CN100435817C - Medicine for treating rheumatism and rheumatoid diseases and preparing method - Google Patents

Medicine for treating rheumatism and rheumatoid diseases and preparing method Download PDF

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CN100435817C
CN100435817C CNB200510105489XA CN200510105489A CN100435817C CN 100435817 C CN100435817 C CN 100435817C CN B200510105489X A CNB200510105489X A CN B200510105489XA CN 200510105489 A CN200510105489 A CN 200510105489A CN 100435817 C CN100435817 C CN 100435817C
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present
parched
honey
group
phlegm
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CN1742845A (en
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张成海
李时海
杨向武
毕文生
陈心
董述祥
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Dalian Melo pharmaceutical Limited by Share Ltd
Dalian Merro Pharmaceutical Co., Ltd.
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DALIAN MERRO PHARMACEUTICAL Co Ltd
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Abstract

The present invention discloses a Chinese medicine composition for treating the affection of the respiratory system. The raw medicinal material of the present invention is composed of Chinese ephedra (steamed with honey), gypsum, bitter apricot kernel (fried), mulberry bark (steamed with honey), lepidium seed (fried), Chinese angelica root, red sage root, earthworm, batryticated silkworm (fried) and liquorice root. The present invention also discloses the application of the Chinese medicine composition in resisting virus, resisting bacteria, clearing away heat, relieving cough, eliminating phlegm, relieving asthma and resisting inflammation, and a preparing method and an active ingredient detecting method of the Chinese medicine composition. The Chinese medicine composition mainly has the functions of removing heat from the lung, dissolving phlegm, relieving cough and asthma, promoting blood circulation and removing blood stasis. The present invention is mainly used for curing acute bronchitis or the convalescent phlegm-heat tussis of pneumonitis, and the present invention is especially suitable for babies.

Description

A kind of Chinese medicine composition for the treatment of diseases in respiratory system and preparation method thereof
Technical field
The present invention relates to a kind of Chinese medicine composition, more particularly, relate to a kind of Chinese medicine composition for the treatment of diseases in respiratory system, with and preparation method thereof.
Background technology
Acute bronchitis is one of frequently-occurring disease the most common in the respiratory system disease, and particularly children's belongs to Susceptible population.According to statistics, this disease accounts for 9~11% in the pediatric disease, because malpractice, the state of an illness is prolonged for a long time, shows effect repeatedly, can seriously influence the healthy and growth of children's's health.Therapeutic Method that at present should disease is more, is that Western medicine or Chinese medicine all have certain curative effect, but all has weak point, and is long such as antibiotic service time, can produce Resistant strain, especially can cause flora disorder, dyspepsia.And current respiratory tract disease is based on viral infection more than 90%, and the gesture of current existing abuse antibiotics cause the excessive burden of medical expense, and the traditional Chinese medical herbal treatment viral infection has certain advantage.
At present, recorded in the Chinese Pharmacopoeia (version in 2005) with market on sale, function cures mainly similar kind that " infantile lung heat cough with asthma oral liquid ", " infantile asthma granule " and JIZHI TANGJIANG (granule) etc. are arranged, because of each side's composition, specific aim and stress differences such as face, so the curative effect that is produced is also different.It all is the plus-minus side of ancient prescription MAXINGSHIGAN TANG that (particularly being applicable to children's's) Chinese patent medicine of such disease of treatment on sale in the market has infantile lung heat cough with asthma oral liquid and infantile asthma granule etc., but does not all have breakthrough on thinking; JIZHI TANGJIANG (granule) (also can be used for children's) is the prescription of forming on the modern pharmacology basis, but lacks the organic conception of Chinese medicine and pharmacy.
Summary of the invention
The present invention has overcome above-mentioned the deficiencies in the prior art, is a kind ofly to be bold in innovation on the theoretical basis of Chinese medicine and pharmacy, particularly the idea of blood circulation promoting and blood stasis dispelling and mediation air flue is introduced Chinese medicinal formulae in the therapeutic scheme of primary disease.
The Chinese medicine composition that the purpose of this invention is to provide a kind of new treatment diseases in respiratory system.
Another object of the present invention provides the preparation method of the above-mentioned Chinese medicine composition of preparation.
Another object of the present invention provides the purposes of above-mentioned Chinese medicine composition.
Another object of the present invention provides a kind of method of checking above-mentioned Chinese medicine composition active ingredient.
The inventor is through research for many years, deliberation repeatedly and long-term clinical practice, design a kind of Chinese medicine composition for the treatment of respiratory system disease, the elite (MAXINGSHIGAN TANG) of ancient prescription had both been inherited in this kind combination, face cardization again in conjunction with modern acute bronchitis belongs to the characteristics of incidence of phlegm-heat cough card and year develop, so we have the dual foundation of ancient prescription and practical experience.Said composition is used for the treatment of acute bronchitis phlegm-heat cough card (particularly children's), has characteristics such as instant effect, short treating period, untoward reaction are few, and the convalescent phlegm-heat cough card of pneumonia is also had curative effect preferably.Its crude drug consists of (to make the 1000g finished product):
Herba Ephedrae (processed with honey) 75-175g
Gypsum Fibrosum 750-1750g
Semen Armeniacae Amarum (stir-fry) 75-175g
Cortex Mori (processed with honey) 75-175g
Semen Lepidii (Semen Descurainiae) (stir-fry) 30-120g
Radix Angelicae Sinensis 125-250g
Radix Salviae Miltiorrhizae 125-250g
Pheretima 75-175g
Bombyx Batryticatus (stir-fry) 75-175g
Radix Glycyrrhizae 75-175g
Preferred raw material consists of:
Herba Ephedrae (processed with honey) 100-150g
Gypsum Fibrosum 1000-1500g
Semen Armeniacae Amarum (stir-fry) 100-150g
Cortex Mori (processed with honey) 100-150g
Semen Lepidii (Semen Descurainiae) (stir-fry) 50-100g
Radix Angelicae Sinensis 150-226g
Radix Salviae Miltiorrhizae 150-226g
Pheretima 100-150g
Bombyx Batryticatus (stir-fry) 100-150g
Radix Glycyrrhizae 100-150g
Particularly preferred crude drug consists of:
Herba Ephedrae (processed with honey) 112-137g
Gypsum Fibrosum 112-1370g
Semen Armeniacae Amarum (stir-fry) 112-137g
Cortex Mori (processed with honey) 112-137g
Semen Lepidii (Semen Descurainiae) (stir-fry) 68-82g
Radix Angelicae Sinensis 170-206g
Radix Salviae Miltiorrhizae 170-26g
Pheretima 112-137g
Bombyx Batryticatus (stir-fry) 112-137g
Radix Glycyrrhizae 112-137g
Most preferred crude drug consists of:
Herba Ephedrae (processed with honey) 125g
Gypsum Fibrosum 1250g
Semen Armeniacae Amarum (stir-fry) 125g
Cortex Mori (processed with honey) 125g
Semen Lepidii (Semen Descurainiae) (stir-fry) 75g
Radix Angelicae Sinensis 188g
Radix Salviae Miltiorrhizae 188g
Pheretima 125g
Bombyx Batryticatus (stir-fry) 125g
Radix Glycyrrhizae 125g
Acute bronchitis belongs to the traditional Chinese medical science " cough " category, and its pathology pathogenesis is relevant with expectorant, and pathogenic site is at lung.Motherland's medical science is thought: " lung governing qi closes fur outward, has one's ideas straightened out in nose, and post is breathed and regulating fluid apssage; lung qi Yi Kaiyi is respectful to fall, and particularly children's's internal organs are tender and lovely, and shape gas fills; skin is scattered; hedge is solid, cold in addition warm can not self-regulated, so and the heresy of six climate exopathogens can be from mouth and nose or fur people; cause occlusion of the pores of skin; impairment of dispersing and descending function of the lung and flu occurs, the rale of coughing, disease such as pant.Be " body of the young sun of young the moon " owing to children's again, YANG often being in excess, YIN often being in shortage ", being invaded by exogenous pathogen is easy to the heat-transformation impairing the lung, and the body fluid of lung is burnt is expectorant, phlegm-heat obstructing in the lung, air flue is unfavorable, loses a surname Yu and falls then cough, and expectorant is thick; Abnormal rising of lung-QI then heat-phlegm hinders in air flue, then gurgling with sputum; Again because of qi as the commander of blood, blood circulation depending on qi flow, the stagnation of QI is blood stasis then.The expectorant heat-coagulation does not disappear, when causing the endogenous pathogenesis of blood stasis.We's characteristic is to dredge air flue in clearing and dissipating phlegm-heat a little, the product of blood circulation promoting and blood stasis dispelling, and obtain good effect repeatly.It is evident in efficacy in clinical confirmation, and because of hot clearing away phlegmization, all cards of the smooth and easy then cough with asthma of lung qi can speed be healed.
