CN113425697B - Preparation and preliminary pharmaceutical evaluation method of compound qi-tonifying intestine-moistening capsule - Google Patents
Preparation and preliminary pharmaceutical evaluation method of compound qi-tonifying intestine-moistening capsule Download PDFInfo
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Abstract
The invention belongs to the technical field of traditional Chinese medicines, and discloses a preparation method and a preliminary pharmaceutical evaluation method of a compound qi-tonifying intestine-moistening capsule, wherein the compound qi-tonifying intestine-moistening capsule consists of fructus cannabis, semen pruni, raw astragalus, radix codonopsis pilosulae, immature bitter orange and polygonatum. The preparation method of the compound qi-tonifying intestine-moistening capsule comprises the following steps: the compound qi-tonifying intestine-moistening capsule is prepared by extracting dried extract powder of raw astragalus, dangshen, fragrant solomonseal rhizome and immature bitter orange, adding hemp seed fine powder and bunge cherry seed fine powder, granulating together, adding pectin, and filling into a capsule shell. The pectin is added, the pectin is not basically absorbed after entering the alimentary canal, and the pectin is absorbed to form the peptone, so that the pectin can not only keep moisture in the intestines, but also increase the volume of excrement in the intestines, thereby stimulating the peristalsis of the intestines to produce stool, having the effect of promoting the medicine effect, having the effects of supplementing qi and nourishing yin, increasing liquid and moistening dryness, promoting qi and removing stagnancy, and relaxing the bowels, meeting the constipation of the elderly patients caused by deficiency of qi and yin, not only relaxing the bowels, but also improving the overall functions of the patients, and playing the role of treating diseases and solving the root cause.
Description
Technical Field
The invention belongs to the technical field of traditional Chinese medicines, and particularly relates to a preparation method and a preliminary pharmaceutical evaluation method of a compound qi-tonifying intestine-moistening capsule.
Background
Currently, constipation (constipation) is a common clinical disease, and along with the influence of factors such as the change of modern eating habits, the increase of social life pressure and the like, the prevalence of constipation is higher and higher, and particularly the prevalence of the elderly is increased year by year. Chronic constipation can lead to a variety of diseases. The chemical medicines are common methods for treating constipation, and the medicines are easy to cause dysregulation of flora in intestinal tracts after long-term use, so that constipation is aggravated in dependence. The traditional Chinese medicine has definite curative effect on constipation. However, the existing products containing traditional Chinese medicine components are mostly used for relieving constipation symptoms.
Through the above analysis, the problems and defects existing in the prior art are as follows: the existing intestine-moistening preparation can act through the effects of clearing heat and purgation, is easy to hurt healthy qi after long-term use, aggravates constipation, and has side effects; it is not suitable for long-term administration because of poor constipation effect due to intestinal dryness.
Because the existing intestine-moistening agent has the defects of viscosity, poor solubility and the like, the technology adopts natural water-soluble dietary fiber pectin as an auxiliary material on the basis of not adding other irritant components, the water absorption multiple of the natural water-soluble dietary fiber pectin is obviously higher than that of the conventional intestine-moistening agent to increase gastrointestinal motility, and simultaneously, the intestinal-moistening agent can remove toxins in human body, so that the intestine-moistening agent with less consumption and high bioavailability is prepared. The preparation has the advantages of greatly improving health care function while playing the drug effect, and being taken for a long time.
The difficulty of solving the problems and the defects is as follows:
the proper prescription with the functions of relaxing bowel, tonifying qi and yin, and tonifying and eliminating the constipation is searched, so that the medicine and the food are homologous, and the constipation can be radically improved after long-term administration.
The meaning of solving the problems and the defects is as follows:
the method for treating the constipation by relaxing the bowels, attacking and tonifying by combining the traditional Chinese medicine is particularly urgent to develop the compound Chinese patent medicine with high safety and definite curative effect by applying the modern preparation technology. Therefore, the development of the bowel relaxing compound Chinese patent medicine without purgation components has higher application value.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention provides a preparation method and a preliminary pharmaceutical evaluation method of a compound qi-tonifying intestine-moistening capsule.
The invention discloses a preparation method of a compound qi-tonifying intestine-moistening capsule, which comprises the following steps:
step one, extracting raw astragalus, dangshen, fragrant solomonseal rhizome and immature bitter orange to obtain dry extract powder;
adding fructus cannabis fine powder and bunge cherry seed fine powder into the obtained dry extract powder, taking microcrystalline cellulose as an auxiliary material, taking ethanol as a wetting agent, granulating and granulating together;
and thirdly, uniformly mixing pectin and micro powder silica gel, mixing with the prepared particles, and filling into a capsule shell to obtain the compound qi-tonifying intestine-moistening capsule.
Further, firstly, weighing raw astragalus, dangshen, fragrant solomonseal rhizome and immature bitter orange medicinal materials according to the proportion of 1:1:1 of a prescription, adding 8 times of water, extracting at 100 ℃ for 2 times, 1 hour each time, combining the two extracting solutions, concentrating and drying to obtain dry extract powder.
In the second step, the usage amount of the auxiliary materials and the main materials is as follows: 1:7.
further, the ethanol concentration was 95%.
Further, the mixing proportion of the particles, pectin and microcrystalline cellulose is as follows: 80:18:2.
Further, the preparation method of the compound qi-tonifying intestine-moistening capsule also comprises the following steps: the environmental humidity of the preparation process is below 76%.
The invention further aims to provide a compound qi-tonifying intestine-moistening capsule which consists of fructus cannabis, semen pruni, radix astragali, radix codonopsis pilosulae, fructus aurantii immaturus, rhizoma polygonati officinalis and pectin;
the hemp seed comprises the following components in percentage by mass: semen Pruni: radix astragali: radix codonopsis pilosulae: immature bitter orange: rhizoma Polygonati Odorati=1.25:1.25:1:1:1:1;
the pectin is used as adjuvant and accounts for 20% of the total mass of fructus Cannabis, semen Pruni, radix astragali, radix Codonopsis, fructus Aurantii Immaturus, rhizoma Polygonati Odorati and pectin.
