CN112870250B - Composition for preventing and treating organ fibrosis and application and preparation thereof - Google Patents
Composition for preventing and treating organ fibrosis and application and preparation thereof Download PDFInfo
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Abstract
The invention provides an emblic leafflower fruit composition for preventing and/or treating organ fibrosis and application and a preparation thereof, wherein tannin and emblic leafflower fruit extract are compounded and combined to obtain the composition which has obvious treatment effects on pulmonary fibrosis, hepatic fibrosis and skin fibrosis, the overall effect is obviously improved, the synergistic effect on the anti-fibrosis aspect is achieved, the composition is reasonable in compatibility, toxicity tests prove that the emblic leafflower fruit composition has no side effect, is suitable for oral administration and external use, has good application value on the aspect of developing anti-fibrosis medical products, and provides an efficient and safer medicine source for treating fibrosis diseases.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to an emblic leafflower fruit composition for preventing and/or treating fibrosis and application and a preparation thereof.
Background
Fibrotic diseases represented by fibrosis of various organs and tissues are diseases in which excessive production or deposition of extracellular matrix proteins occurs in various organs, tissues and the like such as the lung and the liver, and tissue sclerosis or dysfunction is caused. The progress of tissue fibrosis in fibrotic diseases is irreversible in many cases, and although fibrotic diseases are serious diseases such as pulmonary fibrosis or liver cirrhosis which progress to death, no effective therapeutic method is currently available, and there is a serious threat to human health and life. As shown by the relevant statistics in the United states, nearly 45% of the patients fatal to various diseases in this country can be attributed to the tissue fibroproliferative disease. In addition, the development of respiratory virus infection related diseases is also accompanied by pulmonary fibrosis, for example, severe pulmonary fibrosis can be caused by severe infection of novel coronavirus SARS-CoV-2.
The application WO2016015524A1 discloses an application of alkaloid in preparing a pharmaceutical composition for preventing or treating pulmonary fibrosis, and the application provides an alkaloid compound which is proved by experiments to be capable of obviously relieving the inflammation degree of pathological lung tissues, reducing the content of a profibrotic factor TGF-beta in the pathological lung tissues and reducing excessive deposition of collagen in the pathological lung tissues, and has obvious preventing and treating effects on pulmonary fibrosis. However, the compound or most of the existing medicines basically aim at one fibrosis lesion, but have poor effect on the fibrosis lesion generated in other tissues or organs, and the application is limited. Therefore, the search for new drug administration schemes with low cost and improved anti-organ fibrosis effect becomes the current research focus.
Disclosure of Invention
Aiming at the limitation of the existing anti-organ fibrosis drugs, the invention aims to provide a composition with the effect of preventing and/or treating fibrosis, the activity of the obtained composition in the aspect of anti-fibrosis is obviously enhanced after the tannic acid and the emblic leafflower fruit extract are compounded and combined, and the components are synergistic and mutually promoted to achieve good anti-fibrosis effect. Provides a high-efficiency and safer medicine source for treating the fibrosis diseases.
Accordingly, it is a primary object of the present invention to provide a composition of emblic leafflower fruit for preventing and/or treating organ fibrosis.
The invention also aims to provide the application of the emblic leafflower fruit composition in preparing a medicament for preventing and/or treating organ fibrosis.
Another object of the present invention is to provide an oral liquid for preventing and/or treating organ fibrosis.
It is still another object of the present invention to provide a tablet for preventing and/or treating organ fibrosis.
It is a further object of the present invention to provide a spray for the prevention and/or treatment of organ fibrosis.
The above purpose of the invention is realized by the following technical scheme:
the present invention provides an emblic composition for preventing and/or treating fibrosis, comprising tannic acid and/or an emblic leafflower fruit extract; the fructus Phyllanthi extract is fructus Phyllanthi water extract and/or fructus Phyllanthi alcohol extract.
In the emblic composition for preventing and/or treating fibrosis, tannic acid (tannic acid) is a secondary metabolite of some plants, is also called tannic acid in the pharmaceutical medicine, is a natural plant polyphenol, widely exists in gallnut plants, contains a large amount of hydroxyl and carbonyl, is a soluble and polyphenol compound, and has biological functions of diarrhea resistance, bacteriostasis, oxidation resistance, cancer resistance, virus resistance and the like.
The fructus Phyllanthi extract is extracted from Phyllanthus emblica (Phyllanthus emblica Linn) of Phyllanthus of Euphorbiaceae, contains abundant active ingredients such as superoxide dismutase (SOD), vitamin C, polyphenols, and polysaccharides, and has antiinflammatory, antitumor, mutation resisting, hypertension resisting, blood lipid reducing, blood pressure lowering, and liver protecting effects.
The invention compounds tannin and emblic leafflower fruit extract, wherein the tannin can inhibit the expression of collagen-1 and smooth muscle alpha-actin (SMA) induced by TGF-beta, and has the function of anti-fibrosis; the emblic leafflower fruit can accelerate the elimination of superoxide anion free radicals of tissues and has a suppression effect on fibrosis. Experimental results show that after the tannic acid and the emblic leafflower fruit extract are compounded and combined, the anti-fibrosis efficacy of the tannic acid is remarkably improved, and the compounded emblic leafflower fruit composition is remarkably improved in the aspect of treating pulmonary fibrosis, hepatic fibrosis, cardiac fibrosis and skin fibrosis, and has a synergistic effect.
As a preferable implementable method, the method for preparing the aqueous extract of emblic leafflower fruit comprises the steps of:
drying and crushing phyllanthus emblica, adding water with the weight 5-50 times that of the phyllanthus emblica, performing reflux extraction for 1-3 h, filtering, adding water with the weight 5-50 times that of the phyllanthus emblica into filter residues, performing reflux extraction for 1-3 h, filtering, combining filtrate for 2 times, concentrating and drying to obtain the phyllanthus emblica tea.
As a preferable implementable method, the preparation method of the alcohol extract of emblic leafflower fruit comprises the following steps:
drying and crushing phyllanthus emblica, adding 50-100 vol% ethanol solution which is 5-50 times the weight of the phyllanthus emblica, performing reflux extraction for 0.5-3 h, filtering, concentrating and drying filtrate, and thus obtaining the phyllanthus emblica tea.
