RU2548756C2 - Pharmaceutical composition for treating insomnia and method of obtaining - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical composition for treating insomnia. Said composition includes root of Polygonum multiflorum and/or its extracts, seeds of Ziziphus spinosa and/or its extracts, mulberry fruit and/or its extracts, Ganoderma and/or its extracts, lily bulb and/or its extracts, Anemarrhena rhizome and/or its extracts, root of Salvia miltiorrhiza and/or its extracts, chrysanthemum flower and/or its extracts, Poria and/or its extracts and Albizia flower and/or its extracts. Invention also relates to application of said composition.

EFFECT: claimed invention provides sedative and soporific effect, contributes to memory stimulation.

17 cl, 6 tbl, 14 ex

Description

FIELD OF THE INVENTION

The present invention belongs to the field of Chinese galenic preparations, relates to a pharmaceutical composition and a method for its preparation, said pharmaceutical composition comprising a highlander multiflorum root and / or its extracts, spiny jujube and / or its extracts and mulberry fruit and / or its extracts and is used in the treatment of insomnia.

BACKGROUND OF THE INVENTION

Insomnia is not a satisfactory condition regarding the quality and quantity of sleep, which lasts for quite some time. Insomnia is a clinically common and common disease, and its clinical symptoms include difficulty falling asleep, a readiness to wake up from sleep, inability to fall asleep again after waking up, too early waking up in the morning, disturbed sleep, inability to sleep throughout the night, shallow sleep or loss of sleep feeling , and may be accompanied by drowsiness. In addition, insomnia can lead to discomfort after waking up, fatigue, a decrease in the effectiveness of mental activity or an obstacle to social functions. It is estimated that approximately 20% of people aged 20 years suffer from sleep disturbance; this number rises to 50% at the age of 55 and up to 90% at the age of 80. Recent statistics show that more than 42.5% of the Chinese population suffers from sleep disturbances to varying degrees; the incidence of insomnia reaches 10% -20%. The results of the Sanofi-Aventis Sleep Survey, conducted by the Branch Society of Psychiatry, China Medical Association, in 2002, showed that 25.9% of people consider themselves suffering from a sleep disorder that began 2 years (median) ago. It should be noted that, according to the Athenian scale, 45.4% of people do not have ideal sleep quality, of which 28% are related to insomnia, and 17.4% are related to possible insomnia (Xiaohong ZHANG, China Medical Tribune, October 10, 2002 g., issue 831).

In recent years, with the constant improvement of people's living standards and increasing oppression of social competition, especially hard work and study, the incidence of this disease is increasing, which seriously affects the quality of life, work and study of patients and adversely affects work, study and social communication. 45% of traffic accidents are due to lack of sleep, 50% of work-related injuries are due to lack of sleep, and the risk of an accident for a person suffering from chronic insomnia is 4.5 times higher than for a healthy person (Da JING, China Medical Tribune, March 20 2003, issue 853).

With an increased pace of life and increased work pressure, more and more patients with insomnia are observed, and there is an increasingly urgent need for effective prevention and treatment of this disease. Recent studies show that the effectiveness of sedatives alone is low, especially when the toxic and side effects of chemically synthesized drugs became more apparent, and the dependence of the human body, withdrawal symptoms, and recoil symptoms caused widespread concern among practitioners and patients.

Traditional Chinese medicine has a long history of treating insomnia. Based on the holistic concept and the differentiation and treatment of syndromes, the effectiveness of traditional Chinese medicine in treating insomnia is undeniable and long-lasting with appropriate safety as well as satisfactory patient commitment. Therefore, people are trying to prevent and cure insomnia under the guidance of the theory of traditional Chinese medicine, and the demand for the treatment of insomnia with medicines derived from natural traditional Chinese materia medica is also increasing.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a pharmaceutical composition comprising a highlander multiflorum root and / or its extracts, spiny jujube and / or its extracts and mulberry fruit and / or its extracts.

In some embodiments, the pharmaceutical composition of the present invention further comprises a ganoderma and / or its extracts, a lily bulb and / or its extracts, anemarrena rhizome and / or its extracts, sage root and / or its extracts, chrysanthemum flower and / or its extracts and Poria and / or its extracts.

In some embodiments, the pharmaceutical composition of the present invention further comprises an albia flower and / or extracts thereof.

In some embodiments, each of said extracts is independently a solvent extract. Said solvent may be any suitable solvent, for example, water, ethanol, an aqueous solution of ethanol, supercritical carbon dioxide, or any mixture thereof.

In some embodiments, the aforementioned pharmaceutical composition is obtained from medicinal raw materials with the following ratios of parts by weight: highlander root multiflorum 150-270, barbwy seed of barbed 145-275 and mulberry 160-255.

In some embodiments, the pharmaceutical composition is obtained from medicinal raw materials with the following ratios of parts by weight: highlander root multiflorum 150-270, spiny jujube seed 145-275, mulberry fruit 160-255, ganoderma 80-135, lily bulb 75-160, rhizome anemarrenes 50-110, sage root multicorne 120-200, chrysanthemum flower 45-120 and poria 75-145.

In some embodiments, the aforementioned pharmaceutical composition is obtained from medicinal raw materials with the following ratios of parts by weight: highlander root of multiflorum 150-270, barbed sisyphus seed 145-275, mulberry fruit 160-255, ganoderma 80-135, lily bulb 75-160, rhizome anemarrenes 50-110, the sage root of multi-rhizome 120-200, a flower of a chrysanthemum 45-120, a poria 75-145 and a flower of an albitsia 165-288.

In some embodiments, the ratios of the weight parts of the medicinal raw material are: highlander multiflorum root 158, spiny jujube seed 270, mulberry fruit 165, ganoderma 135, lily bulb 80, anemarrhene rhizome 110, sage root multicorne 125, chrysanthemum flower 118, poria 80, and albia flower 280.

In some embodiments, the ratios of the weight parts of the medicinal raw material are: highlander root multiflorum 265, spiny jujube seed 147, mulberry fruit 250, ganoderma 81, lily bulb 158, anemarrena rhizome 55, sage root multicorne 188, chrysanthemum flower 50, poria 145 and flower of albination 170.

In some embodiments, the ratios of weight parts of the medicinal raw material are: highlander 225 multi-flowered root, prickly zyphus seed 163, mulberry fruit 220, ganoderma 83, lily bulb 113, anemarrena rhizome 50, sage root 190, chrysanthemum flower, poria 113, and albia flower 178.

In some embodiments, the ratios of weight parts of the medicinal raw material are: highlander multiflorum root 165, spiny jujube seed 228, mulberry fruit 173, ganoderma 110, lily bulb 75, anemarrhene rhizome 75, sage root multicorne 150, chrysanthemum flower 78, poria 78 and albia flower 218.

In some embodiments, the ratios of the weight parts of the medicinal raw material are: highlander 200 multicolor root, 200 barbed sisyphus seed, 200 mulberry fruit, 100 ganoderma, 100 lily bulb, 66 anemarren rhizome, 166.7 multi-rhizome sage root, 66.7 chrysanthemum flower , Poria 100 and Albisia flower 200.

In some embodiments, each gram of the pharmaceutical composition contains at least 0.5 mg, preferably at least 1.0 mg, more preferably at least 1.5 mg of 2,3,5,4'-tetrahydroxydiphenylethylene-2-O- β-D-glucoside (mainly obtained from the highlander multiflorum root or its extracts) by dry weight of the pharmaceutical composition.

In some embodiments, the dosage form of the pharmaceutical composition is a capsule, tablet, powder, oral solution, soft capsule, pill, infusion, syrup, suppository, gel, spray or injection.

In some embodiments, a method for preparing a pharmaceutical composition comprises preparing an extract from one or more kinds of drug raw materials, individually or together.

In some embodiments, a method for preparing a pharmaceutical composition comprises: weighing the drug material in accordance with the ratio of parts by weight, soaking for 20-40 minutes by adding water, infusing for 30-40 minutes after boiling, filtering and again infusing for 25-30 minutes after adding water and boiling, filtering and combining the two filtrates.

In some embodiments, a method for preparing a pharmaceutical composition comprises the following steps:

a) obtaining an alcoholic extract of the root of the highlander multiflorum, rhizome anemarrena and spiny jujube;

b) obtaining an aqueous extract of the fruit of the mulberry, poria, ganoderma, sage root, multicorne, albicia flower and chrysanthemum flower;

c) obtaining a powder of lily bulbs;

d) the use of an alcoholic extract of step a), an aqueous extract of step b) and a powder of lily bulb of step c) as the active ingredients of this pharmaceutical composition.

