CN107929351B - Preparation process of Aidi injection preparation - Google Patents
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- A61K36/185—Magnoliopsida (dicotyledons)
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- A61K2236/30—Extraction of the material
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Abstract
The invention relates to the field of medicines, in particular to a preparation process of an Aidi injection preparation. The cantharides, ginseng, astragalus and acanthopanax are taken as raw materials, firstly, the ginseng is soaked in warm water and then is extracted by alcohol, then ginseng dregs, the astragalus and the acanthopanax are decocted and extracted by water together, the extracting solution is combined and then is subjected to multiple times of alternate precipitation of alcohol and water and cold storage treatment, so that impurities in the extracting solution are fully precipitated and removed, the impurities in the liquid medicine are greatly reduced, the incidence rate of adverse reactions is reduced, and then, the pH value is adjusted, the ultrafiltration is carried out, and the cold storage is carried out for standby; soaking Mylabris in warm water, extracting with water, precipitating with lime-sulfur method twice, refrigerating, filtering, precipitating with water twice, adjusting pH, refrigerating, ultrafiltering, mixing the Mylabris extract with the extracts of Ginseng radix, radix astragali, and radix Acanthopanacis Senticosi, adding adjuvants, and adjusting pH. Finally, the preparation process of the Aidi injection preparation with higher extraction efficiency and purity and low adverse reaction incidence rate is obtained.
Description
Technical Field
The invention relates to the field of traditional Chinese medicine pharmacy, in particular to a preparation process of an Aidi injection preparation.
Background
The Chinese medicine injection is prepared with Chinese medicinal materials and through extraction, separation, refining and other steps. The traditional administration mode of the traditional Chinese medicine is changed, the traditional Chinese medicine has the characteristics of quick drug effect, high bioavailability and more accurate dosage, is suitable for cases unsuitable for oral administration or acute and severe cases, can ensure that certain medicines can perform directional or positioning administration and the like, and well performs the function of treating acute and severe diseases and stubborn diseases by the traditional Chinese medicine. However, with the increasing clinical application, the adverse drug reactions caused by the traditional Chinese medicine injection are frequently occurred, and the attention of the wide medical workers is attracted. The main reasons for the adverse reaction of the Chinese medicinal injection preparation are as follows: the chemical components of the raw materials of the traditional Chinese medicine injection are very complex, and some high molecular compounds such as tannin and animal and vegetable protein are easy to cause anaphylactic reaction; in addition, the purity of the liquid medicine of individual batch is not good enough due to the undermature production process of the traditional Chinese medicine injection, and allergic reaction is further caused.
The Aidi injection is a Chinese medicinal variety developed by the applicant, is prepared from 4 Chinese medicaments of ginseng, astragalus root, acanthopanax and cantharis, has the effects of clearing heat and removing toxicity, and removing blood stasis and resolving masses, is mainly used for treating primary liver cancer, lung cancer, rectal cancer, malignant lymphoma, gynecological malignant tumors and the like clinically, and is collected in 20 volumes of standards issued by Ministry of health. The applicant discloses a preparation process of an Aidi injection in the patent No. 03117114.1 'Chinese medicinal injection for treating tumor and a preparation method thereof': the method is simple in structure, high in loss of effective medicine components, low in yield, high in energy consumption, complex in production process, long in period, low in efficiency, high in cost, poor in production safety and large in environmental influence, and is easy to cause unstable component change in liquid medicine, and a large amount of polysaccharide components with anti-tumor effects are not utilized.
In the present stage, various improvements are made on the production process of an aidi injection, for example, patent application with the patent application number of CN200510134395.5 discloses an aidi injection and a preparation method thereof, wherein cantharis is ultrasonically extracted by 80-95% ethanol and is centrifuged at high speed; extracting Ginseng radix, radix astragali, and radix Acanthopanacis Senticosi with 80-95% ethanol, and eluting with polyamide column and macroporous resin column; decocting the residue with water, eluting with macroporous resin, and ultrafiltering. For example, patent CN200910102894.4 discloses a Chinese medicinal extract preparation for treating cancer and its preparation method, which is prepared by decocting cantharis with water, and adjusting pH with alkali; extracting Ginseng radix and radix Acanthopanacis Senticosi with alcohol, and eluting with macroporous resin; decocting the residue of Ginseng radix and radix Acanthopanacis Senticosi with radix astragali, extracting with water, precipitating with lime sulfur method, and mixing the extractive solutions. For example, patent application No. CN200510134397.4 discloses a method for preparing an addi injection, which comprises ultrasonic extracting cantharis with 80-95% ethanol, high speed centrifuging, and clathrating with hydroxypropyl-beta-cyclodextrin; extracting Ginseng radix, radix astragali, and radix Acanthopanacis Senticosi with 80-95% ethanol, and eluting with polyamide column and macroporous resin column; decocting Ginseng radix, radix astragali, and radix Et caulis Acanthopanacis Senticosi in water, eluting with macroporous resin, concentrating, and mixing the extractive solutions. For example, patent CN200510003151.3 discloses a method for preparing a Chinese medicinal preparation for treating tumor, which is prepared by extracting cantharis with ethanol, adjusting with alkali, adjusting with acid, filtering, and adjusting with alkali; extracting Ginseng radix with ethanol, and eluting with macroporous resin; mixing radix astragali and radix Acanthopanacis Senticosi with residue of Ginseng radix and Mylabris, decocting in water, precipitating with ethanol, adjusting with alkali, precipitating with ethanol, adjusting with acid, centrifuging, and mixing extractive solutions. For example, patent CN200810301949.X discloses a Chinese medicinal injection for treating cancer and its preparation method, by extracting Ginseng radix with ethanol, decocting Ginseng radix residue and radix et rhizoma Rhei together, and extracting with water; extracting radix Acanthopanacis Senticosi with alcohol; decocting Mylabris, extracting with water, concentrating extractive solution of Ginseng radix, radix astragali, and radix Acanthopanacis Senticosi, microfiltering with inorganic ceramic membrane, refining with polyamide resin, ultrafiltering with organic membrane, and mixing with aqueous extractive solution of Mylabris.
With the improvement of living standard, the extraction efficiency of the existing Aidi injection preparation technology is not ideal enough, and in view of the gradual improvement of the safety requirements of injection preparations, especially traditional Chinese medicine injection preparations, the preparation process of the Aidi injection preparation with higher extraction efficiency and purity and low adverse reaction incidence rate is sought, and the problem to be solved by medical workers at present is solved.
