CN107669866B

CN107669866B - Compound kidney-tonifying traditional Chinese medicine capsule and preparation method thereof

Info

Publication number: CN107669866B
Application number: CN201711180580.7A
Authority: CN
Inventors: 高建云; 胡晓玲; 唐建
Original assignee: Chongqing Sanxia Yunhai Pharmaceutical Co ltd
Current assignee: Chongqing Sanxia Yunhai Pharmaceutical Co ltd
Priority date: 2017-11-23
Filing date: 2017-11-23
Publication date: 2021-04-13
Anticipated expiration: 2037-11-23
Also published as: CN107669866A

Abstract

The invention relates to the technical field of traditional Chinese medicine preparation, and particularly relates to a compound kidney-tonifying traditional Chinese medicine capsule and a preparation method thereof. The compound kidney-tonifying traditional Chinese medicine capsule is a soft capsule and consists of a capsule wall material and a capsule inclusion; the capsule content comprises the following components in percentage by mass: the oily matrix comprises a medicament, a suspending agent and a cosolvent, wherein the cosolvent comprises 1: 1.625-1.705: 0.025-0.035: 0.004-0.006. The invention selects the soft capsule formulation, reduces the granulating link, not only further ensures the thermal degradation of the thermosensitive active substance, furthest ensures the curative effect of the medicine, but also reduces the application of auxiliary materials, and reduces the one-time dosage of a patient by half.

Description

Compound kidney-tonifying traditional Chinese medicine capsule and preparation method thereof

Technical Field

The invention relates to the technical field of traditional Chinese medicine preparation, and particularly relates to a compound kidney-tonifying traditional Chinese medicine capsule and a preparation method thereof.

Background

Huan Shao capsule is the main product of Chongqing Sanxia Yunyan medicine industry, and is mainly used for treating: warm kidney and tonify spleen, nourish blood and benefit essence. Can be used for treating deficiency of spleen and kidney, soreness of waist and knees, sexual impotence, spermatorrhea, tinnitus, blurred vision, essence and blood loss, emaciation, anorexia, and dental pain. Capsules are sold more than 1 billion in 2011 per year, and are currently increasing at a 30% growth rate.

However, the hard capsule dosage form adopted in the existing few capsule production process can cause thermal degradation of the heat-sensitive active substances of the medicines due to the granulation link in the preparation process, and the hard capsule has more auxiliary materials and large medicine dosage.

In view of the above, the present invention is particularly proposed.

Disclosure of Invention

The invention aims to provide a compound kidney-tonifying traditional Chinese medicine capsule to solve the problems.

In order to achieve the above purpose of the present invention, the following technical solutions are adopted:

the invention relates to a compound kidney-tonifying traditional Chinese medicine capsule, which is a soft capsule and consists of a capsule wall material and a capsule inclusion;

the capsule content comprises the following components in percentage by mass:

oily matrix, medicine, suspending agent, cosolvent 1, (1.625-1.705), (0.025-0.035), (0.004-0.006);

the medicine is prepared from the following raw materials in parts by weight:

245-255 parts of prepared rehmannia root, 245-255 parts of fried Chinese yam, 161.75-171.75 parts of achyranthes, 161.75-171.75 parts of wolfberry fruit, 161.75-171.75 parts of dogwood, 245-255 parts of poria cocos, 161.75-171.75 parts of salted eucommia, 161.75-171.75 parts of licorice-processed polygala tenuifolia, 161.75-171.75 parts of fried morinda officinalis, 161.75-171.75 parts of schisandra chinensis, 161.75-171.75 parts of salted fennel, 161.75-171.75 parts of fructus broussonetiae, 161.75-171.75 parts of cistanche, 80.75-86.75 parts of rhizoma acori graminei and 245-255 parts of denucleated Chinese date.

The invention selects the soft capsule formulation, reduces the granulating link, not only further ensures the thermal degradation of the thermosensitive active substance, furthest ensures the curative effect of the medicine, but also reduces the application of auxiliary materials, and reduces the one-time dosage of a patient by half.

The invention also designs a preparation method of the compound kidney-tonifying traditional Chinese medicine capsule, which comprises the following steps:

A. heating gelatin, glycerol, sorbitol and water to obtain sol, and preparing a rubber sheet; B. mixing the capsule contents, and making into soft capsule by soft capsule machine.