In some embodiments, a method for preparing a pharmaceutical composition comprises the following steps:

a) the highlander multiflorum root, anemarrena rhizome and spiny jujube seed are weighed in accordance with the ratios of parts by weight, a 6-12-fold amount of 30% -70% ethanol is added; carry out heating under reflux from 1 to 3 times for 1-3 hours each time; the extract is filtered, combined, and ethanol is regenerated under reduced pressure, and concentrated to a relative density of 1.10-1.15 determined at 60 ° C in order to obtain an alcoholic extract;

b) mulberry fruit, poria, ganoderma, sage root multicorne, albicia flower and chrysanthemum flower are weighed in accordance with the ratio of parts by weight, add 10-15-fold amount of water in order to extract, from 1 to 3 times for 1-3 hours everytime; the extract is filtered, combined and concentrated to a relative density of approximately 1.10-1.15 determined at 60 ° C in order to obtain an aqueous extract;

c) the lily bulb is weighed in accordance with the ratio of parts by weight and ground into a powder of 100 mesh lily bulbs;

d) an alcoholic extract of step a), an aqueous extract of step b) and a powder of lily bulbs of step c) are used as active ingredients of the pharmaceutical composition.

The active ingredients can be obtained in the required dosage forms along with optional pharmaceutical excipients.

The dosage form of the pharmaceutical composition in accordance with the present invention may be any suitable dosage form, for example, capsule, tablet, powder, oral solution, soft capsule, pill, infusion, syrup, suppository, gel, spray or injection.

In order to obtain the aforementioned dosage forms, pharmaceutically acceptable excipients can be added during the preparation of these dosage forms, for example: filler, disintegrant, glidant, suspending agent, binder, sweetener, flavoring agent, preservative and the like. Excipients include starch, pregelatinized starch, lactose, mannitol, chitin, microcrystalline cellulose, sucrose and the like. Baking powder include starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, low substitution hydroxypropyl cellulose, crosslinked sodium carboxymethyl cellulose and the like. Moving substances include magnesium stearate, sodium dodecyl sulfate, talcum powder, silicon dioxide and the like. Suspending agents include polyvinylpyrrolidone, microcrystalline cellulose, sucrose, agar, hydroxypropyl methyl cellulose and the like. Binders include starch suspension, polyvinylpyrrolidone, hydroxypropyl methylcellulose and the like. Sweeteners include sodium saccharin, aspartame, sucrose, sodium cyclamate, glycyrrhetinic acid and the like. Flavoring agents include a sweetener and various essences. Preservatives include parabens, benzoic acid, sodium benzoate, sorbic acid and their salts, benzalkonium bromide, chlorhexidine acetate, eucalyptus oil and the like.

The pharmaceutical composition in accordance with the present invention can be obtained in various ways. Such production methods are well known to specialists in this field of technology and are described in various technical documents, for reference, you can read Remington's Pharmaceutical Manual, etc. These methods include conventional production methods, for example, mixing, dissolving, emulsifying, suspending, etc.

A method of producing a tablet with a pharmaceutical composition in accordance with the present invention includes the following steps:

a) the selected and purified highlander multiflorum root, anemarren rhizome and coarsely ground prickly jujube are weighed in accordance with the ratios, add 6-12-fold amount of 30% -70% ethanol; carry out heating under reflux from 1 to 3 times for extraction for 1-3 hours each time; the extract is filtered, combined, and ethanol is regenerated under reduced pressure, and concentrated to a relative density of 1.10-1.15, determined at 60 ° C, in order to obtain a ready-to-use alcoholic extract;

b) selected and refined mulberry fruit, poria, ganoderma, sage root multicorne, albicia flower and chrysanthemum flower are weighed according to the relationship, add 10-15-fold amount of water in order to extract from 1 to 3 times 1-3 hours every time; the extract is filtered, combined, and concentrated to a relative density of approximately 1.10-1.15, determined at 60 ° C, in order to obtain an aqueous extract ready for use;

c) the selected and purified lily bulb is weighed in accordance with the ratios and pulverized into 100 mesh powder, ready for use;

d) the alcohol extract obtained in stage a), the aqueous extract of stage b) and the finely ground lily bulb powder obtained in stage c) are subjected to dry granulation; after classification of the granules, appropriate auxiliary substances are added; carry out mixing, tabletting and coating.

A method for producing a tablet with a pharmaceutical composition in accordance with the present invention preferably includes the following steps:

a) the selected and purified highlander root, multiflorum, anemarren rhizome and coarsely ground prickly salmon jujube are weighed in accordance with the ratios, and 60% ethanol is added; carry out refluxing twice for extraction, the first time adding a 10-fold amount and extracting it for 2 hours and the second time adding an 8-fold amount and extracting it for 1 hour; the extract is filtered, combined, and ethanol is regenerated under reduced pressure, and concentrated to a relative density of 1.10-1.15, determined at 60 ° C, in order to obtain a ready-to-use alcoholic extract;

b) selected and refined mulberry fruit, poria, ganoderma, sage root multicorne, albicia flower and chrysanthemum flower are weighed according to the relationship, add 11-fold amount of water in order to extract twice for 1.5 hours each time; the extract is filtered, combined, and concentrated to a relative density of approximately 1.10-1.15, determined at 60 ° C, in order to obtain an aqueous extract ready for use;

c) the selected and purified lily bulb is weighed in accordance with the ratios and pulverized into 100 mesh powder, ready for use;

d) the finely ground lily bulb powder obtained in step c) is added to the ingredients container of the spray dryer granulator, the alcohol extract obtained in step a) and the aqueous extract of step b) are sprayed to spray granulation; after classification of the granules, 0.5% magnesium stearate is added; carry out mixing, tabletting and coating.

A method of obtaining a decoction of the pharmaceutical composition in accordance with the present invention includes: highlander multiflorum root, spiny jujube, mulberry fruit, ganoderma, lily bulb, anemarrena rhizome, sage root multicorne, chrysanthemum flower, poria and albicia flower are weighed in accordance with the relationship and placed in boiler; add water for the first time 3-5 cm above the top surface of the drug; medicinal raw materials are soaked for 20-40 minutes, insisted for 30-40 minutes after boiling and filtered; again add water 1-3 cm above the upper surface of the drug; medicinal raw materials are insisted for 25-30 minutes after boiling, filtered and the two filtrates are combined.

A method of producing a wet pill with a pharmaceutical composition in accordance with the present invention includes:

a) the selected and purified highlander multiflorum root, anemarren rhizome and coarsely ground prickly jujube are weighed in accordance with the ratios, add 6-12-fold amount of 30% -70% ethanol; carry out heating under reflux from 1 to 3 times for extraction for 1-3 hours each time; the extract is filtered, combined, and ethanol is regenerated under reduced pressure, concentrated, dried at 60-80 ° C and ground to obtain a dry alcohol extract ready for use;

b) selected and refined mulberry fruit, poria, ganoderma, sage root multicorne, albicia flower and chrysanthemum flower are weighed according to the relationship, add 10-15-fold amount of water in order to extract from 1 to 3 times 1-3 hours every time; the extract is filtered, combined, concentrated and dried at 60-80 ° C and ground to obtain a dry aqueous extract ready for use;

c) the selected and purified lily bulb is weighed in accordance with the ratios and pulverized into 100 mesh powder, ready for use;

From the dry alcoholic extract obtained in stage a), the dry aqueous extract of stage b) and the finely ground lily bulb powder obtained in stage c), dragees are made together.

All of the capsule, powder, oral solution, soft capsule, pill, infusion, syrup, suppository, gel, spray and injection solution of the pharmaceutical composition in accordance with the present invention can be obtained from medicinal raw materials for the pharmaceutical composition in accordance with the present invention or the active ingredients of the pharmaceutical compositions in accordance with the present invention in accordance with conventional pharmaceutical methods.

The pharmaceutical composition in accordance with the present invention can be administered to various animals, including mammals, especially humans. For animals or people in need of administration of a pharmaceutical composition in accordance with the present invention, its dosage can be determined by practitioners in accordance with the condition of the subject, including, for example, the severity of the disease, general health, body weight, age of the patient and the like. The pharmaceutical composition in accordance with the present invention can be administered in various appropriate ways, including, for example, oral, injectable, subcutaneous, transdermal and topical administration, etc. The frequency of administration of the pharmaceutical composition in accordance with the present invention may be determined by various factors, including, for example, the particular disease being treated, the general health of the subject, etc. Typically, for humans, the dosage of the pharmaceutical composition in accordance with the present invention is 14-20 g per day based on the total weight of the medicinal raw material, and can be taken once a day or divided into 2-4 doses per day, preferably 16.8 g per day divided into 3 doses per day.

The terms used in the present invention have the usual meanings in the field of traditional Chinese medicine.