Disclosure of Invention
In order to solve the above technical problems in the prior art, the present invention provides a process for preparing an aidi injection preparation, which comprises the following steps:
(1) selecting raw materials: taking cantharis, ginseng, astragalus and acanthopanax raw materials;
(2) extracting ginseng: soaking Ginseng radix in 30-80% ethanol under warm condition, reflux-extracting under heating for 2 times (2.5-4 hr for 1 time and 1-2 hr for each time), filtering, and recovering ethanol to obtain medicinal liquid;
(3) extracting ginseng, astragalus and acanthopanax: decocting the extracted Ginseng radix residue, radix astragali and radix Acanthopanacis Senticosi with water for 2-4 times, 1 st time for 2.5-4 hr, 2-4 th time for 1-2 hr, filtering, concentrating, mixing with the Ginseng radix liquid obtained in step (2), and concentrating;
(4) purifying ginseng, astragalus and acanthopanax:
alcohol-water alternative treatment: adding ethanol into the concentrated solution to adjust ethanol content to 70-80%, refrigerating, filtering, recovering ethanol, precipitating with water, filtering and concentrating the water-precipitated solution, adding ethanol, precipitating with ethanol, refrigerating for 1-2 times, and adjusting ethanol content of the solution to 85-95% each time;
and (3) multiple water sedimentation treatment: filtering the cold storage liquid, recovering ethanol, then precipitating with water for 2 times or more, filtering, concentrating, sterilizing, refrigerating, filtering the cold storage liquid again, adjusting pH to 7.0-7.6, sterilizing, refrigerating, filtering, concentrating, precipitating with water;
and (3) filtering treatment: filtering the water precipitation solution, ultrafiltering, refrigerating for 2-3 times, and repeatedly to obtain mixed extractive solution of Ginseng radix, radix astragali, and radix Acanthopanacis Senticosi, and refrigerating for use;
(5) extracting cantharis: soaking Mylabris in water, decocting for 0.5-2 hr for 2-5 times, filtering, concentrating, treating with lime sulfur method for 2-3 times, sterilizing, refrigerating, collecting supernatant, and concentrating;
(6) cantharis purification: adding ethanol into a cantharis concentrated solution to adjust the ethanol content of the concentrated solution to 70-90%, carrying out alcohol precipitation for 2-3 times, refrigerating, filtering the refrigerated liquid medicine, recovering the ethanol, precipitating with water for 2-3 times, filtering, adding sulfurous acid into the filtrate to adjust the pH value to 4.0-5.0, sterilizing, filtering after refrigerating, repeatedly carrying out ultrafiltration and refrigerating for 2-4 times, sterilizing to obtain a cantharis extracting solution, and refrigerating for later use;
(7) preparation of injection preparation: and (3) mixing the mixed extract of the ginseng, the astragalus and the acanthopanax in the step (4) with the extract of the cantharis in the step (6), adding auxiliary materials, adding water for dilution, adjusting the pH value, filtering, encapsulating and sterilizing to obtain the traditional Chinese medicine.
The step (1) is to take 1 to 2 parts of cantharis, 30 to 80 parts of ginseng, 80 to 120 parts of astragalus and 180 parts of acanthopanax root by weight. The Aidi injection prepared by the weight ratio has good drug effect and less adverse reaction. Preferably, the weight parts of cantharis 1.5, ginseng 50, astragalus 100 and acanthopanax 150.
And (4) concentrating until the relative density is 1.15-1.25 at 60-70 ℃. At the moment, the solution has moderate density and is more suitable for subsequent alcohol precipitation operation.
And (4) water precipitation, namely adding water into the liquid medicine for boiling, and then refrigerating. The impurities in the waste water are precipitated and removed in a colloid dispersed state by adding water and boiling the waste water and then carrying out water precipitation in a cold storage mode, and the impurity removal rate is higher than that of common water precipitation treatment.
And the cold storage is to refrigerate the liquid medicine for 0.5 to 10 hours at the temperature of between-1 and 8 ℃. The low-temperature refrigeration can obviously remove part of precipitate, and the better cleaning efficiency can be achieved by 0.5-10h of refrigeration.
And (5) concentrating until the relative density is 1.02-1.10 at 60-70 ℃. The solution has a density suitable for processing by a lime sulphur method.
And (4) the alcohol precipitation in the step (6) is carried out by adding ethanol to adjust the alcohol content of the concentrated solution to 75%, 80% and 85% respectively. Preferably, ethanol is added to adjust the alcohol content of the concentrated solution to 75 percent and 85 percent respectively, and alcohol precipitation is carried out twice. The alcohol precipitation efficiency is higher, and the effect is better.
And (5) the step (6) of water precipitation is to add water into the liquid medicine, boil the liquid medicine, adjust the pH value to 4.0-5.0 by using sulfurous acid, and refrigerate the liquid medicine.
And (6) performing ultrafiltration, namely performing cold storage after ultrafiltration, performing ultrafiltration again, and repeating the operation for 2-4 times. The impurities in the solution can be separated out in a colloid dispersed state by refrigeration, and the ultrafiltration effect is improved.
The dilution in step (7) is to dilute the mixed extract to 1000ml of final injection volume per 301.5g of the original material. The final injection obtained by mixing according to the proportion has moderate drug effect and is suitable for direct use in the medical treatment process.
The auxiliary materials in the step (7) can be glycerol and polysorbate-80. Glycerol is a good solubilizer and stabilizer for injections. Polysorbate-80 is a good solubilizer for injection, and also has the effects of preventing denaturation at air-water interface and preventing non-specific adsorption of medicinal liquid on the surface of glass medicine bottle or intravenous infusion tube.
The sterilization in step (7) may be performed at 115 deg.C for 30 min. Most of bacteria can be effectively killed at the moment, and the method is simple and easy to implement.
The lime sulphur method is an injection impurity removing method, can effectively remove a plurality of ineffective impurities, tannin, partial protein and some polysaccharide in the liquid medicine, and can effectively reduce the side effect of the Chinese herbal medicine injection on the human body. Compared with the combination of common lime milk and sulfuric acid, the lime-sulfur method treatment using calcium oxide and sulfurous acid has higher impurity removal efficiency, does not introduce too many impurities, and has better safety.
