Summary of the invention
Technical problem to be solved by this invention is to provide a kind of quality of the pharmaceutical preparations stable according to Chinese medical theory, and determined curative effect, safety are convenient to deposit and the treatment respiratory tract infection used and the Chinese medicine Jing Yin preparation of viral influenza.
The Chinese medicine preparation of treatment respiratory tract infection disclosed by the invention and viral influenza is to be the oral formulations that active component is made with Herba Schizonepetae, Flos Lonicerae, Ilex purpurea Hassk.[I.chinensis Sims, Herba Houttuyniae, Folium Isatidis, Herba Taraxaci, Radix Saposhnikoviae, Fructus Arctii and Radix Glycyrrhizae, and wherein the percentage by weight of each raw material of active component is formed preferred Herba Schizonepetae 3-11%, Flos Lonicerae 3-11%, Ilex purpurea Hassk.[I.chinensis Sims 11-21%, Herba Houttuyniae 11-21%, Folium Isatidis 11-21%, Herba Taraxaci 11-21%, Radix Saposhnikoviae 3-11%, Fructus Arctii 3-11% and Radix Glycyrrhizae 2-8%.
Each active raw materials of the present invention is extracted the acquisition extract through suitable solvent, makes various medically acceptable various peroral dosage forms with pharmaceutic adjuvant, comprises granule, capsule, oral liquid or tablet etc., measures the content of protocatechualdehyde in the preparation with HPLC.
Another technical problem to be solved by this invention is to disclose the preparation method of the Chinese medicine preparation of above-mentioned treatment respiratory tract infection and viral influenza.
The preparation of Chinese medicine preparation of the present invention specifically comprises:
Directly each active raw materials water or alcohol are decocted extraction acquisition concentrated extract, make various preparations according to a conventional method.
Preferable method is to extract earlier the volatile oil of Herba Schizonepetae or Flos Lonicerae, will extract then that other medical materials of respectively distinguishing the flavor of merge in residue and the prescription behind the volatile oil, concentrates acquisition extractum after water or the alcohol extraction; The volatile oil that from Herba Schizonepetae, extracts can be directly or with behind the cyclodextrin inclusion technique enclose with extract extractum and pharmaceutic adjuvant and make various preparations according to a conventional method.
Preferred each formulation preparation method of the present invention comprises:
(1) preparation of mixture
Get the medicinal component of recipe quantity and add extraction solvent decoction secondary, collecting decoction filters, and filtrate concentrating made.
(2) preparation of oral liquid
Get the Herba Schizonepetae and the Flos Lonicerae of recipe quantity and extract volatile oil, the aqueous solution after distillation device is in addition collected.
Herba Schizonepetae behind the extraction volatile oil and Flos Lonicerae medicinal residues and the medicinal component of remaining recipe quantity add extraction solvent and decoct secondary, collecting decoction, filter, filtrate concentrates, and adds precipitant, place, get supernatant and filter, concentrate aqueous precipitation, filter, concentrate, aqueous solution, correctives and antiseptic after adding volatile oil and distilling are made oral liquid according to a conventional method.
(3) solid preparation preparation
A. extract volatile oil: the Herba Schizonepetae of getting recipe quantity is extracted volatile oil, and other puts; Or with volatile oil cyclodextrin inclusion technique enclose, place, filter, washing, drying makes the cyclodextrin clathrate that contains Herba Schizonepetae volatile oil;
B. get the medicinal component of recipe quantity except that Herba Schizonepetae, add the residue after Herba Schizonepetae is extracted volatile oil, add extraction solvent and decoct secondary, collecting decoction filters, and filtrate concentrates, and adds precipitant, and placement is spent the night, and gets supernatant and makes clear paste;
C. get step B and make clear paste and pharmaceutic adjuvant, contain Herba Schizonepetae volatile oil cyclodextrin clathrate mix homogeneously, make granule, capsule or tablet according to a conventional method;
Or get that step B makes clear paste and the pharmaceutic adjuvant mix homogeneously is made granule, or the drying technology makes fine powder, sprays into Herba Schizonepetae volatile oil, makes solid preparation according to a conventional method.
