CN102233026A - Pharmaceutical composition and preparation method and application thereof - Google Patents

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

A kind of pharmaceutical composition and its production and use

Technical field

The present invention relates to field of medicaments, especially relate to Chinese medicine Fructus Aurantii Immaturus 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 the world wide.WHO estimates that 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, the 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 air pollution in the global range and ecological deterioration, pathogenesis of asthma rate and mortality rate present the situation that rises year by year.China's asthma sickness rate is about 1%, and the child is about 2%, in the global range, has every year 180000 people of surpassing to die from asthma.Nearly 10 years, the M ﹠ M of asthma was presented the uptrend attitude, and the research of asthma control and new drug worldwide is subjected to paying close attention to widely.

China has 2,000 ten thousand asthma patients and 4,300 ten thousand chronic obstructive pulmonary disease (being called for short COPD) patient approximately, and year death toll has been squeezed body China disease killer prostatitis more than 1,200,000.In the U.S., estimated at 1,600 ten thousand chronic obstructive pulmonary disease patients in 1994, than the nineteen eighty-two more 60%.1993, chronic obstructive pulmonary disease was the 4th big cause of death, reaches 95910 people, surpassed twice in 1979.From 1979-1993, the chronic obstructive pulmonary disease mortality rate has increased almost 50% (from 14%～20%).And account for 3% of crowd more than 15 years old at China's chronic obstructive pulmonary disease, and 80% patients with pulmonary hypertension comes from chronic obstructive pulmonary disease, is one of common refractory disease.Later stage Chang Bingfa pulmonary heart disease, serious harm people ' s health, its disability rate and mortality rate are all very high, have been subjected 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 that chronic obstructive pulmonary disease is the fourth-largest deadly cause of disease in the world at present, but may rise to the third place in the world cause of disease that causes death greatly to the year two thousand twenty.The decline of environmental quality is to cause one of this disease most important reason occurred frequently, and degradation all damages pulmonary to some extent under smoking, dust, chemical contamination, the air quality, causes the generation of chronic obstructive pulmonary disease.Therefore, the morbidity process of how to treat chronic obstructive pulmonary disease early effectively has significant meaning.Thereby the treatment asthma is more and more paid attention to by people and is paid close attention to.Though it is more to treat the medicament categories of asthma at present, the asthmatic medicament of research and development highly effective and safe is still the task of top priority.

Asthma belongs to categories such as " asthma ", " the syndrome of dyspnea ", " phlegm retention " in motherland's medical science.Classical theory of Chinese medical science thinks that the generation of asthma is latent phlegm retaining in the lung, is added with diseases caused by exogenous pathogenic factor, diet, body void and waits factor after being ill, so that due to the stagnation of phlegm air flue, abnormal rising of lung-QI.Modern medicine thinks that asthma is a kind of air flue chronic inflammatory disease of soaking into based on mastocyte reaction, acidophil.Can cause airway reactivity to increase for this inflammation of susceptible person's (especially the spy answers the disease patient), 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 the asthma pathogenic process, the general immunity dysfunction that body produces, outside the release medium such as a large amount of cytokines, inflammatory cell, inflammatory mediator, acidophil also discharges the crystal basic protein in the inflammatory cell, cationic protein, toxic protein, and coup injury airway epithelia such as peroxidase and lung cause that airway hyperreactivity strengthens, and causes the formation of air flue chronic inflammatory disease.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, and is relevant to the abnormal inflammatory reaction of harmful gas 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 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 affecting such as atmospheric pollution and heredity, lung is impaired, coughs repeatedly, expectorant, breathes heavily, the prolonged a kind of disease that does not more cause.The chronic obstructive pulmonary disease morbidity mainly is to attack repeatedly with exopathogen, and viscera function (particularly lung spleen kidney three is dirty) imbalance is closely related.Early stage how owing to impairment of dispersing and descending function of the lung, living in the phlegm-damp, meet to feel drawing and touch latent phlegm, phlegm rising following QI, obstruction of QI due to retention of phlegm, the knot of fighting mutually, the air flue that is jammed, disorder of QI movement, and cause cough, and to cough up phlegm, the cough with asthma QI rising in reverse order is to mark in fact, to show as the domination of pathogen.Lung is attacked by multiple exopathogen for a long time, declares respectful malfunction, and expectorant is turbid to grow internal resistance in lung, and with the passing of time lung qi loses emptyly, 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 stagnates in the heart, and then the lung expansion is full.The deficiency of the lung with the passing of time, illness of child viscera affecting mother one causes dysfunction of the spleen in transportation, indigestion, retention of water-damp in the body, it is turbid to increase the weight of expectorant, expectorant is turbid superior, accumulates and stores in lung, lung qi is jammed.

