CN115317508B

CN115317508B - Private effervescent tablet for external use and preparation method thereof

Info

Publication number: CN115317508B
Application number: CN202211022710.5A
Authority: CN
Inventors: 张英帅; 岳元媛; 李加兴; 游恩卓; 吴志康; 徐欢欢; 王茹
Original assignee: Xuetian Salt Group Co ltd
Current assignee: Xuetian Salt Group Co ltd
Priority date: 2022-08-24
Filing date: 2022-08-24
Publication date: 2023-08-29
Anticipated expiration: 2042-08-24
Also published as: CN115317508A

Abstract

The application provides a private external effervescent tablet and a preparation method thereof, wherein the private external effervescent tablet is prepared by taking salt, traditional Chinese medicine extract and boric acid as effective components, does not contain antiseptic, chlorhexidine acetate and other sterilization chemical components, is convenient to use and carry, has long shelf life, and has better effects of relieving and nursing edema pain caused by hemorrhoids and pruritus vulvae of men and women; in addition, the salt consumption in the formula is about 50%, and the application uses the process of independently granulating and tabletting the salt, the traditional Chinese medicine extract and the functional components of boric acid in the formula to prepare the acid mixture particles and the alkali mixture particles respectively after mixing, thereby solving the problems of difficult forming and difficult tabletting of the effervescent tablet caused by overlarge salt addition in the raw materials of the formula.

Description

Private effervescent tablet for external use and preparation method thereof

Technical Field

The application relates to an effervescent tablet, in particular to a private external effervescent tablet and a preparation method thereof.

Background

Hemorrhoids are one of the most common anorectal diseases clinically, and the general examination results of the tissue of 1975-1997 of the anorectal society of Chinese medicine in China show that: the total incidence rate of domestic anorectal diseases is 59.1%, wherein the highest incidence rate of hemorrhoids (51.6%) accounts for 87.2% of all anorectal diseases. Hemorrhoids are classified into internal hemorrhoids, external hemorrhoids and mixed hemorrhoids, and epidemiological investigation results show that: the prevalence of mixed hemorrhoids and external hemorrhoids is significantly higher than internal hemorrhoids. Hemorrhoid patients often manifest bleeding, swelling, prolapse, pain, itching, anal discomfort, and the like. The sick people are mainly ill with unhealthy diet (drinking alcohol, spicy diet) and professional people who are engaged in "sedentary standing". The perianal pruritus and the pudendum pruritus are a group of diseases which take external genitalia and perianal local skin pruritus with different degrees as main clinical manifestations, and can be acute or chronic persistent, and are often accompanied with secondary skin lesions such as scratch, pigmentation, mossiness and the like. Perianal itching disease rate is 1% -5% of adult, male is more than female, and its ratio is 4:1. At present, the external treatment of the traditional Chinese medicine for treating the diseases is relatively safe and effective, the clinical application is wide, and the external traditional Chinese medicine formula mainly adopts medicines for clearing heat, detoxifying, eliminating dampness, killing insects and relieving itching. Hemorrhoids, pruritus vulvae of men and women and the like are not serious usually, most patients are sensitive to the traditional thought concept, the patients can choose to buy medicines to a retail pharmacy for treatment in the aspect of treatment, and only serious symptoms appear, the patients can choose to go to the hospital for asking for medical treatment, so that the retail market becomes the main battlefield of private washing and protecting products.

The fumigation and bath therapy is one of the therapies commonly used in anorectal department, and comprises Chinese herbal medicine mixture, potassium permanganate, pricklyash peel water, etc. When the traditional Chinese medicine mixture is used, a large pot is needed to cook soup, the time is long, the procedures are complicated, the use is inconvenient, and the use environment is greatly limited. The other methods are too simple, and the curative effect is not satisfactory. At present, external fumigation lotion for hemorrhoids has brand products such as a hemorrhoid lotion, a Jinxuan hemorrhoid fumigation powder, a hemorrhoid comfort lotion, a hemorrhoid external washing medicine and the like. The external washing and protecting agent for treating male and female pruritus vulvae is mainly occupied by two products, namely, the gynecological inflammation cleaner and the Jieeryin cleaner.

