CN1557389A - Preparing process of cold treating ageratum and chrysanthemum soft capsule - Google Patents
Preparing process of cold treating ageratum and chrysanthemum soft capsule Download PDFInfo
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- CN1557389A CN1557389A CNA2004100139063A CN200410013906A CN1557389A CN 1557389 A CN1557389 A CN 1557389A CN A2004100139063 A CNA2004100139063 A CN A2004100139063A CN 200410013906 A CN200410013906 A CN 200410013906A CN 1557389 A CN1557389 A CN 1557389A
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Abstract
The cold treating soft capsule is prepared with agastache, elsholizia, wild chrysanthemum flower and sweet wormwood herb, and through twice decoction while extracting volatile oil, merging and concentrating decoction liquid, ethanol deposition to eliminate precipitate and obtain supernatant, mixing the supernatant and volatile oil to obtain the active medicine components, and matching the active medicine components with proper amount of medicinal supplementary material to prepare the soft capsule. Compared with available granule, the soft capsule of the present invention has the advantages of fast disintegration, high bioavailability, high stability and others, and thus has obvious curative effect on cold and upper respiratory tract infection.
Description
Technical field
The present invention relates to a kind of preparation method for the treatment of the Chinese medicine pharmaceutical preparation of flu, more particularly, is a kind of preparation method of Folium Crossostephii Chinensis GANMAO RUANJIAONANG preparation.
Background technology
Folium Crossostephii Chinensis cold medicine preparation involved in the present invention, its prescription comes from ancient times Suzhou " clothes Folium Crossostephii Chinensis four flavor soup; it is light that the BITONG tears end the whole body " among the people the earliest and comes, among the people and hospital checking by last a century, definite, tangible curative effect is arranged, the characteristic that south of the River human therapy flu is arranged, Folium Crossostephii Chinensis GANMAO RUANJIAONANG are exactly to have passed through to improve the soft capsule preparation of making on the basis of this basis and Folium Crossostephii Chinensis cold granules.
Flu is a kind of clinical common diseases, and all can fall ill four annual seasons, and particularly at season alternation, under the change of many extraneous natural causes such as climate change, the incidence rate that causes catching a cold rises.The boundary that does not have age, sex of flu, men and women, old and young all fall ill, and the traditional Chinese medical science is divided into anemopyretic cold and anemofrigid cold usually, is many with anemopyretic cold wherein; Doctor trained in Western medicine is exactly common cold and influenza.
By accession to WTO, the generation of PPA incident, the reason that people become the consumption of coldrex, the quick curative effect of Mang Mu pursuit Western medicine no longer, and the side effect of ignorance Western medicine.Add that Chinese medicine also has remarkable advantages and characteristic in treatment flu, people came the consumption attention diversion of flu gradually at nearest 2 years to Chinese medicine, the SARS disturbance in spring in 2003 particularly, firm especially most patients' conviction.
In view of the change of consumer groups' consumption consciousness, add the big market that coldrex is stable, necessary exploitation has definite curative effect, and scientific and technological content is arranged, distinctive Chinese medicine coldrex.
The existing dosage form of Folium Crossostephii Chinensis cold medicine preparation is a granule.Because four flavor Chinese medicines of prescription all contain abundant volatile oil effective ingredient, former dosage form can not effectively keep volatile oil component, and dose is (each 10g) greatly, has limited the application and the curative effect of this medicine, has also buried the characteristic of this medicine.In view of the latest development of above reason and modern technological means, the applicant makes rational soft capsule dosage form the Folium Crossostephii Chinensis cold granules is further meticulous, is convenient to the patient and uses and guarantee curative effect.
Summary of the invention
Folium Crossostephii Chinensis GANMAO RUANJIAONANG of the present invention adopts the novel form new technology, and four flavor Chinese medicines all extract volatile oil, and it is rapid to have a disintegrate, the bioavailability height, and good looking appearance, easy to carry, advantages such as taking convenience, the exploitation of this product has tangible innovation meaning.
Folium Crossostephii Chinensis GANMAO RUANJIAONANG of the present invention, its prescription is composed as follows: Herba Pogostemonis 33.3g, Herba Moslae 20g, Flos Chrysanthemi Indici 33.3g, Herba Artemisiae Annuae 33.3g.The preparation that this recipe quantity is made can be made into 1000 of Folium Crossostephii Chinensis GANMAO RUANJIAONANG.This prescription composition is selected from the 15 Folium Crossostephii Chinensis cold granules of ministry standard standard and constitutes.