The invention also aims to provide a preliminary pharmaceutical evaluation method of the compound qi-tonifying intestine-moistening capsule, which comprises the following steps:
and analyzing the pharmacology of the in-vitro bacteriostasis of the compound qi-tonifying intestine-moistening capsule on common intestinal bacteria by using the constructed mouse animal model.
Further, the constructed mouse animal model comprises:
160 healthy male pure-bred mice, weight (20+/-2) g, SPF grade, are free to drink and eat, and feed at room temperature (22+/-2) DEG C, humidity: 45% -55%, and the mice are normally fed for 1 week, so that the mice adapt to the environment.
Further, the method for analyzing the pharmacology of the in-vitro bacteriostasis of the compound qi-tonifying intestine-moistening capsule on the common intestinal bacteria comprises the following steps:
(1) In vitro bacteriostasis test;
(2) A mouse intestinal propulsion test;
(3) Calculating the intestinal thrust rate of the constipation mice;
(4) And (3) data processing: the variance and statistics analysis is carried out by software, the F test method is adopted to carry out comparison among multiple groups, the t test method is adopted to carry out the comparison among independent samples, the difference significance among the samples is compared, and the result is obtained
The form is expressed with α=5 as a test level.
Further, the step (1) specifically includes:
(1.1) preparation method of bacterial solid culture medium, placing 6.6g of nutrient agar into a conical flask, adding 200mL of water, completely dissolving, and sterilizing in an autoclave for 15min; taking out the solution after the solution is cooled to 50-60 ℃, pouring the solution into a sterile culture dish in a sterile environment, placing the solution in an ultra-clean workbench for ultraviolet sterilization for 15min after solidification, wrapping the solution with a preservative film, and placing the solution into a refrigerator for preservation at 4 ℃;
(1.2) preparation method of bacterial liquid culture medium, placing 4.2g of MH (B) broth powder into a conical flask, adding 200mL of water, completely dissolving, and sterilizing in an autoclave for 15min; taking out the solution after the solution is cooled to 50-60 ℃, and pouring the solution into a sterile culture dish for standby in a sterile environment;
(1.3) preparation of test bacterial liquid, culturing the above-mentioned bacteria at 37℃for 24 hours, and adjusting the bacterial liquid concentration to 1X 10 with a turbidimetric tube 6 CFU/mL for standby;
(1.4) in-vitro bacteriostasis test method, adopting a micro dilution method, taking a 96-well plate to transfer each well into 100 mu L of bacterial liquid culture medium, then continuously transferring the 1 st row into 100 mu L of liquid medicine with the concentration of 100mg/mL, and carrying out gradient dilution to the 6 th row; setting a 7 th behavior positive control group, and adding 10 mu L of gentamicin into each group; setting a 8 th behavior negative control group, and adding 100 mu L of sterile physiological saline; 10 mu L of each bacterial liquid is correspondingly added into each hole, and each bacterium is repeated three times; meanwhile, setting a corresponding dilution gradient of the medicine and a blank of a culture medium as a blank control group on the rightmost side of the 96-well plate, culturing for 24 hours at 37 ℃, and detecting an OD value at 600nm of an enzyme-labeling instrument;
the step (2) specifically comprises: (2.1) dividing 48 Kunming mice with close weight into 6 groups according to a random number table method, wherein the groups comprise a blank control group, a positive medicine western medicine group, a positive medicine Chinese medicine group and YQRC high, medium and low dose groups; after the mice are fasted with water for 20 hours, the corresponding liquid medicine is given, and the dosage is 0.2mL/10g. After 55min of administration, the gastric lavage carbon powder liquid is filled according to the dosage of 0.2 mL/dose; after 20min, the intestine was sacrificed and the pylorus was removed to the ileocecum, and the length recorded as the "total length of small intestine"; the length from the pylorus to the front edge of the ink of the intestinal canal is recorded as the 'ink propelling length', and the intestinal propelling rate of each group of mice is calculated according to a formula;
(2.2) the first defecation time and the defecation weight of 6 hours of the constipation mice are divided into 7 groups of 56 Kunming mice with similar quality according to a random digital table method, wherein the 7 groups comprise a blank control group, a model group, a positive medicine western medicine group, a positive medicine Chinese medicine group and YQRC high, medium and low dose groups; the constipation model was prepared by feeding the mice with mass of 5.0mg/kg of mass of flupirtine hydrochloride for 7 days in addition to distilled water from the blank group. After the molding is finished, the corresponding liquid medicine is filled into the stomach in 8d, and the distilled water filled into the stomach in the model group and the blank control group are respectively 0.2mL/10g. After timing for 55min, the gastric carbon powder liquid is infused according to the dosage of 0.2 mL/dose; after stomach filling, mice are fed normally in a single cage, filter paper is paved at the bottom of the cage to collect faeces, a new filter paper is replaced after each faeces collection, and the first black excrement discharge time and the excrement discharge weight within 6 hours of each mouse are recorded;
the step (3) is to constipation the intestinal thrust rate of the mice: 56 Kunming mice with similar quality were further treated with saline solution at a dose of 0.2mL/10g for 7 days after grouping and molding. After 7 days of gastric lavage, the mice are fasted with water for 20 hours, and the intestinal thrust rate of the mice is calculated according to the dosage of 0.2 mL/dose of gastric lavage carbon powder liquid.
