CN112168934A - Chinese medicine compound granule and preparation method thereof - Google Patents
Chinese medicine compound granule and preparation method thereof Download PDFInfo
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- CN112168934A CN112168934A CN202011106557.5A CN202011106557A CN112168934A CN 112168934 A CN112168934 A CN 112168934A CN 202011106557 A CN202011106557 A CN 202011106557A CN 112168934 A CN112168934 A CN 112168934A
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Abstract
The invention discloses a traditional Chinese medicine compound granule and a preparation method thereof. The traditional Chinese medicine compound granule is prepared from an auxiliary material and a traditional Chinese medicine extract serving as an active ingredient, wherein the auxiliary material contains a filler, and the traditional Chinese medicine extract is a full-ingredient extract extracted from a traditional Chinese medicine composition consisting of the following components in parts by weight: 5-8 parts of cornus officinalis; 3-5 parts of prepared rehmannia root; 2-5 parts of fructus psoraleae; 2-4 parts of radix astragali Preparata; 2-4 parts of angelica; 0.5-3 parts of donkey-hide gelatin; 2-4 parts of caulis spatholobi; 2-4 parts of codonopsis pilosula; 3-5 parts of vinegar turtle shell; and 0.5-2 parts of fructus amomi. The traditional Chinese medicine compound granule can provide patients with good medication compliance, is convenient to carry, store, transport and take, is more storage-resistant, safer to take, has less toxic and side effects, and has good treatment efficacy on thalassemia.
Description
Technical Field
The invention relates to a traditional Chinese medicine compound granule and a preparation method thereof.
Background
Thalassemia is a hereditary hematopathy caused by the inability of a human body to normally synthesize hemoglobin globin due to congenital gene defects, is also called globin aplastic anemia, is a monogenic hereditary disease with the highest incidence and the greatest harm worldwide, belongs to refractory hereditary hemolytic anemia, and is named after being discovered in the Mediterranean region. The pathogenesis of the human body is that the gene which is positioned on the chromosome 11 and the chromosome 16 and regulates the synthesis of globin is mutated or deleted, so that a large number of ineffective red blood cells are generated, hemolytic anemia is finally caused, and the subsequent accumulation influences the functions of human body vital organs such as heart, spleen and the like. Thalassemia has a clear thalassemia profile: sallow complexion, large head, raised cheekbones, depressed nose bridge, puffy eyelids, yellow skin color like loess, pale lips and tongue, and hepatosplenomegaly. According to the report of the WHO secretary, about 1 hundred million people carry thalassemia genes all over the world, and about 30 million infants suffer from thalassemia syndromes every year at birth. China is a high-incidence country of thalassemia. The thalassemia is mainly harmful to two types in China, namely alpha-type and beta-type, and the incidence rate of the thalassemia in southern provinces is high. The number of gene carriers of thalassemia of the three provinces of Guangxi, Guangdong and Hainan reaches 2000 to over ten thousand. The disease is mainly developed by infants and juveniles and is manifested by consumptive disease, vertigo, palpitation, jaundice, scar accumulation in the abdomen, growth and development retardation and the like. The patients have severe anemia and poor appearance. The hemogram has erythrocyte hypochromatism, and can show increase of target cells, reticulocyte, and decrease of nuclear erythrocyte and erythrocyte osmotic pressure. Patients with beta thalassaemia trait, in addition to the above characteristics, exhibit clinically: soreness and weakness of waist and knees, vertigo, palpitation, short breath, asthenia, alopecia, tinnitus, complexion, pale lips, pale nails, feverish palms and soles, night sweat, etc.
Internationally, the treatment principle for thalassemia is still dominated by blood transfusion and iron-removal therapy. Except for the fact that mild thalassemia does not require special treatment clinically (folic acid and vitamin E need to be supplemented properly), the alpha and beta thalassemia intermedia are generally treated by a small amount of red blood cells infusion method, and the beta thalassemia major is treated by high-dose blood transfusion or concentrated red blood cell infusion combined with an iron removal agent, which is a basic treatment measure, and medium and high-dose blood transfusion is given from the early stage to ensure that the growth and development of children patients are close to normal, reduce the iron absorption of intestinal tracts, inhibit splenomegaly and prevent skeletal lesion. The method comprises the following steps: repeatedly infusing concentrated red blood cells to ensure that the hemoglobin content of the children patients reaches 120-150 g/L; then, 10-15 ml/kg of concentrated red blood cells are infused every 2-4 weeks to keep the hemoglobin content above 90-105 g/L. However, this method is likely to cause hemosiderosis, and should be administered with iron chelating agent (deferoxamine mesylate, deferiprone tablet for injection, etc.) to increase iron excretion from urine and feces, but not prevent iron absorption from gastrointestinal tract, and can cause cataract and bone development disorder after long-term administration, and can cause visual and auditory deterioration due to overdose. However, the treatment is only sustained for a maximum of ten years because of massive hemolysis of thalassemia patients to cause the hyperactivity of the large spleen and aggravation of anemia and iron deposition to cause other organ damage. Splenectomy surgical treatment: splenectomy has a better effect on alpha thalassemia and beta thalassemia intermediate, and a poor effect on beta thalassemia heavy. Splenectomy can lead to diminished immune function and severe sequelae. And should be administered after 5-6 years of age and strictly control the indications. Bone marrow and stem cell transplantation: allogeneic hematopoietic stem cell transplantation is the method which can radically cure severe beta thalassemia at present. For example, HLA matched hematopoietic stem cell donors, should be the first choice for the treatment of beta thalassemia major. But is currently limited by the source and the type of marrow, which is difficult to popularize and expensive. Gene therapy: gene therapy can increase gamma gene expression or decrease alpha gene expression to improve the symptoms of beta thalassemia. Although the method is a future development direction, the homologous recombination rate is not solved, and the clinical application is still in the current date. In addition, some chemotherapy drugs such as hydroxyurea, 5-azacytidine, cytarabine, Marilan and isoniazid are tried to perform exploratory treatment at home and abroad, but the clinical application of the drugs is limited due to uncertain curative effect and strong side effect. Therefore, effective treatment of thalassemia remains a worldwide problem, and there are few mediterranean and western drugs effective in treating thalassemia to date.
CN200610078866.X discloses a medicine for treating thalassemia and its preparation process, however, the process route is complicated, the final obtained paste contains Polygoni Multiflori radix extract and organic solvent residue, and is unsafe for long-term administration, and the organic solvent used in the ethanol extraction process is easy to explode, which is a great safety production hidden trouble; in addition, the angelica and the amomum fruit only extract partial effective components in the form of volatile oil, some effective components do not enter final products at all and only part of the effective components enter the final products, so that the final medicine efficacy performance is influenced, and the finally obtained ointment has large weight, is difficult to store and transport, is easy to decay and is inconvenient to take; in addition, the process also needs complex volatile oil inclusion and drying steps, the loss of the volatile oil inclusion compound is large in the drying process, and meanwhile, the production cost is increased.
Thus, there is still a need for improved medicaments for the treatment of thalassemia and processes for their preparation.
Disclosure of Invention
In order to overcome the problems of the prior art, the invention aims to provide the traditional Chinese medicine compound granule which can provide good medication compliance for patients, is convenient to carry, store, transport and take, is more storage-resistant, safer in medication and less in toxic and side effects, and has good efficacy for treating thalassemia.
Another object of the present invention is to provide a method for preparing a compound Chinese medicinal granule, which can avoid the potential safety hazard of organic solvent explosion, reduce the production cost, and extract the effective components of each Chinese medicinal component in full composition, and can prepare a compound Chinese medicinal granule which can provide patients with good compliance, is convenient to carry, store, transport and take, is more storage-resistant, safer to use, has less toxic or side effects, and has good therapeutic efficacy on thalassemia.
In order to achieve the above objects, one aspect of the present invention provides a compound Chinese medicine granule, which is prepared from an adjuvant and a Chinese medicine extract as an active ingredient, wherein the adjuvant contains a filler, and the Chinese medicine extract is a full-ingredient extract extracted from a Chinese medicine composition consisting of the following components in parts by weight: 5-8 parts of cornus officinalis; 3-5 parts of prepared rehmannia root; 2-5 parts of fructus psoraleae; 2-4 parts of radix astragali Preparata; 2-4 parts of angelica; 0.5-3 parts of donkey-hide gelatin; 2-4 parts of caulis spatholobi; 2-4 parts of codonopsis pilosula; 3-5 parts of vinegar turtle shell; and 0.5-2 parts of fructus amomi.