A series of researches and experiments are carried out in the process of the invention, and the following selected partial processes are disclosed:
test example 1: screening tests are carried out on the impurity removal and purification process:
the preliminary sample was prepared by the following steps:
(1) selecting raw materials: taking 1.5g of cantharis, 50g of ginseng, 100g of astragalus and 150g of acanthopanax; extracting ginseng: soaking Ginseng radix in 50% ethanol, heating and reflux-extracting for 3 times (1 st for 3 hr and 1.5 hr each time), filtering, and recovering ethanol to obtain medicinal liquid;
(2) extracting ginseng, astragalus and acanthopanax: decocting the extracted Ginseng radix residue, radix astragali and radix Acanthopanacis Senticosi with water for 3 times, 1 st 3 hr, 2-3 nd 1.5 hr each, filtering, concentrating to relative density of 1.20 at 65 deg.C, mixing with the Ginseng radix liquid obtained in step (2), concentrating to relative density of 1.20 at 65 deg.C, and storing for use.
Averagely dividing the obtained extraction samples into 10 groups, treating according to the step (4), alternately treating 1 group of alcohol and water for 1 time, then precipitating with water for 3 times, and ultrafiltering for 2 times; treating 2 groups of alcohol and water alternately for 2 times, then precipitating with water for 3 times, and ultrafiltering for 2 times; treating 3 groups of alcohol and water alternately for 3 times, then precipitating with water for 3 times, and ultrafiltering for 2 times; treating 4 groups of alcohol and water alternately for 4 times, then precipitating with water for 3 times, and ultrafiltering for 2 times; treating 5 groups of alcohol and water alternately for 3 times, then precipitating with water for 2 times, and ultrafiltering for 2 times; treating 6 groups of alcohol and water alternately for 1 time, then precipitating with water for 2 times, and ultrafiltering for 1 time; alternately treating 7 groups of alcohol and water for 3 times, then precipitating with water for 3 times, and performing suction filtration for 2 times; treating 8 groups of alcohol and water alternately for 3 times, and ultrafiltering for 1 time; treating 9 groups of alcohol and water alternately for 3 times, then precipitating with water for 1 time, and ultrafiltering for 3 times; alternately treating 10 groups of alcohol and water for 3 times, and performing common suction filtration for 2 times; the 11 groups are subjected to alcohol precipitation treatment for 3 times, then water precipitation treatment for 3 times to replace alcohol-water alternate treatment, and ultrafiltration for 2 times. The treated solution was then tested.
The data show that the treatment mode of treating the alcohol water for 1-4 times alternately, precipitating for more than 2 times by combining water and finally performing ultrafiltration for two times has good effect, and can remove most of pyrogen, 5-hydroxymethylfurfural and other impurities in the solution.
In the existing preparation methods of numerous Addie injection, raw materials such as cantharis and the like are extracted only by water extraction or alcohol extraction, extracting solutions of ginseng, astragalus and acanthopanax are treated only by resin elution, and the extracting solution of cantharis is treated by ultrafiltration, so that the impurity removal process is insufficient in impurity treatment, and the probability of adverse reaction is increased; in the drug preparation standard of the Aidi injection in the current drug standards of Ministry of health, the extracting solutions of 4 medicinal materials are mixed and then treated by a lime sulphur method, so that the solution components are complex, the interference among the components is large, the impurity removal efficiency is low, and part of beneficial components are lost.
The invention separately extracts cantharis, ginseng, astragalus and acanthopanax, treats the extracting solution of ginseng, astragalus and acanthopanax by using a method of alternately precipitating with alcohol and water and refrigerating, and fully precipitates and separates out impurities in the extracting solution; only the cantharis extract is treated by the lime-sulfur method, so that the influence among reagents in the impurity removal process is reduced, the effective retention of active ingredients in the liquid medicine is ensured, the impurities are fully removed, and finally, the impurity content in the liquid medicine is greatly reduced under the condition of keeping the drug effect of the liquid medicine.
Compared with the prior art, the invention has the technical effects that:
firstly, the cantharis, the ginseng, the astragalus and the acanthopanax are respectively extracted and treated by different modes, so that the problem that the co-extraction of the plant source traditional Chinese medicine and the animal source traditional Chinese medicine can interfere with each other is avoided, the extraction efficiency is improved, the impurities in the cantharis extracting solution and the ginseng, the astragalus and the acanthopanax extracting solution can be fully removed, and the impurity content in the final liquid medicine is reduced.
And secondly, in the steps (3) and (4), the ginseng dregs, the astragalus and the acanthopanax are decocted by adding water, the concentrated ginseng dregs and the ginseng extract are combined, and after the concentration, the mixed extract is treated by using a mode of alternately precipitating by using alcohol and water and refrigerating, particularly refrigerating for 7 times, precipitating by using water for 3 times and precipitating by using ethanol for 2 times. Through the treatment of combining alcohol and water alternate precipitation and refrigeration for many times, impurities in the liquid medicine can be precipitated to the maximum extent to be removed, and the incidence rate of adverse reactions is greatly reduced. And moreover, multiple times of alcohol precipitation, water precipitation and alcohol-water alternation, and a purification mode combining cold storage and ultrafiltration avoid impurity interception and active ingredient interception in the resin purification process to cause certain loss, avoid the influence and interference of other solvents on the active ingredients of the traditional Chinese medicine, and ensure the extraction efficiency, the content of the active ingredients and the action effect.
Thirdly, the traditional Chinese medicinal materials contain flavonoid, polysaccharide, starch, protein, pigment, various needed and unwanted substances and impurities such as solvent, solid and the like in the early extraction process, so that the impurity removal process of the traditional Chinese medicine is complicated and the impurity removal method is various, and the injection preparation finally obtained by the invention is a preparation with the highest requirement on the safety of the medicine, so that the safety of the preparation must be paid attention to on the basis of ensuring the effectiveness of the preparation. Multiple times of alcohol precipitation, water precipitation, alcohol and water alternation, and a purification mode combining cold storage and ultrafiltration fully considers the factors of the polarity size, the particle volume, the solubility (temperature and solvent), the resolution and the like of impurities so as to fully remove the impurities and ensure the safety of the medicine.