We are monarch drug with Herba Ephedrae, Gypsum Fibrosum.Herba Ephedrae, nature and flavor suffering, hardship, temperature.Xin Erneng looses, and is bitter and can fall, and Wen Erneng is logical, so energy diaphoresis, the diuretic of relievining asthma.Weaken perspiration behind the processed with honey, get the effect of its antiasthmatic-antitussive.Gypsum Fibrosum, acrid in the mouth, sweet, Great Cold.Clearing away heat-fire, relieving restlessness is quenched the thirst.Be mainly used in lung gastric qi branch, excess-heat disease, lung-heat cough with asthma.Acrid in the mouth, sweet, Great Cold and matter is not dry, the power of clearing away heat-fire is very strong, and can clearing away interior-heat and saturating loosing, be used for heat stagnation and lung must not declare fall due to heating, cough, pant the most suitable.Two medicines are harmonious, and play heat clearing away altogether and let out lung, relieving cough and asthma, the effect of relieving restlessness cough-relieving, and as the monarch drug in the side.
Semen Armeniacae Amarum, Cortex Mori, Semen Lepidii (Semen Descurainiae) are ministerial drug altogether.Semen Armeniacae Amarum, the bitter in the mouth tepor, slightly poisonous, relieving cough and asthma.Treatise on Febrile Diseases Herba Ephedrae Semen Armeniacae Amarum Gypsum Fibrosum glycyrrhiza decoction is stopped up heat for controlling the lung-heat cough with asthma in the lung, lung qi loses a surname Yu and falls, and sees the main formula of cough with asthma, card such as thirsty.We are up on the basis, add flavor according to the phlegm-heat cough card, and wherein Cortex Mori is sweet in flavor and cold in property, eliminating pathogen from the lung for relieving asthma, and Gu has saying of " having a surplus of eliminating the pathogens from the lung, non-Cortex Mori ".Semen Lepidii (Semen Descurainiae), toil Great Cold.Eliminating pathogen from the lung for relieving asthma, inducing diuresis to remove edema is lung man edema caused by disorder of QI medicine.Be applicable to accumulation and obstruction of sputum, the respectful mistake department of falling, cough with asthma is uncomfortable in chest must not the person of crouching.Semen Armeniacae Amarum, Cortex Mori, Semen Lepidii (Semen Descurainiae) three medicines are ministerial drug with 5 altogether, to assist monarch drug Herba Ephedrae, Gypsum Fibrosum with clearing heat and purging lung, the effect of relieving cough and asthma.
In the side, Radix Angelicae Sinensis, Radix Salviae Miltiorrhizae, Pheretima, Bombyx Batryticatus are adjuvant drug altogether.Radix Angelicae Sinensis, sweet hot tonifying blood and regulating menstruation, promoting blood circulation and stopping pain are its conventional usage.And " herbal classic " claims its energy " main cough with dyspnea ".The sage of the past is with the person is few in number when belonging to the cough with asthma, and many and expelling phlegm for arresting cough, the same usefulness of anti-asthmatic, as Suzi Jiangqi Tang, and Jinshui Liujun Jian.Radix Salviae Miltiorrhizae, hardship is slightly cold, blood circulation promoting and blood stasis dispelling, the removing heat from blood eliminating carbuncle, relieving restlessness is calmed the nerves.Two medicines share, the function blood circulation promoting and blood stasis dispelling, and expelling phlegm for arresting cough makes expectorant heat stop up to stagnate and is activated dissipation.Pheretima, salty-cold, clearing heat and relieving dyspnea; Bombyx Batryticatus, salty suffering is flat, expelling wind to relieve convulsion, dissipating phlegm and resolving masses.Two medicines are with 5, the heat clearing away spasmolytic, and the dissipating phlegm and resolving masses of relievining asthma makes air flue happy,, expectorant is turbid easily to be coughed up, and hardship of cough with asthma paused and disappeared.The two all has endogenous wind stopping relieving convulsion, dissipating phlegm and resolving masses Bombyx Batryticatus and Pheretima, the effect of relievining asthma and expelling the heat-evil." book on Chinese herbal medicine analyze mentally record " cloud; " Bombyx Batryticatus, acrid in the mouth temperature and property is dry, thus control the wind-phlegm of domination of damp pathogen ... Bombyx Batryticatus is robbed phlegm-damp and the liver-wind that looses, so the master." modern pharmacology also confirmed that Bombyx Batryticatus has hypnosis and anticonvulsant action; That Pheretima has is analgesic, the calm and effect of relievining asthma, modern pharmacology has also shown that it has the effect of significant diastole bronchus, can make the bronchial smooth muscle expansion and reach the purpose that air flue is happy and relieving asthma, play very important effect to alleviating, strengthened we and eliminated the phlegm, relieving asthma and the abirritative effect with treatment acute bronchitis syndrome of phlegm-heat obstructing lung.The present composition makes our compatibility more rigorous careful by increase Bombyx Batryticatus and Pheretima two flavor medicines, thereby has received gratifying clinical effectiveness.Add above four Chinese medicine on the basis of above-mentioned flavour of a drug, particularly back two flavor medicines often prove effective, and can play again simultaneously to prevent from or treat to give birth in its blood stasis and the effect of convulsion is sent out in children's's phlegm dyspnea.Radix Glycyrrhizae is a messenger drug in the side, and nature and flavor are sweet flat.Heat-clearing and toxic substances removing is arranged, and expelling phlegm for arresting cough is relievingd asthma, and assistant is with the merit of phlegm reduction of blood circulation promoting.
We again can blood circulation promoting and blood stasis dispelling based on clearing heat and purging lung, and condensing of the expectorant stasis of blood loose, and more can make air flue happy, and expectorant is turbid easily to be coughed up, and lung-heat gets clearly, declares to rush down and respectfully falls capablely, and then all cards of phlegm-heat obstructing in the lung all remove.We's treating both the principal and secondary aspects of a disease is to take stopgap measures.Side's medicine adds the product of letting out the blood stasis dispelling expelling wind to relieve convulsion clearly based on Zhong Jing Herba Ephedrae Semen Armeniacae Amarum Gypsum Fibrosum glycyrrhiza decoction, the our characteristics of real genus.
The preparation method of Chinese medicine composition of the present invention can adopt the conventional preparation method of Chinese patent medicine preparation, wherein the leaching method of Chinese medicine ingredients can be referring to " pharmaceutics " (third edition) chapter 2 (People's Health Publisher of Xi Nianzhu chief editor, 1996), and adopt the preparation method of conventional formulation this Chinese medicine composition to be prepared into dosage forms such as granule, capsule, tablet, oral liquid and unguentum.
The preparation method of this Chinese medicine composition can be: take by weighing above ten flavor crude drug, add 20~3 times in water, preferred 10~4 times; Decoct preferred 2~3 times 1~4 time; Each 0.5~4 hour, preferred 0.5~2 hour, collecting decoction filtered, and filtrate is left standstill, and gets supernatant and is evaporated to the clear paste that relative density is 1.0-1.3 (50~80 ℃).Requirement according to the preparation dosage form adds corresponding auxiliary material, for example prepares granule, and an amount of citric acid is added the clear paste of gained, dissolving, mixing, add again 1~5 times of dried cream amount cane sugar powder or and other adjuvant and ethanol an amount of, granulate, packing promptly gets granule; For example prepare oral liquid, proper honey and preservative sodium benzoate are added in the spissated supernatant, boil and make its dissolving, it is an amount of to add water, stirs evenly, and cold preservation 24~48 hours filters, embedding, and sterilization promptly gets oral liquid; For example prepare capsule, put the clear paste that obtains cold, add ethanol and make and contain alcohol amount and reach more than 65%, stir evenly, leave standstill more than 24 hours, filter, filtrate recycling ethanol and to be concentrated into relative density be (about 70 ℃) more than 1.0 adds the dextrin of 2.5 times of dried cream amounts, after spray drying gets powder, carry out one-step palletizing again, will make the encapsulated capsule that promptly gets of granule; For example prepare tablet, put the clear paste that obtains cold, add ethanol and make and contain alcohol amount and reach more than 65%, stir evenly, leave standstill more than 24 hours, filter, filtrate recycling ethanol and to be concentrated into relative density be (about 70 ℃) more than 1.0 adds the pregelatinized Starch of 2 times of amounts of dried cream, after spray drying gets powder, carry out one-step palletizing again, granulate, tabletting or bag film-coat or sugar-coat promptly get tablet.