According to the traditional Chinese medicine compound granule, the traditional Chinese medicine composition is further composed of the following components in parts by weight: 6 parts of cornus officinalis; 4 parts of prepared rehmannia root; 3 parts of fructus psoraleae; 3 parts of radix astragali Preparata; 3 parts of Chinese angelica; 1 part of donkey-hide gelatin; 3 parts of caulis spatholobi; 3 parts of codonopsis pilosula; 4 parts of vinegar turtle shell; and 1 part of fructus amomi.
The traditional Chinese medicine compound granule is characterized in that the amount of the filler is 10-70 wt% based on the total weight of the traditional Chinese medicine compound granule.
According to the compound traditional Chinese medicine granule, the filler is selected from sucrose, soluble starch or a combination of the sucrose and the soluble starch.
According to the traditional Chinese medicine compound granule, the auxiliary material further contains a flavoring agent, and the amount of the flavoring agent is 0.1-10 wt% based on the total weight of the traditional Chinese medicine compound granule.
Another aspect of the present invention provides a method for preparing the chinese herbal compound granule described in any one of the above, comprising the steps of: steam distilling fructus Amomi and collecting volatile oil and distilled water solution; decocting Corni fructus, radix rehmanniae Preparata, fructus Psoraleae preparata, radix astragali Preparata, radix Angelicae sinensis, radix Codonopsis, caulis Spatholobi and carapax Trionycis processed with vinegar with water to obtain water extractive solution; mixing the distilled water solution with the water extracting solution and concentrating into thick paste; drying the thick paste to obtain dry paste; grinding colla Corii Asini and the dry extract and adding adjuvant containing filler to dry mix to obtain dry mixture; dry granulating the dry blend to obtain a semi-finished granulate; granulating the semi-finished product particles; spraying the volatile oil into the granulated semi-finished product particles, and sealing and moistening to obtain the traditional Chinese medicine compound granule.
According to the method of the invention, further, the method comprises a step of dry granulation of the semifinished granules removed after finishing.
According to the method, the step of mixing the distilled water solution and the water extracting solution and concentrating the mixture into thick paste is further carried out at the temperature of 40-100 ℃ under the reduced pressure condition.
According to the method, the step of drying the thick paste to obtain dry paste is further carried out at the temperature of 40-100 ℃ under reduced pressure.
According to the method of the invention, further, the method comprises the step of drying the sized semi-finished pellets so that the moisture content of the pellets does not exceed 13% by weight.
Advantageous effects
According to the method, the process route is simple, organic solvent extraction processes such as ethanol and the like are not adopted, and organic solvent is not required, so that the potential safety production hazard of organic solvent explosion is avoided, the cost is reduced, a complex fructus amomi volatile oil inclusion process is not required, the cost is further reduced, the fructus amomi adopts a full-component distillation extraction process to extract the full components (including volatile oil and distilled water solution) of the fructus amomi, the angelica sinensis adopts a water decoction process to extract the full components of the radix angelicae sinensis, the full components enter a final preparation product, the drug effect is better played, and the clinical effect of the traditional Chinese medicine decoction is better met; moreover, according to the method of the invention, a dry granulation process is adopted, the obtained traditional Chinese medicine compound preparation is granules, is convenient for patients to carry, store, transport and take, has good compliance, high drug loading, better storage resistance and less possibility of putrefaction, does not contain polygonum multiflorum extract with hepatotoxicity and organic solvent residues, is safer to use and has less toxic and side effects. In addition, the fructus psoraleae with the active ingredients which are easy to dissolve and have stronger kidney tonifying effect and the vinegar turtle shell with the active ingredients which are easy to dissolve and have stronger hardness softening and resolving effects are further combined, so that the traditional Chinese medicine compound granule has the functions of nourishing yin and tonifying kidney, benefiting marrow and generating blood, and tonifying qi and strengthening spleen, and is suitable for treating alpha-and beta-thalassemia.
Animal toxicity experiments show that the traditional Chinese medicine compound granule has better safety and lower toxic and side effects, and the maximum dosage can reach 162.36g crude drug/kg, which is equivalent to 104.75 times of clinical dosage; and no drug delayed toxic reaction is seen after the drug is administered for 6 months within the dosage range of 9-36 g/kg/d, which indicates that the safe use dosage of the granules at the level of SD rats is at least over 36 g/kg.
The research result of the influence of the traditional Chinese medicine compound granules on the proliferation and differentiation of the early hematopoietic progenitor cells of the mouse bone marrow shows that the increase of each dose group is 3.5Gy60The number of peripheral blood leukocytes in mouse kidney deficiency marrow damage model blood caused by Co-gamma ray irradiation promotes the proliferation of CFU-GM and CFU-E, CFU-Meg, and increases the content of CFU-GM and CFU-E, CFU-Meg in mouse bone marrowCD34+ cell number, wherein the high-dose group has significant effect on peripheral blood leukocyte, the high-and medium-dose groups have significant effect on bone marrow hematopoietic stem/progenitor cells, and the low-dose group has significant effect on 0D34+ cells. The Chinese medicinal compound granule can be used for preventing and treating60The pharmacodynamics research result of the Co-gamma ray induced rat aplastic anemia shows that the medicine is used for treating the aplastic anemia60The curative effect of the aplastic anemia of the rats induced by the Co-gamma rays is positive.
Detailed Description
The traditional Chinese medicine compound granule is prepared from an auxiliary material and a traditional Chinese medicine extract serving as an active ingredient, wherein the auxiliary material contains a filler, and the traditional Chinese medicine extract is a full-ingredient extract extracted from a traditional Chinese medicine composition consisting of the following components in parts by weight: 5-8 parts of cornus officinalis; 3-5 parts of prepared rehmannia root; 2-5 parts of fructus psoraleae; 2-4 parts of radix astragali Preparata; 2-4 parts of angelica; 0.5-3 parts of donkey-hide gelatin; 2-4 parts of caulis spatholobi; 2-4 parts of codonopsis pilosula; 3-5 parts of vinegar turtle shell; and 0.5-2 parts of fructus amomi.
The traditional Chinese medicine preparation takes the cornus pulp as a monarch drug, has the effects of nourishing yin and tonifying kidney, and aims to tonify the kidney and the genuine yin (essence) to nourish the genuine yin, so that the marrow sea is full, and the blood has a source of life, so that the pulp can be benefited, the essence can be generated, and the blood can be transformed. Prepared rehmannia root, radix astragali preparata, radix codonopsitis, angelica, salt fructus psoraleae and donkey-hide gelatin are used as ministerial drugs. The prepared rehmannia root and the salt fructus psoraleae assist the monarch drugs in producing essence and blood and strengthening the function of tonifying the kidney, and the salt fructus psoraleae tonify the kidney yang and grow the yang qi, so that the effective components are easier to dissolve out and the kidney tonifying effect is stronger compared with the fructus psoraleae. Radix astragali Preparata tonifies middle-jiao and qi, and colla Corii Asini nourishes yin and blood, and has the effect of tonifying qi and blood. The kidney-tonifying medicine is used for fundamentally treating thalassemia and can be used for treating root causes, while the blood-tonifying medicine is used for treating symptoms and root causes, and the treatment of both symptoms and root causes brings out the best in each other. In this disease, the spleen fails to warm and nourish spleen due to kidney deficiency, and the spleen governs qi and blood, while spleen deficiency causes qi weakness and fails to direct qi and blood, resulting in blood stasis and scar accumulation. Radix astragali Preparata and radix Codonopsis can tonify qi, qi is commander of blood, and qi circulation is blood circulation. The caulis spatholobi and the vinegar turtle shell are used as adjuvant drugs, and the caulis spatholobi and the vinegar turtle shell nourish yin and blood, so that the hard lumps are softened and dissipated, and scar and mass in the abdomen are dissipated, wherein the vinegar turtle shell has the advantages that the effective ingredients are easier to dissolve out and the hard lumps are softened and dissipated more strongly compared with the turtle shell. Make fructus Amomi as a guiding drug, reduce the greasy taste of yin-nourishing and blood-tonifying drugs, so that the medicine does not affect spleen and stomach after long-term administration. The Chinese medicinal preparation combines monarch, minister, assistant and guide to play the roles of nourishing yin and tonifying kidney, benefiting marrow and generating blood, and tonifying qi and strengthening spleen. Can treat both principal and secondary aspects of diseases, and is very suitable for treatment based on syndrome differentiation and treatment with the etiology and pathogenesis of thalassemia.