By combining all the technical schemes, the invention has the advantages and positive effects that: the invention is composed of 6 medicinal and edible traditional Chinese medicines such as fructus cannabis, bunge cherry seed, raw astragalus root, dangshen, immature bitter orange, fragrant solomonseal rhizome and the like. Fructus Cannabis is a principal drug in the recipe, is sweet and neutral in nature and moistens, enters the stomach meridian of foot yang and large intestine meridian of hand yang, and is mainly used for treating dryness-heat of intestines and stomach, constipation caused by dry stool due to deficiency of body fluid, dryness-moistening and intestine-smoothing. The ministerial function of the bunge cherry seed is to strengthen the efficacy of relaxing bowel. With the assistance of qi-tonifying and spleen-strengthening of raw astragalus and codonopsis pilosula, the fragrant solomonseal rhizome nourishes yin and increases liquid, the qi is supplemented to promote the large intestine conduction, and the liquid increasing is a method of 'increasing water and moving the boat', the immature bitter orange is used for descending qi and removing food retention, so as to strengthen the effect of descending qi and relaxing the bowels. And fructus cannabis and semen pruni can promote qi circulation and remove body fluid, and can tonify qi and nourish yin without damaging the healthy energy. The whole prescription combines the intestine-moistening and qi-breaking medicine with the qi-tonifying and yin-nourishing medicine, has the effects of tonifying qi and yin, increasing liquid and moistening dryness, promoting qi circulation and removing stagnation, and relaxing bowel, is suitable for the people with the deficiency of qi and yin due to constipation caused by intestinal dryness, and accords with the constipation of the elderly patients caused by the deficiency of qi and yin. In addition, pectin is added as an auxiliary material, so that the water-absorbing gelling effect is good, the water in the intestinal tract can be absorbed, the volume of excrement in the intestinal tract is increased, the intestinal tract is stimulated to produce stool, and the defecation is promoted. The whole prescription can relieve constipation and improve the overall function of the patient, and has the effects of curing diseases and solving the root.
The compound qi-tonifying intestine-moistening capsule provided by the invention has the advantages that the contraction frequency of large and small intestines is increased, the contraction amplitude is increased, the propulsive peristalsis is obviously enhanced, the defecation time is shortened, the defecation amount is increased, the liquid amount in the intestinal cavity is obviously increased, the volume is increased, and the intestinal mucosa has no hyperemia and reddening phenomenon and is obvious in oil.
Drawings
Fig. 1 is a flow chart of a preparation method of the compound qi-tonifying intestine-moistening capsule provided by the embodiment of the invention.
Fig. 2 is a graph showing the moisture absorption percentage of dry extract powder according to the embodiment of the present invention.
Fig. 3 is a schematic diagram showing a graph of critical relative humidity of a drug powder according to an embodiment of the present invention.
FIG. 4 is a schematic diagram of a graph showing critical relative humidity of particles according to an embodiment of the present invention.
Fig. 5 is a schematic diagram showing the effect of the compound qi-tonifying intestine-moistening capsule provided by the embodiment of the invention on intestinal propulsion of a normal mouse.
Fig. 6 is a schematic diagram showing the effect of the compound qi-tonifying intestine-moistening capsule provided by the embodiment of the invention on the first black stool discharge time of a constipation mouse.
Fig. 7 is a schematic diagram showing the effect of the compound qi-tonifying intestine-moistening capsule provided by the embodiment of the invention on the weight of constipation mice in 6h defecation.
Fig. 8 is a schematic diagram of the effect of the compound qi-tonifying intestine-moistening capsule provided by the embodiment of the invention on constipation mice intestinal propulsion.
Detailed Description
The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
Aiming at the problems existing in the prior art, the invention provides a preparation method of a compound qi-tonifying intestine-moistening capsule, and the invention is described in detail below with reference to the accompanying drawings.
The compound qi-tonifying intestine-moistening capsule provided by the embodiment of the invention consists of fructus cannabis, semen pruni, raw astragalus, codonopsis pilosula, immature bitter orange and polygonatum.
The hemp seed comprises the following components in percentage by mass: semen Pruni: radix astragali: radix codonopsis pilosulae: immature bitter orange: rhizoma Polygonati Odorati=1.25:1.25:1:1:1:1;
the pectin is used as adjuvant and accounts for 20% of the total mass of fructus Cannabis, semen Pruni, radix astragali, radix Codonopsis, fructus Aurantii Immaturus, rhizoma Polygonati Odorati and pectin.
The preparation method of the compound qi-tonifying intestine-moistening capsule provided by the embodiment of the invention comprises the following steps:
the compound qi-tonifying intestine-moistening capsule is prepared by extracting dried extract powder of raw astragalus, dangshen, fragrant solomonseal rhizome and immature bitter orange, adding hemp seed fine powder and bunge cherry seed fine powder, granulating together, adding pectin, and filling into a capsule shell.
As shown in fig. 1, the preparation method of the compound qi-tonifying intestine-moistening capsule provided by the embodiment of the invention comprises the following steps:
s101, extracting raw astragalus, dangshen, fragrant solomonseal rhizome and immature bitter orange to obtain dry extract powder;
s102, adding fructus cannabis fine powder and bunge cherry seed fine powder into the obtained dry extract powder, granulating and granulating together by taking microcrystalline cellulose as an auxiliary material and 95% ethanol as a wetting agent;
s103, uniformly mixing pectin and micro powder silica gel, mixing with the prepared particles, and filling into a capsule shell to obtain the compound qi-tonifying intestine-moistening capsule.
The auxiliary materials and the main materials provided by the embodiment of the invention are used in the following amounts: 1:7.
the mixing proportion of the particles, pectin and microcrystalline cellulose provided by the embodiment of the invention is as follows: 80:18:2.
The preparation method of the compound qi-tonifying intestine-moistening capsule provided by the embodiment of the invention further comprises the following steps: the environmental humidity of the preparation process is below 76%.
The invention also provides a preliminary pharmaceutical evaluation method of the compound qi-tonifying intestine-moistening capsule, which comprises the following steps:
and analyzing the pharmacology of the in-vitro bacteriostasis of the compound qi-tonifying intestine-moistening capsule on common intestinal bacteria by using the constructed mouse animal model.
The constructed mouse animal model comprises:
160 healthy male pure-bred mice, weight (20+/-2) g, SPF grade, are free to drink and eat, and feed at room temperature (22+/-2) DEG C, humidity: 45% -55%, and the mice are normally fed for 1 week, so that the mice adapt to the environment.
The method for analyzing the pharmacology of the in-vitro bacteriostasis effect of the compound qi-tonifying intestine-moistening capsule on the common intestinal bacteria comprises the following steps:
(1) In vitro bacteriostasis test;
(2) A mouse intestinal propulsion test;
(3) Calculating the intestinal thrust rate of the constipation mice;
(4) And (3) data processing: the variance and statistics analysis is carried out by software, the F test method is adopted to carry out comparison among multiple groups, the t test method is adopted to carry out the comparison among independent samples, the difference significance among the samples is compared, and the result is obtained
Formally expressed as α=5And (5) checking the level.
The technical scheme of the invention is further described below with reference to specific embodiments.