Therefore, the cantharides, the ginseng, the astragalus and the acanthopanax are taken as raw materials, firstly the ginseng is soaked in warm water and then is extracted by alcohol, then the ginseng dregs, the astragalus and the acanthopanax are decocted and extracted by water together, the extracting solution is combined and then is subjected to multiple times of alternate precipitation of alcohol and water and cold storage treatment, so that impurities in the ginseng dregs are fully precipitated and removed, the impurities in the liquid medicine are greatly reduced, the incidence rate of adverse reactions is reduced, and then the pH value is adjusted, the ultrafiltration is carried out, and the cold storage is carried out for standby; soaking Mylabris in warm water, extracting with ethanol, precipitating with lime-sulfur method twice, refrigerating, filtering, precipitating with water twice, adjusting pH, refrigerating, ultrafiltering, mixing the Mylabris extract with the extracts of Ginseng radix, radix astragali, and radix Acanthopanacis Senticosi, adding adjuvants, and adjusting pH. Finally, the preparation process of the Aidi injection preparation with higher extraction efficiency and purity and low adverse reaction incidence rate is obtained.
Detailed Description
The technical solution of the present invention is further defined below with reference to the specific embodiments, but the scope of the claims is not limited to the description.
Example 1
(1) Selecting raw materials: taking 1.5g of cantharis, 50g of ginseng, 100g of astragalus and 150g of acanthopanax;
(2) extracting ginseng: soaking Ginseng radix in 50% ethanol, heating and reflux-extracting for 2 times (1 st for 3 hr and 1.5 hr) for the second time, filtering, and recovering ethanol to obtain medicinal liquid;
(3) extracting ginseng, astragalus and acanthopanax: decocting the extracted Ginseng radix residue, radix astragali and radix Acanthopanacis Senticosi with water for 3 times, 1 st 3 hr, 2 nd 1.5 hr, 3 rd 1 hr, filtering, mixing with the Ginseng radix liquid medicine obtained in step (2), and concentrating to relative density of 1.15-1.20 at 60-70 deg.C;
(4) purifying ginseng, astragalus and acanthopanax:
alcohol-water alternative treatment: adding ethanol into the concentrated solution to adjust ethanol content to 75%, refrigerating, filtering, recovering ethanol, precipitating the medicinal liquid with water (boiling in water, refrigerating), filtering, concentrating to relative density of 1.15-1.20 at 60-70 deg.C, adding ethanol to adjust ethanol content to 90%, and refrigerating;
and (3) multiple water sedimentation treatment: filtering the cold storage solution, recovering ethanol, and precipitating the liquid medicine with water twice; filtering, concentrating the filtrate, sterilizing, and refrigerating; sterilizing, refrigerating, filtering the refrigerated solution again, adjusting pH to 7.0-7.6, sterilizing, refrigerating, filtering, concentrating, and precipitating with water;
and (3) filtering treatment: filtering the water precipitation solution, ultrafiltering, refrigerating, ultrafiltering again to obtain mixed extractive solution of Ginseng radix, radix astragali, and radix Acanthopanacis Senticosi, and refrigerating for use;
(5) extracting cantharis: soaking Mylabris in water, decocting for 4 times (each for 1 hr), filtering, concentrating, treating with lime-sulfur method (calcium oxide and sulfurous acid) for 2 times, sterilizing, refrigerating, collecting supernatant, and concentrating to relative density of 1.02-1.10 at 60-70 deg.C;
(6) cantharis purification: precipitating Mylabris concentrate with ethanol twice, adding ethanol to ethanol content of 75% and 85%, cold preserving, filtering, recovering ethanol, adding water into the medicinal liquid, boiling, adjusting pH to 4.5 with sulfurous acid, precipitating with cold-preserved water for 2 times, filtering the precipitated solution, adding sulfurous acid into the filtrate to adjust pH to 4.0-5.0, sterilizing, cold preserving, filtering, ultrafiltering, and cold preserving; ultrafiltering, sterilizing to obtain Mylabris extract, and refrigerating;
(7) preparation of injection preparation: and (3) mixing the mixed extract of the ginseng, the astragalus and the acanthopanax in the step (4) with the extract of the cantharis in the step (6), adding glycerol and polysorbate-80, adding water to dilute to 1000ml, adjusting the pH value, filtering, encapsulating, and sterilizing at 115 ℃ for 30min to obtain the traditional Chinese medicine.
The cold storage is to refrigerate the liquid medicine for 5h at 3 ℃.
Example 2
(1) Selecting raw materials: taking 1g of cantharis, 30g of ginseng, 80g of astragalus and 130g of acanthopanax;
(2) extracting ginseng: soaking Ginseng radix in 30% ethanol, heating and reflux-extracting for 3 times (2.5 hr for 1 time and 2 hr for each time), filtering, and recovering ethanol to obtain medicinal liquid;
(3) extracting ginseng, astragalus and acanthopanax: decocting the extracted Ginseng radix residue, radix astragali and radix Acanthopanacis Senticosi with water for 2 times (1 st time for 2.5 hr and 2 nd time for 2 hr), filtering, concentrating, mixing with the Ginseng radix liquid obtained in step (2), and concentrating;
(4) purifying ginseng, astragalus and acanthopanax:
alcohol-water alternative treatment: adding ethanol into the concentrated solution to adjust the ethanol content to 70%, refrigerating, filtering, recovering ethanol, precipitating with water, filtering and concentrating the water-precipitated solution, adding ethanol, precipitating with ethanol, refrigerating for 1 time, and adjusting the ethanol content to 85%;
and (3) multiple water sedimentation treatment: filtering the cold storage liquid, recovering ethanol, then precipitating with water for 3 times, filtering, concentrating, sterilizing, refrigerating, adjusting pH to 7.0-7.6 after the cold storage liquid is filtered again, sterilizing, refrigerating, filtering, concentrating, precipitating with water;
and (3) filtering treatment: filtering the water precipitation solution, ultrafiltering, refrigerating for 2 times, and repeatedly to obtain mixed extractive solution of Ginseng radix, radix astragali, and radix Acanthopanacis Senticosi, and refrigerating for use;
(5) extracting cantharis: soaking Mylabris in water, decocting for 2 times (each for 2 hr), filtering, concentrating, treating with lime sulfur method for 2 times, sterilizing, refrigerating, collecting supernatant, and concentrating;
(6) cantharis purification: adding ethanol into the concentrated cantharis solution to adjust the ethanol content of the concentrated cantharis solution to 70%, carrying out ethanol precipitation for 3 times, refrigerating, filtering the refrigerated liquid medicine, recovering the ethanol, precipitating with water for 2 times, filtering, adding sulfurous acid into the filtrate to adjust the pH value to 4.0-5.0, sterilizing, filtering after refrigerating, repeatedly carrying out ultrafiltration and refrigerating for 2 times, sterilizing to obtain a cantharis extracting solution, and refrigerating for later use;
(7) preparation of injection preparation: and (3) mixing the mixed extract of the ginseng, the astragalus and the acanthopanax in the step (4) with the extract of the cantharis in the step (6), adding auxiliary materials, adding water for dilution, adjusting the pH value, filtering, encapsulating and sterilizing to obtain the traditional Chinese medicine.