Highlander Root Multiflorum: POLYGONI MULTIFLORI RADIX. It is a dry root tuber of Polygonum multiflorum Thunb. It is harvested in autumn and winter when the leaves dry; both ends cut off; it is peeled and large tubers are cut into pieces; and then dried.

The processed root of the Polygonum highlander (POLYGONI MULTIFLORI RADIX PRAEPARATA) is a processed product of the Polygonum highlander. Take mugs or slices of the highlander multiflorum root and mix evenly with the juice of hyacinth beans and carry out the cooking method (Appendix II D of the Chinese Pharmacopoeia, edition 2010) in an appropriate non-ferrous container until the juice is boiled out, or the steam treatment method ( Appendix II D of the Chinese Pharmacopoeia, 2010 edition), and it is steamed separately or steamed after even mixing with hyacinth bean juice until brown on all sides, dried in the sun until incomplete drying , then cut into circles, and dried again. For every 100 kg of circles (pieces) of the root of the highlander multiflorum, 10 kg of hyacinth beans are used. A method of obtaining juice of hyacinth beans: take 10 kg of hyacinth beans and add the appropriate amount of water; boil for 4 hours in order to obtain approximately 15 kg of juice, and add additional water to the remainder of the beans and boil for 3 hours in order to obtain approximately 10 kg of juice; the juice is combined and approximately 25 kg of hyacinth bean juice is obtained.

Prickly Seed of Zizyphus: ZIZIPHI SPINOSAE SEMEN. It is a dried ripe seed of Ziziphus jujuba Mill, var. spinosa (Bunge) Hu ex H. FChou, which is a plant from the buckthorn family. Ripe fruits are harvested in late autumn and early winter, the flesh and casing (endocarpy) are removed and dried in the sun.

Prickly spiky jujube seed stirring: take the peeled spiky jujube seed and bake in accordance with a simple method of stirring roasting (Appendix II D of the Chinese Pharmacopoeia, 2010 edition), so that it grows in volume and takes on a slightly darker color. Crushed into pieces before use.

Mulberry fruit: MORI FRUCTUS. It is a dried spike-fruit of Morus alba L., which is a plant of the mulberry family. Raw materials are harvested from April to June, when the fruits turn red, and dried in the sun or dried after quick steam treatment.

Ganoderma: GANODERMA. It is a dried sporophore of Ganoderma lucidum (Leyss. Ex Fr.) Karst. or Ganoderma sinense Zhao, Xu et Zhang (polypore family). Raw materials are collected all year; remove foreign material, adhering wood dust, sand or the lower layer of the nutrient substrate; dried in the shade or dryer at 40-50 ° C.

Lily bulb: LILII BULBUS. It is a dried fleshy scaly leaf of Lilium lancifolium Thunb., Lilium brownii FE. Brown var. viridulum Baker or Lilium pumilum DC, which are plants of the lily family. Raw materials are collected in the fall and washed, and the scaly sheets are removed, treated for a moment with boiling water and dried.

Anemarren rhizome: ANEMARRHENAE RHIZOMA. It is a dried rhizome of Anemarrhena asphodeloides Bge., Which is a plant of the lily family. The raw materials are collected in autumn or winter, the fibrous roots and soil are removed, dried in the sun, which is known as "Maozhimu"; or remove external tissue and dry in the sun.

Sage Root Root: SALVIAE MILTIORRHIZAE RADIX ET RHIZOMA. It is a dried root and rhizome of Salvia miltiorrhiza Bge., Which is a plant of the family Labiaceae. Raw materials are collected in spring or autumn, soil is removed and dried.

Chrysanthemum Flower: CHRYSANTHEMI FLOS. It is a dried head of Chrysanthemum morifolium Ramat., Which is a plant of the family Asteraceae. Raw materials are collected in batches from September to November when flowering, dried in the shade or by baking, or dried in the sun after treatment with smoke and steam. It is referred to as “Boju”, “Chuju”, “Gongju” and “Hangju” according to various production locations and variations of processing methods.

Poria: PORIA. It is a dried sclerotia of Porta cocos (Schw.) Wolf mushrooms, (polypore family). Raw materials are collected mainly from July to September, soil is removed, stacked on a moist surface, then distributed on a dry surface. Repeat several times until wrinkles appear and the internal water evaporates, then dried in the shade, this is known as "Fulingge"; or fresh sclerotia is cut and dried in the shade according to the chopped pieces, which are known as "Fulingpian" and "Fulingkuai".

Flower of Albition: ALBIZIAE FLOS. It is a dried inflorescence of Albizia julibrissin Durazz, which is a bean family plant. They are harvested on sunny days in the summer when the flower blooms, and dried in the sun without delay.

The traditional Chinese material medica of the present invention can be replaced by a traditional Chinese material medica of the same or similar effectiveness, and all of these material medica can be processed in accordance with the "National processing standards for traditional Chinese material medica" or "Dictionary of Traditional Chinese Medicine". For example, the root of a highlander multiflorum can be replaced by the treated root of a highlander multiflorum, and the seed of a spiny thornfish can be replaced by the baked when stirring the seed of a spiny thorn; although efficiency after replacement may become higher than that of the original medicinal raw materials, they all belong to the scope of the present invention.

In another aspect, the present invention provides the use of a pharmaceutical composition for treating symptoms of insomnia, amnesia, dizziness, fatigue and / or soreness and weakness in the lower back and knees, etc.

In another aspect, the present invention further provides the use of a pharmaceutical composition for calming, hypnosis, stimulating memory, reducing fatigue and / or alleviating pain.

In another aspect, the present invention further provides a method for treating insomnia, which comprises administering a pharmaceutical composition to a patient with insomnia.

The functions and indications for the use of the pharmaceutical composition in accordance with the present invention are to replenish the kidney cells and improve the brain, nourish the heart in order to calm the spirit, and it is used for insomnia, which is caused by heart and kidney failure, and the symptoms of which include sleep disturbance, e.g. difficulty falling asleep, shallow sleep, nocturnal awakening, excessive dreams, etc., accompanied by amnesia, dizziness, palpitations, fatigue, soreness, and weakness in the lower back and knees.

The present invention was made by Professor WU Yiling with repeated application in practice based on a theoretical study of traditional Chinese medicine in the treatment of insomnia in combination with clinical results. Clinically observed that the symptoms of insomnia, such as amnesia, dizziness, palpitations, fatigue, soreness and weakness in the lower back and knees, etc., caused by heart and kidney failure, can be effectively improved.

Detailed embodiments of the present invention

The following examples are provided only to illustrate the preparation of a pharmaceutical composition in accordance with the present invention, but they do not in any way limit the scope of the present invention.

Example 1: Preparation of a tablet with a pharmaceutical composition in accordance with the present invention (also known as Jiannao Anshen tablet)

Medicinal raw materials: root of the highlander multiflorum 200 g; spiny jujube 200 g; mulberry fruit 200 g; Ganoderma 100 g; lily bulb 100 g; anemarren rhizome 66.7 g; multi-rhizome sage root 166.7 g; chrysanthemum flower 66.7 g; poria 100 g; and Albisia flower 200 g.

Production Method:

a) the selected and refined root of the highlander multiflorum, the rhizome of anemarren and the coarsely ground prickly sisyphus seed were weighed according to the ratios, 60% ethanol was added; heated under reflux in order to extract, twice, the first time 10-fold amount of ethanol was added and extracted for 2 hours and the second time 8-fold amount of ethanol was added and extracted for 1 hour; the extract was filtered, combined, and ethanol was regenerated under reduced pressure, and concentrated to a relative density of 1.10-1.15 determined at 60 ° C in order to obtain a ready-to-use alcoholic extract;

b) the selected and refined mulberry fruit, poria, ganoderma, sage root multicorne, albicia flower and chrysanthemum flower were weighed according to the ratios, 11-fold amount of water was added in order to extract twice for 1.5 hours each time; the extract was filtered, combined and concentrated to a relative density of approximately 1.10-1.15 determined at 60 ° C in order to obtain an aqueous extract ready for use;

c) the selected and purified lily bulb was weighed according to the ratios and pulverized into 100 mesh powder, ready for use;

d) the finely ground lily bulb powder obtained in step c) was added to the ingredients container of the spray granulator dryer, the alcohol extract obtained in step a) and the aqueous extract of step b) were sprayed to spray granulate; after granular classification, 0.5% magnesium stearate was added; mixing, tabletting and coating were carried out in order to obtain 975 tablets of said tablet (0.4 g per tablet).

Example 2: Preparation of a capsule with a pharmaceutical composition in accordance with the present invention

Medicinal raw materials: highlander multiflorum root 158 g; spiny jujube seed 270 g; Mulberry fruit 165 g; Ganoderma 135 g; lily bulb 80 g; anemarren rhizome 110 g; Sage root of multi-rhizome 125 g; chrysanthemum flower 118 g; poria 80 g; and flower of albition 280 g.