Example 1:
the invention takes dry extract powder obtained by extracting raw astragalus, dangshen, fragrant solomonseal rhizome and immature bitter orange, adds hemp seed fine powder and bunge cherry seed fine powder to granulate together, and takes repose angle, bulk density and hygroscopicity as indexes to examine the types of auxiliary materials and the dosage of the auxiliary materials, and adds pectin into the No. 0 capsule shell. Lays a foundation for the subsequent test of the compound capsule for tonifying qi and moistening intestines.
1 main instrument and materials
1.1 pharmaceutical products and reagents
The required drugs and reagents are shown in Table 1.
Table 1 experimental drugs and reagents
Note that: the Chinese medicinal decoction pieces meet the relevant regulations of the first part of Chinese pharmacopoeia of 2015 edition.
1.2 major instrumentation
The required instrumentation is shown in Table 2.
Table 2 laboratory apparatus
2 test methods and results
2.1 investigation of the Performance of the Dry extract powder
2.1.1 Dry extract powder flowability test
The fluidity of the dry extract powder was measured by a fixed hopper method, the hopper was fixed on a hopper frame, the outlet at the lowermost end was leveled, and the lowermost end of the hopper was made to be located at a height of 1.20cm (H) from the horizontal coordinate paper, and when the extract powder was dropped from the hopper, the radius (R) of the bottom surface of the powder cone was measured when the upper end of the formed powder cone reached the lower end of the hopper, the angle of repose (α) was calculated, the test was repeated 5 times, and the average value was taken, and specific data were shown in Table 3.
The calculation formula is as follows:
TABLE 3 Angle of repose results for dry extract powders
When the angle of repose of the drug powder is 30 DEG < alpha <40 DEG, the powder flowability is good. As is clear from Table 3, the average repose angle measured for the dry extract powder was 51.90℃which indicates poor flowability of the powder, and thus the flowability was increased by granulating.
2.1.2 hygroscopicity test of dry extract powder
Placing saturated NaCl solution in a dryer at normal temperature for 24h, placing dry extract powder in a weighing bottle dried to constant weight, placing the dry extract powder into a weighing bottle with the thickness of 2mm, weighing, placing the dry extract powder in the dryer, sampling at regular time, weighing for three times, taking an average value, and drawing a moisture absorption percentage curve of the dry extract powder according to the moisture absorption percentage of the dry extract powder, wherein the moisture absorption percentage curve is shown in Table 4 and fig. 2.
TABLE 4 percent hygroscopicity of dry extract powders
As can be seen from table 4 and fig. 2, the moisture absorption rate of the dry extract powder was >15% after the dry extract powder was left to stand for 12 hours in a desiccator containing a saturated NaCl solution, which suggests that the dry extract powder has a strong moisture absorption property, and it is considered that the moisture absorption property was lowered by adding an auxiliary material.
2.2 investigation of the parameters of the pelletization Process
2.2.1 selection of auxiliary Material types
15 parts of dry extract powder are taken and divided into 5 groups, the 5 groups of dry extract powder are respectively mixed with excipient auxiliary materials of different types, the excipient auxiliary materials account for 10 percent of the dry extract powder, 95 percent of ethanol is sprayed, a 20-mesh screen is used for granulating, the temperature of an oven is 60 ℃, the drying is carried out for 1 hour, a 10-mesh screen is used for finishing the granules, and each index of the granules is inspected, wherein the granule moisture absorption percentage test method is the same as the step of the moisture absorption test of the dry extract powder of 2.1.2. The test results are shown in Table 5.
The standard of the qualified particles is as follows: can pass through a 10 mesh screen and cannot pass through an 80 mesh screen.
TABLE 5 selection of adjuvant classes
As is clear from Table 5, the soft material state obtained from dextrin, mannitol and microcrystalline cellulose is preferable. Mannitol and microcrystalline cellulose are easy to granulate. Compared with the hygroscopicity and the granule yield, the microcrystalline cellulose has more ideal granulating effect, so the microcrystalline cellulose is selected as an auxiliary material for granulating in the experiment.
2.2.2 adjuvant usage and wetting agent concentration test
According to the dosage requirement of the prescription, 1.2g of dry extract powder, 1.5g of fructus cannabis powder and 1.5g of semen pruni powder are taken daily (hereinafter, the three powder mixtures are collectively called as "drug powder"). The pre-experiment shows that the dosage of each capsule shell of the No. 0 capsule is 0.5g, calculated by taking 12 capsules per day, and the dosage of all auxiliary materials except the medicine powder is 1.8g, wherein about 20 percent of pectin, namely about 1.2g, is needed to be added before the capsules are filled after the granulation is completed. Therefore, the daily amount of other auxiliary materials is at most 0.6g.
In order to examine the dosage of microcrystalline cellulose as an auxiliary material, a proper amount of medicine powder and microcrystalline cellulose are mixed according to the proportion of 10:1, 8.5:1 and 7:1, 3 parts of each group are respectively sprayed with ethanol with the concentration of 85%, 90% and 95%, and the mixture is sieved by a 20-mesh sieve for granulation, and the dosage of the auxiliary material and the concentration of a wetting agent are examined. The results are shown in Table 6.
TABLE 6 microcrystalline cellulose dosage and wetting agent concentration
As shown in Table 6, the medicine powder is sensitive to humidity, and the auxiliary materials are used in a small amount and a large moisture absorption percentage when the medicine auxiliary ratio is 10:1 and 8.5:1, so that the auxiliary materials are used in a medicine auxiliary ratio of 7:1. The wetting agent has lumps when the concentration is 85% and 90% of ethanol, the soft material is not easy to loosen, 95% of ethanol is selected, and the granule yield is high. Therefore, microcrystalline cellulose with the medicine auxiliary ratio of 7:1 and ethanol with the concentration of 95% are finally selected for granulation.
2.2.3 examination of the drying time of the granules
As is clear from preliminary experiments and reference documents, the drying temperature is set to 60 ℃ when the particles with higher polysaccharide content are dried, so that the drying temperature of the particles is 60 ℃.