In the medicine of asthma and chronic obstructive pulmonary disease, a clinical line medication at present is substantially based on Western medicine, first-selected glucocorticoid whole body of Drug therapy commonly used clinically or local application, 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 the prolonged application side effect is obvious, be necessary from Chinese medicine, to seek the strong active drug of specificity.

To asthma, chronic obstructive pulmonary disease, the traditional Chinese medical science is emphasized " take stopgap measures when sending out, effect a permanent cure at ordinary times ", because the asthma morbidity is anxious, how to improve the high response and the airway remodeling of air flue, has proposed higher requirement for vast medical worker.At pathogenesis of asthma characteristics and modern disease pharmacological research achievement, the present invention intends starting with from the height reaction and the airway inflammation that improve air flue, relief of symptoms, and control disease further worsens, and improves patient's quality of life.

Fructus Aurantii Immaturus of the present invention, Radix Glycyrrhizae two flavor medicines are just on the books in Shennong's Herbal.Fructus Aurantii Immaturus cold nature in the side, spleen, stomach warp are gone in bitter in the mouth, suffering, acid.Has the diffusing painful abdominal mass of reducing phlegm, the merit of dispelling the stagnated QI removing food stagnancy.The basic pathology of asthma attack phase is changed to " latent phlegm " and meets sense and draw and touch, and expectorant is assorted with gas, obstruction of QI due to retention of phlegm, and rich mutually knot, the Yong Sai air flue, the lung pipe is narrow, and is unobstructed unfavorable, and lung qi a surname falls not normal, and priming stops the expectorant that amasss, and causes rale as shouting the breath dyspnea with rapid and short breath.The pathological factor of asthma is based on expectorant, and the pathology link during outbreak is that stagnation of phlegm is gas-tight, based on the domination of pathogen, so with dyspnea, conscious exhalation is fast.Reduce phlegm with the Fructus Aurantii Immaturus dispelling the stagnated QI this moment, improves the air flue spasm, thereby reach the effect of eliminating the phlegm, relievining asthma.Modern study shows, alkaloids composition such as Neosynephrine have the effect of expansion bronchus in the Fructus Aurantii Immaturus, adenyl cyclase in can active cell, catalysis ATP is converted into cAMP, cAMP concentration increases in the cell, and then make bronchial smooth muscle keep diastole for a long time, thus improve the reaction of air flue superelevation, increase ventilatory function.

Radix Glycyrrhizae property is flat in the side, and sweet in the mouth is returned 12 warps.Have invigorating the spleen and replenishing QI, grow and to cough lung moistening, the emergency detoxifcation is in harmonious proportion the merit of hundred medicines.Detoxifcation arranged, eliminate the phlegm, pain relieving, spasmolytic and pharmacological action such as anticancer.Modern study shows that Radix Glycyrrhizae has antiinflammatory, antibiotic, antiallergic action, immunomodulating, antiviral activity, has the effect of glucocorticoid sample simultaneously.Monosodium glycyrrhetin has that the stripped guinea pig trachea that antihistamine or acetylcholine are caused is shunk and the 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 the eliminating phlegm and relieving cough effect.Eosinophilic granulocyte's chemotactic and infiltration in bronchoalveolar lavage fluid when ammonium glycyrrhizinate can suppress the Cavia porcellus allergic asthma.Glycyrrhizic acid can reduce NO content and NOS activity in the asthma group mice serum, and the prompting glycyrrhizic acid suppresses NOS activity in the asthma mice serum, reduces NO content, and bronchial asthma is had certain therapeutical effect.