Production Method:

a) the selected and refined root of the highlander, multiflorum, anemarrhena rhizome and coarsely ground prickly sisyphus seed were weighed in accordance with the ratios, 6-fold amount of 30% ethanol was added; heated under reflux in order to extract, 3 times for 3 hours each time; the extract was filtered, combined, and ethanol was regenerated under reduced pressure, and concentrated to a relative density of 1.10-1.15 determined at 60 ° C in order to obtain a ready-to-use alcoholic extract;

b) selected and refined mulberry fruit, poria, ganoderma, sage root multicorne, albicia flower and chrysanthemum flower were weighed according to the relations, 10-fold amount of water was added in order to extract, 3 times for 3 hours each time; the extract was filtered and combined, the ethanol being regenerated under reduced pressure, and concentrated to a relative density of about 1.10-1.15, determined at 60 ° C, in order to obtain an aqueous extract ready for use;

c) the selected and purified lily bulb was weighed according to the ratios and pulverized into 100 mesh powder, ready for use;

d) the alcohol extract obtained in stage a), the aqueous extract of stage b) and the finely ground lily bulb powder obtained in stage c) were subjected to dry granulation; after classification of the granules, appropriate auxiliary substances were added; mixed evenly and filled the capsules in order to obtain 983 capsules (0.42 g per capsule).

Example 3: Obtaining a powder of a pharmaceutical composition in accordance with the present invention

Medicinal raw materials: highlander multiflorum root 265 g; spiny jujube 147 g; Mulberry fruit 250 g; Ganoderma 81 g; lily bulb 158 g; anemarren rhizome 55 g; multi-rhizome sage root 188 g; chrysanthemum flower 50 g; Poria 145 g and Albisia flower 170 g.

Production Method:

a) the selected and refined root of the highlander multiflorum, the rhizome of anemarrena and the coarsely ground seed of barbed jujube were weighed in accordance with the ratios, a 12-fold amount of 70% ethanol was added; heated under reflux in order to extract, 2 times for 2 hours each time; the extract was filtered and combined, the ethanol being regenerated under reduced pressure, and concentrated to a relative density of 1.10-1.15 determined at 60 ° C in order to obtain a ready-to-use alcoholic extract;

b) the selected and refined mulberry fruit, poria, ganoderma, sage root multicorne, albicia flower and chrysanthemum flower were weighed according to the relations, 15-fold amount of water was added in order to extract, 2 times for 2 hours each time; the extract was filtered, combined and concentrated to a relative density of approximately 1.10-1.15 determined at 60 ° C in order to obtain an aqueous extract ready for use;

c) the selected and purified lily bulb was weighed according to the ratios and pulverized into 100 mesh powder, ready for use;

d) the alcohol extract obtained in stage a), the aqueous extract of stage b) and the finely ground lily bulb powder obtained in stage c) were dried to obtain 400 g of powder, which was distributed in 2 g per packet.

Example 4: Obtaining an oral solution of a pharmaceutical composition in accordance with the present invention

Medicinal raw materials: root of the highlander multiflorum 225 g; spiny jujube seed 163 g; Mulberry fruit 220 g; Ganoderma 83 g; lily bulb 113 g; anemarren rhizome 50 g; sage root multicorne 190 g; Chrysanthemum flower 45 g; Poria 113 g and flower of albition 178 g.

Production Method:

a) the selected and refined root of the highlander multiflorum, the rhizome of anemarren and coarsely ground seed of barbed sisyphus were weighed in accordance with the ratios, a 10-fold amount of 50% ethanol was added; heated under reflux in order to extract for 3 hours; the extract was filtered, and ethanol was regenerated under reduced pressure, and concentrated to a relative density of 1.10-1.15, determined at 60 ° C, in order to obtain a ready-to-use alcoholic extract;

b) the selected and refined mulberry fruit, poria, ganoderma, sage root multicorne, albicia flower and chrysanthemum flower were weighed according to the ratios, 12-fold amount of water was added to extract for 3 hours; the extract was filtered and concentrated to a relative density of approximately 1.10-1.15 determined at 60 ° C in order to obtain an aqueous extract ready for use;

c) the selected and purified lily bulb was weighed according to the ratios and pulverized into 100 mesh powder, ready for use;

d) from the alcohol extract obtained in stage a), the aqueous extract of stage b) and the finely ground lily bulb powder obtained in stage c), an oral solution was prepared according to conventional methods (Chunlin CAO, Pharmaceutics of Traditional Chinese Medicine, Shanghai Science & Technology Press, 1st edition in November 1986, 8th edition in October 1993: method for preparing an oral solution, pp. 477-488), in order to obtain 10,000 ml of an oral solution, which was distributed in 10 ml per container.

Example 5: Preparation of a soft capsule with a pharmaceutical composition in accordance with the present invention

Medicinal raw materials: root of the highlander multiflorum 225 g; spiny jujube seed 163 g; Mulberry fruit 220 g; Ganoderma 83 g; lily bulb 113 g; anemarren rhizome 50 g; sage root multicorne 190 g; Chrysanthemum flower 45 g; Poria 113 g and flower of albition 178 g.

Production Method:

a) the selected and refined root of the highlander multiflorum, the rhizome of anemarrena and the coarsely ground seed of barbed jujube were weighed in accordance with the ratios, a 12-fold amount of 70% ethanol was added; heated under reflux in order to extract for 1.5 hours; the extract was filtered, combined, and ethanol was regenerated under reduced pressure, and concentrated to a relative density of 1.10-1.15 determined at 60 ° C in order to obtain a ready-to-use alcoholic extract;

b) the selected and refined mulberry fruit, poria, ganoderma, sage root multicorne, albicia flower and chrysanthemum flower were weighed according to the relations, 15-fold amount of water was added in order to extract, 3 times for 1 hour each time; the extract was filtered and concentrated to a relative density of approximately 1.10-1.15 determined at 60 ° C in order to obtain an aqueous extract ready for use;

c) the selected and purified lily bulb was weighed according to the ratios and pulverized into 100 mesh powder, ready for use;

d) soft capsules were prepared from the alcoholic extract obtained in stage a), the aqueous extract of stage b) and the finely ground lily bulb powder obtained in stage c) in accordance with conventional methods (Chunlin CAO, Pharmaceutics of Traditional Chinese Medicine, Shanghai Science & Technology Press, 1st edition in November 1986, 8th edition in October 1993: method for producing a soft capsule, pp. 232-235), in order to obtain 980 soft capsules (0.6 g per capsule) .

Example 6: Preparation of a Pill with a Pharmaceutical Composition of the Present Invention

Medicinal raw materials: highlander multiflorum root 165 g; spiny jujube seed 228 g; mulberry fruit 173 g; Ganoderma 110 g; lily bulb 75 g; anemarren rhizome 75 g; sage root multicorneal 150 g; chrysanthemum flower 78 g; Poria 78 g and flower of albition 218 g.

Production Method:

a) the selected and refined root of the highlander multiflorum, the rhizome of anemarren and the coarsely ground thorny jujube seed were weighed in accordance with the ratios, an 8-fold amount of 40% ethanol was added; heated under reflux in order to extract twice for 2 hours each time; the extract was filtered, combined, and ethanol was regenerated under reduced pressure, and concentrated to a relative density of 1.10-1.15 determined at 60 ° C in order to obtain a ready-to-use alcoholic extract;

b) the selected and refined mulberry fruit, poria, ganoderma, sage root multicorne, albicia flower and chrysanthemum flower were weighed according to the relations, 12-fold amount of water was added to extract twice for 1.5 hours each time; the extract was filtered and concentrated to a relative density of approximately 1.10-1.15 determined at 60 ° C in order to obtain an aqueous extract ready for use;

c) the selected and purified lily bulb was weighed according to the ratios and pulverized into 100 mesh powder, ready for use;

d) from the alcohol extract obtained in stage a), the aqueous extract of stage b) and the finely ground lily bulb powder obtained in stage c), dragees were prepared in accordance with conventional methods (Chunlin CAO, Pharmaceutics of Traditional Chinese Medicine, Shanghai Science & Technology Press, 1st edition in November 1986, 8th edition in October 1993: method for producing a pill, pp. 248-280), in order to obtain 900 tablets (0.5 g per pill).