Contribution of the present invention is the extraction of active ingredients preparation in the soft capsule, preparation method of the present invention is different with in the past preparation method, and Herba Pogostemonis, Herba Moslae, Flos Chrysanthemi Indici, Herba Artemisiae Annuae all need to extract other effective ingredient through extracting to decoct behind the volatile oil effective ingredient again in the method for the present invention.
The active component of soft capsule preparation of the present invention obtains by preparation method of the present invention, and this preparation method comprises the steps:
A, form by the prescription of Folium Crossostephii Chinensis cold-treating preparation and to get: Herba Pogostemonis 33.3g, Herba Moslae 20g, Flos Chrysanthemi Indici 33.3g, Herba Artemisiae Annuae 33.3g, standby;
B, Herba Pogostemonis, Herba Moslae, Flos Chrysanthemi Indici, Herba Artemisiae Annuae decoct and extract volatile oil simultaneously twice;
After c, decoction liquor merging concentrate, add ethanol and dispel precipitation;
After the supernatant concentration behind d, the precipitate with ethanol, add volatile oil;
The product that e, above step obtain is combined by different combinations and is formed active constituents of medicine of the present invention, and active component mixes with proper quantity of medicinal auxiliary material, and last encapsulating machine is made soft capsule, promptly.
Above preparation process is further optimized, and can more specifically select to adopt following two kinds of different schemes:
One of scheme specifically may further comprise the steps:
A, take by weighing Herba Pogostemonis 33.3g according to Folium Crossostephii Chinensis cold granules prescription ratio, Herba Moslae 20g, Flos Chrysanthemi Indici 33.3g, Herba Artemisiae Annuae 33.3g, standby;
B, Herba Pogostemonis, Herba Moslae, Flos Chrysanthemi Indici and Herba Artemisiae Annuae, steam distillation extracts volatile oil twice, is respectively 1-3 hour, and Best Times is 3 hours for the first time, 1 hour for the second time, collect volatile oil, standby;
C, twice decocting liquid merge, and being evaporated to relative density is 1.00-1.50, and optimum density is 1.10 (60 ℃), add a certain amount of ethanol, precipitation, best ethanol content is 80%, supernatant behind the precipitate with ethanol is collected and is concentrated into density is 1.00-1.50, and optimum density is 1.35 (60 ℃), and is standby;
The concentrated solution of the volatile oil of d, step b and step c merges, and adds a certain amount of adjuvant, as the plant wet goods, and mixing, standby;
E, get the above active component that obtains, last encapsulating machine is made soft capsule, promptly.
Two of scheme specifically may further comprise the steps:
A, take by weighing Herba Pogostemonis 33.3g according to Folium Crossostephii Chinensis cold granules prescription ratio, Herba Moslae 20g, Flos Chrysanthemi Indici 33.3g, Herba Artemisiae Annuae 33.3g, standby;
B, Herba Pogostemonis, Herba Moslae, Flos Chrysanthemi Indici and Herba Artemisiae Annuae, supercritical fluid extraction volatile oil is collected volatile oil, and is standby;
C, twice medicinal residues merge, and decoct twice, are respectively 1-3 hour, Best Times is 3 hours for the first time, 1 hour for the second time, merges decoction liquor, being evaporated to relative density is 1.00-1.50, optimum density is 1.10 (60 ℃), adds a certain amount of ethanol, precipitation, best ethanol content is 80%, supernatant behind the precipitate with ethanol is collected and is concentrated into density is 1.00-1.50, and optimum density is 1.35 (60 ℃), and is standby;
The volatile oil of d, gained and concentrated solution merge, and add a certain amount of adjuvant, as the plant wet goods, and mixing, standby;
The concentrated solution of the volatile oil of e, step b and step c merges, and adds a certain amount of adjuvant, as plant wet goods, mixing; Last encapsulating machine is made soft capsule, promptly.