Summary of the invention

The inventor adopts Fructus Aurantii Immaturus and Radix Glycyrrhizae coupling, at expansion bronchus simultaneously, utilize the antiinflammatory action medicine, suppress the gathering and the activation of neutrophilic granulocyte, inhibition mastocyte, eosinophilic granulocyte take off granule, make inflammatory mediator, discharge minimizing as histamine, leukotriene, prostaglandin etc., reduce vascular permeability, reduce and ooze out to alleviate the swelling of air flue, promote the bronchorrhea secretion and increase ciliary movement, reduce the airway hyperreactivity that anaphylactogen causes, improve 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 the diastole bronchus, improve pulmonary function, can suppress the abnormal inflammatory reaction of pulmonary again, stop further developing of its state of an illness harmful gas or deleterious particle.

Purpose of the present invention just provides a kind of pharmaceutical composition that is used to prevent and treat asthma, chronic obstructive pulmonary disease.Described pharmaceutical composition is made up of Radix Glycyrrhizae, Fructus Aurantii Immaturus or their extract.

The present invention also aims to provide a kind of pharmaceutical composition that is used to prevent and treat asthma, chronic obstructive pulmonary disease.Described pharmaceutical composition comprises Radix Glycyrrhizae extract and Furctus Aurantii Immaturus extract, further, in the described Radix Glycyrrhizae extract in total saponins and the Furctus Aurantii Immaturus extract total alkaloids account for the percentage by weight of described pharmaceutical composition between 10～80%.

This pharmaceutical composition can produce synergism, raising evident in efficacy, overcome the deficiency that single Chinese medicine is difficult to satisfy the demand for the treatment of asthma, chronic obstructive pulmonary disease drug combination clinically, avoid medicine simply to mix the side reaction that use may cause, in the control airway inflammation factor, improve the high response of air flue.A kind of better efficacy clinically, convenient Chinese medicine compound compositions 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 singly using with the dosage Furctus Aurantii Immaturus extract or singly using with dosage Radix Glycyrrhizae extract effect and all improve greatly, prove that through pharmacodynamics test it is evident in efficacy.In the control airway inflammation factor, improve the high response of air flue, thereby reach the purpose of treatment asthma, chronic obstructive pulmonary disease.

The purpose of this invention is to provide a kind of pharmaceutical composition for the treatment of diseases such as asthma, chronic obstructive pulmonary disease, said composition contain the Furctus Aurantii Immaturus extract that extracts by the Chinese medicine Fructus Aurantii Immaturus and by the Radix Glycyrrhizae extract that extracts in the Radix Glycyrrhizae as active component.

In the pharmaceutical composition of diseases such as above-mentioned treatment asthma, chronic obstructive pulmonary disease, total alkaloid contents is more than 50% in the described Furctus Aurantii Immaturus extract, and total saponin content is more than 50% in the described Radix Glycyrrhizae extract.

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 that is extracted by Fructus Aurantii Immaturus, the Radix Glycyrrhizae extract 0.1-10 part of being extracted by Radix Glycyrrhizae.Preferably, the weight proportion of two kinds of extracts is in the pharmaceutical composition of the present invention: 1 part of the extract that is extracted by Fructus Aurantii Immaturus, the Radix Glycyrrhizae extract 0.2-8 part of being extracted by Radix Glycyrrhizae.Preferred, the weight proportion of two kinds of extracts is in the pharmaceutical composition of the present invention: 1 part of the Furctus Aurantii Immaturus extract that is 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 prepares with conventional method.For example, can adopt following method preparation: extracting liquorice medical material 10Kg, be ground into coarse powder, extract three times with 10 times of amount 0.5% ammonia mercerations, each 3h filters, and merges three times ammonia extraction liquid, reclaims solvent, be concentrated into about 20L, add 10% sulphuric acid and transfer pH value 2-3, leave standstill 12h, centrifugal, collecting precipitation is with suitable quantity of water dissolving and accent PH6-7, the AB-8 macroporous resin adsorption that last 10L is wet, with the 40L washing, reuse 10% concentration ethanol 40L desorption is collected eluent earlier, concentrate, drying promptly gets Radix Glycyrrhizae extract.

Described Radix Glycyrrhizae extract also can be according to the preparation of following method: extracting liquorice medical material 10Kg, and with 10 times of water gaging reflux, extract, three times, each 2h, filtration, merge three times aqueous extract, reclaim solvent, be concentrated into about 10L, add ethanol to the alcohol amount of containing and reach about 75%, leave standstill 12h, centrifugal; Supernatant reclaims ethanol to there not being the alcohol flavor, and with the wet HPD-300 macroporous resin adsorption of 10L, with the 90L washing, reuse 50% concentration ethanol 75L desorption is collected 50% ethanol elution, reclaims ethanol earlier, and drying under reduced pressure promptly gets Radix Glycyrrhizae extract.