Example 7: Obtaining the infusion of the pharmaceutical composition in accordance with the present invention

Medicinal raw materials: highlander multiflorum root 158 g; spiny jujube seed 270 g; Mulberry fruit 165 g; Ganoderma 135 g; lily bulb 80 g; anemarren rhizome 110 g; Sage root of multi-rhizome 125 g; chrysanthemum flower 118 g; 80 g poria and 280 g of albicia flower

Production Method:

a) the selected and purified polygonum highlander root, anemarrena rhizome and coarsely ground prickly salmon jujube were weighed in accordance with the ratios, an 11-fold amount of 60% ethanol was added; heated under reflux in order to extract, 3 times for 1 hour each time; the extract was filtered, combined, and ethanol was regenerated under reduced pressure, and concentrated to a relative density of 1.10-1.15 determined at 60 ° C in order to obtain a ready-to-use alcoholic extract;

b) selected and refined mulberry fruit, poria, ganoderma, sage root multicorne, albicia flower and chrysanthemum flower were weighed in accordance with the relations, 14-fold amount of water was added in order to extract, 3 times for 1.5 hours each time; the extract was filtered and concentrated to a relative density of approximately 1.10-1.15 determined at 60 ° C in order to obtain an aqueous extract ready for use;

c) the selected and purified lily bulb was weighed according to the ratios and pulverized into 100 mesh powder, ready for use;

d) from the alcohol extract obtained in stage a), the aqueous extract of stage b) and the finely ground lily bulb powder obtained in stage c), an infusion was prepared in accordance with conventional methods (Chunlin CAO, Pharmaceutics of Traditional Chinese Medicine, Shanghai Science & Technology Press, 1st edition in November 1986, 8th edition in October 1993: method for producing infusion, pp. 163-165), in order to obtain 10,000 ml of infusion, which was distributed in 10 ml per container.

Example 8: Obtaining a syrup with a pharmaceutical composition in accordance with the present invention

Medicinal raw materials: highlander multiflorum root 265 g; spiny jujube 147 g; Mulberry fruit 250 g; Ganoderma 81 g; lily bulb 158 g; anemarren rhizome 55 g; multi-rhizome sage root 188 g; chrysanthemum flower 50 g; Poria 145 g and Albisia flower 170 g.

Production method: 10,000 ml of syrup was obtained in accordance with conventional methods (Chunlin CAO, Pharmaceutics of Traditional Chinese Medicine, Shanghai Science & Technology Press, 1st edition in November 1986, 8th edition in October 1993: production method syrup, pp. 166-170) and dispensed 10 ml per container.

Example 9: Preparation of a suppository with a pharmaceutical composition in accordance with the present invention

Medicinal raw materials: highlander multiflorum root 158 g; spiny jujube seed 270 g; Mulberry fruit 165 g; Ganoderma 135 g; lily bulb 80 g; anemarren rhizome 110 g; Sage root of multi-rhizome 125 g; chrysanthemum flower 118 g; poria 80 g; Albition flower 280 g.

Production method: 500 suppositories were prepared according to conventional methods (Chunlin CAO, Pharmaceutics of Traditional Chinese Medicine, Shanghai Science & Technology Press, 1st edition in November 1986, 8th edition in October 1993: method for preparing a suppository , p. 352-361), 0.5 g per suppository.

Example 10: Preparation of a gel with a pharmaceutical composition in accordance with the present invention

Medicinal raw materials: root of the highlander multiflorum 225 g; spiny jujube seed 163 g; Mulberry fruit 220 g; Ganoderma 83 g; lily bulb 113 g; anemarren rhizome 50 g; sage root multicorne 190 g; Chrysanthemum flower 45 g; Poria 113 g and flower of albition 178 g.

Production method: 3000 g of gel was prepared according to conventional methods (Chunlin CAO, Pharmaceutics of Traditional Chinese Medicine, Shanghai Science & Technology Press, 1st edition in November 1986, 8th edition in October 1993: preparation method gel, pp. 349-350) and dispensed 10 g per container.

Example 11: Obtaining a spray with a pharmaceutical composition in accordance with the present invention

Medicinal raw materials: root of the highlander multiflorum 225 g; spiny jujube seed 163 g; Mulberry fruit 220 g; Ganoderma 83 g; lily bulb 113 g; anemarren rhizome 50 g; sage root multicorne 190 g; Chrysanthemum flower 45 g; Poria 113 g and flower of albition 178 g.

Production method: 10000 ml of spray was obtained in accordance with conventional methods (Chunlin CAO, Pharmaceutics of Traditional Chinese Medicine, Shanghai Science & Technology Press, 1st edition in November 1986, 8th edition in October 1993: production method spray, pp. 454-466) and dispensed 100 ml per container.

Example 12: Preparation of an Injection Solution with a Pharmaceutical Composition of the Present Invention

Medicinal raw materials: highlander multiflorum root 165 g; spiny jujube seed 228 g; mulberry fruit 173 g; Ganoderma 110 g; lily bulb 75 g; anemarren rhizome 75 g; sage root multicorneal 150 g; chrysanthemum flower 78 g; Poria 78 g and flower of albition 218 g.

Production method: 1000 injections were obtained in accordance with conventional methods (Chunlin CAO, Pharmaceutics of Traditional Chinese Medicine, Shanghai Science & Technology Press, 1st edition in November 1986, 8th edition in October 1993: injection method solution, pp. 364-4193), 5 ml per container.

Example 13: Obtaining a decoction of the pharmaceutical composition in accordance with the present invention

Medicinal raw materials: the same as in example 1.

Production Method:

Highlander root, multiflorum, thorny jujube, mulberry fruit, ganoderma, lily bulb, anemarrena rhizome, sage root, chrysanthemum flower, poria and albia flower, weighed in accordance with the relationship and placed in a boiler; water was added for the first time 3-5 cm above the upper surface of the medicinal product; soaked for 30 minutes and insisted for 35 minutes after boiling and filtered; water was again added 1-3 cm above the upper surface of the medicinal product; infused for 30 minutes after boiling, filtered and the two filtrates were combined to obtain 200 doses, 500 ml per dose.

Example 14: Obtaining a wet pill with a pharmaceutical composition in accordance with the present invention

Medicinal raw materials: the same as in example 1.

Production Method:

a) the selected and refined root of the highlander multiflorum, the rhizome of anemarren and the coarsely ground thorny jujube seed were weighed in accordance with the ratios, an 8-fold amount of 60% ethanol was added; heated under reflux in order to extract twice for 2 hours each time; the extract was filtered, combined, and ethanol was regenerated under reduced pressure, concentrated and dried at 75 ° C and crushed in order to obtain a dry alcohol extract ready for use;

b) the selected and refined mulberry fruit, poria, ganoderma, sage root multicorne, albicia flower and chrysanthemum flower were weighed according to the relations, 12-fold amount of water was added in order to extract twice for 1 hour each time; the extract was filtered, combined, concentrated and dried at 75 ° C and crushed in order to obtain a dry aqueous extract (yield of dry extract was 20%), ready for use;

c) the selected and purified lily bulb was weighed according to the ratios and pulverized into 100 mesh powder, ready for use;

d) from the dry alcohol extract obtained in stage a), the dry aqueous extract of stage b) and the finely ground lily bulb powder obtained in stage c), dragees were prepared together and 1 kg of wet dragee was obtained, which was distributed in 100 g per packet.

Pharmacological test

In order to confirm the activity of the pharmaceutical composition in accordance with the present invention in the treatment of insomnia, the tablets obtained in accordance with the method of example 1 (hereinafter referred to as the pharmaceutical preparation in accordance with the present invention) were used in order to carry out the following pharmacological test.

1. Sedative effect of the pharmaceutical preparation in accordance with the present invention

1.1 Experimental materials

1.1.1 Experimental animals

90 healthy male pure breed Kunming mice (body weight 18-22 g) were purchased from the Hebei Province Laboratory Animal Center (License No: SCXK (JI) 2003-1-003, Certificate No: DK0409-0040) and kept at the Yiling Pharmacology Laboratory Research Institute when illuminated for 12 hours a day, at a temperature of 20-23 ° C and a relative humidity of 40-60%. Mice were planted in cells of 6 mice per cell. The mice were fed a complete, granular feed proposed by the Hebei Laboratory Animal Center and provided the mice with sufficient drinking water. Mice acclimatized for 3 days.

1.1.2 Experimental drug

The pharmaceutical preparation in accordance with the present invention (tablet of Example 1) is the equivalent of 3.47 g of the medicinal product per g, and the dosage for humans is 17.0 g of the medicinal product per day, i.e. 0.28 g of medicinal raw materials per kg of body weight (standard body weight of 60 kg). A suspension with 0.5% CMC-Na is obtained from it and stored at 4 ° C. In pharmacological experiments, the term “medicinal raw material” refers to the aforementioned “medicinal raw material” or “materia medica”, and the amount of “medicinal raw material” refers to the converted amount of “material medica”.

