CN114601893B

CN114601893B - Wen Weia Yaran tablet, tablet core raw material, preparation method and quality control method thereof

Info

Publication number: CN114601893B
Application number: CN202111187543.5A
Authority: CN
Inventors: 尹强; 尹海龙; 穆丹丹; 周琴; 孙黎; 朱姝; 夏玲玲; 木尼热·艾合买提; 哈斯特尔·木他西; 李珊; 马小燕; 田芳; 张鹏
Original assignee: Xinjiang Uygur Pharmaceutical Co ltd
Current assignee: Xinjiang Uygur Pharmaceutical Co ltd
Priority date: 2021-10-12
Filing date: 2021-10-12
Publication date: 2023-06-27
Anticipated expiration: 2041-10-12
Also published as: CN114601893A

Abstract

The invention discloses stomach-warming alairan tablets, tablet core raw materials for Wen Weia alairan tablets, a preparation method and a quality control method. The tablet core raw material for Wen Weia yaor tablets comprises an active ingredient and auxiliary materials, wherein the active ingredient consists of an active ingredient A and an active ingredient B, and the mass ratio of the active ingredient A to the active ingredient B is 394:50; the auxiliary materials comprise the following components in parts by mass based on 375 parts of active ingredient A: 10-100 parts of filler; 0-80 parts of disintegrating agent; 1-60 parts of lubricant. The prescription is determined through prescription screening, and the prescription of the preparation is reasonable and the technological parameters are definite; the product has high hardness, good stability and good processability; the preparation process is simple and stable, the operation is easy to form, the production process can be effectively controlled, and the preparation process is suitable for mass production; the quality standard is high, the quality control method is high in speed, precision and stability, good in repeatability and high in recovery rate, and the quality of the product can be effectively controlled.

Description

Wen Weia Yaran tablet, tablet core raw material, preparation method and quality control method thereof

Technical Field

The invention relates to stomach-warming alairan and tablet, tablet core raw materials, a preparation method and a quality control method thereof.

Background

The original standard of the product is received in Uygur medicine division (WS-BW-0192-98) of the medicine Standard of the Ministry of health of the people's republic of China. Has effects of eliminating abnormal black bile in stomach, relieving swelling, and stimulating appetite. Can be used for treating stomach fullness pain and anorexia. The medicine is prepared from aloe 200g, herba cuscutae 40g, pulp Citrulli 57g, herba seu radix Kadsurae Longipedunculatae 97g, mu Ku myrrh 50g, wherein the first four medicinal materials are crushed into fine powder, mu Ku myrrh is extracted by adding water, the filtrate is concentrated into paste, the fine powder, monosaccharide syrup and starch are added, and the mixture is uniformly mixed, granulated, dried and pressed into 1000 tablets.

The extraction water adding amount and the concentration process parameters of the traditional Chinese medicinal materials with original quality standard are not clear, the types and the using amount of auxiliary materials are not determined, and the preparation operation and the forming of the product are not suitable for adding the single syrup and the starch through a pre-test. The prescription of the preparation is to be optimized, the original preparation is a plain tablet, the taste is bitter, the dosage is large, the compliance of patients is poor, and in addition, the medicine is unstable due to the poor moisture resistance of the plain tablet.

The aloin has good effects of resisting bacteria and oxidation, promoting defecation, regulating tumor cell apoptosis and the like, but has lower quality control standard, needs to be improved and lacks a content control method. There is a lack of modern scientific control means for the production process and formulation products.

Disclosure of Invention

The invention provides a stomach-warming alairan tablet, a tablet core raw material, a preparation method and a quality control method thereof, and aims to solve the problems of poor stability, large dosage, poor product processability and the like of the tablet of Wen Weia alairan in the prior art. The prescription is determined through prescription screening, and the prescription of the preparation is reasonable and the technological parameters are definite; the product has high hardness, good stability and good processability; the preparation process is simple and stable, the operation is easy to form, the production process can be effectively controlled, and the preparation process is suitable for mass production; the quality standard is high, the quality control method is high in speed, precision and stability, good in repeatability and high in recovery rate, and the quality of the product can be effectively controlled.

The invention adopts the following technical scheme to solve the technical problems:

the invention provides a tablet core raw material for stomach-warming alairan and tablets, which comprises an active ingredient and auxiliary materials, wherein the active ingredient consists of an active ingredient A and an active ingredient B, wherein the active ingredient A consists of aloe, herba cuscutae, pulp Citrulli and caulis polygoni multiflori in a mass ratio of 200:40:57:97; the active ingredient B is Mu Ku myrrh, and the mass ratio of the active ingredient A to the active ingredient B is 394:50; the auxiliary materials comprise the following components in parts by mass based on 375 parts of the active ingredient A: 10-100 parts of filler; 0-80 parts of disintegrating agent; 1-60 parts of lubricant.

In the present invention, the filler may be conventional in the art, preferably comprises starch and/or microcrystalline cellulose, more preferably starch.

In the present invention, the content of the filler is preferably 20 to 80 parts, for example, 30 parts, 47.5 parts, 50 parts, 60 parts or 75 parts.

In the present invention, the disintegrant may be conventional in the art, and preferably comprises crospovidone and/or sodium carboxymethyl starch, more preferably crospovidone.

In the present invention, the content of the disintegrant is preferably 15 to 60 parts, for example, 20 parts, 25 parts, 30 parts, 40 parts or 50 parts.

In the present invention, the lubricant may be conventional in the art, preferably comprises silica and/or magnesium stearate, more preferably silica and magnesium stearate.

In the present invention, the content of the lubricant is preferably 5 to 30 parts, for example, 27.5 parts.

Preferably, the lubricant is magnesium stearate, and the content of the magnesium stearate is 5 parts.