Compared with the prior art, the invention has the beneficial effects that:

(1) the optimal process conditions for hot reflux extraction of the capsules are discussed by using an orthogonal experimental method, and the optimal process conditions for hot reflux extraction of the capsules are obtained by analyzing through a sps 18 data analysis software. Compared with the prior art, the extraction time is shortened from seven days to one day, and the three-time extraction is changed into two times, so that the loss of ethanol is reduced, the yield of the product is improved, and the comprehensive production cost is saved by about 15%.

(2) Through single factor experiments, the forming process of the soft capsule is researched, the optimal raw material proportion is obtained, and the technical problem that the soft capsule is not suitable to be prepared from the traditional Chinese medicine extract with high moisture content, multiple components and higher water-soluble components is solved through an emulsification technology.

(3) Through the research of drug equivalence, the preparation formulation is improved, a large amount of auxiliary materials are reduced, the effective drug of each drug is highly concentrated, and the daily dose is changed from 15 to 6.

Detailed Description

the capsule content comprises the following components in percentage by mass:

the medicine is prepared from the following raw materials in parts by weight:

245-255 parts of prepared rehmannia root, 245-255 parts of fried Chinese yam, 161.75-171.75 parts of achyranthes bidentata, 161.75-171.75 parts of wolfberry fruit, 161.75-171.75 parts of dogwood, 245-255 parts of poria cocos, 161.75-171.75 parts of salted eucommia, 161.75-171.75 parts of licorice-processed polygala tenuifolia, 161.75-171.75 parts of fried morinda officinalis, 161.75-171.75 parts of schisandra chinensis, 161.75-171.75 parts of salted fennel, 161.75-171.75 parts of fructus broussonetiae, 161.75-171.75 parts of cistanche, 80.75-86.75 parts of rhizoma acori graminei and 245-255 parts of denucleated Chinese date;

more preferably, the capsule content comprises the following components in percentage by mass:

oily matrix, medicine, suspending agent, cosolvent 1:1.665:0.03: 0.005.

Preferably, the compound kidney-tonifying traditional Chinese medicine capsule is characterized in that the oily matrix is selected from soybean oil or peanut oil; more preferably soybean oil.

Preferably, the compound kidney-tonifying traditional Chinese medicine capsule is prepared by mixing the above raw materials, and adding the suspending agent.

Preferably, the compound kidney-tonifying traditional Chinese medicine capsule is characterized in that the cosolvent is tween; preferably tween-80.

Preferably, the compound kidney-tonifying traditional Chinese medicine capsule is 80-120 meshes of dry medicine powder; more preferably 100 mesh.

Preferably, the compound kidney-tonifying traditional Chinese medicine capsule comprises the following raw material components in percentage by mass:

gelatin: mixing agent: water 1 (0.83-1.03) and (1.5-1.7); wherein the mixing agent is glycerol with the mass ratio of (18-20) to 1: sorbitol;

more preferably, the capsule wall material comprises the following raw materials in percentage by mass:

gelatin: mixing agent: water 1:0.93: 1.6; wherein the mixture is glycerol with the mass ratio of 19: 1: sorbitol.

Preferably, the compound kidney-tonifying traditional Chinese medicine capsule also contains edible pigment;

preferably, the food color comprises one or more of brilliant blue, indigo, lemon yellow, sunset yellow, erythrosine, carmine, amaranth, tomato red, grape purple, light green, and cocoa brown.

Preferably, in the compound kidney-tonifying traditional Chinese medicine capsule, the edible pigment is amaranth accounting for 0.4-0.6% of the capsule wall material by mass; more preferably 0.5% amaranth.

Preferably, the compound kidney-tonifying traditional Chinese medicine capsule is prepared by the following method:

1) crushing the fried Chinese yam to obtain Chinese yam powder, and adding water to decoct the denucleated Chinese date and remove the peel to obtain date paste;

2) extracting fructus Schisandrae chinensis, rhizoma Acori Graminei, and fructus Foeniculi processed with salt with water, and distilling to obtain volatile oil and residue;

heating and refluxing the residues, radix rehmanniae Preparata, Achyranthis radix, fructus Lycii, Corni fructus, Poria, cortex Eucommiae preparata, cortex et radix Polygalae (processed with Glycyrrhrizae radix), radix Morindae officinalis preparata, fructus Broussonetiae, and herba cistanches with ethanol to obtain extractive solution;

3) mixing the yam powder, the jujube paste and the leaching solution uniformly, drying and mixing with the volatile oil to obtain a medicine;

wherein the steps 1) and 2) are not in sequence.

The product has the following main functions: warm kidney and tonify spleen, nourish blood and benefit essence. Can be used for treating deficiency of spleen and kidney, soreness of waist and knees, sexual impotence, spermatorrhea, tinnitus, blurred vision, essence and blood loss, emaciation, anorexia, and dental pain.