The dried granules are taken and put into a dried weighing bottle, the thickness of the dried granules is about 2mm, the dried granules are weighed and put into a 60 ℃ oven, the dried granules are weighed regularly, and the influence of different drying times on the moisture content in the granules is examined. The water content of the granule is calculated according to a drying method in a water content measuring method of Chinese pharmacopoeia of 2015 edition. The specific results are shown in Table 7.
TABLE 7 moisture content in granules at different drying times
Comprehensively considering the problems of moisture content and production cost in the particle drying process, and finally determining the particle drying time to be 2h.
2.3 investigation of content properties of capsules
Through preliminary experiments, when pectin accounts for about 20% of the total content, the effect of the pectin on the intestinal propulsion of the mice is ideal, so that the prepared particles and pectin are uniformly mixed according to the proportion of 8:2, the fluidity of the particles after pectin is added is measured by referring to a method of a 2.1.1 dry extract powder fluidity test, and the average value of repose angles is 40.68 degrees after 3 times of tests are performed in parallel. In order to make the capsule filling effect more ideal, the experiment considers adding a proper amount of micro silica gel to further improve the particle fluidity. The pectin and the aerosil account for 20% of the total content, and the pectin and the aerosil are mixed uniformly according to a certain proportion, then mixed with the prepared particles (hereinafter referred to as "capsule content") and filled into a capsule shell.
2.3.1 Capsule content flow test
Mixing the granule, pectin and aerosil at the ratio of 80:19:1, 80:18:2 and 80:17:3, and determining granule fluidity by reference to "2.1.1 dry extract powder fluidity test". The results are shown in Table 8.
TABLE 8 influence of the amount of micro silica gel on the flowability of the capsule contents
| Dosage of micro silica gel | Radius R (cm) | H(cm) | Tanα | Angle of repose α (°) |
| 1％ | 2.00 | 1.20 | 0.60 | 30.96 |
| 2％ | 2.45 | 1.20 | 0.49 | 26.06 |
| 3％ | 2.75 | 1.20 | 0.44 | 23.57 |
As can be seen from Table 8, the fluidity of the contents of the present capsule increased after adding the silica gel micropowder, and the fluidity was better when the addition amounts were 2% and 3%.
2.3.2 capsule content bulk Density test
Uniformly mixing the particles, pectin and aerosil according to the proportions of 80:19:1, 80:18:2 and 80:17:3, respectively taking equal amounts, respectively filling into 10mL measuring cylinders, tilting 50 times on a test bed, reading the volume of the capsule content in the measuring cylinders, and calculating the bulk density of each group. The results are shown in Table 9.
TABLE 9 influence of the amount of silica gel micropowder on the bulk Density of the capsule Contents
Note that: bulk density ρ (g/mL) =content mass (g)/content volume (mL)
As can be seen from Table 9, the bulk density of the capsule contents increased and the capsule loading increased after adding the silica gel micropowder. And the addition amounts of 2% and 3% are not very different.
2.3.3 moisture absorption test of the content of the Capsule
Uniformly mixing the particles, pectin and aerosil according to the proportion of 80:19:1, 80:18:2 and 80:17:3, standing for 2 hours at 60 ℃ and drying, and examining the influence of the aerosil with different dosages on the hygroscopicity of the capsule content by a measuring method under a test of hygroscopicity of 2.1.2 dry extract powder. The results are shown in Table 10.
TABLE 10 influence of the amount of silica gel micropowder on hygroscopicity of the capsule contents
As can be seen from Table 10, the hygroscopicity of the capsule contents was reduced by adding the silica gel micropowder, and the hygroscopicity was minimized at the dosages of 2% and 3%. Comparing repose angle, bulk density and hygroscopicity, and taking the principle of reducing the dosage of auxiliary materials as much as possible, 2% of micropowder silica gel is selected as glidant to be added into the content of the capsule.
2.3.4 investigation of critical relative humidity
The drug powder and the particles were precisely weighed 7 parts each, placed in a weighing bottle with a thickness of about 2mm, placed in a desiccator in 7 different humidity environments, and placed at room temperature for 7 days. The moisture absorption of the drug powder and granules was calculated and is shown in table 11. And the moisture absorption curve is drawn, see in particular figures 3 and 4.
Table 11 investigation of hygroscopicity of drug powders and granules
As is clear from table 11, fig. 3 and 4, the critical relative humidity of the drug powder was about 76%, the critical relative humidity of the pellet was about 82%, and the hygroscopicity of the drug powder after being formed into pellets was reduced. Therefore, in the steps of crushing, mixing and the like of the dry extract, the ambient humidity is lower than 76%; in the steps of particle production, packaging and the like, the ambient humidity is below 82%.
3 in the analysis of the preparation, the dry extract powder is added with hemp seed fine powder and bunge cherry seed fine powder, microcrystalline cellulose is taken as an auxiliary material, the dosage is 7:1 (namely 10 percent of the total capsule content), and 95 percent ethanol is taken as a wetting agent for granulating. Mixing the obtained granule with 18% pectin and 2% aerosil, and making into capsule. Meanwhile, the critical relative humidity test shows that the environmental humidity is below 76% in the steps of crushing, mixing and the like of the dry extract; in the steps of particle production, packaging and the like, the ambient humidity is controlled below 82%.
Example 2: in-vitro antibacterial and mouse intestinal propulsion experimental study of compound qi-tonifying intestine-moistening capsule
The in vitro antibacterial effect of the compound qi-tonifying intestine-moistening capsule (YQRC) on common intestinal bacteria is studied, and the in vitro antibacterial effect on the defecation and intestinal propulsion of mice is studied. MIC values of the capsule to various common clinical pathogens are measured by adopting a micro dilution method so as to evaluate the in-vitro antibacterial activity of the capsule; the effect of the capsule on the intestinal propulsive rate of male Kunming SPF mice with the age of 5 weeks and the effect of the capsule on the first defecation time, the 6-hour stool weight and the intestinal propulsive rate of male Kunming constipation mice with the age of 5 weeks are observed through experiments. Preliminary research is carried out on pharmacodynamics evaluation of the compound qi-tonifying intestine-moistening capsule.
1 main instrument and materials
1.1 pharmaceutical products and reagents
The required drugs and reagents are shown in Table 12.
Table 12 experimental drugs and reagents
1.2 major instrumentation
The required instrumentation is shown in Table 13.