Extraction solvent of the present invention is selected from the alcoholic solution of water or 30-90%.
Precipitant of the present invention is the 75-95% alcoholic solution.
Pharmaceutic adjuvant of the present invention is a pharmaceutic adjuvant commonly used in the preparation.
Herba Schizonepetae volatile oil cyclodextrin inclusion technique of the present invention can be saturated water solution method (electronic paddling process, ultrasonic method, high speed tissue are smashed method to pieces), polishing, liquid-liquid method, wherein used enclose material is a cyclodextrin, comprises beta-schardinger dextrin-or hydroxypropyl.
Essential oil extraction method of the present invention comprises steam distillation or super critical extraction.
Dry technology of the present invention comprises vacuum drying, spray drying and Freeze Drying Technique.
A technical problem more to be solved by this invention is to disclose the application of above-mentioned preparation in preparation treatment respiratory tract infection and viral influenza medicine.
It is the respiratory tract infection and the viral influenza of primary symptom with heating, aversion to wind, pharyngalgia, cough that Chinese medicine preparation of the present invention is specially adapted to treat the wind and heat in the lung meridian card.
Oral each dosage is the preparation that contains protocatechualdehyde 0.6-2.6mg, and obey 2-3 every day.
The active component prescription is got the meaning of Lonicerae and Forsythiae Powder in the preparation of the present invention, relieving the exterior syndrome with drugs of pungent in flavor and cool in nature, and heat-clearing and toxic substances removing, and overweight heat clearing away.
Epidemic febrile disease from the beginning of, evil defending branch, harmony is in throat on the wind heat, Lung Qi obstraction is felt in pathogenic warmth, so the disease of heating, pharyngalgia, cough is arranged, the wind person dredges it, disease with heat symptoms should be treated by cooling, controlling should the dispelling wind expelling pathogenic factors from the exterior, heat-clearing and toxic substances removing.
Herba Schizonepetae, Flos Lonicerae are monarch drug in the side, and the hot temperature of Herba Schizonepetae is discongested, and is warm and not dry, goes into lung liver two warps, for controlling the principal agent of pathogenic wind-warm.Compendium of Material Medica records: " loose wind heat, refresh oneself, throat, clear scar of Herba Schizonepetae swells, controls stiffness of the nape." Zhang Shanlei also says: " and Herba Schizonepetae little suffering of distinguishing the flavor of, and band fragrance, its gas is very clear, and matter lightly floats again, and the heat of leaking informaton, can be let out lung-heat and reaches fur last all diseases at table, and the cough due to pathogenic wind-heat be shoulded it, and wind heat headache due to invasion of exogenous pathogens cold and heat also are principal agents." Flos Lonicerae sweet in the mouth cold in nature, go into lung, stomach, the heart, spleen channel, heat-clearing and toxic substances removing has a surname's expelling pathogenic factors from the exterior that looses again, and not only clearing heat in QI system, but also the branch heat that can purify the blood also can be induced sweat.The Compendium of Material Medica record: " it is swollen that Flos Lonicerae cures mainly the cold and heat body, all toxic swellings, heat radiation detoxifcation." be the key medicine of heat-clearing and toxic substances removing, its main component is chlorogenic acid chemical compound, flavonoid and xylostein etc.Modern pharmacological research proof Flos Lonicerae antibacterial range is bigger, and Gram-positive, negative bacterium are all had inhibitory action, and Respirovirus such as influenza Asia first type, dust arc virus (ECHO 11) and herpesvirus are all had certain inhibitory action.Prescription is equipped with the merit that Radix Saposhnikoviae helps the Herba Schizonepetae dispelling wind to relieve the exterior syndrome, but power relaxes, and makes slight perspiration and heat is moved back it, and Li Gao is referred to as meaning: " the profit agent also in the wind." more being equipped with Folium Isatidis, Ilex purpurea Hassk.[I.chinensis Sims, Herba Taraxaci, dosage is heavier, focuses in heat-clearing and toxic substances removing, and the heat of lung heat clearing is to be ministerial drug, and assistant is with Herba Houttuyniae, Fructus Arctii dispersing lung-QI and dissipating phlegm, resolving toxin and disinhibiting the throat.Radix Glycyrrhizae detoxifcation and in, coordinating the actions of various ingredients in a prescription is messenger drug for it.