Preferably, the lubricant is a combination of silicon dioxide and magnesium stearate, wherein the content of the magnesium stearate is 2.5 parts, and the content of the silicon dioxide is 25 parts.

In certain preferred embodiments of the present invention, the auxiliary materials comprise the following components in parts by mass: 20-80 parts of filler; 15-60 parts of disintegrating agent; 5-30 parts of lubricant.

Preferably, the auxiliary materials comprise the following components in parts by mass: 75 parts of filler; 25 parts of disintegrating agent; 5 parts of lubricant.

Preferably, the auxiliary materials comprise the following components in parts by mass: 50 parts of filler; 50 parts of disintegrating agent; 5 parts of lubricant.

Preferably, the auxiliary materials comprise the following components in parts by mass: 50 parts of filler; 30 parts of disintegrating agent; 27.5 parts of lubricant.

In certain preferred embodiments of the present invention, the auxiliary materials comprise the following components in parts by mass: 80-100 parts of filler; 1-10 parts of lubricant.

Preferably, the auxiliary materials comprise the following components in parts by mass: 100 parts of filler; 5 parts of lubricant.

In a specific embodiment of the invention, the auxiliary materials comprise the following components in parts by weight: 75 parts of starch; 25 parts of sodium carboxymethyl starch; 5 parts of magnesium stearate.

In a specific embodiment of the invention, the auxiliary materials comprise the following components in parts by weight: 75 parts of starch; 25 parts of crosslinked povidone; 5 parts of magnesium stearate.

In a specific embodiment of the invention, the auxiliary materials comprise the following components in parts by weight: 50 parts of starch; 50 parts of crosslinked povidone; 5 parts of magnesium stearate.

In a specific embodiment of the invention, the auxiliary materials comprise the following components in parts by weight: 47.5 parts of starch; 30 parts of crosslinked povidone; 25 parts of silicon dioxide and 2.5 parts of magnesium stearate.

In a specific embodiment of the invention, the auxiliary materials comprise the following components in parts by weight: 100 parts of starch; 5 parts of magnesium stearate.

In a specific embodiment of the invention, the auxiliary materials comprise the following components in parts by weight: 100 parts of microcrystalline cellulose; 5 parts of magnesium stearate.

In a specific embodiment of the invention, the auxiliary materials comprise the following components in parts by weight: 50 parts of microcrystalline cellulose; 50 parts of starch; 5 parts of magnesium stearate.

The invention provides a preparation method of stomach-warming alairan and tablets, which comprises the step of preparing tablet cores by adopting the tablet core raw materials for Wen Weia alairan and tablets.

Preferably, the preparation of the tablet core comprises the following steps:

(1) Mixing, pulverizing, sieving and recording the active ingredient A as fine powder A;

(2) Decocting the active ingredient B in water, filtering, mixing filtrates, concentrating, and recording as extract B;

wherein the order of (1) and (2) is not sequential;

(3) Adding the fine powder A, the filler and part of the disintegrating agent into the extract B, uniformly mixing, granulating and drying;

(4) And adding the lubricant and the rest of the disintegrating agent, uniformly mixing, and tabletting to obtain the tablet core.

In step (1), the mixing may be carried out by mixing methods conventional in the art.

In step (1), the pulverization may be performed using a pulverization method conventional in the art, in a pulverizer conventionally used in the art. The screen is preferably a 100 mesh screen.

In the step (2), preferably, the water is added in an amount of preferably 6 to 12 times, more preferably 8 times, the mass of the Mu Ku myrrh.

In step (2), preferably, the number of times of the decoction is 3. The decoction time is one hour each time.

In step (2), the filtration may be carried out by filtration methods conventional in the art.

In step (2), the concentration may be carried out by a concentration method conventional in the art.

In step (2), the relative density of the extract B is preferably 1.0-1.15g/mL.

In step (3), the granulation may be performed by conventional granulation methods in the art, preferably wet granulation, more preferably by using an aqueous ethanol solution. Wherein the concentration of the aqueous ethanol solution is preferably 80%.

In step (3), the drying may be performed by a conventional drying method in the art, such as drying. The drying temperature is preferably 55 to 65 ℃, more preferably 60 ℃.

In step (3), the drying step generally further comprises a sieving step, so that the obtained particles have uniform particle sizes. The particle size of the sieved granules is preferably 16 to 50 mesh, more preferably 16 mesh.

In the step (3), the mass of the part of the disintegrating agent accounts for 0-100% of the total mass of the disintegrating agent. The sum of the masses of the part of the disintegrant of step (3) and the remaining of the disintegrant of step (4) is equal to the total mass of the disintegrant.

In step (3), when the mass of the part of the disintegrant is 0% of the total mass of the disintegrant, it means that the disintegrant is not added in step (3) but only added in step (4), called external addition.

In step (3), when the mass of the part of the disintegrant is 100% of the mass of the disintegrant, it means that the disintegrant is added only in step (3) and not in step (4), which is called internal addition.

Step (3) when the mass of the part of the disintegrant is neither 0 nor 100 in terms of the mass of the disintegrant, means that the disintegrant is added in both step (3) and step (4), called internal and external addition.

In the step (4), the tabletting may be performed in a tabletting machine conventional in the art, using a tabletting method conventional in the art.

In the present invention, the Wen Weia tablets are preferably prepared by a process which further comprises a coating.

In the present invention, the coating may be performed using a coating method conventional in the art.

Preferably, the coating comprises the steps of:

(1) Preparing an aqueous solution of the raw materials of the coating as a coating solution; and is also provided with

(2) And adding the tablet cores into a coating pot, spraying the coating liquid, and controlling weight gain of the tablet cores.

In the step (1), the concentration of the coating solution is preferably 22%, and the percentage is the mass percentage of the raw materials of the coating solution.