In the present invention, the term "full ingredient extract" means that all the effective ingredients of each component of the Chinese medicinal material composition are extracted and enter the final Chinese medicinal compound granule during extraction.
In the compound traditional Chinese medicine granule, the traditional Chinese medicine composition preferably comprises the following components in parts by weight: 6 parts of cornus officinalis; 4 parts of prepared rehmannia root; 3 parts of fructus psoraleae; 3 parts of radix astragali Preparata; 3 parts of Chinese angelica; 1 part of donkey-hide gelatin; 3 parts of caulis spatholobi; 3 parts of codonopsis pilosula; 4 parts of vinegar turtle shell; and 1 part of fructus amomi.
The traditional Chinese medicine compound granules contain auxiliary materials. The adjuvant should contain a filler. In some more specific embodiments, the adjuvant may contain a flavoring agent in addition to the filler. The filler may be selected from sucrose, soluble starch or a combination thereof, and the flavoring agent may be selected from steviosin and the like. When the compound traditional Chinese medicine granule contains a filler, the amount of the filler can be 10-70 wt% based on the total weight of the compound traditional Chinese medicine granule. When the compound traditional Chinese medicine granules contain the flavoring agent, the amount of the flavoring agent can be 0.1-10 wt% based on the total weight of the compound traditional Chinese medicine granules.
The traditional Chinese medicine compound granule is prepared by the preparation method of the traditional Chinese medicine compound granule. The method may comprise the steps of: steam distilling fructus Amomi and collecting volatile oil and distilled water solution; decocting Corni fructus, radix rehmanniae Preparata, fructus Psoraleae preparata, radix astragali Preparata, radix Angelicae sinensis, radix Codonopsis, caulis Spatholobi and carapax Trionycis processed with vinegar with water to obtain water extractive solution; mixing the distilled water solution with the water extracting solution and concentrating into thick paste; drying the thick paste to obtain dry paste; grinding colla Corii Asini and the dry extract and adding adjuvant containing filler to dry mix to obtain dry mixture; dry granulating the dry blend to obtain a semi-finished granulate; granulating the semi-finished product particles; spraying the volatile oil into the granulated semi-finished product particles, and sealing and moistening to obtain the traditional Chinese medicine compound granule.
In the method according to the present invention, amomum villosum may be subjected to steam distillation and the volatile oil and the distilled aqueous solution may be collected. Specifically, fructus Amomi can be added into volatile oil extraction tank, water is added, heating is carried out, steam distillation is carried out, volatile oil is collected (sealed), distilled water solution can be collected in another container, and impurity removal and clarification treatment is carried out by centrifugation or filtration. Before the amomum villosum is put into the volatile oil extraction tank, a grinder or a pulverizer can be used for mashing the amomum villosum, and the added water can be 6-10 times of the amomum villosum. The fructus amomi can be soaked in water for 0-4 hours before distillation, or the soaking can be omitted. The time for steam distillation may be 6 hours. Most preferably, the distillation extraction is carried out with 8 times of water for 6 hours because the extraction amount of the volatile oil is the largest.
In the method according to the present invention, a premix of cornus officinalis, rehmanniae radix preparata, salted psoralea corylifolia, astragalus membranaceus preparata, angelica sinensis, codonopsis pilosula, spatholobus stem and vinegar-processed turtle shell may be decocted with water to obtain an aqueous extract. This step may be performed using an extractor set. The decoction can be carried out several times. The decoction time can be 0.5-4 hours. In some embodiments, the decoction may be added with water and decocted three times, each for 1 hour. The amount of water added can be 6-8 times of the amount of the premix. In some more specific embodiments, the water is added in an amount 8 times (first), 6 times (second), 6 times (third) the amount of the premix for 1.0 hour each time in three times. After the decoction, the water extract may be clarified by centrifugation or filtration to remove impurities.
Then, the distilled water solution of the fructus amomi and the water extracting solution can be mixed and concentrated into thick paste. The concentration may be carried out at a temperature of 40 to 100 ℃ under reduced pressure (e.g., vacuum). The relative density of the concentrated thick paste is usually 1.34-1.38 (70-80 ℃).
After concentration, the thick paste may be dried to a dry paste. The drying may be carried out at a temperature of 40 to 100 ℃ under reduced pressure (e.g., vacuum). The drying time may be 12 hours or more.
According to the method of the present invention, after obtaining a dry paste, donkey-hide gelatin and the dry paste may be ground and added with an adjuvant containing a filler to be dry-mixed to obtain a dry mixture. The donkey-hide gelatin and the dry extract may be separately ground into fine powders (e.g., 80 mesh), and then mixed together with adjuvants containing fillers to obtain a dry mixture; alternatively, the donkey-hide gelatin and the dry extract may be ground together into a fine powder and then mixed together with an adjuvant containing a filler to obtain a dry mixture. The grinding may be performed using a pulverizer or a grinder. The weight ratio of the dry paste powder to the filler can be 9: 1-3: 7, preferably 1: 1-3: 1.
the dry blend may then be dry granulated to obtain a semi-finished granulate. Dry granulation may be carried out using a dry granulator. The rotating speed of the roller can be 10-20 rpm, the rotating speed of the blanking paddle can be 20-40 rpm, the pressure of the roller can be in the range of 4-8 MPa, and the pressure of the side seal can be in the range of 1-3 MPa.
According to the invention, after dry granulation, the semi-finished granules can be subjected to size stabilization. The granulation can be carried out as follows: screening with a 12-mesh sieve, then sorting with 10-mesh and 30-mesh sieves, and collecting particles which pass through the 10-mesh sieve but cannot pass through the 30-mesh sieve.
After finishing the granules, spraying the amomum villosum volatile oil into the granulated semi-finished product granules and sealing and moistening to obtain the traditional Chinese medicine compound granules. After spraying the fructus amomi volatile oil, mixing and moistening in a closed container can be carried out. The moistening time is usually 2 hours or more.
The process according to the invention may also comprise a step of dry granulation of the semifinished granules removed after finishing. Specifically, the granules that could not pass through a 10 mesh sieve and could pass through a 30 mesh sieve could be re-granulated. The conditions for re-granulation were as described above.
The moisture content of the semi-finished product granules obtained by dry granulation is not more than 13%, preferably 5.0%, if the moisture content exceeds the standard, the semi-finished product granules need to be dried at the temperature of below 80 ℃ until the moisture content reaches the standard. Thus, the process according to the invention may also comprise a step of drying the sized pellets of the semi-finished product so that the moisture of the pellets does not exceed 5.0% by weight. The drying temperature can be 50-80 ℃.
In addition, the method can also comprise the step of mixing the Chinese herbal compound granules. The total mixing time may be 15 minutes.
Hereinafter, the present invention will be specifically described by some examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the present invention in any way.
Example 1
Preparation of Chinese medicine compound granules
Firstly, removing impurities and non-medicinal parts from fructus amomi, and then crushing the fructus amomi by using a crusher. Putting 62.5g of crushed fructus amomi into a volatile oil extraction tank group, adding 8 times of water, heating, carrying out steam distillation for 6 hours, collecting volatile oil (sealing), collecting distilled water solution in another container, and filtering (the aperture of a filter is not less than 200 meshes).