And (4) concentrating until the relative density is 1.15-1.25 at 60-70 ℃.
The step (4) of water precipitation is to add water into the liquid medicine for boiling and then refrigerate;
the cold storage is to refrigerate the liquid medicine for 0.5h at the temperature of minus 1 ℃;
the concentration in the step (5) is carried out until the relative density is 1.02-1.10 at the temperature of 60-70 ℃;
the alcohol precipitation in the step (6) is carried out by adding ethanol to adjust the alcohol content of the concentrated solution to 75%, 80% and 85% respectively;
the step (6) of water precipitation is to add water into the liquid medicine, boil the liquid medicine, adjust the PH value to 4.0-5.0 by sulfurous acid, and refrigerate the liquid medicine;
performing ultrafiltration, refrigerating, performing ultrafiltration again, and repeating the operation for 2 times;
the dilution in step (7) is to dilute the mixed extract to 1000ml of final injection volume per 301.5g of the original material.
Example 3
(1) Selecting raw materials: taking 2g of cantharis, 80g of ginseng, 120g of astragalus and 180g of acanthopanax;
(2) extracting ginseng: soaking Ginseng radix in 80% ethanol, heating and reflux-extracting for 2 times (4 hr for 1 time and 1 hr for each time), filtering, and recovering ethanol to obtain medicinal liquid;
(3) extracting ginseng, astragalus and acanthopanax: decocting the extracted Ginseng radix residue, radix astragali and radix Acanthopanacis Senticosi with water for 4 times, 1 st 4 hr, 2-4 th, and 1 hr each, filtering, concentrating, mixing with the Ginseng radix liquid obtained in step (2), and concentrating;
(4) purifying ginseng, astragalus and acanthopanax:
alcohol-water alternative treatment: adding ethanol into the concentrated solution to adjust the ethanol content to 80%, refrigerating, filtering, recovering ethanol, precipitating with water, filtering and concentrating the water-precipitated solution, adding ethanol, precipitating with ethanol, refrigerating for 2 times, and adjusting the ethanol content of the solution to 95% each time;
and (3) multiple water sedimentation treatment: filtering the cold storage liquid, recovering ethanol, then precipitating with water for 2 times, filtering, concentrating, sterilizing, refrigerating, adjusting pH to 7.0-7.6 after the cold storage liquid is filtered again, sterilizing, refrigerating, filtering, concentrating, precipitating with water;
and (3) filtering treatment: filtering the water precipitation solution, ultrafiltering, refrigerating for 3 times, and repeatedly to obtain mixed extractive solution of Ginseng radix, radix astragali, and radix Acanthopanacis Senticosi, and refrigerating for use;
(5) extracting cantharis: soaking Mylabris in water, decocting for 5 times (each for 0.5 hr), filtering, concentrating, treating with lime sulfur method for 3 times, sterilizing, refrigerating, collecting supernatant, and concentrating;
(6) cantharis purification: adding ethanol into the concentrated cantharis solution to adjust the ethanol content of the concentrated cantharis solution to 90%, carrying out ethanol precipitation for 2 times, refrigerating, filtering the refrigerated liquid medicine, recovering the ethanol, precipitating with water for 3 times, filtering, adding sulfurous acid into the filtrate to adjust the pH value to 4.0-5.0, sterilizing, filtering after refrigerating, repeatedly carrying out ultrafiltration and refrigerating for 4 times, sterilizing to obtain a cantharis extracting solution, and refrigerating for later use;
(7) preparation of injection preparation: and (3) mixing the mixed extract of the ginseng, the astragalus and the acanthopanax in the step (4) with the extract of the cantharis in the step (6), adding auxiliary materials, adding water for dilution, adjusting the pH value, filtering, encapsulating and sterilizing to obtain the traditional Chinese medicine.
And (4) concentrating until the relative density is 1.15-1.25 at 60-70 ℃.
The step (4) of water precipitation is to add water into the liquid medicine for boiling and then refrigerate;
the cold storage is to refrigerate the liquid medicine for 1.5h at the temperature of 0 ℃;
the concentration in the step (5) is carried out until the relative density is 1.02-1.10 at the temperature of 60-70 ℃;
the alcohol precipitation in the step (6) is to add ethanol to adjust the alcohol content of the concentrated solution to 75 percent and 85 percent respectively and carry out two times of alcohol precipitation;
the step (6) of water precipitation is to add water into the liquid medicine, boil the liquid medicine, adjust the PH value to 4.0-5.0 by sulfurous acid, and refrigerate the liquid medicine;
performing ultrafiltration, refrigerating, performing ultrafiltration again, and repeating the operation for 4 times;
the dilution in step (7) is to dilute the mixed extract to 1000ml of final injection volume per 301.5g of the original material.