Disclosure of Invention

In the prior art, although people can use low-concentration saline warm water to carry out hip bath on private parts to relieve the morbidity symptoms of hemorrhoids, male and female pruritus vulvae and the like, the curative effect is limited, and the concentration of the salt cannot be accurately controlled. The private external brand products on the market are almost all liquid preparations, and the liquid preparations are large in packaging volume due to large consumption in hip bath or private part cleaning, so that the products are inconvenient to carry when going out; in addition, the liquid preparation is mainly prepared from traditional Chinese medicine extracts, is easy to deteriorate after long-term storage, usually needs to be added with preservative such as sodium benzoate, and is not beneficial to human health if the liquid preparation is continuously used for a long time. Aiming at the problems, the application provides a private external effervescent tablet and a preparation method thereof, wherein the private external effervescent tablet is prepared by taking salt, a traditional Chinese medicine extract and boric acid as effective components, does not contain antiseptic, chlorhexidine acetate and other sterilization chemical components, is convenient to use and carry, has long shelf life, and has better effects of relieving and nursing edema pain caused by hemorrhoids and pruritus vulvae of men and women; in addition, the salt consumption in the formula is about 50%, and the application uses the process of independently granulating and tabletting the salt, the traditional Chinese medicine extract and the functional components of boric acid in the formula to prepare the acid mixture particles and the alkali mixture particles respectively after mixing, thereby solving the problems of difficult forming and difficult tabletting of the effervescent tablet caused by overlarge salt addition in the raw materials of the formula.

The application is realized by the following technical scheme.

A private effervescent tablet for external use is characterized by comprising 45-55% of salt by mass fraction; in the prior art, although in the case of a private topical lotion product, table salt may be used alone or in a formulation as an active ingredient. However, for the prescription design of the effervescent tablet, the prior art generally does not consider using such high content of salt, because salt is used as an effective component on one hand and also as a filler on the other hand, but because the salt has poor compressibility and does not have other processing ability, the use performance of the effervescent tablet is affected as the tablet is not easy to form in the prescription. However, applicants have found that hypertonic brine at a suitable concentration can cause capillary contraction, localized clotting of the capillaries and portions within small blood vessels, but no effect on medium and large blood vessels; in addition, the hypertonic saline can dehydrate cells, is favorable for recovering the function of a sodium pump of a cell membrane and balancing the concentration of ions inside and outside the cells, so that the edema pain caused by hemorrhoids can be relieved to a certain extent; in addition, considering the bacteriostatic effect of high salt content, the shelf life of the effervescent tablet can be prolonged; based on the factors, the applicant innovatively designs a private external effervescent tablet which takes salt as a main functional component, particularly has the salt content up to 45% -55%, and has better relieving and nursing effects on edema pain caused by hemorrhoids, male and female pruritus vulvae; in addition, the applicant reduces the adverse effect of high-content salt on the preparation process of the effervescent tablet by improving the preparation process of the conventional effervescent tablet.

Preferably, the effervescent tablet also contains 21-25% of traditional Chinese medicine extract by mass.

Preferably, the effervescent tablet comprises, by mass, 45% -55% of table salt, 21% -25% of a traditional Chinese medicine extract, 8% -12% of citric acid, 8% -10% of sodium bicarbonate, 1% -3% of polyethylene glycol and 3% -6% of boric acid.

Preferably, the effervescent tablet comprises 50% of salt, 23% of traditional Chinese medicine extract, 10% of citric acid, 10% of sodium bicarbonate, 2% of polyethylene glycol and 5% of boric acid in percentage by mass.

Preferably, the traditional Chinese medicine extract is cortex phellodendri extract, radix sophorae flavescentis extract, fructus cnidii extract, wild chrysanthemum extract and peppermint extract; the effervescent tablet comprises 6% of phellodendron bark extract, 6% of lightyellow sophora root extract, 4% of common cnidium fruit extract, 4% of wild chrysanthemum flower extract and 3% of peppermint extract in percentage by mass.

The preparation method of the private effervescent tablet for external use is characterized by comprising the following steps:

s1: weighing salt, chinese medicinal extract, citric acid, sodium bicarbonate, polyethylene glycol and boric acid according to the formula, and respectively keeping for later use; in the formula, the content of salt is 45-55% by mass percent;

s2: uniformly mixing salt, a traditional Chinese medicine extract and boric acid, and dividing a main material mixture into two parts of a main material mixture A and a main material mixture B; dissolving polyethylene glycol with ethanol to obtain a lubricant, and then dividing the lubricant into two parts of a lubricant C and a lubricant D according to the mass ratio of the main material mixture A to the main material mixture B;

s3: adding citric acid and lubricant C into the main material mixture A, uniformly mixing to prepare a soft material, sieving, granulating and drying to prepare acid mixture particles; adding sodium bicarbonate and lubricant D into the main material mixture B, uniformly mixing to prepare a soft material, sieving, granulating and drying to prepare alkali mixture particles;

s4: the acid mixture particles and the alkali mixture particles are uniformly mixed, and then tabletting is carried out.

Preferably, in the step S1, the particle size of the salt is controlled to be 0.42 mm-0.85 mm, and the particle sizes of the Chinese medicine extract, the citric acid, the sodium bicarbonate and the boric acid are controlled to be 0.15 mm-0.18 mm.

Preferably, in the step S2, the mass ratio of the main material mixture a to the main material mixture B is 0.8-1.2:1.

Preferably, in the step S2, the polyethylene glycol is dissolved with 80% ethanol by volume to obtain the lubricant.

Specifically, in the step S3, the drying parameter is that the temperature is 45-55 ℃ and the time is 2.5-4 hours; preferably, the drying temperature is 50 ℃ and the time is 3 hours.

