CN108126062A - A kind of oral Chinese medicine composition for treating depression and its preparation and preparation method - Google Patents
A kind of oral Chinese medicine composition for treating depression and its preparation and preparation method Download PDFInfo
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- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
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Abstract
The invention belongs to the field of Chinese medicines, more particularly to a kind of oral Chinese medicine composition for treating depression and its preparation and preparation method.The oral Chinese medicine composition of the treatment depression is made of pharmaceutically acceptable pharmaceutic adjuvant and radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig, Manjusri orchid, elm mushroom, wherein radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig, elm mushroom, which are adopted, is extracted with water the extraction of the alcohol precipitation method, and Manjusri orchid uses volatile oil component of the extraction by steam distillation relative density below 1.0.The dosage form of the oral Chinese medicine composition is preferably oral liquid.The oral Chinese medicine composition has good therapeutic effect and safety to depression.
Description
Technical field
The invention belongs to the field of Chinese medicines, and in particular to a kind of oral Chinese medicine composition for treating depression and its preparation and system
Preparation Method.
Background technology
Depression is a kind of emotional handicap syndrome, and patient is mainly shown as significantly and lasting depressed, compassion of feeling oneself inferior
See world-weary, decreased energy, appetite changes, more or less, decreased attention of sleeping;Lack social interaction desire and explore and be intended to
It hopes, introgression even occurs in serious patient.It is not fully understood at present about the pathogenic factor of depression and pathogenesis.
It is believed that depression may be the result of physiology, psychology and social factor interaction.Rhythm of life accelerate and work,
Study and social pressure increasing may be the external environmental factor for leading to depression.It is reported that Chinese depression illness rate is about
3% ~ 5%, the regional disparity of illness rate is larger.Chinese incidence of depression has increased 10 ~ 20 times in the past 30 years, and still in rising
Trend becomes and seriously affects public's health even Neurological disease of patient's personal safety.
Modern medicine mainly adjusts certain relevant neurotransmitters to the treatment of depression using chemicals, to reach control
The purpose of depression clinical symptoms processed.The chemicals listed include:Tricyclic drugs, monoamine oxidase inhibit class medicine
Object, serotonin reuptake transporter inhibit, norepinephrine reuptake inhibits, and serotonin and norepinephrine reuptake are dual
Inhibitor, 5-hydroxytryptamine receptor retarding agent etc., specific drug such as Mirtazapine, Duloxetine, imipramine etc..Said medicine exists
Significant psychiatric system side effect is such as had a headache, nausea, is had a sleepless night.
Research about Chinese medicine class antidepressant has been achieved with certain progress.It has now been discovered that radix bupleuri adds keel
It is oyster soup, banxia houpu decoction, ganmai dazao decoction, Baihe Dihuang Decoction with additives, Xiao Jianzhong Tang, solution Yu Hehuan soup, Chai Hu Shu Gan San, free and unfettered
The Chinese medicine compound prescriptions such as distant scattered, Yueju Wan have depression certain therapeutic effect, and good security(Wang Yan, old a little perfume resist
The progress contemporary Chinese Chinese medicines of depressed Chinese medicine compound prescription, 2009,11 (4):6-9.).In the research to single medicinal material
In it has been found that Guttiferae hypericum hypericum perforatum, Rubiaceae Morinda plant Morinda officinalis, the black liter of cohosh
Fiber crops, Araliaceae herbaceos perennial ginseng are respectively provided with antidepressant effect.But presently, the domestic existing anti-depression Chinese medicament in China
Less varieties lack compound preparation product.
Invention content
For the above-mentioned prior art, an object of the present invention is to provide a kind of oral traditional Chinese medicine combination for treating depression
Object.To achieve the above object, the technical solution adopted by the present invention is as follows:
A kind of oral Chinese medicine composition for treating depression, by pharmaceutically acceptable pharmaceutic adjuvant and following traditional Chinese medicinal material raw materials
It is made:Radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig, Manjusri orchid, elm mushroom;Wherein radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig, elm mushroom use water
The extraction of the alcohol precipitation method is extracted, Manjusri orchid uses volatile oil component of the extraction by steam distillation relative density below 1.0.
Preferably, the weight part ratio of the traditional Chinese medicinal material raw materials is:21~35 parts by weight of radix bupleuri, 16~20 parts by weight of Radix Angelicae Sinensis,
16~20 parts by weight of Radix Paeoniae Alba, 7~13 parts by weight of cassia twig, 2~7 parts by weight of Manjusri orchid, 2~6 parts by weight of elm mushroom.
Preferably, the weight part ratio of the traditional Chinese medicinal material raw materials is:33 parts by weight of radix bupleuri, 19 parts by weight of Radix Angelicae Sinensis, 19 weight of Radix Paeoniae Alba
Measure part, 12 parts by weight of cassia twig, 6 parts by weight of Manjusri orchid, 5 parts by weight of elm mushroom.
Preferably, the weight part ratio of the traditional Chinese medicinal material raw materials is:30 parts by weight of radix bupleuri, 18 parts by weight of Radix Angelicae Sinensis, 18 weight of Radix Paeoniae Alba
Measure part, 11 parts by weight of cassia twig, 3 parts by weight of Manjusri orchid, 4 parts by weight of elm mushroom.