Putting 375g of dogwood fruit, 250g of prepared rehmannia root, 187.5g of fried astragalus, 187.5g of codonopsis pilosula, 187.5g of angelica, 187.5g of fructus psoraleae, 187.5g of caulis spatholobi and 250g of vinegar turtle shell into an extraction machine set, adding water for decocting for three times (8 times of water is added for the first time, 6 times of water is added for the second time and the third time), each time for 1 hour, filtering decoction (the aperture of a filter is not less than 200 meshes), combining the filtrate with distilled aqueous solution of fructus amomi, and concentrating in vacuum at 70 ℃ to form thick paste with the relative density of 1.34-1.38 (70-80 ℃). Vacuum drying the soft extract at 80 deg.C for 12 hr to obtain dry extract, and cooling. Pulverizing the dry extract into fine powder (80 mesh) with pulverizer to obtain dry extract powder.
62.5g of donkey-hide gelatin is pulverized into fine powder (80 meshes) by a pulverizer. Then dry extract powder, donkey-hide gelatin powder and 10g of steviosin and sucrose powder (the weight ratio of dry extract powder to sucrose is about 1: 1) are put into a mixer in sequence and dry-mixed for 5 minutes. Granulating with 20 mesh sieve using dry granulator (granulating conditions: roller rotation speed is 15rpm, blanking paddle rotation speed is 30rpm, roller pressure is 6MPa, and side sealing pressure is 2MPa) to obtain semi-finished granules. The whole grain is sieved by a 12-mesh sieve, and the grains are sieved by a 10-mesh sieve and a 30-mesh sieve, and the grains which pass through the 10-mesh sieve but cannot pass through the 30-mesh sieve are collected. The granules which could not pass through a 10 mesh sieve and could pass through a 30 mesh sieve were re-granulated. The granules obtained after granulation are combined with the granules after size stabilization.
And finally, spraying the fructus amomi volatile oil into the granules in a mixer while stirring, carrying out dry mixing for 5 minutes, transferring into a material barrel, and sealing and moistening for 2 hours. Finally, the granules are mixed for 15 minutes and bagged.
Example 2
Firstly, removing impurities and non-medicinal parts from fructus amomi, and then crushing the fructus amomi by using a crusher. Putting 62.5g of crushed fructus amomi into a volatile oil extraction tank group, adding 8 times of water, heating, carrying out steam distillation for 6 hours, collecting volatile oil (sealing), collecting distilled water solution in another container, and filtering (the aperture of a filter is not less than 200 meshes).
Putting 500g of cornus officinalis, 250g of prepared rehmannia root, 187.5g of prepared astragalus root, 187.5g of codonopsis pilosula, 125g of angelica, 187.5g of fructus psoraleae, 125g of caulis spatholobi and 250g of vinegar turtle shell into an extraction machine set, adding water for decocting for three times (8 times of water is added for the first time, 6 times of water is added for the second time and the third time), filtering decoction (the aperture of a filter is not less than 200 meshes) each time for 1 hour, combining the filtrate with the distilled aqueous solution of fructus amomi, and concentrating in vacuum at 80 ℃ to form thick paste with the relative density of 1.34-1.38 (70-80 ℃). Vacuum drying the soft extract at 90 deg.C for 12 hr to obtain dry extract, and cooling. Pulverizing the dry extract into fine powder (80 mesh) with pulverizer to obtain dry extract powder.
187.5g colla Corii Asini is pulverized into fine powder (80 mesh) by pulverizer. Then dry extract powder, donkey-hide gelatin powder and 10g of steviosin and sucrose powder (the weight ratio of dry extract powder to sucrose is about 3: 1) are put into a mixer in sequence and dry-mixed for 5 minutes. Granulating with 20 mesh sieve using dry granulator (granulating conditions: roller rotation speed is 15rpm, blanking paddle rotation speed is 30rpm, roller pressure is 6MPa, and side sealing pressure is 2MPa) to obtain semi-finished granules. The whole grain is sieved by a 12-mesh sieve, and the grains are sieved by a 10-mesh sieve and a 30-mesh sieve, and the grains which pass through the 10-mesh sieve but cannot pass through the 30-mesh sieve are collected. The granules which could not pass through a 10 mesh sieve and could pass through a 30 mesh sieve were re-granulated. The granules obtained after granulation are combined with the granules after size stabilization.
And finally, spraying the fructus amomi volatile oil into the granules in a mixer while stirring, carrying out dry mixing for 5 minutes, transferring into a material barrel, and sealing and moistening for 2 hours. Finally, the granules are mixed for 15 minutes and bagged.
Example 3
Firstly, removing impurities and non-medicinal parts from fructus amomi, and then crushing the fructus amomi by using a crusher. Putting 62.5g of crushed fructus amomi into a volatile oil extraction tank group, adding 8 times of water, heating, carrying out steam distillation for 6 hours, collecting volatile oil (sealing), collecting distilled water solution in another container, and filtering (the aperture of a filter is not less than 200 meshes).
Putting 375g of dogwood fruit, 312.5g of prepared rehmannia root, 187.5g of fried astragalus, 125g of codonopsis pilosula, 187.5g of angelica, 187.5g of fructus psoraleae, 187.5g of caulis spatholobi and 250g of vinegar turtle shell into an extraction machine set, adding water for decocting for three times (8 times of water is added for the first time, 6 times of water is added for the second time and the third time), 1 hour for each time, filtering decoction (the aperture of a filter is not less than 200 meshes), combining the filtrate with distilled aqueous solution of fructus amomi, and concentrating in vacuum at 70 ℃ to form thick paste with the relative density of 1.34-1.38 (70-80 ℃). Vacuum drying the soft extract at 80 deg.C for 12 hr to obtain dry extract, and cooling. Pulverizing the dry extract into fine powder (80 mesh) with pulverizer to obtain dry extract powder.
62.5g of donkey-hide gelatin is pulverized into fine powder (80 meshes) by a pulverizer. Then dry extract powder, donkey-hide gelatin powder and 10g of steviosin and soluble starch (the weight ratio of dry extract powder to soluble starch is about 5: 1) are put into a mixer in sequence and dry-mixed for 5 minutes. Granulating with 20 mesh sieve using dry granulator (granulating conditions: roller rotation speed is 15rpm, blanking paddle rotation speed is 30rpm, roller pressure is 6MPa, and side sealing pressure is 2MPa) to obtain semi-finished granules. The whole grain is sieved by a 12-mesh sieve, and the grains are sieved by a 10-mesh sieve and a 30-mesh sieve, and the grains which pass through the 10-mesh sieve but cannot pass through the 30-mesh sieve are collected. The granules which could not pass through a 10 mesh sieve and could pass through a 30 mesh sieve were re-granulated. The granules obtained after granulation are combined with the granules after size stabilization.
And finally, spraying the fructus amomi volatile oil into the granules in a mixer while stirring, carrying out dry mixing for 5 minutes, transferring into a material barrel, and sealing and moistening for 2 hours. Finally, the granules are mixed for 15 minutes and bagged.
Example 4
Examples 1 to 3 toxicity test on animals related to Compound granule of Chinese medicinal herbs
1. Acute toxicity test in animals
40 Kunming mice (clean grade, weight of 19-21 g, half male and female, provided by Beijing Huafukang biotech GmbH) are taken, half male and female, and 20 mice in a normal control group and a drug administration group are taken. The mice were kept for 2 days in the experimental environment, were fasted for 16 hours before administration, and the example drugs were formulated with distilled water to 1.353g of crude drug/ml in an administration volume of 0.4ml/10g, and the control group was given the same volume of distilled water. The medicinal liquid is administered by intragastric administration for 3 times a day at intervals of 6 hr, with dosage of 54.12g crude drug/kg each time, and cumulative dosage of 162.36g crude drug/kg each day. Immediately after administration, the behavior and response, appearance, limb movement, food intake, drinking, excretion, etc. of the animals were observed once a day for 14 days, and the response of each animal was recorded in detail. Daily food intake and body weight were also recorded.
The results showed that the mice were able to lie on the day of administration and some mice were diarrhea. The food intake is obviously reduced on the 1 st day after the administration, and the food intake is gradually recovered later. The weight of the male mice slowly increases 1 day after the administration, and the weight of the male mice is obviously different from that of a normal control group (P is less than 0.05), and the male mice return to normal after 2 days. No obvious abnormality was seen in others. At the end of 14 days of observation, no animal death was found.