The assay of total saponins in the above-mentioned Radix Glycyrrhizae extract

The preparation of reference substance solution: it is an amount of that precision takes by weighing the monoammonium glycyrrhizinate reference substance, makes the solution that every ml contains 0.10mg with 30% ethanol.

The preparation of need testing solution: precision takes by weighing the about 20mg of this product, puts in the 100ml measuring bottle, adds 30% dissolve with ethanol and is diluted to scale, shakes up promptly.

Algoscopy: accurate respectively reference substance and each 0.5ml of need testing solution of drawing, place 2 bands from plug heart test tube respectively, 70 ℃ of water-baths volatilize, add freshly prepared 5% vanillin-glacial acetic acid solution 0.2ml, perchloric acid 0.8ml is in 55 ℃ of water-bath colour developing 15min, put ice-water bath cooling 2-3min, add glacial acetic acid 5ml and shake up, retinue reagent (vanillin, glacial acetic acid) is done blank, measures trap at the 595nm place.

Another active component Furctus Aurantii Immaturus extract in the present composition can adopt following method to extract from Fructus Aurantii Immaturus: get Fructus Aurantii Immaturus medical material 10Kg, with 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 the alcohol amount of containing and reach about 75%, leave standstill 12h, centrifugal; Supernatant reclaims ethanol to there not being the alcohol flavor, and with the wet D001-CC resin absorption of 5L, with the 30L washing, reuse 1mol/L ammonia desorption is collected eluent, concentrates earlier, and drying promptly gets Furctus Aurantii Immaturus extract.

Described Furctus Aurantii Immaturus extract also can prepare according to following method: get Fructus Aurantii Immaturus medical material 10Kg, be ground into coarse powder, use the 0.5mol/L soak with hydrochloric acid, spend the night, percolation on the secondth is collected the percolate of 5 times of amounts, last D061 cation exchange resin column treats that the percolation liquid level drops to when equal with post surface, stops, left standstill 2 hours, earlier with 30L washing, reuse 0.5mol/L ammonia desorption, collect eluent, concentrate, drying promptly gets Furctus Aurantii Immaturus extract.

The mensuration of total alkaloids (ultraviolet visible spectrophotometry) in the above-mentioned Furctus Aurantii Immaturus extract

The preparation of reference substance solution: it is an amount of that precision takes by weighing the Neosynephrine reference substance, makes the solution that every ml contains 15 μ g with 0.1mol/LNaOH solution, promptly.

The preparation of need testing solution: precision takes by weighing the about 10mg of above-mentioned total alkaloids, puts in the 250ml measuring bottle, with 0.1mol/LNaOH solution dissolving and be diluted to scale, shakes up, promptly.

Algoscopy: getting reference substance and need testing solution respectively, is blank with 0.1mol/LNaOH solution, according to ultraviolet visible spectrophotometry (appendix VA of Chinese Pharmacopoeia version in 2005)), measure trap at 292nm wavelength place, calculate, promptly.

Another object of the present invention has provided the preparation method of drug combination preparation of the present invention, and this method can adopt the conventional method of pharmaceutical field, uses conventional pharmaceutical carrier to carry out.After for example adopting conventional method with Furctus Aurantii Immaturus extract and Radix Glycyrrhizae extract uniform mixing, mix, make various required dosage forms then with carrier or the adjuvant used always on any or more than one pharmaceuticss.Described carrier is excipient, filler, diluent, lubricant, wetting agent, disintegrating agent, surfactant, antiseptic, sweeting agent, aromatic etc. for example.Concrete, described carrier is starch, dextrin, lactose, microcrystalline Cellulose, hydroxypropyl methylcellulose, Polyethylene Glycol, magnesium stearate, micropowder silica gel, glucose, mannitol, xylitol, glycine etc. for example.

As required, pharmaceutical composition of the present invention can be made into the preparation that is suitable for various approach medications, particularly is 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 injecting can be injection, transfusion or powder injection formulation.