Specifically, in the step S4, the pressure controlled by tabletting is 0.7-0.11 Mpa; preferably, the pressure of the tabletting control is 0.9Mpa.

In the prior art, wet granulation is a conventional preparation process of effervescent tablets, and the wet granulation comprises two methods of acid-base mixed granulation and acid-base independent granulation. For this, the applicant tried to prepare effervescent tablets by acid-base mixed granulation and acid-base independent granulation under the condition that the salt content in the formula is up to 45% -55%, and found that the acid-base independent granulation has shorter disintegration time and higher foaming amount; in addition, the applicant improves the process of granulating the acid and the alkali separately, namely, the functional components of salt, traditional Chinese medicine extract and boric acid are uniformly mixed and then are divided into two parts, and then are respectively mixed with an acid source and an alkali source to prepare acid mixture particles and alkali mixture particles, and finally, the acid mixture particles and the alkali mixture particles are uniformly mixed, sieved and tableted, so that the effervescent tablet with shorter disintegration time, higher hardness and higher foaming amount can be prepared, but the product still has a larger improvement space.

In the present application, the content of salt is up to 45% -55%, and other necessary components, such as two functional components of Chinese medicine extract and boric acid, and disintegrating agent (citric acid, sodium bicarbonate) and lubricant, are added, if filler is added, the content of salt can be diluted, so that the present application is contrary to the intention and original purpose of the present application, therefore, the present application omits the use of filler in conventional effervescent tablets, but increases the difficulty of preparing effervescent tablets, although the present application can prepare effervescent tablets with up-to-standard performance by single granulation of acid and alkali, the present application also needs to be improved from other technological links of effervescent tablets, so as to improve the quality of effervescent tablets. In the conventional process, salt, traditional Chinese medicine extract, citric acid, sodium bicarbonate and boric acid are powder or granular, so that the granularity of the salt, the traditional Chinese medicine extract, the citric acid, the sodium bicarbonate and the boric acid cannot be controlled again in order to save working procedures and reduce production cost, and especially the materials are respectively controlled to be in different granularity ranges, even if the granularity is controlled, the materials are sieved by adopting a screen mesh with the same specification, so that the formula raw materials in the same granularity range are obtained; in this regard, the applicant has tried to improve the quality of effervescent tablets starting from the particle size of the raw materials, and obviously has tried the two conventional solutions described above, one being to maintain the original physical properties of the raw materials of the formulation, without crushing and sieving these raw materials; secondly, crushing the formula raw materials, and then sieving the crushed formula raw materials with a screen mesh of the same mesh number to obtain the formula raw materials with the same particle size range; however, the effervescent tablet prepared by the first mode has unstable disintegration time, is easy to absorb moisture and has lower hardness; the effervescent tablet prepared by the second mode is easy to absorb moisture in an environment with higher humidity, and the appearance of the effervescent tablet is greatly influenced by different particle sizes of raw materials and auxiliary materials (the tablet is easy to be stuck and washed when the particle size is small, the surface is uneven, the surface color difference is serious when the particle size is large), the hardness and the disintegration time limit are greatly influenced; based on the two conventional modes, the applicant has found that, through experimental finding, if the particle size of the salt is controlled to be 3-5 times that of other raw materials (traditional Chinese medicine extract, citric acid, sodium bicarbonate and boric acid), namely, the particle size of the salt is controlled to be 0.42-0.85 mm, and the particle size of the traditional Chinese medicine extract, citric acid, sodium bicarbonate and boric acid is controlled to be 0.15-0.18 mm, the effervescent tablet with better quality can be prepared.

The application has the beneficial effects that:

1) The private external effervescent tablet is an effervescent tablet prepared by taking salt, traditional Chinese medicine extract and boric acid as effective components, does not contain any preservative, is convenient to use and carry, has long shelf life, and has better effects of relieving and nursing edema pain caused by hemorrhoids and pruritus vulvae of men and women.

2) The application improves the process of acid-base independent granulation, and the functional components of salt, traditional Chinese medicine extract and boric acid are uniformly mixed and then divided into two parts, and then are respectively mixed with an acid source and an alkali source to prepare acid mixture particles and alkali mixture particles, and finally, the acid mixture particles and the alkali mixture particles are uniformly mixed, sieved and tabletted, so that the effervescent tablet with shorter disintegration time, higher hardness and higher foaming amount can be prepared.

3) The private external effervescent tablet takes salt as a main active ingredient, especially the content of the salt is up to 45% -55%, thereby increasing the added value of salt products and enriching the variety of the salt products.

