CN109568430B - A kind of preparation method and application of immune enhancer - Google Patents
A kind of preparation method and application of immune enhancer Download PDFInfo
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- CN109568430B CN109568430B CN201910106642.2A CN201910106642A CN109568430B CN 109568430 B CN109568430 B CN 109568430B CN 201910106642 A CN201910106642 A CN 201910106642A CN 109568430 B CN109568430 B CN 109568430B
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Classifications
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- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/75—Rutaceae (Rue family)
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/19—Acanthaceae (Acanthus family)
- A61K36/195—Strobilanthes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/31—Brassicaceae or Cruciferae (Mustard family), e.g. broccoli, cabbage or kohlrabi
- A61K36/315—Isatis, e.g. Dyer's woad
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
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- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/70—Polygonaceae (Buckwheat family), e.g. spineflower or dock
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- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/71—Ranunculaceae (Buttercup family), e.g. larkspur, hepatica, hydrastis, columbine or goldenseal
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- A—HUMAN NECESSITIES
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- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
- A61K2236/331—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using water, e.g. cold water, infusion, tea, steam distillation or decoction
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- A—HUMAN NECESSITIES
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明公开了一种免疫增强剂的制备方法和应用，包括以下步骤：（1）按处方将黄柏、大黄、黄芩、板蓝根和黄连加水煎煮，得到煎液，过滤得到滤液，滤液浓缩得到浸膏；（2）加入95%乙醇使含醇量为30~60％，搅拌，静置，滤过，并回收乙醇，浓缩得到稠膏；（3）在稠膏中加入辅料，混匀，干燥得到所述免疫增强制剂。本发明基于现有炎可宁片的制备工艺，将现有工艺中水煎煮后的浓缩液，进行二次工艺创新和提升，保留的有效成分重量变小，提高了提取成分的转移率，减少了药品每日服用量，更有利于各种制剂的制备，可以整体提升该品种的质量。另外，本发明的免疫增强剂可作为一种新的免疫增强剂，可开发应用。The invention discloses a preparation method and application of an immune enhancer, comprising the following steps: (1) adding water to decoct Cortex Phellodendri, Rhubarb, Scutellaria baicalensis, Radix Isatidis and Rhizoma Coptidis to obtain a decoction, filtering to obtain a filtrate, and concentrating the filtrate to obtain an infusion (2) Add 95% ethanol to make the alcohol content 30~60%, stir, let stand, filter, recover the ethanol, and concentrate to obtain a thick paste; (3) Add auxiliary materials to the thick paste, mix well, and dry The immune-enhancing preparation is obtained. Based on the preparation process of the existing Yankening tablets, the invention carries out secondary process innovation and improvement of the concentrated solution after decoction in the existing process, the weight of the retained effective components is reduced, and the transfer rate of the extracted components is improved. The daily dosage of medicines is reduced, which is more conducive to the preparation of various preparations, and can improve the quality of the variety as a whole. In addition, the immunopotentiator of the present invention can be developed and applied as a novel immunopotentiator.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method and application of an immunopotentiator.
Background
The Pinyin name of the Yankening tablet is as follows: YanKeNingPian, from the seventh volume of the drug Standard Chinese medicinal formulary preparation of the Ministry of public health of the people's republic of China (book page number: Z7-104, standard number: WS 3-B-1368-93). Yankening tablet is prepared with five kinds of Chinese medicinal materials, including phellodendron bark, skullcap root, Chinese goldthread, isatis root and rhubarb, and has the functions of clearing away heat, purging fire, diminishing inflammation and stopping dysentery. The modern medicine is used for treating acute tonsillitis, bacterial pneumonia, acute conjunctivitis, otitis media, furuncle carbuncle scrofula, acute mastitis, enteritis, bacillary dysentery and acute urinary tract infection.