When pharmaceutical composition of the present invention was made into the dosage form that is suitable for injecting such as injection or injectable powder, wherein total alkaloid content was more than 80% in the Furctus Aurantii Immaturus extract, and Radix Glycyrrhizae total saponins content is more than 80% in the Radix Glycyrrhizae extract.

Another object of the present invention has provided the application of pharmaceutical composition of the present invention aspect 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 various dosage forms as required, for clinical provide convenient, more effectively, the more controlled modern Chinese medicine of quality, for the patient brings more benefits, thereby produce the huge social benefit.

The specific embodiment

The present invention is described in further detail below in conjunction with the specific embodiment, and the embodiment that provides 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, with 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 and purely measures approximately 75% to containing, and leaves standstill 12h, and is centrifugal; Supernatant reclaims ethanol to there not being the alcohol flavor, and with the wet HPD-100 macroporous resin adsorption of 10L, first water 50L eluting, reuse 30% concentration ethanol 40L desorption is collected 30% ethanol elution, reclaims ethanol, and drying under reduced pressure promptly gets Radix Glycyrrhizae extract.Wherein Radix Glycyrrhizae total saponins content is 73.02%.

Other gets Fructus Aurantii Immaturus medical material 10kg, is ground into coarse powder, with the hydrochloric acid water logging bubble of 0.5mol/L, spend the night, percolation on the secondth is collected the percolate of 5 times of amounts, last 001 * 7 cation exchange resin column (2000ml column volume), treat that the percolation liquid level drops to when equal with post surface, stop, leaving standstill 2 hours, wash 8L with water, with containing 0.5mol ammonia 30% alcoholic solution 6L eluting, reclaim solvent to doing, promptly get Furctus Aurantii Immaturus extract.Total alkaloid contents is 80% in extract obtained.

With the above-mentioned extract obtained fine powder that is ground into, it is an amount of to add lactose, with the about 400ml wet granulation of 75% ethanol, adds magnesium stearate 5g, Pulvis Talci 3g, and 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, being concentrated into does not have the alcohol flavor, is diluted with water to 20L, centrifugal, the HPD-300 macroporous resin adsorption that supernatant wets with 8L, first water 48L eluting, reuse 50% concentration ethanol 40L desorption, collect 50% ethanol elution, reclaim ethanol, drying under reduced pressure promptly gets Radix Glycyrrhizae extract.Wherein Radix Glycyrrhizae total saponins content is 78.05%.

Other gets Fructus Aurantii Immaturus medical material 5kg, and with 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 does not have the alcohol flavor, and thin up is to 10L, with the wet D001-CC cationic resin absorption of 8L, the water 40L of elder generation eluting, reuse 1mol/L ammonia spirit 20L desorption, eluent, reclaim solvent, drying under reduced pressure promptly gets Furctus Aurantii Immaturus extract.Wherein the Fructus Aurantii Immaturus total alkaloid content is 88.04%.

With the above-mentioned extract obtained fine powder that is ground into, PEG6000 is an amount of, and 85 ℃ of fusions add above-mentioned powder among the fused PEG6000 with solid dispersion technology, are coolant with 5 ℃ of liquid paraffin, 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, transfer PH2-3 with 10% sulphuric acid, placement is spent the night, centrifugal, the precipitation water makes dissolving, transfers PH6-7, with the wet AB-8 macroporous resin adsorption of 10L, water 40L, 10% ethanol 40L eluting are collected eluent successively, concentrate, drying under reduced pressure promptly gets Radix Glycyrrhizae extract.Wherein Radix Glycyrrhizae total saponins content is 80.02%.

Other gets Fructus Aurantii Immaturus medical material 15kg, and with 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 does not have the alcohol flavor, and thin up is to 30L, with the wet D380 resin anion (R.A.) absorption of 10L, the water 40L of elder generation eluting, reuse 0.5mol/L aqueous hydrochloric acid solution 40L desorption is collected eluent, reclaim solvent, drying under reduced pressure promptly gets Furctus Aurantii Immaturus extract.Wherein the Fructus Aurantii Immaturus total alkaloid content is 68.06%.