Drawings

FIG. 1 is an external view of the product of the present application;

FIG. 2 is a graph showing the results of a chick embryo test with a solvent control at 0min of reaction;

FIG. 3 is a graph showing the results of a chick embryo test with a solvent control at 5min of reaction;

FIG. 4 is a graph showing the results of a chick embryo test of a negative control at 0min of reaction;

FIG. 5 is a graph showing the results of a chick embryo test of a negative control at 5min of reaction;

FIG. 6 is a graph showing the results of the chick embryo test of positive control 1 at 2min of reaction;

FIG. 7 is a graph showing the results of the chick embryo test of positive control 1 at 5min of reaction;

FIG. 8 is a graph showing the results of the chick embryo test of positive control 2 at 5min of reaction;

FIG. 9 is a graph showing the results of the chick embryo test of positive control 5 at 5min of reaction;

FIG. 10 is a graph showing the results of the chick embryo test for sample 3 at 0min of reaction;

FIG. 11 is a graph showing the results of the chick embryo test for sample 3 at 5min of reaction;

FIG. 12 is a graph showing the results of the chick embryo test for sample 6 at 0min of reaction;

FIG. 13 is a graph showing the results of the chick embryo test for sample 6 at 5min of reaction;

FIG. 14 is a graph showing the results of the chick embryo test for sample 7 at 5min of reaction;

FIG. 15 is a graph showing the results of the chick embryo test for sample 8 at 5min of reaction;

FIG. 16 is a graph showing the results of the chick embryo test for sample 2 at 0min of reaction;

FIG. 17 is a graph showing the results of the chick embryo test of sample 2 at 5min of reaction;

FIG. 18 is a graph showing the results of the chick embryo test of sample 15 at 0min of reaction;

FIG. 19 is a graph showing the results of the chick embryo test of sample 15 at 5min of reaction;

FIG. 20 is a graph showing the results of the chick embryo test of sample 17 after 5 minutes of reaction.

Detailed Description

The present application will be further described with reference to the following specific embodiments, but it should be noted that the following embodiments are merely illustrative of the present application, and the scope of the present application is not limited thereto, and all equivalents thereof by those skilled in the art to which the present application pertains fall within the scope of the present application.

Example 1

A private effervescent tablet for external use contains 45-55% of salt (namely 45-55% of salt in the formula of the effervescent tablet) by mass fraction, and other functional components with therapeutic effect on hemorrhoids, male and female pruritus vulvae, as well as auxiliary materials such as disintegrating agent, adhesive, lubricant, filler and the like commonly used in the preparation of effervescent tablets.

Example 2

A private effervescent tablet for external use comprises 45-55% of table salt (namely 45-55% of table salt in the formula of the effervescent tablet) and 21-25% of traditional Chinese medicine extract (namely 21-25% of traditional Chinese medicine extract in the formula of the effervescent tablet), as well as auxiliary materials such as disintegrating agent, adhesive, lubricant, filler and the like which are commonly used in the preparation of the effervescent tablet.

Example 3

The private effervescent tablet for external use comprises, by mass, 45% -55% of table salt, 21% -25% of a traditional Chinese medicine extract, 8% -12% of citric acid, 8% -10% of sodium bicarbonate, 1% -3% of polyethylene glycol and 3% -6% of boric acid.

Example 4

The private effervescent tablet for external use comprises, by mass, 50% of salt, 23% of a traditional Chinese medicine extract, 10% of citric acid, 10% of sodium bicarbonate, 2% of polyethylene glycol and 5% of boric acid.

Example 5

The private effervescent tablet for external use comprises, by mass, 50% of salt, 6% of phellodendron bark extract, 6% of radix sophorae flavescentis extract, 4% of fructus cnidii extract, 4% of wild chrysanthemum flower extract, 3% of peppermint extract, 10% of citric acid, 10% of sodium bicarbonate, 2% of polyethylene glycol and 5% of boric acid.

Example 6

A method for preparing a private topical effervescent tablet, comprising the steps of:

s1: respectively pulverizing salt, chinese medicinal extract, citric acid, sodium bicarbonate, polyethylene glycol and boric acid, sieving, and weighing according to formula; in the formula, the content of salt is 45-55% by mass percent;

Example 7

s1: respectively crushing salt, a traditional Chinese medicine extract, citric acid, sodium bicarbonate, polyethylene glycol and boric acid, sieving with a 50-mesh sieve, weighing the traditional Chinese medicine extract 21-25%, the citric acid 8-12%, the sodium bicarbonate 8-10%, the polyethylene glycol 1-3% and the boric acid 3-6% according to the formula of 45-55% of salt, and respectively for later use; wherein, the granularity of the salt is controlled to be 0.42 mm-0.85 mm, and the granularity of the traditional Chinese medicine extract, the citric acid, the sodium bicarbonate and the boric acid is controlled to be 0.15 mm-0.18 mm

S2: uniformly mixing salt, a traditional Chinese medicine extract and boric acid, and dividing the main material mixture into a main material mixture A and a main material mixture B according to a mass ratio of 1:1; dissolving polyethylene glycol with 80% ethanol to obtain a lubricant, and dividing the lubricant into two parts of lubricant C and lubricant D according to the mass ratio of the main material mixture A to the main material mixture B, namely 1:1;

s3: adding citric acid and a lubricant C into the main material mixture A, uniformly mixing to prepare a soft material, sieving with a 18-mesh sieve, granulating, and drying at 45-55 ℃ for 2.5-4 h to prepare acid mixture particles; adding sodium bicarbonate and a lubricant D into the main material mixture B, uniformly mixing to prepare a soft material, sieving with a 18-mesh sieve, granulating, and drying at 45-55 ℃ for 2.5-4 h to prepare alkali mixture particles;

s4: the acid mixture particles and the alkali mixture particles are uniformly mixed, and then pressed into tablets under the pressure of 0.7-0.11 Mpa.