Preferably, the weight part ratio of the traditional Chinese medicinal material raw materials is:27 parts by weight of radix bupleuri, 18 parts by weight of Radix Angelicae Sinensis, 17 weight of Radix Paeoniae Alba
Measure part, 9 parts by weight of cassia twig, 5 parts by weight of Manjusri orchid, 4 parts by weight of elm mushroom.
Preferably, the weight part ratio of the traditional Chinese medicinal material raw materials is:25 parts by weight of radix bupleuri, 19 parts by weight of Radix Angelicae Sinensis, 17 weight of Radix Paeoniae Alba
Measure part, 10 parts by weight of cassia twig, 6 parts by weight of Manjusri orchid, 4 parts by weight of elm mushroom.
Preferably, the weight part ratio of the traditional Chinese medicinal material raw materials is:22 parts by weight of radix bupleuri, 17 parts by weight of Radix Angelicae Sinensis, 18 weight of Radix Paeoniae Alba
Measure part, 8 parts by weight of cassia twig, 3 parts by weight of Manjusri orchid, 3 parts by weight of elm mushroom.
Another aspect provides a kind of traditional Chinese medicine oral liquid for treating depression, by pharmaceutically acceptable medicine
It is made of auxiliary material and following traditional Chinese medicinal material raw materials:Radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig, Manjusri orchid, elm mushroom;Wherein described Chinese medicine
The weight part ratio of raw material is:21~35 parts by weight of radix bupleuri, 16~20 parts by weight of Radix Angelicae Sinensis, 16~20 parts by weight of Radix Paeoniae Alba, cassia twig 7~13
Parts by weight, 2~7 parts by weight of Manjusri orchid, 2~6 parts by weight of elm mushroom;Wherein described radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig, elm mushroom
It adopts and the extraction of the alcohol precipitation method is extracted with water, the Manjusri orchid uses volatilization of the extraction by steam distillation relative density below 1.0
Oily component;The pharmaceutically acceptable pharmaceutic adjuvant includes beta-cyclodextrin and Tween-80.
Another aspect of the invention provides a kind of preparation method of above-mentioned traditional Chinese medicine oral liquid, includes the following steps:
A, recipe quantity radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig, elm mushroom is taken to crushed 50 mesh sieve respectively, medicinal material coarse powder is mixed to obtain, adds water
It decocts 2 times, the water of the 1st addition 7 times of weight of medicinal material coarse powder decocts 4 hours, the decocting of the 2nd addition 3 times of weight of medicinal material coarse powder
It boils 2 hours, filtering merges decocting liquid, is concentrated into the concentrate that relative density is 1.20, stands cooling, second is added in into concentrate
Alcohol makes the percent by volume of ethyl alcohol be 75%, and 4 DEG C overnight, is filtered to remove insoluble matter, collects filtrate decompression distillation removal ethyl alcohol, obtains
Refined liquid, by refined liquid be concentrated under reduced pressure for 60 °C when relative density be that 1.22~1.25 liquid extracts are spare;
B, recipe quantity Manjusri orchid is taken to be ground into fine powder, adds in volatile oil extractor, 10 are added in by every gram of fine powder~13 milliliters of water
Ratio into fine powder plus water, impregnate 1 hour, extraction by steam distillation, Extracting temperature is 75 DEG C, and extraction time is 8~11
Hour, volatile oil of the separation relative density below 1.0 is spare;
C, beta-cyclodextrin is taken using the ratio of 7 grams of beta-cyclodextrins according to every milliliter of volatile oil, the saturation that distilled water is added to be made 50 DEG C
Volatile oil obtained by step B is slowly dropped into beta-cyclodextrin saturated aqueous solution under heat-retaining condition and stirred 1 hour by aqueous solution, and freezing is dry
It is dry to obtain Benexate Hydrochloride;
D, Benexate Hydrochloride obtained by step C is added in into liquid extract obtained by step A, 0.8 is added according to every 100 milliliters of liquid extracts
The ratio of gram Tween-80 adds in Tween-80, stirs evenly, dispenses to obtain the final product.
Preferably, liquid extract relative density is 1.24 in above-mentioned steps A;Every gram of fine powder adds in 12 milliliters of water in step B, carries
It is 10 hours to take the time.
