CN111249334B

CN111249334B - Vitality-maintaining and nerve-soothing capsule, preparation method and application

Info

Publication number: CN111249334B
Application number: CN201911118638.4A
Authority: CN
Inventors: 阳勇; 王云红; 郭延垒; 秦伟瀚; 张小梅; 花雷; 王计瑞
Original assignee: China Academy of Chinese Medical Sciences CACMS
Current assignee: China Academy of Chinese Medical Sciences CACMS
Priority date: 2019-11-15
Filing date: 2019-11-15
Publication date: 2021-08-24
Anticipated expiration: 2039-11-15
Also published as: CN111249334A

Abstract

The invention relates to a capsule for protecting vitality and soothing nerves, wherein the capsule for protecting vitality and soothing nerves comprises the active ingredients of astragalus, ginseng, liquorice and cinnamon. The dissolution problem of each active component of the prescription is fully solved, and the process is ensured to meet the process requirements of the capsule preparation. Can directly improve sleep and improve nonspecific immunity of human body.

Description

Vitality-maintaining and nerve-soothing capsule, preparation method and application

Technical Field

The invention relates to a traditional Chinese medicine preparation technology, in particular to a preparation method of a capsule for protecting vitality and soothing nerves.

Background

Capsules (Capsules) refer to solid preparations prepared by filling drugs or appropriate excipients into hollow hard Capsules or sealing into soft Capsules, and can be divided into hard Capsules, soft Capsules (gelatin Capsules), sustained-release Capsules, controlled-release Capsules and enteric Capsules, which are mainly used for oral administration.

According to 2015 th edition of Chinese pharmacopoeia (second part), the capsule meets the following requirements:

1. the appearance of the capsule should be neat, free from adhesion, deformation, leakage or rupture of the capsule shell, and free from foreign odor.

2. Moisture the Chinese medicinal hard capsule should be inspected for moisture. The content of the sample was measured by a moisture measuring method (general formula 0832). Unless otherwise specified, should not exceed 9.0%. The hard capsule contents were liquid or semisolid without checking for moisture.

3. The content difference inspection method comprises weighing 20 samples (10 Chinese medicinal materials), weighing, pouring out the content (without loss of capsule shell), and cleaning the capsule shell with small brush or other suitable tool; the soft capsule or hard capsule shell with semisolid or liquid content is cleaned with volatile solvent such as diethyl ether, placed in ventilated place to volatilize the solvent, and the weight of the capsule shell is precisely weighed to obtain the content and average content of each content. The amount of each capsule is compared with the average amount (the amount of each capsule is compared with the labeled amount), and the amount exceeding the difference limit of the amount is not more than 2 capsules, and not more than 1 capsule exceeds the limit by 1 time.

4. The disintegration time should be determined to be in accordance with the standards, except for the other standards, according to the disintegration time test method (general rule 0921). Capsules with a prescribed dissolution rate or release rate to be checked are generally not checked for disintegration time.

5. The microbial limit is a capsule prepared from non-monomer components of animal, plant and mineral sources, and the capsule of biological products is checked according to the microbial limit of non-sterile products: the microorganism count method (general rule 1105), the control bacteria inspection (general rule 1106) and the non-sterile medicine microorganism limit standard (general rule 1107) should meet the regulations. The biological product capsule for detecting the mixed bacteria is specified, and the microbial limit detection can be avoided.

Disclosure of Invention

In order that the preparation of the capsule with the active ingredients of astragalus, ginseng, liquorice and cinnamon achieves the technical indexes, the invention provides a preparation method of the capsule with the active ingredients of astragalus, ginseng, liquorice and cinnamon, and the method comprises the following steps:

1) pulverizing Ginseng radix and sieving with 80 mesh sieve to obtain Ginseng radix coarse powder;

2) sieving radix astragali, Glycyrrhrizae radix and cortex Cinnamomi powder with 10 mesh sieve, soaking in 6 times of water by weight of medicinal materials for 0.5 hr, decocting for 2 hr, extracting for 2 times, mixing to obtain extractive solution, and filtering;

3) cooling the extractive solution, standing for 3 hr, collecting supernatant, and spray drying at 60 deg.C to obtain extract with density of 1.16-1.20 g/ml;

4) mixing the extract, Ginseng radix coarse powder, starch and the extract to obtain soft material, sieving with 50 mesh sieve, drying at 50 deg.C for 3 hr, adding magnesium stearate, and making into medicinal granule;

5) encapsulating the medicinal granules to obtain the vitality-maintaining and nerve-soothing capsules.