Anshenbunao Ye: It is obtained from deer antlers, a treated highlander multiflorum root, goryanka grass, ginger rhizome (dried ginger), jujube fruit, and vitamin B1; functions and indications for use: improving the brain and calming the spirit, producing essences and strengthening the spinal cord, replenishing qi and eating blood; and it is usually used for neurasthenia, insomnia, amnesia, dizziness, fatigue; it is produced by JILIN AODONG YANBIAN PHARMACEUTICAL CO., LTD, registration number: Z22022453 (SFDA); clinical dosage for adults: 20 ml per day; Lot Number: 040269.

The estazolam tablet, a benzodiazepine anxiolytic, can cause inhibition of various parts of the central nervous system; clinical manifestations can range from mild sedation to hypnosis and even coma, and with an increase in the dosage used. It is offered by Shijiazhuang Pharmaceutical Group Co., LTD; Registration No: H13020974 (SFDA); active substance content: 1 mg; clinical dosage for adults: 2-4 mg each time for hypnosis and 1-2 mg each time for sedation, 3 times a day; Lot number: 040101.

1.1.3 Experimental equipment

A mouse locomotor activity setup (locomotor chamber, locomotor software) purchased from Beijing Shuolin Xueyuan Science and Technology Co., LTD.

AB204-N Electronic Analytical Balance purchased from Mettler-Toledo Instruments (Shanghai) Co., Ltd.

1.2. Experimental method

1.2.1 Principles of dosage

In this experiment, for a pharmaceutical preparation in accordance with the present invention, groups of 5.6 g of medicinal raw material per kg, 2.8 g of medicinal raw material per kg and 1.4 g of medicinal raw material per kg were determined, which is equivalent to 20, 10 and 5-fold clinical dosage for humans (0.28 g of medicinal raw materials per kg), respectively. The 13 ml / kg Anshenbunao Ye group and the 2.67 mg / kg estazolam group were determined according to the results of preliminary experiments. Mice were divided into 6 groups in accordance with the above dosage definition, as shown in table 1.

Table 1 The effect of the pharmaceutical preparation in accordance with the present invention on the locomotor activity of mice Groups Dosage Number of animals Clinical dosage ratio equivalent (ratio) Empty Control Group - 12 - Anshenbunao Ye Group 13 ml / kg 12 39 Estazolam group 2.67 mg / kg 12 27 A pharmaceutical preparation in accordance with the present invention 5.6 g of medicinal raw materials per kg 12 twenty 2.8 g of medicinal raw materials per kg 12 10 1.4 g of medicinal raw materials per kg 12 5

1.2.2 Method of administration

The injected concentrations of the pharmaceutical preparation in accordance with the present invention were 0.08 g of dry powder per ml, 0.04 g of dry powder per ml and 0.02 g of dry powder per ml, respectively; the administered concentration for the Anshenbunao Ye group was 0.65 ml of concentrated liquid per ml, and the administered concentration of estazolam was 0.13 mg / ml. 0.2 ml per 10 g was administered through a gastric tube daily, which corresponds to the clinically recommended oral route, for 7 consecutive days, and estazol was administered only once on the seventh day.

1.2.3 Experimental period: 7 days.

1.2.4 Detection indicators and detection methods

The mice were trained once in the morning, afternoon and evening on the 1st day for each time, the mice were acclimatized for 5 minutes after each training, and the number of cases of locomotor activity was recorded for 10 minutes. 72 mice with an average amount of 150-250 times in 10 minutes were selected to participate in the experiment. The number of cases of locomotor activity was determined 1 hour after the last injection, the mice were acclimatized for 5 minutes, and then the number of cases of locomotor activity for 10 minutes was recorded.

1.2.5 Statistical method: One-way ANOVA was used using the spss11.5 statistical software.

1.3 Experimental results

The number of cases of locomotor activity of mice in the Anshenbunao Ye and estazolam groups decreased compared with the empty control group (P <0.01 or P <0.05). Compared with the empty control group, the number of cases of locomotor activity of mice in the groups of the pharmaceutical preparation in accordance with the present invention in dosages of 5.6 g of drug material per kg and 2.8 g of drug material per kg was significantly reduced (P <0.05), and the level of inhibition was 27.5% and 23.4%, respectively. For a group of 1.4 g of drug raw material per kg, the number of cases of locomotor activity of mice tended to decrease, and the inhibition rate was 9.7%. The results are shown in table 2.

table 2 The impact of the pharmaceutical preparation in accordance with the present invention on the number of cases of locomotor activity of mice (¯x ± s, n = 12) Groups Dosage The number of cases of locomotor activity (for 10 min) Inhibition Level (%) Empty Control Group 240.3 ± 30.1 Anshenbunao Ye Group 13 ml / kg 159.7 ± 34.2 ** 33.5 Estazolam group 2.76 mg / kg 174.0 ± 58.9 * 27.5 The pharmaceutical group of the invention 5.6 g of medicinal raw materials per kg 173.3 ± 50.1 * 27.8 2.8 g of medicinal raw materials per kg 184.0 ± 55.2 * 23,4 1.4 g of medicinal raw materials per kg 216.8 ± 72.6 9.7 Note: * P <0.05, ** P <0.01, compared with the empty control group

1.4 Conclusion

The pharmaceutical preparation in accordance with the present invention can reduce the incidence of locomotor activity in mice, which confirms that the pharmaceutical preparation in accordance with the present invention has a sedative effect.

2. Hypnotic effect of the pharmaceutical preparation in accordance with the present invention

2.1 Experimental materials

2.1.1 Experimental animals

72 healthy male pure breed Kunming mice (body weight 18-22 g) were purchased from the Hebei Province Laboratory Animal Center (License No: SCXK (JI) 2003-1-003, Certificate No: DK0409-0016). They were kept in the Laboratory of Pharmacology at the Yiling Research Institute under illumination for 12 hours a day, at a temperature of 20-23 ° C and a relative humidity of 40-60%. Mice were planted in cells of 6 mice per cell. A full-fledged granular feed for mice was proposed by the Hebei Province Laboratory Animal Center, and the mice were provided with sufficient drinking water. Mice acclimatized for 3 days.

2.1.2 Experimental drug

The pharmaceutical preparation in accordance with the present invention is the equivalent of 3.47 g of the medicinal product per g of dry powder, and the dosage for humans is 17.0 g of the medicinal product per day, i.e. 0.28 g of medicinal raw materials per kg of body weight (standard body weight of 60 kg). It is offered by Shijiazhuang Yiling Pharmaceutical Co., LTD (lot No. 20040201). A suspension with 0.5% CMC-Na is obtained from it and stored at 4 ° C.

Anshenbunao Ye: It is obtained from deer antlers, a treated highlander multiflorum root, goryanka grass, ginger rhizome (dried ginger), jujube fruit, and vitamin B1; functions and indications for use: improving the brain and calming the spirit, producing essences and strengthening the spinal cord, replenishing qi and eating blood; and it is usually used for neurasthenia, insomnia, amnesia, dizziness, fatigue; it is produced by JILIN AODONG YANBIAN PHARMACEUTICAL CO., LTD, registration number: Z22022453 (SFDA); clinical dosage for adults: 20 ml per day; Lot Number: 040269.

The estazolam tablet, a benzodiazepine anxiolytic, can cause inhibition of various parts of the central nervous system; clinical manifestations can range from mild sedation to hypnosis and even coma, and with an increase in the dosage used. It is offered by Shijiazhuang Pharmaceutical Group Co., LTD; Registration No: H13020974 (SFDA); active substance content: 1 mg; clinical dosage for adults: 2-4 mg each time for hypnosis and 1-2 mg each time for sedation, 3 times a day; Lot number: 040101.

2.1.3 Experimental reagent

Sodium pentobarbital offered by Sinopharm (Group) Shanghai Chemical Reagent Co., Ltd, lot no .: F20030816.

2.2 Experimental method

2.2.1 Principles of dosage

In this experiment, for a pharmaceutical preparation in accordance with the present invention, groups of 5.6 g of medicinal raw material per kg, 2.8 g of medicinal raw material per kg and 1.4 g of medicinal raw material per kg were determined, which is equivalent to 20, 10 and 5-fold clinical dosage for humans (0.28 g of medicinal raw materials per kg), respectively. The 13 ml / kg Anshenbunao Ye group and the 2.67 mg / kg estazolam group were determined according to the results of preliminary experiments. Mice were divided into 6 groups in accordance with the above definition of dosage, as shown in table 3.