Preferably, in the compound kidney-tonifying traditional Chinese medicine capsule, in the step 1), the removing of the peel of the denucleated Chinese dates by adding water is specifically to add 2.5 to 3.5 times of water to the denucleated Chinese dates for decocting for 25 to 35min, extrude the denucleated Chinese dates and pass through a 30 to 50-mesh sieve for peeling;

more preferably, the denucleated Chinese date is added with 3 times of water and decocted for 30min, extruded and sieved by a 40-mesh sieve to remove the peel.

Preferably, in the compound kidney-tonifying traditional Chinese medicine capsule, in the step 2), when the schisandra chinensis, the acorus gramineus soland and the salted fennel are extracted by adding water, the solid-liquid ratio of the added water to the total mass of the schisandra chinensis, the acorus gramineus soland and the salted fennel is 1 g: 7mL to 9mL, and the extraction time is 5h to 7 h;

more preferably, the solid-liquid ratio of the added water to the total mass of the schisandra chinensis, the acorus gramineus and the salted fennel is 1 g: 8mL, extraction time 6 h.

Preferably, in the step 2), the concentration of ethanol in the ethanol heating reflux extraction is 65 v/v% -75 v/v%; preferably, the solid-liquid ratio of the addition amount of the ethanol to the material to be extracted is 1 g: 4 mL-5 mL;

more preferably, in step 2), the ethanol concentration at the time of the ethanol heat reflux extraction is 70 v/v%.

Preferably, in the compound kidney-tonifying traditional Chinese medicine capsule, in the step 2), the single extraction time of the ethanol during heating, refluxing and leaching is 110min to 130 min;

more preferably, in the step 2), the extraction time of the ethanol during heating reflux extraction is 115min to 125min, and can be 120 min.

Preferably, in the step 2), the extraction temperature of the ethanol during heating, refluxing and leaching is 65-75 ℃; more preferably 68 ℃ to 72 ℃ and optionally 70 ℃.

Preferably, in the step 2), the extraction times of the ethanol during heating, refluxing and leaching are 1-3 times; more preferably 2 times.

The invention also relates to a preparation method of the compound kidney-tonifying traditional Chinese medicine capsule, which comprises the following steps:

Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by manufacturers, and are all conventional products available on the market.

Example 1

1. Prescription:

prepared rehmannia root: 250g of the total weight of the mixture; rhizoma dioscoreae (parched): 250g of the total weight of the mixture; achyranthes root: 166.75 g; wolfberry fruit: 166.75 g; dogwood fruit: 166.75 g; tuckahoe, poria cocos: 250g of the total weight of the mixture; eucommia ulmoides (stir-baked with salt): 166.75 g; polygala tenuifolia (roasted with licorice): 166.75 g; radix Morindae officinalis (parched): 166.75 g; schisandra chinensis: 166.75 g; fennel (salt-roasted): 166.75 g; papermulberry fruit: 166.75 g; cistanche deserticola: 66.75 g; grassleaf sweelflag rhizome: 83.75 g; chinese date (core removal): 250 g.

2. The preparation method comprises the following steps: crushing the Chinese yam into fine powder, sieving the fine powder with a 130-mesh sieve, adding 3.5 times of water into the Chinese date, decocting for 35min, extruding and sieving the decoction with a 30-mesh sieve to remove peel, and preparing the Chinese date paste for later use; extracting fructus Schisandrae chinensis, rhizoma Acori Graminei, and fructus Foeniculi with 7 times of water to obtain volatile oil for 5h, collecting the distilled water solution, extracting the residue and the rest ten medicinal materials such as radix rehmanniae Preparata with 4 times of 65 v/v% ethanol under reflux at 65 deg.C for 3 times (110 min each time), mixing the extractive solutions, recovering ethanol, mixing with fructus Jujubae paste and rhizoma Dioscoreae powder, drying under reduced pressure, and mixing with volatile oil to obtain the final product. Grinding the dry paste of the medicine into 80-mesh powder, adding a proper amount of soybean oil, beeswax and tween-80, and uniformly mixing to prepare 1000 soft capsules.

Each granule of the product contains deoxyschizandrin (C) extracted from fructus Schisandrae chinensis₂₄H₃₂O₆) Calculated, the content of the active ingredient should not be less than 0.1 mg.

Specification: each pill is 0.5 g.

The usage and dosage are as follows: the preparation is orally taken 2 granules at a time, and 2-3 times a day.