The addition amount of each raw material of each 1000 capsules is 313g of astragalus, 156g of ginseng, 78g of liquorice, 31g of cinnamon, 90g of starch and 20g of magnesium stearate.

The beneficial technical effects of the invention are as follows: the capsule preparation method provided by the invention fully solves the dissolution problem of each active component in the formula and ensures that the process requirement of the capsule preparation is met by adopting the process. Meanwhile, the Baoyuan tranquilizing capsule prepared by adopting a preparation modifying method has no direct sleeping effect on mice through direct sleeping, pentobarbital sodium sleeping time and other experiments; the sleep time of the sodium pentobarbital can be prolonged; the sample has sleep improving effect according to the evaluation standard of health food function. The capsule can obviously improve immune organ index and lysozyme content, and has good capability of improving non-specific immunity of organisms.

Drawings

FIG. 1 Critical relative humidity;

FIG. 2 is an extended sleep time diagram;

FIG. 3 is a graph of subliminal hypnotic effect;

FIG. 4 is a graph of sleep latency effect;

FIG. 5 spleen index comparison;

FIG. 6 thymus index map;

FIG. 7 is a graph showing a comparison of lysosome contents.

Detailed Description

Example 1 study of extraction Process

1.1 optimization of extraction Process parameters

Using orthogonal L₉(3⁴) The experimental method optimizes and researches the extraction process.

1.2 orthogonal Table design

With 3 factors of water consumption, extraction times and extraction time which have great influence on the investigation index, the orthogonal table head is designed according to four factors and three levels, and the factor level table 1:

TABLE 1 orthogonal factor horizon

1.3 test methods and procedures

Weighing 9 parts of medicinal materials according to the prescription amount, weighing 1 part of medicinal materials according to the prescription amount, adding 1 volume of water for the first decoction, soaking for 0.5h, arranging a test according to an orthogonal table, and measuring each index. The optimal screening process takes the transfer rate and the cream yield of calycosin glucoside and liquiritin as indexes.

Total score (calycosin glucoside transfer rate + glycyrrhizin transfer rate + cream extraction rate) 100-

The results are shown in tables 2 and 3.

TABLE 2 according to L₉(3⁴) Results and analysis of orthogonal Table implementation experiments

TABLE 3 ANOVA TABLE

F_0.01(2,2)＝99.00

As can be seen from the table, the influence degree of each factor on the extraction is A in sequence>B>C; the anova results show that a (vehicle dose) has significance within the selected levels, and B (extraction time) and C (extraction times) have no significance within the selected levels. In order to save cost and improve efficiency and extract effective components as much as possible, the dosage of the solvent is selected to be 6 times, and the extraction time is selected to be 1 hour. Combining visual analysis and analysis of variance results with A₃B₁C₂The combination is good, and the best process is as follows by combining the results of water absorption and soaking time: weighing the medicinal materials according to the prescription, adding 7 times of water by volume for the first time, adding 6 times of water by volume for the second time, and heating and extracting for 1 hour.

The test is repeated for 3 times under the optimized process condition, and the result shows that the content of each verification test of the selected process condition is not greatly different and the reproducibility is good. The extraction process is shown to be relatively stable, and the results are shown in Table 4 below.

Table 4 extraction of optimum Process verification test

The results show that the decoction process results are better in parallelism.

1.4 investigation of extraction method of Ginseng radix

Because ginseng is a precious medicinal material, the decoction may cause that effective components cannot be dissolved out to a great extent to cause great waste of resources, and the treatment of ginseng is further investigated on the basis of an optimal extraction process for reasonably utilizing the resources. The cream yield was evaluated by the results thereof.

Weighing the medicinal materials according to the prescription respectively, extracting the other medicinal materials except the ginseng according to an extraction process, and measuring the cream yield. The results are given in Table 5 below.

TABLE 5 Effect of Ginseng extraction on cream yield

As can be seen from the above table: the ginseng extract adding rate is only 3.01 percent higher than that of the ginseng lacking rate, in order to ensure that precious and fine medicinal materials can be reasonably and fully utilized, the ginseng medicinal materials are considered to be pulverized, and meanwhile, the using amount of auxiliary materials can be reduced.