The medicine is administrated by gavage for 3 times in one day, and the cumulative dosage is 162.36g crude drug/kg, wherein the maximum allowable concentration of the medicine is 1.353g crude drug/ml, and the maximum gavage volume of a mouse is 0.4ml/10 g. After 14 days of observation, except that the mice crouch and move little on the day of administration, part of the mice have diarrhea, the food consumption is obviously reduced on the 1 st day after the administration, the weight of the male mice is slowly increased on the 1 st day after the administration, other mice have no obvious abnormality, and the mice do not die in the observation period. The results show that when the cumulative administration amount of the crude drug is 162.36 g/kg in one day, death and serious adverse reaction caused by drug toxicity are not seen. The clinical test recommends that the daily dose of the crude drug for human is 93g, and the daily dose of the crude drug for clinical human is 1.55 g/kg according to the average weight of human being of 60kg, so that the maximum dose of the mouse is 104.75 times of the daily dose of the human being in clinical test.
2. Long term toxicity test in animals
The experiment uses SPF SD rat as rodent species for long-term toxicity test, which is provided by experimental animal center of military medical academy of sciences, 160 animals are 5-6 weeks old, half male and female, each group comprises 30 animals, and the weight is 120-160 g. The test animals are grouped after being adapted for one week, the weight, the food intake and the water intake of the animals are weighed, and the test animals are grouped according to the balanced and random principles of sex, weight and the like of the animals, wherein each group comprises 30 animals, and each animal is half male and female. 3 administration groups and 1 control group were set, and each group had 15 animals per sex. The administration dose of each group of rats with long toxicity is respectively set as 9g/kg of low dose group, 18g/kg of medium dose group and 36g/kg of high dose group according to the maximum administration dose. The administration route in the rat test is intragastric. The medicine is taken 6 times a week, the administration time is 8: 30-10: 30 in the morning every day, and the gavage volume is 1.56ml/100g body weight; after the test for 40 days, the dosage concentration is adjusted because the animal weight is larger, the intragastric volume is adjusted to 1.25ml/100g of the animal weight, and the control group animals are intragastric with distilled water with corresponding volume. The administration period is 6 months, and 30 days are observed after the medicine is stopped. The general states of the animals including the external state of the animal fur, the existence of secretion of nasal cavity, anus and the like, the activity condition and the like are observed every day in the test process; measuring body weight once per week, and simultaneously measuring food intake and water intake; 40 rats (10 per group, half each male and female) were killed 3 months, 6 months and 30 days after drug withdrawal, urine biochemical analysis, peripheral blood visible component index, blood coagulation index, serum biochemical index, gross dissection, organ weight weighing and organ coefficient calculation, and histopathological examination was performed.
The results show that the low dose group (9g/kg, equivalent to 13.75 times the recommended daily clinical dose in humans) is a basic safe dose for 6 months in rats continuously orally administered the granules. Although the middle dose group (18g/kg, equivalent to 27.50 times of the recommended clinical daily dose of human) and the high dose group (36g/kg, equivalent to 55.00 times of the recommended clinical daily dose of human) a few animals have abnormal blood, protein, urea nitrogen (URE) and phosphocreatine kinase (CK) in post-drug urine biochemical analysis (the control group also has abnormal), the animal is actually a normal reaction with the higher dose; and 1 month after stopping drug administration, except that the content of phosphocreatine kinase (CK) in a large dose group of female rats is obviously lower than that in a control group, all other indexes have no obvious difference compared with the control group, which indicates that no drug delayed toxic reaction is found after the granules are administered for 6 months within the dose range of 9-36 g/kg/d, and indicates that the safe use dose of the granules at the level of SD rats is at least over 36 g/kg.
The observation indexes of tested Chinese medicinal compound granules SD rat which change in 6 months after oral administration except body weight and phosphocreatine kinase (CK) content recover to normal levels in 1 month after the administration is stopped, which indicates that the toxic reaction of the medicament to the organism is reversible. The compound Chinese medicinal granule preparation with low, medium and high doses can cause slight to mild spleen extramedullary hematopoiesis and marrow erythropoiesis enhancement after being orally administered to SD rats for 3 months, 6 months and 1 month after stopping administration, belongs to the curative effect outside the treatment effect, and shows that the clinical treatment effect of the medicine is more obvious; the medicine has no damage to organs, organs and tissues of hemopoietic system and immune system.
Example 5
Pharmacological test of Chinese medicinal compound granule
1. Research on influence of traditional Chinese medicine compound granules on proliferation and differentiation of early hematopoietic progenitor cells of mouse bone marrow
1.1 Experimental materials
1.1.1 Experimental animals
132 mice of Kunming species, two-stage, 102 females, 30 males. Wherein, the peripheral blood index detection comprises 10 per group, 60 per group and half of males and females; hematopoietic progenitor cell cultures were 3 per group, 36 total at both time points, female; CD34+Cells were tested in 6, 36 total, females per group.
The age of the mice is 6-8 weeks, and the weight of the mice is 18-22 g. Purchased from laboratory animal center of military medical science institute of the liberation force.
1.1.2 Experimental drugs
Example 1 granules, drug concentration: each g of the Chinese medicinal compound granules is equivalent to 2.368g of crude drugs.
Positive drugs: recombinant human granulocyte stimulating factor injection (G-CSF): beijing Shuanglu pharmaceutical industry, Inc.
1.1.3 Main instruments and reagents
Model F820 hematology analyzer: hissemcang, Japan. CO 22Incubator (model: HEPA class 100): thermo Forma corporation.
RPMI 1640: purchased from Gibco BRL. Fetal bovine serum, horse serum: purchased from the veterinary control center in the Beijing military. Methyl cellulose: purchased from Whatman company. FITC-labeled rat anti-mouse CD34 antibody and control antibody: purchased from Becton Dickinson, usa. Epo, IL-3, IL-11, L-glutamine: purchased from Sigma. Hemolysin, diluent and cleaning solution are all produced by Shandong lan bridge science and technology Limited.
1.2 test methods
1.2.1 modeling
3.5Gy for the test60Co-gamma ray irradiation, dose of 3.5Gy, dose rate of 1.31Gy.min-1。
1.2.2 peripheral blood sample detection experiment
1.2.2.1 grouping and administration
The experiment is divided into 6 groups, namely a normal control group, a model control group, a positive drug control group, a high-dose group of the Chinese medicinal compound granule, a medium-dose group of the Chinese medicinal compound granule and a low-dose group of the Chinese medicinal compound granule. Each group of experimental mice had 10 mice, each half of which was male and female.
2 days after the administration of the traditional Chinese medicine compound granule drug group by gastric lavage,60co-gamma ray 3.5Gy irradiation causes hemopoiesis inhibition of mouse bone marrow and reduction of visible components in peripheral blood image, and administration is continued for 14 days after molding, 1 time per day. The normal group and the model group were gavaged with distilled water of equal volume, and the positive control group was injected subcutaneously with recombinant human granulocyte stimulating factor injection (G-CSF) for 14 days 1 time a day.
Normal control group: equal amount of distilled water was administered for intragastric administration.
Model control group: equal amount of distilled water was administered for intragastric administration.
G-CSF positive drug control group: mu.g/kg (injection volume: 0.1ml/10 g).
High dose group of compound traditional Chinese medicine granules: the dose was 10.0g/kg body weight.
The traditional Chinese medicine compound granule comprises the following dosage groups: the dose was 5.0g/kg body weight.
The low-dose group of the traditional Chinese medicine compound granules comprises: the dose was 2.5g/kg body weight.
1.3.3.2 observation index and detection method
20 μ l of blood was taken from the tail vein of each mouse before and 1, 3, 5, 7, 11, 13, 15, 17, 21 days after the light. Peripheral hemograms were measured using a Sysmex-800 automated hemocytometer.
1.2.3 hematopoietic progenitor cell assay
1.2.3.1 grouping and administration
The experiment is divided into 6 groups, namely a normal control group, a model control group, a positive drug control group, a high-dose group of the Chinese medicinal compound granule, a medium-dose group of the Chinese medicinal compound granule and a low-dose group of the Chinese medicinal compound granule. Mice were 6 per group, female.
2 days after the administration of the traditional Chinese medicine compound granule drug group by gastric lavage,60co-gamma ray 3.5Gy irradiation is adopted for molding, and the drug is continuously administered for 7 days after molding, 1 time per day. The normal group and the model group were gavaged with distilled water of equal volume, and the positive control group was injected subcutaneously with recombinant human granulocyte stimulating factor injection (G-CSF) for 7 days 1 time per day.