In other words, Folium Crossostephii Chinensis GANMAO RUANJIAONANG preparation of the present invention is made up of soft capsule shell and content, and content is made up of through extracting active component and the pharmaceutic adjuvant be processed into the raw material of above prescription.Soft capsule of the present invention is preferably filled a prescription and consisted of every soft capsule and contain: active component 0.01~0.5 gram, PEG400 or vegetable oil are the 0.01-0.5 gram; Be more preferably active component 0.05~0.2 gram, PEG400 or vegetable oil are the 0.05-0.3 gram; Particularly preferredly is active component 0.1-0.15 gram, PEG400 or vegetable oil are the 0.08-0.2 gram, and even with the mixture content of adjuvant by the principal agent of this ratio preparation, good fluidity is fit to pack into, and the soft capsule loading amount of preparation is accurate, even.
Step b described in the above method decocts and extracts volatile oil simultaneously twice, is to adopt steam distillation to extract volatile oil; Or adopt supercritical fluid extraction volatile oil, be respectively 1-3 hour for twice.
Described pharmaceutic adjuvant be can with the aqueous material of active component mix homogeneously, be selected from PEG400, Tween 80, glycerol, propylene glycol, isopropyl alcohol, dehydrogenation soybean oil, vegetable oil, aromatic oil, the Cera Flava one or more.The proportioning of described active constituents of medicine and pharmaceutic adjuvant is an active component: pharmaceutic adjuvant=1: 0.5-1: 5 by weight; Wherein in every soft capsule, the content of active component is by the normal capsules grain, and every contains active component 0.01~0.5 gram; Soft capsule shell prepares with conventional method, is generally filled a prescription in certain proportion by gelatin, G ﹠ W and makes, and by weight, gelatin, G ﹠ W preferred proportion are 10: 2~5: 7~15.
The method for preparing soft capsule can adopt following steps:
1, the preparation of soft capsule rubber: get glycerol, water adds food coloring, grinds with colloid mill, make mix homogeneously, in the inputization glue jar, heating, add gelatin and stir, be heated to uniform temperature, insulation a period of time, evacuation stirs a period of time, till jar interior no bubble, cross 60 order filter clothes, insulation promptly gets the be complementary rubber solution of color of soft capsule and food coloring, and is standby;
2, compression moulding: start encapsulating machine, after preparing qualified rubber, carry out ball readjustment examination with liquid paraffin earlier, after treating that loading amount difference is qualified, the suspension of medicine and adjuvant is put into the liquid reservoir at machine top, elder generation's closing liquid paraffin inlet valve, open the medicine inlet valve again, the soft capsule that contains medicine is promptly suppressed and is finished, the soft capsule that elder generation extrudes, by " under an appendix IL of Chinese pharmacopoeia version in 2000 item regulation of soft capsule content uniformity to soft capsule content carry out content uniformity claim fixed, qualified back start continuous production.The soft capsule that suppresses falls into the drum-type drying machine of making net bottom with thin copper wire, and molding in 10-12 hour does not stop to roll;
3, drying: the soft capsule of forming is loaded onto drying cart place in the hothouse that dehydrating unit is housed, regulate temperature, humidity, allow the interior moisture content of rubber slowly evaporate, and gently stir soft capsule every now and then, to prevent the adhesion of soft capsule pill, dry a period of time;
4, deoil, granulate, finished product: the soft capsule that drying is good is put into coating pan with the gauze of cleaning and is rolled, the gauze that rolls can absorb and clean the PEG400 and the liquid paraffin on soft capsule surface, qualified soft capsule cleans once with ethanol, to clean PEG400 and the liquid paraffin of soft capsule appearance remnants, qualified soft capsule, dry in dry sieve, check, packing promptly get the soft capsule finished product.
The dosage form of soft capsule of the present invention has following beneficial effect:
The Folium Crossostephii Chinensis GANMAO RUANJIAONANG that adopts preparation method of the present invention to make has following beneficial effect:
Adopt in above two kinds of preparation methoies any one, the Folium Crossostephii Chinensis GANMAO RUANJIAONANG that makes has been avoided the shortcoming of granule, and it is rapid to have a disintegrate, the bioavailability height, and good stability, good looking appearance, easy to carry, advantages such as taking convenience.