It is to be noted, for a person skilled in the art, when the various dosage form of the Chinese medicine composition of the present invention for preparing, can adopt and add other adjuvants or reduce adjuvant or improvement technology, these used changes or modification all are means commonly used in the drug preparation technique, still are scope of the present invention.
The active matter method of inspection is in the Chinese medicine composition of the present invention:
Discrimination method
(1) get present composition 10g, porphyrize adds strong ammonia solution 2ml, adds chloroform 30ml again, and reflux 1 hour is put coldly, filters, the filtrate evaporate to dryness, and residue adds methanol 1ml makes dissolving, as need testing solution.Other gets the ephedrine hydrochloride reference substance, adds methanol 1ml and makes the solution that every 1ml contains 1mg, in contrast product solution.Test according to thin layer chromatography (appendix VIB of Chinese Pharmacopoeia version in 2000), draw above-mentioned two kinds of each 2-5ul of solution, put respectively on same silica gel g thin-layer plate, with chloroform-methanol-strong ammonia solution (20: 5: 0.5) is developing solvent, launch, take out, dry, spray is with 0.2% 1,2,3-indantrione monohydrate ethanol test solution, about 5 minutes of 105 ℃ of bakings.In the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show identical punctation.
(2) get present composition 10g, porphyrize adds ethanol 20ml, and supersound process 20 minutes is put coldly, filters, and filtrate evaporate to dryness, residue add ethanol 2ml makes dissolving, as need testing solution.Other is extracting liquorice control medicinal material 1g, shine medical material solution in pairs with legal system,, draw need testing solution 5ul according to thin layer chromatography (appendix VIB of Chinese Pharmacopoeia version in 2000) test, control medicinal material solution 1-3ul, putting respectively on same silica gel g thin-layer plate, is developing solvent with toluene-ethyl acetate-glacial acetic acid (10: 10: 0.5), launches, taking-up is dried, spray, is put under the ultra-violet lamp (365nm) and is inspected about 5 minutes of 105 ℃ of bakings with 10% ethanol solution of sulfuric acid.In the test sample chromatograph, with the corresponding position of control medicinal material chromatograph on, show identical blue purple fluorescence principal spot.
(3) get present composition 10g porphyrize, add methanol 30ml, supersound process 20 minutes, filter, the filtrate evaporate to dryness, residue dissolves with 1% ammonia solution 15ml gradation, merge, use chloroform extraction 2 times, each 20ml, discard chloroform solution, get aqueous slkali and add dilute hydrochloric acid 2ml, mixing, with ether extraction 2 times, each 20ml merges ether solution, volatilize, residue adds methanol 1ml makes dissolving, as need testing solution.Other gets the ferulic acid reference substance, adds methanol and makes the solution that every 1ml contains 1mg, in contrast product solution.Test according to thin layer chromatography (appendix VIB of Chinese Pharmacopoeia version in 2000), draw need testing solution 5-10ul, reference substance solution 5ul puts respectively on same silica gel g thin-layer plate, with benzene-methanol-glacial acetic acid (30: 3: 1) is developing solvent, launch, take out, dry, put in the iodine vapor smoked several minutes clear to the speckle colour developing, in the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show the speckle of same color.
(4) get Radix Salviae Miltiorrhizae control medicinal material 1g, add water 30ml and decocted 30 minutes, put coldly, filter, filtrate adds dilute hydrochloric acid 2ml, use the ether extraction secondary, each 20ml, and the merging ether solution volatilizes, and residue adds methanol 1ml makes dissolving, in contrast medical material solution.Test according to thin layer chromatography (an appendix VI of Chinese Pharmacopoeia nineteen ninety-five version B), draw and differentiate (3) item need testing solution 5ul down, reference substance solution 2ul, put respectively on same silica gel g thin-layer plate, with benzene-ethyl acetate-formic acid (4: 1: 0.2) is developing solvent, launches, and takes out, dry, put under the uviol lamp (365nm) and inspect.In the test sample chromatograph, with the corresponding position of control medicinal material chromatograph on, should show the fluorescence speckle of same color.
Assay (Herba Ephedrae):
It is an amount of that the preparation precision of assay method 1 reference substance solution takes by weighing the ephedrine hydrochloride reference substance, adds water and make the solution that every 1ml contains 0.02mg, promptly.
It is an amount of that the present composition is got in the preparation of need testing solution, carries out vapor distillation after adding sodium chloride and 40% sodium hydroxide solution, and distillate is put in the measuring bottle that contains dilute hydrochloric acid, makes need testing solution with 40% sodium hydroxide solution adjust pH to 6.0-7.0.
Algoscopy is got above-mentioned two kinds of solution and is added the citric acid-sodium hydrogen phosphate buffer that contains bromothymol blue respectively, respectively adds chloroform again and extracts, and divides and gets chloroform layer, measures trap at 414nm wavelength place with spectrophotography, calculates promptly.Particular content is: above-mentioned two kinds of each 3ml of solution of accurate absorption, put respectively in the tool plug triangular flask, each accurate citric acid-sodium hydrogen phosphate buffer (pH7.6) 10ml that contains 0.0125% bromothymol blue that adds, after shaking up, each precision adds chloroform 10ml again, shake well 3 minutes, in the impouring separatory funnel, shake static 10 minutes gently, divide and get chloroform layer, static 5 minutes is blank with the reagent corresponding, according to spectrophotography (appendix VB of Chinese Pharmacopoeia version in 2000) test, measure trap at 414nm wavelength place, calculate promptly.
The preparation of assay method 2 contrast solutions with the ephedrine hydrochloride dilute with water after, it is an amount of with sodium hydroxide solution to add periodic acid, with hydrochloric acid adjusting pH to 7, adds methanol and makes reference substance solution in right amount.
The preparation of need testing solution is got and is added after an amount of hydro-oxidation sodium solution of this product shakes up in right amount that sodium chloride is an amount of to carry out distillation extraction to filling in the measuring bottle of hydrochloric acid solution in advance after ultrasonic again, get and add periodic acid again after an amount of dilution and sodium hydroxide solution is an amount of, regulate pH to 7 with hydrochloric acid, get subsequent filtrate promptly after adding an amount of dissolution filter of methanol.
It is the chromatograph of liquid of filler that algoscopy gets that above-mentioned two kinds of solution inject respectively with the octadecylsilane chemically bonded silica, is mobile phase with methanol-water (1: 1); The detection wavelength is 254nm, and theoretical cam curve is calculated by ephedrine hydrochloride should be not less than 3000.
Calculate with above-mentioned two kinds of methods, the every 1g of the present composition contains Herba Ephedrae with ephedrine hydrochloride (C 10H 15NOHCL) meter must not be less than 0.30mg.
Prove that by animal experiment compositions of the present invention has antiviral, antibiotic, analgesic, antitussive, eliminates the phlegm, relievings asthma and antiinflammatory action.
Show by clinical trial: compositions of the present invention is better than clinical " particles for acute bronchitis " commonly used to infantile acute bronchitis phlegm-heat cough disease, can obviously improve clinical symptoms and sign.Have short treating period, instant effect, dosage form is stable, the characteristics of no obvious toxicity.Therefore, compositions of the present invention can be used for treating acute bronchitis or the convalescent phlegm-heat cough card of pneumonia, particularly is applicable to children's.
Compositions of the present invention is example by oral administration with the mixture, and is one-year-old to three years old one time 10ml, more than three years old to seven years old one time 15ml, more than seven years old to 12 years old one time 20ml, more than 12 years old to 14 years old one time 30ml, 14 years old with last 40ml, three times on the one; Or follow the doctor's advice.The dosage form that can take other with reference to the dosage of oral liquid (with the content conversion of active ingredient).
Description of drawings
Fig. 1 represents normal mice lung tissue (* 200)
Fig. 2 represents that little blood vessel is slightly expanded (* 100) in the alveolar wall
Fig. 3 represents that the little blood vessel of alveolar wall is obviously expanded, hyperemia (* 100)
Fig. 4 represents little vasodilation hyperemia in the alveolar wall, with focal hemorrhage (* 100)
Fig. 5 represents the heat clearing away effect of preparation of the present invention
The specific embodiment
Specifically describe embodiments of the present invention below by embodiment; those skilled in the art will be appreciated that; these specific embodiments only show selects the technical scheme implemented in order to reach purpose of the present invention; but not restriction to technical scheme; is obvious according to prior art to improving of technical solution of the present invention, all belongs to the scope of protection of the invention.