In step (1), the coating material may be a coating material commonly used in pharmaceutical formulations, preferably a film coating premix.

In step (2), the core weight gain refers to the percentage of the coating mass to the core mass. The core weight gain is preferably 1-3%.

The invention provides stomach-warming alairan tablets which are prepared by a preparation method of Wen Weia alairan tablets.

Preferably, the Wen Weia tablets comprise a core and a coating. Wherein the coating may be a conventional coating in the art, preferably a gastric-soluble film coating.

In the present invention, the Wen Weia standard and tablet specifications may be conventional in the art, such as 0.51g per tablet.

The invention provides a quality control method of Wen Weia Yan and tablet, which is used for measuring the content of aloin, wherein the content of aloin in each tablet of Wen Weia Yan and tablet is not less than 17mg.

In the present invention, preferably, the method for determining the content of the aloin is to determine according to high performance liquid chromatography:

(1) Chromatographic conditions: chromatographic column: shimadzu C ₁₈ (4.6X105 mm,5 μm); mobile phase: acetonitrile-water (24:76); detection wavelength: 359nm; flow rate: 1.0mL/min; column temperature: the temperature is 25-40 ℃, and the sample injection amount is controlled to be 10 mu L by an automatic sample injector quantitative loop; the theoretical plate number should not be lower than 2000 in terms of aloin peak;

(2) Preparation of a control solution: taking appropriate amount of aloin reference substance, precisely weighing, and dissolving in methanol to obtain reference substance solution;

(3) Preparation of test solution: taking Wen Weia Xiyan and tablets, removing the coating, grinding, taking a proper amount of powder, precisely weighing, placing in a brown measuring flask, adding methanol, performing ultrasonic treatment (59 KHz) for 15-60 min, cooling, diluting to a scale with the methanol, shaking uniformly, filtering, and taking the subsequent filtrate as a sample solution;

(4) And (3) measuring: and respectively sucking the reference substance solution and the sample solution according to the sample injection amount, injecting the reference substance solution and the sample solution into the high performance liquid chromatograph, recording a chromatogram and calculating the content.

In step (1), the column temperature used for the high performance liquid chromatography is preferably 40 ℃.

In the step (2), the mass concentration of the reference substance solution is preferably 0.005g/mL.

In step (3), the mass concentration of the Wen Weia and tablet in the methanol is preferably 0.00065-0.0011g/mL, more preferably 0.00077g/mL.

In step (3), the time of the ultrasonic treatment is preferably 30 minutes.

In step (3), the brown measuring flask preferably has a capacity of 100mL.

In step (3), the volume of methanol is preferably 70mL.

On the basis of conforming to the common knowledge in the field, the above preferred conditions can be arbitrarily combined to obtain the preferred examples of the invention.

The reagents and materials used in the present invention are commercially available.

The invention has the positive progress effects that:

1. the invention optimizes the prescription of the preparation, and has large hardness, good stability and good processability. Further, the tablet obtained by coating has the advantages of improving appearance, good moisture resistance, good stability and poor compliance of patients. The Wen Weia tablets of the invention can effectively relieve difficult defecation and unsmooth defecation for patients with functional constipation.

2. In the Wen Weia partial preparation method and the tablet preparation method, the process parameters are exactly beneficial to standardized operation of production and control of product quality; the operation is easy to form, the process is simple, and the sample is more stable to store; the preparation process is stable, the production process can be effectively controlled, and the preparation method is suitable for mass workshop production.

3. The invention controls the quality of Wen Weia Yaranand tablets by measuring the content of aloin in aloe, and can effectively ensure the safety and effectiveness of the medicine. The standard of the aloin in each Wen Weia and tablet is defined as the content of not less than 17mg, and Wen Weia is improved; in addition, the quality control method has high precision, stability, good repeatability and high recovery rate, thereby ensuring the quality uniformity of the medicine, effectively controlling the quality of the product and effectively controlling the production process. In a word, the quality control method of the invention is a quick, simple, safe and reliable evaluation method.

Drawings

FIG. 1 is an ultraviolet scan profile of an aloin control in a selection experiment of detection wavelengths in chromatographic conditions of a quality control example.

FIG. 2 is a graph of the linear relationship between the aloin concentration and peak area in a linear relationship test of quality control example.

FIG. 3 is an HPLC profile of the aloin control in the specificity test of the quality control example.

Fig. 4 is an HPLC profile of a test sample in a proprietary test of quality control examples.

Figure 5 is a negative sample HPLC profile in a proprietary test of a quality control example.

Detailed Description

The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.

The experimental materials and experimental instruments used in the following examples and comparative examples are as follows:

1. experimental materials

Starch: anhui mountain river pharmaceutical excipients, inc., product standard: two parts of Chinese pharmacopoeia 2010 edition.

Crospovidone: anhui mountain river pharmaceutical excipients, inc., product standard: two parts of Chinese pharmacopoeia 2010 edition.

Magnesium stearate: anhui mountain river pharmaceutical excipients, inc., product standard: two parts of Chinese pharmacopoeia 2010 edition.

Silica: anhui mountain river pharmaceutical excipients, inc., product standard: two parts of Chinese pharmacopoeia 2010 edition.

Gastric-soluble film coating premix: beijing Yingmao pharmaceutical Co.

Aloin control: chinese medicine biological products institute.

Chromatographic methanol: fisher Chemical.

Chromatographic acetonitrile: fisher Chemical.

2. Experimental instrument

BS124S electronic balance (beijing certolis instruments systems limited).

DT500A electronic counter balance (gold sheep balance Instrument Co., ltd., mature city gold sheep weight instruments Co., ltd.).

DFY-300 swing type high speed pulverizer for Chinese medicine (Wen Lingshi Dade Chinese medicine mechanical Co., ltd.).