With the above-mentioned extract obtained fine powder that is ground into, microcrystalline Cellulose 600g, hyprolose 240g and micropowder silica gel 30g mix homogeneously, tabletting promptly 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, soaks with 0.5% ammonia, spend the night, percolation on the secondth is collected the percolate of 5 times of amounts, transfer PH3-4 with 20% sulphuric acid, placement is spent the night, and is centrifugal, the precipitation water makes dissolving, transfers PH6-7, with the wet DM301 macroporous resin adsorption of 500ml, water 3L, 30% ethanol 3L eluting are collected eluent successively, concentrate, drying under reduced pressure promptly gets Radix Glycyrrhizae extract.Wherein Radix Glycyrrhizae total saponins content is 70.02%.

Other gets Fructus Aurantii Immaturus medical material 10kg, is ground into coarse powder, extracts each 10h three times with 10 times of amount 0.5mol/L acetum mercerations, 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 does not have the alcohol flavor, and thin up is to 30L, with the wet polyamide absorption of 20L, the water 60L of elder generation eluting, reuse 30% ethanol 60L desorption is collected eluent, reclaim solvent, drying under reduced pressure promptly gets Furctus Aurantii Immaturus extract.Wherein the Fructus Aurantii Immaturus total alkaloid content is 68.06%.

With the above-mentioned extract obtained fine powder that is ground into, dextrin 200g, hyprolose 100g granulates, and promptly makes the granule forms of pharmaceutical compositions 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, adds ethanol and measures and reach about 80% to containing alcohol, leaves standstill 12h, and is centrifugal; Supernatant reclaims ethanol to there not being the alcohol flavor, is diluted with water to 10L, transfers PH2-3 with 20% hydrochloric acid, precipitation is filtered collecting precipitation, water makes dissolving, transfers PH7-8, with the wet D101 macroporous resin adsorption of 15L, wash with 60L earlier, reuse 20% ethanol 30L desorption is collected eluent, concentrates, drying under reduced pressure promptly gets Radix Glycyrrhizae extract.Wherein Radix Glycyrrhizae total saponins content is 85.52%.

Other gets Fructus Aurantii Immaturus medical material 1kg, measures 70% alcohol reflux three times, each 1h with 10 times, filter, merge three times extracting solution, reclaim solvent, be concentrated into relative density 1.15, thin up is to 5L, and is centrifugal, collect supernatant, transfer PH5-6, with the wet D151 resin absorption of 2L, the water 10L of elder generation eluting, reuse 0.5mol/L hydrochloric acid 30% ethanol 8L desorption is collected eluent, reclaim solvent, spray drying promptly gets Furctus Aurantii Immaturus extract.Wherein the Fructus Aurantii Immaturus total alkaloid content is 75.06%.

With the above-mentioned extract obtained fine powder that is ground into, polyvinylpyrrolidone 300g, HPMC 200g mixing is granulated, sieves, tabletting, drying promptly 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 transfer pH value 2-3, leave standstill 12h, centrifugal, collecting precipitation is with suitable quantity of water dissolving and accent PH6-7, the AB-8 macroporous resin adsorption that last 10L is wet, with the 40L washing, reuse 10% concentration ethanol 40L desorption is collected eluent earlier, concentrate, drying promptly gets Radix Glycyrrhizae extract.Wherein Radix Glycyrrhizae total saponins content is 80.42%.

Other gets Fructus Aurantii Immaturus medical material 10Kg, and with 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 ℃), adds ethanol and measures and reach about 75% to containing alcohol, leaves standstill 12h, and is centrifugal; Supernatant reclaims ethanol to there not being the alcohol flavor, and with the wet D001-CC resin absorption of 5L, with the 30L washing, reuse 1mol/L ammonia desorption is collected eluent, concentrates earlier, and drying promptly gets Furctus Aurantii Immaturus extract.Wherein the Fructus Aurantii Immaturus total alkaloid content is 85.08%.

With the above-mentioned extract obtained fine powder that is ground into, microcrystalline Cellulose 300g, mixing is used 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, with 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 and reaches about 75% to containing pure measuring, and leaves standstill 12h, and is centrifugal; Supernatant reclaims ethanol to there not being the alcohol flavor, and with the wet HPD-300 macroporous resin adsorption of 10L, with the 90L washing, reuse 50% concentration ethanol 75L desorption is collected 50% ethanol elution, reclaims ethanol earlier, and drying under reduced pressure promptly gets Radix Glycyrrhizae extract.Wherein Radix Glycyrrhizae total saponins content is 76.92%.