Normal control group: equal amount of distilled water was administered for intragastric administration.
Model control group: equal amount of distilled water was administered for intragastric administration.
G-CSF positive drug control group: mu.g/kg (injection volume: 0.1ml/10 g).
High dose group of compound traditional Chinese medicine granules: the dose was 10.0g/kg body weight.
The traditional Chinese medicine compound granule comprises the following dosage groups: the dose was 5.0g/kg body weight.
The low-dose group of the traditional Chinese medicine compound granules comprises: the dose was 2.5g/kg body weight.
1.2.3.2 colony culture
(1) At 2 time points 3 days and 7 days after molding, 3 mice in each group were sacrificed by dislocation of cervical vertebrae. Soaking mouse with dislocation of cervical vertebra in 75% alcohol for a while for sterilizing, taking off femur of mouse, flushing out bone marrow cells with RPMI 1640 culture solution, passing through No. 4 needle to obtain single cell suspension, counting cells and calculating inoculated cellsAmount of suspension according to which nucleated cells are seeded 1X 105Calculated by a/ml system.
(2) Complex culture system (horse serum 2 ml; G-CSF100 ng; cell 1X 10)5Per ml; 1640 to 7.6ml), preheating for 10min at 37 ℃ by a constant-temperature water bath method, adding 0.5ml of 5% boiled agar, immediately mixing uniformly, and quickly mixing uniformly by adding and shaking with a 5ml syringe. Dropping 1ml of the above system into each dish, placing into a plastic box, placing several dishes with water, and adding 5% CO at 37 deg.C2The number of cells counted was observed after culturing for 6 days under the condition (2), and more than 50 cells were one cell colony.
(3) Prepared with red, mixed and megakaryocyte culture system (mercaptoethanol 1X 10)-4M0.2 ml; 0.03ml of 3 percent L-glutamine; horse serum 0.7 ml; epo 100U; IL-360 ng; IL-1150 ng; 0.7ml of 2.7 percent methyl cellulose; cell 1X 105/ml), put on a shaker for a while, added to a 24-well plate at 0.2ml per well, 5% CO at 37 ℃2Culturing for 3 days under the condition of (1), observing and counting CFU-E, CFU-Meg; BFU-E, CFU-mix was observed and counted for 6 days of culture.
1.2.4 CD34+Cell detection assay
1.2.4.1 grouping and administration
The experiment is divided into 6 groups, namely a normal control group, a model control group, a positive drug control group, a high-dose group of the Chinese medicinal compound granule, a medium-dose group of the Chinese medicinal compound granule and a low-dose group of the Chinese medicinal compound granule. Each group of experimental mice was 6, female.
2 days after the administration of the traditional Chinese medicine compound granule drug group by gastric lavage,60co-gamma ray 3.5Gy irradiation is adopted for molding, and the drug is continuously administered for 7 days after molding, 1 time per day. The normal group and the model group were gavaged with distilled water of equal volume, and the positive control group was injected subcutaneously with recombinant human granulocyte stimulating factor injection (G-CSF) for 7 days 1 time per day.
Normal control group: equal amount of distilled water was administered for intragastric administration.
Model control group: equal amount of distilled water was administered for intragastric administration.
G-CSF positive drug control group: mu.g/kg (injection volume: 0.1ml/10 g).
High dose group of compound traditional Chinese medicine granules: the dose was 10.0g/kg body weight.
The traditional Chinese medicine compound granule comprises the following dosage groups: the dose was 5.0g/kg body weight.
The low-dose group of the traditional Chinese medicine compound granules comprises: the dose was 2.5g/kg body weight.
1.2.4.2 Observation index and detection method
The mice were sacrificed by cervical dislocation 7 days after molding, the bone marrow cells of femur of the mice were washed out with PBS buffer containing 0.2% bovine serum albumin, and 1X 10 cells were taken6Mu.l of mouse serum is added to each cell and reacted for 10min to block non-specific binding sites, 10. mu.I of FITC-labeled rat anti-mouse CD34 antibody is added to the cells, and the cells are reacted for 30min at 4 ℃ in the dark with the corresponding control antibody added to the control tube. Adding 2ml erythrocyte lysate, acting for 5min, washing the cells twice with PBS buffer containing 0.2% bovine serum albumin and 0.1% sodium azide, adding PI staining solution with final concentration of 3 mug/ml, and detecting on a machine.
1.2.5 data processing and statistics
Inputting the measurement results of all animals at different time, and calculating the mean, standard deviation and significance t test of the mean among groups.
1.3 test results
1.3.1 peripheral hemograms
1.3.1.1 peripheral blood white blood cell
Compared with a normal control group, the number of white blood cells of the irradiation control group is obviously reduced (P is less than 0.01-0.001) in 1-21 days after the model is built, which indicates that the model is successfully built. Compared with the irradiation control group, the number of leucocytes of the positive medicine group is obviously increased (P is less than 0.05-0.001) in 1-17 days (except 3 and 11 days) after the model is built; each dosage group of the traditional Chinese medicine compound granule can increase the number of leucocytes, and the high, medium and low dosage groups can obviously promote the increase of the number of leucocytes (P is less than 0.05-0.01) on the 5 th, 7 th, 13 th and 17 th days after the model building respectively, and the results are shown in table 1.
TABLE 1 Pair of Chinese medicinal compound granules 3.5Gy60Co-gamma irradiation of peripheral blood leukocytes (WBC 1X 10) of mice9L) (n 10,
)
note: p < 0.05, P < 0.01, P < 0.001, compared to normal controls; compared with the irradiation control group, # P < 0.05, # P < 0.01, # P < 0.001
1.3.1.2 peripheral Red blood cells and hemoglobin
Compared with a normal control group, peripheral red blood cells and hemoglobin of the irradiation control group after the model building are reduced to a certain degree, the red blood cells are obviously reduced (P is less than 0.05-0.001) in 3-21 days, and the hemoglobin is obviously reduced (P is less than 0.05-0.001 except in 17 days) in 3-21 days, which indicates that the model building is successful. The red blood cells and hemoglobin of each dosage group of the positive traditional Chinese medicine and traditional Chinese medicine compound granules are obviously higher than those of an irradiation control group (P is less than 0.05-0.01) in 15 or 17 days, and the results are shown in tables 2 and 3.
TABLE 2 Pair of Chinese medicinal compound granules 3.5Gy60Co-gamma irradiation of peripheral red blood cells (RBC 1X 10)12L) (n 10,
)
note: p < 0.05, P < 0.01, P < 0.001, compared to normal controls; compared with the irradiation control group, # P < 0.05, # P < 0.01, # P < 0.001
TABLE 3 Pair of Chinese medicinal compound granules 3.5Gy60Effect of Co-gamma irradiation on peripheral blood hemoglobin (HGBg/L) in mice (n 10,
)
note: p < 0.05, P < 0.01, P < 0.001, compared to normal controls; compared with the irradiation control group, # P < 0.05, # P < 0.01
1.3.1.3 platelet counts
The platelet count of the irradiation control group and the drug group is in a trend of descending after 1 day after irradiation and descending after 3-5 days after irradiation, and reaches a minimum value 7 days after irradiation, and then slowly rises. But each dosage group of the Chinese medicinal compound granule recovers faster than a control group from 5 days after irradiation, wherein the high dosage groups are on the 5 th, 11 th and 13 th days; the middle dose group was significantly higher than the irradiated control group on day 13 (P < 0.05-0.001), and the results are shown in Table 4.
TABLE 4 Pair of Chinese medicinal compound granules 3.5Gy60Peripheral blood platelets (PLT 1X 10) from mice irradiated with Co-gamma radiation9L) (n 10,
)
note: p < 0.05, P < 0.01, P < 0.001, compared to normal controls; compared with the irradiation control group, # P < 0.05, # P < 0.01, # P < 0.001
1.3.2 hematopoietic progenitor cells
Compared with an irradiation control group, the positive medicine and the traditional Chinese medicine compound granule promote the proliferation of CFU-GM and CFU-E (P is less than 0.05-0.001) in each dose group after 3 and 7 days of irradiation; the high and medium dosage groups of the Chinese herbal compound granules also promote the proliferation of CFU-Meg and CFU-Mix (P is less than 0.05-0.01) after 3 and 7 days of the administration, and the results are shown in Table 5.