Example 8

s1: respectively crushing and sieving salt, chinese medicinal extract, citric acid, sodium bicarbonate, polyethylene glycol and boric acid, weighing 50% of salt, 6% of cortex phellodendri extract, 6% of radix sophorae flavescentis extract, 4% of fructus cnidii extract, 4% of wild chrysanthemum extract, 3% of mint extract, 10% of citric acid, 10% of sodium bicarbonate, 2% of polyethylene glycol and 5% of boric acid according to a formula, and respectively standby;

s2: mixing salt, chinese medicinal extracts (i.e. cortex Phellodendri extract, radix Sophorae Flavescentis extract, fructus Cnidii extract, flos Chrysanthemi Indici extract, herba Menthae extract) and boric acid uniformly, and dividing the main material mixture into main material mixture A and main material mixture B at a mass ratio of 1:1; dissolving polyethylene glycol with 80% ethanol to obtain a lubricant, and dividing the lubricant into two parts of lubricant C and lubricant D according to the mass ratio of the main material mixture A to the main material mixture B, namely 1:1;

s3: adding citric acid and lubricant C into the main material mixture A, uniformly mixing to prepare a soft material, sieving with a 18-mesh sieve, granulating, and drying at 50 ℃ for 3 hours to prepare acid mixture particles; adding sodium bicarbonate and lubricant D into the main material mixture B, mixing uniformly to prepare a soft material, sieving with 18 mesh sieve, granulating, and drying at 50deg.C for 3 hr to obtain alkali mixture particles;

s4: the acid mixture particles and the alkali mixture particles were uniformly mixed, and then compressed under a pressure of 0.9Mpa.

Example 9

Comparison of wet granulation acid base granulation alone and acid base mix granulation process.

1. Experimental method

1) Acid-base mixed granulating

Salt, phellodendron extract, kuh-seng extract, cnidium fruit extract, wild chrysanthemum flower extract, peppermint extract, citric acid, sodium bicarbonate and boric acid are respectively weighed and crushed according to the formula of the example 8, then are uniformly mixed, polyethylene glycol ethanol solution (ethanol with the volume fraction of 80 percent is used for dissolving ethylene glycol) is added as a lubricant, wetting is carried out, a soft material is prepared, the soft material is sieved by a 18-mesh sieve, and is granulated, dried for 3 hours at the temperature of 50 ℃, and then tabletting is carried out under the condition that the pressure is 0.9Mpa.

2) Acid-base independent granulation

An effervescent tablet was prepared as in example 8.

2. Experimental results

The two processes were evaluated using indexes such as disintegration time, hardness, foaming amount, and viscosity-impact degree, and the results are shown in the following table.

Table 1 comparison of acid-base granulation alone and acid-base mix granulation process

As can be seen from table 1, by comparing the foaming amount, disintegration time, hardness and viscosity of the two processes, the results show that the acid-base mixture granulation is adopted, and a small amount of water in the solvent ethanol easily causes the advanced neutralization of acid and base, thereby reducing the amount of acid and base, further prolonging the disintegration time, so that the acid-base single granulation is more suitable.

Example 10

The application discloses screening of acid source, alkali source and lubricant of private external effervescent tablets.

1. Selection of acid sources

Alternative acid sources are citric acid and tartaric acid. The citric acid has good water solubility and antioxidation, but has strong hygroscopicity and is easy to be stuck and washed; tartaric acid has good water solubility and stronger acidity than citric acid and weaker hygroscopicity than citric acid, so equal amounts of citric acid and tartaric acid are respectively mixed with salt and the traditional Chinese medicine extract, and a proper amount of sodium bicarbonate is added, so that hygroscopicity of the mixed powder is inspected, and the disintegration time limit and the foaming amount of the prepared granules are inspected. The experimental results are as follows:

table 2 acid source investigation of effervescent tablets

Acid source	Disintegration time/min	Foaming amount/mg/tablet
			Citric acid	5.2	100.2
Tartaric acid	6.3	84.2

As can be seen from table 2, when citric acid and tartaric acid are used as acid sources, respectively, the effervescent tablets prepared with citric acid as acid source disintegrate faster and foam more, so citric acid is preferred as acid source in the present application.