Immunity is a physiological function of the human body, and the human body recognizes "self" and "non-self" components by virtue of the function, thereby destroying and rejecting antigen substances (such as germs and the like) entering the human body, or damaged cells and tumor cells generated by the human body per se, and the like, so as to maintain the health of the human body.
The immunopotentiator is an immunotherapy medicine which can enhance the immunity of the organism in different modes. The immunopotentiator is mainly used for enhancing the anti-tumor effect and anti-infection capability of the body and correcting immunodeficiency, and the medicine can activate one or more immunocompetent cells, enhance the specific and non-specific immune function of the body and restore the low immune function to normal. For people with low immunity or livestock and poultry, the immunity of the livestock and poultry can be improved by taking the immunopotentiator, so that the occurrence of diseases is prevented. Therefore, it is important to find an immunopotentiator capable of enhancing the body's ability to resist pathogen infection.
Disclosure of Invention
In order to solve the above problems, the present invention provides a method for preparing an immunopotentiator.
The technical scheme of the invention is as follows: a method for preparing an immunopotentiator, comprising the steps of:
(1) decocting cortex Phellodendri, radix et rhizoma Rhei, Scutellariae radix, radix Isatidis and Coptidis rhizoma in water, filtering the decoction to obtain filtrate, and concentrating the filtrate to obtain extract;
(2) adding 95% medical ethanol to make the alcohol content be 30-60%, stirring, standing, filtering, recovering ethanol, and concentrating to obtain soft extract;
(3) adding auxiliary materials into the thick paste, uniformly mixing and drying to obtain the immunopotentiating preparation.
The formula comprises the following components: phellodendron bark, cortex Phellodendri has effects of clearing heat, eliminating dampness, purging pathogenic fire and removing toxic substance; scutellariae radix has effects of clearing heat, eliminating dampness, purging pathogenic fire, removing toxic substances, cooling blood, and stopping bleeding; the coptis has the effects of clearing heat, eliminating dampness, purging fire and removing toxin; the radix isatidis has the effects of clearing away heat and toxic materials, cooling blood and relieving sore throat; the rhubarb has the effects of purging and eliminating accumulation, clearing heat and purging fire, cooling blood and detoxifying, removing stasis and stimulating the menstrual flow, and promoting diuresis and removing jaundice.
Based on the existing preparation process of the Yankening tablet, the concentrated solution obtained after water decoction in the existing process is subjected to secondary process lifting, the concentrated solution is treated by 95% medical ethanol in the invention, the ethanol content reaches 30-60%, the ethanol is recovered to obtain the thick paste of the ethanol concentrated solution, the weight of the thick paste can be 15% of that of the thick paste obtained after the original water decoction, and as a large amount of ethanol precipitate is discarded, the weight of the reserved effective components is reduced, the transfer rate of the extracted components is improved, the daily dosage of the medicine is reduced, the preparation of various preparations is facilitated, and the quality of the immunopotentiator can be integrally improved.
Preferably, in the step (1), the phellodendron, the rhubarb, the scutellaria baicalensis, the isatis root and the coptis chinensis are decocted with water for three times, each time lasts for 2 hours, and the decoction liquid of each time is combined.
Preferably, the density of the extract is 1-1.3 g/cm-3(temperature 60 ℃ C.).
Preferably, the density of the extract is 1.2g/cm-3(temperature 60 ℃ C.).
Preferably, the immunopotentiating agent is a chewable tablet, a capsule, a granule or a tablet.
The invention also provides an immunopotentiator prepared by the preparation method.
Thymus and spleen are important central and peripheral immune organs of the body, thymus being the main site of T lymphocyte maturation, and spleen being the main site of B lymphocyte maturation. The thymus index and the spleen index can directly reflect the development state of immune organs and the immune level of organisms. Through animal grouping and an immunization method thereof, the thymus index and the spleen index are taken as indexes, and the immune enhancement preparation is proved to have the immune enhancement effect, can restore the thymus and the spleen of an immunodeficient mouse caused by dexamethasone hydrochloride, and obviously improves the spleen index and the thymus index of the mouse.
