CN102233026B - Pharmaceutical composition and preparation method and application thereof - Google Patents
Pharmaceutical composition and preparation method and application thereof Download PDFInfo
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- CN102233026B CN102233026B CN201010158323.5A CN201010158323A CN102233026B CN 102233026 B CN102233026 B CN 102233026B CN 201010158323 A CN201010158323 A CN 201010158323A CN 102233026 B CN102233026 B CN 102233026B
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- radix glycyrrhizae
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- aurantii immaturus
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Abstract
The invention provides a pharmaceutical composition composed of traditional Chinese medicinal materials namely immature bitter orange and licorice or the extracts thereof for preventing and treating asthma and chronic obstructive disease of lung, and a preparation process and preparation of the pharmaceutical composition mainly containing the active components such as immature bitter orange extract, licorice extract and the like. The invention also relates to the application of the pharmaceutical composition in preventing and treating bronchial asthma and chronic obstructive disease of lung.
Description
Technical field
The present invention relates to field of medicaments, especially relate to traditional Chinese medicine citrus aurantium and Radix Glycyrrhizae, particularly a kind of pharmaceutical composition of preventing and treating asthma, chronic obstructive pulmonary disease that contains Radix Glycyrrhizae extract and Furctus Aurantii Immaturus extract.
Background technology
Bronchial asthma is commonly encountered diseases, the frequently-occurring disease of serious threat health of people in world wide.WHO estimation, global asthma patient is up to 300,000,000 people, and Patients with Chronic Obstructive Pulmonary Disease 2.1 hundred million people; From epidemiological survey and analysis, respiratory system disease sickness rate accounts for 16% of total population prevalence, accounts for the 3rd of city general mortality rate, and asthma prevalence is about 5% in industrialized country.Along with the air pollution in global range and ecological deterioration, the M & M of asthma presents the situation that rises year by year.China's asthma sickness rate is about 1%, and child is 2% left and right, in global range, has every year 180000 people of surpassing to die from asthma.Nearly 10 years, the M & M of asthma was presented uptrend state, and the research of asthma control and new drug is worldwide paid close attention to widely.
Approximately there is 2,000 ten thousand asthma patients and 4,300 ten thousand chronic obstructive pulmonary disease (being called for short COPD) patient in China, and year death toll is more than 1,200,000, Yi Ji body China disease killer prostatitis.In the U.S., within 1994, estimate at 1,600 ten thousand chronic obstructive pulmonary disease patients undergoings, than nineteen eighty-two more 60%.1993, chronic obstructive pulmonary disease was the 4th large cause of death, reaches 95910 people, surpassed the twice of 1979.From 1979-1993, chronic obstructive pulmonary disease mortality rate has increased almost 50% (from 14%～20%).Er China chronic obstructive pulmonary disease accounts for 15 years old above crowd's 3%, and 80% patients with pulmonary hypertension comes from chronic obstructive pulmonary disease, is one of common refractory disease.Normal Complicated with Pulmonary cardiopathia of later stage, serious harm people ' s health, its disability rate and mortality rate are all very high, have been subject to the generally attention of medical circle.At on the November 20th, 2002 of first world chronic obstructive pulmonary disease on day, domestic senior respiratory disease expert points out, chronic obstructive pulmonary disease is the fourth-largest lethal cause of disease in the world at present, but may rise to the large lethal cause of disease in third place in the world to the year two thousand twenty.The decline of environmental quality is to cause one of this disease most important reason occurred frequently, and under smoking, dust, chemical contamination, air quality, degradation all damages pulmonary to some extent, causes the generation of chronic obstructive pulmonary disease.The Development process of therefore, how effectively to treat early chronic obstructive pulmonary disease has great meaning.Thereby treatment asthma is more and more valued by the people and pays close attention to.Although it is more to treat at present the medicament categories of asthma, the asthmatic medicament of research and development highly effective and safe is still the task of top priority.
Asthma belongs to the categories such as " asthma ", " the syndrome of dyspnea ", " phlegm retention " in motherland's medical science.Classical TCM theory is thought, the generation of asthma is latent phlegm retaining in the lung, is added with diseases caused by exogenous pathogenic factor, diet, the body void factor such as after being ill, so that due to stagnation of phlegm air flue, abnormal rising of lung-QI.Modern medicine thinks that asthma is that a kind of to take mastocyte reaction, eosinophil infiltration be main chronic airway inflammation.For this inflammation of susceptible person's (especially spy answers disease patient), can cause airway reactivity to increase, and can cause in various degree, widely, the clinical symptoms of reversibility airway pressure obstacle, show as suddenly, asthma, dyspnea and the cough of outbreak repeatedly.In asthma process, the general immunity dysfunction that body produces, outside the release medium such as a large amount of cytokines, inflammatory cell, inflammatory mediator, in inflammatory cell, acidophil also discharges crystal basic protein, cationic protein, toxic protein, and the coup injury airway epithelia such as peroxidase and lung cause that airway hyperreactivity strengthens, and causes the formation of chronic airway inflammation.Chronic obstructive pulmonary disease is a kind of disease that can prevent and treat with flow limitation feature, and flow limitation is not exclusively reversible, be and carry out sexual development, relevant to the abnormal inflammatory reaction of the harmful gass such as smoke from cigarette or deleterious particle with pulmonary.Its definite mechanism of action is also unclear at present.