DZTW type temperature-regulating electrothermal sleeve (medical instruments factory in Guangming, beijing city).

HN101-2 electric heating blast drying oven (Nantonghai Nannan scientific instruments Co., ltd.).

VFP-7 rotary variable speed tablet press (Chemie, dragon City, changzhou, inc.).

YPJ-200A type tablet hardness tester (Shanghai yellow sea medical testing instruments Co., ltd.).

FT-2000A friability tester (Tianjin university Wireless Power plant).

ZB-1D intelligent disintegration apparatus (Tianjin university precision instruments).

JJ-1 booster electric stirrer (medical instruments works in Jintan).

BY-400 sugar coating machine (Jiangsu Taixing Zhongzhi pharmaceutical machinery Co., ltd.).

Chromatographic column Shimadzu C ₁₈ (4.6×150mm,5μm)。

Preparation examples 1 to 9

The cores of Wen Weia Yaruan tablets of examples 1-9 were prepared according to the following procedure, the following amounts being one fifth of the 1 prescribed amounts, wherein the amount of fine powder was the amount obtained after the pulverization loss of the medicinal material:

TABLE 1 preparation formulations of examples 1-9

The cores of Wen Weia yaand tablets were prepared as follows:

(1) Weighing the components of the active ingredient A according to the mass ratio of 200:40:57:97, namely aloe, herba cuscutae, pulp Citrulli and herba seu radix Kadsurae Longipedunculatae, mixing, crushing in a crusher, sieving with a 100-mesh sieve, and marking as fine powder A;

(2) Weighing Mu Ku myrrh according to the mass ratio of 394:50 of the active ingredient A to the active ingredient B, adding 8 times of water into Mu Ku myrrh, decocting for 3 times, each time for one hour, filtering, combining the filtrates, concentrating, and recording as extract B; the relative density of the extract B is 1.06g/mL;

(3) According to the formula of Table 1, adding fine powder A, filler and partial disintegrating agent into extract B, mixing, wet granulating with 80% ethanol water solution, oven drying at 60deg.C for 20 min; sieving the granules, wherein the particle size of the sieved granules is 16 meshes;

(4) Adding lubricant and the rest disintegrating agent, mixing, tabletting with tablet machine to obtain tablet core.

Preparation example 10

The original standard does not require coating, but the tablet core has extremely bitter taste and large dosage, and the patient can take 3-5 tablets each time, which reduces the compliance of taking the tablet, and in addition, the hygroscopicity of the tablet core is considered to increase the stability of the tablet core, so the preparation of the coating is studied.

The coating of this example 10 was prepared as follows:

(1) 1 500ml beaker was taken, 173ml distilled water was added and placed on a stirrer. Starting a stirrer, regulating the rotating speed to enable the liquid level to just form a vortex, weighing 38g of gastric-soluble film coating premix according to the dosage, slowly adding the premix into the vortex formed by water in a beaker, regulating the rotating speed until the vortex does not appear after the addition is finished, and stirring for 45 minutes to obtain the gastric-soluble film coating premix. Transferring the prepared coating solution into a spray gun for standby. The concentration of the coating liquid is 18%, and the percentage is the mass percentage of the coating raw material in the coating liquid.

(2) 1kg of tablet cores prepared according to the formula and the preparation method of example 6 are placed in a coating pan, hot air is opened, the rotating speed is adjusted, and the tablet cores are preheated to the temperature of about 40-50 ℃; opening a compressed air switch, and adjusting the flow rate and air pressure of the coating liquid to form mist; aiming at the tablet bed, spraying evenly until the coating liquid is sprayed. Closing compressed air, blow-drying the sheet surface, closing hot air, cooling, and discharging the sheet.

Weight gain of the tablet core produced = coating mass/tablet core mass = (173 g+38 g)/1000 g = 2.11%

Effect example 1

The properties of Wen Weia and cores, friability, disintegration time and the like of the tablets prepared in preparation examples 1 to 9 were measured, and the results are shown in Table 2.

TABLE 2 core Performance results for examples 1-9

From the above results, it can be seen that the tablet cores prepared in examples 1 to 9 described above all meet the standard requirements in terms of hardness, friability, and disintegration time.

More preferably, as can be seen from examples 7, 8 and 9, the tablet cores prepared from the above three materials have equivalent effects of hardness, friability and disintegration time, and the microcrystalline cellulose filler added in example 2 has higher cost from the viewpoint of cost, and starch is selected as a more preferable filler.

More preferably, as can be seen from examples 7 and 3, the addition of the disintegrant crospovidone in example 3 significantly shortens the disintegration time and increases the hardness of the tablet cores prepared in example 3 compared with example 7;

more preferably, as can be seen from examples 3, 4 and 5, the crospovidone in example 3 belongs to the internal addition, the crospovidone in example 4 belongs to the external addition, the crospovidone in example 5 belongs to the internal and external addition, the disintegration time of the tablet core of example 5 is significantly shortened, the hardness is higher and the friability is lower than that of the tablet cores prepared in examples 3 and 4.

In addition, as can be seen from examples 5 and 6, in example 6, the silica tablet was added more than example 5 with the addition of magnesium stearate as a lubricant, the hardness of the tablet cores of example 6 was significantly improved, and the disintegration time was also controlled within a satisfactory range.

The coating effect of example 10 was examined comprehensively from factors such as smoothness of the tablet surface, degree of abrasion, presence or absence of pits, cracks, disintegration time, etc. The film coated tablet prepared in the embodiment 10 has smooth surface, small abrasion degree, less phenomena of broken tablets such as pits and cracks and high success rate. The disintegration time is 30 minutes, and the disintegration time is small.