Table 3 The effect of the pharmaceutical preparation in accordance with the present invention on sleep time caused by sodium pentobarbital in mice Groups Dosage Number of animals Clinical dosage ratio equivalent (ratio) Empty Control Group - 12 - Anshenbunao Syrup Group 13 ml / kg 12 39 Estazolam group 2.67 mg / kg 12 27 The pharmaceutical group of the invention 5.6 g of medicinal raw materials per kg 12 twenty 2.8 g of medicinal raw materials / kg 12 10 1.4 g of medicinal raw materials / kg 12 5

2.2.2 Method of administration

The injected concentrations of the pharmaceutical preparation in accordance with the present invention were 0.08 g of dry powder per ml, 0.04 g of dry powder per ml and 0.02 g of dry powder per ml, respectively; the administered concentration for the Anshenbunao Ye group was 0.65 ml of concentrated liquid per ml, and the administered concentration of estazolam was 0.13 mg / ml. 0.2 ml per 10 g was administered through a gastric tube daily, which corresponds to the clinically recommended oral route, for 7 consecutive days, and estazol was administered only once on the seventh day.

2.2.3 Method of creating an animal model

One hour after the last administration, 45 mg / kg of sodium pentobarbital sodium was administered in each group by intraperitoneal injection.

2.2.4 Experimental period: 7 days.

2.2.5 Detection indicators and detection methods

For these experiments, a reference is made to "Methodology on Pharmacology of Experiment" (3rd edition). The intraperitoneal dosage of sodium pentobarbital, which caused sleep in 100% of mice and did not lead to too long sleep time, was determined in preliminary experiments as 45 mg / kg. After 1 hour after the last injection, 45 mg / kg of sodium pentobarbital sodium was administered in each group by intraperitoneal injection and the sleep time of mice was recorded (the period from the disappearance of the rectification reflex to the restoration of the rectification reflex).

2.2.6 Statistical method: The t-test was used with the spss11.5 statistical software.

2.3 Experimental Results

Sleep time of mice in the estazolam group increased compared with the control group of the model (P <0.01). The sleep time of mice in the groups of the pharmaceutical preparation in accordance with the present invention in dosages of 5.6 g of medicinal raw materials per kg and 2.8 g of medicinal raw materials per kg increased compared to the control group of the model (P <0.05 or 0.01). The results are shown in table 4.

Table 4 The effect of the pharmaceutical preparation in accordance with the present invention on sleep time caused by sodium pentobarbital in mice (¯x ± s, n = 12) Groups Dosage Sleep time (min) Model Control Group 26.64 ± 18.50 Anshenbunao Ye Group 13 ml / kg 21.60 ± 11.01 Estazolam group 2.76 mg / kg 72.89 ± 18.01 ** Pharmaceutical Product Groups of the Invention 5.6 g of medicinal raw materials per kg 41.55 ± 14.28 * 2.8 g of medicinal raw materials / kg 57.90 ± 17.04 ** 1.4 g of medicinal raw materials / kg 25.75 ± 16.69 Note: * P <0.05, ** P <0.01, compared with the model control group

2.4 Conclusion

The pharmaceutical preparation in accordance with the present invention has an effect of increasing sleep time induced by sodium pentobarbital in mice.

3. Stimulating memory effects of a pharmaceutical preparation in accordance with the present invention

3.1 Experimental materials

3.1.1 Experimental animals

72 healthy male pure breed Kunming mice (body weight 18-22 g) were purchased from the Hebei Province Laboratory Animal Center (License No: SCXK (JI) 2003-1-003, Certificate No: DK0409-0016). They were kept in the Laboratory of Pharmacology at the Yiling Research Institute under illumination for 12 hours a day, at a temperature of 20-23 ° C and a relative humidity of 40-60%. Mice were planted in cells of 6 mice per cell. Granulated feed for mice was proposed by the Hebei Province Laboratory Animal Center, and the mice were provided with sufficient drinking water. Mice acclimatized for 3 days.

3.1.2 Experimental drug

A pharmaceutical preparation in accordance with the present invention was proposed by Shijiazhuang Yiling Pharmaceutical Co., LTD, lot No. 20040201. A suspension with 0.5% CMC-Na was prepared from it and stored at 4 ° C.

HABOYIN (Huperzine A Tablet). Huperzine A is a reversible, highly selective acetylcholinesterase inhibitor. It is manufactured by Henan Zhulinzhongsheng Pharmaceutical Co., Ltd. Registration No: HI0940156 (SFDA); active substance content: 0.05 mg per tablet; lot no: 050201.

Scopolamine Hydrobromide Injection, Registration No: H31021519 (SFDA), Shanghai Hefeng Pharmaceutical Co., Ltd .; lot no: 4A18003. Active substance content: 0.3 mg.

3.1.3 Experimental equipment: SMG-2 programmed water labyrinth manufactured at the Materia Medica Institute of the Chinese Academy of Medical Sciences.

3.2 Experimental method

3.2.1 Dosage determination principles

In this experiment, for a pharmaceutical preparation in accordance with the present invention, groups of 5.6 g of medicinal raw material per kg, 2.8 g of medicinal raw material per kg and 1.4 g of medicinal raw material per kg were determined, which is equivalent to 20, 10 and 5-fold clinical dosage for humans (0.28 g of medicinal raw materials per kg), respectively. The empty control, model control and 0.4 mg / kg huperzine A groups were additionally identified. Mice were divided into 6 groups in accordance with the above definition of dosage, as shown in table 5.

Table 5 The effect of the pharmaceutical preparation in accordance with the present invention on impaired recovery of mouse memory caused by scopin Groups Dosage Number of animals Clinical dosage ratio equivalent (ratio) Empty Control Group - 12 - Model Control Group - 12 - Huperzine Group A 0.4 mg / kg 12 - The pharmaceutical group of the invention 5.6 g of medicinal raw materials per kg 12 twenty 2.8 g of medicinal raw materials per kg 12 10 1.4 g of medicinal raw materials per kg 12 5

3.2.2 Method of administration

The injected concentrations of the pharmaceutical preparation in accordance with the present invention were 0.08 g of dry powder per ml, 0.04 g of dry powder per ml and 0.02 g of dry powder per ml, respectively, and the administered concentration in the group of huperzine A was 0.02 mg / ml 0.2 ml per 10 g was administered through a gastric tube daily, which corresponds to the clinically recommended oral route, for 14 consecutive days.

3.2.3 Method of creating an animal model

30 minutes after the administration, on the 14th day, 2 mg / kg scopolamine hydrobromide was administered by intraperitoneal injection, excluding the empty control group, to create a model of memory restoration impairment.

3.2.4 Experimental period: 14 days.

3.2.5 Detection indicators and detection methods

Mice were trained (water temperature 24-26 ° C, water depth 10 cm). During the training, the mouse was initially placed on the platform for 10 seconds, so that it knew about the existence of this security zone, then the mouse was placed next to the platform in order to allow it to climb the stairs on its own to get acquainted with the exit route. All training was divided into 5 days: point A on the 9th day, point B on the 10th day, point B on the 11th day, point S on the 12th day and point S on the 13th day, mice were trained one once a day daily, each training was 2 minutes, and the animal was sent to the side of the platform using a glass rod in case of delay. At the beginning of swimming, the head of the mouse was turned toward the wall of the starting point. After training for point S was completed, the mice were required to be able to swim to the platform in 2 minutes, otherwise they would be excluded. 30 minutes after the administration, on the 14th day, 2 mg / kg scopolamine hydrobromide was administered by intraperitoneal injection, excluding the empty control group, to create a model of memory restoration impairment. The study was carried out 30 minutes after modeling. The mice began to swim from point S, and the number of errors (the number of entries to the dead end) and the latent period (the period of time that occupied swimming from point S to the platform) were recorded.

3.2.6 Statistical method: A nonparametric criterion was used using the spss11.5 statistical software.

3.3 Experimental Results

The latent period during swimming in mice in the model group increased compared with the empty control group (P <0.01). The latent period during swimming in mice in the groups of huperzine A was reduced compared with the model group (P <0.01). The latent period in the group of the pharmaceutical preparation in accordance with the present invention at a dosage of 5.6 g of the drug raw material per kg was reduced (P <0.05). The results are shown in table 6.

Table 6 The effect of the pharmaceutical preparation in accordance with the present invention on the impaired memory recovery of mice caused by scopin (¯x ± s, n = 12) Groups Dosage Number of errors (times) Latent period (sec.) Empty Control Group 11.58 ± 7.94 54.50 ± 37.61 Model Control Group 21.08 ± 13.13 109.3 * 19.7ΔΔ Huperzine Group A 0.4 mg / kg 16.83 ± 14.21 63.33 ± 44.30 ** Pharmaceutical Product Groups of the Invention 5.6 g of medicinal raw materials per kg 18.83 ± 11.68 79.67 ± 40.96 * 2.8 g of medicinal raw materials / kg 17.83 ± 13.56 67.75 ± 50.67 1.4 g of medicinal raw materials / kg 23.67 ± 13.49 92.92 ± 34.29 Note: ΔΔP <0.01, compared with the empty control group;
* P <0.05, ** P <0.01, compared with the model control group

3.4 Conclusion

The pharmaceutical preparation in accordance with the present invention has an improvement effect in memory impairment caused by scopin in mice.

