Application of a traditional Chinese medicine composition in the preparation of a drug for nervous headache

Abstract

This invention relates to the application of a traditional Chinese medicine composition in the preparation of a drug for neurogenic headache. The composition is characterized by being prepared from Rehmannia glutinosa (processed), Cornus officinalis, Dioscorea opposita, Alisma plantago-aquatica, Paeonia suffruticosa, and Poria cocos. The composition significantly reduces the number of head scratches in rats with nitroglycerin-induced neurogenic headache, decreases the levels of neurogenic headache-related factors (NO, CGRP) in plasma, improves reserpine-induced low serotonin (5-HT) symptoms in mice, and increases clotting time, suggesting that this traditional Chinese medicine composition has a good therapeutic effect on neurogenic headache.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine technology and relates to a new use of a traditional Chinese medicine composition, specifically the application of a traditional Chinese medicine composition in the preparation of a drug for nervous headache. Background Technology

[0002] Neuropathic headaches mainly refer to tension headaches, functional headaches, and vascular headaches, often caused by mental stress or anger. The main symptoms are persistent dull pain, pressure, and heaviness in the head; some patients describe a "tight band" sensation around the head. Most patients experience bilateral headaches, primarily in the temples, back of the head, top of the head, or the entire head. Neuropathic headaches originate from the tension and contraction of the head muscles, causing a tight or pressing sensation, heaviness, and often a throbbing pain, which is exacerbated by excessive smoking and drinking. This is often caused by irregular lifestyle, excessive smoking and drinking, and insufficient sleep, mainly due to prolonged tension and fatigue in the nervous system, or strong mental stimulation causing brain dysfunction, resulting in a lowered pain tolerance threshold and tension in the head muscles, thus causing headaches. Neuropathic headaches mainly include headaches caused by neurasthenia and headaches caused by hysteria. Its prevention and treatment is a very complex and meticulous task, requiring a comprehensive approach combining psychological, pharmacological, and other therapies to achieve better results.

[0003] Tension headache is a common chronic neurovascular disease caused by neurovascular dysfunction, characterized by recurrent, unilateral or bilateral headaches. With the increasingly fast pace of life and growing work pressure, the incidence of tension headache is on the rise, becoming a common ailment troubling modern people. Summary of the Invention

[0004] To address the aforementioned technical problems, this invention provides an application of a traditional Chinese medicine composition in the preparation of a remedy for nervous headaches. This composition is prepared from Rehmannia glutinosa (processed), Cornus officinalis, Dioscorea opposita, Alisma plantago-aquatica, Paeonia suffruticosa, and Poria cocos. The term "used for" can refer to any method beneficial to improving the corresponding symptoms of the patient, including treatment or prevention.

[0005] Specifically, tension headaches mainly include headaches caused by neurasthenia and headaches caused by hysteria.

[0006] Furthermore, the traditional Chinese medicine composition comprises, by weight, 6-8 parts of Rehmannia glutinosa, 3-4 parts of Cornus officinalis, 3-4 parts of Dioscorea opposita, 2-3 parts of Alisma plantago-aquatica, 2-3 parts of Paeonia suffruticosa, and 2-3 parts of Poria cocos.

[0007] Preferably, the traditional Chinese medicine composition may be made from Rehmannia glutinosa, Cornus officinalis, Dioscorea opposita, Alisma plantago-aquatica, Paeonia suffruticosa and Poria cocos in a weight ratio of 8:4:4:3:3:3.

[0008] The above-mentioned composition can be made by directly grinding raw materials into powder and mixing, or it can be an extract or other form obtained by conventional means. The raw materials used can also be used by directly grinding them into powder, extracting them, or using other processed forms.

[0009] Preferably, the traditional Chinese medicine composition provided by the present invention comprises, by weight, 11.4-17% polysaccharide, 1.85-2.27% total glycosides composed of monosodium glutamate, loganin and paeoniflorin, and 23.5-35.5% mannotriose.

[0010] Specifically, the drug dosage forms for neurogenic headache provided by the present invention include oral dosage forms, injectable dosage forms, or topical dosage forms.