Because Folium Crossostephii Chinensis GANMAO RUANJIAONANG of the present invention can fully keep the volatile oil component in the four Chinese medicine product, has more dispelling wind to relieve the exterior syndrome, clearing away heat and eliminating dampness, fragrant summer-heat removing effects.Cure mainly pestilent cold, to fever and headache, disease such as uncomfortable in chest, lossless is preferably, upper respiratory tract infection.Disease is seen: heating, headache, uncomfortable in chest, lossless, body of the tongue is light red, thin fur or yellow greasy, floating and rapid pulse.
The applicant has formulated new quality standard simultaneously, respectively Herba Pogostemonis, Herba Moslae, Flos Chrysanthemi Indici and Herba Artemisiae Annuae has been carried out the qualitative investigation of TLC, all obtains satisfied result, and with this discriminating project as this product.Select for use effective ingredient in Herba Pogostemonis, Herba Moslae, Flos Chrysanthemi Indici and the Herba Artemisiae Annuae as quantitative target, adopt the HPLC method, carried out precision test, repeatability test, solvent stability test and application of sample recovery test respectively, method of proof is feasible, as the quantitative approach of preparation.
By the Folium Crossostephii Chinensis GANMAO RUANJIAONANG that above preparation technology, moulding process and quality standard are produced, the product that becomes high in technological content, steady quality and be easy to control.
Folium Crossostephii Chinensis GANMAO RUANJIAONANG of the present invention experimental results show that its beneficial effect through following Folium Crossostephii Chinensis cold granules pharmacological toxicology:
The research of Folium Crossostephii Chinensis cold granules preclinical pharmacology:
Utilization egg inoculation virus N 1N 1 strain and Embryo Gallus domesticus urine hemagglutinative titer mensuration and poliv, VSV virus inoculation cause CPE in Hep-2, Wish cell; to the inhibitory action of escherichia coli, Bacillus typhi etc., the refrigeration function of endotoxic protection of mice iv lethal dose and carrageenin pyrogenicity is studied.The result shows that the Folium Crossostephii Chinensis cold granules has stronger antivirus action, anti-endotoxin effect and refrigeration function.
Bacteriostatic test shows that the Folium Crossostephii Chinensis cold granules is to causing the common bacteria of respiratory tract disease, and except that the fungistatic effect of staphylococcus aureus was on the low side, other antibacterials all had the obvious suppression effect, even some Bacterium entericum is also had stronger bacteriostasis.Propagation to Poliv and VSV virus also all has inhibitory action.
The research of Folium Crossostephii Chinensis cold granules clinical pharmacology:
Folium Crossostephii Chinensis cold granules treatment acute upper respiratory tract infection heating clinical observation on the therapeutic effect shows: 66 routine wind heat patients are treated, and body temperature is all more than 38 ℃, Most patients total white blood cells<5000, and wherein neutrophil cell is the highest by 94, and minimum 30.The result: total effective rate reaches 96.6%.
Folium Crossostephii Chinensis cold granules treatment cold, fever 305 examples are summed up---and show in attached 50 example contrasts and the experimentation: 305 examples are organized in treatment as a result, total effective rate 95.4%; Matched group 50 examples, total effective rate 94%.The Folium Crossostephii Chinensis cold granules is to three class pattern of syndrome such as wind and cold, wind heat, fire wrapped by cold, and effect is similar substantially, so be applicable to pestilent cold heating disease.The Folium Crossostephii Chinensis cold granules proves to have better cooling refrigeration function again through zoopery, compare extremely significant difference (P≤0.01) of tool with matched group, and is safe and effective.
Through clinical observation, the Folium Crossostephii Chinensis cold granules is 94.5% to the wind-chill cold effective percentage, is 92.85% to the common cold due to wind heat effective percentage, it is 80% that wind and cold is held pattern of fever (being commonly called as fire wrapped by cold) flu effective percentage under the arm, total effective rate is 92.9%, and is evident in efficacy, do not find toxic and side effects.
The specific embodiment
The present invention is further described by the following examples.
Embodiment 1
Prescription: Herba Pogostemonis 33.3g, Herba Moslae 20g, Flos Chrysanthemi Indici 33.3g, Herba Artemisiae Annuae 33.3g.