In addition, in the mouse model of impaired memory recovery caused by scopin, the latent period when swimming in the group of the pharmaceutical preparation in accordance with the present invention at a dosage of 5.6 g of the drug substance per kg was reduced. In addition, in the mouse model of acquired dysmnesia caused by scopin, the latent period when swimming in the groups of a pharmaceutical preparation in accordance with the present invention in dosages of 5.6 g of drug material per kg and 2.8 g of drug material per kg was reduced. These results indicate that the pharmaceutical preparation according to the present invention has a memory improving effect.

In an experiment with swimming mice, the swimming time in the pharmaceutical group of the invention in a dosage of 5.6 g of drug per kg was increased, and the swimming time in the pharmaceutical group of the invention in doses of 2.8 g of drug per kg and 1.4 g of medicinal raw materials per kg tended to increase by 25.5% and 11.3%, respectively. In experiments with rotarod, the time of rotarod in the groups of a pharmaceutical preparation in accordance with the present invention in dosages of 5.6 g, 2.8 g and 1.4 g of medicinal raw material per kg tended to increase by 93.6%, 55.9% and 3.0% respectively. These results indicate that the pharmaceutical preparation in accordance with the present invention has the effect of reducing fatigue to some extent.

In the torsion experiment, the latent torsion period in mice in the pharmaceutical group of the invention in a dosage of 5.6 g of drug material per kg increased and the number of torsions decreased. In the experiment with the hot plate, the pain threshold of mice in the group of the pharmaceutical preparation in accordance with the present invention at a dosage of 2.8 medicinal raw materials per kg increased. These results indicate that the pharmaceutical preparation according to the present invention has a pain relief effect.

In conclusion, the pharmaceutical preparation according to the present invention has the effects of sedation, hypnosis, memory stimulation, fatigue reduction and pain relief. The clinically recommended dosage of the pharmaceutical composition in accordance with the present invention is 17.0 g of the medicinal product per day (standard weight 60 kg), and in the toxicity test of the pharmaceutical composition in accordance with the present invention, no acute toxic reaction was observed in mice at a maximum dosage of 166, 80 g of medicinal raw materials per kg; and no noticeable toxic reaction was observed in rats when 5.6, 11.2, and 22.4 g of drug raw material per kg was administered through a gastric tube for 3 consecutive months, therefore, such a composition can be recommended for clinical use.

Claims (17)

1. A pharmaceutical composition for treating insomnia, comprising a highlander multiflorum root and / or its extracts, spiny jujube and / or its extracts, a mulberry fruit and / or its extracts, a ganoderma and / or its extracts, a lily bulb and / or its extracts, anemarrhene rhizome and / or its extracts, sage root and / or its extracts, chrysanthemum flower and / or its extracts, poria and / or its extracts and albicia flower and / or its extracts. 2. The pharmaceutical composition according to claim 1, containing extracts obtained using a solvent such as water, ethanol, an aqueous solution of ethanol, supercritical carbon dioxide, or any mixture thereof. 3. The pharmaceutical composition according to claim 1, where the pharmaceutical composition is obtained from medicinal raw materials with the following ratios of parts by weight: highlander root multiflorum 150-270, spiny jujube seed 145-275, mulberry fruit 160-255, ganoderma 80-135, lily bulb 75 -160, anemarrhene rhizome 50-110, sage root 120–200, chrysanthemum flower 45–120, poria 75–145, and albicia flower 165–288. 4. The pharmaceutical composition according to claim 1, in which the ratio of the weight parts of the medicinal raw material is: highlander root multiflorum 158, spiny jujube seed 270, mulberry fruit 165, ganoderma 135, lily bulb 80, anemarren rhizome 110, sage root multicorn 125, chrysanthemum flower 118, poria 80 and flower of albition 280. 5. The pharmaceutical composition according to claim 1, in which the ratios of the weight parts of the medicinal raw material are: highlander root multiflorum 265, spiny jujube seed 147, mulberry fruit 250, ganoderma 81, lily bulb 158, anemarrhena rhizome 55, sage root 188, chrysanthemum flower 50, Poria 145 and flower of Albition 170. 6. The pharmaceutical composition according to claim 1, in which the ratios of the weight parts of the medicinal raw material are: highlander root 225 multiflorum, prickly sisyphus seed 163, mulberry fruit 220, ganoderma 83, lily bulb 113, anemarrhene rhizome 50, 190 sage root, chrysanthemum flower 45, poria 113 and flower of albition 178. 7. The pharmaceutical composition according to claim 1, in which the ratio of the weight parts of the medicinal raw material is: highlander multiflorum root 165, spiny jujube seed 228, mulberry fruit 173, ganoderma 110, lily bulb 75, rhizome anemarrena 75, 150 sage root, chrysanthemum flower 78, Poria 78 and Albisia flower 218. 8. The pharmaceutical composition according to claim 1, in which the ratios of the weight parts of the medicinal raw material are: highlander root of multiflorum 200, barbed seed jujube 200, mulberry fruit 200, ganoderma 100, lily bulb 100, anemarren rhizome 66.7, sage root multicorne 166, 7, Chrysanthemum flower 66.7, Poria 100 and Albition flower 200. 9. The pharmaceutical composition according to claim 1, in which each gram of the pharmaceutical composition contains not less than 0.5 mg, preferably not less than 1.0 mg, more preferably not less than 1.5 mg 2,3,5,4 '-Tetrahydroxydiphenylethylene-2-O-β-D-glucoside, calculated on the dry weight of the pharmaceutical composition. 10. The pharmaceutical composition according to claim 1, wherein the dosage form of the pharmaceutical composition is a capsule, tablet, powder, oral solution, soft capsule, pill, infusion, syrup, suppository, gel, spray or injection. 11. The pharmaceutical composition according to claim 2, where the method of obtaining this pharmaceutical composition comprises obtaining an extract from one or more types of medicinal raw materials individually or together. 12. The pharmaceutical composition according to claim 11, where the method of obtaining this pharmaceutical composition comprises weighing the medicinal substances in accordance with the ratio of the weight parts, soaking for 20-40 minutes by adding water, infusion for 30-40 minutes after bringing to a boil, filtering and again insisting for 25-30 minutes after adding water and boiling, filtering and combining the filtrates. 13. The pharmaceutical composition according to claim 1, where the method of obtaining this pharmaceutical composition comprises the following steps:
a) obtaining an alcoholic extract of the root of the highlander multiflorum, rhizome anemarrena and spiny jujube;
b) obtaining an aqueous extract of the fruit of the mulberry, poria, ganoderma, sage root, multicorne, albicia flower and chrysanthemum flower;
c) obtaining a powder of lily bulbs; and
d) the use of an alcoholic extract of stage a), an aqueous extract of stage b), and lily powder of a stage c) as active ingredients of this pharmaceutical composition. 14. The pharmaceutical composition according to claim 1, wherein the method for producing the pharmaceutical composition comprises the following steps:
a) highlander multiflorum root, anemarrena rhizome and spiny jujube seed are weighed in accordance with the ratio of parts by weight, a 6-12-fold amount of 30% -70% ethanol is added; carry out heating under reflux in order to extract from 1 to 3 times for 1-3 hours each time; the extract is filtered and combined to regenerate ethanol under reduced pressure, and concentrated to a relative density of 1.10-1.15, determined at 60 ° C, in order to obtain an alcoholic extract;
b) mulberry fruit, poria, ganoderma, sage root multicorne, albicia flower and chrysanthemum flower are weighed in accordance with the ratio of parts by weight, add 10-15 times the amount of water in order to extract, from 1 to 3 times for 1-3 hours each time; the extract is filtered, combined and concentrated to a relative density of approximately 1.10-1.15 determined at 60 ° C in order to obtain an aqueous extract;
c) the lily bulb is weighed in accordance with the ratio of parts by weight and ground into a powder of 100 mesh lily bulbs; and
d) the alcohol extract of step a), the aqueous extract of station b) and the powder of the bulb of lily of step c) are used as the active ingredients of this pharmaceutical composition. 15. The use of the pharmaceutical composition according to any one of paragraphs. 1-9 for the treatment of symptoms of insomnia, amnesia, dizziness, fatigue and / or soreness and weakness in the lower back and knees. 16. The use of the pharmaceutical composition according to any one of paragraphs. 1-9 to soothe, hypnosis, stimulate memory, reduce fatigue and / or relieve pain. 17. A method of treating insomnia, including the introduction of a pharmaceutical composition according to any one of paragraphs. 1-9 to a patient with insomnia.