[0011] The dosage form of the drug of the present invention is prepared by weighing the raw material in proportion, and then adding pharmaceutically acceptable excipients or additives, such as fillers, disintegrants, lubricants, suspending agents, binders, sweeteners, flavoring agents, preservatives, and matrices, in accordance with conventional pharmaceutical production methods, to produce a pharmaceutically acceptable conventional dosage form, including but not limited to decoctions, granules, capsules, tablets, oral liquids, pills, tinctures, syrups, suppositories, gels, sprays, and injections.

[0012] Further, the preparation method of the aforementioned traditional Chinese medicine composition is as follows: i) The mixture composed of Rehmannia glutinosa, Cornus officinalis, Dioscorea opposita, Alisma plantago-aquatica, Paeonia suffruticosa and Poria cocos is boiled in boiling water and then concentrated to extract; ii) Ethanol is added to the extract to a concentration of 30 v / v%, centrifuged, washed, and the supernatant and washings are combined to form a supernatant; iii) The supernatant is concentrated, and 95 v / v% ethanol is added to the concentrate to a concentration of 60 v / v%, and the mixture is left to separate fraction A and the supernatant; iv) The supernatant in iii) is subjected to column chromatography on a macroporous adsorption resin, eluted with water and a polar organic solvent, and the organic solvent eluent is concentrated to obtain fraction B; v) The water eluent in iv) is concentrated and loaded onto an activated carbon column, eluted with ethanol, and the ethanol eluent is concentrated to obtain fraction C; vi) Fraction A in iii), fraction B in iv), and fraction C in v) are mixed.

[0013] Further, the preparation method of the aforementioned traditional Chinese medicine composition is as follows: i) The mixture composed of Rehmannia glutinosa, Cornus officinalis, Dioscorea opposita, Alisma plantago-aquatica, Paeonia suffruticosa and Poria cocos in a ratio of 8:4:4:3:3:3 is boiled twice with boiling water and then concentrated to an extract; ii) Ethanol is added to the extract with stirring until the ethanol concentration is 30 v / v%, left to stand, centrifuged, washed, and the supernatant and washings are combined to form a supernatant; iii) The supernatant is concentrated, and 95 v / v% ethanol is added to the concentrate with stirring until the ethanol concentration is 60 v / v%, left to stand, and fraction A and supernatant are separated; iv) The supernatant in iii) is subjected to column chromatography on a macroporous adsorption resin, eluted with water and a polar organic solvent, and the organic solvent eluent is concentrated to obtain fraction B; v) The water eluent in iv) is concentrated and loaded onto an activated carbon column, eluted with ethanol, and the ethanol eluent is concentrated to obtain fraction C; vi) Fraction A in iii), fraction B in iv), and fraction C in v) are mixed.

[0014] Furthermore, the preparation method of the aforementioned traditional Chinese medicine composition includes:

[0015] The raw herbs were prepared according to the following weight ratios: Rehmannia glutinosa: Cornus officinalis: Dioscorea opposita: Alisma plantago-aquatica: Paeonia suffruticosa: Poria cocos (8:4:4:3:3:3), or with some herbs added or subtracted, to form a total of 1500 grams of raw herbs. The herbs were decocted twice with six times their weight of raw herbs in boiling water, two hours each time. The decoction was filtered through gauze and absorbent cotton, and concentrated under reduced pressure until the ratio of raw herbs (by weight) to extract (by volume) was 1:1. Ethanol was added to the extract while stirring until the final ethanol concentration reached 30% (v / v), stirred, and left overnight. The mixture was then centrifuged (2500 rpm, 25 min). The precipitate was washed four times with 30% ethanol, centrifuged, and the precipitate was discarded. The supernatants were combined and concentrated to 1000 mL. The final ethanol concentration was adjusted to 60% with 95% ethanol, stirred, and left to stand overnight. The precipitate was then centrifuged again using the same method. The precipitate was then subjected to a second alcohol precipitation treatment with 60% ethanol. The resulting precipitate was dissolved in water, concentrated to remove alcohol, and then freeze-dried to obtain fraction A. The supernatants from the three treatments were combined, and the ethanol was removed by rotary evaporation. The precipitate was then subjected to HP-20 macroporous adsorption resin column chromatography with a column bed volume (mL) to sample amount (g) ratio of 10:1. The precipitate was then eluted sequentially with water and 30% ethanol. The fraction eluted with 30% ethanol was concentrated to remove alcohol and then freeze-dried to obtain fraction B. The fraction eluted with water was concentrated and then subjected to activated carbon column chromatography with an activated carbon column bed volume (mL) to sample amount (g) ratio of 20:1. The fraction eluted with water and 30% ethanol was then eluted sequentially. The fraction eluted with 30% ethanol was concentrated to remove alcohol and then freeze-dried to obtain fraction C. Fractions A, B, and C were combined to form the extract.