Herba Pogostemonis, Herba Moslae, Flos Chrysanthemi Indici and Herba Artemisiae Annuae, steam distillation extracts volatile oil twice, was respectively 3 hours for the first time, 1 hour for the second time, collect volatile oil, standby;
Twice decocting liquid merges, and being evaporated to relative density is 1.10 (60 ℃), adds an amount of ethanol, precipitation, and ethanol content is 80%, the supernatant collection behind the precipitate with ethanol is concentrated into density and is 1.35 (60 ℃), and is standby;
The concentrated solution that volatile oil that extracts and decocting boil merges, and adds an amount of vegetable oil, and mixing gets the preparation content;
Above-mentioned preparation content is added in the soft capsule skin repressed one-tenth soft capsule finished product:
The preparation of soft capsule rubber: get glycerol, water adds food coloring, grinds with colloid mill, make mix homogeneously, in the inputization glue jar, heating, add gelatin and stir, be heated to uniform temperature, insulation a period of time, evacuation stirs a period of time, till jar interior no bubble, cross 60 order filter clothes, insulation promptly gets soft capsule rubber solution, and is standby;
Compression moulding: start encapsulating machine, after preparing qualified rubber, carry out ball readjustment examination with liquid paraffin earlier, after treating that loading amount difference is qualified, the suspension of medicine and adjuvant is put into the liquid reservoir at machine top, elder generation's closing liquid paraffin inlet valve, open the medicine inlet valve again, the soft capsule that contains medicine is promptly suppressed and is finished, the soft capsule that elder generation extrudes, by " under an appendix IL of Chinese pharmacopoeia version in 2000 item regulation of soft capsule content uniformity to soft capsule content carry out content uniformity claim fixed, qualified back start continuous production.The soft capsule that suppresses falls into the drum-type drying machine of making net bottom with thin copper wire, and molding in 10-12 hour does not stop to roll;
Dry: as the soft capsule of forming to be loaded onto drying cart place in the hothouse that dehydrating unit is housed, regulate temperature, humidity, allow the interior moisture content of rubber slowly evaporate, and gently stir soft capsule every now and then, to prevent the adhesion of soft capsule pill, dry a period of time;
Deoil, granulate, finished product: the soft capsule that drying is good is put into coating pan with the gauze of cleaning and is rolled, the gauze that rolls can absorb and clean the PEG400 and the liquid paraffin on soft capsule surface, qualified soft capsule cleans once with ethanol, to clean PEG400 and the liquid paraffin of soft capsule appearance remnants, qualified soft capsule, dry in dry sieve, check, packing promptly get the soft capsule finished product.
Embodiment 2
Prescription: Herba Pogostemonis 33.3g, Herba Moslae 20g, Flos Chrysanthemi Indici 33.3g, Herba Artemisiae Annuae 33.3g.
Herba Pogostemonis, Herba Moslae, Flos Chrysanthemi Indici and Herba Artemisiae Annuae, supercritical fluid extraction volatile oil is collected volatile oil, and is standby;
Twice medicinal residues merges, and decocts twice, is respectively 1 hour for the second time 3 hours for the first time, merge decoction liquor, being evaporated to relative density is 1.10 (60 ℃), adds an amount of ethanol, precipitation, ethanol content is 80%, and the supernatant collection behind the precipitate with ethanol is concentrated into density and is 1.35 (60 ℃), and is standby;
The concentrated solution that volatile oil that extracts and decocting boil merges, and adds an amount of PEG400, and mixing gets the preparation content;
Above-mentioned preparation content is added in the soft capsule skin repressed one-tenth soft capsule finished product.The soft capsule moulding process is with embodiment 1.
Claims (5)
1, a kind of preparation method of Folium Crossostephii Chinensis GANMAO RUANJIAONANG preparation may further comprise the steps:
A, form by the prescription of Folium Crossostephii Chinensis cold-treating preparation and to get: Herba Pogostemonis 33.3g, Herba Moslae 20g, Flos Chrysanthemi Indici 33.3g, Herba Artemisiae Annuae 33.3g, standby;
B, Herba Pogostemonis, Herba Moslae, Flos Chrysanthemi Indici, Herba Artemisiae Annuae decoct and extract volatile oil simultaneously twice;
After c, decoction liquor merging concentrate, add ethanol and dispel precipitation;
After the supernatant concentration behind d, the precipitate with ethanol, add volatile oil;
The product that e, above step obtain is combined the active constituents of medicine of composition, mixes with proper quantity of medicinal auxiliary material, makes soft capsule.