As a preferably practicable method, the alcohol extract of emblic leafflower fruit and the preparation method of the alcohol extract of emblic leafflower fruit comprise the following steps:
drying and crushing phyllanthus emblica, adding water with the weight 5-50 times that of the phyllanthus emblica, performing reflux extraction for 1-3 hours, filtering, adding water with the weight 5-50 times that of the phyllanthus emblica into filter residues, performing reflux extraction for 1-3 hours, filtering, and combining filtrates for 2 times; and adding the obtained filter residue into 50-100 vol% ethanol solution which is 5-50 times the weight of the emblic leafflower fruits, performing reflux extraction for 0.5-3 h, filtering, combining the ethanol extract filtrate and the water extract filtrate, concentrating and drying to obtain the phyllanthus emblic extract.
Preferably, the tannin and the emblic leafflower fruit extract comprise the following components in parts by weight: 9-40 parts of tannic acid and 9-30 parts of emblic leafflower fruit extract.
Preferably, the tannin and the emblic leafflower fruit extract comprise the following components in parts by weight: 9-25 parts of tannic acid and 9-15 parts of emblic leafflower fruit extract.
More preferably, the weight parts of the tannic acid and the emblic extract are as follows: 16 parts of tannin and 10 parts of emblic leafflower fruit extract.
The invention also provides application of the emblic leafflower fruit composition in preparing products for preventing and/or treating organ fibrosis.
Further, the product can be a drug for preventing and/or treating organ fibrosis, a food for preventing or treating organ fibrosis or for eating during organ fibrosis treatment, or a health care product for preventing or treating organ fibrosis or for eating during organ fibrosis treatment.
The use of the claimed phyllanthus emblica composition for the manufacture of a medicament for the prevention and/or treatment of organ fibrosis includes, but is not limited to, administering to a patient an effective amount of the phyllanthus emblica composition of the present invention to manufacture a medicament for the prevention or treatment of fibrosis-induced diseases, alleviation of symptoms of fibrosis-induced diseases, or delay of the development or onset of fibrosis-induced diseases.
In addition to being beneficial for human therapy, the presently claimed phyllanthus compositions may find application in veterinary therapy for pets, for animals of the introduced species and for animals in farms, including mammals, rodents and the like. Other examples of animals include horses, dogs, cats, and the like.
Preferably, the organ fibrosis comprises pulmonary fibrosis, hepatic fibrosis, cardiac fibrosis, skin fibrosis.
Preferably, the medicine is prepared by adding pharmaceutically acceptable auxiliary materials into the emblic leafflower fruit composition for preventing and/or treating organ fibrosis and preparing into different dosage forms. The dosage form can be oral liquid, tablet, spray, etc.
The present invention also provides an oral liquid for preventing and/or treating fibrosis comprising the above phyllanthus emblica composition.
Preferably, the oral liquid comprises the following components in parts by weight: 9-40 parts of tannic acid, 9-30 parts of emblic leafflower fruit extract, 4-20 parts of antioxidant, 2-12 parts of sweetening agent, 2-13 parts of bacteriostatic agent and 50-200 parts of purified water.
More preferably, the oral liquid comprises the following components in parts by weight: 10-30 parts of tannic acid, 10-20 parts of emblic leafflower fruit extract, 14-18 parts of antioxidant, 7-12 parts of sweetener, 7-12 parts of bacteriostatic agent and 100-200 parts of purified water.
The anti-organ fibrosis oral liquid provided by the invention has reasonable compatibility of all components, wherein the tannic acid can inhibit the expression of collagen-1 and smooth muscle alpha-actin (SMA) induced by TGF-beta, and plays a role in anti-fibrosis; the emblic leafflower fruit contains a large amount of flavone and phenolic substances, has the function of anti-fibrosis, has very obvious function of improving the activity of superoxide dismutase (SOD) of a human body, and can enhance the oxidation resistance of an organism; the antioxidant can prevent the oxidation of the original medicine, so that the stability of the antioxidant is good; the sweetener can improve the taste feeling of a user, so that the adaptability of the sweetener is good; the bacteriostatic agent can effectively prevent the oral liquid from deteriorating; purified water acts as a solvent for dissolution. The obtained anti-fibrosis oral liquid has obvious effects of resisting pulmonary fibrosis, hepatic fibrosis, cardiac fibrosis and skin fibrosis, is beneficial to treatment and rehabilitation of patients, and improves the life quality.
Further, the antioxidant can be tea polyphenol, vitamin C, vitamin E, etc.; the sweetener can be sucrose, lactose, starch sugar, etc.; the bacteriostatic agent can be herba Salvia officinalis flos Caryophylli, herba Rosmarini officinalis, etc.
As a preferable embodiment, the method for preparing the oral liquid comprises the steps of:
s1, weighing 9-40 parts of tannic acid, 9-30 parts of emblic leafflower fruit extract, 4-20 parts of antioxidant, 2-12 parts of sweetener, 2-13 parts of bacteriostatic agent and 50-200 parts of purified water;
s2, sufficiently dissolving the tannin, the emblic leafflower fruit extract, the antioxidant, the sweetening agent and the bacteriostatic agent in water according to the parts by weight, adding purified water until the mixture is completely dissolved, and subpackaging to obtain the finished product.
The present invention also provides a tablet for preventing and/or treating organ fibrosis comprising the above phyllanthus composition.
Preferably, the tablet comprises the following components in parts by weight: 9-40 parts of tannic acid, 9-30 parts of emblic extract, 4-30 parts of filler, 2-18 parts of binder and 2-22 parts of lubricant.
More preferably, the tablet comprises the following components in parts by weight: 16-40 parts of tannic acid, 9-20 parts of emblic leafflower fruit extract, 20-25 parts of filler, 12-14 parts of adhesive and 6-14 parts of lubricant.