The macrophage can engulf and destroy the injured tissue, and is helpful for the rehabilitation process of human body. Although they play a critical role at the site of injury, once the task is completed, it is necessary to evacuate as quickly as possible, ending the inflammatory response, opening the way for the regeneration process. The presence of persistent macrophages is detrimental to tissue recovery. The secretion expression of macrophage tumor necrosis factor (TNF-alpha) is detected by enzyme-linked immunosorbent assay (ELISA), and the results of in vitro macrophage (RAW264.7) activation inhibition experiments show that the immunopotentiator has better inhibition effect on macrophage activation, can inhibit mouse macrophages from excessively releasing tumor necrosis factor (TNF-alpha), and brings new hope for treating diseases such as chronic airway inflammation and the like. Therefore, the immunopotentiator can be used as a novel immunopotentiator for enhancing the immunity of human bodies.
Compared with the prior art, the invention has the beneficial effects that:
based on the existing preparation process of the Yankening tablet, the invention carries out secondary process innovation and promotion, the weight of the reserved effective components is reduced, the transfer rate of the extracted components is improved, the daily dose of the medicine is reduced, the preparation of various preparations is facilitated, and the quality of the variety can be integrally improved. In addition, the immunopotentiator of the present invention may be developed and applied as one new kind of immunopotentiator.
Detailed Description
The advantageous effects of the present invention are further illustrated by the following experimental examples and examples.
Experimental example 1
The immunopotentiator preparation has the effect of enhancing the immunity of mice, and the specific experiment is as follows:
the method adopts a mouse experiment as a pharmacological basis and adopts an immune organ weight test method: clinically, using dexamethasone hydrochloride to cause the immune deficiency of a mouse, picking the spleen and the thymus, weighing, and calculating the spleen index and the thymus index; adopting Microsoft Office Excel 2003 statistical software, SPSS for windows 12.0 statistical system, the experimental data is in mean plus standard deviation
Indicating that the mathematical statistics are carried out by using a group t test.
Mouse immunization experiment:
administration dose:
normal control group (saline): the concentration is 9 mg/mL;
model group (dexamethasone sodium phosphate injection): dissolving 4 pieces in 20mL water (each containing 5mg dexamethasone) at concentration of 1mg/mL, and injecting each injection at 0.3 mL;
positive control group (levamisole): 68mg dissolved in 20mL water at a concentration of 3.4 mg/mL;
immunopotentiator high dose group: 3.2g of the extract is dissolved in 20mL of water, and the concentration is 0.16 g/mL;
immunopotentiator low dose group: 1.6g was dissolved in 20mL of water at a concentration of 0.08 g/mL.
Animal grouping, modeling and administration:
dividing 50 clean-grade Kunming mice with the age of 6-8 weeks into 5 groups at random, wherein each group comprises 10 mice (each half of a female and a male), each mouse weighs 30g, and the mice are divided into 5 groups: a normal control group (physiological saline 9mg/mL), a model group (dexamethasone 1mg/mL), a positive control group (levamisole 3.4mg/mL), an immune preparation sample high-dose group (160mg/mL), and an immune preparation sample low-dose group (80 mg/mL).
Intragastric administration: the administration was continued for 8 days, and the control group and the model group were each administered with physiological saline, and the others were administered with the corresponding agents. Beginning on day 1, 0.2mL was gavaged daily in the afternoon. By day 3, except for the normal control group, the other groups were administered with dexamethasone (10 mg/Kg. d-1)0.3mL by intraperitoneal injection in the morning and 0.2mL by intragastric administration in the afternoon. On day 8, after 24h of the last gavage, the mice were weighed, sacrificed by dislocation of the cervical vertebrae, the spleen and thymus were removed, surface blood was blotted dry, and the wet weight was weighed with an electronic balance. Spleen and thymus indices were calculated.
Thymus index and spleen index K-values: k (mg/g) ═ organ weight/mouse body weight.