Other gets Fructus Aurantii Immaturus medical material 4Kg, is ground into coarse powder, uses the 0.5mol/L soak with hydrochloric acid, spend the night, percolation on the secondth is collected the percolate of 5 times of amounts, the D061 cation exchange resin column that last 5L is wet treats that the percolation liquid level drops to when equal with the post surface, stops, left standstill 2 hours, earlier with 30L washing, reuse 0.5mol/L ammonia desorption, collect eluent, concentrate, drying promptly gets Furctus Aurantii Immaturus extract.Wherein the Fructus Aurantii Immaturus total alkaloid content is 78.05%.

With the above-mentioned extract obtained fine powder that is ground into, vegetable oil 1000g, mixing is made capsule casing material with gelatin, 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 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 transfer pH value 2-3, leave standstill 12h, centrifugal, collecting precipitation is with suitable quantity of water dissolving and accent PH6-7, the AB-8 macroporous resin adsorption that last 10L is wet is earlier with 40L washing, reuse 10% concentration ethanol 40L desorption, collect eluent, being condensed into relative density is the thick paste of 1.5 (50 ℃), promptly gets Radix Glycyrrhizae extract.Wherein Radix Glycyrrhizae total saponins content is 78.72%.

Other gets Fructus Aurantii Immaturus medical material 10Kg, and with 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 ℃), adds ethanol and measures and reach about 75% to containing alcohol, leaves standstill 12h, and is centrifugal; Supernatant reclaims ethanol to there not being the alcohol flavor, and with the wet D001-CC resin absorption of 5L, with the 30L washing, reuse 1mol/L ammonia desorption is collected eluent earlier, and being condensed into relative density is the thick paste of 1.4 (50 ℃), promptly gets Furctus Aurantii Immaturus extract.Wherein the Fructus Aurantii Immaturus total alkaloid content is 88.65%.

With above-mentioned extract obtained merging, azone 30g, pressure sensitive adhesive 500g, ethyl acetate 100g mixing are made and are coated with cream liquid, are applied on the elastic force cloth, and the lid lining is cut, 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 to induce 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 is according to the method preparation of embodiment 8;

(2) Radix Glycyrrhizae extract: buff powder, lot number 090311 is according to the method preparation of embodiment 8;

Face with preceding and Fructus Aurantii Immaturus total extract and Radix Glycyrrhizae extract are taken by weighing different test samples in proportion mix the back and add an amount of tween 80 and fully grind, be mixed with the suspension of 100mg/kg with purified water, standby.

(3) terbutaline (terbutaline sulphate sheet), lot number 0708040, AstraZeneca pharmaceutical Co. Ltd in Wuxi City, Jiangsu Province produces, and faces with preceding to be made into the suspension of 0.83mg/kg with purified water, and is standby.

(4) aminophylline injection: lot number 0705223, Tianjin gold credit aminoacid company limited is produced specification

2ml：0.25g。Face with preceding and be made into the solution of 200mg/kg with purified water, standby

2, animal

Cavia porcellus, the male and female dual-purpose, regular grade is provided by Beijing section space animal cultivation center.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 into 12 groups at random, every group 8, male and female half and half, if blank group (giving normal saline), positive controls (aminophylline 0.2g/kg) with volume, Furctus Aurantii Immaturus extract and Radix Glycyrrhizae extract are by different proportion unitized dose group (giving compositions 100mg/kg respectively), and commercially available matched group (terbutaline 0.83mg/kg) is pressed body weight difference gastric infusion (5ml/kg) 1 time.After administration 1 hour, adopt the method identical with trial test, observe and the record administration after Cavia porcellus (asthma is fallen with tic and is as the criterion incubation period that asthma takes place, 6 minutes persons of keeping one's legs, be designated as 360 seconds incubation period), calculate and to draw the prolongation of latency rate of breathing heavily, with matched group relatively and carry out statistical procedures.

The different proportionings of table 1. are induced the influence of Cavia porcellus asthma to histamine phosphate

Annotate *: compare P＜0.05 with matched group.△: with comparison P＜0.05 before the administration.*: compare P＜0.01 with matched group.△ △: with comparison P＜0.01 before the administration

(3) experiment conclusion

Above experimental result shows that 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 embodiment of the present invention now 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.All these changes and improvements think all within the scope of the present invention that its feature is determined by above-mentioned description.