Wherein, the soybean oil is dry powder of the medicine, beeswax, tween-80, 1, 705, 0, 025 and 0.004;

the capsule wall material mainly comprises the following raw materials in percentage by mass:

gelatin: mixing agent: water 1:0.83: 1.7; wherein the mixture is glycerol with the mass ratio of 20: 1: sorbitol; the capsule wall material also contains amaranth accounting for 0.4 percent of the mass of the capsule wall material.

Example 2

1. Prescription: the same as in example 1.

2. The preparation method comprises the following steps: crushing the Chinese yam into fine powder, sieving the fine powder with a 110-mesh sieve, adding 2.5 times of water into the Chinese dates, decocting the Chinese dates for 25min, extruding the decoction, sieving the decoction with a 50-mesh sieve, and peeling the skin to prepare jujube paste for later use; extracting fructus Schisandrae chinensis, rhizoma Acori Graminei and fructus Foeniculi with 9 times of water to obtain volatile oil for 7h, collecting the distilled water solution, extracting the residue and the rest ten medicinal materials such as radix rehmanniae Preparata with 5 times of 75 v/v% ethanol under reflux at 75 deg.C for 1 time, each time for 130min, mixing the extractive solutions, recovering ethanol, mixing with fructus Jujubae paste and rhizoma Dioscoreae powder, drying under reduced pressure, and mixing with volatile oil to obtain the final product. Grinding the dry paste of the medicine into 120-mesh powder, adding a proper amount of soybean oil, beeswax and tween-80, and uniformly mixing to prepare 1000 soft capsules.

Specification: each pill is 0.5 g.

Wherein the soybean oil is dry powder of the medicine, beeswax, tween-80, 1, 625, 0, 035 and 0, 006;

gelatin: mixing agent: water 1:1.03: 1.5; wherein the mixture is glycerol with the mass ratio of 18: 1: sorbitol; the capsule wall material also contains amaranth accounting for 0.6 percent of the mass of the capsule wall material.

Example 3

1. Prescription: the same as in example 1.

2. The preparation method comprises the following steps: crushing the Chinese yam into fine powder, sieving the fine powder with a 120-mesh sieve, adding 3 times of water into the Chinese date, decocting the Chinese date for 30 minutes, extruding the decoction, sieving the decoction with a 40-mesh sieve, and peeling the skin to prepare the Chinese date paste for later use; extracting volatile oil of fructus Schisandrae chinensis, rhizoma Acori Graminei and fructus Foeniculi with 8 times of water for 6 hr, collecting the distilled water solution, extracting the residue and the rest ten medicinal materials such as radix rehmanniae Preparata with 5 and 4 times of 75% ethanol under reflux at 70 deg.C for 2 hr twice, mixing the extractive solutions, recovering ethanol, mixing with fructus Jujubae paste and rhizoma Dioscoreae powder, drying under reduced pressure, and mixing with volatile oil to obtain the final product. Grinding the dry paste of the medicine into 100-mesh powder, adding a proper amount of soybean oil, beeswax and tween-80, and uniformly mixing to prepare 1000 soft capsules.

Specification: each pill is 0.5 g.

Wherein the soybean oil is dry powder of the medicine, beeswax, tween-80, 1, 665, 0.03, 0.005;

gelatin: mixing agent: water 1:0.93: 1.6; wherein the mixture is glycerol with the mass ratio of 19: 1: sorbitol; the capsule wall material also contains amaranth accounting for 0.5 percent of the mass of the capsule wall material.

Examples of the experiments

1.1 reduced Soft Capsule thermal reflux extraction orthogonal test

1.1.1 test materials

Raw materials: prepared rehmannia root, achyranthes root, wolfberry fruit, dogwood, tuckahoe, polygala root, morinda root, desertliving cistanche, paper mulberry fruit and eucommia bark (the mixture ratio is shown in the example 1).

Reagent: ethanol

1.1.2 test methods

Processing radix rehmanniae Preparata, Achyranthis radix, fructus Lycii, Corni fructus, Poria, cortex et radix Polygalae, radix Morindae officinalis, Cistanchis herba, fructus Broussonetiae, and Eucommiae cortex at a ratio of capsule prescription, and mixing. Taking a certain amount of mixture, and extracting by an ethanol hot reflux method, wherein the dosage of the ethanol is calculated by a cold soaking method. Detecting the total extract amount and 70% ethanol extract amount, and respectively inspecting the influence of ethanol concentration, extraction temperature, extraction time and extraction frequency on the extraction effect. Before the extraction times are considered, a 3-factor-3-level orthogonal test is designed by adopting an orthogonal test design method, and the optimal extraction conditions are determined. The design of the experiment is shown in the following table:

on the basis of determining the optimal extraction conditions, the extraction times are determined by considering the influence of the wiping extraction times on the cream yield.