Above-mentioned each medicine side of being combined into has the dispelling wind expelling pathogenic factors from the exterior, heat-clearing and toxic substances removing, and the merit of lung qi dispersing sore-throat relieving is used for the treatment of anemopyretic cold and violates heating, pharyngalgia, cough due to exterior syndrome and the wind-warm lung-heat disease syndrome of wind-heat invading lung.The hot cold of prescription is then flat, and bitter cold is then fallen, and tool is made a distinction between the important and the lesser one, treating both the principal and secondary aspects of a disease, eliminating evil and do not hinder positive characteristics.
With the pharmacodynamics test that Chinese medicine preparation of the present invention (Jing Yin granule) has carried out relevant antivirus test and preventing respiratory infection, the result is as follows:
1. antivirus test
1.1. extracorporeal antivirus effect test
1.1.1. toxicity test to the Hep-2 cultured cell
Observe by toxicity test, two kinds of dilution Jing Yin granule medicinal liquid cell growth of 0.85mg/ml, 1.70mg/ml do not have obvious influence, make antivirus test usefulness so get these two kinds of dilution medicinal liquids.
1.1.2. influence to the pathological changes caused by virus effect
Be subjected to examination virus: parainfluenza-1, RSV, CoxB
4, CoxB
5, CoxB
6, ADV
3, ADV
7, HSV-I, HSV-II.
Table 1 Jing Yin granule is to the influence of pathological changes caused by virus effect
Virus-virus azoles Jing Yin granule
0.125mg/ml 0.85mg/ml 1.70mg/ml
Parainfluenza-1 ++++
RSV ++ ++ ++
CoxB
4 + - +
CoxB
5 + + +
CoxB
6 + + +
ADV
3 + + +
ADV
7 + + +
HSV-I + + ++
HSV-II + + +
The result as seen, the Jing Yin granule all has stronger inhibitory action to 9 kinds of viruses of try, in institute's amount of reagent (0.85mg/ml, 1.70mg/ml) scope, inhibition strength is suitable with the positive control drug virazole, not only 5 kinds of RNA viruses institute cytopathogenic effects such as RSV there is in various degree inhibitory action, and to ADV
3Etc. the caused cytopathic effect of DNA viruses the obvious suppression effect is also arranged, show that the particulate antivirus action of Jing Yin is wider.
1.2. the interior effect of body to influenza virus
1.2.1. effect to mice influenza virus property pneumonia
The influence that table 2 Jing Yin granule becomes pneumonopathy due to the mouse infection influenza virus
Group dosage Mus is counted lung exponential quantity suppression ratio
The P value
(g/kg/d) (only) (M ± S) (I%)
Virus control--11 1.58 ± 0.23
Normal control--11 1.00 ± 0.12
Virazole 0.07 11 1.08 ± 0.14 31.34<0.01
Jing Yin granule 5.0 10 1.23 ± 0.13 22.14<0.01
10.0 9 1.30±0.18 17.83 <0.01
With 5,10g/kg/d irritates the stomach mice, can significantly alleviate the lung index of infecting mouse, because influenza infection causes pneumonia, along with the infiltration of inflammation, ooze out, lung weight increased, the lung exponential quantity raises.The size of lung weight has reflected the order of severity of pneumonia, and the Jing Yin granule can significantly reduce the lung index of infecting mouse, shows the degree that can alleviate pneumonia due to the influenza virus.
1.2.2. influence to proliferation of influenza virus amount in the mouse lung
Table 3 Jing Yin granule is to the influence of proliferation of influenza virus amount in the mouse lung
Dosage Mus number is checked positive positive rate suppression ratio
Group P value
(g/kg/d) (M ± S) (%) (I%) for (only) total number
Virus control 0.00 9 329 226 68.97 ± 3.90
Virazole 0.07 9 302 139 46.02 ± 6.80 33.27<0.01
Jing Yin granule 5.0 9 213 118 55.53 ± 4.64 19.49<0.01
10.0 9 191 104 54.45±2.95 20.37 <0.01
Table 3 is the result show, the Jing Yin granule in institute's amount of reagent scope to mouse lung in the proliferation of influenza virus amount significant inhibitory effect is all arranged.