[0016] The composition of this invention can significantly reduce the number of head scratches in rats with nitroglycerin-induced neurogenic headache, reduce the content of neurogenic headache-related factors (NO, CGRP) in plasma, improve the symptoms of low serotonin (5-HT) in mice induced by reserpine, and increase coagulation time, thus having a good therapeutic effect on neurogenic headache. Detailed Implementation

[0017] Neuropathic headaches mainly refer to tension headaches, functional headaches, and vascular headaches. Neuropathic headaches are a common neurological condition, caused by prolonged stress, anxiety, fatigue, and other factors that lead to dilation of arteries and muscle contraction around the head. The main symptoms are persistent dull pain, pressure, and heaviness in the head. Most patients experience bilateral headaches, primarily in the temples, back of the head, top of the head, or the entire head. Vascular headaches, also known as migraines, are recurrent headaches caused by vasospasm resulting from dysfunction of intracranial and extracranial blood vessel vasomotor function and cerebral cortex dysfunction.

[0018] Most common Western medicines use vasoconstrictors, neurotrophic agents, and analgesics to relieve pain symptoms. Traditional Chinese medicine treats tension headaches according to the principle of "treating the symptoms in acute cases and addressing the root cause in chronic cases," using syndrome differentiation and targeted medication to greatly reduce patients' dependence on certain drugs.

[0019] In view of this, the present invention aims to provide an application of a traditional Chinese medicine composition in the preparation of a medicine for nervous headache. The following will describe this in detail with reference to specific experiments.

[0020] Unless otherwise specified, all experiments in the following experiments were conducted under standard conditions or conditions recommended by the manufacturer. Active pharmaceutical ingredients (APIs) or excipients, as well as reagents or instruments whose manufacturers are not specified, are all commercially available products. Unless otherwise stated, all percentages, ratios, proportions, or parts are by weight.

[0021] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to this invention.

[0022] Example 1: Preparation of the Traditional Chinese Medicine Composition

[0023] Referring to the preparation and detection methods in CN100500193, the traditional Chinese medicine composition of this embodiment was prepared according to the following method:

[0024] According to the weight ratio of each herb, namely Rehmannia glutinosa: Cornus officinalis: Dioscorea opposita: Alisma plantago-aquatica: Paeonia suffruticosa: Poria cocos (8:4:4:3:3:3), a total of 1500 grams of raw herbs are prepared. Boil them twice with six times the weight of the raw herbs, each time for two hours. Filter the solution through gauze (six layers) and absorbent cotton, and concentrate it under reduced pressure until the ratio of raw herbs (weight) to extract (volume) is 1:1.

[0025] The extract was added with ethanol with stirring until the final ethanol concentration reached 30% (v / v), stirred, and left overnight. It was subjected to centrifugation (2500 rpm, 25 min). The precipitate was rinsed 4 times with 30% ethanol, centrifuged, and the precipitate was discarded. The supernatants were combined and concentrated to 1000 mL, and the final ethanol concentration was adjusted to 60% with 95% ethanol, stirred, and left overnight, and centrifuged in the same way. The precipitate was subjected to secondary ethanol precipitation with 60% ethanol. The obtained precipitate was dissolved in water and concentrated to remove ethanol, and then freeze-dried to obtain a grayish-white powder (Part A, 51.92 g). The three supernatants were combined, rotary thin-film evaporation was carried out to remove ethanol, and HP-20 macroporous adsorption resin column chromatography was carried out. The ratio of the resin column bed volume (mL) to the sample loading amount (g) was 10:1, and then eluted successively with water and 30% ethanol. The 30% ethanol elution part was concentrated to remove ethanol and then freeze-dried to obtain a brownish-yellow powder (Part B, 38.6 g). The water elution part was concentrated and then subjected to activated carbon column chromatography. The ratio of the activated carbon column bed volume (mL) to the sample loading amount (g) was (20:1), and eluted successively with water and 30% ethanol. The 30% ethanol elution part was concentrated to remove ethanol and then freeze-dried to obtain a white powder (Part C, 151 g). Parts A, B, and C were combined to form an extract.