Chronic obstructive pulmonary disease belongs to the categories such as the traditional Chinese medical science " cough ", " the syndrome of dyspnea ", " pulmonary distension ", is in smoking, recurrent respiratory tract infection, under the factor impacts such as atmospheric pollution and heredity, lung is impaired, repeatedly coughs, expectorant, breathes heavily, the prolonged a kind of disease more not causing.Pathogenesis of chronic obstructive pulmonary disease is mainly repeatedly to attack with exopathogen, and viscera function (particularly lung spleen kidney three is dirty) is lacked of proper care closely related.Early stage many due to impairment of dispersing and descending function of the lung, raw in phlegm-damp, meet sense and draw tactile latent phlegm, phlegm rising following QI, obstruction of QI due to retention of phlegm, the knot of mutually fighting, the air flue that is jammed, disorder of QI movement, and cause cough, and to cough up phlegm, cough with asthma QI rising in reverse order, is to mark real to be main, to show as the domination of pathogen.Lung is attacked by multiple exopathogen for a long time, declares respectful malfunction, and expectorant is turbid grows internal resistance in lung, lung qi virtual loss with the passing of time, and gas exchange is obstructed, and clearing heat in QI system can not transport to moisten supports the whole body, and foul smell is difficult to discharge, and stagnant in the heart, lung expansion is full.With the passing of time, illness of child viscera affecting mother one, causes dysfunction of the spleen in transportation to the deficiency of the lung, indigestion, and retention of water-damp in the body, increases the weight of expectorant turbid, and expectorant is turbid superior, accumulates and stores in lung, and lung qi is jammed.
In the medicine of asthma and chronic obstructive pulmonary disease, a clinical line medication at present be take Western medicine substantially as main, the first-selected glucocorticoid whole body of conventional Drug therapy or local application clinically, the medicine of clinical treatment asthma still has beta 2 receptor analeptic, anti-leukotriene medicine, theophylline class medicine, anticholinergic agent, inflammatory cell stabilizing agent, anti-infection drug expectorant, glucocorticoid and antioxidant etc.Because prolonged application side effect is obvious, be necessary to find the active drug that specificity is strong from Chinese medicine.
To asthma, chronic obstructive pulmonary disease, the traditional Chinese medical science is emphasized " while sending out, take stopgap measures, effect a permanent cure at ordinary times ", because asthma is anxious, how to improve high response and the airway remodeling of air flue, has proposed higher requirement to vast medical worker.For characteristics of incidence and the modern disease pharmacological research achievement of asthma, the present invention intends starting with from improving height reaction and the airway inflammation of air flue, and relief of symptoms, controls disease and further worsen, and improves quality of life of patients.
Fructus Aurantii Immaturus of the present invention, Radix Glycyrrhizae two taste medicines are just on the books in the > > of < < Sheng Nong's herbal classic.Fructus Aurantii Immaturus cold nature in side, bitter in the mouth, pungent, sour, enters spleen, stomach warp.There is the loose painful abdominal mass of reducing phlegm, the merit of dispelling the stagnated QI removing food stagnancy.The basic pathology of Paroxysmal asthma is changed to " latent phlegm " and meets sense and draw tactilely, and expectorant is assorted with gas, obstruction of QI due to retention of phlegm, and rich knot mutually, Yong Sai air flue, lung pipe is narrow, unobstructed unfavorable, and lung qi a surname falls not normal, and priming stops the expectorant amassing, and causes rale as shouted, breath dyspnea with rapid and short breath.The pathological factor of asthma be take expectorant as main, and pathology link during outbreak is that stagnation of phlegm is gas-tight, take the domination of pathogen as main, therefore with dyspnea, conscious exhalation is fast.Now with Fructus Aurantii Immaturus dispelling the stagnated QI, reduce phlegm, improve air flue spasm, thereby reach the effect of eliminating the phlegm, relievining asthma.Modern study shows, in Fructus Aurantii Immaturus, alkaloids composition has the effect of expansion bronchus as Neosynephrine, adenyl cyclase in can active cell, catalysis ATP is converted into cAMP, in cell, cAMP concentration increases, and then make bronchial smooth muscle keep for a long time diastole, thus improve the reaction of air flue superelevation, increase ventilatory function.
In side, Radix Glycyrrhizae property is flat, and sweet in the mouth, returns 12 warps.There is invigorating the spleen and replenishing QI, grow and cough lung moistening, emergency removing toxic substances, the merit of mediation hundred medicines.Have removing toxic substances, eliminate the phlegm, pain relieving, spasmolytic and the pharmacological action such as anticancer.Modern study shows that Radix Glycyrrhizae has antiinflammatory, antibacterial, antiallergic action, immunomodulating, antiviral activity, has the effect of glucocorticoid sample simultaneously.Monosodium glycyrrhetin has that the in vitro guinea pig trachea that antihistamine or acetylcholine are caused is shunk and lung spillway discharge reduces, and its antihistamine effect is better than cholinolytic effect.Radix Glycyrrhizae can also make the easy expectoration of expectorant by promoting throat and bronchial secretion, presents eliminating phlegm and relieving cough effect.Eosinophilic granulocyte's chemotactic and infiltration in bronchoalveolar lavage fluid when ammonium glycyrrhizinate can suppress Cavia porcellus allergic asthma.Glycyrrhizic acid can reduce NO content and NOS activity in asthma group mice serum, and it is active that prompting glycyrrhizic acid suppresses mouse asthma serum NO S, reduces NO content, and bronchial asthma is had to certain therapeutical effect.