It is yet another aspect of the present invention to provide a kind of extract oral tablet for treating depression, by pharmaceutically acceptable
Pharmaceutic adjuvant and following traditional Chinese medicinal material raw materials are made:Radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig, Manjusri orchid, elm mushroom;Wherein described Chinese medicine
The weight part ratio of material raw material is:21~35 parts by weight of radix bupleuri, 16~20 parts by weight of Radix Angelicae Sinensis, 16~20 parts by weight of Radix Paeoniae Alba, cassia twig 7~
13 parts by weight, 2~7 parts by weight of Manjusri orchid, 2~6 parts by weight of elm mushroom;Wherein described radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig, elm are yellow
Mushroom, which is adopted, is extracted with water the extraction of the alcohol precipitation method, and the Manjusri orchid uses extraction by steam distillation relative density waving below 1.0
Hair oil component;The auxiliary material of the tablet includes beta-cyclodextrin, starch, microcrystalline cellulose and magnesium stearate, the system of the granule
Preparation Method includes the following steps:
A, recipe quantity radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig, elm mushroom is taken to crushed 50 mesh sieve respectively, medicinal material coarse powder is mixed to obtain, adds water
It decocts 2 times, the water of the 1st addition 7 times of weight of medicinal material coarse powder decocts 4 hours, the decocting of the 2nd addition 3 times of weight of medicinal material coarse powder
It boils 2 hours, filtering merges decocting liquid, is concentrated into the concentrate that relative density is 1.20, stands cooling, second is added in into concentrate
Alcohol makes the percent by volume of ethyl alcohol be 75%, and 4 DEG C overnight, is filtered to remove insoluble matter, collects filtrate decompression distillation removal ethyl alcohol, obtains
Refined liquid, by refined liquid be concentrated under reduced pressure for 60 °C when relative density be that 1.24 liquid extracts are spare;
B, recipe quantity Manjusri orchid is taken to be ground into fine powder, adds in volatile oil extractor, the ratio of 12 milliliters of water is added in by every gram of fine powder
Example is into fine powder plus water, immersion 1 hour, extraction by steam distillation, Extracting temperature are 75 DEG C, and extraction time is 10 hours, point
It is spare from volatile oil of the relative density below 1.0;
C, beta-cyclodextrin is taken using the ratio of 7 grams of beta-cyclodextrins according to every milliliter of volatile oil, the saturation that distilled water is added to be made 50 DEG C
Volatile oil obtained by step B is slowly dropped into beta-cyclodextrin saturated aqueous solution under heat-retaining condition and stirred 1 hour by aqueous solution, and freezing is dry
It is dry to obtain Benexate Hydrochloride;
D, Benexate Hydrochloride obtained by step C is added in into liquid extract obtained by step A, it is fine that starch, crystallite is added in into liquid extract
Dimension element mixing wet granulation, crosses 20 mesh sieve series grains, and 60 DEG C of dryings cross 18 mesh sieve whole grain, add in magnesium stearate tabletting.Wherein form sediment
Powder, microcrystalline cellulose dosage be respectively 0.4 times and 0.3 times of liquid extract weight, magnesium stearate dosage is dry particl total weight
0.01 times.
Radix bupleuri described in technical solution of the present invention is umbelliferae bupleurum Bupleurum chinense DC. or narrow leaves
The dry root of radix bupleuri Bupleurum scorzonerifolium Willd..It is recorded in 2015 editions《People's Republic of China's medicine
Allusion quotation》.
Working as described in technical solution of the present invention, is classified as umbelliferae angelica Angelica sinensis (Oliv.)
The dry root of Diels.It is recorded in 2015 editions《Pharmacopoeia of People's Republic of China》.
Radix Paeoniae Alba described in technical solution of the present invention is the dry of ranunculaceae plant Radix Paeoniae Alba Paeonia lactiflora Pall.
Dry.It is recorded in 2015 editions《Pharmacopoeia of People's Republic of China》.
The drying that cassia twig described in technical solution of the present invention is canella Chinese cassia tree Cinnamomum cassia Presl
Spray.It is recorded in 2015 editions《Pharmacopoeia of People's Republic of China》.
Manjusri orchid described in technical solution of the present invention is Amaryllidaceae Crinum herbaceos perennial crinum asiaticum
The drying flower of Crinum asiaticum L. var. sinicum.It is recorded in《National Chinese herbal medicine compilation》With《Chinese book on Chinese herbal medicine
(Dai medicine is rolled up)》.The medicine is mostly used as medicine with leaf and bulb, rarely seen to be used as medicine with flower.
Elm mushroom described in technical solution of the present invention is Pleurotaceae Pleurotus elm mushroom Pleurotu s
The drying fructification of citrinipileatus Sing.
Beta-cyclodextrin described in technical solution of the present invention acts on starch for ring dextrin glucosyl transferase and generates
The cyclic oligosaccharide that is combined with α-Isosorbide-5-Nitrae-glycosidic bond of 7 glucose;Tween-80 described in technical solution of the present invention is oil
Smooth 20 Sorbitan Oleate of polyoxyethylene formed with ethylene oxide polymerization of sour sorb.Beta-cyclodextrin and Tween-80 are normal
With pharmaceutic adjuvant, it is recorded in 2015 editions《Pharmacopoeia of People's Republic of China》.
The present inventor has found that radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig composition compound have certain resist in experimental study
Depression effect;Manjusri orchid does not have antidepressant effect, but has synergistic effect, elm to radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig compound
Yellow mushroom then can inhibit the toxic side effect of Manjusri orchid.Radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig, Manjusri orchid, elm mushroom Six-element medicinal material group
There is good antidepressant effect, and good security into compound.
Specific embodiment
The present invention is further explained with reference to embodiment.It should be understood that following embodiment is only used for solving
It releases the present invention rather than limits the scope of the invention.