TABLE 5 Pair of Chinese medicinal compound granules 3.5Gy60Effect of Co-gamma irradiation on mouse hematopoietic progenitor cells (n-3,
)
note: p < 0.05, P < 0.01, P < 0.001, compared to normal controls; compared with the irradiation control group, # P < 0.05, # P < 0.01, # P < 0.001
1.3.3 CD34+Cells
Bone marrow CD34 in the irradiated control group 7 days after molding, compared with the normal control group+The cells are obviously reduced (P is less than 0.01), which indicates that the molding is successful. Irradiation model set CD34+The cell number is obviously reduced, and the CD34 is treated by positive drugs+The cell number is obviously increased, and each dosage group of the traditional Chinese medicine compound granule can increase CD34 in mouse bone marrow+The cell number, among which, the low dose group was significantly different (P < 0.05) from the irradiation model control group, and the results are shown in Table 6.
TABLE 6 Pair of Chinese medicinal compound granules 3.5Gy60Effect of Co-gamma irradiation on bone marrow CD34+ cells in mice for 7 days (n-6,
)
note: p < 0.05, P < 0.01, P < 0.001, compared to normal controls; compared with the irradiation control group, # P < 0.05, # P < 0.01, # P < 0.001
The results show that the method has the advantages of high yield,the Chinese medicinal compound granule can increase peripheral blood leukocyte, promote proliferation of CFU-GM and CFU-E, CFU-Meg, and increase CD34 in mouse bone marrow+The number of cells is determined by the number of cells, wherein the high-dose group has obvious effect on peripheral blood white cells, the high-and medium-dose groups have obvious effect on bone marrow hematopoietic stem/progenitor cells, and the low-dose group has obvious effect on CD34+The cell effect is obvious.
2. Chinese medicinal compound granule for preventing and treating diseases60Pharmacodynamic study of Co-gamma ray induced rat aplastic anemia
2.1 test materials
Rat: purchased from Huafukang biotech GmbH, Beijing.
Example 1 granules, drug concentration: each g of the Chinese medicinal compound granules is equivalent to 2.368g of crude drugs.
Cyclophosphamide for injection: shanxi Pude pharmaceutical industry Co., Ltd., 0.2 g/count.
Positive drugs: stanozolol tablets (conmerone, clinically used for the treatment of aplastic anemia, possibly improving the hematopoietic function of bone marrow, especially erythropoiesis), Guangxi Nanning Baihui pharmaceutical group Co., Ltd., 2 mg/tablet.
2.2 test methods
2.2.1 test animals and adaptive feeding
80 SD rats weighing 180-200 g are purchased and placed in an animal room with constant temperature (24 +/-0.5 ℃) and constant humidity (50 +/-10%) for adaptive feeding for 1 week, and water and food are freely drunk.
2.2.2 test grouping and administration
After 1 week of adaptive feeding, 10 normal control groups were randomly assigned according to body weight. The rest 70 are only used in the cobalt source room of the university of Beijing at the chemical institute60Co-gamma irradiation of 4.0Gy showed poor rat status after irradiation, curling and reduced mobility. By using60After 4.0Gy irradiation, surviving rats were randomly assigned to 5 groups by body weight. The experiment was divided into 6 groups in total: normal control group, model control group, positive drug control group, small dosage group of Chinese medicinal compound granule, medium dosage group of Chinese medicinal compound granule, and large dosage group of Chinese medicinal compound granule.
Cyclophosphamide administration 25.0 mg/kg starting from 4d-1Intraperitoneal injection is carried out for 3 consecutive days, and a rat model of aplastic anemia animals is prepared.
Continuously injecting cyclophosphamide for 3 days, wherein on the day of the last injection administration, the weight of the positive medicine group is 2.8mg/kg, and the administration doses of the small, medium and large dose groups of the traditional Chinese medicine compound granules are respectively as follows: 7.2g/kg, 4.16g/kg and 2.4g/kg, dissolving the medicine in deionized water, carrying out intragastric administration on rats according to the weight of 1ml/100g, and carrying out intragastric administration on the rats in a normal control group and a model control group by using the same deionized water.
2.2.3 Observation index
(1) Effect on general condition of rats in aplastic model: activity, diet, stool and urine, fur, diarrhea, emaciation, development, mental state
(2) Effect on peripheral hemograms in rats in the aplastic model: blood WBC, RBC, HGB and Pt changes
(3) Effect on number of nucleated bone marrow cells in rats in aplastic model: counting the number of nucleated cells in bone marrow of each femoral rat
(4) Influence on immune function of rat model with aplastic anemia
Flow cytometry detection: CD (compact disc)3、CD4、CD8And CD4/CD8。
Detection by a radioimmunoassay: TGF-beta1IL-1, IFN gamma, TNF alpha, etc.
2.3 test results
2.3.1 Effect on general conditions of rats in the aplastic model
The rats in the model control group have reduced activity and diet, poor mental state, thin defecate, bloody urine, upright fur, emaciation and dysplasia, weight loss, pale ears, lips and nails and obvious anemia condition. The symptoms of each dosage group of the Chinese medicinal compound granule are improved to different degrees, particularly the anemia symptoms are obviously improved, and the weight is obviously increased, wherein the state of rats in the dosage groups in the Chinese medicinal compound granule is the best.
Some animals died during the molding and treatment process, and the rats in each group survived, as shown in Table 7. Total assay periphery in surviving animalsBlood images; in view of experimental feasibility and satisfying statistical requirements, 6 bone marrow nucleated cells, CD4, CD8, CD3, CD4/CD8, TGF-beta were randomly selected from each group of surviving animals for determination of bone marrow nucleated cell number, CD4, CD8, CD3, CD4/CD8, TGF-beta1、IL-1。
2.3.2 Effect on peripheral hemograms in rats in the aplastic model shown in Table 7
TABLE 7 Chinese medicinal compound granule for 60Influence of Co-gamma ray induced peripheral blood picture of aplastic anemia in rat
Note: compared with the normal control group, the composition has the advantages that,#P＜0.05，##p is less than 0.01; p < 0.05, P < 0.01, compared to model control; compared with the positive medicine group,△P＜0.05，△△P＜0.01。
in the experiment60Co-gamma ray 4.0Gy irradiation combined with cyclophosphamide 25.0 mg/kg-1The abdominal cavity injection rat aplastic animal model has reduced WBC, RBC and HGB of peripheral hemogram whole cells, and compared with a normal control group, the statistical treatment has significant difference (P is less than 0.01) respectively, which indicates that the model building is successful. After treatment of each dosage group of the traditional Chinese medicine compound granule, peripheral hemogram is remarkably increased and has remarkable difference (P is less than 0.01) compared with a model control group, compared with a positive medicine group, the traditional Chinese medicine compound granule has remarkable difference (P is less than 0.05) of WBC index, large and medium dosage groups and HGB index and small dosage group, and the effect of the traditional Chinese medicine compound granule is better than that of a stanozolol tablet, and the treatment effect of the traditional Chinese medicine compound granule has dose dependence.
2.3.3 Effect on bone marrow nucleated cell number in rats in aplastic model see Table 8
TABLE 8 Chinese medicinal Compound granule60Influence of nuclear cell number of bone marrow of rat aplastic anemia induced by Co-gamma ray
| Group of | n | Bone marrow nucleated cell number × 107 |
| Normal control group | 6 | 6.510±0.191 |
| Model control group | 6 | 1.042±0.322## |
| Positive drug group | 6 | 4.632±0.473** |
| Low dose group | 6 | 4.734±0.171** |
| Middle dose group | 6 | 4.470±0.369** |
| High dose group | 6 | 5.042±0.354** |
Note: compared with the normal control group, the composition has the advantages that,#P＜0.05，##p is less than 0.01; p < 0.05, P < 0.01, compared to model control; compared with the positive medicine group,△P＜0.05，△△P＜0.01。
compared with the normal control group, the model control group animals have statistically significant differences (P is less than 0.01) indicating successful molding. After treatment of each dosage group of the traditional Chinese medicine compound granule, the number of bone marrow nucleated cells is remarkably increased, and the obvious difference (P is less than 0.01) is obtained compared with that of a model control group.