Effect example 2

The process of coating tablet cores was performed as in example 10 for 3 consecutive batches of pilot scale-up to 100 prescriptions and for 6 months of accelerated (temperature 40±2 ℃, relative humidity 75±5%) and 6 months of long-term (temperature 25±2 ℃, relative humidity 60±10%) stability studies were performed on three batches of pilot samples, including: the characteristics, identification, disintegration time limit, content measurement and microorganism limit inspection show no obvious change in each measurement index, and the product has reasonable production process, stable medicine quality and controllable standard.

Effect example 3

In this example, the constipation treating function of Wen Weia and tablets of the present invention was tested

1 object and method:

(1) Wen Weia Yaranhe tablets prepared by the process of example 10 of the present invention were used as test samples, 0.51 g/tablet. The recommended dosage for human body is 2 times per day, 3 tablets per time, and the dosage is 3.06 g/day.

(2) Selecting a population meeting the following conditions as a tested population:

a. reference is made to the standard of the consensus opinion of constipation medical science and diagnosis specialists (2017 edition): the number of times of defecation of patients before the patients enter the group is reduced, namely, the number of times of autonomous defecation is less than 3 times 1 week before randomization;

b. age 18-65 years (18 and 65 inclusive), and is not limited to men and women;

and excludes the following populations:

a. constipation caused by organic lesions of digestive tract (such as tumor, crohn's disease, tuberculosis of digestive tract, etc.) or other diseases of digestive tract system (such as neuromuscular lesions, neuropsychiatric disorders, metabolic endocrine disorders);

b. a person with dyschezia caused by constipation or anal lesions with outlet obstruction;

c. constipation caused by drug factors or secondary constipation with other definite causes;

d. positive patients with irritable bowel syndrome or fecal occult blood test;

e. an abdominal, pelvic or retroperitoneal operator was received 6 months prior to screening;

f. screening patients with related symptoms or diseases caused by gastric acid hypersecretion such as acid regurgitation, peptic ulcer and gastroesophageal reflux disease within 3 months before screening;

g. a patient who uses a drug for treating constipation 3 days before randomization;

h. laboratory safety index: ALT and AST are more than or equal to 1.5 times of the upper limit of the normal value, and Cr is more than the upper limit of the normal value;

i. patients with severe primary diseases of the cardiovascular and cerebrovascular, liver, kidney, endocrine, hematopoietic and nervous systems, with severe mental diseases;

j. allergic to the test drug ingredients;

k. women during the test period, pregnant or scheduled pregnant women, lactating women;

(3) Experimental design and grouping: the population of subjects was randomly divided into experimental and control groups, the experimental group: wen Weia and tablet test agent, specification: 0.51 g/tablet provided by Xinjiang Uygur pharmaceutical Co., ltd; control group: wen Weia and tablet placebo, specification: 0.51 g/tablet, supplied by Xinjiang Uighur pharmaceutical Co.

(4) Dosing method and period:

the medicine taking method comprises the following steps: orally administered 3 tablets at a time, 2 times a day, 6 times (about 3 days) continuously, and 2 hours after meal.

Stopping standard: the women stop taking the test medicines in the physiological period; the number of times of defecation is more than 4 in the day after taking the medicine, and the test medicine is stopped taking.

2. And (3) observing the indexes:

2.1 major efficacy index

The proportion of complete autonomous defecation occurs within 24 hours after the first administration of the medicine by the subject; ( Fully autonomous bowel movement (complete spontaneous bowel movement, CSBM) is defined as: defecation is voluntarily and with a complete feeling of exhaustion without taking remedial laxatives or assistance of manipulations. (in this test, no remedial laxatives or other adjunctive therapy was taken 24 before defecation, considered voluntary defecation) )

3. Analysis of results

The main curative effect index is as follows:

the subject had a fully voluntary bowel movement rate within 24 hours after the first dose.

The number and percentage of cases were calculated as whether or not complete voluntary bowel movement occurred within 24 hours after dosing.

Statistical analysis was done using SPSS.22 version statistical analysis software. When self-comparison data adopts paired t-test, two groups of average comparison adopts grouped t-test, the latter needs to carry out variance alignment test, proper variable conversion is carried out on data with non-normal distribution or uneven variance, and t-test is carried out on converted data after normal variance alignment is met; if the conversion data still cannot meet the normal variance alignment requirement, t' test or rank sum test is used instead; however, data with too large a coefficient of variation (CV > 50%) were subjected to rank sum test. The effective rate and the total effective rate of the efficacy index are checked by adopting X2 test. When the total number of cases in the four-grid table is smaller than 40, or the total number of cases is equal to or larger than 40 but the theoretical number of occurrences is equal to or smaller than 1, the exact probability method is adopted instead.

4. Experimental results

The group of subjects was randomly divided into an experimental group and a control group, and the group of subjects meets 70 cases of standard persons and 35 cases of each group. The test items before the test of the subject are as follows:

(1) Physical examination, vital signs (heart rate, respiration, body temperature and blood pressure)

(2) Laboratory examination: stool routine + occult blood test, blood routine (HGB, RBC, WBC, PLT), urine routine (GLU, PRO, LEU, ERY), liver function (ALT, AST, tbil, ALP, gamma-GT), kidney function (Cr, bun), blood electrolytes (Na+, K+, cl-, ca++, pH), blood pregnancy test.

(3) Electrocardiogram examination

The examination results are all in the normal range, the grouping conditions are shown in Table 3, and the age, sex, course and constipation of the two groups of patients are not obviously different (P is more than 0.05), so that the patients are comparable. The subjects have no obvious changes in spirit, sleep, diet, urination and defecation, blood pressure and the like before and after taking the medicine. The general data comparison is shown in Table 3.