Example 4
(1) Selecting raw materials: taking 1.5g of cantharis, 50g of ginseng, 100g of astragalus and 150g of acanthopanax;
(2) extracting ginseng: soaking Ginseng radix in 40% ethanol, heating and reflux-extracting for 3 times (1 st for 3 hr and 1.5 hr each time), filtering, and recovering ethanol to obtain medicinal liquid;
(3) extracting ginseng, astragalus and acanthopanax: decocting the extracted Ginseng radix residue, radix astragali and radix Acanthopanacis Senticosi with water for 3 times, 1 st for 3 hr, 2-3 rd for 1 hr, filtering, concentrating, mixing with the Ginseng radix liquid obtained in step (2), and concentrating;
(4) purifying ginseng, astragalus and acanthopanax:
alcohol-water alternative treatment: adding ethanol into the concentrated solution to adjust the ethanol content to 75%, refrigerating, filtering, recovering ethanol, precipitating with water, filtering and concentrating the water-precipitated solution, adding ethanol, precipitating with ethanol, refrigerating for 2 times, and adjusting the ethanol content of the solution to 90% each time;
and (3) multiple water sedimentation treatment: filtering the cold storage liquid, recovering ethanol, then precipitating with water for 3 times, filtering, concentrating, sterilizing, refrigerating, adjusting pH to 7.0-7.6 after the cold storage liquid is filtered again, sterilizing, refrigerating, filtering, concentrating, precipitating with water;
and (3) filtering treatment: filtering the water precipitation solution, ultrafiltering, refrigerating for 2 times, and repeatedly to obtain mixed extractive solution of Ginseng radix, radix astragali, and radix Acanthopanacis Senticosi, and refrigerating for use;
(5) extracting cantharis: soaking Mylabris in water, decocting for 4 times (each for 1.5 hr), filtering, concentrating, treating with lime sulfur method for 2 times, sterilizing, refrigerating, collecting supernatant, and concentrating;
(6) cantharis purification: adding ethanol into the concentrated cantharis solution to adjust the ethanol content of the concentrated cantharis solution to 75%, carrying out alcohol precipitation for 3 times, refrigerating, filtering the refrigerated liquid medicine, recovering the ethanol, precipitating with water for 3 times, filtering, adding sulfurous acid into the filtrate to adjust the pH value to 4.0-5.0, sterilizing, filtering after refrigerating, repeatedly carrying out ultrafiltration and refrigerating for 3 times, sterilizing to obtain a cantharis extracting solution, and refrigerating for later use;
(7) preparation of injection preparation: and (3) mixing the mixed extract of the ginseng, the astragalus and the acanthopanax in the step (4) with the extract of the cantharis in the step (6), adding auxiliary materials, adding water for dilution, adjusting the pH value, filtering, encapsulating and sterilizing to obtain the traditional Chinese medicine.
And (4) concentrating until the relative density is 1.15-1.25 at 60-70 ℃.
The step (4) of water precipitation is to add water into the liquid medicine for boiling and then refrigerate;
the cold storage is to refrigerate the liquid medicine for 10 hours at the temperature of 8 ℃;
the concentration in the step (5) is carried out until the relative density is 1.02-1.10 at the temperature of 60-70 ℃;
the alcohol precipitation in the step (6) is carried out by adding ethanol to adjust the alcohol content of the concentrated solution to 75%, 80% and 85% respectively;
the step (6) of water precipitation is to add water into the liquid medicine, boil the liquid medicine, adjust the PH value to 4.0-5.0 by sulfurous acid, and refrigerate the liquid medicine;
performing ultrafiltration, refrigerating, performing ultrafiltration again, and repeating the operation for 3 times;
the dilution in step (7) is to dilute the mixed extract to 1000ml of final injection volume per 301.5g of the original material.
Example 5
(1) Selecting raw materials: taking 1.5g of cantharis, 50g of ginseng, 100g of astragalus and 150g of acanthopanax;
(2) extracting ginseng: soaking Ginseng radix in 60% ethanol, heating and reflux-extracting for 2 times (1 st for 3.5 hr and 2 hr each time), filtering, and recovering ethanol to obtain medicinal liquid;
(3) extracting ginseng, astragalus and acanthopanax: decocting the extracted ginseng residue, radix astragali and radix Acanthopanacis Senticosi in water for 2 times, 1 st 4 hr, 2 nd 1 hr, filtering, concentrating, mixing with the ginseng liquid obtained in step (2), and concentrating;
(4) purifying ginseng, astragalus and acanthopanax:
alcohol-water alternative treatment: adding ethanol into the concentrated solution to adjust the ethanol content to 80%, refrigerating, filtering, recovering ethanol, precipitating with water, filtering and concentrating the water-precipitated solution, adding ethanol, precipitating with ethanol, refrigerating for 1 time, and adjusting the ethanol content to 85%;
and (3) multiple water sedimentation treatment: filtering the cold storage liquid, recovering ethanol, then precipitating with water for 2 times, filtering, concentrating, sterilizing, refrigerating, adjusting pH to 7.0-7.6 after the cold storage liquid is filtered again, sterilizing, refrigerating, filtering, concentrating, precipitating with water;
and (3) filtering treatment: filtering the water precipitation solution, ultrafiltering, refrigerating for 2 times, and repeatedly to obtain mixed extractive solution of Ginseng radix, radix astragali, and radix Acanthopanacis Senticosi, and refrigerating for use;
(5) extracting cantharis: soaking Mylabris in water, decocting for 3 times (each for 1 hr), filtering, concentrating, treating with lime sulfur method for 3 times, sterilizing, refrigerating, collecting supernatant, and concentrating;
(6) cantharis purification: adding ethanol into the concentrated cantharis solution to adjust the ethanol content of the concentrated cantharis solution to 85%, carrying out alcohol precipitation for 2 times, refrigerating, filtering the refrigerated liquid medicine, recovering the ethanol, precipitating with water for 2 times, filtering, adding sulfurous acid into the filtrate to adjust the pH value to 4.0-5.0, sterilizing, filtering after refrigerating, repeatedly carrying out ultrafiltration and refrigerating for 2 times, sterilizing to obtain a cantharis extracting solution, and refrigerating for later use;
(7) preparation of injection preparation: and (3) mixing the mixed extract of the ginseng, the astragalus and the acanthopanax in the step (4) with the extract of the cantharis in the step (6), adding auxiliary materials, adding water for dilution, adjusting the pH value, filtering, encapsulating and sterilizing to obtain the traditional Chinese medicine.
And (4) concentrating until the relative density is 1.15-1.25 at 60-70 ℃.
The step (4) of water precipitation is to add water into the liquid medicine for boiling and then refrigerate;
the cold storage is to refrigerate the liquid medicine for 5 hours at 5 ℃;
the concentration in the step (5) is carried out until the relative density is 1.02-1.10 at the temperature of 60-70 ℃;
the alcohol precipitation in the step (6) is to add ethanol to adjust the alcohol content of the concentrated solution to 75 percent and 85 percent respectively and carry out two times of alcohol precipitation;
the step (6) of water precipitation is to add water into the liquid medicine, boil the liquid medicine, adjust the PH value to 4.0-5.0 by sulfurous acid, and refrigerate the liquid medicine;
performing ultrafiltration, refrigerating, performing ultrafiltration again, and repeating the operation for 2 times;
the dilution in step (7) is to dilute the mixed extract to 1000ml of final injection volume per 301.5g of the original material.
Comparative example 1: the injection is prepared according to the preparation method of the Aidi injection in the twentieth volume of the traditional Chinese medicine prescription preparation of the current ministry of health drug standards.