Embodiment 1
Crude drug
Herba Ephedrae (processed with honey) 125g Gypsum Fibrosum 1250g Semen Armeniacae Amarum (stir-fry) 125g
Cortex Mori (processed with honey) 125g Semen Lepidii (Semen Descurainiae) (stir-fry) 75g Radix Angelicae Sinensis 188g
Radix Salviae Miltiorrhizae 188g Pheretima 125g Bombyx Batryticatus (stir-fry) 125g
Radix Glycyrrhizae 125g
Preparation method: above ten flavors add 6.5 times of decoctings and boil three times, each 1.5 hours, collecting decoction filters, and filtrate is left standstill, get supernatant and be evaporated to the clear paste that relative density is 1.2-1.25 (50 ℃), add citric acid 2.5g, dissolving, mixing, it is an amount of to add cane sugar powder (for 2.99 times of dried cream amount) and ethanol again, granulates, and makes 1000g granule I-A of the present invention, promptly get 250 bags or 25 bottles (every packed 4g/ bag, or every bottled 40g).
According to above-mentioned active ingredient detection method, record every 1g and contain Herba Ephedrae with ephedrine hydrochloride (C 10H 15NOHCL) meter is greater than 0.60mg.
Embodiment 2
With reference to embodiment 1, do not exist together for: add 8 times of decoctings and boil secondary, each 2 hours.Make granule I-B of the present invention.
Embodiment 3
Herba Ephedrae (processed with honey) 175g Gypsum Fibrosum 750g Semen Armeniacae Amarum (stir-fry) 175g
Cortex Mori (processed with honey) 75g Semen Lepidii (Semen Descurainiae) (stir-fry) 120g Radix Angelicae Sinensis 125g
Radix Salviae Miltiorrhizae 250g Pheretima 75g Bombyx Batryticatus (stir-fry) 175g
Radix Glycyrrhizae 75g
Get above ten flavor crude drug, add 8 times of decoctings and boil 2~3 times, each 2 hours, collecting decoction filters filtrate, it is 1.1-1.2 (50 ℃) that filtrate decompression is concentrated into relative density, adds the sodium benzoate of proper honey and 0.2%, boils to make dissolving, it is an amount of to add water, stirs evenly cold preservation 24~48 hours, filter, embedding, sterilization promptly gets 100 bottles of (every bottle of 10ml) oral liquid formulations II-A of the present invention.
Embodiment 4
With reference to embodiment 3, do not exist together for: add 6 times of decoctings and boil 2~3 times, each 1 hour.Promptly get oral liquid formulations II-B of the present invention.
Embodiment 5
Herba Ephedrae (processed with honey) 150g Gypsum Fibrosum 1500g
Semen Armeniacae Amarum (stir-fry) 150g Cortex Mori (processed with honey) 150g
Semen Lepidii (Semen Descurainiae) (stir-fry) 100g Radix Angelicae Sinensis 226g
Radix Salviae Miltiorrhizae 226g Pheretima 150g
Bombyx Batryticatus (stir-fry) 150g Radix Glycyrrhizae 150g
Take by weighing above ten flavor crude drug, adding 12 times of decoctings boils 2 times, each 2 hours, collecting decoction, filter, filtrate is concentrated into the clear paste of relative density 1.1~1.25 (80 ℃), puts coldly, adds ethanol and makes and contain alcohol amount and reach more than 65%, stir evenly, leave standstill more than 24 hours, filter, filtrate recycling ethanol and to be concentrated into relative density be (about 70 ℃) more than 1.0, the dextrin that adds 2.5 times of dried cream amounts, after spray drying gets powder, carry out one-step palletizing again, will make that granule is encapsulated promptly to get 3000 capsule preparations III-A of the present invention.
Embodiment 6
With reference to embodiment 5, do not exist together for: add 10 times in water and decoct each 2 hours 3 times.Promptly get capsule preparations III-B of the present invention.
Embodiment 7
Herba Ephedrae (processed with honey) 137g Gypsum Fibrosum 1370g
Semen Armeniacae Amarum (stir-fry) 137g Cortex Mori (processed with honey) 137g
Semen Lepidii (Semen Descurainiae) (stir-fry) 82g Radix Angelicae Sinensis 206g
Radix Salviae Miltiorrhizae 206g Pheretima 137g
Bombyx Batryticatus (stir-fry) 137g Radix Glycyrrhizae 137g
Take by weighing above ten flavor crude drug, add 10 times in water, decoct 2~3 times, each 1~2 hour, collecting decoction filters, and filtrate is concentrated into the clear paste of relative density 1.1~1.25 (80 ℃), put cold, add ethanol and make and contain alcohol amount and reach more than 65%, stir evenly, leave standstill more than 24 hours, filter, filtrate recycling ethanol and to be concentrated into relative density be (about 70 ℃) more than 1.0 adds the pregelatinized Starch of 2 times of amounts of dried cream, after spray drying gets powder, carry out one-step palletizing again, granulate, tabletting and bag film-coat promptly get 1600 tablet formulation IV-A of the present invention.
Embodiment 8 tablet 4-2
With reference to embodiment 7, do not exist together for: add 8 times in water.Promptly get tablet formulation IV-B of the present invention.
Following examples will be studied the performance of Chinese medicine composition of the present invention
Test objective: observe Chinese medicine composition of the present invention antiviral, antibiotic, analgesic, antitussive, eliminate the phlegm, relieving asthma and antiinflammatory action, be given the test agent with the granule I-A of embodiment 1.
Test material
1, medicine and reagent (※ is the complementary testing content)
The granule I-A of the present invention of preparation of the present invention: embodiment 1.
Content; Suitable crude drug 2.45g/g granule.
Blank (excipient): make by oneself by the inventor.(prepare the method for granule with reference to embodiment 1, made by sucrose and citric acid fine powder, both ratios are 2.99: 0.01)
Bacterial endotoxin: the national standard product, lot number: 924, Nat'l Pharmaceutical ﹠ Biological Products Control Institute.
Streptococcus pneumoniae: bacterium number: 31001, lot number: 20, be reference culture, by Nat'l Pharmaceutical ﹠ Biological Products Control Institute.
Respiratory syncytial virus (RSV): standard strain Long strain, Vero cell monolayer culture fluid.TCID50=10-6。Provide by Wuhan Virology Institute,Chinan academy of Sciences.
Dipyrone: lot number: 950810, Shenyang the 5th pharmaceutical factory.
JIZHI TANGJIANG: lot number: 950121, by Fuling Pharmaceutical Factory, Sichuan Prov production
The ※ lot number: 980907104, produce by Tai Ji group Fuling Pharmaceutical Factory.
Aspirin: lot number: 950710, Chinese Taiyuan, Shanxi Jin Yang pharmaceutical factory.
Sodium phenobarbital: lot number: 951124, new Asia, Shanghai Pharma Inc..
※ hydrocortisone: Shenyang No. 1 Pharmaceutical Factory production, lot number: 950605.
Ammonia chloride: lot number: 950608, Beijing pharmaceutical factory that faces south.
SHUANGHUANGLIAN CHONGJI: lot number: 970101, Harbin work of nature pharmaceutical Co. Ltd.
SHUANGHUANGLIAN KOUFUYE: lot number; 971,103 41, Chinese Zhengzhou all living creatures pharmaceutical factory.
2, medicine preparation
Facing the time spent is made into variable concentrations with distilled water, the isometric(al) administration.
3, animal
Kunming mouse, the SD rat provides by Dalian Medical Univ's Experimental Animal Center.The quality certification number: No. the 522nd, the real moving word of the Liao Dynasty, regular grade one-level laboratory animal.
The Balb/c Mus is provided by medical science zoopery center, Hubei Province.The quality certification number No. 042.
※ Kunming kind white mice, male and female half and half, body weight 18-22g.
The Wistar rat, male and female half and half, body weight 200-250g.
Cavia porcellus, male and female half and half, body weight 252.1 ± 46.6g.
Above animal is purchased the animal feeding room in Shenyang Pharmaceutical University, animal quality certification number: No. 033, the real moving word of the Liao Dynasty, the laboratory animal environmental facility quality certification number: No. 036, the real moving word of the Liao Dynasty.
4, instrument
751 type ultraviolet spectrophotometers.
Duration of test laboratory temperature: 18-22 ℃.
The in vivo test of embodiment 9 Chinese medicine composition anti respiratory syncytial virus of the present invention
(1) virus virulence is measured
1. it is clinical to infect RSV: 5 of Balb/c Mus infect with the cell culture and virus collunarium, get stock solution 50-60 μ l collunarium.24h mice appearance hair is alarmmed after infecting, movable minimizing, symptoms such as lack of appetite.Symptom takes a turn for the better after 3-4 days, appetite, mental restoration.Cutd open in the 8th day and kill, get blood system, get lung from blood.