The anti-organ fibrosis tablet provided by the invention has reasonable compatibility of all components, wherein the tannic acid can inhibit the expression of collagen-1 and smooth muscle alpha-actin (SMA) induced by TGF-beta, and plays a role in resisting fibrosis; the emblic leafflower fruit contains a large amount of flavone and phenolic substances, has the function of anti-fibrosis, has very obvious function of improving the activity of superoxide dismutase (SOD) of a human body, and can enhance the oxidation resistance of an organism; the filler can increase the volume and weight, reduce the cost of the material and play a role in improving the performance of the material; the adhesive is capable of joining two separate materials together by virtue of its adhesive properties, such that it effectively adjusts viscosity; the lubricant can reduce the friction resistance of the friction pair and slow down the abrasion of the friction pair, so that the friction pair has good lubricating performance; the obtained anti-fibrosis tablet has obvious effects of resisting pulmonary fibrosis, hepatic fibrosis, heart fibrosis and skin fibrosis, is helpful for treatment and rehabilitation of patients, inhibits loss of organ functions, and protects health and life of people.
Wherein the filler, the adhesive and the lubricant are pharmaceutically acceptable auxiliary materials, and the filler can be starch, dextrin, powdered sugar, microcrystalline cellulose, milk essence, compressible starch and the like; the binder can be acacia, sodium alginate, polyacrylamide, polyethylene glycol, polyvidone, hydroxypropyl cellulose, etc.; the lubricant can be magnesium stearate, hydrogenated vegetable oil, silica gel micropowder, pulvis Talci, etc.
As a preferable mode of execution, the above-mentioned tablet preparation method comprises the steps of:
s1, mixing tannic acid, fructus Phyllanthi extract and filler, adding appropriate amount of binder to obtain soft material (to be capable of forming into block when holding with hand and to be capable of spalling when pressing lightly with finger instead of powder), squeezing with hand, and sieving to obtain granule without strip, block and fine powder. When mass production is carried out, the soft material passes through the sieve pores by the extrusion of a roller (or a rubbing plate) of the granulator, and granules are prepared;
s2, drying at 70 deg.C by wet granule drying method (drying in electric oven for small-scale preparation, drying in steam oven for mass production), and granulating, sieving, grading, adding adjuvants such as lubricant, and tabletting.
The present invention also provides a spray for preventing and/or treating organ fibrosis comprising the above phyllanthus composition.
Preferably, the spray comprises the following components in parts by weight: 9-40 parts of tannic acid, 9-30 parts of emblic leafflower fruit extract, 9-20 parts of cosolvent, 2-20 parts of antioxidant, 4-18 parts of bacteriostatic agent and 50-250 parts of purified water.
More preferably, the spray comprises the following components in parts by weight: 10-35 parts of tannic acid, 10-25 parts of emblic leafflower fruit extract, 9-15 parts of cosolvent, 13-20 parts of antioxidant, 11-17 parts of bacteriostatic agent and 100-250 parts of purified water.
The anti-organ fibrosis spray provided by the invention has reasonable compatibility of all components, wherein the tannic acid can inhibit the expression of collagen-1 and smooth muscle alpha-actin (SMA) induced by TGF-beta, and plays a role in resisting fibrosis; the emblic leafflower fruit contains a large amount of flavone and phenolic substances, has the function of anti-fibrosis, has very obvious function of improving the activity of superoxide dismutase (SOD) of a human body, and can enhance the oxidation resistance of an organism; after the cosolvent and the drug form a complex, the solubility of the drug can be increased by times or even tens of times; the antioxidant can prevent the oxidation of the original medicine, so that the stability of the antioxidant is good; the bacteriostatic agent can effectively prevent the spray from deteriorating; the purified water is used as a solvent to play a dissolving role; the obtained anti-fibrosis spray has obvious effect of resisting skin fibrosis, is beneficial to the treatment and rehabilitation of patients, improves the life quality, and can be used as an effective method for preventing normal people from daily protection and fibrotic diseases.
Further, the antioxidant may be sodium sulfite, vitamin C, vitamin E, etc.; the cosolvent can be p-aminobenzoic acid, urea, sodium benzoate and the like; the bacteriostatic agent can be flos Caryophylli, herba Salvia officinalis, herba Rosmarini officinalis, etc.
In a preferred embodiment, the method for preparing the spray comprises the following steps:
mixing tannic acid, fructus Phyllanthi extract, cosolvent, antioxidant, and bacteriostatic agent, adding purified water to dissolve completely, and packaging into spray bottle.
Compared with the prior art, the invention has the beneficial effects that:
the emblic composition for preventing and/or treating fibrosis is prepared by compounding and combining tannic acid and emblic extract, has obvious treatment effects on pulmonary fibrosis, hepatic fibrosis and skin fibrosis, remarkably improves the overall effect, achieves synergistic effect in the aspect of fibrosis resistance, is reasonable in combination compatibility, has no side effect as proved by toxicity tests, is suitable for oral administration and external use, has good application value in the aspect of developing anti-fibrosis medicinal products, and provides an efficient and safer medicament source for treating fibrosis diseases
Detailed Description
The present invention will be further described with reference to specific embodiments, but the present invention is not limited to the embodiments in any way. The starting reagents employed in the examples of the present invention are, unless otherwise specified, those that are conventionally purchased.
Example 1 preparation of an aqueous extract of Phyllanthus emblica
The preparation method of the emblic extract comprises the following steps:
drying and crushing phyllanthus emblica, weighing 60g of phyllanthus emblica powder, adding into 500mL of water, carrying out reflux extraction for 1.5h, filtering, adding 500mL of water into filter residues, carrying out reflux extraction for 1.5h, filtering, combining 2 filtrates, concentrating and drying to obtain the phyllanthus emblica tea.
Example 2 preparation of an alcohol extract of Phyllanthus emblica
The preparation method of the emblic leafflower fruit extract comprises the following steps:
drying and crushing emblic leafflower fruit, weighing 60g of emblic leafflower fruit powder, adding into 500mL of 70 vol% ethanol solution, extracting under reflux for 1.5h, filtering, concentrating and drying filtrate at 80 ℃ to obtain the emblic leafflower fruit extract.
EXAMPLE 3 preparation of an extract of Phyllanthus emblica
The preparation method of the emblic extract comprises the following steps:
drying and crushing phyllanthus emblica, weighing 60g of phyllanthus emblica powder, adding into 500mL of water, carrying out reflux extraction for 1.5h, filtering, adding 500mL of water into filter residues, carrying out reflux extraction for 1.5h, filtering, combining 2 filtrates, concentrating and drying at 80 ℃ to obtain the phyllanthus emblica tea.