1.1.3 results and analysis

When the orthogonal test optimizes the extraction conditions, the influence of 3 factors on the total extracted paste amount and the extracted paste amount is respectively considered, and the experimental results and the analysis results are shown in the following table:

TABLE 1 results of the experiment

TABLE 1.1Tests of Between-Subjects Effects

Dependent Variable Total cream amount

a.R Squared＝.989(Adjusted R Squared＝.955)

TABLE 1.2 ethanol concentration

Dependent Variable Total cream amount

TABLE 1.3 extraction temperature (. degree. C.)

Dependent Variable Total cream amount

TABLE 1.4 extraction time (min)

Dependent Variable Total cream amount

TABLE 1.5Tests of Between-Subjects Effects

Dependent Variable amount of extract

a.R Squared＝.935(Adjusted R Squared＝.742)

TABLE 1.6 ethanol concentration

Dependent Variable amount of extract

TABLE 1.7 extraction temperature (. degree. C.)

Dependent Variable amount of extract

TABLE 1.8 extraction time (min)

Dependent Variable amount of extract

Table one is the raw data measured according to the orthogonal experimental design, and the results after the analysis by the sps software processing are shown in tables 1.1-1.8. As can be seen from table 1.1: the influence of the three factors on the total paste yield is different, and the comparison of the type III square sum shows that the influence on the total paste yield is that the ethanol concentration is more than the extraction time and more than the extraction temperature. Observing tables 1.2, 1.3, 1.4, the optimal levels for the 3 factors can be found to be: the ethanol concentration is 65%, the extraction time is 120min, and the extraction temperature is 70 ℃.

As can be seen from table 1.5: the three factors have different influences on the extraction paste rate, and the comparison of the type III square sums shows that the influence on the extraction paste rate is that the extraction time is longer than the extraction temperature and the ethanol concentration is longer than the extraction temperature. Observing tables 1.6, 1.7, 1.8, the optimal levels for the 3 factors are: the ethanol concentration is 75%, the extraction time is 120min, and the extraction temperature is 70 ℃.

In the process of quality control of the capsule extraction process, the total amount of alcohol extract (the total amount of the alcohol extract and the percentage content of the alcohol extract) is mainly considered, namely, the total amount of the alcohol extract is required to be as large as possible, the content of the alcohol extract is required to be as high as possible, and the total dry amount of the extract is controlled in a certain range as possible. From the data in tables 1 and 2, the optimum extraction conditions were: the ethanol concentration is 75%, the extraction time is 120min, and the extraction temperature is 70 ℃.

1.2 determination of the number of extractions

1.2.1 test materials

Raw materials: radix rehmanniae Preparata, Achyranthis radix, fructus Lycii, Corni fructus, Poria, cortex et radix Polygalae, radix Morindae officinalis, Cistanchis herba, fructus Broussonetiae, and Eucommiae cortex.

Reagent: ethanol

1.2.2 test methods

Processing radix rehmanniae Preparata, Achyranthis radix, fructus Lycii, Corni fructus, Poria, cortex et radix Polygalae, radix Morindae officinalis, Cistanchis herba, fructus Broussonetiae, and Eucommiae cortex according to the original formula, and mixing. Extracting raw materials by cold soaking method and hot reflux method for 3 times, and testing the respective paste yield.

1.2.3 results and analysis

The raw materials were extracted by cold soaking and hot reflux methods, respectively, and the results of the detection of the cream yield are reported in table 2 below:

TABLE 2 comparison of cream yields for two extraction methods

Extraction method	First extraction	Second extraction	Extracting for the third time
				Cold dipping method	11％	5％	1％
Hot reflux process	18％	3％	0.2％

The test results show that the paste yield of the hot reflux method is obviously improved by seven percent compared with the paste yield of the cold soaking method in the first extraction. From the second extraction, the extraction rate of the hot reflux method is lower than that of the cold soaking method, and the extraction rate of the hot reflux extraction is only 0.2 percent by the third extraction, which indicates that the raw material extraction is nearly complete.

In conclusion, the effect of twice extraction is better than that of three times extraction by a cold soaking method by adopting a hot reflux extraction method, so that the economic value of raw materials is improved, the extraction time is saved for people, and the productivity is increased.