Embodiment 1 treats traditional Chinese medicine oral liquid and its preparation of depression
Preparation method:
A, recipe quantity radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig, elm mushroom is taken to crushed 50 mesh sieve respectively, medicinal material coarse powder is mixed to obtain, adds water
It decocts 2 times, the water of the 1st addition 7 times of weight of medicinal material coarse powder decocts 4 hours, the decocting of the 2nd addition 3 times of weight of medicinal material coarse powder
It boils 2 hours, filtering merges decocting liquid, is concentrated into the concentrate that relative density is 1.20, stands cooling, second is added in into concentrate
Alcohol makes the percent by volume of ethyl alcohol be 75%, and 4 DEG C overnight, is filtered to remove insoluble matter, collects filtrate decompression distillation removal ethyl alcohol, obtains
Refined liquid, by refined liquid be concentrated under reduced pressure for 60 °C when relative density be that 1.24 liquid extracts are spare;
B, recipe quantity Manjusri orchid is taken to be ground into fine powder, adds in volatile oil extractor, the ratio of 12 milliliters of water is added in by every gram of fine powder
Example is into fine powder plus water, immersion 1 hour, extraction by steam distillation, Extracting temperature are 75 DEG C, and extraction time is 10 hours, point
It is spare from volatile oil of the relative density below 1.0;
C, beta-cyclodextrin is taken using the ratio of 7 grams of beta-cyclodextrins according to every milliliter of volatile oil, the saturation that distilled water is added to be made 50 DEG C
Volatile oil obtained by step B is slowly dropped into beta-cyclodextrin saturated aqueous solution under heat-retaining condition and stirred 1 hour by aqueous solution, and freezing is dry
It is dry to obtain Benexate Hydrochloride;
D, Benexate Hydrochloride obtained by step C is added in into liquid extract obtained by step A, 0.8 is added according to every 100 milliliters of liquid extracts
The ratio of gram Tween-80 adds in Tween-80, stirs evenly, dispenses to obtain the final product.
Embodiment 2 treats traditional Chinese medicine oral liquid and its preparation of depression
Preparation method:
A, recipe quantity radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig, elm mushroom is taken to crushed 50 mesh sieve respectively, medicinal material coarse powder is mixed to obtain, adds water
It decocts 2 times, the water of the 1st addition 7 times of weight of medicinal material coarse powder decocts 4 hours, the decocting of the 2nd addition 3 times of weight of medicinal material coarse powder
It boils 2 hours, filtering merges decocting liquid, is concentrated into the concentrate that relative density is 1.20, stands cooling, second is added in into concentrate
Alcohol makes the percent by volume of ethyl alcohol be 75%, and 4 DEG C overnight, is filtered to remove insoluble matter, collects filtrate decompression distillation removal ethyl alcohol, obtains
Refined liquid, by refined liquid be concentrated under reduced pressure for 60 °C when relative density be that 1.24 liquid extracts are spare;
B, recipe quantity Manjusri orchid is taken to be ground into fine powder, adds in volatile oil extractor, the ratio of 12 milliliters of water is added in by every gram of fine powder
Example is into fine powder plus water, immersion 1 hour, extraction by steam distillation, Extracting temperature are 75 DEG C, and extraction time is 10 hours, point
It is spare from volatile oil of the relative density below 1.0;
C, beta-cyclodextrin is taken using the ratio of 7 grams of beta-cyclodextrins according to every milliliter of volatile oil, the saturation that distilled water is added to be made 50 DEG C
Volatile oil obtained by step B is slowly dropped into beta-cyclodextrin saturated aqueous solution under heat-retaining condition and stirred 1 hour by aqueous solution, and freezing is dry
It is dry to obtain Benexate Hydrochloride;
D, Benexate Hydrochloride obtained by step C is added in into liquid extract obtained by step A, 0.8 is added according to every 100 milliliters of liquid extracts
The ratio of gram Tween-80 adds in Tween-80, stirs evenly, dispenses to obtain the final product.
Embodiment 3 treats traditional Chinese medicine oral liquid and its preparation of depression
Preparation method:
A, recipe quantity radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig, elm mushroom is taken to crushed 50 mesh sieve respectively, medicinal material coarse powder is mixed to obtain, adds water
It decocts 2 times, the water of the 1st addition 7 times of weight of medicinal material coarse powder decocts 4 hours, the decocting of the 2nd addition 3 times of weight of medicinal material coarse powder
It boils 2 hours, filtering merges decocting liquid, is concentrated into the concentrate that relative density is 1.20, stands cooling, second is added in into concentrate
Alcohol makes the percent by volume of ethyl alcohol be 75%, and 4 DEG C overnight, is filtered to remove insoluble matter, collects filtrate decompression distillation removal ethyl alcohol, obtains
Refined liquid, by refined liquid be concentrated under reduced pressure for 60 °C when relative density be that 1.24 liquid extracts are spare;
B, recipe quantity Manjusri orchid is taken to be ground into fine powder, adds in volatile oil extractor, the ratio of 12 milliliters of water is added in by every gram of fine powder
Example is into fine powder plus water, immersion 1 hour, extraction by steam distillation, Extracting temperature are 75 DEG C, and extraction time is 10 hours, point
It is spare from volatile oil of the relative density below 1.0;
C, beta-cyclodextrin is taken using the ratio of 7 grams of beta-cyclodextrins according to every milliliter of volatile oil, the saturation that distilled water is added to be made 50 DEG C
Volatile oil obtained by step B is slowly dropped into beta-cyclodextrin saturated aqueous solution under heat-retaining condition and stirred 1 hour by aqueous solution, and freezing is dry
It is dry to obtain Benexate Hydrochloride;
D, Benexate Hydrochloride obtained by step C is added in into liquid extract obtained by step A, 0.8 is added according to every 100 milliliters of liquid extracts
The ratio of gram Tween-80 adds in Tween-80, stirs evenly, dispenses to obtain the final product.