EXAMPLE 4 Phyllanthus composition for the prevention and/or treatment of fibrosis
The present practice provides a series of emblic compositions for the prevention and/or treatment of fibrosis:
composition 1: 9 parts of tannic acid, 9 parts of the emblic leafflower fruit extract of example 1;
composition 2: 19 parts of tannic acid, 12 parts of emblic leafflower fruit extract in example 2;
composition 3: 16 parts of tannic acid, 10 parts of emblic leafflower fruit extract in example 3;
composition 4: 39 parts of tannic acid, 25 parts of the emblic leafflower fruit extract of example 1;
composition 5: 40 parts of tannic acid and 30 parts of the emblic leafflower fruit extract in example 1.
Comparative example 1 composition
This comparative example provides a series of compositions:
composition 6: 1 part of tannic acid, 2 parts of emblic extract of example 1;
composition 7: 8 parts of tannic acid, 10 parts of the emblic leafflower fruit extract in example 1;
composition 8: 13 parts of tannic acid and 45 parts of the emblic leafflower fruit extract in example 1.
Experimental example 1 acute toxicity test of compositions 1 to 5
1. Experimental method
The test is carried out by the maximum tolerance method of acute toxicity. Setting six groups of blank groups and compositions 1-5 (the concentration of the drug is 1.2g/mL), selecting 60 quarantine-qualified SPF-grade ICR mice, dividing male mice and female mice into halves, randomly grouping according to the sex and body weight by adopting a zone random method, wherein each group comprises 10 mice, fasting for more than 12h before administration, no administration is carried out in the blank groups, and the compositions 1-5 are 0.5mL/10g during test Body weight The mice were subjected to one-time intragastric administration. On the day of administration, particularly, the poisoning performance and characteristics, the occurrence and recovery time of toxic reaction, the death condition and the like of each group of animals are closely observed and recorded within 0-4 h after administration. The observation was then carried out 2 times a day, i.e., 1 time each in the morning and afternoon, for 14 consecutive days. Respectively atBefore and 7 days and 14 days after the administration, the body mass of the mice was weighed using an electronic balance. All mice were anesthetized and sacrificed by pentobarbital sodium intraperitoneal injection after the experiment was finished, and the general dissection was performed, the position, size, color, adhesion and other conditions of the organs were visually observed, and abnormal changes of the texture, effusion, tumor and the like of the surfaces and sections of the organs were examined. Gross dissection should be performed during the trial if there are animals that are not scheduled to die (including moribund animals).
2. Results of the experiment
(1) General activity status of mice
Before administration and during 14 days of observation, mice in the blank group and the composition 1-5 six groups have normal autonomous activities and have no abnormal or dead phenomena.
(2) Toxic symptoms and death in mice
No abnormality and death of the mice were observed during the whole experimental period.
(3) Changes in physical constitution
The weight of the composition is weighed before administration, at the 7 th day and at the 14 th day after administration respectively, compared with the blank group, the results show that the weight change of five groups of mice of the composition 1-5 has no significant difference, and the body mass growth is within a normal range, which shows that the body mass growth of ICR mice is not obviously influenced by oral drench of the composition 1-5, and the concrete contents are shown in Table 1.
TABLE 1 Effect of compositions 1-5 on mouse body weight
(4) Gross anatomical examination results
No obvious abnormal condition is found on the surface and section of each organ of each group of mice.
Experimental example 2 Long-term toxicity test of compositions 1 to 5
1. Experimental methods
Take composition 1 as an example. 80 rats were randomly divided into 4 groups of 20 rats, a control group, a composition 1 high dose group (800mg/kg), a medium dose group (400mg/kg), and a low dose group (200 mg/kg). The administration was 1 time per day, and 10 rats were sacrificed separately for each fraction after 3 months of administration and 2 weeks of withdrawal (recovery period) for index testing. Composition 2, composition 3, composition 4, composition 5 the methods described above. The following experiment was performed thereafter.
The skin, mucous membranes, secretions and excretions of the rats were observed daily for normality, while the general manifestations, toxic manifestations and death of the rats were recorded. The water intake, feed intake and body weight of the rats were recorded every 7 d. Collecting blood and performing cesarean examination on a certain number of rats on both day 30 and day 45, and detecting hematology and blood biochemical indexes, wherein the hematology indexes comprise: differential counting of White Blood Cells (WBC) and Neutrophils (NE), Eosinophils (EO), Basophils (BA), Lymphocytes (LY), Monocytes (MO), Red Blood Cells (RBC) and Hemoglobin (HB), etc.; the biochemical indexes of the blood comprise: alanine aminotransferase (alanine aminotransferase, ALT), aspartate aminotransferase (aspartate aminotransferase, AST), Albumin (ALB), urea nitrogen (BUN), and Triglyceride (TG), and the like. The weight of the major organs (heart, liver, spleen, lung, kidney, gastrointestinal and reproductive organs) of each group of rats was weighed and the organ coefficient was calculated, and pathological examination was performed on the control group and the high dose group of rats.
2. Results of the experiment
(1) Weight change
During the test period, rats in all groups had good mental status, normal drinking water and appetite, normal defecation and urination, and smooth and clean hair color. The weight growth trend of the test group and the blank group has no significant difference.
(2) Blood routine and blood biochemical detection
After 3 months of administration, the SD rats with high, medium and low doses of the compositions 1-5 have no obvious difference in blood routine and blood biochemical detection compared with a control group.
(3) Histopathological changes
The organ coefficients of each group on the 30 th day and the 45 th day have no difference significance. No obvious abnormality is found on the surfaces of organs such as heart, liver, spleen, lung, kidney, stomach, small intestine, testis and ovary of rats in each group of eye observation; no obvious lesions were observed in each tissue section of the test and blank groups.