TABLE 1 mouse thymus index and spleen index
Comparison with the normal group:△△P<0.01，△P<0.05; comparison with model groups: p<0.01，*P<0.05。
The test results show that: the immunopotentiator has proliferation effect on thymus of mice with immunodeficient dexamethasone hydrochloride, and compared with a model group: the high and low dose groups have very significant difference (P < 0.01); the immunopotentiator has proliferation effect on spleen of mice with immunodeficiency caused by dexamethasone hydrochloride, and compared with a model group: the high and low dose groups have very significant difference (P < 0.01).
The experiment proves that the immunopotentiator has the function of enhancing the immune function of the mouse. After the molding, the thymus of the mouse is seriously atrophied, and the positive medicine and the immune preparation sample can recover the normal thymus of the mouse; after the model is made, the spleen of the mouse is seriously atrophied, and the positive medicine and the immune preparation sample can enable the spleen of the mouse to be recovered to be normal, so that the spleen atrophy-strengthening agent has good application prospect.
Experimental example 2
Enzyme-linked immunosorbent assay (ELISA) detects the secretory expression of macrophage tumor necrosis factor (TNF-alpha). TNF-alpha is a cytokine which can directly kill tumor cells without obvious toxicity to normal cells, is one of bioactive factors which have the strongest effect of directly killing tumors and is discovered so far, but the excessive secretion of TNF-alpha can cause diseases such as chronic airway inflammation and the like. The specific experiment is as follows:
screening models: macrophage (RAW264.7) activation inhibition model.
The screening method comprises the following steps: enzyme-linked immunosorbent assay (ELISA) detects the secretory expression of macrophage tumor necrosis factor (TNF-alpha).
Screening samples: an immunopotentiator.
Model principle: macrophages are activated by relevant factors and secrete expression of TNF-alpha. Adding Lipopolysaccharide (LPS) into macrophage, culturing for a certain time, adding the sample to be tested, incubating and culturing for a certain time, taking cell supernatant to measure the content of TNF-alpha, and judging the activation inhibition effect of the sample on the cell. (Note: TNF-alpha kills some tumor cells or cell lines in vitro and in vivo, while many normal cells cultured in vitro have no cytotoxic effect
Calculating the formula: activation index-content of TNF- α in sample group/content of TNF- α in Normal group
Activation inhibition ratio (%) [ (LPS activation index-sample activation index)/LPS activation index ] × 100
And (4) screening results: see table 2.
TABLE 2 inhibition of macrophage (RAW264.7) activation results
The experimental results show that: the activation inhibition rate of the sample at low concentration of 0.2 mu g/mL is also 28.82 +/-2.17, which indicates that the immunopotentiator has better inhibition effect on macrophage activation and can effectively inhibit the over-secretion expression of macrophage tumor necrosis factor (TNF-alpha).
The dosage depends on the effect to be achieved, the treatment time and the mode of administration; the dosage and effective dosage of the original preparation Yankening tablet for human use are taken as reference, and the dosage is equivalent to 65mg of active ingredients of immune preparation samples contained in daily oral dosage of adults.
Example 3
A method for preparing an immunopotentiator, comprising the steps of:
(1) decocting 413.8g of cortex Phellodendri, 82.8g of radix et rhizoma Rhei, 310.3g of Scutellariae radix, 310.3g of radix Isatidis and 20.7g of Coptidis rhizoma in the prescription of YANKENING tablet in ministerial standard with water for three times, each for 2 hr, mixing decoctions, filtering, concentrating the filtrate into extract with density of 1.2g/cm-3(temperature 60 ℃) and cooling, yield 53%;
(2) adding 95% medical ethanol to ethanol content of 50%, stirring, standing, filtering, recovering ethanol, and concentrating the ethanol solution to obtain soft extract with yield of 7.6%;
(3) taking 65mg of the thick paste in the step (2) according to 65mg of granules containing the active compound, respectively adding 1835mg of dextrin and 8100mg of sucrose, and preparing the granules by a conventional technology.