Table 3 two groups of patient conditions

Project	Test group	Control group
			Number of examples	35	35
Male/female	13/22	12/23

The results of the therapeutic effects after administration of the test drugs are shown in Table 4

Table 4 two sets of data compare cases

From the above experimental results, 70 constipation subjects meeting the requirements are randomly divided into a test group and a control group, and the test group takes Wen Weia and tablets of the medicine according to the requirements for 3 days, and the total effective rate is 21 out of 35, and the total effective rate is 80%. Before and after taking the medicine, all examination indexes of the test cases except constipation are in a normal range, which shows that the medicine has no adverse effect on the physical health of a subject; no allergic or other adverse reaction is observed in the taking process, and the Wen Weia tablets have the effect of treating constipation.

Quality control examples

1. Method for establishing quality control

Instrument and reagent:

chromatographic column Shimadzu C ₁₈ (4.6×150mm,5μm)。

Aloin control: chinese medicine biological products institute

Chromatographic methanol: fisher Chemical

Chromatographic acetonitrile: fisher Chemical

Test article: wen Weia and tablets were prepared by the procedure of example 10.

Negative samples: aloe vera Wen Weia and tablet cores were prepared by the process of example 10, but lacked aloe vera.

1. Preparation of test solutions

(1) Selection of extraction solvent and extraction mode

The aloin is easy to dissolve in pyridine, and is dissolved in glacial acetic acid, methanol, acetone, water and ethanol, and in consideration of the solubility of the aloin and the distribution of the aloin in a mobile phase, the aloin in a sample is extracted by adopting an ultrasonic extraction mode by selecting methanol as a solvent according to a pharmacopoeia method.

(2) Selection of extraction concentration

Setting 3 groups of experiments, preparing Wen Weia Yaranhe tablets according to example 10, removing the coating, taking 3 parts of the same batch of sample powder, weighing each part of the sample powder by precision, respectively placing the sample powder into a 100mL measuring flask, respectively adding 50mL, 70mL and 90mL of methanol, carrying out ultrasonic extraction for 30 minutes, cooling, fixing the volume to a scale by using the methanol, shaking uniformly, filtering by using a microporous filter membrane (0.45 μm), discarding the primary filtrate, and injecting the subsequent filtrate into a liquid phase instrument for measurement, wherein the content is calculated, and the result is shown in Table 5.

TABLE 5 results of measurement of the extraction concentration of test sample solutions

Numbering device	Sample weighing (g)	Solvent volume (ml)	Peak area	Content (mg/g)
					1	0.0542	50	601244	73.39
2	0.0536	70	606129	74.81
					3	0.0588	90	663644	74.67

Conclusion: as can be seen from Table 5, the amounts of aloin measured at different extraction concentrations differ little, and 0.00077g/mL, which is a relatively high measured amount, is preferred as the extraction concentration.

(3) Selection of extraction time

Taking 4 parts of the same batch of sample powder in the step (2), precisely weighing 55mg of each part, respectively placing into 100ml measuring bottles, respectively adding 70ml of methanol, respectively carrying out ultrasonic treatment for 15, 30, 45 and 60 minutes, cooling, diluting to a scale with methanol, shaking uniformly, filtering with a microporous filter membrane (0.45 mu m), discarding the primary filtrate, and injecting the subsequent filtrate into a liquid phase instrument for measurement, wherein the content is calculated, and the result is shown in Table 6.

TABLE 6 results of measurement of extraction time of sample solution

Numbering device	Sample weighing (g)	Ultrasonic time (min)	Peak area	Content (mg/g)
					1	0.0563	15	644223	75.54
2	0.0561	30	667853	78.59
					3	0.0588	45	661250	74.24
4	0.0587	60	653757	73.52

Conclusion: as can be seen from Table 6, the difference in the amounts of aloin measured at different extraction times is small, and ultrasonic extraction is preferred for 30min in order to ensure sufficient extraction and save time.

The preparation method of the finally determined sample solution comprises the following steps: after Wen Weia yaku and tablets prepared in example 10, 20 tablets were taken, the coatings were removed, precisely weighed, ground, about 55mg was taken, precisely weighed, placed in a 100mL brown measuring flask, 70mL of methanol was added, sonicated (59 KHz) for 30min, cooled, diluted to scale with methanol, shaken well, filtered, and the subsequent filtrate was taken as a test solution.

2. Chromatographic conditions

(1) Selection of detection wavelength

The maximum absorption at 359+ -2 nm, as shown in FIG. 1, was found by ultraviolet scanning of the aloin control solution, so 359nm was selected as the detection wavelength. FIG. 1 is an ultraviolet scan profile of a selected sample of detection wavelengths in the chromatographic conditions of quality control example 1.

3. Test of Linear relation

Accurately weighing 18.7mg of aloin reference substance, placing in a 100ml measuring flask, adding methanol for dissolving, fixing volume to scale, shaking, and making into 187 μg/ml solution as reference substance stock solution. Precisely measuring

control stock solutions

1, 2, 3, 4, 5 and 6mL, respectively placing into 10mL measuring flask, adding methanol to scale, shaking, preparing into solutions with concentrations of 18.7, 37.4, 56.1, 74.8, 93.5 and 112.2 μg/mL, precisely sucking 10 μl of each control series solution, injecting into liquid chromatograph, and recording peak area. Drawing a standard curve by taking the sample injection concentration (mug/mL) as an abscissa and the peak area as an ordinate, and obtaining a standard curve equation: y=15024x+3843.5, r=0.9998. The results show that the aloin has good linear relationship in the range of 18.7ug/ml to 112.2ug/ml, and the results are shown in Table 7 and FIG. 2. FIG. 2 is a graph showing the linear relationship between the aloin concentration and the peak area in the linear relationship test of quality control example 1.