Comparative example 2: prepared according to example 3 of patent CN 200910102894.4.
Comparative example 3: prepared according to example 1 of patent cn200810301949. x.
Comparative example 4: prepared according to example 6 of patent CN 200510003151.3.
Test example 2: determination of content of active ingredient
The samples obtained in examples 1-5 and comparative examples 1-4 were tested according to the standards promulgated by the existing ministry and compared with the ginsenoside Re and cantharidin content as follows:
| ginsenoside Re content (mg/ml) | Cantharidin content (mu g/ml) | |
| Example 1 | 0.28 | 2.52 |
| Example 2 | 0.26 | 2.33 |
| Example 3 | 0.26 | 1.91 |
| Example 4 | 0.29 | 2.04 |
| Example 5 | 0.27 | 2.27 |
| Comparative example 1 | 0.20 | 1.85 |
| Comparative example 2 | 0.22 | 1.68 |
| Comparative example 3 | 0.23 | 1.63 |
| Comparative example 4 | 0.19 | 1.55 |
From the above data, the aidi injection obtained by the preparation method of the present invention is superior to the aidi injection obtained by the prior art of comparative examples 1-4 in the contents of ginsenoside Re and cantharidin.
Test example 3: pharmacodynamic experiments were conducted on the Addi injection solutions obtained in examples 1-5 and comparative examples 1-4.
1. Material
1.1 Experimental animals
SPF-grade KM mice, half male and half female, with a body weight of 20 + -2 g. Animals are raised in a raising environment that meets the requirements of environmental facilities for medical experimental animals. Feeding conditions are as follows: the room temperature is 25 +/-2 ℃, and the humidity is 60 +/-20%.
1.2 test drugs
Ady injection solutions obtained in examples 1 to 6 and comparative examples 1 to 4.
2. Method and results
The method comprises the following steps: collecting S180 mouse with good growth after passage, extracting ascites under aseptic condition, diluting with aseptic normal saline at a ratio of 1: 3, counting under microscope, and adjusting tumor cell number to 1.0 × 107 cells/ml (placing in ice bath); then, 200 test mice were divided into 10 groups of 20 mice, and 0.2ml of the test mice were inoculated subcutaneously to the axilla of each mouse and weighed after 24 hours. The Addi injection solutions obtained in examples 1-5 and comparative examples 1-4 were injected into 1-9 groups of mice, respectively, at an injection dose of 3.0g/kg, and the injection solutions obtained in examples 1-5 and comparative examples 1-4 were administered once per day to the tail vein of the mice, and 0.2ml of physiological saline was administered to the tail vein of the control group continuously for 10 days, and 24 hours after the last administration, the mice were sacrificed, and tumors were dissected and weighed. The results are as follows.
From the above data, it is understood that the aidi injection obtained by the preparation method of the present invention is superior to the prior art aidi injections of comparative examples 1 to 4 in the tumor inhibition rate.
Test example 4: safety test
Rabbit and guinea pig were selected according to the technical guidelines for drug stimulation, allergy and hemolysis studies, the Addie injections obtained in examples 1-5 and comparative examples 1-4 were subjected to vascular stimulation, allergy and hemolysis tests, and subsequent follow-up recording work was done. The results obtained show that the preparations of examples 1 to 5 of the present invention, after a number of vascular irritation tests (14 to 21 days), were visually observed to have no hyperemia, necrotic edema, etc. in rabbits; in anaphylaxis test, 1ml of intravenous Aidi preparation is injected 14 days and 21 days after the first injection, the phenomena of hair erection, trembling, retching, continuous sneezing for 3 times, continuous coughing for 3 times, purpura, dyspnea and the like of the guinea pig are not obvious in 30 minutes after the injection, and the phenomena of stool incontinence, unstable gait or falling, convulsion, shock and death are not generated; hemolysis and erythrocyte coagulation did not occur within 3 hours after the hemolytic test was performed. The scientific contract of the preparation process of the invention is shown, and the problem of adverse reaction is greatly reduced. In addition, the Addie injection preparations obtained in comparative examples 1-4 have positive reactions of different degrees in multiple vascular irritation tests, anaphylaxis tests and hemolysis tests, but the cases are not serious.
From the above data, the aidi injection prepared by the method of preparing the aidi injection of the present invention has advantages in reducing the incidence of adverse reactions and higher safety compared to the prior art aidi injections of comparative examples 1 to 4.
Finally, it should be noted that the above embodiments are merely representative examples of the present invention. Obviously, the technical solution of the present invention is not limited to the above-described embodiments, and many variations are possible. All modifications which can be derived or suggested by a person skilled in the art from the disclosure of the present invention are to be considered within the scope of the invention.