2. Concentration process

Extracting according to an extraction process, dividing the extracting solution into 9 parts, and concentrating by 3 modes of reduced pressure concentration, electromagnetic oven concentration and electric furnace concentration respectively.

TABLE 6 Effect of different concentration modes

As can be seen from table 6 above: when the temperature is high or the pressure is high, foaming phenomenon exists, the concentration process is influenced, normal concentration can be realized after vacuum concentration and defoaming, and therefore, the vacuum concentration is selected as the concentration mode. The liquid medicine is concentrated to a density of 1.16-1.20g/ml (60 ℃) according to the operability of freeze drying and spray drying.

3. Research on preparation forming process

3.1 dosage form selection

The common preparation forms of the health food are tablets, capsules, oral liquid, soft capsules and the like, and the health food is designed into the capsules according to the characteristics of suitable people and formulas, and has the following advantages:

(1) the capsule preparation can cover the taste of the raw materials, and has neat and beautiful appearance and convenient taking.

(2) The capsule has no adhesive, the medicine is directly dispersed and dissolved in the digestive tract after the capsule shell is dissolved, the disintegration and dissolution processes are avoided, the absorption rate is better, and the bioavailability is higher.

(3) Has good stability, and can protect the medicine from the action of humidity, oxygen in air and light, thereby improving the stability of the medicine.

3.2 method for measuring Angle of repose and bulk Density

The method for measuring the angle of repose adopts a fixed funnel method, namely 3 funnels are connected in series and fixed at a proper height on horizontally placed coordinate paper, the distance between a lower opening of each funnel and the coordinate paper is H, a sample is carefully poured into the uppermost funnel along the wall of each funnel until the tip of a cone of medicinal powder of the lowermost funnel is in contact with the opening of each funnel, the diameter R of the bottom of each cone is measured by the coordinate paper at the moment, and the angle of repose (tan theta is 2H/R) is calculated.

Method for measuring bulk density: a measuring cylinder method is adopted, a proper amount of mixed materials are precisely weighed and filled in a 10mL measuring cylinder, the measuring cylinder is vertically dropped on a wood board from a height of 5cm by hand, after 5 times of repeated vibration, the volume of the materials is measured for 3 times, the bulk density is calculated, and the average value is calculated.

3.3 investigation of the types of adjuvants

Grinding ginseng into powder, sieving with a 80-mesh sieve, adding 20g of different auxiliary materials, mixing with the extract to prepare a soft material, sieving with a 40-mesh sieve for granulation, drying at 50 ℃ for 3 hours, and inspecting the influence of the auxiliary material types on the granules. The results are shown in tables 7, 8, 9 and 10 below.

TABLE 7 sample State for different adjuvants

TABLE 8 Effect of adjuvant type on Angle of repose of granules

TABLE 9 Effect of adjuvant type on bulk particle Density

TABLE 10 granulation results for adjuvant types

The experiments show that the soft material formed by mixing the ginseng and the extract has high viscosity, auxiliary materials are not added, and sugar is difficult to granulate.

3.4 investigation of the amount of adjuvant

Grinding Ginseng radix into powder, sieving with 80 mesh sieve, adding starch (the ratio of adjuvant amount to the amount of medicinal materials), mixing with the extract to obtain soft material, sieving with 40 mesh sieve, granulating, drying at 50 deg.C for 3 hr, and examining the influence of adjuvant amount on the granule. The results are shown in tables 11, 12 and 13 below.

TABLE 11 Effect of adjuvant dosage on the Angle of repose of the granules

TABLE 12 Effect of adjuvant dosage on bulk particle Density

TABLE 13 results of granulation of adjuvant amounts

From the above experiments, the influence of the amount of the auxiliary material on the flowability of the granules is as follows: in the investigation range, the larger the auxiliary material dosage, the better, but the different of the several examined proportions is not large, considering the cost factor, the provisional 5% is the auxiliary material dosage, namely 28.9g of starch for one prescription.

3.5 investigation of ground particle size of Ginseng radix

Weighing Ginseng radix powder with different mesh numbers, adding starch, mixing with the extract to obtain soft material, sieving with 40 mesh sieve, granulating, drying at 50 deg.C for 3 hr, and examining influence of Ginseng radix pulverizing degree on granule. The results are shown in tables 14, 15 and 16 below.