Experimental example 3 anti-pulmonary fibrosis experiment
The experiment is to perform anti-pulmonary fibrosis experiment on the compositions 1-8 prepared in the embodiment 4, the tannic acid and the emblic leafflower fruit extract, and the specific method comprises the following steps:
1. cell experiments
(1) Cell culture
Culturing lung fibroblast in high-glucose DMEM medium containing 10% fetal calf serum, 1% penicillin and streptomycin double antibody and glucose concentration of 4.5g/L, placing the cells at 37 deg.C and 5% CO 2 Incubator, 2d change once cell culture fluid. When the cell density is 80-90%, the cells are digested by pancreatin and resuspended for passage.
(2) Cell grouping process
After observing that the cells had good growth status, the cells were digested, resuspended, and fibroblasts were seeded on a black 96-well plate at a density of 3000 cells per well. 24h after cell inoculation, 10ng/ml TGF-beta is added into each hole 1 And establishing a cell pulmonary fibrosis model. After 24h of incubation.
Administration group: after the cells adhered, tannic acid, emblic extract, composition 1, composition 2, composition 3, composition 4, composition 5, composition 6, composition 7, composition 8 were administered, respectively. The administration concentrations were set to 1.56. mu.g/mL at low concentration, 6.25. mu.g/mL at medium concentration and 25. mu.g/mL at high concentration, and after administration, the 96-well plate was placed in a cell incubator in the dark and the culture was continued for 24 hours.
Control group: compared with the administration group, the administration is not carried out.
Blank control group: compared with the administration group, the difference is that TGF-beta is not added 1 Nor administered.
To avoid systematic errors. Each set was designed with 6 replicate wells, and each set of experiments was replicated 3 times.
(3) CCK8 detection
Cell proliferation rate was measured using CCK 8. According to the kit instruction operation, 10 microliter of CCK8 reagent with the concentration of 10 percent is added into each hole, and after 2 hours, the OD value of the cells is detected by adopting a 450nm wavelength of an enzyme labeling instrument.
(4) Cell survival rate
Cell viability was calculated as OD values of cells detected in each group. The cell survival rate (administration group OD value-blank control group OD value)/(control group OD value-blank control group OD value) × 100%
(5) The experimental results are as follows: see table 2.
TABLE 2 survival rate of abnormally proliferating lung fibroblasts (%)
| Group of | Low concentration (1.56. mu.g/mL) | Middle concentration (6.25. mu.g/mL) | High concentration (25. mu.g/mL) |
| Composition 1 | 42±2.3 | 35±2.5 | 10±3.2 |
| Composition 2 | 48±1.3 | 32±1.5 | 12±1.4 |
| Composition 3 | 49±1.4 | 36±3.2 | 14±1.8 |
| Composition 4 | 45±1.3 | 31±1.2 | 12±3.1 |
| Composition 5 | 49±1.8 | 34±2.0 | 14±1.4 |
| Composition 6 | 55±1.6 | 46±1.9 | 26±1.5 |
| Composition 7 | 56±2,2 | 47±3.2 | 24±2.5 |
| Composition 8 | 55±3.3 | 46±1.3 | 25±2.2 |
| Tannic acid | 60±2.4 | 52±2.5 | 30±1.5 |
| Phyllanthus emblica extract | 71±1.6 | 63±2.1 | 65±4.2 |
As can be seen from table 2, the survival rate of lung fibroblasts is lower in the compositions 1 to 5 than in the compositions 6 to 8 when the tannic acid or the emblic leafflower fruit extract is used alone, which indicates that the two compositions have the effect of synergistically reducing the survival rate of abnormally-proliferating lung fibroblasts when used in combination through a proper proportion. The effect of the compositions 6-8 is better than that of the tannin and the emblic leafflower fruit extract, but is worse than that of the compositions 1-5, and the survival rate of the lung fibroblast abnormally proliferated cells cannot be obviously reduced by the compositions 6-8.
2. Animal experiments
(1) Animal grouping: SPF grade Wistar rats, randomly divided into 12 groups of 30 rats by body weight. Respectively a false operation group, a model group, a composition group of 1-8, a tannic acid group and an emblic extract group.
(2) Preparing a model:
the experimental animals are bred regularly after being purchased and are adaptive to the environment for 7 d. In the experiment, the animals are anesthetized by intraperitoneal injection of 3ml/kg of 10% chloral hydrate, fixed on a rat board in a supine manner, and the neck is sheared. Disinfecting the skin by a conventional method, and making a neck incision with the length of about 0.5-1 cm under aseptic operation. And stripping the exposed trachea layer by layer, and then lifting the head end of the rat board to form an angle of 30-35 degrees with the experiment table board. The method comprises the steps of penetrating a trachea with a 1mL syringe under direct vision, enabling the syringe to be as close to the bifurcation of the trachea as possible, keeping the direction of a needle head consistent with the direction of an airway, quickly injecting and injecting bleomycin hydrochloride (BLOCIN) and 0.2mL of physiological saline solution (15 mg of each bleOCIN, the concentration of the prepared physiological saline solution is 5mg/mL before use, and administering according to the weight of 5 mg/kg), immediately pulling out the needle head, erecting a rat plate, keeping the rat in an upright position, and rotating the rat plate back and forth for 3min to enable liquid medicine to reach the lungs on two sides as far as possible and to be uniformly distributed. Suturing skin, continuously injecting penicillin solution into abdominal cavity for 3 days to prevent wound infection, and placing into cage for conventional breeding after animal naturally revives. The operation method of the rat operation in the sham operation group is the same as that in other groups, except that the same amount of physiological saline is injected into the trachea after the operation to replace the bleomycin hydrochloride.
(3) Administration:
each group of rats was administered 1 intragastrically daily from day 2 after intratracheal injection of bleomycin hydrochloride for modeling. 200 mg/(kg. d) of the compositions 1-8 and tannin and Phyllanthus emblica extract alone were administered for 28 days in succession.
(4) Collecting and detecting a specimen:
respectively 1h after the administration on 7 th day, 14 th day and 28 th day after the model making, randomly selecting 10 animals in each group, dissecting and taking right lung tissue after the sacrifice, adding 9ml of normal saline into each gram of lung tissue to prepare 10% tissue homogenate, centrifuging at 3000r/min for 10min, taking supernatant, and detecting the SOD activity of the lung tissue by adopting a spectrophotometry method.
(5) The experimental results are as follows: see table 3.