Summary of the invention
The inventor adopts Fructus Aurantii Immaturus and Radix Glycyrrhizae coupling, at expansion bronchus simultaneously, utilize antiinflammatory action medicine, suppress gathering and the activation of neutrophilic granulocyte, suppress mastocyte, Eosinophil Degranulation, make inflammatory mediator, as discharging, histamine, leukotriene, prostaglandin etc. reduce, reduce vascular permeability, reduce the swelling of oozing out to alleviate air flue, promote bronchorrhea secretion and increase ciliary movement, reducing the airway hyperreactivity that anaphylactogen causes, improving the pulmonary function of Patients with Chronic Obstructive Pulmonary Disease.The two coupling simultaneously acts on a plurality of links of inflammation, the genetic transcription of regulation and control target cell, suppress the activation of multiple inflammatory cell and the generation of inflammatory factor, give full play to the synergism of the two use in conjunction, both can diastole bronchus, improve pulmonary function, can suppress again the abnormal inflammatory reaction of pulmonary to harmful gas or deleterious particle, stop further developing of its state of an illness.
Object of the present invention is just to provide a kind of for preventing and treating the pharmaceutical composition of asthma, chronic obstructive pulmonary disease.Described pharmaceutical composition is comprised of Radix Glycyrrhizae, Fructus Aurantii Immaturus or their extract.
The present invention also aims to provide a kind of for preventing and treating the pharmaceutical composition of asthma, chronic obstructive pulmonary disease.Described pharmaceutical composition comprises Radix Glycyrrhizae extract and Furctus Aurantii Immaturus extract, and further, the percentage by weight that in described Radix Glycyrrhizae extract, in total saponins and Furctus Aurantii Immaturus extract, total alkaloids accounts for described pharmaceutical composition is between 10～80%.
This pharmaceutical composition can produce synergism, raising evident in efficacy, overcome the deficiency that single Chinese medicine is difficult to meet the demand for the treatment of clinically asthma, chronic obstructive pulmonary disease drug combination, avoid medicine simply to mix the side reaction that use may cause, when controlling the airway inflammation factor, improve the high response of air flue.A kind of better efficacy clinically, convenient Traditional Chinese medicine compound composition and preparation thereof are provided.
Compared with prior art, the invention has the beneficial effects as follows: this pharmaceutical composition contains Furctus Aurantii Immaturus extract and Radix Glycyrrhizae extract, energy antiinflammatory, the generation synergistic function of relievining asthma, than alone same dosage Furctus Aurantii Immaturus extract or alone same dosage Radix Glycyrrhizae extract effect, all greatly improve, through pharmacodynamics test, prove that it is evident in efficacy.When controlling the airway inflammation factor, improve the high response of air flue, thereby reach the object for the treatment of asthma, chronic obstructive pulmonary disease.
The object of this invention is to provide a kind of pharmaceutical composition for the treatment of the diseases such as asthma, chronic obstructive pulmonary disease, said composition contains the Furctus Aurantii Immaturus extract being extracted by traditional Chinese medicine citrus aurantium and the Radix Glycyrrhizae extract extracting in Radix Glycyrrhizae as active component.
In the pharmaceutical composition of the diseases such as above-mentioned treatment asthma, chronic obstructive pulmonary disease, in described Furctus Aurantii Immaturus extract, the content of total alkaloids is more than 50%, and in described Radix Glycyrrhizae extract, total saponin content is more than 50%.
In aforementioned pharmaceutical compositions of the present invention, the quality proportioning of two kinds of extracts is: 1 part of the Furctus Aurantii Immaturus extract being extracted by Fructus Aurantii Immaturus, the Radix Glycyrrhizae extract 0.1-10 part of being extracted by Radix Glycyrrhizae.Preferably, in pharmaceutical composition of the present invention, the weight proportion of two kinds of extracts is: 1 part of the extract being extracted by Fructus Aurantii Immaturus, the Radix Glycyrrhizae extract 0.2-8 part of being extracted by Radix Glycyrrhizae.Preferred, in pharmaceutical composition of the present invention, the weight proportion of two kinds of extracts is: 1 part of the Furctus Aurantii Immaturus extract being extracted by Fructus Aurantii Immaturus, the Radix Glycyrrhizae extract 0.4-5 part of being extracted by Radix Glycyrrhizae.
One of active component in said composition Radix Glycyrrhizae extract is prepared by conventional method.For example, can adopt following method preparation: extracting liquorice medical material 10Kg, be ground into coarse powder, with 10 times of amount 0.5% ammonia mercerations, extract three times, each 3h, filters, and merges three times ammonia extraction liquid, reclaims solvent, be concentrated into about 20L, add 10% sulphuric acid and adjust pH value 2-3, standing 12h is centrifugal, collecting precipitation, dissolves and adjusts PH6-7, the AB-8 macroporous resin adsorption that upper 10L is wet by suitable quantity of water, first with 40L, wash, then use 10% concentration ethanol 40L desorption, collect eluent, concentrated, dry, obtain Radix Glycyrrhizae extract.