Table 13 laboratory apparatus
1.3 test seed and test animals
Staphylococcus aureus is resistant to methicillin Lin Zhu M1233, staphylococcus aureus is resistant to methicillin Lin Zhu M1805, klebsiella pneumoniae ATCC13883, salmonella typhimurium ATCC14028, bacillus cereus ATCC63303, enterococcus faecalis ATCC29212, pseudomonas aeruginosa ATCC27853, micrococcus luteus ATCC10240, all provided by the microorganism textroom of the present school. 160 healthy male Kunming pure-bred mice, weight (20+ -2) g, SPF grade (experimental animal license number: SCXK (robust) 20140007), free drinking water and eating, feeding room temperature (22+ -2) deg.C, humidity: 45% -55%, and the mice are normally fed for 1 week, so that the mice adapt to the environment.
2 test method
2.1 in vitro bacteriostasis test
2.1.1 preparation method of solid bacterial Medium
6.6g of nutrient agar was placed in a conical flask, 200mL of water was added, and after complete dissolution, the mixture was sterilized in an autoclave for 15min. And (3) taking out the solution after the solution is cooled to 50-60 ℃, pouring the solution into a sterile culture dish in a sterile environment, placing the solution in an ultra-clean workbench for ultraviolet sterilization for 15min after solidification, wrapping the solution with a preservative film, and storing the solution in a refrigerator at 4 ℃.
2.1.2 preparation method of bacterial liquid Medium
4.2g of MH (B) broth powder was placed in an Erlenmeyer flask, 200mL of water was added, and after complete dissolution, sterilized in an autoclave for 15min. And (5) taking out the solution after the solution is cooled to 50-60 ℃, and pouring the solution into a sterile culture dish for standby in a sterile environment.
2.1.3 preparation of laboratory bacteria liquid
After culturing each of the above bacteria at 37℃for 24 hours, the concentration of the bacterial solution was adjusted to 1X 10 by using a turbidimetric tube 6 CFU/mL was ready for use.
2.1.4 in vitro bacteriostasis test method
By micro dilution, 96-well plates were used to transfer 100. Mu.L of the bacterial liquid medium under item "2.1.2", followed by continuous transfer of 100. Mu.L of 100mg/mL of the liquid medium to line 6. A7 th behavioural positive control group was set, and 10. Mu.L of gentamicin was added each. A behavior negative control group of 8 was set, and 100. Mu.L of sterile physiological saline was added. Each well was added with 10. Mu.L of each bacterial solution, and each bacteria was repeated three times. Meanwhile, a corresponding dilution gradient of the medicine and a blank of a culture medium are arranged on the rightmost side of the 96-well plate as a blank control group, the culture is carried out for 24 hours at 37 ℃, an OD value is detected at 600nm of an enzyme-labeling instrument, and a macroscopic observation and statistics result is combined.
2.2 intestinal propulsion test in mice
2.2.1 intestinal Propulsion in Normal mice
According to the random number table method, 48 Kunming mice with close body weight are divided into 6 groups, including a blank control group (distilled water), a positive medicine western medicine group (phenolphthalein tablet 0.030 g/kg), a positive medicine Chinese medicine group (xiangdan 0.243 g/kg) and YQRC high, medium and low dose groups (1.820 g/kg, 0.910g/kg and 0.455g/kg respectively). After the mice are fasted with water for 20 hours, the corresponding liquid medicine is given, and the dosage is 0.2mL/10g. After 55min of administration, the gastric carbon powder liquid is infused according to the dosage of 0.2 mL/dose. After 20min, the intestine was sacrificed and the pylorus was removed to the ileocecum, and the length recorded as the "total length of small intestine"; the length of the intestinal canal from the pylorus to the ink front is designated as the "ink advancing length", and the intestinal advancing rate of each group of mice is calculated according to the formula.
2.2.2 Constipation mice first defecation time and 6h defecation weight
According to the random number table method, 56 Kunming mice with similar quality are divided into 7 groups, including a blank control group (distilled water), a model group (fludioxonil hydrochloride 0.25 mg/mL), a positive medicine western medicine group (phenolphthalein tablet 0.030 g/kg), a positive medicine Chinese medicine group (xiangdan 0.243 g/kg) and YQRC high, medium and low dose groups (1.820 g/kg, 0.910g/kg and 0.455g/kg respectively). The constipation model was prepared by feeding the mice with mass of 5.0mg/kg of mass of flupirtine hydrochloride for 7 consecutive days, except for the control group to which distilled water was administered. After the molding is finished, the corresponding liquid medicine is filled into the stomach in 8d, and the distilled water filled into the stomach in the model group and the blank control group are respectively 0.2mL/10g. After timing for 55min, the gastric carbon powder liquid is infused according to the dosage of 0.2 mL/dose. After stomach filling, mice are fed normally in a single cage, feces are collected by paving filter paper at the bottom of the cage, a new filter paper is replaced after each feces collection, and the first black feces discharge time and the feces discharge weight within 6 hours of each mouse are recorded.
2.2.3 intestinal Propulsion in constipation mice
56 Kunming mice with similar quality were further taken, and after grouping and molding according to the method of "step 2.2.2", physiological saline was administered to the blank control group and the model group in a continuous 7d with the corresponding liquid medicine administered at a dose of 0.2mL/10g. After 7 days of gastric lavage, mice were fasted with water for 20h, and were sacrificed after 20min at a dose of 0.2 mL/dose of gastric lavage carbon powder, intestinal tracts were removed and the intestinal thrust rate of mice was calculated as in the method under item "2.2.1".
2.2.4 data processing
Variance and statistics analysis are carried out by adopting SPSS 22.0 software and Graphpad Prism 8.0 software, multiple groups are compared by adopting an F test method, the groups are compared by adopting a t test method between independent samples, the significance of the difference between the samples is compared, and the result is that
The form is expressed with α=5 as a test level.