2.3.4 Effect on aplastic rats CD4, CD8, CD3, CD4/CD8 in Table 9
TABLE 9 Chinese medicinal Compound granule60Co-gamma ray induced effects of aplastic anemia CD4, CD8, CD3, CD4/CD8 in rats
Note: compared with the normal control group, # P < 0.05, # P < 0.01; p < 0.05, P < 0.01, compared to model control; compared with the positive medicines, the delta P is less than 0.05, and the delta P is less than 0.01.
Compared with the normal control group, the peripheral blood CD8, CD3 and CD4/CD8 of the model control group animals are increased to different degrees, and the statistical treatment shows that the difference is significant (P is less than 0.05), which indicates that the molding is successful. The traditional Chinese medicine compound granule can be obviously reduced after treatment of each dosage group, has significant difference (P is less than 0.05 or P is less than 0.01) compared with a model control group, and has no significant difference compared with a positive medicine group; after treatment of each dosage group of the traditional Chinese medicine compound granule, the CD4 can be obviously increased, compared with a model control group, the traditional Chinese medicine compound granule has significant difference (P is less than 0.05 or P is less than 0.01) except for a small dosage group, and the treatment effect of the traditional Chinese medicine compound granule has a dose dependent relation.
2.3.5 Effect on rat serum TGF-. beta.1 and IL-1 in aplastic model see Table 10
TABLE 10 pairs of Chinese medicinal compound granules60Co-gamma ray induced aplastic anemia rat serum TGF-beta1Influence of IL-1
| Group of | n | TGF-β1 | IL～1 |
| Normal control group | 6 | 13.839±0.405 | 0.267±0.012 |
| Model control group | 6 | 28.411±0.714## | 0.150±0.009## |
| Positive drug group | 6 | 17.646±0.605** | 0.214±0.005** |
| Granule small dose group | 6 | 18.777±0.257** | 0.153±0.002△ |
| Dosage group in granules | 6 | 13.421±1.277**△ | 0.195±0.008* |
| Granular formulation high dose group | 6 | 16.658±1.080** | 0.209±0.006** |
Note: compared with the normal control group, # P < 0.05, # P < 0.01; p < 0.05, P < 0.01, compared to model control; compared with the positive medicines, the delta P is less than 0.05, and the delta P is less than 0.01.
Model control group animal rat serum TGF-beta1Compared with a normal control group, the injection mold is obviously increased, and has obvious difference (P is less than 0.01) after being statistically treated, and IL-1 is obviously reduced compared with the normal control group, and has obvious difference (P is less than 0.01) after being statistically treated, thereby indicating that the molding is successful. TGF-beta after treatment of each dose group of the Chinese medicinal compound granules1Obviously reduced, compared with a model control group, has significant difference (P is less than 0.01), and compared with a positive medicine group, has significant difference (P is less than 0.05) in a medium dosage group; after treatment of each dosage group of the traditional Chinese medicine compound granule, IL-1 is obviously increased, compared with a model control group, the middle and high dosage groups have significant difference (P is less than 0.05 or P is less than 0.01), and compared with a positive medicine group, the small dosage group has significant difference (P is less than 0.05); the treatment effect of the Chinese medicinal compound granules has a dose dependence relationship.
2.3.6 Effect on serum IFN-. gamma.and TNF-. alpha.of rats in aplastic anemia model is shown in Table 11
TABLE 11 pairs of Chinese medicinal compound granules60Influence of IFN-gamma and TNF-alpha of rat serum for inducing aplastic anemia by Co-gamma ray
Note: compared with the normal control group, # P < 0.05, # P < 0.01; p < 0.05, P < 0.01, compared to model control; compared with the positive medicines, the delta P is less than 0.05, and the delta P is less than 0.01.
Compared with the normal control group, the serum IFN-gamma and TNF-d of the rat of the model control group are obviously increased, and the statistical treatment shows that the difference is obvious (P is less than 0.01), which indicates that the model building is successful. Compared with model control group, the Chinese medicinal compound granule obviously reduces IFN-gamma and TNF-alpha after treatment of each dosage group, and hasIs remarkable in thatSex differences (P < 0.01); compared with the positive medicine, the high-dosage group of the traditional Chinese medicine compound granule has significant difference (P is less than 0.05), and the treatment effect of the traditional Chinese medicine compound granule has dosage dependence.
Similar pharmacological tests of the granules of examples 2 to 3 showed no significant difference from the granules of example 1.
The above-described embodiments are merely illustrative of the present invention and are not intended to limit the present invention. It will be appreciated by those skilled in the art that modifications and variations to the embodiments of the present invention are within the scope of the present invention without departing from the spirit and scope of the invention. And the scope of the invention should be determined from the appended claims.
Claims (10)
1. The traditional Chinese medicine compound granule is prepared from an auxiliary material and a traditional Chinese medicine extract serving as an active ingredient, wherein the auxiliary material contains a filler, and the traditional Chinese medicine extract is a full-ingredient extract extracted from a traditional Chinese medicine composition consisting of the following components in parts by weight: 5-8 parts of cornus officinalis; 3-5 parts of prepared rehmannia root; 2-5 parts of fructus psoraleae; 2-4 parts of radix astragali Preparata; 2-4 parts of angelica; 0.5-3 parts of donkey-hide gelatin; 2-4 parts of caulis spatholobi; 2-4 parts of codonopsis pilosula; 3-5 parts of vinegar turtle shell; and 0.5-2 parts of fructus amomi.
2. The compound traditional Chinese medicine granule as claimed in claim 1, wherein the traditional Chinese medicine composition comprises the following components in parts by weight: 6 parts of cornus officinalis; 4 parts of prepared rehmannia root; 3 parts of fructus psoraleae; 3 parts of radix astragali Preparata; 3 parts of Chinese angelica; 1 part of donkey-hide gelatin; 3 parts of caulis spatholobi; 3 parts of codonopsis pilosula; 4 parts of vinegar turtle shell; and 1 part of fructus amomi.
3. The compound Chinese medicinal granule according to claim 1 or 2, wherein the amount of the filler is 10 to 70 wt% based on the total weight of the compound Chinese medicinal granule.
4. The compound Chinese medicine granule as claimed in claim 1 or 2, wherein the filler is selected from sucrose, soluble starch or their combination.
5. The compound traditional Chinese medicine granule as claimed in claim 1 or 2, wherein the adjuvant further comprises a flavoring agent, and the amount of the flavoring agent is 0.1-10 wt% based on the total weight of the compound traditional Chinese medicine granule.
6. A method for preparing the traditional Chinese medicine compound granule of any one of claims 1-5, the method comprises the following steps:
steam distilling fructus Amomi and collecting volatile oil and distilled water solution;
decocting Corni fructus, radix rehmanniae Preparata, fructus Psoraleae preparata, radix astragali Preparata, radix Angelicae sinensis, radix Codonopsis, caulis Spatholobi and carapax Trionycis processed with vinegar with water to obtain water extractive solution;
mixing the distilled water solution with the water extracting solution and concentrating into thick paste;
drying the thick paste to obtain dry paste;
grinding colla Corii Asini and the dry extract and adding adjuvant containing filler to dry mix to obtain dry mixture;
dry granulating the dry blend to obtain a semi-finished granulate;
granulating the semi-finished product particles;
spraying the volatile oil into the granulated semi-finished product particles, and sealing and moistening to obtain the traditional Chinese medicine compound granule.
7. The method according to claim 6, characterized in that it further comprises a step of dry granulation of the semifinished granules removed after finishing.
8. The method according to claim 6 or 7, wherein the step of mixing the distilled aqueous solution with the water extract and concentrating into a thick paste is performed at a temperature of 40 to 100 ℃ under reduced pressure.
9. The method according to claim 6 or 7, wherein the step of drying the thick paste to obtain a dry paste is performed at a temperature of 40 to 100 ℃ under reduced pressure.
10. The method according to claim 6 or 7, further comprising the step of drying the sized pellets so that the moisture content of the pellets does not exceed 13% by weight.
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