groups received treatment for 6 weeks.

[0122] 1.3 Observation Indicators

[0123] (1) Comparison of treatment effects between the two groups. The criteria for judging the efficacy were: significant effect: headache was significantly reduced, the number of attacks was reduced, and the interval between headaches was longer; effective: headache was reduced, but the number of attacks was not significantly reduced; ineffective: headache was not significantly improved.

[0124] (2) Comparison of clinical indicators between the two groups, recording the number of headaches and duration before and after treatment (within one month after the end of medication).

[0125] (3) Occurrence of adverse reactions in the two groups

[0126] (4) Transcranial Doppler ultrasound findings in the two groups (mean blood flow velocity of the basilar artery)

[0127] 1.4 Statistical Analysis

[0128] All experimental data were analyzed using GraphPad Prism 10.0 statistical software. Quantitative data are presented as mean ± standard deviation. A p-value < 0.05 was considered statistically significant, and a p-value < 0.01 was considered highly statistically significant.

[0129] 1.4 Results

[0130] (1) Treatment efficacy of the two groups

[0131] The results showed that the total effective rate of treatment in the study group was higher than that in the control group (97.5% vs. 73.17%, P<0.01), as detailed in Table 1.

[0132] Table 1 Comparison of overall treatment effects between the two groups

[0133]

[0134] (4) Clinical indicators of the two groups

[0135] The results are shown in Table 2. After treatment, the number of headache attacks and the duration of each headache attack were lower in both groups than before treatment, and the study group was lower than the control group.

[0136] Table 2 Comparison of clinical indicators of headache symptoms between the two groups

[0137]

[0138] Note: Comparison between the two groups before / after treatment ns P>0.05, **P<0.01; Between groups, before and after treatment, && P<0.01.

[0139] (5) Occurrence of adverse reactions in the two groups

[0140] Regarding safety evaluation, the overall incidence of adverse reactions in the study group (5.00%) was significantly lower than that in the control group (19.51%), and the difference was statistically significant (P=0.0471<0.05). Specifically, no gastrointestinal reactions occurred in the study group, and the incidence of liver function impairment and gastrointestinal reactions was lower than that in the control group.

[0141] Table 3 Comparison of adverse reactions between the two groups

[0142]

[0143] (4) Transcranial Doppler ultrasound findings in the two groups

[0144] The results showed that before treatment, there was no statistically significant difference in the mean blood flow velocity of the basilar artery between the two groups (P>0.05); after treatment, the intracranial blood flow velocity in the study group was lower than that in the control group (P<0.01), as detailed in Table 4.

[0145] Table 4 Comparison of transcranial Doppler ultrasound between the two groups

[0146]

[0147] Note: Comparison between the two groups before / after treatment ns P>0.05, **P<0.01; Between groups, before and after treatment, & P<0.05, && P<0.01.

[0148] 1.5 Discussion

[0149] Clinical research results have fully verified the outstanding beneficial effects of the traditional Chinese medicine preparation of this invention, mainly reflected in the following aspects:

[0150] 1. Definite clinical efficacy: The study group was superior to the control group in reducing the number of migraine attacks, shortening the duration of attacks, and improving related accompanying symptoms. It could also effectively optimize intracranial blood flow velocity and had a significantly higher overall effective rate.

[0151] 2. High drug safety: During the treatment, the incidence of adverse reactions in the study group was much lower than that in the control group, showing a higher safety margin in clinical drug use.

[0152] In summary, this traditional Chinese medicine preparation can not only effectively control migraine symptoms and improve cerebral hemodynamics, but also has good safety and high tolerability, and has good clinical translation and promotion value.

[0153] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A traditional Chinese medicine preparation for migraine, characterized in that, The traditional Chinese medicine preparation is made from the following herbal raw materials in parts by weight: 1-18 parts of Panax notoginseng flower, 9-45 parts of Acanthopanax senticosus bark, 9-40 parts of sunflower leaf, 1-18 parts of sandalwood, 8-40 parts of white-backed leaf root, 1-20 parts of globe amaranth, and 10-40 parts of corn silk.