3 test results
3.1 results of in vitro bacteriostasis test
As can be seen from the results in Table 14, the bacteria grew better in the negative control group, the positive control group did not grow significantly, and the medium blank group did not pollute. The compound qi-tonifying intestine-moistening capsule has better broad-spectrum antibacterial effect: the minimum inhibitory concentration MIC for Klebsiella pneumoniae and Staphylococcus aureus methicillin-resistant Lin Zhu M1233 was 3.125mg/mL, the MIC for Staphylococcus aureus methicillin-resistant Lin Zhu M1805, pseudomonas aeruginosa, bacillus cereus, enterococcus faecalis and Micrococcus luteus was 6.25mg/mL, and the MIC for Salmonella typhimurium was 25mg/mL.
Table 14 in vitro antibacterial results of compound qi-tonifying intestine-moistening capsule (n=3)
Note that: +: turbidity of the medium-: clarification of the Medium
3.2 results of the intestinal thrust test in mice
3.2.1 intestinal Propulsion in normal mice
The results in table 15 and fig. 5 show that the capsule has higher intestinal thrust rate than the blank group for normal mice in the high, medium and low dose groups, and the difference is significant (P <0.05, P < 0.01). And the intestinal propulsion effect of the high-dose group is better than that of the two positive groups.
Table 15 influence of Compound Qi-tonifying intestine-moistening Capsule on intestinal propulsion of normal mice
n＝8)/>
Note that: in contrast to the blank group, △ P<0.05， △△ P<0.01
3.2.2 effects on first bowel movement time and 6h bowel movement weight in constipation mice
As can be seen from table 16 and fig. 7, in the first stool blacking time experiment, the time taken by the constipation model group mice was significantly longer than that of the blank control group, and the model group mice were heavier than the blank control group (P < 0.05) for 6 hours, indicating that the modeling was successful. The first granule black stool discharge time of the mice of the compound capsule for supplementing qi and moisturizing the intestines is shorter than that of the mice of the model group (P is less than 0.05 and P is less than 0.01), and the 6h stool weight of the mice of the YQRC high-dose group and the YQRC medium-dose group is higher than that of the mice of the model group (P is less than 0.05 and P is less than 0.01), and the difference is remarkable. And the defecation effect of the YQRC high-dose administration group mice on the first granule black stool discharge and 6h stool weight is better than that of the positive medicine western medicine group.
TABLE 16 influence of Qi-tonifying intestine-moistening capsule on first-time defecation-blackening time and defecation weight of 6h of constipation mice
n＝8)
Note that: in contrast to the blank group, △ P<0.05; in contrast to the set of models, * P<0.05， ** P<0.01
3.2.3 intestinal Propulsion in constipation mice
The results in Table 17 show that the average intestinal thrust rate of the mice in the constipation model group is significantly lower (P < 0.05) than that of the blank group, indicating that the modeling was successful. The compound capsule for supplementing qi and moistening the intestines has higher intestinal propulsion rate than that of a constipation model group (P is less than 0.01) in high, medium and low dose administration groups. And the high-dose group of the compound qi-tonifying intestine-moistening capsule has higher intestinal propulsion rate than the western medicine group of positive medicine for constipation mice.
TABLE 17 influence of Qi-tonifying intestine-moistening Capsule on constipation mice intestinal propulsion
n＝8)/>
Note that: in contrast to the blank group, △ P<0.05， △△ P<0.01; in contrast to the set of models, * P<0.05， ** P<0.01
the traditional Chinese medicine considers that constipation can be divided into heat-excess and fluid-deficiency type, yin-cold stagnation type, qi-blood and fluid-deficiency type and the like. The main treatment scheme for the common qi deficiency constipation of the elderly is to regulate qi and blood circulation, and achieve the effects of tonifying qi and nourishing yin, promoting qi circulation and removing food stagnation, and relaxing bowel.
Test results prove that the compound qi-tonifying intestine-moistening capsule has a better broad-spectrum antibacterial effect and has an inhibition effect on various common intestinal bacteria. The capsule has the effects of promoting the intestinal propulsive rate of mice and the defecation amount of mice for 6 hours, relaxing bowel, conforming to the treatment scheme of senile constipation caused by deficiency of qi, blood and fluid, and has definite curative effect.
The foregoing is merely illustrative of specific embodiments of the present invention, and the scope of the invention is not limited thereto, but any modifications, equivalents, improvements and alternatives falling within the spirit and principles of the present invention will be apparent to those skilled in the art within the scope of the present invention.
Claims (7)
1. The preparation method of the compound qi-tonifying intestine-moistening capsule is characterized by comprising the following steps of:
step one, extracting raw astragalus, dangshen, fragrant solomonseal rhizome and immature bitter orange to obtain dry extract powder;
adding the obtained dry extract powder into the fructus cannabis fine powder and the bunge cherry seed fine powder with the prescription amount, taking microcrystalline cellulose as an auxiliary material, taking ethanol as a wetting agent, granulating and granulating together;
step three, after the pectin and the micro powder silica gel are uniformly mixed, the mixture is mixed with the prepared particles and then is filled into a capsule shell, and then the compound qi-tonifying intestine-moistening capsule is obtained; the mixing proportion of the particles, the pectin and the micro powder silica gel is as follows: 80:18:2;
firstly, weighing raw astragalus, dangshen, fragrant solomonseal rhizome and immature bitter orange medicinal materials according to the proportion of 1:1:1 of a prescription, adding 8 times of water, extracting at 100 ℃ for 2 times, 1h each time, combining the two extracting solutions, concentrating and drying to obtain dry extract powder;
in the second step, the dosage of the auxiliary materials and the main materials is as follows: 1:7, preparing a base material; the ethanol concentration is 95%;
the hemp seed comprises the following components in percentage by mass: semen Pruni: radix astragali: radix codonopsis pilosulae: immature bitter orange: rhizoma Polygonati Odorati=1.25: 1.25:1:1:1:1.
2. the method for preparing the compound qi-tonifying intestine-moistening capsule according to claim 1, wherein the method for preparing the compound qi-tonifying intestine-moistening capsule further comprises the following steps: the environmental humidity of the preparation process is below 76%.
3. The compound qi-tonifying intestine-moistening capsule is characterized by comprising fructus cannabis, semen pruni, radix astragali, radix codonopsis pilosulae, immature bitter orange, rhizoma polygonati officinalis and pectin;
the hemp seed comprises the following components in percentage by mass: semen Pruni: radix astragali: radix codonopsis pilosulae: immature bitter orange: rhizoma Polygonati Odorati=1.25: 1.25:1:1:1:1, a step of;
the pectin is used as adjuvant and accounts for 20% of the total mass of fructus Cannabis, semen Pruni, radix astragali, radix Codonopsis, fructus Aurantii Immaturus, rhizoma Polygonati Odorati and pectin.