Example 4
A method for preparing an immunopotentiator, comprising the steps of:
(1) 413.8g of cortex Phellodendri, 82.8g of radix et rhizoma Rhei, 310.3g of Scutellariae radix, 310.3g of radix Isatidis and 20.7g of Coptidis rhizoma in the prescription of YANKENING tablet in ministerial standardDecocting in water for three times, each for 2 hr, mixing decoctions, filtering, concentrating the filtrate to obtain extract with density of 1.2g/cm-3(temperature 60 ℃) and cooling, the yield is 47%;
(2) adding 95% medical ethanol to ethanol content of 60%, stirring, standing, filtering, recovering ethanol, and concentrating the ethanol solution to obtain soft extract with yield of 8.1%;
(3) and (3) taking 65mg of the thick paste in the step (2) to be respectively added with 230mg of corn starch, 3mg of talcum powder and 2mg of calcium hydrophosphate according to the capsule containing 65mg of the active compound, and preparing the capsule according to the conventional technology.
Example 5
A method for preparing an immunopotentiator, comprising the steps of:
(1) decocting 413.8g of cortex Phellodendri, 82.8g of radix et rhizoma Rhei, 310.3g of Scutellariae radix, 310.3g of radix Isatidis and 20.7g of Coptidis rhizoma in the prescription of YANKENING tablet in ministerial standard with water for three times, each for 2 hr, mixing decoctions, filtering, concentrating the filtrate into extract with density of 1.2g/cm-3(temperature 60 ℃) and cooling, yield 49%;
(2) adding 95% medical ethanol to ethanol content of 55%, stirring, standing, filtering, recovering ethanol, and concentrating the ethanol solution to obtain soft extract with yield of 7.3%;
(3) taking 65mg of the thick paste in the step (2) based on 65mg of the tablet containing the active compound, respectively adding 213mg of starch, 2mg of magnesium stearate and 20mg of sodium carboxymethyl starch, and preparing the tablet according to the conventional technology.
Example 6
A method for preparing an immunopotentiator, comprising the steps of:
(1) decocting 413.8g of cortex Phellodendri, 82.8g of radix et rhizoma Rhei, 310.3g of Scutellariae radix, 310.3g of radix Isatidis and 20.7g of Coptidis rhizoma in the prescription of YANKENING tablet in ministerial standard with water for three times, each for 2 hr, mixing decoctions, filtering, concentrating the filtrate into extract with density of 1.2g/cm-3(temperature 60 ℃) and cooling, the yield is 46%;
(2) adding 95% medical ethanol to ethanol content of 45%, stirring, standing, filtering, recovering ethanol, and concentrating the ethanol solution to obtain soft extract with yield of 6.9%;
(3) taking 65mg of the thick paste in the step (2) and adding 100mg of dextrin, 200mg of starch, 65mg of mannitol, 65mg of sorbitol and 5mg of magnesium stearate into the thick paste respectively according to 65mg of the active compound contained in the chewable tablet, and preparing the chewable tablet according to the conventional technology.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention in any way, and any simple modification, equivalent change and modification made to the above embodiment according to the technical spirit of the present invention are within the scope of the present invention without departing from the technical spirit of the present invention.
Claims (5)
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| Title |
|---|
| 中医药治疗亚急性甲状腺炎53例;魏华等;《世界中医药》;20100131;第5卷(第01期);第43页 * |
| 姜玲艳等.正交试验法优选健胃清肠合剂的水提醇沉工艺.《中国实验方剂学杂志》.2013,(第17期), * |
| 正交试验法优选健胃清肠合剂的水提醇沉工艺;姜玲艳等;《中国实验方剂学杂志》;20131231(第17期);第35-37页 * |
| 魏华等.中医药治疗亚急性甲状腺炎53例.《世界中医药》.2010,第5卷(第01期), * |
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