Claims (12)

1. a pharmaceutical composition is characterized in that being made up of Chinese medicine Fructus Aurantii Immaturus, Radix Glycyrrhizae.

2. pharmaceutical composition according to claim 1, the weight proportion of wherein said two kinds of medical materials is: Fructus Aurantii Immaturus 1-10 part, Radix Glycyrrhizae 0.1-100 part.

3. pharmaceutical composition according to claim 2, the weight proportion of wherein said two kinds of medical materials is preferably: Fructus Aurantii Immaturus 5-10 part, Radix Glycyrrhizae 0.2-10 part.

4. pharmaceutical composition according to claim 3, the weight proportion of wherein said two kinds of medical materials be more preferably: Fructus Aurantii Immaturus 5-8 part, Radix Glycyrrhizae 0.4-5 part.

5. pharmaceutical composition according to claim 1, compound recipe is prepared to a kind of dosage form for approving on the pharmaceutics through extracting, making with extra care, and can be made into the preparation that is suitable for various approach medications.

6. extraction as claimed in claim 5, refining is characterized in that, when these methods of use are prepared, comprises following one or several step:

Extract: solvent for use can be water or any one lower alcohols, or the mixed solvent formed by a certain percentage of these solvents, or the acidity or the basic solvent that are made into by these solvents and acid, alkali, salt; Extracting method can be decoction, reflux, supersound extraction, merceration, percolation, microwave extraction, high pressure extract, supercritical extraction etc.;

Filter: comprise methods such as centrifugal, sucking filtration, filter pressing, plate filter, use or do not use following any clarifier or its combination: the precipitate with ethanol agent, the acid precipitation agent, various resins, chitosan and natural clarifying agent are as 101 fruit juice clarifiers, ZTA+1 natural clarifying agent etc.;

Concentrate: comprise rotary evaporation and decocting and concentrating under normal pressure or the reduced pressure, thin film concentration etc.

Dry: as to comprise vacuum drying, spray drying, lyophilization etc.

7. method for preparing extractive as claimed in claim 6, it is characterized in that when using macroporous adsorbent resin, used macroporous resin can be nonpolar, low pole, middle polarity, any types such as alkalescence or faintly acid and highly acid or strong basicity, as D101, HPD100, DM301, HPD300, HPD500, HPD600, NKA-9, NKA-12,001 * 7,001 * 1, D001-CC, D061, D151, D152, D380,201 * 7 etc., DM301 preferably wherein, HPD100, HPD300, D001-CC etc., used eluant are water and aqueous ethanol, methanol, sour water and aqueous alkali.

8. method for preparing extractive as claimed in claim 6, it is characterized in that: select for use nonpolar or low pole macroporous resin such as AB-8, HPD100, HPD300 as the purification resin, sample solution concentration is 0.02-1g/ml (in the crude drug amount), absorption flow velocity 1～5BV/h, resin column blade diameter length ratio 1: 6～1: 15, applied sample amount is 0.5～10g/ml (in the crude drug amount), 1～4 times of resin volume of water elution carries out remove impurity, with 3～6 times of resin volumes of 30～90% ethanol elutions, elution flow rate is 2～4%BV/h.

9. method for preparing extractive as claimed in claim 6, it is characterized in that: select 001 * 7 for use, strong acid such as D001-CC or weakly acidic resin are as the purification resin, sample solution concentration is 0.05～1g/ml (in the crude drug amount), absorption flow velocity 1～5BV/h, resin column blade diameter length ratio 1: 5～1: 10, applied sample amount is 0.5～10g/ml (in the crude drug amount), 1～8 times of resin volume of water elution carries out remove impurity, and with PH1-12 water or 2～5 times of resin volumes of pure eluting, elution flow rate is 2～4%BV/h.

10. pharmaceutical composition according to claim 1 is characterized in that: Radix Glycyrrhizae total saponins that contains in the extract and Fructus Aurantii Immaturus total alkaloids are more than 50% of gross weight.

11. the application of pharmaceutical composition according to claim 1 in preparing prevention and treatment bronchial asthma, chronic obstructive pulmonary disease medicine.

12. pharmaceutical composition according to claim 1 can be made into oral, external, injection type.