2. agar diffusion method detects serum RSV antibody: with RSV-McAb antibody is contrast, and sample serum diluted with 1: 50 at 1: 100.37 ℃ are spent the night behind the application of sample, precipitation line all occurs, are to show with 1: 50 sample especially.
3. mouse lung homogenate with 10% Mus lung suspension supernatant (behind the filter cleaning), is cultivated mensuration RSV50=10 at Vero -1--3
Table 1 virus virulence measurement result
Figure C20051010548900171
(2) medicine antivirus test
The Balb/c mice begins administration with the every nostril of RSV virus stock solution used 50 μ l collunariums after 4 hours, presses the successive administration of dosage shown in the table 28 days, once a day.Cutd open mice extremely on the 8th day after the administration, get blood system, detect RSV antibody with the indirect IF staining method from serum; Observe pulmonary's pathological change; Measure lung suspension virus titer (TCID50) in the Vero cell.
1. grouping and administration
Get female 6 age in week 110 of Balb/c mices, body weight 18-22 gram, be divided into eight groups (seeing Table 2) at random: first group is normal control group (mice does not infect RSV), the isometric(al) distilled water; Second group to the 8th grade is infected RSV; Second group is the distilled water group; The 3rd group is the blank group; The 4th group is the Moroxydine group, and dosage is 0.01g/kg/d; The 5th group is the SHUANGHUANGLIAN KOUFUYE group, and dosage is 11.0ml/kg/d; The 6th group is granule I-A small dose group of the present invention (6g/kg/d); The 7th group is dosage group (9g/kg/d) among the granule I-A of the present invention; The 8th group is the heavy dose of group of granule I-A of the present invention (12.5g/kg/d).Ig administration eight days, once a day.
The anti-RSV-Balb/c Mus of table 2 preparation of the present invention in vivo test grouping
Figure C20051010548900181
Annotate: normal control group mice does not infect RSV.
2. the mensuration of serum RSV antibody
With 1: 50 and 1: 100 dilute serum, adopt RSV-McAb and Vero cell to detect serum RSV antibody with indirect immunofluorescence.The results are shown in Table 3.
The measurement result of table 3Balb/c mice serum RSV antibody
Figure C20051010548900182
N: number of animals
3. the mensuration of virus titer
The Balb/c mice was in administration the 8th day, and preparation Mus lung suspension carries out virus titer and measures in the Vero cell, the results are shown in Table 4.
The measurement result of table 4 lung suspension virus titer
Figure C20051010548900191
4. the Balb/c mice is got the Mus lung tissue and does paraffin embedding in administration the 8th day, section, and HE dyeing, light microscopic (* 100, * 200) is observed pneumonopathy down and is become:
C1, C2 organize the interior little blood vessel of indivedual Mus alveolars and slightly expand;
C3, B1, B2, A1 group Mus lung tissue is normal;
The little blood vessel of A2, A3 group mice alveolar wall is obviously expanded, hyperemia, and with focal hemorrhage in the alveolar.
Referring to Fig. 1,2,3,4.
In sum, preparation of the present invention shows in the in vivo test of anti-RSV mice, oral granule I-A9g-12.5g/kg/d of the present invention, tangible anti-RSV effect is arranged, with matched group notable difference is arranged relatively, it is 94.4% that indirect immunofluorescence detects the negative antibody rate, approaching with the anti-RSV effect of positive control medicine Moroxydine; Mus lung tissue section as seen, granule I-A of the present invention treatment is after 8 days, it is normal that lung tissue is recovered, and negative control group presents the lung inflammation performance; In the Vero cell culture, can not survey virus titer with this sample treatment back Mus lung suspension.Above-mentioned result of the test shows that preparation of the present invention has obvious anti respiratory syncytial virus (RSV) effect.
Embodiment 10 Chinese medicine composition bacteriostatic tests of the present invention
(1) to the endogenous protective effect of streptococcus pneumoniae infection mice
Get 90 of Kunming mouses, be divided into 6 groups at random, group forming criterion and situation are with the antitussive action item.Positive controls is SHUANGHUANGLIAN CHONGJI group (ig80% SHUANGHUANGLIAN CHONGJI 25ml/kg, quite SHUANGHUANLIAN 20g/kg); 15 of every treated animals, administration every day secondary (morning 9:00 once, afternoon 3:00 once), the prevention administration is after 7 days, be used in streptococcus pneumoniae bacterium liquid (bacterial concentration the is 106/ml) infecting mouse of cultivating in the serum broth culture fluid 18 hours, lumbar injection, every Mus 0.5ml.Each group continues ig administration 7 days by former dosage after infecting, twice observation every day reaction of animals, and record animal dead number the results are shown in Table 5.
Table 5 preparation of the present invention is to the endogenous protective effect of streptococcus pneumoniae infection mice
Figure C20051010548900201
By table 5 as seen, granule I-A of the present invention can reduce the animal dead number when used big or middle two dosage, have certain bacteriostasis.
(2) external bacteriostasis (test tube doubling dilution)
Get S. pneumoniae strains and increase bacterium cultivation (37 ℃, 6 hours), be diluted to 1:105 test organisms liquid with meat soup.Sample is made into the sample solution (PH=7.2) of 1g/ml with meat soup, gets three groups in sterilization test tube, 10 every group.Every in vitro adds sample solution 0.5ml, and every group is carried out the twice dilution then, and last pipe is done negative control.Each test tube respectively adds test organisms liquid 0.5ml, and mix homogeneously is cultivated observed result after 18 hours with three groups of test tubes in 37 ℃ of incubators.The triplicate experiment the results are shown in Table 6.
Table 6 preparation extracorporeal bacteria inhibitor test of the present invention result
Figure C20051010548900211
The MIC of SHUANGHUANLIAN is 0.125g/ml, and the MIC of granule I-A of the present invention is 0.25g/ml, and adjuvant is not antibacterial.
By table 6 as seen, granule I-A of the present invention has certain bacteriostasis in extracorporeal bacteria inhibitor test.
Embodiment 11 Chinese medicine compositions of the present invention separate heat test
Get the SD rat, male and female half and half, body weight 160-180 gram, with rectal temperature instrumentation rectal temperature, survey once per half an hour, surveys twice altogether, with the meansigma methods of the twice temperature normal body temperature as this Mus.Select only 0.5 ℃ of twice temperature difference, normal body temperature is 37.0-38.0 ℃ rat, and lumbar injection bacterial endotoxin (600Eu/Kg) was surveyed body temperature once after 1 hour, select fervescence 1-2 ℃ 60 of rats, be divided into 6 groups at random: distilled water matched group (the isometric distilled water of ig); Blank group (the isometric excipient of ig); Tried object height dosage group (quite crude drug 61.3g/kg is about 4.92 times of clinical dosages for ig100% granule I-A25ml/kg of the present invention, suitable granule 25g/kg); Tried dosage group in the thing (quite crude drug 30.7g/kg is about 2.46 times of clinical dosages for ig50% granule I-A of the present invention solution 25ml/kg, suitable granule 12.5g/kg); Tried thing low dose group (quite crude drug 15.3g/kg is about 1.23 times of clinical dosages for ig 25% granule I-A solution 25ml/kg of the present invention, suitable granule 6.25g/kg); Dipyrone matched group (ig8% dipyrone solution 25ml/kg); Every group 10, ig is administered once, and survey body temperature once per half an hour after the administration, surveys altogether 6 times.Record body temperature calculates liter (falling) value of body temperature and pyrogenicity temperature after the administration, carries out t and checks, and the results are shown in Table 7, Fig. 5.
Figure C20051010548900221
By table 7 as seen, granule I-A of the present invention has tangible heat clearing away effect when big or middle two dosage.The heat clearing away effect of dipyrone is highly significant also, and is suitable with the effect of heavy dose group.