Described Radix Glycyrrhizae extract also can be prepared by the following method: extracting liquorice medical material 10Kg, and by 10 times of water gaging reflux, extract, three times, each 2h, filters, merge three times aqueous extract, reclaim solvent, be concentrated into about 10L, add ethanol to reaching approximately 75% containing alcohol amount, standing 12h is centrifugal; Supernatant reclaims ethanol to without alcohol taste, by the wet HPD-300 macroporous resin adsorption of 10L, first with 90L washing, then uses 50% concentration ethanol 75L desorption, collects 50% ethanol elution, reclaims ethanol, and drying under reduced pressure, obtains Radix Glycyrrhizae extract.
The assay of total saponins in above-mentioned Radix Glycyrrhizae extract
The preparation of reference substance solution: it is appropriate that precision takes monoammonium glycyrrhizinate reference substance, makes every ml containing the solution of 0.10mg with 30% ethanol.
The preparation of need testing solution: precision takes the about 20mg of this product, puts in 100ml measuring bottle, adds 30% dissolve with ethanol and is diluted to scale, shakes up and get final product.
Algoscopy: precision is drawn reference substance and each 0.5ml of need testing solution respectively, be placed in respectively 2 and take away plug heart test tube, 70 ℃ of water-baths volatilize, add freshly prepared 5% vanillin-glacial acetic acid solution 0.2ml, perchloric acid 0.8ml, in 55 ℃ of water-bath colour developing 15min, put the cooling 2-3min of ice-water bath, add glacial acetic acid 5ml and shake up, retinue reagent (vanillin, glacial acetic acid) is done blank, measures trap at 595nm place.
Another active component Furctus Aurantii Immaturus extract in the present composition can adopt following methods to extract from Fructus Aurantii Immaturus: get Fructus Aurantii Immaturus 10Kg, by 10 times of water gaging reflux, extract, three times, each 1h, filter, merge three times extracting solution, reclaim solvent, be concentrated into relative density 1.15-1.20 (60 ℃), add ethanol to reaching approximately 75% containing alcohol amount, standing 12h is centrifugal; Supernatant reclaims ethanol to without alcohol taste, with the wet D001-CC resin absorption of 5L, first with 30L washing, then uses 1mol/L ammonia desorption, collects eluent, concentrated, dry, obtains Furctus Aurantii Immaturus extract.
Described Furctus Aurantii Immaturus extract also can be prepared by the following method: get Fructus Aurantii Immaturus 10Kg, be ground into coarse powder, use 0.5mol/L soak with hydrochloric acid, spend the night, second day percolation, collects the percolate of 5 times of amounts, upper D061 cation exchange resin column, drops to when equal with post surface until percolation liquid level, stops, standing 2 hours, first with 30L washing, then use 0.5mol/L ammonia desorption, collect eluent, concentrated, dry, obtain Furctus Aurantii Immaturus extract.
The mensuration of total alkaloids (ultraviolet visible spectrophotometry) in above-mentioned Furctus Aurantii Immaturus extract
The preparation of reference substance solution: it is appropriate that precision takes Neosynephrine reference substance, makes every ml containing the solution of 15 μ g with 0.1mol/LNaOH solution, obtains.
The preparation of need testing solution: precision takes the about 10mg of above-mentioned total alkaloids, puts in 250ml measuring bottle, with 0.1mol/LNaOH solution, dissolves and is diluted to scale, shakes up, and obtains.
Algoscopy: get respectively reference substance and need testing solution, take 0.1mol/LNaOH solution as blank, according to ultraviolet visible spectrophotometry (appendix VA of Chinese Pharmacopoeia version in 2005)), at 292nm wavelength place, measure trap, calculate, obtain.
Another object of the present invention has been to provide the preparation method of drug combination preparation of the present invention, and the method can adopt the conventional method of pharmaceutical field, uses conventional pharmaceutical carrier to carry out.For example adopt conventional method by after Furctus Aurantii Immaturus extract and the even mixing of Radix Glycyrrhizae extract, mix with carrier or adjuvant conventional on any or more than one pharmaceuticss, then make various required dosage forms.Described carrier such as excipient, filler, diluent, lubricant, wetting agent, disintegrating agent, surfactant, antiseptic, sweeting agent, aromatic etc.Concrete, described carrier such as starch, dextrin, lactose, microcrystalline Cellulose, hydroxypropyl methylcellulose, Polyethylene Glycol, magnesium stearate, micropowder silica gel, glucose, mannitol, xylitol, glycine etc.
As required, pharmaceutical composition of the present invention can be made into the preparation that is suitable for various approach medications, is particularly suitable for the dosage form of oral, external and injection.Described to be suitable for oral dosage form can be to be selected from following arbitrary dosage form: tablet, capsule, soft capsule, granule, drop pill, dispersible tablet, slow releasing tablet, controlled release tablet or oral cavity quick disintegrating slice.The described dosage form that is suitable for external can be ointment, rubber-emplastrum or cataplasma.The described dosage form that is suitable for injection can be injection, transfusion or powder injection formulation.
The dosage form that is made into be suitable for injection when pharmaceutical composition of the present invention is during as injection or injectable powder, and wherein in Furctus Aurantii Immaturus extract, total alkaloid content is more than 80%, and in Radix Glycyrrhizae extract, Radix Glycyrrhizae total saponins content is more than 80%.
Another object of the present invention has been to provide the application of pharmaceutical composition of the present invention aspect the respiratory disorders such as treatment asthma, chronic obstructive pulmonary disease, and described respiratory system disease mainly comprises class chronic bronchitis, chronic obstructive pulmonary disease, bronchial asthma etc.