Embodiment 4 treats traditional Chinese medicine oral liquid and its preparation of depression
Preparation method:
A, recipe quantity radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig, elm mushroom is taken to crushed 50 mesh sieve respectively, medicinal material coarse powder is mixed to obtain, adds water
It decocts 2 times, the water of the 1st addition 7 times of weight of medicinal material coarse powder decocts 4 hours, the decocting of the 2nd addition 3 times of weight of medicinal material coarse powder
It boils 2 hours, filtering merges decocting liquid, is concentrated into the concentrate that relative density is 1.20, stands cooling, second is added in into concentrate
Alcohol makes the percent by volume of ethyl alcohol be 75%, and 4 DEG C overnight, is filtered to remove insoluble matter, collects filtrate decompression distillation removal ethyl alcohol, obtains
Refined liquid, by refined liquid be concentrated under reduced pressure for 60 °C when relative density be that 1.24 liquid extracts are spare;
B, recipe quantity Manjusri orchid is taken to be ground into fine powder, adds in volatile oil extractor, the ratio of 12 milliliters of water is added in by every gram of fine powder
Example is into fine powder plus water, immersion 1 hour, extraction by steam distillation, Extracting temperature are 75 DEG C, and extraction time is 10 hours, point
It is spare from volatile oil of the relative density below 1.0;
C, beta-cyclodextrin is taken using the ratio of 7 grams of beta-cyclodextrins according to every milliliter of volatile oil, the saturation that distilled water is added to be made 50 DEG C
Volatile oil obtained by step B is slowly dropped into beta-cyclodextrin saturated aqueous solution under heat-retaining condition and stirred 1 hour by aqueous solution, and freezing is dry
It is dry to obtain Benexate Hydrochloride;
D, Benexate Hydrochloride obtained by step C is added in into liquid extract obtained by step A, 0.8 is added according to every 100 milliliters of liquid extracts
The ratio of gram Tween-80 adds in Tween-80, stirs evenly, dispenses to obtain the final product.
Embodiment 5 treats traditional Chinese medicine oral liquid and its preparation of depression
Preparation method:
A, recipe quantity radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig, elm mushroom is taken to crushed 50 mesh sieve respectively, medicinal material coarse powder is mixed to obtain, adds water
It decocts 2 times, the water of the 1st addition 7 times of weight of medicinal material coarse powder decocts 4 hours, the decocting of the 2nd addition 3 times of weight of medicinal material coarse powder
It boils 2 hours, filtering merges decocting liquid, is concentrated into the concentrate that relative density is 1.20, stands cooling, second is added in into concentrate
Alcohol makes the percent by volume of ethyl alcohol be 75%, and 4 DEG C overnight, is filtered to remove insoluble matter, collects filtrate decompression distillation removal ethyl alcohol, obtains
Refined liquid, by refined liquid be concentrated under reduced pressure for 60 °C when relative density be that 1.24 liquid extracts are spare;
B, recipe quantity Manjusri orchid is taken to be ground into fine powder, adds in volatile oil extractor, the ratio of 12 milliliters of water is added in by every gram of fine powder
Example is into fine powder plus water, immersion 1 hour, extraction by steam distillation, Extracting temperature are 75 DEG C, and extraction time is 10 hours, point
It is spare from volatile oil of the relative density below 1.0;
C, beta-cyclodextrin is taken using the ratio of 7 grams of beta-cyclodextrins according to every milliliter of volatile oil, the saturation that distilled water is added to be made 50 DEG C
Volatile oil obtained by step B is slowly dropped into beta-cyclodextrin saturated aqueous solution under heat-retaining condition and stirred 1 hour by aqueous solution, and freezing is dry
It is dry to obtain Benexate Hydrochloride;
D, Benexate Hydrochloride obtained by step C is added in into liquid extract obtained by step A, 0.8 is added according to every 100 milliliters of liquid extracts
The ratio of gram Tween-80 adds in Tween-80, stirs evenly, dispenses to obtain the final product.
6 depression drug effect of embodiment and safety experiment
First, the foundation of animal model
SPF grades of healthy male SD rats, 180~220g of weight are provided by Beijing dimension tonneau China animal experimental center, raised in black
Longjiang university of TCM Experimental Animal Center, during the experiment keep free water and feed, and feeding environment temperature is 23~25 DEG C,
Humidity is 50~60%, and adaptability is fed 1 week before experiment.
Rat 72 is taken, receives the chronic mild unpredictability stress stimulation of 35 days by a definite date, including ice water swimming, round the clock
Reverse, binding constraint, folder tail, oscillation, fasting and taboo water.Every group of animal gives a kind of stimulation at random daily, and same stimulation is accumulative
It uses no more than 5 times.Each stress concrete operation method it is as follows:
(1)Ice water is swum:Rat is put into 20 liters of buckets for filling 4 DEG C of cold water, continues 5 minutes;
(2)It overturns round the clock:Rat is placed in the dark space that black cloth surrounds by daytime, continues 12 hours, rat is placed in by night
In the bright space of incandescent lamp irradiation, continue 12 hours;
(3)Binding constraint, rat is placed in 550 milliliters of mineral water bottles, it is prevented to continue 3 hours from freely activity;
(4)Press from both sides tail:It is clamped with bamboo clip away from 1 centimeters of root of the tail portion, rat is made to cry with a whine, continue 2 minutes;
(5)Oscillation:Rat is placed in horizontal oscillator tube, oscillation stops after 2 minutes;
(6)Fasting:Stop supply feed 24 hours;
(7)Prohibit water:Stop supplying water 24 hours.