TABLE 3 pulmonary tissue SOD Activity in animal models of pulmonary fibrosis
As can be seen from Table 3, the SOD activity in the lung tissues of three batches of animals in the model group after molding is obviously lower than that in the sham operation group, and the SOD activity is reduced along with the extension of the molding time; the results show that the function of the anti-free radical protection system in the lung tissue of the model animal is reduced, and the formation of pulmonary fibrosis is indirectly promoted. The compositions 1-5 inhibit the progress of pulmonary fibrosis by increasing SOD activity in lung tissues in the process of excessive proliferation and secretion of a large amount of collagen by fibroblasts. Compositions 6-8 were more effective than tannic acid and Phyllanthus emblica extract, but less effective than compositions 1-5.
EXAMPLE 4 anti-hepatic fibrosis test
The experiment is to perform anti-hepatic fibrosis experiment on the compositions 1-8 prepared in the embodiment 4, the tannic acid and the emblic leafflower fruit extract, and the specific method comprises the following steps:
1. cell experiments
(1) Cell culture
Culturing hepatic fibroblast with high glucose DMEM medium containing 10% fetal calf serum, 1% penicillin and streptomycin double antibody and glucose concentration of 4.5g/L, placing the cell at 37 deg.C and 5% CO 2 Incubator, 2d change once cell culture fluid. When the cell density is 80-90%, the cells are digested by pancreatin and resuspended for passage.
(2) Cell grouping process
After observing that the cells had good growth status, the cells were digested, resuspended, and fibroblasts were seeded on a black 96-well plate at a density of 3000 cells per well. 24h after cell inoculation 10ng per well/ml TGF-β 1 And establishing a cell pulmonary fibrosis model. After 24h of incubation.
Administration group: after the cells adhered, tannic acid, emblic extract, composition 1, composition 2, composition 3, composition 4, composition 5, composition 6, composition 7, composition 8 were administered, respectively. The administration concentrations were set to 1.56. mu.g/mL at low concentration, 6.25. mu.g/mL at medium concentration and 25. mu.g/mL at high concentration, and after administration, the 96-well plate was placed in a cell incubator in the dark and the culture was continued for 24 hours.
Control group: compared with the administration group, the administration is not carried out.
Blank control group: compared with the administration group, the difference is that TGF-beta is not added 1 Nor administered.
To avoid systematic errors. Each set was designed with 6 replicate wells, and each set of experiments was replicated 3 times.
(3) CCK8 detection
Cell proliferation rate was measured using CCK 8. According to the kit specification operation, 10 microliter of CCK8 reagent with the concentration of 10% is added into each well, and after 2 hours, the OD value of the cells is detected by adopting a microplate reader with the wavelength of 450 nm.
(4) Cell survival rate
Cell viability was calculated as OD values of cells detected in each group. The cell survival rate was (dose OD value-blank OD value)/(control OD value-blank OD value) × 100%.
(5) The experimental results are as follows: see table 4.
TABLE 4 survival rate of abnormally proliferating hepatic fibroblasts (%)
As can be seen from Table 4, the compositions 1-5 have better effect than the single use of the tannic acid or the emblic leafflower fruit extract, and the two are used in a compounding way, so that the survival rate of the liver fibroblast abnormally proliferated cells can be obviously reduced, and the synergistic effect is realized. The effect of the compositions 6-8 is better than that of the tannin and the emblic leafflower fruit extract, but is worse than that of the compositions 1-5, and the survival rate of the liver fibroblast abnormally proliferated cells cannot be obviously reduced by the compositions 6-8.
3. Animal experiments
(1) Animal grouping: SPF grade mice were randomly divided into 12 groups of 30 mice per group by body weight. Respectively a false operation group, a model group, a composition group of 1-8, a tannic acid group and an emblic extract group.
(2) Preparing a model:
using classical CCl 4 An induction method, establishing a mouse hepatic fibrosis model: mixing CCl 4 The injection is prepared into an oil solution with olive oil according to the volume ratio of 1: 1, and then the subcutaneous injection is carried out on mice, the injection volume is 3mL/kg, 2 times per week (interval of 3d), and the continuous injection is carried out for 6 weeks. The blank control group mice were injected with an equal volume of olive oil by the same method.
(3) Administration:
each group of mice was dosed 1 time daily by gavage from day 2 after modeling. 200mg/(kg d) of the composition 1 to 8, 200mg/(kg d) of tannic acid, 200mg/(kg d) of an extract of Phyllanthus emblica were administered separately for 28 days in succession.
(6) Collecting and detecting a specimen:
respectively 1h after the drug administration on 7 th day, 14 th day and 28 th day after the model making, randomly selecting 10 animals in each group, dissecting and taking liver tissues after death, adding 9ml of normal saline into each gram of liver tissues to prepare 10% tissue homogenate, centrifuging at 3000r/min for 10min, taking supernatant, and detecting the SOD activity of the liver tissues by adopting a spectrophotometry method.
(7) The experimental results are as follows: see table 5.
TABLE 5 hepatic fibrosis animal model hepatic tissue SOD Activity
As can be seen from Table 5, the SOD activity in the liver tissues of three batches of animals in the model group after the model was made was significantly lower than that in the sham operation group, and the SOD activity was seen to decrease with the extension of the model making time; the results show that the function of the anti-free radical protection system in the liver tissue of the model animal is reduced, and the formation of hepatic fibrosis is indirectly promoted. The compositions 1 to 5 inhibit the hepatic fibrosis process by increasing SOD activity in liver tissues in the process of excessive proliferation and secretion of a large amount of collagen of fibroblasts. Compositions 6-8 were more effective than tannic acid and Phyllanthus emblica extract, but less effective than compositions 1-5.
Experimental example 5 anti-dermal fibrosis experiment
The experiment is to perform an anti-skin fibrosis experiment on the compositions 1-8 prepared in the example 4, the tannic acid and the emblic leafflower fruit extract, and the specific method comprises the following steps:
1. cell experiments
(1) Cell culture
Culturing skin fibroblast in high-glucose DMEM medium containing 10% fetal calf serum, 1% penicillin and streptomycin double antibody and glucose concentration of 4.5g/L, placing the cell at 37 deg.C and 5% CO 2 Incubator, 2d change once cell culture fluid. When the cell density is 80-90%, the cells are digested by pancreatin and resuspended for passage.