[0026] After detection, in this extract, polysaccharide was 14.2% by weight, total glycosides (composed of morroniside, loganin, and paeoniflorin) were 2.06% by weight, and oligosaccharide was 29.5% by weight.

[0027] Effect of Example 2 of Experiments on a Rat Model of Nitroglycerin-Induced Neuropathic Headache

[0028] 1. Experimental Materials

[0029] Animals: SD rats, SPF grade, male, a total of 60 rats, weighing 180 - 200 g. Purchased from Nantong University, license number: SCXK (Beijing) 2019 - 0001.

[0030] Drugs: Sumatriptan succinate, Tianjin Huajin Pharmaceutical Co., Ltd., batch number 7F6927T.

[0031] Reagents: Calcitonin gene-related peptide (CGRP) assay kit, Nanjing Jiancheng Bioengineering Institute, product number: D731034; nitric oxide (NO) assay kit, Nanjing Jiancheng Bioengineering Institute, product number: A013 - 2 - 1; nitroglycerin injection, Beijing Yimin Pharmaceutical Co., Ltd., batch number: H11020289; 0.9% sodium chloride injection, Zhejiang Guojing Pharmaceutical Co., Ltd., batch number C22072207.

[0032] Instruments: Ultra-low temperature freezer, Haier, model: DW-86L728; Electronic balance, Sartorius Scientific Instruments, model: BSA224S-CW; Microplate reader, American Microplate Molecular, model: Flexstation 3.

[0033] 2. Dosage design

[0034] The human daily dose of sumatriptan succinate is 50 mg, and the clinical dose for an adult (60 kg) is 0.83 mg / kg. The equivalent dose for rats is calculated to be 5.17 mg / kg.

[0035] The daily human dose of the traditional Chinese medicine composition is 1.24g, and the clinical dose for an adult (based on a weight of 60kg) is 0.021g / kg. The equivalent dose for rats is calculated to be 0.13g / kg. Using this dose as the medium dose, and designing a dose ratio of 0.5:1:2, the low, medium, and high doses of the traditional Chinese medicine composition are 0.065, 0.13, and 0.26g / kg, respectively.

[0036] 3. Experimental Methods

[0037] Sixty male SD rats were randomly divided into six groups according to their body weight: a blank control group, a model control group, a sumatriptan succinate group (positive control, 5.17 mg / kg), and low (0.065 g / kg), medium (0.13 g / kg), and high (0.26 g / kg) dose groups of the composition of this invention (based on extract weight), with 10 rats in each group. The blank control group received a subcutaneous injection of physiological saline in the neck and back, while the other groups received a subcutaneous injection of nitroglycerin (10 mg / kg) in the neck and back, once a week for three consecutive weeks. After the second week of injection, each group began to receive the corresponding drug by gavage at a volume of 10 ml / kg, once daily for seven days. The blank control group and the model control group received pure water by gavage.

[0038] Two hours after the last injection of nitroglycerin, the rats were anesthetized, blood was collected, and plasma was collected by centrifugation.

[0039] Detection indicators: ① Nitroglycerin was injected 1 hour after the last administration, and the number of times rats scratched their heads within 2 hours was observed in each group. ② The levels of nitric oxide (NO) and calcitonin gene peptide (CGRP) in plasma were detected using an ELISA kit.

[0040] 4. Experimental Results

[0041] Results showed that nitroglycerin significantly increased the release of NO in vivo, dilated blood vessels, induced the release of CGRP by neurons, and caused headache. Compared with the blank control group, the number of head scratching times of rats in the model control group increased significantly within 2 h (P<0.01), and plasma NO and CGRP increased (P<0.01). Compared with the model control group, the number of head scratching times in the positive drug sumatriptan group and the low, medium, and high dose groups of the composition of the present invention decreased significantly (P<0.05, P<0.01), and the plasma NO and CGRP contents decreased significantly (P<0.05, P<0.01). The results are shown in Table 1 and Table 2.