Chinese medicine composition raw material sources of the present invention are easy to get, technical process is easy to industrialization, can make as required various dosage forms, for clinical provide convenient, more effectively, the more controlled modern Chinese medicine of quality, for patient brings more interests, thereby produce huge social benefit.
The specific embodiment
Below in conjunction with the specific embodiment, the present invention is described in further detail, and the embodiment providing is only in order to illustrate the present invention, rather than in order to limit the scope of the invention.
Embodiment 1
Extracting liquorice medical material 10Kg, by 10 times of water gaging reflux, extract, three times, each 2h, filters, and merges three times aqueous extract, reclaims solvent, is concentrated into about 10L, adds ethanol to containing alcohol amount approximately 75%, and standing 12h is centrifugal; Supernatant reclaims ethanol to without alcohol taste, with the wet HPD-100 macroporous resin adsorption of 10L, first water 50L eluting, then uses 30% concentration ethanol 40L desorption, collects 30% ethanol elution, reclaims ethanol, and drying under reduced pressure, obtains Radix Glycyrrhizae extract.Wherein Radix Glycyrrhizae total saponins content is 73.02%.
Separately get Fructus Aurantii Immaturus 10kg, be ground into coarse powder, with the hydrochloric acid water of 0.5mol/L, soak, spend the night, second day percolation, collects the percolate of 5 times of amounts, upper 001 * 7 cation exchange resin column (2000ml column volume), until percolation liquid level, drop to when equal with post surface, stop standing 2 hours, wash 8L with water, with containing 0.5mol ammonia 30% alcoholic solution 6L eluting, reclaim solvent to dry, obtain Furctus Aurantii Immaturus extract.The content of extract obtained middle total alkaloids is 80%.
By the above-mentioned extract obtained fine powder that is ground into, add lactose appropriate, with the about 400ml wet granulation of 75% ethanol, add magnesium stearate 5g, Pulvis Talci 3g, tabletting, makes the pharmaceutical composition of the tablet that contains 1 part of Furctus Aurantii Immaturus extract and 1 part of Radix Glycyrrhizae extract.
Embodiment 2
Extracting liquorice medical material 10Kg, measures 70% alcohol reflux three times, each 1.5h with 8 times, filter, merge three times extracting solution, reclaim solvent, be concentrated into without alcohol taste, be diluted with water to 20L, centrifugal, the wet HPD-300 macroporous resin adsorption of 8L for supernatant, first water 48L eluting, then use 50% concentration ethanol 40L desorption, collect 50% ethanol elution, reclaim ethanol, drying under reduced pressure, obtains Radix Glycyrrhizae extract.Wherein Radix Glycyrrhizae total saponins content is 78.05%.
Separately get Fructus Aurantii Immaturus 5kg, by 10 times of water gaging reflux, extract, three times, each 1h, filters, merge three times extracting solution, reclaim solvent, be concentrated into relative density 1.15, add ethanol and make it contain alcohol amount to reach 75%, standing over night, filters, filtrate decompression is concentrated into without alcohol taste, is diluted with water to 10L, with the wet D001-CC cationic resin absorption of 8L, first water 40L eluting, then use 1mol/L ammonia spirit 20L desorption, eluent, reclaim solvent, drying under reduced pressure, obtains Furctus Aurantii Immaturus extract.Wherein Fructus Aurantii Immaturus total alkaloid content is 88.04%.
By the above-mentioned extract obtained fine powder that is ground into, PEG6000 is appropriate, and 85 ℃ of meltings, add above-mentioned powder in the PEG6000 of melting with solid dispersion technology, and the 5 ℃ of liquid paraffin of take are coolant, make drop pill.Make the pharmaceutical composition of the drop pill that contains 1 part of Furctus Aurantii Immaturus extract and 2 parts of Radix Glycyrrhizae extracts.
Embodiment 3
Extracting liquorice medical material 10Kg, is ground into coarse powder, extracts three times each 3h with 8 times of amount 0.5% ammonia mercerations, filter, merge three times extracting solution, reclaim solvent, be concentrated into 20L, with 10% sulphuric acid, adjust PH2-3, placement is spent the night, centrifugal, precipitation water makes to dissolve, and adjusts PH6-7, by the wet AB-8 macroporous resin adsorption of 10L, water 40L, 10% ethanol 40L eluting, collect eluent successively, concentrated, drying under reduced pressure, obtains Radix Glycyrrhizae extract.Wherein Radix Glycyrrhizae total saponins content is 80.02%.
Separately get Fructus Aurantii Immaturus 15kg, by 10 times of water gaging reflux, extract, three times, each 1h, filters, merge three times extracting solution, reclaim solvent, be concentrated into relative density 1.15, add ethanol and make it contain alcohol amount to reach 75%, standing over night, filters, filtrate decompression is concentrated into without alcohol taste, is diluted with water to 30L, with the wet D380 resin anion (R.A.) absorption of 10L, first water 40L eluting, then use 0.5mol/L aqueous hydrochloric acid solution 40L desorption, collect eluent, reclaim solvent, drying under reduced pressure, obtains Furctus Aurantii Immaturus extract.Wherein Fructus Aurantii Immaturus total alkaloid content is 68.06%.