1.3 research on Soft Capsule Molding Process

1.3.1 test materials

Soybean oil, original dry powder, beeswax, glycerol, gelatin, tween-80 and other auxiliary materials which are all medicinal grade.

1.3.2 test methods

The optimum proportion of the content and the main material of the capsule wall material is respectively determined through tests, the obtained parameters are used for granulating according to the original medicine scheme, and finally, a disintegration test is carried out to check whether the content meets the regulations.

1.3.3 results and analysis

Test 1: screening the dosage of the suspending agent.

Researches show that the type of oil, the thickness of medicinal powder and the dosage of a wetting agent have great influence on the stability of contents in the soft capsule, therefore, on the basis of referring to a plurality of literature data, soybean oil is selected as a solvent of the soft capsule, crude dry paste is crushed and sieved by a 100-mesh sieve, and the dosage of the wetting agent Tween-80 is 0.5 percent of the solvent.

Beeswax is taken as a suspending agent, different amounts of beeswax are added into suspension of the soybean oil crude drug powder, the suspension is kept stand, observation is carried out, the time of sedimentation and delamination is recorded, the optimal proportion of the suspending agent can be determined through time comparison, and the results are shown in table 3.1:

TABLE 3.1 screening results for suspending agent dosage

Experimental number	Suspending agent%	Settling time h
			1	0	0.4
2	1	6
			3	3	24
4	5	32

From the test results, it can be seen that the greater the amount of suspending agent, the longer the time required for the suspension to settle and delaminate, and the better the stability of the suspension. When the mass fraction of the suspending agent and the solvent reaches more than 3 percent, the solid matter in the suspension before the encapsulation can be effectively prevented from settling, the fluidity of the suspension is good, if the dosage of the suspension is continuously increased, the viscosity of the suspension is increased, the fluidity is poor, and therefore the mass fraction of the beeswax serving as the suspending agent and the solvent is determined to be 3 percent.

The administration method of the hard capsule comprises the following steps: 0.42g of tablets, three times a day, five tablets at a time. Has the problems of large dose, inconvenient carrying and the like. The newly developed soft capsule needs to increase the drug loading of a single drug, and the mass ratio of the suspension of the content is as follows: when soybean oil, raw medicine powder, beeswax, tween-80, 1:1.665, 0.03:0.005 are added, the drug-loading amount of 6 soft capsules is equivalent to 15 hard capsules according to the specification of 0.5g, so that the aim of reducing and not reducing the effect can be achieved.

Experiment 2 determination of the ratio of main materials of soft capsule wall material

The soft capsule is a relatively novel preparation, and can quantitatively inject various amorphous drugs into a capsule membrane in a pressing way and encapsulate the amorphous drugs into sealed capsules with various specifications. Compared with other preparations, it has the advantages of high bioavailability, accurate content, good uniformity, and good appearance. In recent years, with the progress of science and technology, research on soft capsules has been conducted vigorously, and numerous results have been obtained. In the aspect of the proportioning of the capsule wall materials, researches show that the proportioning of the main materials is as follows: gelatin: glycerol: when the water is 1:0.93:1.6, the capsule shell is well formed and has a larger dissolution rate; in the aspect of selecting the additive, 0.5 percent of amaranth is added, so that the capsule has good light-shading property and color impression. Therefore, the experiment uses the main materials as compared with gelatin: glycerol: the optimal proportion of the capsule wall material is determined by taking water as 1:0.93:1.6, adding 0.5% amaranth as a basic condition and sorbitol as an additive as a variable and investigating disintegration time, the specific experimental method refers to a disintegration time limit measurement method in Chinese pharmacopoeia 2010, and the experimental result is shown in a table 3.2:

TABLE 3.2 Experimental results of the main ingredient ratio of the soft capsule wall material

Experimental number	Amount of sorbitol instead of glycerin	Length of disintegration (h)
			1	1％	1.5
2	3％	0.8
			3	5％	0.3
4	7％	0.1
			5	9％	＜0.1

The experimental result shows that when the sorbitol replaces the glycerin by more than 5%, the disintegration time of the capsule is less than 0.3h, the national standard for the disintegration time of the capsule to be less than 1h is met, and the addition of the sorbitol as an additive is determined to be 5% in consideration of cost factors.

In conclusion, the proportion of the soft capsule wall material is determined as follows: gelatin: blending agent (glycerin: sorbitol): water 1:0.93(19:1):1.6, and 0.5% amaranth.