[0042] Table 1 Effects on the number of head scratching times of model rats within 2 h

[0043]

[0044]

[0045] Note: Compared with the blank control group, ## P<0.01; compared with the model control group, * P<0.05, ** P<0.01.

[0046] Table 2 Effects on the contents of plasma NO and CGRP

[0047]

[0048] Note: Compared with the blank control group, ## P<0.01; compared with the model control group, * P<0.05, ** P<0.01.

[0049] Experimental Example 3 Effects on the reserpine-induced mouse model of neuropathic headache

[0050] 1. Experimental materials

[0051] Animals: ICR mice, SPF grade, male, a total of 60 mice, weighing 18 - 20 g. Purchased from Nantong University, license number: SCXK(Beijing)2019 - 0001.

[0052] Drugs: Zhengtian Pills, China Resources Sanjiu Medical & Pharmaceutical Co., Ltd., batch number: Z20220025.

[0053] Reagents: Reserpine injection, Tianjin KingYork Amino Acid Co., Ltd., batch number: 220311; 5 - hydroxytryptamine (5 - HT) ELISA kit, elabscience company, product number: E - EL - 0033c; 0.9% sodium chloride injection, Zhejiang Guojing Pharmaceutical Co., Ltd., batch number: C22072207.

[0054] Instruments: Electronic balance, Sartorius Scientific Instruments, model: BSA224S-CW; Refrigerated centrifuge, CENTRFUGE5840, eppendorf; Microplate reader, American Microplate Molecular, model: Flexstation 3.

[0055] 2. Dosage design

[0056] The daily dosage of Zheng Tian Wan for humans is 18g. The clinical dose for adults (based on a weight of 60kg) is 0.3g / kg. The calculated equivalent dose for mice is 3.69g / kg.

[0057] The daily human dose of the traditional Chinese medicine composition is 1.24g, and the clinical dose for an adult (based on a weight of 60kg) is 0.021g / kg. The equivalent dose for mice is calculated to be 0.26g / kg. Using this dose as the medium dose, and designing a dose ratio of 0.5:1:2, the low, medium, and high doses of the traditional Chinese medicine composition are 0.13, 0.26, and 0.52g / kg, respectively.

[0058] 3. Experimental Methods

[0059] Sixty mice were randomly divided into six groups according to their body weight: a blank control group, a model control group, a Zheng Tian Wan group (positive control drug, 3.69 g crude drug / kg), and low (0.13 g / kg), medium (0.26 g / kg), and high (0.52 g / kg) dose groups of the composition of this invention, with 10 mice in each group. Except for the blank control group, the other groups were subcutaneously injected with reserpine injection at 0.25 mg / kg daily for 10 consecutive days. Starting from the 4th day of modeling, each group was administered the corresponding drug by gavage once daily for 7 consecutive days. The blank control group and the model control group were administered pure water by gavage. Thirty minutes after the last administration, blood was collected by enucleation, and the coagulation time was measured by slide method. Brainstem tissue was collected and frozen at -80℃.

[0060] Detection indicators: ① Clotting time. ② ELISA kit for detecting 5-HT in brain tissue.

[0061] 4. Experimental Results

[0062] The results showed that reserpine, a monoamine neurotransmitter depleting agent, depleted 5-HT in the model animals, leading to decreased 5-HT levels in plasma and brain tissue, excessive vasodilation, and thus inducing headaches. Compared with the blank control group, the model control group showed significantly reduced clotting time and brain tissue 5-HT levels (P<0.01); compared with the model control group, the positive control group (Zheng Tian Wan) and the medium and high dose groups of the present invention showed significantly increased clotting time (P<0.05, P<0.01), and the 5-HT levels in the Zheng Tian Wan group and the low, medium, and high dose groups of the present invention were significantly increased (P<0.05, P<0.01). The high dose of the present invention was even more effective than Zheng Tian Wan. The results are shown in Table 3.

[0063] Table 3. Effects of reserpine on clotting time and intracranial 5-HT levels in a mouse model of neurogenic headache.

[0064]

[0065] Note: Compared with the model group, *P<0.05, **P<0.01.