(2) Cell grouping process
After observing that the cells had good growth status, the cells were digested, resuspended, and fibroblasts were seeded on a black 96-well plate at a density of 3000 cells per well. 24h after cell inoculation, 10ng/ml TGF-beta is added into each hole 1 And establishing a cell pulmonary fibrosis model. After 24h of incubation.
Administration group: after the cells adhered, tannic acid, emblic extract, composition 1, composition 2, composition 3, composition 4, composition 5, composition 6, composition 7, composition 8 were administered, respectively. The administration concentrations were set to 1.56. mu.g/mL at low concentration, 6.25. mu.g/mL at medium concentration and 25. mu.g/mL at high concentration, and after administration, the 96-well plate was placed in a cell incubator in the dark and the culture was continued for 24 hours.
Control group: compared with the administration group, the administration is not carried out.
Blank control group: compared with the administration group, the composition has the advantages that,with the difference that TGF-beta is not added 1 Nor administered.
To avoid systematic errors. Each set was designed with 6 replicate wells, and each set of experiments was replicated 3 times.
(3) CCK8 detection
Cell proliferation rate was measured using CCK 8. According to the kit specification operation, 10 microliter of CCK8 reagent with the concentration of 10% is added into each well, and after 2 hours, the OD value of the cells is detected by adopting a microplate reader with the wavelength of 450 nm.
(4) Cell survival rate
Cell viability was calculated as OD value of cells detected in each group. The cell survival rate was (dose OD value-blank OD value)/(control OD value-blank OD value) × 100%.
(5) The experimental results are as follows: see table 6.
TABLE 6 survival rate of skin fibroblast with abnormal proliferation (%)
| Group of | Low concentration (1.56. mu.g/mL) | Middle concentration (6.25. mu.g/mL) | High concentration (25. mu.g/mL) |
| Composition 1 | 42±2.1 | 33±2.3 | 11±1.2 |
| Composition 2 | 41±1.5 | 32±1.6 | 14±1.7 |
| Composition 3 | 46±3.5 | 33±1.5 | 14±1.6 |
| Composition 4 | 45±4.6 | 31±1.4 | 13±1.3 |
| Composition 5 | 44±1.4 | 33±1.4 | 10±4.2 |
| Composition 6 | 46±3.0 | 37±2.9 | 18±2.9 |
| Composition 7 | 47±2.9 | 36±2.4 | 17±1.5 |
| Composition 8 | 49±3.9 | 38±3.5 | 18±3.2 |
| Tannic acid | 52±1.5 | 41±2.4 | 21±2.2 |
| Emblic leafflower fruitSeed extract | 71±1.1 | 67±4.2 | 54±6.4 |
As can be seen from Table 6, the compositions 1-5 have better effect than the single use of the tannin or the emblic leafflower fruit extract, and the two are used in a compounding way, so that the survival rate of the skin fibroblast abnormally proliferated can be obviously reduced, and the synergistic effect is realized. The effect of compositions 6 to 8 was better than that of tannic acid and emblic extract, but was inferior to that of compositions 1 to 5, and it can be seen that the survival rate of abnormally proliferating skin fibroblasts could not be significantly reduced by compositions 6 to 8.
2. Animal experiments
(1) Animal grouping: SPF grade 6 week old male BALB/c mice were randomly divided into 12 groups of 30 mice per group by body weight. Respectively including sham operation group, simple Phosphate Buffer Solution (PBS) group, composition 1-5 group, tannic acid, and fructus Phyllanthi extract.
(2) Preparing a model:
the placebo mice were not treated at all; the back skin of mice in the PBS only group and the composition group were injected subcutaneously with 100. mu.L of PBS and bleomycin (1mg/mL), respectively.
(3) Administration:
each group of mice was gavaged 2 times daily on day 2 after being modeled with bleomycin. Administering 200mg/(kg d) of the composition 1-8, 200mg/(kg d) of tannic acid, 200mg/(kg d) of Phyllanthus emblica extract, respectively, for 28 d.
(8) Collecting and detecting a specimen:
respectively taking 10 animals in each group 1h after the administration on 7 th day, 14 th day and 28 th day after the model making, observing the change of the back skin of the mouse by naked eyes, killing the mouse after the observation, taking back skin tissue, adding 9ml of physiological saline into each gram of the skin tissue to prepare 10% tissue homogenate, centrifuging at 3000r/min for 10min, taking supernatant, and detecting the SOD activity of the skin tissue by adopting a spectrophotometry.
(9) The experimental results are as follows: see table 7.
TABLE 7 Effect of compositions 1-8 on skin tissue SOD Activity in animal models of skin fibrosis
As can be seen from Table 7, the SOD activity in the skin tissues of three batches of animals in the model group after molding is obviously lower than that in the sham operation group, and the SOD activity is reduced along with the extension of the molding time; the results show that the function of the anti-free radical protection system in the skin tissue of the model animal is reduced, and the formation of skin fibrosis is indirectly promoted. The compositions 1-5 inhibit the skin fibrosis process by increasing SOD activity in skin tissues during the process of excessive proliferation and secretion of a large amount of collagen of fibroblasts. Compositions 6-8 were more effective than tannic acid and Phyllanthus emblica extract, but less effective than compositions 1-5.
Example 5 oral liquid 1 for prevention and/or treatment of fibrosis
1. The embodiment provides an oral liquid which comprises the following components in parts by weight: 16 parts of tannic acid, 10 parts of emblic leafflower fruit extract, 9 parts of cane sugar, 18 parts of tea polyphenol, 7 parts of rosemary and 120 parts of purified water.
2. Preparation method
(1) Drying and crushing phyllanthus emblica, weighing 50g of phyllanthus emblica powder, adding 500mL of water, and performing reflux extraction for 2 hours; filtering, adding 500mL of water into filter residue, extracting for 2h under reflux, filtering, and combining the two filtrates; concentrating and drying at 80 deg.C to obtain fructus Phyllanthi water extract;
(2) mixing tannic acid, fructus Phyllanthi extract, sucrose, tea polyphenols, and herba Rosmarini officinalis, adding purified water, dissolving completely, and packaging to obtain oral liquid.