The cough-relieving test of embodiment 12 Chinese medicine compositions of the present invention
(1) mice ammonia draws the method for coughing
Get 60 of Kunming mouses, male and female half and half, body weight 18-22 gram is divided into 6 groups: distilled water matched group (the isometric distilled water of ig) at random; Blank group (the isometric excipient of ig); Tried object height dosage group (quite crude drug 122.5g/kg is about 4.84 times of clinical dosages for ig200% granule I-A of the present invention solution 25ml/kg, suitable granule 50g/kg); Tried dosage group in the thing (quite crude drug 61.3g/kg is about 2.42 times of clinical dosages for ig100% granule I-A of the present invention solution 25ml/kg, suitable granule 25g/kg); Tried thing low dose group (quite crude drug 30.6g/kg is about 1.21 times of clinical dosages for ig granule I-A of the present invention solution 25ml/kg, suitable granule 12.5g/kg); JIZHI TANGJIANG matched group (ig original liquid 50ml/kg, approximately with to be tried in the thing dosage suitable).10 of every treated animals.Administration seven days, once a day, the last administration is after 1 hour, mice is placed the 500ml beaker, and beaker is built, quantitatively spray into ammonia in the beaker with sprayer unit with plate, observe and write down cough latent period of mice and the cough number of times in 2 minutes then, the results are shown in table 8, tried the thing group as can be known and compare, can obviously prolong cough latent period with the blank group, reduce the cough number of times, through t check very meaningful statistically (p<0.01, p<0.05), and be good dose-effect relationship.The antitussive action of JIZHI TANGJIANG is highly significant also, and is suitable with the effect of middle dosage group.
The antitussive action of table 8 preparation of the present invention (mice ammonia draws the method for breathing heavily)
Figure C20051010548900231
*P<0.05 *P<0.01 (comparing) with the blank group
The method of coughing is drawn in the acid of ※ (2) Cavia porcellus Chinese holly rubber
Get 47 of Cavia porcelluss, body weight 132.9 ± 20.2g is divided into five groups at random.First group of Cavia porcellus irritated stomach isometric(al) normal saline; Second group of Cavia porcellus irritated stomach JIZHI TANGJIANG 30ml/kg; The 3rd First Five-Year Plan group Cavia porcellus filling stomach granule I-A30g/kg of the present invention, 15g/kg and 7.5g/kg, continuous irrigation stomach 7 days, after the last administration 40 minutes, Cavia porcellus is put in the 700ml glass bell jar, in bell jar, sprays into 10 seconds of 17.5% Chinese holly rubber acid solution, observe the cough latent period and the number of times of coughing in 5 minutes of Cavia porcellus, data are carried out the t check, the results are shown in Table 9.
Table 9 preparation of the present invention causes guinea pig cough's influence to the acid of structure rubber
Figure C20051010548900241
Annotate: * and normal saline group be P<0.05 relatively
* and normal saline group be P<0.01 relatively
* * and normal saline group be P<0.001 relatively
By table 9 data as can be seen, granule I-A of the present invention has apparent in view inhibition because of the acid of Chinese holly rubber causes guinea pig cough's effect, and the cough latent period of Cavia porcellus is obviously prolonged, and 5 minutes cough number of times obviously reduces.
The test of reducing phlegm of embodiment 13 Chinese medicine compositions of the present invention
(1) expectoration of rat glass capillary is mensuration
Get 60 of SD rats, male and female half and half, body weight 180-220 gram is divided into 6 groups at random, and group forming criterion and situation are with the antitussive action item.Positive controls is ammonia chloride group (ig is joined ammonia chloride solution 25ml/kg, quite ammonia chloride 1g/kg).Fasting 12 hours behind sodium phenobarbital (100mg/kg) intraperitoneal injection of anesthesia, is faced upward the position and is fixed.Cut off the positive middle part of neck skin, isolate trachea.Hit exactly between two cartilaginous rings at the thyroid cartilage lower edge and to prick an aperture, insert one of capillary glass tube then, make capillary tube just contact the trachea lower surface, so as to drawing the sputum at trachea rear portion with sharp-pointed syringe needle.When being full of by expectorant in the capillary tube, change one immediately in addition.Draw sputum length as the effect of reducing phlegm of estimating medicine with capillary tube.Record administration preceding 2 hours normal secretory volume by dosed administration shown in above once, continues to observe 4 hours the record secretory volume.Compare the average secretory volume hourly in administration front and back.The results are shown in table 10, tried thing group and blank group as can be known relatively, the sputum output is obviously increased,, and dose-effect relationship is arranged through t check very meaningful statistically (P<0.01).The resolve phlegm effect of ammonia chloride is highly significant also, and is suitable with the heavy dose group.
The resolve phlegm effect of table 10 preparation of the present invention (expectoration of capillary glass-tube is mensuration)
Figure C20051010548900251
* P<0.01 (comparing) with the blank group
The phenol red method of ※ (2) mice trachea section
Get 50 of Kunming mouses, male and female half and half, body weight 20.3 ± 1.1g is divided into five groups at random, 10 every group.First group of its mouse oral irritated stomach isometric(al) normal saline; Second group of its mouse oral irritated stomach JIZHI TANGJIANG 30ml/kg; The three-five group of its mouse oral irritated stomach granule I-A of the present invention agent 30,15,7.5g/kg, and administration is after 30 minutes, and lumbar injection 5% phenol red 0.1ml/10g body weight was injected phenol red back 30 minutes, put to death mice, peeled off the trachea surrounding tissue.Cut one section trachea down to the trachea bifurcation from thyroid cartilage, put into the test tube that fills the 2.0ml normal saline, add 2 5% NaOH after 10 minutes, at wavelength 546nm place's photometry density value, calculate phenol red excretion amount by phenol red standard curve, significance with the matched group comparing difference the results are shown in Table 11.
Table 11 preparation of the present invention is to the influence of the phenol red excretion amount of mice trachea
Figure C20051010548900252
Annotate: * and normal saline group be P<0.05 relatively
* and normal saline group be P<0.01 relatively
* * and normal saline group be P<0.001 relatively
Shown that by table 11 data granule I-A of the present invention has tangible phlegm-dispelling functions, big or middle dosage has obvious facilitation to phenol red excretion amount, and the excretion amount increases, and the effect of JIZHI TANGJIANG group is the most obvious, compares P<0.001 with the normal saline matched group.
The antiasthmatic effect of embodiment 14 Chinese medicine compositions of the present invention
Get 50 of Cavia porcelluss, male and female half and half, body weight 120 ± 17g is divided into five groups at random, 10 every group.First treated animal is irritated stomach isometric(al) normal saline; Second treated animal is irritated stomach JIZHI TANGJIANG 3ml/100g body weight; Irritate stomach granule I-A30g/kg of the present invention for the three-five group, 15g/kg and 7.5g/kg, successive administration 7 days, the last of administration 40 minutes, Cavia porcellus is put in the 700ml glass bell jar, by only regularly spraying in 10 seconds with 2% acetylcholine and histamine's mixed liquor of 0.1%, observe drawing to breathe heavily incubation period and (promptly beginning to asthma attack of Cavia porcellus from spraying, breathing is the devil, until the time that tic is fallen), the results are shown in Table 12.
Table 12 preparation of the present invention is to the antiasthmatic effect of Cavia porcellus
Figure C20051010548900261
Annotate: * and normal saline group be P<0.05 relatively
* and normal saline group be P<0.01 relatively
* * and normal saline group be P<0.001 relatively
By table 12 data as can be seen, the dyspnea that the guinea pig bronchial spasm that granule I-A of the present invention has apparent in view inhibition to be brought out by the Ach-His mixed liquor is caused, the effect of panting, can make to draw to breathe heavily to prolong significantly incubation period, illustrate that granule I-A of the present invention has significantly antiasthmatic effect.
The antiinflammatory action of embodiment 15 Chinese medicine compositions of the present invention
(1) the scorching method of mouse ear caused by dimethylbenzene xylene
Get 60 of Male Kunming strain mice, body weight 26-30 gram is divided into 6 groups: distilled water matched group (the isometric distilled water of ig) at random; Blank group (the isometric excipient of ig); Tried object height dosage group (quite crude drug 147.0g/kg is about 5.80 times of clinical dosages for ig200% granule I-A of the present invention solution 30ml/kg, suitable granule 60g/kg); Tried dosage group in the thing (quite crude drug 73.5g/kg is about 2.90 times of clinical dosages for ig 100% granule I-A solution 30ml/kg of the present invention, suitable granule 30g/kg); Tried thing low dose group (quite crude drug 36.8g/kg is about 1.45 times of clinical dosages for ig 50% granule I-A solution 30ml/kg of the present invention, suitable granule 15.0g/kg); Aspirin group (ig joins aspirin soln 25ml/kg, quite aspirin 0.2g/kg).Ig administration ten days, once a day, 1h is coated with 0.05ml caused by dimethylbenzene xylene inflammation in mouse right ear after the last administration.Behind the 2h dislocation of mice cervical vertebra is put to death, cut two ears along the auricle baseline, lay round auricle at the same position of the left and right auricle of mice respectively with diameter 9mm card punch, weigh, with the difference of two auricle weight as the swelling degree, carry out the t check, and be calculated as follows and respectively organize inhibitory rate of intumesce, the results are shown in table 13, tried thing and the comparison of blank group as can be known and can significantly be suppressed little habit ear swelling due to the dimethylbenzene, through t check very meaningful statistically (P<0.01), and dose-effect relationship is arranged.The antiinflammatory action of aspirin is highly significant also, and is suitable with the effect of heavy dose group.