2nd, the grouping and administration of animal pattern
Rat is randomly divided into 9 groups, every group 8 after modeling.Gavage gives physiological saline, as model after first group of modeling
Group.Second to the 6th group is experimental group, and gavage gives the oral liquid of the preparation of embodiment 1,2,3,4,5 respectively.7th to the 9th group
For positive controls, gavage gives radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig compound respectively;Radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig, Manjusri orchid
Compound or radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig, elm mushroom compound oral liquid.Unit dosage form is calculated with radix bupleuri raw medicinal herbs
0.3g/kg, daily gastric infusion 1 time, successive administration 28 days.
Wherein radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, the prescription of cassia twig compound and preparation method are as follows:Radix bupleuri 66g, Radix Angelicae Sinensis 38g, Radix Paeoniae Alba
38g, cassia twig 24g.
Recipe quantity radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig is taken to crushed 50 mesh sieve respectively, medicinal material coarse powder is mixed to obtain, adds water to cook 2
Secondary, the water of the 1st addition 7 times of weight of medicinal material coarse powder decocts 4 hours, and the water decoction 2 of the 2nd addition 3 times of weight of medicinal material coarse powder is small
When, filtering merges decocting liquid, is concentrated into the concentrate that relative density is 1.20, stands cooling, and ethyl alcohol is added in into concentrate to be made
The percent by volume of ethyl alcohol is 75%, and 4 DEG C overnight, is filtered to remove insoluble matter, collects filtrate decompression distillation removal ethyl alcohol, obtains refined
Liquid, by refined liquid be concentrated under reduced pressure for 60 °C when relative density be 1.24 liquid extracts;12 grams of beta-cyclodextrins is taken to add in liquid extract, according to
The ratio that every 100 milliliters of liquid extracts add in 0.8 gram of Tween-80 adds in Tween-80, stirs evenly, oral liquid is made
Body preparation.
Radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig, the prescription of Manjusri's orchid compound and preparation method are as follows:Radix bupleuri 66g, Radix Angelicae Sinensis 38g,
Radix Paeoniae Alba 38g, cassia twig 24g, Manjusri orchid 12g.
A, recipe quantity radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig is taken to crushed 50 mesh sieve respectively, medicinal material coarse powder is mixed to obtain, adds water to cook
2 times, the water of the 1st addition 7 times of weight of medicinal material coarse powder decocts 4 hours, and the water decoction 2 of the 2nd addition 3 times of weight of medicinal material coarse powder is small
When, filtering merges decocting liquid, is concentrated into the concentrate that relative density is 1.20, stands cooling, and ethyl alcohol is added in into concentrate to be made
The percent by volume of ethyl alcohol is 75%, and 4 DEG C overnight, is filtered to remove insoluble matter, collects filtrate decompression distillation removal ethyl alcohol, obtains refined
Liquid, by refined liquid be concentrated under reduced pressure for 60 °C when relative density be that 1.24 liquid extracts are spare;
B, recipe quantity Manjusri orchid is taken to be ground into fine powder, adds in volatile oil extractor, the ratio of 12 milliliters of water is added in by every gram of fine powder
Example is into fine powder plus water, immersion 1 hour, extraction by steam distillation, Extracting temperature are 75 DEG C, and extraction time is 10 hours, point
It is spare from volatile oil of the relative density below 1.0;
C, beta-cyclodextrin is taken using the ratio of 7 grams of beta-cyclodextrins according to every milliliter of volatile oil, the saturation that distilled water is added to be made 50 DEG C
Volatile oil obtained by step B is slowly dropped into beta-cyclodextrin saturated aqueous solution under heat-retaining condition and stirred 1 hour by aqueous solution, and freezing is dry
It is dry to obtain Benexate Hydrochloride;
D, Benexate Hydrochloride obtained by step C is added in into liquid extract obtained by step A, 0.8 is added according to every 100 milliliters of liquid extracts
The ratio of gram Tween-80 adds in Tween-80, stirs evenly, oral liquid is made.
Radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig, the prescription of elm mushroom compound and preparation method are as follows:It is radix bupleuri 66g, Radix Angelicae Sinensis 38g, white
Chinese herbaceous peony 38g, cassia twig 24g, elm mushroom 10g.
Recipe quantity radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig, elm mushroom is taken to crushed 50 mesh sieve respectively, medicinal material coarse powder is mixed to obtain, adds
Water decocts 2 times, and the water of the 1st addition 7 times of weight of medicinal material coarse powder decocts 4 hours, the water of the 2nd addition 3 times of weight of medicinal material coarse powder
It decocts 2 hours, filtering merges decocting liquid, is concentrated into the concentrate that relative density is 1.20, stands cooling, added in into concentrate
Ethyl alcohol makes the percent by volume of ethyl alcohol be 75%, and 4 DEG C are overnight, are filtered to remove insoluble matter, collects filtrate decompression distillation removal ethyl alcohol,
Refined liquid, by refined liquid be concentrated under reduced pressure for 60 °C when relative density be 1.24 liquid extracts;12 grams of beta-cyclodextrins is taken to add in stream leaching
Cream, the ratio that 0.8 gram of Tween-80 is added according to every 100 milliliters of liquid extracts add in Tween-80, stir evenly, be made
Oral liquid.
3rd, observation index
1. safety indexes:Animal defecation and diet drinking-water state are observed in administration process daily, rat heart rate was used every 4 days
Measuring instrument(Shanghai Yu Yan scientific instrument Co., Ltd)Measure heart rate under every group of rat rest state, every rat is surveyed in 5 minutes
It is 3 times fixed, mean value is taken to represent the heart rate value of this day.