2. The traditional Chinese medicine preparation according to claim 1, characterized in that, The traditional Chinese medicine preparation is made from the following herbal raw materials: 3-10 parts of Panax notoginseng flower, 15-30 parts of Acanthopanax senticosus bark, 15-30 parts of sunflower leaf, 5-10 parts of sandalwood, 15-30 parts of white-backed leaf root, 5-10 parts of globe amaranth, and 12-30 parts of corn silk.

3. The traditional Chinese medicine preparation according to claim 1, characterized in that, The traditional Chinese medicine preparation is made from the following herbal raw materials: 6 parts of Panax notoginseng flower, 20 parts of Acanthopanax senticosus bark, 20 parts of sunflower leaf, 6 parts of sandalwood, 20 parts of white-backed leaf root, 8 parts of globe amaranth, and 15 parts of corn silk.

4. The use of the traditional Chinese medicine preparation according to any one of claims 1 to 3 in the preparation of a medicament for migraine, characterized in that, The traditional Chinese medicine preparation is made from the above-mentioned proportions of Chinese herbs by weight as raw materials, supplemented with pharmaceutically acceptable excipients, and can be prepared into any one of oral liquid, capsule, tablet, pill, or granule.

5. The application of the traditional Chinese medicine preparation as described in claim 4 in the preparation of a drug for migraine, characterized in that, The traditional Chinese medicine preparation is a granule made from the above-mentioned proportions of Chinese herbal medicines by weight, supplemented with pharmaceutically acceptable excipients, and prepared according to the following steps: (1) Weigh each Chinese medicinal material according to the above weight proportions, wash them, and dry them at 50℃; (2) Crush sandalwood into coarse powder, add 6-8 times the amount of water, soak for 1 hour, extract by steam distillation for 4-6 hours, collect sandalwood aromatic water, volatile oil and dregs, seal and refrigerate the volatile oil for later use, and keep the aromatic water and dregs for later use. (3) Mix the dregs from step (2) with the remaining medicinal materials, add 8-10 times the amount of water, soak for 40 minutes, boil and decoct twice, each time for 1-2 hours, combine the two decoctions and filter to obtain the filtrate. Add the sandalwood aromatic water from step (2) to the filtrate and combine to obtain the total filtrate. (4) The total filtrate obtained in step (3) is concentrated to a clear paste with a relative density of 1.10-1.15 (measured at 60℃) under the conditions of temperature 60-70℃ and vacuum of -0.06 to 0.08MPa; (5) The clear extract obtained in step (4) is vacuum dried at 60~70℃ to obtain a dry extract powder. After being pulverized, it is passed through an 80-mesh sieve to obtain a dry extract powder. (6) The sandalwood volatile oil collected in step (2) is mixed with β-cyclodextrin and an appropriate amount of purified water at a weight ratio of volatile oil to β-cyclodextrin of 1:6 to 1:

10. The mixture is stirred and incorporated at a constant temperature of 40 to 50°C for 1 to 2 hours. It is then refrigerated at 2 to 6°C for 24 hours, filtered, and the precipitate is dried under reduced pressure below 50°C and pulverized to obtain the sandalwood volatile oil β-cyclodextrin inclusion complex. (7) The dry extract powder obtained in step (5), the sandalwood volatile oil β-cyclodextrin inclusion complex obtained in step (6), and any one of the following excipients—dextrin, soluble starch, and sucrose powder—are mixed thoroughly in a mixer at a weight ratio of 1:1 to 1:

3. 70% to 80% ethanol is added to form a soft mass, which is then granulated using a swaying granulator to obtain wet granules. (8) Place the wet granules obtained in step (7) in a fluidized bed dryer or oven and dry them at 60℃~80℃ until the moisture content is less than 4.0%. After drying, granulate the granules through a 14~16 mesh sieve to remove fine powder and broken particles. Pack the granulated granules into 15g bags and seal them to obtain the traditional Chinese medicine granules of the present invention.

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