EXAMPLE 6 oral liquid 2 for prevention and/or treatment of fibrosis
1. The embodiment provides an oral liquid which comprises the following components in parts by weight: 30 parts of tannic acid, 15 parts of emblic extract, 14 parts of vitamin C, 12 parts of lactose, 12 parts of salvia and 200 parts of purified water.
2. The preparation process is referred to example 5.
Example 7 oral liquid 3 for prevention and/or treatment of fibrosis
1. The embodiment provides an oral liquid which comprises the following components in parts by weight: 10 parts of tannic acid, 20 parts of emblic leafflower fruit extract, 16 parts of vitamin E, 7 parts of starch sugar, 8 parts of clove and 100 parts of purified water.
2. The preparation process is referred to example 5.
EXAMPLE 8 tablet 1 for the prevention and/or treatment of fibrosis
1. The embodiment provides a tablet which comprises the following components in parts by weight: 16 parts of tannic acid, 10 parts of emblic extract, 23 parts of compressible starch, 14 parts of polyethylene glycol and 6 parts of micro silica gel.
2. Preparation method
(1) Preparing wet granules: mixing tannic acid, fructus Phyllanthi extract and filler, adding appropriate amount of binder to obtain soft material (with a degree of forming into mass when held by hand and breaking into powder when pressed by finger), squeezing with hand, and sieving to obtain granule without strip, block or fine powder.
(2) And (3) wet granule drying: granulating the raw materials with filler, drying at 70 deg.C, sieving, grading, crystallizing with granular medicine, adding adjuvants such as lubricant, and tabletting.
EXAMPLE 9 tablet 2 for the prevention and/or treatment of fibrosis
1. The embodiment provides a tablet which comprises the following components in parts by weight: 25 parts of tannic acid, 15 parts of emblic extract, 20 parts of microcrystalline cellulose, 14 parts of povidone and 10 parts of talcum powder.
2. The preparation process is referred to example 8.
Example 10 tablet 3 for the prevention and/or treatment of fibrosis
1. The embodiment provides a tablet which comprises the following components in parts by weight: 40 parts of tannic acid, 9 parts of emblic extract, 25 parts of milk essence, 12 parts of hydroxypropyl cellulose and 14 parts of hydrogenated vegetable oil.
2. The preparation process is referred to example 8.
Example 11 spray for prevention and/or treatment of fibrosis 1
1. The embodiment provides a spray which comprises the following components in parts by weight: 16 parts of tannic acid, 10 parts of emblic extract, 13 parts of p-aminobenzoic acid, 13 parts of sodium sulfite, 11 parts of clove and 100 parts of purified water.
2. Preparation method
(1) Drying and crushing emblic leafflower fruit, weighing 50g of emblic leafflower fruit powder into 500mL of 60 vol% ethanol solution, performing reflux extraction for 1h, filtering, concentrating and drying filtrate to obtain the emblic leafflower fruit ethanol extract.
(2) Mixing tannic acid, fructus Phyllanthi extract, p-aminobenzoic acid, sodium sulfite and flos Caryophylli in the above weight parts, adding purified water to dissolve completely, and packaging into spray bottle.
Example 12 spray for prevention and/or treatment of fibrosis 2
1. The embodiment provides a spray which comprises the following components in parts by weight: 10 parts of tannic acid, 25 parts of emblic leafflower fruit extract, 15 parts of urea, 20 parts of vitamin C, 12 parts of rosemary and 180 parts of purified water.
2. The preparation process is referred to example 11.
Example 13 spray for prevention and/or treatment of fibrosis 3
1. The embodiment provides a spray which comprises the following components in parts by weight: 35 parts of tannic acid, 10 parts of emblic extract, 9 parts of sodium benzoate, 14 parts of vitamin E, 17 parts of sage and 250 parts of purified water.
2. The preparation process is referred to example 11.
It should be understood that the above-described embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.
Claims (8)
1. The emblic leafflower fruit composition for preventing and/or treating organ fibrosis is characterized by comprising tannic acid and an emblic leafflower fruit extract, wherein the components in parts by weight are as follows: 9-40 parts of tannic acid and 9-30 parts of emblic leafflower fruit extract; the emblic extract is an aqueous extract and/or an alcohol extract of emblic; the organ fibrosis is pulmonary fibrosis or skin fibrosis.
2. Use of the phyllanthus emblica composition according to claim 1 for the preparation of a medicament for the prevention and/or treatment of organ fibrosis, wherein the organ fibrosis is pulmonary fibrosis or skin fibrosis.
3. The use according to claim 2, wherein the medicament is an oral liquid comprising the emblic composition according to claim 1.
4. The use of claim 3, wherein the oral liquid comprises the following components in parts by weight: 9-40 parts of tannic acid, 9-30 parts of emblic leafflower fruit extract, 4-20 parts of antioxidant, 2-12 parts of sweetening agent, 2-13 parts of bacteriostatic agent and 50-200 parts of purified water.
5. The use according to claim 2, wherein the pharmaceutical product is a tablet comprising the phyllanthus composition according to claim 1.
6. The tablet according to claim 5, comprising the following components in parts by weight: 9-40 parts of tannic acid, 9-30 parts of emblic extract, 4-30 parts of filler, 2-18 parts of binder and 2-22 parts of lubricant.
7. The use of claim 2, wherein the pharmaceutical product is a spray, said spray comprising the phyllanthus composition of claim 1.
8. The application of claim 7, wherein the spray comprises the following components in parts by weight: 9-40 parts of tannic acid, 9-30 parts of emblic leafflower fruit extract, 9-20 parts of cosolvent, 2-20 parts of antioxidant, 4-18 parts of bacteriostatic agent and 50-250 parts of purified water.
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| 余甘子抗大鼠免疫性肝纤维化作用（Ι）;李萍等;《中国实验方剂学杂志》;20100630;第16卷(第6期);171 * |
| 李萍等.余甘子抗大鼠免疫性肝纤维化作用（Ι）.《中国实验方剂学杂志》.2010,第16卷(第6期),171. * |
| 高效液相色谱法测定余甘子中单宁酸的含量;郭佳莉;《光谱实验室》;20070930;第24卷(第5期);912 * |
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