By the above-mentioned extract obtained fine powder that is ground into, microcrystalline Cellulose 600g, hyprolose 240g, and micropowder silica gel 30g mix homogeneously, tabletting, makes the pharmaceutical composition of the tablet formulation that contains 1 part of Radix Glycyrrhizae extract and 1.5 parts of Furctus Aurantii Immaturus extracts.
Embodiment 4
Extracting liquorice medical material 1Kg, is ground into coarse powder, with 0.5% ammonia, soaks, spend the night, second day percolation, collects the percolate of 5 times of amounts, with 20% sulphuric acid, adjust PH3-4, placement is spent the night, centrifugal, precipitation water makes to dissolve, and adjusts PH6-7, by the wet DM301 macroporous resin adsorption of 500ml, water 3L, 30% ethanol 3L eluting, collect eluent successively, concentrated, drying under reduced pressure, obtains Radix Glycyrrhizae extract.Wherein Radix Glycyrrhizae total saponins content is 70.02%.
Separately get Fructus Aurantii Immaturus 10kg, be ground into coarse powder, with 10 times of amount 0.5mol/L acetum mercerations, extract three times each 10h, filter, merge three times extracting solution, reclaim solvent, be concentrated into relative density 1.15, add ethanol and make it contain alcohol amount to reach 70%, standing over night, filters, filtrate decompression is concentrated into without alcohol taste, is diluted with water to 30L, with the wet polyamide absorption of 20L, first water 60L eluting, then use 30% ethanol 60L desorption, collect eluent, reclaim solvent, drying under reduced pressure, obtains Furctus Aurantii Immaturus extract.Wherein Fructus Aurantii Immaturus total alkaloid content is 68.06%.
By the above-mentioned extract obtained fine powder that is ground into, dextrin 200g, hyprolose 100g granulates, and makes the pharmaceutical composition of the granule dosage form that contains 1 part of Radix Glycyrrhizae extract and 10 parts of Furctus Aurantii Immaturus extracts.
Embodiment 5
Extracting liquorice medical material 10Kg, with 8 times of amount 60% alcohol reflux three times, each 1h, filters, and merges three times extracting solution, reclaims solvent, is concentrated into relative density 1.10-1.15, and add ethanol and reach approximately 80% to containing alcohol amount, standing 12h is centrifugal; Supernatant reclaims ethanol to without alcohol taste, is diluted with water to 10L, with 20% hydrochloric acid, adjusts PH2-3, precipitation, filters collecting precipitation, water makes to dissolve, and adjusts PH7-8, by the wet D101 macroporous resin adsorption of 15L, first with 60L, wash, use again 20% ethanol 30L desorption, collect eluent, concentrated, drying under reduced pressure, obtains Radix Glycyrrhizae extract.Wherein Radix Glycyrrhizae total saponins content is 85.52%.
Separately get Fructus Aurantii Immaturus 1kg, with 10 times, measure 70% alcohol reflux three times, each 1h, filter, merge three times extracting solution, reclaim solvent, be concentrated into relative density 1.15, be diluted with water to 5L, centrifugal, collect supernatant, adjust PH5-6, with the wet D151 resin absorption of 2L, first water 10L eluting, then use 0.5mol/L hydrochloric acid 30% ethanol 8L desorption, collect eluent, reclaim solvent, spraying is dry, obtains Furctus Aurantii Immaturus extract.Wherein Fructus Aurantii Immaturus total alkaloid content is 75.06%.
By the above-mentioned extract obtained fine powder that is ground into, PVPK30 0g, HPMC 200g mixes, and granulates, and sieves, and tabletting, is dried, and makes the pharmaceutical composition of the slow releasing tablet dosage form that contains 10 parts of Radix Glycyrrhizae extracts and 1 part of Furctus Aurantii Immaturus extract.
Embodiment 6
Extracting liquorice medical material 10Kg, is ground into coarse powder, extracts three times each 3h with 10 times of amount 0.5% ammonia mercerations, filter, merge three times ammonia extraction liquid, reclaim solvent, be concentrated into about 20L, add 10% sulphuric acid and adjust pH value 2-3, standing 12h is centrifugal, collecting precipitation, dissolves and adjusts PH6-7, the AB-8 macroporous resin adsorption that upper 10L is wet by suitable quantity of water, first with 40L, wash, then use 10% concentration ethanol 40L desorption, collect eluent, concentrated, dry, obtain Radix Glycyrrhizae extract.Wherein Radix Glycyrrhizae total saponins content is 80.42%.
Separately get Fructus Aurantii Immaturus 10Kg, by 10 times of water gaging reflux, extract, three times, each 1h, filters, and merges three times extracting solution, reclaims solvent, is concentrated into relative density 1.15-1.20 (60 ℃), and add ethanol and reach approximately 75% to containing alcohol amount, standing 12h is centrifugal; Supernatant reclaims ethanol to without alcohol taste, with the wet D001-CC resin absorption of 5L, first with 30L washing, then uses 1mol/L ammonia desorption, collects eluent, concentrated, dry, obtains Furctus Aurantii Immaturus extract.Wherein Fructus Aurantii Immaturus total alkaloid content is 85.08%.
By the above-mentioned extract obtained fine powder that is ground into, microcrystalline Cellulose 300g, mixes, and uses 80% alcohol granulation, in incapsulating, makes capsule.Make the capsule that contains 1 part of Furctus Aurantii Immaturus extract and 1 part of Radix Glycyrrhizae extract.