2. curative effect index:
24 hours after the last administration, using the Behavioral feature of spacious field measuring rat.Spacious bottom face is 100 cm x 100
Centimetre, it is 40 centimetres high to be divided into 25 square lattices, and spacious case head cover setting camera is for observing activities in rats.It tested
Rat is put into center grid by Cheng Zhong, and observation rat is passed through lined(At least 3 pawls stride into)With it is upright(Two forelimbs are from bottom surface at least
1 cm)Number.Every 5 min of rat minute, rat passes through lined quantity and upright number in 4 min after record.
Lined quantity is wherein passed through as horizontal movement score, upright number is as vertical movement score.Every rat measures 1 time, surveys
Case being opened with alcohol scrub clean after fixed and measuring next rat again, smell is avoided to interfere.
Data carry out statistical disposition using 17. 0 softwares of SPSS.Comparison among groups use one-way analysis of variance and Post
Hoc is examined.P<0. 05 are considered as difference with statistical significance.The spacious field experimental result of each group rat see the table below:
Compared with first group and model group: A:P<0.01;Compared with the 7th group:C:P<0.05, D:P<0.01.
By rat model horizontal movement and vertical movement scores as it can be seen that the second to nine group rat horizontal movement score and
Vertical movement score is all remarkably higher than first group(P<0.01), illustrate containing radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig compound oral administration preparation
Be significantly improved to the Behavioral feature of depression rat effect.
Compared with the 7th group i.e. radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig compound oral liquid preparation administration group, the 9th group i.e. radix bupleuri,
Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig, the horizontal movement score of elm mushroom compound oral liquid preparation administration group and vertical movement score are without aobvious
It writes and improves, illustrate elm mushroom to radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig compound without synergistic effect.8th group i.e. radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba,
Cassia twig, the horizontal movement score of Manjusri's orchid compound oral liquid body preparation administration group and vertical movement score are significantly increased(P<
0.05 or P<0.01), illustrate that Manjusri orchid has synergistic effect to radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig compound.Second to the 6th group
The horizontal movement score and vertical movement score of rat are all remarkably higher than the 7th group(P<0.05 or P<0.01), but with the 8th group of phase
Than without significant difference, illustrating the addition of elm mushroom does not influence synergy of the Manjusri orchid to radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig compound
Effect.
Since after first administration the 16th day, the 8th group of rat, that is, radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig, Manjusri's orchid compound mouth
It taking 7 rats of liquid preparation administration group and the deformed symptom of loose watery stool occurs, there is increased heart rate phenomenon in 8 rats, from
The heart rate for starting the 8th group of rat on the 16th is between 347~362 beats/min after first administration, the heart of other each group rats
Rate is between 324~341 beats/min, until experiment, which terminates above-mentioned symptom, has no improvement.Other group of rat is showed no above-mentioned disease
Shape.Illustrate radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig without above-mentioned toxic effect, the addition of Manjusri orchid may be to lead to rat loose watery stool
And the reason of increased heart rate, and the addition of elm mushroom then inhibits the toxic effect of Manjusri orchid.
Claims (10)
1. a kind of oral Chinese medicine composition for treating depression, former by pharmaceutically acceptable pharmaceutic adjuvant and following Chinese medicine
Material is made:Radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig, Manjusri orchid, elm mushroom;Wherein radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig, elm mushroom use
Water extraction alcohol precipitation method extraction, Manjusri orchid use volatile oil component of the extraction by steam distillation relative density below 1.0.
2. the oral Chinese medicine composition for the treatment of depression according to claim 1, which is characterized in that the traditional Chinese medicinal material raw materials
Weight part ratio be:21~35 parts by weight of radix bupleuri, 16~20 parts by weight of Radix Angelicae Sinensis, 16~20 parts by weight of Radix Paeoniae Alba, 7~13 weight of cassia twig
Part, 2~7 parts by weight of Manjusri orchid, 2~6 parts by weight of elm mushroom.
3. the oral Chinese medicine composition for the treatment of depression according to claim 2, which is characterized in that the traditional Chinese medicinal material raw materials
Weight part ratio be:33 parts by weight of radix bupleuri, 19 parts by weight of Radix Angelicae Sinensis, 19 parts by weight of Radix Paeoniae Alba, 12 parts by weight of cassia twig, 6 weight of Manjusri orchid
Measure part, 5 parts by weight of elm mushroom.
4. the oral Chinese medicine composition for the treatment of depression according to claim 2, which is characterized in that the traditional Chinese medicinal material raw materials
Weight part ratio be:30 parts by weight of radix bupleuri, 18 parts by weight of Radix Angelicae Sinensis, 18 parts by weight of Radix Paeoniae Alba, 11 parts by weight of cassia twig, 3 weight of Manjusri orchid
Measure part, 4 parts by weight of elm mushroom.
5. the oral Chinese medicine composition for the treatment of depression according to claim 2, which is characterized in that the traditional Chinese medicinal material raw materials
Weight part ratio be:27 parts by weight of radix bupleuri, 18 parts by weight of Radix Angelicae Sinensis, 17 parts by weight of Radix Paeoniae Alba, 9 parts by weight of cassia twig, 5 weight of Manjusri orchid
Part, 4 parts by weight of elm mushroom.
6. the oral Chinese medicine composition for the treatment of depression according to claim 2, which is characterized in that the traditional Chinese medicinal material raw materials
Weight part ratio be:25 parts by weight of radix bupleuri, 19 parts by weight of Radix Angelicae Sinensis, 17 parts by weight of Radix Paeoniae Alba, 10 parts by weight of cassia twig, 6 weight of Manjusri orchid
Measure part, 4 parts by weight of elm mushroom.