Quality evaluation of Soft capsules

2.1 Soft Capsule quality test

Taking the hard capsule as a reference, detecting various indexes of the soft capsule according to the quality standard of the soft capsule, wherein the detection results are shown in table 4:

TABLE 4 Soft Capsule quality test results

As can be seen from Table 4, the properties of the hard and soft capsules meet the relevant standards stipulated by the pharmacopoeia for disintegration time; detecting characteristic features and spots under the identification items; in the aspect of detecting the content of the deoxyschizandrin, the content of the soft capsule is improved by more than 2.5 times compared with that of the hard capsule, namely the content of the deoxyschizandrin in 2 soft capsules is basically consistent with that in five hard capsules, so that the reduction without the reduction effect is really realized; on other indexes, the soft capsule and the hard capsule are kept consistent and meet the relevant national standards.

2.2 Long-term stability test of Soft capsules

2.2.1 test materials

Soft capsule finished products and other experimental medicines required by relevant detection.

2.2.2 test methods

The experimental design is carried out according to the relevant regulations in the document No. 2006-278 of the State food and drug administration of State guidelines on the stability research technology of traditional Chinese medicines and natural medicines, and the examination items are detected according to the quality standard of the soft capsule.

2.2.3 results and analysis

The results of the three batches are shown in the following table:

the name of the drug: fusha soft capsule batch No. 110601 packaging conditions:

the name of the drug: fusha soft capsule batch No. 110602 packaging conditions:

the name of the drug: fusha soft capsule batch No. 110603 packaging conditions:

the test results of three batches of drugs can show that: the soft capsule has stable quality when the storage time is below 6 months: the appearance is good, the content is not obviously changed, and the liquid is a tawny oily liquid and has special smell; detecting special microscopic features and characteristic spots under all identification detection items; the disintegration time is less than 1 hour, and the requirements of relevant national regulations are met; the n-butanol extract contained in each granule exceeds 100mg and reaches about 120 mg; the deoxyschizandrin contained in each granule exceeds 0.1mg and reaches more than 0.16 mg; the limit inspection of bacteria, mould, microzyme and colibacillus all meets the requirement. However, over time, soft capsules exhibit severe instability phenomena: the capsule shell gradually becomes damp, is adhered, the content leaks, the disintegration time is obviously prolonged, and the like. Two reasons are presumed to be responsible for its instability: firstly, the content of glycerin in the capsule shell is very high, the capsule shell has very strong water absorption, and the content finally leaks due to the fact that the glycerin becomes damp and adhered after continuous water absorption; and secondly, although sorbitol is added into the capsule shell to effectively prevent external oxygen from entering, the content components are complex and can spontaneously generate oxidation reaction to generate aldehyde substances, thereby promoting the gelatin in the capsule shell to generate a cross-linking reaction to form a macromolecular polymer, preventing water molecules from entering and prolonging the disintegration time. At present, the problem of long-term stability of soft capsules is solved by methods such as adjusting the proportion of contents and adding proper auxiliary materials.

Therapeutic effect of few capsules on perimenopausal syndrome

Applicant summons 90 female subjects with perimenopausal syndrome at about 55 years of age, randomized into 3 groups, blank control, experimental and control groups, respectively. Wherein the blank control group is administered with placebo, and the control group is administered with capsule (also known as Z50020249) and tablet (0.42 g) three times a day, five tablets at a time; the experimental group was administered with the new process of preparation of example 3 with few capsules, three times a day, two capsules at a time. The control group and the experimental group were continuously administered for 30 days. After 30 days, extracting the content of estrogen in the blood serum of the subject, and the specific detection result is shown in table 1; the therapeutic effect on perimenopausal syndrome is shown in table 2.

According to the detection results in table 1, the lac capsules prepared in example 3 of the present invention can significantly enhance the ability of the test subjects to secrete estradiol, estrone and estriol, as can be seen by comparing the blank control group with the experimental group; compared with the hard capsules prepared by the old process, the soft capsules prepared by the new process have more obvious drug effect due to the improvement of the preparation process.

TABLE 1 Effect of Fukuai capsules on Estrogen levels in Subjects

	Estradiol (ng/mL)	Estrone (ng/mL)	Estriol (ng/mL)
				Blank control group	30.1	0.27	0.35
Experimental group	58.2	1.53	1.57
				Comparison group	39.9	0.87	0.74

The invention adopts a perimenopausal syndrome quality of life rating scale (MENQOL) to evaluate the quality of life of a patient.

The scale was developed by Hilditch, a Canada scholars 1996, for a total of 29 entries. The present invention focuses on the evaluation of vasomotor symptoms and sexual life symptoms. The item scores are shown in table 2.