TABLE 14 Effect of the degree of pulverization of Ginseng radix on the angle of repose of the granules

TABLE 15 Effect of Ginseng radix pulverization degree on particle bulk Density

TABLE 16 granulation results of Ginseng radix grinding degree

From the above tests, the influence of the pulverization degree of ginseng on the flowability of the granules is: the influence of the pulverization degree of ginseng on the granules is not particularly significant and may be related to the size of the mesh number of the granulated granules, and the pulverization degree is tentatively 80 mesh for the process to be feasible.

3.6 examination of the granulation mesh count

The preparation is selected from capsules, and the content of the capsules is small, so that the problem of filling amount is considered, the granules are required not to be too large, and the filling amount difference in the filling process is also avoided. The test selects 40 meshes, 50 meshes and 65 meshes of screen mesh for granulation, and the mesh number is examined by taking the angle of repose and the bulk density as indexes, and the results are shown in tables 17, 18 and 19.

TABLE 17 results of angle of repose for different granulation mesh numbers

TABLE 18 different granulation mesh number bulk density results

TABLE 19 granulation results for different granulation mesh numbers

The data show that 50-mesh and 60-mesh sieves in different granulation mesh numbers have good granulation effects, and 50 meshes are selected according to the granularity of medicinal materials.

3.7 investigation of the type and amount of Lubricant

Pulverizing Ginseng radix, sieving with 80 mesh sieve, adding starch, mixing with the extract to obtain soft material, sieving with 50 mesh sieve, granulating, adding different kinds and dosage of lubricant, drying at 50 deg.C for 3 hr, and examining the influence of the kinds and dosage of lubricant (the dosage is a prescription addition) on the granule. The results are shown in tables 20, 21 and 22 below.

TABLE 20 Effect of lubricant type and amount on particle Angle of repose

TABLE 21 Effect of lubricant type and amount on particle bulk Density

TABLE 22 granulation results for lubricant type and amount

The tests show that the fluidity of the granules can be improved after the lubricant is added, and the addition of the talcum powder can improve the fluidity of the granules, so that the cost and the consumption of the auxiliary materials are comprehensively considered, and 20g of magnesium stearate is added into one prescription to serve as the lubricant.

3.7 formulation shaping Process study conclusion

The above results show that the optimal granulation process is: preparing extract according to extraction process, pulverizing Ginseng radix, sieving with 80 mesh sieve, adding starch, mixing with extract, making into soft mass, sieving with 50 mesh sieve, drying at 50 deg.C for 3 hr, and adding magnesium stearate.

3.8 selection of empty Capsule Shell models

According to the measured bulk density, the volume of the content of each capsule is calculated, and then the empty capsule shell matched with the volume is selected. The bulk density is 0.5407g/ml, the dosage is 0.66g per time, and 0# capsule is selected according to the capsule size.

3.9 determination of the percent moisture absorption and the critical relative humidity of the granules

Moisture absorption rate measuring method: and (3) placing the glass dryer with different solutions at the bottom into a constant-temperature drying box at 25 ℃ for constant temperature for 24 hours. And (3) putting about 3g of particles at the bottom of a constant-weight weighing bottle, accurately weighing the particles, putting the particles into glass driers with different humidities (the cover of the weighing bottle is opened), carrying out a hygroscopicity test at the temperature of 25 ℃, and calculating the hygroscopicity.

Moisture absorption rate (m after moisture absorption-m before moisture absorption)/m before moisture absorption x 100%

According to the optimal screening process, capsule contents (granules) are prepared, sampled and placed in closed containers with different humidity for 5 days, and the moisture absorption rate is measured. The specific enclosed containers with different humidity are shown in the table. And drawing a moisture absorption curve by taking the relative humidity as an abscissa and the moisture absorption rate as an ordinate, drawing two tangent lines at an inflection point, and obtaining the relative humidity corresponding to the intersection point of the two tangent lines, namely the CRH (critical humidity), wherein the CRH is 68.3 percent. The temperature of a clean workshop is 18-26 ℃, the relative humidity is 45-65%, and the process requirement can be met. The results are shown in table 23 and fig. 1.

TABLE 23 Critical relative humidity determination test results

EXAMPLE 2 Activity of the preparation of the Baoyuan Anshen capsule

Test animal and breeding environment

The experiment adopts 200 male SPF ICR rats with the weight of 20 +/-2 g, provided by the center of the research animal of the Chongqing Chinese medicine institute, and the license number (SYXK (Yu) 2017 and 0003). The Chinese medicinal herbs are bred in Chongqing institute barrier environment, license number [ SYXK (Yu) 2012-000 ].