2. Selection of the alkali source

The most commonly used alkali sources are sodium bicarbonate, sodium carbonate, potassium carbonate and potassium bicarbonate, but potassium carbonate and potassium bicarbonate are expensive, and sodium carbonate requires a larger amount to neutralize the same amount of acid than sodium bicarbonate, so sodium bicarbonate is selected as the alkali source of the present study.

3. Lubricant selection

The most commonly used lubricants of the effervescent tablet are polyethylene glycol, silicon dioxide, magnesium stearate, sodium dodecyl sulfonate and the like, and the lubricating agents are adopted in the embodiment, and the appearance, the safety, the steam pocket phenomenon, the insoluble substances and the sticking degree are taken as investigation indexes for investigation, and the results are shown in the following table.

TABLE 3 comparison of Performance of different lubricants

As shown in Table 3, the experiment shows that polyethylene glycol is better in water solubility, non-sticking, smooth in appearance and better in safety than other lubricants, so that polyethylene glycol is selected as the lubricant.

Example 11

The application discloses screening of the dosage of citric acid, sodium bicarbonate, extract and polyethylene glycol of a private external effervescent tablet.

The test shows that the best proportion of effervescent agent (citric acid and sodium bicarbonate), chinese medicinal extract and polyethylene glycol 6000 is optimized by orthogonal test, L is selected ₉ (3 ⁴ ) Orthogonal table experiments were performed with the protocols shown in table 4 and the results shown in table 5.

TABLE 4 level of orthogonal test factors

Horizontal level	Citric acid/%	B sodium bicarbonate/%	C extract/%	D polyethylene glycol/%
					1	8	8	21	1
2	10	9	23	2
					3	12	10	25	3

TABLE 5 results of orthogonal test table

As can be seen from Table 5, the lower the disintegration time of the effervescent tablet, the better the pH for the skin mucosa, which is in the range of 5.5 to 6.0, whereas the higher the hardness of the tablet. As is clear from Table 5, A3 is preferable because the higher the citric acid content is, the faster the disintegration is, A1B3 is preferable because the pH is larger in relation to the amount of citric acid and sodium bicarbonate added, A1B3 is preferable because the hardness is larger in relation to the amount of extract added, and C2D2 is preferable because the effect of the amount of polyethylene glycol added on the hardness is greatest. In view of the fact that the addition of citric acid affects both acidity and disintegration, the addition of citric acid needs to be comprehensively considered, so that the disintegration time limit, pH and hardness are used as evaluation indexes for comprehensive evaluation, and an optimal formula is determined. The scoring criteria are shown in table 6.

Table 6 scoring criteria for each index

TABLE 7 results of orthogonal test table

As can be seen from tables 6 and 7, the three indexes of disintegration time limit, pH and hardness are comprehensively examined, and the primary and secondary order of influence of each factor on the scoring index is D>A>B>C, the optimal combination is A ₂ B ₃ C ₂ D ₂ 。

For the effervescent tablet prepared under the optimal combination condition, the effervescent tablet prepared by the optimal formulation of 50% of salt, 23% of traditional Chinese medicine extract, 10% of citric acid, 10% of sodium bicarbonate, 5% of boric acid and 2% of polyethylene glycol is subjected to disintegration test (the average tablet weight of the effervescent tablet is 5.0 g), and the effervescent tablet has the disintegration time limit of 3.25min, the pH value of 5.6 and the hardness of 30.2kg.

Example 12

The preparation process parameters of the private external effervescent tablet are optimized.

1. Preparation process of effervescent tablet

S1: according to the formula of 50% of salt, 6% of phellodendron extract, 6% of kuh-seng extract, 4% of cnidium fruit extract, 4% of wild chrysanthemum extract, 3% of peppermint extract, 10% of citric acid, 10% of sodium bicarbonate and 5% of boric acid, respectively weighing the above raw materials, pulverizing and sieving for later use;

s2: uniformly mixing salt, a traditional Chinese medicine extract and boric acid, and dividing the main material mixture into a main material mixture A and a main material mixture B according to a mass ratio of 1:1; dissolving ethylene glycol with 80% ethanol by volume fraction as a lubricant according to a formula, and then dividing the lubricant into two parts of lubricant C and lubricant D according to the mass ratio of the main material mixture A to the main material mixture B, namely 1:1;

2. Selection of drying temperature and time

The soft material prepared by adopting the wet granulation can be subjected to the next operation after being subjected to the drying treatment, and the drying temperature and the drying time are two factors influencing the quality of the particles. As for the drying temperature, since sodium bicarbonate is present such that the temperature is not higher than 60 ℃, otherwise the sodium bicarbonate is decomposed by heat, the drying temperature of this embodiment selects 45 ℃,50 ℃,55 ℃ as an alternative drying temperature.