TABLE 2

Item	Group of	Number of examples	Before intervention	After 30 days of administration
					Vasomotor symptoms	Experimental group	30	5.02±0.83	2.42±0.75
	Blank control group	30	4.95±1.12	4.81±0.71
						Comparison group	30	4.97±0.89	3.26±1.13
Symptoms of sexual life	Experimental group	30	3.69±0.96	1.69±0.83
						Blank control group	30	3.72±1.11	3.78±1.03
	Comparison group	30	3.70±0.83	2.20±0.86

The results show that: the vasomotor symptom and sexual life symptom scores of the experimental group and the comparative group after being taken for 30 days are lower than those of the blank control group, and the statistical significance (p is less than 0.05) is achieved, but the drug effect of the experimental group is remarkably better than that of the comparative group, so that the new pharmaceutical method can remarkably improve the drug effect and has remarkable curative effect on perimenopausal syndrome.

Therapeutic effect of fewer capsules on male sexual function

90 male subjects aged 50 or so were recruited and randomized into 3 groups, blank control, experimental and control groups, respectively. Wherein the blank control group is administered with placebo, and the control group is administered with capsule (also known as Z50020249) and tablet (0.42 g) three times a day, five tablets at a time; the experimental group was administered with the new process of preparation of example 3 with few capsules, three times a day, two capsules at a time. The control group and the experimental group were continuously administered for 30 days. After 30 days, the content of testosterone in serum of the subjects is extracted, and the sexual functions of the subjects are evaluated through an international erectile function scoring table (IIEF-5), and the specific detection results are shown in a table 2.

According to the detection results in the table 3, the comparison of the experimental group and the blank comparison group shows that the capsules prepared in the embodiment 3 of the invention can obviously enhance the capability and the sexual function of the testee for secreting testosterone; compared with the hard capsules prepared by the old process, the soft capsules prepared by the new process have more obvious drug effect due to the improvement of the preparation process.

TABLE 3 Effect of Fusha capsules on testosterone levels and the International erectile index in subjects

	Testosterone (mu g/L)	International index of erectile function
			Blank comparison group	3.2	12
Experimental group	4.7	22
			Comparison group	3.8	17

Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A compound kidney-tonifying traditional Chinese medicine capsule is characterized in that the capsule is a soft capsule and consists of a capsule wall material and capsule contents;

the capsule wall material comprises the following raw materials in percentage by mass:

gelatin: mixing agent: water is 1: 0.83-1.03: 1.5-1.7; wherein the mixing agent is glycerol with the mass ratio of 18-20: 1: sorbitol; the capsule content comprises the following components in percentage by mass:

an oily substrate, a medicament, a suspending agent and a cosolvent, wherein the cosolvent is 1: 1.625-1.705: 0.025-0.035: 0.004-0.006;

the medicine is prepared from the following raw materials in parts by weight:

the oily matrix is selected from soybean oil or peanut oil;

the suspending agent is beeswax;

the cosolvent is tween-80;

the medicine is prepared by the following method:

3) uniformly mixing the Chinese yam powder, the jujube paste and the leaching solution, drying, and mixing with the volatile oil to obtain a medicine;

wherein, the steps 1) and 2) are not in sequence;

in the step 2), the concentration of the ethanol during the heating reflux extraction of the ethanol is 65 v/v% -75 v/v%;

in the step 2), the extraction temperature of the ethanol during heating reflux extraction is 65-75 ℃.

2. The compound kidney-tonifying traditional Chinese medicine capsule as claimed in claim 1, wherein the medicine is 80-120 mesh dry powder.

3. The compound kidney-tonifying traditional Chinese medicine capsule as claimed in claim 1, wherein the capsule wall material further contains an edible pigment.

4. The compound kidney-tonifying traditional Chinese medicine capsule as claimed in claim 3, wherein the food color comprises one or more of brilliant blue, indigo, lemon yellow, sunset yellow, erythrosine, carmine, amaranth, tomato red, grape purple, light leaf green, and cocoa brown.

5. The compound kidney-tonifying traditional Chinese medicine capsule as claimed in claim 3, wherein the edible pigment is amaranth accounting for 0.4-0.6% of the capsule wall material by mass.

6. The method for preparing the compound kidney-tonifying traditional Chinese medicine capsule as claimed in any one of claims 1 to 5, which comprises the following steps:

A. heating gelatin, glycerol, sorbitol and water to obtain sol, and preparing a rubber sheet;

B. mixing the capsule contents, and making into soft capsule by soft capsule machine.