TABLE 7 aloin concentration and peak area relationship Table

4. Precision test

Sucking 10 μl of the control solution (56.1 μg/ml) in the step 3, repeating the sample injection for 6 times, and measuring the peak areas of the aloin as follows: 852307, 847974, 847657, 844766, 847394, 845168. RSD value (n=6) was calculated to be 0.32%. The results show good precision (RSD < 2%) and are shown in table 8.

TABLE 8 control aloin peak area and RSD data

5. Stability test

The same sample solutions were taken and assayed at 0, 2, 4, 6, 8, 24h after preparation, respectively, and RSD (%) was calculated, which indicated that the samples were stable for 24h (RSD < 4%), as shown in table 9.

TABLE 9 sample aloin peak area and RSD data

6. Repeatability test

7 parts of the test sample are respectively weighed precisely, the operation is carried out according to the preparation and determination methods of the test sample solution, and the content of aloin is calculated, and the result is shown in Table 10. As can be seen from table 10, the repeatability was good (RSD < 4%).

TABLE 10 sample aloin content and RSD data

7. Recovery test

Recovery was determined by standard additive method. 10 parts of sample powder of the test sample are taken, each part is 0.03g, and the sample powder is precisely weighed. Taking the first part as a blank, dividing the rest into three groups, precisely adding 1.122mg/ml of reference substance solution respectively, adding 1ml of each part of the first group, adding 2ml of each part of the second group, adding 3ml of each part of the third group, and volatilizing methanol. Each sample was prepared according to the preparation method of the sample solution, 10. Mu.l of each sample solution was sucked and poured into a liquid phase meter for measurement, and the content and the recovery rate of each sample were calculated, and the results are shown in Table 11. As is clear from Table 11, the recovery rate was good (85% -110%, RSD < 4%)

TABLE 11 sample solution content and addition recovery data

8. Specificity test

Test solution: taking 20 tablets of a test sample, removing a coating, precisely weighing, grinding, taking about 55mg, precisely weighing, placing in a 100mL brown measuring flask, adding 70mL of methanol, performing ultrasonic treatment (59 KHz) for 30min, cooling, diluting to a scale with methanol, shaking uniformly, and filtering to obtain a subsequent filtrate as a test sample solution.

Negative sample control solution: prepared by the procedure of reference example 10, but lacking aloe vera. The negative sample solution is prepared according to the preparation method of the sample solution.

Precisely sucking 10 μl of each of the control solution, the sample solution, and the negative sample control solution, and measuring with high performance liquid chromatograph. The results are shown in fig. 3 to 5, wherein fig. 3 is an aloin reference HPLC profile in the specificity test of quality control example 1, fig. 4 is a test sample HPLC profile in the specificity test of quality control example 1, and fig. 5 is a negative sample HPLC profile in the specificity test of quality control example 1. The spectrum of the corresponding chromatographic peak of the chromatograph of the test sample is consistent with that of the control aloin, and the negative is not interfered.

9. Limit of detection test

(1) Aloin reference

Preparation of aloin control solution: accurately weighing appropriate amount of aloin reference substance, placing into brown measuring flask, and adding methanol to obtain solution containing 60 μg per 1 ml.

Precisely sucking aloin reference solution, adding methanol solution, gradually diluting, and measuring chromatogram to obtain aloin reference detection limit solution with signal-to-noise ratio of about 2:1 or 3:1.

The results are shown in Table 12, and the detection limit of the aloin control is 0.01566. Mu.g/mL.

Table 12 limit of detection of aloin control

Name of the name	Concentration (μg/mL)	s/n
			Detection limit	0.01566	2.2

2. Determination of Altar and Altar content in tablets for warming stomach

(1) Chromatographic conditions: mobile phase: acetonitrile-water (24:76); detection wavelength: 359nm; flow rate: 1.0ml/min; column temperature: the sample injection amount is controlled to be 10 mu L by an automatic sample injector quantitative loop at 40 ℃; the theoretical plate number should not be lower than 2000 in terms of aloin peak;

(2) Preparation of a control solution: precisely weighing appropriate amount of aloin reference substance, placing into brown measuring flask, and adding methanol to obtain solution containing 60 μg per 1 ml;

(3) Preparation of test solution: taking 20 tablets of a test sample, removing a coating, precisely weighing, grinding, taking about 55mg, precisely weighing, placing in a 100mL brown measuring flask, adding 70mL of methanol, performing ultrasonic treatment (59 KHz) for 30min, cooling, diluting to a scale with methanol, shaking uniformly, filtering, and taking the subsequent filtrate as a test sample solution;

(4) And (3) measuring: 10. Mu.l of each of the control solution and the sample solution was precisely aspirated, and the samples were injected into a high performance liquid chromatograph, the chromatogram was recorded, and the content was calculated and measured on 10 batches of samples of Wen Weia Yaruhe and tablets prepared in reference example 10 according to the above measurement method, and the results are shown in Table 13.

TABLE 13 determination of ten samples (mg/tablet)

Sample lot number	Content (mg/tablet)
		110601	37.21
110602	41.12
		110603	40.65
110604	38.06
		110605	38.22
110606	37.68
		110607	36.60
111001	29.34
		111002	31.37
111003	29.65

According to the measurement results of the table, the content of each of Wen Weia Yaruand tablets, calculated as aloin, was determined to be not less than 17 mg/tablet.

The foregoing description of embodiments of the invention is merely illustrative of the invention and is not intended to be limiting. It will be appreciated by persons skilled in the art that many variations, modifications, and even equivalents may be made thereto without departing from the spirit and scope of the invention as defined in the appended claims.