Figure C20051010548900271
The influence of table 13 preparation xylol of the present invention induced mice ear swelling
Figure C20051010548900272
* P<0.01 (comparing) with the blank group
※ (2) rat toes Ovum Gallus domesticus album causes scorching method
Get 50 of rats, body weight 252.1 ± 46.6g, male and female half and half are divided into five groups at random, 10 every group.Irritate stomach isometric(al) distilled water for first group; Irritate stomach granule I-A30g/kg of the present invention for second group the-the 4th group, 15g/kg and 7.5g/kg, gastric infusion is 7 days continuously; The 5th group of rat subcutaneous injection hydrocortisone 30mg/kg in the time of the 7th day, after the administration of all animals last 20 minutes subcutaneous only in the right back foot of rat to joint direction injection fresh albumen 0.1ml/, respectively at behind the albumen injection 30,45,60,90 minutes, measure paw swelling with the rat paw edema instrument respectively, the results are shown in Table 14.
Paw swelling=albumen injection metapedes volume-albumen injection front foot volume
Table 14 preparation of the present invention is to the influence of rat paw edema
Figure C20051010548900281
Annotate: * and normal saline group be P<0.05 relatively
* * and normal saline group be P<0.001 relatively
Table 14 data show that preparation of the present invention has the effect of obvious suppression rat toes swelling.
Conclusion: preparation of the present invention has significant antiviral, analgesic, antitussive, eliminates the phlegm, relievings asthma, antiinflammatory and certain bacteriostasis.
In sum,, fully proved the effectiveness and the safety of preparation of the present invention, both provided foundation, the reference dose of safe medication also is provided for the clinical trial medication for preparation of the present invention carries out clinical trial by the research of Pharmacodynamic test of active extract aspect.
Embodiment 16 clinical experiments
Granule I-A matched group of the present invention: particles for acute bronchitis
According to the plan of II clinical trial phase, adopt the contrast method of multi-center randomized double dual analog to carry out clinical observation research.Whole 213 routine study subjects all derive from three tame countries Pediatric Clinic, ward or the ER Observation Room of (Hospital No.1 Attached to Tianjin Traditional Chinese Medicine College, Nanjing Traditional Chinese Medicine Univ. affiliated hospital, first Affiliated Hospital of Henan Province university of TCM) clinical pharmacological centre.In 213 examples, except that 5 examples do not require to include statistics person's 208 examples in the rejecting because of meeting test plan, comprise test group 102 examples, wherein clinic case 73 examples account for 71.57%, and inpatient's 21 examples account for 20.59%, and observation ward's case 8 examples account for 7.84%; Matched group 106 examples, wherein clinic case 73 examples account for 68.87%, and inpatient's 24 examples account for 22.64%, and observation ward's case 9 examples account for 8.49%.X is compared in two groups of case sources 2=0.1820, P>0.05, difference does not have the significance meaning.
Table 15 liang group patients acuity bronchitis total effects relatively
Figure C20051010548900291
Annotate: total effective rate, refer to cure rate+obvious effective rate (being cure-remarkable-effectiveness rate), below herewith.
Ridit analyzes: U=2.4404, P<0.05.Two groups relatively, and difference has the significance meaning.
Model case
Case 1:
GY, woman, 5 years old.Begin test March 5 calendar year 2001.Random number: A-grade in the first class 10.
Main suit: coughed 2 days.
History of present illness: began cough before 2 days, coughed before 1 day and obviously increase the weight of.Cough now is frequent, has amount of expectoration few, and the expectorant yellow skin is white, and is thirsty, urinate not yellow, dry stool greatly.
Have a medical check-up: 36.3 ℃ of body temperature, refreshing clear, spirit is fair, breathes flat.Pharyngeal hyperemia, two pulmonary respiration sounds are coarse, and idol is heard and is done the ring sound, and hear sounds is strong, and heart rate 85 times/minute is not heard and noise, and abdomen is soft.Red tongue, yellow fur, rolling pulse.
Lab testing:
Routine blood test: WBC8.4 * 109/L, N30.8%, HB112g/L, RBC4.69 * 1012/L.
The Chest X-rays of X line: two lung marking are many slightly.
Diagnosis is with dialectical: infantile acute bronchitis (phlegm-heat cough card)
Diagnosis and treatment process: give No. 10 trial drugs of A-grade in the first class after making a definite diagnosis.Give medicine of the present invention and particles for acute bronchitis simulation medicine each 15ml at every turn, every day 3 times, oral.Treated 3 days, cough alleviates, and has expectorant as before, and two lungs are done the ring sound and disappeared, and respiratory murmur is still coarse.Treated 5 days, cough, all card of expectorant disappear, and 36.5 ℃ of body temperature are swallowed not redly, and two pulmonary respiration sounds are clear, and hear sounds is strong, heart rate 86 times/minute.Body of the tongue is light red, thin fur, normal pulse.Check routine blood test: WBC8.7 * 109/L, N44.9%, HB126g/L, RBC4.83 * 1012/L.The Chest X-rays of X line shows that still cardiopulmonary do not have work and become.According to efficacy assessment standard, total effects is recovery from illness (0/15=0), and therapeutic effect of syndrome is produce effects (0/11=0).In the test.Find no any untoward reaction, safety evaluatio is an one-level.
Case 2:
ZMY, woman, 4 years old.April 4 calendar year 2001 hospitalization.Random number: second D10.
Main suit: coughed 2 days.
History of present illness: infant began cough before 2 days., paroxysm of cough has amount of expectoration few, and the expectorant yellow skin is white, urinates not yellowly, and stool does not do.
Have a medical check-up: 37.2 ℃ of body temperature, refreshing clear, spirit is fair, breathes flat.Pharyngeal hyperemia, two pulmonary respiration sounds are coarse, and hear sounds is strong, and heart rate 120 times/minute is not heard and noise, and abdomen is soft.Red tongue, yellow fur, rapid pulse.
Lab testing:
Routine blood test: WBC5.0 * 109/L, L32.9%, N59.0%, HB119g/L, PLT222 * 109/L.
Routine urinalysis, just conventional (-).
X line Chest X-rays: two enhanced lung markings disorders.
Diagnosis is with dialectical: infantile acute bronchitis (infantile cough phlegm-heat cough card)
Diagnosis and treatment process: give second D10 trial drug after making a definite diagnosis.Give medicine of the present invention and particles for acute bronchitis simulation medicine each 15ml at every turn, every day 3 times, oral.Treated 1 day, cough alleviates, and treats 4 days, coughs, has expectorant, all cards of big dry stool to disappear, 36.2 ℃ of body temperature, and two pulmonary respiration sounds are clear, and hear sounds is strong, heart rate 110 times/minute.Body of the tongue is light red, thin fur, normal pulse.Check routine blood test: WBC10.0 * 109/L, L19%, N77.0%, HB143g/L, PLT179 * 109/L.X line Chest X-rays: (-).According to efficacy assessment standard, total effects, therapeutic effect of syndrome all are chosen as recovery from illness.In the test, find no any untoward reaction, safety evaluatio is an one-level.
Case 3:
YC, man, 2 years old.Begin test July 3 calendar year 2001.Random number: third D06.
Main suit: cough, low grade fever 1 day.
History of present illness: began cough, heating before 1 day.Cough now is frequent, and the rale sound is arranged between larynx, and low grade fever is mouthful thirsty, urinate not yellowly, and stool normally.
Have a medical check-up: 37.9 ℃ of body temperature, refreshing clear, spirit is fair, breathes slightly and urgees, 31 times/minute.Pharyngeal hyperemia, two pulmonary respiration sounds are coarse, and idol is heard and the rale sound, and hear sounds is strong, and heart rate 120 times/minute is not heard and noise, and abdomen is soft.Red tongue, yellow fur, fingerprint purple.
Lab testing:
Routine blood test: WBC3.7 * 109/L, N75.8%, HB125g/L, RBC4.25 * 1012/L, PLT129 * 109/L.Routine urinalysis, stool routine examination: (-).
The Chest X-rays of X line: two lung marking are big and heavy.