Claims (7)
1. A preparation process of an Aidi injection preparation is characterized by comprising the following steps:
(1) selecting raw materials: taking cantharis, ginseng, astragalus and acanthopanax raw materials;
(2) extracting ginseng: soaking Ginseng radix in 30-80% ethanol under warm condition, reflux-extracting under heating for 2 times (2.5-4 hr for 1 time and 1-2 hr for each time), filtering, and recovering ethanol to obtain medicinal liquid;
(3) extracting ginseng, astragalus and acanthopanax: decocting the extracted Ginseng radix residue, radix astragali and radix Acanthopanacis Senticosi with water for 2-4 times, 1 st time for 2.5-4 hr, 2-4 th time for 1-2 hr, filtering, concentrating, mixing with the Ginseng radix liquid obtained in step (2), and concentrating;
(4) purifying ginseng, astragalus and acanthopanax:
alcohol-water alternative treatment: adding ethanol into the concentrated solution to adjust ethanol content to 70-80%, refrigerating, filtering, recovering ethanol, precipitating with water, filtering and concentrating the water-precipitated solution, adding ethanol, precipitating with ethanol, refrigerating for 1-2 times, and adjusting ethanol content of the solution to 85-95% each time;
and (3) multiple water sedimentation treatment: filtering the cold storage liquid, recovering ethanol, then precipitating with water for 2 times or more, filtering, concentrating, sterilizing, refrigerating, filtering the cold storage liquid again, adjusting pH to 7.0-7.6, sterilizing, refrigerating, filtering, concentrating, precipitating with water;
and (3) filtering treatment: filtering the water precipitation solution, ultrafiltering, refrigerating for 2-3 times, and repeatedly to obtain mixed extractive solution of Ginseng radix, radix astragali, and radix Acanthopanacis Senticosi, and refrigerating for use;
the step (4) of water precipitation is to add water into the liquid medicine for boiling and then refrigerate;
(5) extracting cantharis: soaking Mylabris in water, decocting for 0.5-2 hr for 2-5 times, filtering, concentrating, treating with lime sulfur method for 2-3 times, sterilizing, refrigerating, collecting supernatant, and concentrating;
(6) cantharis purification: adding ethanol into a cantharis concentrated solution to adjust the ethanol content of the concentrated solution to 70-90%, carrying out alcohol precipitation for 2-3 times, refrigerating, filtering the refrigerated liquid medicine, recovering the ethanol, precipitating with water for 2-3 times, filtering, adding sulfurous acid into the filtrate to adjust the pH value to 4.0-5.0, sterilizing, filtering after refrigerating, repeatedly carrying out ultrafiltration and refrigerating for 2-4 times, sterilizing to obtain a cantharis extracting solution, and refrigerating for later use;
the alcohol precipitation in the step (6) is carried out by adding ethanol to adjust the alcohol content of the concentrated solution to 75%, 80% and 85% respectively; the step (6) of water precipitation is to add water into the liquid medicine, boil the liquid medicine, adjust the PH value to 4.0-5.0 by sulfurous acid, and refrigerate the liquid medicine;
(7) preparation of injection preparation: mixing the mixed extract of the ginseng, the astragalus and the acanthopanax in the step (4) with the extract of the cantharis in the step (6), adding auxiliary materials, adding water for dilution, adjusting the pH value, filtering, encapsulating and sterilizing to obtain the compound cantharis extract;
and the cold storage is to refrigerate the liquid medicine for 0.5 to 10 hours at the temperature of between-1 and 8 ℃.
2. The preparation process of the Aidi injection as claimed in claim 1, wherein the step (1) comprises weighing Mylabris 1-2 parts, Ginseng radix 30-80 parts, radix astragali 80-120 parts, and radix Acanthopanacis Senticosi 130-180 parts by weight.
3. The process for preparing an Adi injection preparation according to claim 1, wherein the concentration in the steps (3) and (4) is carried out to a relative density of 1.15 to 1.25 at 60 ℃ to 70 ℃.
4. The process for preparing an Adi injection preparation according to claim 1, wherein the concentration in the step (5) is performed to a relative density of 1.02 to 1.10 at a temperature of 60 ℃ to 70 ℃.
5. The process for preparing an Adie injection preparation according to claim 1, wherein the ultrafiltration in step (6) is performed by performing cold storage after ultrafiltration, performing ultrafiltration again, and repeating the operation 2-4 times.
6. The process for preparing an Adi injection preparation according to claim 1, wherein the dilution in step (7) is to dilute the mixed extract to a final injection volume of 1000ml per 301.5g of the original material.
7. The process for preparing an Adi injection formulation according to claim 1, wherein the steps are as follows:
(1) selecting raw materials: taking 1.5g of cantharis, 50g of ginseng, 100g of astragalus and 150g of acanthopanax;
(2) extracting ginseng: soaking Ginseng radix in 50% ethanol, heating and reflux-extracting for 2 times (1 st for 3 hr and 1.5 hr) for the second time, filtering, and recovering ethanol to obtain medicinal liquid;
(3) extracting ginseng, astragalus and acanthopanax: decocting the extracted Ginseng radix residue, radix astragali and radix Acanthopanacis Senticosi with water for 3 times, 1 st 3 hr, 2 nd 1.5 hr, 3 rd 1 hr, filtering, mixing with the Ginseng radix liquid medicine obtained in step (2), and concentrating to relative density of 1.15-1.20 at 60-70 deg.C;
alcohol-water alternative treatment: adding ethanol into the concentrated solution to adjust the ethanol content to 75%, refrigerating, filtering, recovering ethanol, precipitating the medicinal liquid with water, specifically, adding water, boiling, refrigerating, filtering, concentrating to relative density of 1.15-1.20 at 60-70 deg.C, adding ethanol to adjust the ethanol content to 90%, and refrigerating;
and (3) multiple water sedimentation treatment: filtering the cold storage solution, recovering ethanol, and precipitating the liquid medicine with water twice; filtering, concentrating the filtrate, sterilizing, and refrigerating; sterilizing, refrigerating, filtering the refrigerated solution again, adjusting pH to 7.0-7.6, sterilizing, refrigerating, filtering, concentrating, and precipitating with water;
and (3) filtering treatment: filtering the water precipitation solution, ultrafiltering, refrigerating, ultrafiltering again to obtain mixed extractive solution of Ginseng radix, radix astragali, and radix Acanthopanacis Senticosi, and refrigerating for use;
(5) extracting cantharis: soaking Mylabris in water, decocting for 4 times (each for 1 hr), filtering, concentrating, treating for 2 times with lime-sulfur method, specifically with calcium oxide and sulfurous acid, sterilizing, refrigerating, collecting supernatant, and concentrating to relative density of 1.02-1.10 at 60-70 deg.C;
(6) cantharis purification: precipitating Mylabris concentrate with ethanol twice, adding ethanol to ethanol content of 75% and 85%, cold preserving, filtering, recovering ethanol, adding water into the medicinal liquid, boiling, adjusting pH to 4.5 with sulfurous acid, precipitating with cold-preserved water for 2 times, filtering the precipitated solution, adding sulfurous acid into the filtrate to adjust pH to 4.0-5.0, sterilizing, cold preserving, filtering, ultrafiltering, and cold preserving; ultrafiltering, sterilizing to obtain Mylabris extract, and refrigerating;
(7) preparation of injection preparation: and (3) mixing the mixed extract of the ginseng, the astragalus and the acanthopanax in the step (4) with the extract of the cantharis in the step (6), adding glycerol and polysorbate-80, adding water to dilute to 1000ml, adjusting the pH value, filtering, encapsulating, and sterilizing at 115 ℃ for 30min to obtain the traditional Chinese medicine.
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Address after: 550008 No. 220-1 Baiyun Avenue, Yunyan District, Guiyang City, Guizhou Province Applicant after: Yibai Pharmaceutical Co., Ltd., Guizhou Address before: 550008 Baiyun District, Baiyun District, Guiyang, Guizhou Province, No. 220-1 Applicant before: Yibai Pharmaceutical Co., Ltd., Guizhou |
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