7. the oral Chinese medicine composition for the treatment of depression according to claim 2, which is characterized in that the traditional Chinese medicinal material raw materials
Weight part ratio be:22 parts by weight of radix bupleuri, 17 parts by weight of Radix Angelicae Sinensis, 18 parts by weight of Radix Paeoniae Alba, 8 parts by weight of cassia twig, 3 weight of Manjusri orchid
Part, 3 parts by weight of elm mushroom.
8. a kind of traditional Chinese medicine oral liquid for treating depression, by pharmaceutically acceptable pharmaceutic adjuvant and following traditional Chinese medicinal material raw materials system
Into:Radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig, Manjusri orchid, elm mushroom;The weight part ratio of wherein described traditional Chinese medicinal material raw materials is:Radix bupleuri 21
~35 parts by weight, 16~20 parts by weight of Radix Angelicae Sinensis, 16~20 parts by weight of Radix Paeoniae Alba, 7~13 parts by weight of cassia twig, 2~7 weight of Manjusri orchid
Part, 2~6 parts by weight of elm mushroom;Wherein described radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig, elm mushroom, which are adopted, is extracted with water the extraction of the alcohol precipitation method,
The Manjusri orchid uses volatile oil component of the extraction by steam distillation relative density below 1.0;It is described pharmaceutically to connect
The pharmaceutic adjuvant received includes beta-cyclodextrin and Tween-80.
9. the preparation method of the traditional Chinese medicine oral liquid for the treatment of depression according to any one of claims 8, includes the following steps:
A, recipe quantity radix bupleuri, Radix Angelicae Sinensis, Radix Paeoniae Alba, cassia twig, elm mushroom is taken to crushed 50 mesh sieve respectively, medicinal material coarse powder is mixed to obtain, adds water
It decocts 2 times, the water of the 1st addition 7 times of weight of medicinal material coarse powder decocts 4 hours, the decocting of the 2nd addition 3 times of weight of medicinal material coarse powder
It boils 2 hours, filtering merges decocting liquid, is concentrated into the concentrate that relative density is 1.20, stands cooling, second is added in into concentrate
Alcohol makes the percent by volume of ethyl alcohol be 75%, and 4 DEG C overnight, is filtered to remove insoluble matter, collects filtrate decompression distillation removal ethyl alcohol, obtains
Refined liquid, by refined liquid be concentrated under reduced pressure for 60 °C when relative density be that 1.22~1.25 liquid extracts are spare;
B, recipe quantity Manjusri orchid is taken to be ground into fine powder, adds in volatile oil extractor, 10~13 milliliters of water are added in by every gram of fine powder
Ratio into fine powder plus water, impregnate 1 hour, extraction by steam distillation, Extracting temperature is 75 DEG C, and extraction time is 8~11
Hour, volatile oil of the separation relative density below 1.0 is spare;
C, beta-cyclodextrin is taken using the ratio of 7 grams of beta-cyclodextrins according to every milliliter of volatile oil, the saturation that distilled water is added to be made 50 DEG C
Volatile oil obtained by step B is slowly dropped into beta-cyclodextrin saturated aqueous solution under heat-retaining condition and stirred 1 hour by aqueous solution, and freezing is dry
It is dry to obtain Benexate Hydrochloride;
D, Benexate Hydrochloride obtained by step C is added in into liquid extract obtained by step A, 0.8 is added according to every 100 milliliters of liquid extracts
The ratio of gram Tween-80 adds in Tween-80, stirs evenly, dispenses to obtain the final product.
10. the preparation method of the traditional Chinese medicine oral liquid for the treatment of depression according to claim 9, which is characterized in that the step
Liquid extract relative density is 1.24 in rapid A;Every gram of fine powder adds in 12 milliliters of water in the step B, and extraction time is 10 hours.
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104069171A (en) * | 2014-07-03 | 2014-10-01 | 成都中医药大学 | Antidepressant medicine composition as well as preparation method and application thereof |
CN105477126A (en) * | 2015-12-30 | 2016-04-13 | 广东药学院 | Traditional Chinese medicine extract composition used for treating depression and preparation method and application thereof |
-
2018
- 2018-03-09 CN CN201810196624.3A patent/CN108126062B/en active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104069171A (en) * | 2014-07-03 | 2014-10-01 | 成都中医药大学 | Antidepressant medicine composition as well as preparation method and application thereof |
CN105477126A (en) * | 2015-12-30 | 2016-04-13 | 广东药学院 | Traditional Chinese medicine extract composition used for treating depression and preparation method and application thereof |
Non-Patent Citations (5)
Title |
---|
国家中医药管理局《中华本草》编委会: "《中华本草.傣药卷》", 31 December 2005, 上海科学技术出版社 * |
张洁: "文殊兰属植物化学成分提取分离及其生物活性", 《哈尔滨商业大学学报(自然科学版)》 * |
李越兰等: "柴胡-白芍水煎剂对行为绝望抑郁模型小鼠的影响", 《甘肃中医学院学报》 * |
王新志等: "《中风脑病诊疗全书》", 31 March 2017, 中国中医药出版社 * |
谢忠礼: "加味四逆散对恶劣心境障碍模型大鼠行为学影响", 《陕西中医学院学报》 * |
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