Diagnosis is with dialectical: infantile acute bronchitis (phlegm-heat cough card)
Diagnosis and treatment process: give the third D06 trial drug after making a definite diagnosis.Give medicine of the present invention and particles for acute bronchitis simulation medicine each 15ml at every turn, every day 3 times, oral.Treated 3 days, low grade fever disappears, and the cough number of times reduces, and still has wheezing sound in the throat, and body temperature is normal, breathes steadily, and two pulmonary respiration sounds are coarse.Treated 5 days, cough, all card of expectorant disappear, and 36.4 ℃ of body temperature are swallowed redly slightly, and two pulmonary respiration sounds are clear, and hear sounds is strong, heart rate 86 times/minute.Body of the tongue is light red, thin fur, and fingerprint is pale purple.Check routine blood test: WBC5.2 * 109/L, N77.9%, HB137g/L, RBC4.18 * 1012/L, PLT117 * 109/L.Routine urinalysis, stool routine examination: (-).The Chest X-rays of X line shows that still cardiopulmonary do not have work and become.According to efficacy assessment standard, total effects is recovery from illness (0/15=0), and therapeutic effect of syndrome is produce effects (0/11=0).Safety evaluatio is an one-level.
Above result shows that granule I-A of the present invention is with removing heat from the lung and dissipating phlegm, relieving cough and asthma, and assistant is main effect new Chinese medicine with blood circulation promoting and blood stasis dispelling, cures mainly infantile acute bronchitis phlegm-heat cough card.Result of the test shows, the total effects of test group, cure rate are 34.31%, and total effective rate (recovery from illness+obvious effective rate) is 86.27%; And the cure rate of matched group is 21.70%, and total effective rate is 74.53%.Two groups relatively, and the test group curative effect is higher than matched group, and difference has the significance meaning.Test group is 27.45% to the cure rate of phlegm-heat cough syndrome, and total effective rate is 90.20%; And the cure rate of matched group is 19.81%, and total effective rate is 75.47%.Two groups relatively, and difference does not have the significance meaning.The average of the total mark value of test group and syndrome integrated value difference also all is higher than matched group, and difference has the significance meaning.
Every index is improved the statistic analysis result of situation, symptom, unusual tongue arteries and veins and pulmonary's signs such as coughing, cough up phlegm after two groups of treatments are all than having clear improvement before the treatment, the improvement effect of wherein test group cough, unusual tongue fur is better than matched group, and difference has the significance meaning.Before the treatment, two groups of patients' blood leukocytes counting and X line rabat abnormal conditions compare, and difference that there are no significant has comparability.After the treatment, two groups of blood leukocytes counting all has clear improvement, and X line rabat unusually also has improvement to a certain degree, but between two groups of groups relatively, difference there are no significant meaning.Illustrate that two medicines increase close with the improvement effect of X line rabat increased bronchovascular shadows to the blood leukocytes counting.Two groups of pharyngeal viruses of treatment prenasal detect and the comparison of throat swab positive rate of bacterial culture, and difference does not have the significance meaning; Negative conversion rate after two groups of treatments relatively, difference does not have the significance meaning yet, but two groups negative conversion rate illustrates that all more than 80% two medicines all have antiviral and antibacterial action preferably.
This organizes 213 routine infants, except that lip dry (safety evaluatio is " secondary ") appears in 1 example (test group case) in therapeutic process, all finds no untoward reaction, and safety evaluatio is " one-level ".Lab index comprises hematuria just routine, hepatic and renal function, electrocardiogram treatment front and back mutation analysis, also finds the abnormal change relevant with trial drug.Illustrate that granule I-A of the present invention presses the test dose clinical practice, relatively safety.
Conclusion
Granule I-A of the present invention presses test dose, application 5 day course of treatment, infantile bronchitis phlegm-heat cough card had better curative effect, it improves and the tcm syndrome aspects such as minimizing of always scoring in total effects, cough primary symptom, all apparently higher than contrast medicine (particles for acute bronchitis), fully confirm the effect of its removing heat from the lung and dissipating phlegm, relieving cough and asthma, in addition, by nasopharynx part virus before and after infant is taken medicine detect and the throat swab bacteria cultivation results also from having confirmed antiviral that this product had and antibacterial action (III phase positive negative conversion rate is 100%) clinically, and do not see obvious toxic-side effects.

Claims (10)

1. Chinese medicine composition for the treatment of diseases in respiratory system, its crude drug consists of, to make the 1000g finished product:
Processed with honey Herba Ephedrae 75-175g Gypsum Fibrosum 750-1750g
Semen Armeniacae Amarum (parched) 75-175g processed with honey Cortex Mori 75-175g
Semen Descurainiae (parched) 30-120g Radix Angelicae Sinensis 125-250g
Radix Salviae Miltiorrhizae 125-250g Pheretima 75-175g
Bombyx Batryticatus (parched) 75-175g Radix Glycyrrhizae 75-175g.
2. compositions according to claim 1, wherein crude drug consists of, to make the 1000g finished product:
Processed with honey Herba Ephedrae honey 100-150g Gypsum Fibrosum 1000-1500g
Semen Armeniacae Amarum (parched) 100-150g processed with honey Cortex Mori 100-150g
Semen Descurainiae (parched) 50-100g Radix Angelicae Sinensis 150-226g
Radix Salviae Miltiorrhizae 150-226g Pheretima 100-150g
Bombyx Batryticatus (parched) 100-150g Radix Glycyrrhizae 100-150g.
3. compositions according to claim 2, wherein crude drug consists of, to make the 1000g finished product:
Processed with honey Herba Ephedrae 112-137g Gypsum Fibrosum 112-1370g
Semen Armeniacae Amarum (parched) 112-137g processed with honey Cortex Mori 112-137g
Semen Descurainiae (parched) 68-82g Radix Angelicae Sinensis 170-206g
Radix Salviae Miltiorrhizae 170-26g Pheretima 112-137g
Bombyx Batryticatus (parched) 112-137g Radix Glycyrrhizae 112-137g.
4. compositions according to claim 3, wherein crude drug consists of, to make the 1000g finished product:
Processed with honey Herba Ephedrae 125g Gypsum Fibrosum 1250g
Semen Armeniacae Amarum (parched) 125g processed with honey Cortex Mori 125g
Semen Descurainiae (parched) 75g Radix Angelicae Sinensis 188g
Radix Salviae Miltiorrhizae 188g Pheretima 125g
Bombyx Batryticatus (parched) 125g Radix Glycyrrhizae 125g.
5. according to the described compositions of the arbitrary claim of claim 1 to 4, the dosage form that can prepare is selected from granule, capsule, oral liquid, unguentum or tablet.
6. the described preparation of compositions method of the arbitrary claim of claim 1 to 4, it comprises the steps:
(1) takes by weighing the flavor of ten described in the described compositions of the arbitrary claim of claim 1 to 4 crude drug, add 20~3 times in water, decoct each 0.5~4 hour 1~4 time;
(2) collecting decoction filters, and filtrate is left standstill;
(3) getting supernatant, to be evaporated to relative density be the clear paste of 1.0-1.3 in the time of 50~80 ℃.
7. preparation method according to claim 6, it comprises the steps:
(1) takes by weighing described ten flavor crude drug, add 20~4 times in water, decoct each 0.5~4 hour 2~4 times;
(2) collecting decoction filters, and filtrate is left standstill;
(3) getting supernatant, to be evaporated to relative density be the clear paste of 1.0-1.3 in the time of 50~80 ℃.
The described compositions of the arbitrary claim of claim 1 to 4 preparation antiviral, antibiotic, analgesic, antitussive, eliminate the phlegm, relieving asthma or anti-inflammatory drug in application.
9. application according to claim 8, it is the application in preparation treatment acute bronchitis or the convalescent phlegm-heat cough card of pneumonia medicine.
10. test right requires the method for the active matter content of the described compositions of 1 to 4 arbitrary claim, and it comprises:
It is an amount of that the preparation precision of reference substance solution takes by weighing the ephedrine hydrochloride reference substance, adds water and make every 1ml and contain the 0.02mg reference substance solution;
The preparation weighting profit of need testing solution requires the described compositions of 1 to 4 arbitrary claim, carry out vapor distillation after adding sodium chloride and 40% sodium hydroxide solution, distillate is put in the measuring bottle that contains dilute hydrochloric acid, makes need testing solution with 40% sodium hydroxide solution adjust pH to 6.0-7.0;
Algoscopy is got above-mentioned two kinds of solution and is added the citric acid-sodium hydrogen phosphate buffer that contains bromothymol blue respectively, respectively adds chloroform again and extracts, and divides and gets chloroform layer, measures trap at 414nm wavelength place with spectrophotography, calculates promptly;
With the ephedrine hydrochloride is reference substance, contains Herba Ephedrae with ephedrine hydrochloride (C with the described compositions of the every 1g of Herba Ephedrae content in the spectrophotometry test sample 10H 15NOHCL) meter must not be less than 0.30mg.
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