Table 8 semi-finished product drying temperature investigation table

From the above table, the drying temperature of 50 ℃ or the drying time of 3 hours or the drying temperature of 55 ℃ is selected, the moisture content of the particles tends to be stable after the drying time of 3 hours, and no significant change occurs, and meanwhile, the drying temperature of 50 ℃ is selected for 3 hours in consideration of the fact that the higher the temperature is, the easier the decomposition of carbon dioxide is caused.

3. Inspection of the ethanol usage of wetting agent

The wet granulation adopts ethanol solution as wetting agent, and the effect of the ethanol solutions with different ethanol contents on the granulation is larger, and the embodiment examines the effect of 60%,70%,80% and 90% ethanol solution on the wet granulation process, and screens the optimal ethanol proportion by taking the viscosity of soft materials and the appearance of granules as evaluation indexes.

TABLE 9 optimal ethanol ratio screening of wetting agents

Ethanol ratio/%	Viscosity of soft material	Particle appearance
			60％	+++	Non-uniform color
70％	++	Non-uniform color
			80％	+	The color is relatively uniform
90％	-	The color is relatively uniform

From the above table, it can be seen that when 60% and 70% ethanol is used as wetting agent for wet granulation, the soft material is too viscous to be sieved and granulated, and the color difference of the dried acid-base mixture is large. When 80% ethanol is adopted as a wetting agent for granulating, the soft material has moderate viscosity, the granulating effect is good, and the color difference of the dried acid-base mixture is small. When 90% ethanol is adopted as a wetting agent for granulation, the soft material has smaller viscosity, and the fine powder is more during sieving and granulating. 80% ethanol was chosen as the wetting agent.

4. Effervescent tablet tabletting pressure parameter investigation

The pressure of the effervescent tablet tablets in this example is examined in the following table.

Table 10 effervescent tablet compression pressure investigation

pressure/MPa	Friability/%	Hardness/kg	Disintegration time/min
				0.7	1.3	28.1	4.2
0.9	0.90	30.2	4.3
				1.1	0.85	32.3	4.6

As can be seen from the above table, when a tabletting pressure of 0.7MPa is adopted, the tablet hardness is insufficient, the friability is more than 1%, the tablet quality is unqualified, when a tabletting pressure parameter of 1.1MPa is adopted, the tablet friability and hardness are better, but the disintegration time is slightly longer than that of tablets adopting 0.7MPa and 0.9MPa, and when a tabletting pressure of 0.9MPa is adopted, the tablet friability, hardness and disintegration time are better, so the tabletting pressure parameter is selected to be 0.9MPa.

Example 13

Influence of the particle size of the raw materials on the preparation of effervescent tablets.

Experimental group: the granularity of raw materials and auxiliary materials is controlled to be in the same granularity range, specifically, raw materials and auxiliary materials of a formula (the raw materials and auxiliary materials can be crushed according to the requirement) are respectively sieved by a 80-mesh sieve, a 100-mesh sieve, a 40-mesh sieve, a 80-mesh sieve, a 20-mesh sieve and a 40-mesh sieve, and intermediate materials obtained by sieving twice are collected to prepare raw materials and auxiliary materials with three granularity levels of small granularity, medium granularity and large granularity, wherein the granularity ranges of the raw materials and the auxiliary materials are 0.15mm to 0.18mm, 0.18mm to 0.42mm, 0.42mm to 0.85mm, and the raw materials and the auxiliary materials are respectively prepared into effervescent tablets according to the embodiment 8;

comparison group: the original physical properties of the raw materials and the auxiliary materials of the formula are maintained without controlling the granularity of the raw materials and the auxiliary materials, and the raw materials and the auxiliary materials are not crushed and sieved, so that the effervescent tablet is prepared according to the embodiment 8; specifically, the salt is granular, meets the corresponding national standard, and the granularity of the salt is 85% in proportion of 0.15-0.85 mm; the plant extract is in powder form and passes through a 40-mesh sieve; the citric acid is crystalline powder with granularity of 30-100 meshes, namely 0.11-0.60 mm; boric acid is white crystalline powder with granularity smaller than 0.15mm; the sodium bicarbonate is white crystalline powder with granularity of 20-120 meshes, namely 0.124-0.85 mm; the method comprises the steps of carrying out a first treatment on the surface of the

The effervescent tablets prepared in the above comparative and experimental groups were examined using appearance, hygroscopicity, hardness and disintegration as examination indexes, and the results are shown in the following table.