3. Dosage and grouping

The animals used in each experiment are divided into 4 groups according to physical quality, and each group contains 10 animals, and the weight is set at 58.3, 116.6 and 349.8mg/kg^-1.d^-1(corresponding to 5 times, 10 times and 30 times of the recommended daily intake of adult per kilogram of body mass, 3 sample dose groups and a negative control group (double distilled water)

4. Experimental items and results

4.1 direct and prolonged pentobarbital sodium sleep test

Direct sleep test: the animals in each dose group are given corresponding test substances, the animals in the control group are given double distilled water with the same volume, the disappearance of the righting reflex is used as an index to observe whether the animals have sleep, and the disappearance of the righting reflex and the recovery time are used as indexes to record the sleep time of the sleeping animals.

② test for prolonging the sleep time of pentobarbital sodium: each group of animals was injected with 55mg/kg of sodium pentobarbital in the abdominal cavity 15min after last gavage, the injection amount was 0.2ml/20g, and the results of observing whether the samples could prolong the sleep time of pentobarbital are shown in Table 24 and FIG. 2 by using the disappearance of righting reflex of mice as an index.

TABLE 24 action of Baoyuan Anshen Jiaonang for prolonging sleep time of pentobarbital sodium

4.2 Pentobarbital sodium subthreshold dose hypnosis test

Injecting 130mg/kg of barbital sodium into abdominal cavity of each group of animals after last gastric lavage for 15min, wherein the injection amount is 0.2ml/20g, and recording the number of mice falling asleep in each group within 30min according to the standard that mice turn over positive reflex and disappear for more than 1 min; specific results are shown in table 25 and fig. 3.

TABLE 25 influence of Baoyuan Anshen Capsule on subthreshold hypnotic action of Barbituric sodium

4.3 Barbituric sodium sleep latency test

The animals in each group were injected with barbiturate 215mg/k g in the abdominal cavity 15min after last gavage, the injection amount was 0.2ml/20g, the disappearance of mouse positive reflex was used as an index, and the sleep latency of the animals in each group was recorded, and the results are shown in table 26 and fig. 3.

TABLE 26 influence of Baoyuan Anshen Capsule on sleep latency of barbital sodium

4.4 Effect on immune organ index

Mice were weighed before sacrifice, and after sacrifice by removal of the neck, spleen and thymus were taken and weighed, respectively. The corresponding immune organ index was calculated according to the following formula: the results are shown in table 27 and fig. 4, in which the spleen index is spleen weight (g)/body weight (g), and the thymus index is thymus weight (g)/body weight (g).

TABLE 27 Effect of dose groups on immune organ index

P <0.05, significant; p <0.01, very significant.

4.5 Effect on serum Lysozyme content

The non-anticoagulated blood after standing, centrifugal serum, according to lysozyme kit instructions determination of serum lysozyme content, the results are shown in Table 28, figure 5.

TABLE 28 Effect of the various dose groups on serum lysozyme content

P <0.05, significant; p <0.01, very significant.

5. Conclusion of the experiment

Experiments such as direct sleep, pentobarbital sodium sleep time and the like show that the capsule preparation has no direct sleep effect on mice; the sleep time of the sodium pentobarbital can be prolonged; the sample has sleep improving effect according to the evaluation standard of health food function. The capsule can obviously improve immune organ index and lysozyme content, and has good capability of improving non-specific immunity of organisms.

Claims

1. A preparation method of a capsule for protecting vitality and soothing nerves is characterized by comprising the following steps: the method comprises the following steps:

5) encapsulating the medicinal granules to obtain the vitality-maintaining and nerve-soothing capsules;

wherein the addition amount of each raw material of each 1000 capsules is 313g of astragalus, 156g of ginseng, 78g of liquorice, 31g of cinnamon, 90g of starch and 20g of magnesium stearate.

2. A capsule for protecting vitality and soothing nerves is characterized in that: the capsule is prepared by the method of claim 1, wherein the capsule comprises astragalus root, ginseng, licorice and cinnamon as active ingredients.

3. The use of the capsule of claim 2 for improving sleep.

4. The use of the capsule of claim 2 for improving nonspecific immunity.