4. A method of preliminary pharmaceutical evaluation of a compound qi-tonifying intestine-moistening capsule according to claim 3, wherein the method of preliminary pharmaceutical evaluation of a compound qi-tonifying intestine-moistening capsule comprises:
and analyzing the pharmacology of the in-vitro bacteriostasis of the compound qi-tonifying intestine-moistening capsule on common intestinal bacteria by using the constructed mouse animal model.
5. The preliminary pharmaceutical evaluation method of the compound qi-tonifying intestine-moistening capsule according to claim 4, wherein the constructed mouse animal model comprises the following steps:
160 healthy male pure-bred mice, weight (20+/-2) g, SPF grade, are free to drink and eat, and feed at room temperature (22+/-2) DEG C, humidity: 45% -55%, and the mice are normally fed for 1 week, so that the mice adapt to the environment.
6. The method for preliminary pharmaceutical evaluation of the compound qi-tonifying intestine-moistening capsule according to claim 4, wherein the method for analyzing the in-vitro bacteriostasis pharmacology of the compound qi-tonifying intestine-moistening capsule on common intestinal bacteria comprises the following steps:
(1) In vitro bacteriostasis test;
(2) A mouse intestinal propulsion test;
(3) Calculating the intestinal thrust rate of the constipation mice;
(4) And (3) data processing: the variance and statistics analysis is carried out by software, the F test method is adopted to carry out comparison among multiple groups, the t test method is adopted to carry out the comparison among independent samples, the difference significance among the samples is compared, and the result is obtained
The form is expressed with α=5 as a test level.
7. The preliminary pharmaceutical evaluation method of the compound qi-tonifying intestine-moistening capsule as set forth in claim 6, wherein the step (1) specifically includes:
(1.1) preparation method of bacterial solid culture medium, placing 6.6g of nutrient agar into a conical flask, adding 200mL of water, completely dissolving, and sterilizing in an autoclave for 15min; taking out the solution after the solution is cooled to 50-60 ℃, pouring the solution into a sterile culture dish in a sterile environment, placing the solution in an ultra-clean workbench for ultraviolet sterilization for 15min after solidification, wrapping the solution with a preservative film, and placing the solution into a refrigerator for preservation at 4 ℃;
(1.2) preparation method of bacterial liquid culture medium, placing 4.2g MH (B) broth powder into a conical flask, adding 200mL water, completely dissolving, and sterilizing in an autoclave for 15min; taking out the solution after the solution is cooled to 50-60 ℃, and pouring the solution into a sterile culture dish for standby in a sterile environment;
(1.3) preparation of test bacterial liquid, culturing the above-mentioned bacteria at 37℃for 24 hours, and adjusting the bacterial liquid concentration to 1X 10 with a turbidimetric tube 6 CFU/mL for standby;
(1.4) in-vitro bacteriostasis test method, adopting a micro dilution method, taking a 96-well plate to transfer each well into 100 mu L of bacterial liquid culture medium, then continuously transferring the 1 st row into 100 mu L of liquid medicine with the concentration of 100mg/mL, and carrying out gradient dilution to the 6 th row; setting a 7 th behavior positive control group, and adding 10 mu L of gentamicin into each group; setting a 8 th behavior negative control group, and adding 100 mu L of sterile physiological saline; 10 mu L of each bacterial liquid is correspondingly added into each hole, and each bacterium is repeated three times; meanwhile, setting a corresponding dilution gradient of the medicine and a blank of a culture medium as a blank control group on the rightmost side of the 96-well plate, culturing for 24 hours at 37 ℃, and detecting an OD value at 600nm of an enzyme-labeling instrument;
the step (2) specifically comprises: (2.1) dividing 48 Kunming mice with close weight into 6 groups according to a random number table method, wherein the groups comprise a blank control group, a positive medicine western medicine group, a positive medicine Chinese medicine group and YQRC high, medium and low dose groups; after the mice are fasted and fed with water for 20 hours, the corresponding liquid medicine is administered, the dosage is 0.2mL/10g, and after 55 minutes of administration, the gastric lavage carbon powder liquid is administered according to the dosage of 0.2 mL/dose; after 20min, the intestine was sacrificed and the pylorus was removed to the ileocecum, and the length recorded as the "total length of small intestine"; the length from the pylorus to the front edge of the ink of the intestinal canal is recorded as the 'ink propelling length', and the intestinal propelling rate of each group of mice is calculated according to a formula;
(2.2) first defecation time and 6h defecation weight of constipation mice: according to the random digital table method, dividing 56 Kunming mice with similar quality into 7 groups, including blank control group, model group, positive medicine western medicine group, positive medicine Chinese medicine group and YQRC high, medium and low dose group; the method comprises the steps of (1) continuously feeding the distilled water to the mice except the blank control group for 7d, and feeding the pyrobutamine hydrochloride according to the mass of 5.0mg/kg to manufacture a constipation model, and after the model is manufactured, filling corresponding liquid medicine into the stomach at the 8d, filling the model group and the blank control group with the distilled water into the stomach according to the volume of 0.2mL/10g, and filling the stomach with the carbon powder liquid according to the volume of 0.2 mL/dose after timing for 55 min; after stomach filling, mice are fed normally in a single cage, filter paper is paved at the bottom of the cage to collect faeces, a new filter paper is replaced after each faeces collection, and the first black excrement discharge time and the excrement discharge weight within 6 hours of each mouse are recorded;
the step (3) is to constipation the intestinal thrust rate of the mice: taking 56 Kunming mice with similar quality, grouping and modeling, and continuously administering corresponding liquid medicine at a dose of 0.2mL/10g for 7d, and administering normal saline to the blank control group and the model group; after 7 days of gastric lavage, the mice are fasted with water for 20 hours, and the intestinal thrust rate of the mice is calculated according to the dosage of 0.2 mL/dose of gastric lavage carbon powder liquid.
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