2, the preparation method of Folium Crossostephii Chinensis GANMAO RUANJIAONANG preparation according to claim 1 is characterized in that, described step b decocts and extracts volatile oil simultaneously twice, is to adopt steam distillation to extract volatile oil; Or adopt supercritical fluid extraction volatile oil, be respectively 1-3 hour for twice.
3, the preparation method of Folium Crossostephii Chinensis GANMAO RUANJIAONANG preparation according to claim 1 and 2 is characterized in that: described pharmaceutic adjuvant is selected from one or more in PEG400, Tween 80, glycerol, propylene glycol, isopropyl alcohol, dehydrogenation soybean oil, vegetable oil, aromatic oil, the Cera Flava.
4, the preparation method of Folium Crossostephii Chinensis GANMAO RUANJIAONANG preparation according to claim 3 is characterized in that: described active constituents of medicine is 1 with the ratio of the weight of described pharmaceutic adjuvant: 0.5-1: 5.
According to the preparation method of the described Folium Crossostephii Chinensis GANMAO RUANJIAONANG of claim 4 preparation, it is characterized in that 5, the soft capsule moulding process may further comprise the steps:
The preparation of soft capsule rubber: get glycerol, water adds food coloring, grinds with colloid mill, make mix homogeneously, in the inputization glue jar, heating, add gelatin and stir, be heated to uniform temperature, insulation a period of time, evacuation stirs a period of time, till jar interior no bubble, cross 60 order filter clothes, insulation promptly gets soft capsule rubber solution, and is standby;
Compression moulding: start encapsulating machine, after preparing qualified rubber, carry out ball readjustment examination with liquid paraffin earlier, after treating that loading amount difference is qualified, the suspension of medicine and adjuvant is put into the liquid reservoir at machine top, elder generation's closing liquid paraffin inlet valve, open the medicine inlet valve again, the soft capsule that contains medicine is promptly suppressed and is finished, the first soft capsule that extrudes, by " under an appendix IL of Chinese pharmacopoeia version in 2000 item regulation of soft capsule content uniformity to soft capsule content carry out content uniformity claim fixed, qualified back start continuous production, the soft capsule that suppresses falls into the drum-type drying machine of making net bottom with thin copper wire, and molding in 10-12 hour does not stop to roll;
Dry: as the soft capsule of forming to be loaded onto drying cart place in the hothouse that dehydrating unit is housed, regulate temperature, humidity, allow the interior moisture content of rubber slowly evaporate, and gently stir soft capsule every now and then, to prevent the adhesion of soft capsule pill, dry a period of time;
Deoil, granulate, finished product: the soft capsule that drying is good is put into coating pan with the gauze of cleaning and is rolled, the gauze that rolls can absorb and clean the PEG400 and the liquid paraffin on soft capsule surface, qualified soft capsule cleans once with ethanol, to clean PEG400 and the liquid paraffin of soft capsule appearance remnants, qualified soft capsule, dry in dry sieve, check, packing promptly get the soft capsule finished product.
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100347539C (en) * | 2002-12-09 | 2007-11-07 | 张瑞祥 | Herba Moslae quality control |
CN102145091B (en) * | 2010-02-04 | 2012-10-17 | 天津中新药业集团股份有限公司达仁堂制药厂 | Traditional Chinese medicinal composition for eliminating wind and relieving heat and preparation method thereof |
CN111150755A (en) * | 2020-02-28 | 2020-05-15 | 雷允上药业集团有限公司 | Traditional Chinese medicine composition for preventing and treating viral diseases and application thereof |
-
2004
- 2004-01-15 CN CN 200410013906 patent/CN1251705C/en not_active Expired - Fee Related
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100347539C (en) * | 2002-12-09 | 2007-11-07 | 张瑞祥 | Herba Moslae quality control |
CN102145091B (en) * | 2010-02-04 | 2012-10-17 | 天津中新药业集团股份有限公司达仁堂制药厂 | Traditional Chinese medicinal composition for eliminating wind and relieving heat and preparation method thereof |
CN111150755A (en) * | 2020-02-28 | 2020-05-15 | 雷允上药业集团有限公司 | Traditional Chinese medicine composition for preventing and treating viral diseases and application thereof |
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