[0066] The composition proposed in this invention can significantly reduce the number of head scratches in rats with nitroglycerin-induced neurogenic headache, and decrease the levels of nitric oxide (NO) and calcitonin gene-related peptide (CGRP) in serum; it can also significantly improve reserpine-induced low 5-HT in mice and increase clotting time. In summary, the composition of this invention has a definite therapeutic effect on neurogenic headache.

[0067] The above embodiments of the present invention are merely examples to clearly illustrate the present invention and are not intended to limit the implementation of the present invention. Those skilled in the art can make other variations or modifications based on the above description. It is neither necessary nor possible to exhaustively describe all embodiments here. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. Use of a traditional Chinese medicine composition in the preparation of a medicament for treating a neuropathic headache, characterized in that, The traditional Chinese medicine composition, by weight, is prepared from the following raw materials: Prepared Rehmannia root 6-8 parts, Cornus officinalis 3-4 parts, Dioscorea opposita 3-4 parts, Alisma plantago-aquatica 2-3 parts, Paeonia suffruticosa 2-3 parts, and Poria cocos 2-3 parts; The product, by weight, includes: 11.4-17% polysaccharides, 1.85-2.27% total glycosides composed of monosodium glutamate, loganin and paeoniflorin, and 23.5-35.5% mannotriose.

2. Use according to claim 1, characterized in that, The preparation method of the traditional Chinese medicine composition is as follows: i) The mixture consisting of Rehmannia glutinosa, Cornus officinalis, Dioscorea opposita, Alisma plantago-aquatica, Paeonia suffruticosa and Poria cocos is boiled in boiling water and then concentrated into an extract; ii) Add ethanol to the extract to a concentration of 30 v / v, centrifuge, rinse, and combine the supernatant with the washings to form a supernatant; iii) Concentrate the supernatant, add 95 v / v% ethanol to the concentrate until the ethanol concentration is 60 v / v%, let stand, and separate part A and the supernatant; iv) The supernatant from iii) was subjected to column chromatography on a macroporous adsorption resin, eluted with water and a polar organic solvent, and the eluent was concentrated to obtain fraction B; v) iv) After the water eluent is concentrated, it is loaded onto an activated carbon column and eluted with ethanol. The ethanol eluent is then concentrated to obtain fraction C. vi) Mix part A in iii), part B in iv), and part C in v).

3. Use according to claim 1, characterized in that, The preparation method of the traditional Chinese medicine composition is as follows: i) A mixture of Rehmannia glutinosa, Cornus officinalis, Dioscorea opposita, Alisma plantago-aquatica, Paeonia suffruticosa and Poria cocos in a ratio of 8:4:4:3:3:3 is boiled twice with boiling water and then concentrated into an extract; ii) Add ethanol to the extract while stirring until the ethanol concentration is 30 v / v%. Let stand, centrifuge, rinse, and combine the supernatant and washings into a supernatant. iii) Concentrate the supernatant, add 95 v / v% ethanol to the concentrate with stirring until the ethanol concentration is 60 v / v%, let stand, and separate fraction A and supernatant; iv) The supernatant from iii) was subjected to column chromatography on a macroporous adsorption resin, eluted with water and a polar organic solvent, and the eluent was concentrated to obtain fraction B; v) iv) After the water eluent is concentrated, it is loaded onto an activated carbon column and eluted with ethanol. The ethanol eluent is then concentrated to obtain fraction C. vi) Mix part A in iii), part B in iv), and part C in v).

4. Use according to claim 1, characterized in that, The traditional Chinese medicine composition comprises, by weight, 14.2% polysaccharide, 2.06% total glycosides composed of monosodium glutamate, loganin and paeoniflorin, and 29.5% mannotrisaccharide.

5. The application according to claim 1, characterized in that, The dosage form of the medication for nervous headaches is an oral dosage form.

6. The application according to claim 1, characterized in that, The medication for nervous headaches is in the form of decoction, granules, capsules, tablets, oral liquid, pills, tinctures, or syrup.

7. The application according to claim 1, characterized in that, The drug for neurogenic headache can be prepared from the traditional Chinese medicine composition and pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients are fillers, disintegrants, lubricants, suspending agents, binders, sweeteners, flavoring agents or preservatives.

8. The application according to claim 1, characterized in that, The aforementioned neurogenic headache includes headaches caused by neurasthenia and headaches caused by hysteria.

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