Above internal and external test shows that the Jing Yin granule has good antivirus action, and dying for clinical treatment respirovirus sexuality provides pharmacological basis.
2. in-vitro antibacterial test
2.1. tube dilution method
With the positive contrast medicine of SHUANGHUANGLIAN KELI, testing drug is to staphylococcus aureus, colon bacillus, staphylococcus epidermidis, A group streptococcus, the antibacterial action of Klebsiella Pneumoniae, clostridium perfringen.
Jing Yin granule and SHUANGHUANGLIAN KELI 50mg/ml do not have antibiotic effect to colon bacillus, clostridium perfringen, three kinds of gram negative bacterias of Klebsiella Pneumoniae.These two kinds of medicines are identical to the staphylococcic MIC of epidermis, are 20mg/ml.The Jing Yin granule is 20mg/ml to the MIC of staphylococcus aureus, is lower than the 50mg/ml of SHUANGHUANGLIAN KELI.The Jing Yin granule suppresses the growth of A group streptococcus when 50mg/ml, and SHUANGHUANLIAN when this concentration to A group streptococcus unrestraint effect.Prompting Jing Yin granule slightly is better than SHUANGHUANGLIAN KELI to the antibacterial action of staphylococcus aureus and A group streptococcus.
2.2. serum method
With SHUANGHUANGLIAN KELI and the positive contrast medicine of cefalexin, testing drug is to staphylococcus aureus, colon bacillus, A group streptococcus, the antibacterial action of Klebsiella Pneumoniae.
Clothes Jing Yin granule rabbit anteserum, clothes SHUANGHUANGLIAN KELI rabbit anteserum and normal control rabbit anteserum all do not have antibiotic effect in each concentration to colon bacillus and Klebsiella Pneumoniae.Staphylococcus aureus and A group streptococcus are grown in containing the culture medium of normal rabbit serum in the culture medium control tube that does not more contain serum for few, and clothes Jing Yin granule rabbit anteserum kimonos SHUANGHUANGLIAN KELI rabbit anteserum makes being grown in of these 2 kinds of antibacterials grow still less or not grow than normal serum in the higher culture medium of concentration, and prompting has certain inhibitory action.The cefalexin rabbit anteserum all is utmost point significant inhibitory effect to 4 kinds of antibacterials being tried.
3. immunity test
Heavy dose of group of Jing Yin granule and middle dosage group can significantly improve the phagocytic percentage and the phagocytic index (P<0.05) of Turnover of Mouse Peritoneal Macrophages.Point out this medicine that the mice non-specific immunity is had certain potentiation.
4. antiinflammatory test
The effect of ear swelling due to the anti-dimethylbenzene of table 4 Jing Yin granule
Group number of animals swelling rate
(a)
Normal control group 10 1.660 ± 0.184
Positive controls 10 1.341 ± 0.239
*
Jing Yin small dose group 10 1.296 ± 0.203
*
And dosage group 10 1.378 ± 0.360 in the silver
*
The heavy dose of group 10 1.466 ± 0.220 of Jing Yin
*
(a) swelling rate=(cause scorching ear weigh-do not cause scorching ear heavy)/do not cause scorching ear is heavy
*P<0.05
**P<0.0?1
The large, medium and small dosage group of Jing Yin granule all has the effect of anti-dimethylbenzene induced mice auricle edema, wherein the effect of small dose group is remarkable, compared highly significant difference (P<0.01) with physiology eye water group, big or middle dosage group compares with the normal saline group that also there were significant differences (P<0.05).
5. cough-relieving test
The method of coughing is drawn in the Cavia porcellus mechanical stimulus: the codeine group has significant antitussive effect, and effect is fast and lasting.Suppress on the percentile numerical value from cough, each dosage group of Jing Yin has cough-relieving trend, little, the heavy dose of group of Jing Yin 30min after medication wherein, and the heavy dose of group of Jing Yin is at 60min, and its cough suppresses percentage rate and compares with the normal control group that there were significant differences (P<0.05).