Embodiment 7
Extracting liquorice medical material 10Kg, by 10 times of water gaging reflux, extract, three times, each 2h, filters, and merges three times aqueous extract, reclaims solvent, is concentrated into about 10L, and add ethanol and reach approximately 75% to containing alcohol amount, standing 12h is centrifugal; Supernatant reclaims ethanol to without alcohol taste, by the wet HPD-300 macroporous resin adsorption of 10L, first with 90L washing, then uses 50% concentration ethanol 75L desorption, collects 50% ethanol elution, reclaims ethanol, and drying under reduced pressure, obtains Radix Glycyrrhizae extract.Wherein Radix Glycyrrhizae total saponins content is 76.92%.
Separately get Fructus Aurantii Immaturus 4Kg, be ground into coarse powder, use 0.5mol/L soak with hydrochloric acid, spend the night, second day percolation, collects the percolate of 5 times of amounts, the D061 cation exchange resin column that upper 5L is wet, drops to when equal with post surface until percolation liquid level, stops, standing 2 hours, first with 30L washing, then use 0.5mol/L ammonia desorption, collect eluent, concentrated, dry, obtain Furctus Aurantii Immaturus extract.Wherein Fructus Aurantii Immaturus total alkaloid content is 78.05%.
By the above-mentioned extract obtained fine powder that is ground into, vegetable oil 1000g, mixes, and with gelatin, makes capsule casing material, is pressed into soft capsule, makes the soft capsule that contains 1 part of Furctus Aurantii Immaturus extract and 2.5 parts of Radix Glycyrrhizae extracts.
Embodiment 8
Extracting liquorice medical material 10Kg, be ground into coarse powder, with 10 times of amount 0.5% ammonia mercerations, extract three times, each 3h, filters, merge three times ammonia extraction liquid, reclaim solvent, be concentrated into about 20L, add 10% sulphuric acid and adjust pH value 2-3, standing 12h, centrifugal, collecting precipitation, dissolves and adjusts PH6-7 by suitable quantity of water, the AB-8 macroporous resin adsorption that upper 10L is wet, first with 40L, wash, then use 10% concentration ethanol 40L desorption, collect eluent, being condensed into relative density is the thick paste of 1.5 (50 ℃), obtains Radix Glycyrrhizae extract.Wherein Radix Glycyrrhizae total saponins content is 78.72%.
Separately get Fructus Aurantii Immaturus 10Kg, by 10 times of water gaging reflux, extract, three times, each 1h, filters, and merges three times extracting solution, reclaims solvent, is concentrated into relative density 1.15-1.20 (60 ℃), and add ethanol and reach approximately 75% to containing alcohol amount, standing 12h is centrifugal; Supernatant reclaims ethanol to without alcohol taste, with the wet D001-CC resin absorption of 5L, first with 30L washing, then uses 1mol/L ammonia desorption, collects eluent, and being condensed into relative density is the thick paste of 1.4 (50 ℃), obtains Furctus Aurantii Immaturus extract.Wherein Fructus Aurantii Immaturus total alkaloid content is 88.65%.
By above-mentioned extract obtained merging, azone 30g, pressure sensitive adhesive 500g, ethyl acetate 100g mix, and make and are coated with cream liquid, are applied on stretch fabric, and lid lining, cuts, and makes the emplastrum that contains 1 part of Furctus Aurantii Immaturus extract and 1 part of Radix Glycyrrhizae extract.
The test of pesticide effectiveness of embodiment 9 pharmaceutical compositions of the present invention
The curative effect of medicine of the present invention is proved by following pharmacodynamics test: designed Furctus Aurantii Immaturus extract, Radix Glycyrrhizae extract and both different proportioning samples, adopt histamine phosphate induction guinea pig asthmatic model to observe the antiasthmatic effect of Furctus Aurantii Immaturus extract and the different proportionings of Radix Glycyrrhizae extract, determine best proportioning.
(1) experiment material
1, medicine and reagent
(1) Furctus Aurantii Immaturus extract: chocolate brown powder, lot number 090301, according to the method preparation of embodiment 8;
(2) Radix Glycyrrhizae extract: buff powder, lot number 090311, according to the method preparation of embodiment 8;
Before use Fructus Aurantii Immaturus total extract and Radix Glycyrrhizae extract are taken in proportion after different test samples mix and add appropriate tween 80 fully to grind, by purified water, be mixed with the suspension of 100mg/kg, standby.
(3) terbutaline (terbutaline sulphate sheet), lot number 0708040, Wuxi City, Jiangsu Province AstraZeneca pharmaceutical Co. Ltd produces, and is made into before use the suspension of 0.83mg/kg by purified water, standby.
(4) aminophylline injection: lot number 0705223, Tianjin Jin Yao aminoacid company limited produces, specification
2ml：0.25g。By purified water, be made into before use the solution of 200mg/kg, standby
2, animal
Cavia porcellus, male and female dual-purpose, regular grade, is provided by KeYu animal cultivation center, Beijing.The quality certification number: SCXK (capital) 2007-0003.