Claims

1. A method for preparing stomach-warming alairan and tablets is characterized by comprising the steps of preparing tablet cores by adopting a Wen Weia alairan and tablet core raw material;

the Wen Weia yaor tablet core raw material comprises an active ingredient and auxiliary materials, wherein the active ingredient consists of an active ingredient A and an active ingredient B, and the active ingredient A consists of aloe, cuscuta chinensis, pulp Citrulli and hedyotis cinerea in a mass ratio of 200:40:57:97; the active ingredient B is Mu Ku myrrh, and the mass ratio of the active ingredient A to the active ingredient B is 394:50;

the auxiliary materials consist of the following components in parts by mass based on 375 parts of the active ingredient A: the filler is 50 parts of starch; 50 parts of cross-linked povidone as a disintegrating agent; the lubricant is 5 parts of magnesium stearate;

or the auxiliary materials comprise the following components in parts by weight: the filler is 47.5 parts of starch; 30 parts of cross-linked povidone as a disintegrating agent; the lubricant comprises 25 parts of silicon dioxide and 2.5 parts of magnesium stearate;

the preparation method of the tablet core comprises the following steps:

wherein the order of (1) and (2) is not sequential;

(4) Adding the lubricant and the rest of the disintegrating agent, uniformly mixing, and tabletting to obtain the tablet core;

the disintegrating agent is added in an internal and external addition mode.

2. The method of preparing Wen Weia yaand tablets of claim 1, wherein in step (1), the sieving is a 100 mesh sieve;

and/or, in the step (2), the water adding amount of the water is 6-12 times of the mass of the Mu Ku myrrh;

and/or, in the step (2), the times of decoction are 3 times, and the time of decoction is one hour each time;

and/or in the step (2), the relative density of the extract B is 1.0-1.15g/mL;

and/or, in step (3), the granulating is wet granulating;

and/or, in the step (3), the drying is drying;

and/or, in the step (3), the drying temperature is 55-65 ℃;

and/or, in the step (3), the drying step further comprises a sieving step, so that the obtained particles have uniform particle sizes.

3. The method for preparing Wen Weia yan and tablet according to claim 2, wherein in the step (2), the water amount of the water is 8 times the mass of the Mu Ku myrrh;

and/or, in the step (3), the granulating is carried out by adopting an ethanol water solution for wet granulating;

and/or, in step (3), the drying temperature is 60 ℃;

and/or in the step (3), the particle size of the particles after the sieving step is 16-50 meshes.

4. The method for preparing Wen Weia yaand tablets of claim 3, wherein in step (3), the concentration of the aqueous ethanol solution is 80%;

and/or, in the step (3), the particle size of the particles after the sieving step is 16 meshes.

5. The method of preparing Wen Weia and tablets of claim 1, wherein the method of preparing Wen Weia and tablets further comprises coating.

6. A method of preparing Wen Weia tablets according to claim 5, wherein the coating comprises the steps of:

(1) Preparing an aqueous solution of the raw materials of the coating as a coating solution;

(2) And adding the tablet cores into a coating pot, spraying the coating liquid, and controlling the weight gain of the tablet cores.

7. The method of claim 6, wherein in step (1), the concentration of the coating liquid is 22%, and the percentage is the mass percentage of the raw materials of the coating liquid;

and/or in the step (2), the raw materials of the coating are film coating premix;

and/or in the step (2), the weight gain of the tablet core is 1-3%, wherein the weight gain of the tablet core refers to the percentage of the coating mass to the tablet core mass.

8. A stomach warming alairam and tablet prepared by the method of preparing Wen Weia alairam and tablets according to any one of claims 1-7.

9. The Wen Weia sub-natural and tablet of claim 8, wherein said Wen Weia sub-natural and tablet comprises a tablet core and a coating.

10. The Wen Weia sub-natural and tablet according to claim 9, wherein said coating is a gastric-soluble film coating.

11. The Wen Weia sub-assembly and tablet of claim 9, wherein said Wen Weia sub-assembly and tablet is of a gauge of 0.51g per tablet.

12. A method of quality control of Wen Weia sub-natural and tablets according to any one of claims 8 to 11, comprising determining the aloin content, each of said Wen Weia sub-natural and tablets having an aloin content of not less than 17mg.

13. The method for quality control of Wen Weia yaand tablets of claim 12, wherein said method for determining the content of aloin is by high performance liquid chromatography:

(1) Chromatographic conditions: chromatographic column: shimadzu C ₁₈ 4.6X105 mm,5 μm; mobile phase: acetonitrile-water 24:76; detection wavelength: 359nm; flow rate: 1.0mL/min; column temperature: the temperature of 25-40 ℃ and the sample injection amount are controlled to be 10 mu L by an automatic sample injector quantitative loop; the theoretical plate number should not be lower than 2000 in terms of aloin peak;

(3) Preparation of test solution: taking Wen Weia Xiyan and tablets, removing the coating, grinding, taking a proper amount of powder, precisely weighing, placing in a brown measuring flask, adding methanol, performing ultrasonic treatment at 59KHz for 15-60 min, cooling, diluting to a scale with the methanol, shaking uniformly, filtering, and taking the subsequent filtrate as a sample solution;

14. The method for quality control of Wen Weia ya and tablets according to claim 13, wherein in step (1), the column temperature employed by the high performance liquid chromatography is 40 ℃;

and/or, in the step (2), the mass concentration of the reference substance solution is 0.005g/mL;

and/or, in the step (3), the mass concentration of the Wen Weia sub-component and the tablet in the methanol is 0.00065-0.0011g/mL in the sample solution;

and/or, in the step (3), the ultrasonic treatment time is 30min;

and/or, in step (3), the brown measuring flask has a capacity of 100mL;

and/or, in the step (3), the volume of the methanol is 70mL.

15. The method for quality control of Wen Weia ninja and tablets according to claim 14, wherein in step (3), the mass concentration of Wen Weia ninja and tablets in the methanol is 0.00077g/mL.