Carry out relevant toxicity test with preparation of the present invention:
1. acute toxicity: the maximum tolerated dose that the Jing Yin preparation is irritated the stomach mice is crude drug 200g/kg.
2. long term toxicity test: give SD rats gavaged Jing Yin preparation (extractum), establish high, medium and low three dosage groups and matched group, be equivalent to crude drug 6g, 25g, 100g/kg respectively, maximum dose level is 60 times of clinical dosage.Matched group gives normal feedstuff.The administration cycle: once a day, continuous one month, observed for two weeks after the drug withdrawal.Observe general situation every day, measure body weight and food-intake weekly.Rat is movable from start to finish normal as a result, any symptom or death do not occur.Administration end and convalescent period, the blood of animal, serum biochemistry, uroscopy all took place significantly to change when stopping, and each organ weights and coefficient are not also seen tangible tendency variation; Histopathologic examination, no significant difference between medication group and matched group is not also seen the specificity pathological change relevant with empirical factor.
Conclusion: prompting Jing Yin preparation is safe in utilization.
By the diagnostic criteria of dialectical standard of traditional Chinese medical science wind and heat in the lung meridian disease and doctor trained in Western medicine upper respiratory tract infection (flu), carry out clinical research with Jing Yin granule and Jing Yin mixture to going into to organize patient, every group 30 example, the result shows as follows:
Jing Yin granule therapy upper respiratory tract infection (wind and heat in the lung meridian card) obvious effective rate 66.67%, total effective rate 96.67%, Jing Yin mixture obvious effective rate 63.33%, total effective rate 96.67% compares with SHUANGHUANGLIAN KELI, all no difference of science of statistics.Studies show that the upper respiratory tract infection determined curative effect of Jing Yin preparation for treating wind and heat in the lung meridian card is reliable, and certain antivirus action is arranged.Safety evaluatio explanation, Jing Yin preparation be to liver, renal function, routine blood test, and routine urinalysis and stool routine have no adverse reaction, and erythra and anaphylaxis do not appear in 60 routine test patients.
Prompting Jing Yin preparation is clinical safe in utilization effective.
The specific embodiment
The preparation of embodiment 1 Jing Yin mixture
Get Herba Schizonepetae 14kg, Flos Lonicerae 15kg, Ilex purpurea Hassk.[I.chinensis Sims 30kg, Herba Houttuyniae 30kg, Folium Isatidis 30kg, Herba Taraxaci 20kg, Radix Saposhnikoviae 14kg, Fructus Arctii 9kg and Radix Glycyrrhizae 6kg, adding water 1680L decocted 20 minutes, be total to secondary, collecting decoction filters, and concentrates, with sucrose 10kg, ethylparaben 0.1kg, sodium benzoate 0.6kg, adjust volume to 200L, packing, sterilization is promptly.
The preparation of embodiment 2 Jing Yin oral liquids
1. get Herba Schizonepetae 21kg, Flos Lonicerae 12kg extracts Aromatic water with steam distillation, other puts.
2. get step 1 medicinal residues and Ilex purpurea Hassk.[I.chinensis Sims 20kg, Herba Houttuyniae 25kg, Folium Isatidis 30kg, Herba Taraxaci 30kg, Radix Saposhnikoviae 17kg, Fructus Arctii 10kg and Radix Glycyrrhizae 6kg, add 65% ethanol extraction secondary, each 40 minutes, merge secondary raffinate, reclaim ethanol, being concentrated into relative density is the clear paste of 1.06-1.08 (90 ℃), adds ethanol and makes and contain alcohol amount to 60%, and cold preservation is more than 48 hours, reclaim ethanol and be concentrated into and do not have the alcohol flavor, thin up is to 120L, and cold preservation filtered more than 48 hours, in filtrate, add Herba Schizonepetae and Flos Lonicerae Aromatic water, stevioside, sorbic acid, Fructus Citri Limoniae essence, add water and adjust volume to 200L, embedding, sterilization, promptly.