(2) experimental technique and result
Get to draw and breathe heavily 96 of the qualified Cavia porcelluss of trial test, be divided at random 12 groups, every group 8, male and female half and half, if blank group (giving the normal saline of same volume), positive controls (aminophylline 0.2g/kg), Furctus Aurantii Immaturus extract and Radix Glycyrrhizae extract are by different proportion unitized dose group (giving respectively compositions 100mg/kg), and commercially available matched group (terbutaline 0.83mg/kg), distinguishes gastric infusion (5ml/kg) 1 time by body weight.After administration 1 hour, adopt the method identical with trial test, the incubation period of observing and recording Cavia porcellus generation asthma after administration, (asthma was as the criterion to twitch to fall, 6 minutes persons of keeping one's legs, be designated as 360 seconds incubation period), the prolongation of latency rate of breathing heavily is drawn in calculating, with matched group relatively and carry out statistical procedures.
The impact of the different proportionings of table 1. on histamine phosphate induction Experimental Asthma In Guinea-pigs
Note *: compare P < 0.05 with matched group.△: with comparison P < 0.05 before administration.*: compare P < 0.01 with matched group.△ △: with comparison P < 0.01 before administration
(3) experiment conclusion
Above experimental result shows, the Furctus Aurantii Immaturus extract of different proportionings, Radix Glycyrrhizae extract all have significant antiasthmatic effect.The effect of different compatibility group is better than isodose Furctus Aurantii Immaturus extract or Radix Glycyrrhizae extract, and showing has certain synergism.Wherein, (Furctus Aurantii Immaturus extract: Radix Glycyrrhizae extract) 7: 3 compatibility group best results.
Described now embodiment of the present invention in detail, clearly can do a lot of improvement and variation for a person skilled in the art and can not deviate from essence spirit of the present invention.Within all these changes and improvements are all thought scope of the present invention, its feature is determined by above-mentioned description.
Claims (12)
1. there is antiinflammatory, a pharmaceutical composition for the effect of relievining asthma, it is characterized in that: by traditional Chinese medicine citrus aurantium extract, Radix Glycyrrhizae extract, formed; The extract weight proportioning of two kinds of described medical materials is: 1 part of Furctus Aurantii Immaturus extract, Radix Glycyrrhizae extract 0.1-10 part.
2. a preparation method for the pharmaceutical composition as described in claim l, is characterized in that: Fructus Aurantii Immaturus, Radix Glycyrrhizae, through extracting, refining, are made the preparation that is suitable for various approach medications.
3. preparation method as claimed in claim 2, is characterized in that: described extraction, refiningly comprise following one or several step:
Extract: solvent for use is water or any one lower alcohols, or the mixed solvent that forms by a certain percentage of these solvents, or the acidity or the basic solvent that by these solvents and acid, alkali, salt, are made into; Extracting method is decoction, reflux, supersound extraction, merceration, percolation, microwave extraction, high pressure extract, supercritical extraction;
Filter: comprise centrifugal, sucking filtration, filter pressing, plate filtering method, use or do not use following any clarifier or its combination: precipitate with ethanol agent, the heavy agent of acid, various resins, chitosan and natural clarifying agent; Described natural clarifying agent comprises 101 fruit juice clarifiers, ZTA+1 natural clarifying agent;
Concentrated: to comprise rotary evaporation and decocting and concentrating under normal pressure or reduced pressure, thin film concentration;
Dry: to comprise that vacuum drying, spraying are dried, lyophilization.
4. preparation method as claimed in claim 3, it is characterized in that: when using macroporous adsorbent resin, macroporous resin used is any in nonpolar, low pole, middle polarity, alkalescence or faintly acid and highly acid or strong basicity, and eluant used is water and moisture ethanol, methanol, sour water and aqueous alkali.
5. preparation method as claimed in claim 4, is characterized in that: described macroporous resin is D101, HPD100, DM301, HPD300, HPD500, HPD600, NKA-9, NKA-12,001 * 7,001 * 1, D001-CC, D061, D151, D152, D380,201 * 7, AB-8.
6. preparation method as claimed in claim 5, is characterized in that: described macroporous resin is DM301, HPD100, HPD300, D001-CC.
7. preparation method as claimed in claim 3, it is characterized in that: select nonpolar or low pole macroporous resin AB-8, HPD100, HPD300 as purification resin, sample solution concentration is 0.02-1g/ml, absorption flow velocity 1～5BV/h, resin column blade diameter length ratio 1:6～1:15, applied sample amount is 0.5～10g/ml, 1～4 times of resin volume of water elution carries out remove impurity, with 3～6 times of resin volumes of 30～90% ethanol elution, elution flow rate is 2～4%BV/h.
8. preparation method as claimed in claim 3, it is characterized in that: select strong acid or weakly acidic resin 001 * 7, D001-CC as purification resin, sample solution concentration is 0.05～1g/ml, absorption flow velocity 1～5BV/h, resin column blade diameter length ratio 1:5～1:10, applied sample amount is 0.5～10g/ml, 1～8 times of resin volume of water elution carries out remove impurity, with PH1-12 water or 2～5 times of resin volumes of alcohol eluting, elution flow rate is 2～4%BV/h.
According to described in claim l pharmaceutical composition, it is characterized in that: in described Radix Glycyrrhizae extract, total saponin content is more than 50%.
According to described in claim l pharmaceutical composition, it is characterized in that: in described Furctus Aurantii Immaturus extract, total alkaloid content is more than 50%.
11. pharmaceutical compositions according to claim 1 are in preparation prevention and treat the application in bronchial asthma, chronic obstructive pulmonary disease medicine.
12. pharmaceutical compositions according to claim 1, is characterized in that: make oral, external, injection type.
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