The particulate preparation of embodiment 3 Jing Yin
1. get Herba Schizonepetae 420g and add 3000ml water, extract volatile oil with steam distillation, must about 2.5ml Herba Schizonepetae volatile oil, the aqueous solution after distillation device is in addition collected.
2. take by weighing beta-schardinger dextrin-20g, adding distil water 400ml heating for dissolving slowly adds Herba Schizonepetae oil, restir 1.5h while stirring in the time of 40 ℃, leave standstill, cold preservation 24h filters, and uses the washing with alcohol filtering residue, dry,, get Herba Schizonepetae volatile oil Benexate Hydrochloride 14g at 60 ℃ of dry 2h.
3. get step 1 medicinal residues and Flos Lonicerae 700g, Ilex purpurea Hassk.[I.chinensis Sims 1400g, Herba Houttuyniae 1400g, Folium Isatidis 1400g, Herba Taraxaci 1400g, Radix Saposhnikoviae 420g, Fructus Arctii 420g and Radix Glycyrrhizae 280g, decoct with water secondary, each 1 hour, amount of water is 70 liters for the first time, amount of water is 60 liters for the second time, merge the secondary decocting liquid, filter, filtrate and above-mentioned aqueous solution merge, be concentrated into an amount of, add ethanol and make that to contain alcohol amount be 70%, place, get supernatant concentration and become clear paste 1.4kg (relative density 1.22~1.25,90 ℃), add dextrin 2.65kg, microcrystalline Cellulose 0.15kg, Herba Schizonepetae volatile oil Benexate Hydrochloride 14g, mixing is made the 3.5kg granule, dry, packing, every bag 6.5g contains protocatechualdehyde 0.65mg.
The capsular preparation of embodiment 4 Jing Yin
1. get Herba Schizonepetae 520g supercritical CO
2Extraction volatile oil must about 15ml Herba Schizonepetae extract.
2. take by weighing hydroxypropyl 20g, adding distil water 300ml heating for dissolving slowly adds Herba Schizonepetae extract while stirring in the time of 40 ℃, stirs the 1h postlyophilization, gets about the about 20g of Herba Schizonepetae volatile oil hydroxypropyl clathrate.
3. get step 1 medicinal residues and Flos Lonicerae 600g, Ilex purpurea Hassk.[I.chinensis Sims 1400g, Herba Houttuyniae 1400g, Folium Isatidis 1400g, Herba Taraxaci 1400g, Radix Saposhnikoviae 420g, Fructus Arctii 420g and Radix Glycyrrhizae 280g, add 75% ethanol extraction secondary, 60 minutes for the first time, 45 minutes for the second time, each alcohol adding amount is 70L, merge the secondary ethanol extract, filter, reclaim ethanol and be concentrated into relative density 1.08-1.10, spray drying gets the about 1.1kg of dry powder, add 20g Herba Schizonepetae volatile oil hydroxypropyl clathrate, promptly encapsulated behind the mixing.
Embodiment 5
1. get Herba Schizonepetae 1.68kg and extract, get the 10ml Herba Schizonepetae volatile oil, add 200ml ethanol, get the Herba Schizonepetae oil alcoholic solution with steam distillation.
2. get step 1 medicinal residues and Flos Lonicerae 2.8kg, Ilex purpurea Hassk.[I.chinensis Sims 5.6kg, Herba Houttuyniae 5.6kg, Folium Isatidis 5.6kg, Herba Taraxaci 5.6kg, Radix Saposhnikoviae 1.68kg, Fructus Arctii 1.68kg and Radix Glycyrrhizae 1.12kg, decoct with water 2 times, 45 minutes for the first time, 30 minutes for the second time, merge the secondary decocting liquid, filter, be concentrated in right amount, high speed centrifugation is got supernatant concentration and is become clear paste 6kg, add dextrin 12kg, make granule, spray into the Herba Schizonepetae volatile oil alcoholic solution, mixing dries, packing, every bag 6.5g contains protocatechualdehyde 0.8mg.