Table 11 particle size selection comparison

As can be seen from table 11, although salt, the extract of the Chinese medicine, citric acid, sodium bicarbonate and boric acid are in powder or granule form and have smaller particle sizes, experiments show that if the particle sizes of the raw materials and the auxiliary materials are not controlled, the prepared effervescent tablet has unstable disintegration time, and has poorer appearance (serious chromatic aberration) and hardness indexes than those of the effervescent tablet of the group (particle size control of the raw materials and the auxiliary materials), so the particle sizes of the raw materials and the auxiliary materials are required to be controlled; however, although the performance and quality of the prepared effervescent tablet are improved after the granularity of the raw and auxiliary materials is controlled, the problem that, for example, the raw and auxiliary materials with small granularity are easy to stick and wash when the effervescent tablet is prepared, the product is easy to absorb moisture (especially salt is easy to absorb moisture and agglomerate) in the environment with high humidity, and the product is not easy to store still exists; when the large-granularity raw and auxiliary materials are used for preparing effervescent tablets, the tablets are not smooth enough, and the color difference between the tablets is obvious; when preparing the discon tablet, the above defects are not obvious but still can not reach the ideal state compared with the small-granularity and large-granularity raw and auxiliary materials. Based on the above, it is difficult to prepare effervescent tablets with stable and excellent quality by adopting a conventional method, namely, controlling the particle sizes of raw materials and auxiliary materials to be in the same particle size range.

Because the content of the salt in the product formula is up to 45% -55%, and the salt does not have other processing properties, the salt cannot replace the effect of a conventional filling agent in preparing effervescent tablets, but rather, the preparation difficulty of the product and the uncertainty of improving the quality of the product are only increased by adding a large amount of salt; based on the above difficulties, the applicant tried to control the salt particle size alone and control the particle sizes of the traditional Chinese medicine extract, citric acid, sodium bicarbonate and boric acid alone under the condition that the salt accounts for about 50% of the product formula, and then prepared effervescent tablets based on the above, and the specific experimental method is as follows:

and (3) raw material and auxiliary material treatment: salt (which can be crushed according to the need) is respectively sieved by 80 meshes and 100 meshes, 40 meshes and 80 meshes, 20 meshes and 40 meshes, and the intermediate of the two sieves is collected to prepare small-granularity, medium-granularity and large-granularity salt with granularity ranging from 0.15mm to 0.18mm, 0.18mm to 0.42mm and 0.42mm to 0.85mm; the traditional Chinese medicine extract, citric acid, sodium bicarbonate and boric acid (the raw materials can be crushed according to the requirement) are respectively sieved by a 80-mesh sieve and a 100-mesh sieve, a 40-mesh sieve and a 80-mesh sieve, a 20-mesh sieve and a 40-mesh sieve, and intermediate products obtained by sieving twice are collected to prepare raw materials with three granularity levels of small granularity, medium granularity and large granularity, wherein the granularity ranges from 0.15mm to 0.18mm, from 0.18mm to 0.42mm and from 0.42mm to 0.85mm; the above three particle size grades of table salt were used in combination with the above three particle size grades of raw materials (Chinese medicinal extract, citric acid, sodium bicarbonate and boric acid), effervescent tablets were prepared according to example 8, and the above prepared effervescent tablets were examined with respect to appearance, hygroscopicity, hardness and disintegration as examination indexes, and the results are shown in the following table.

Table 12 salt particle size selection

As is clear from Table 12, it was found through experiments that the salt had a large particle size of 0.42mm to 0.85mm because the salt had a lower hygroscopicity and a shorter disintegration time when the salt had a large particle size, but the difference in hardness and appearance was not significant. Experiments show that the salt with the large granularity of 0.42-0.85 mm is adopted, and the other raw and auxiliary materials with the small granularity have lower hygroscopicity, shorter disintegration time, higher hardness and better appearance, so the other auxiliary materials with the small granularity of 0.15-0.18 mm are selected. Thus, if the granularity of the salt is controlled to be 3-5 times of the granularity of other raw materials (the traditional Chinese medicine extract, the citric acid, the sodium bicarbonate and the boric acid), namely, the granularity of the salt is controlled to be 0.42-0.85 mm, and the granularity of the traditional Chinese medicine extract, the citric acid, the sodium bicarbonate and the boric acid is controlled to be 0.15-0.18 mm, the effervescent tablet with better quality can be prepared.

Example 14

In the embodiment, the eye irritation of the product is inspected by adopting a chick embryo chorioallantoic membrane test method, so that the safety and effect of the product are evaluated. The test was performed with reference to "cosmetic eye irritation/corrosiveness chick embryo chorioallantoic membrane test" (SN/T2329-2009).

1. Basic principle of

The chick embryo chorioallantoic membrane assay is an in vitro evaluation of ocular irritation that has been used earlier, and chorioallantoic membrane (CAM) is a respiratory membrane surrounding chick embryos. The test utilizes the characteristics of complete, clear and transparent chorioallantoic membrane vascular system in the middle period of the hatched chick embryo, a certain amount of the test object is directly contacted with the chick embryo allantoic membrane, and changes of chorioallantoic membrane toxicity effect indexes (such as bleeding, coagulation and vascular thawing) are observed after a period of action, the indexes reflect changes of morphological structures, colors and permeability of blood vessels and vascular networks, and reflect phenomena such as chorioallantoic membrane protein denaturation and the like and damage degree thereof, and then a score is obtained by combining the results, so that the eye irritation of the test object is evaluated. The purpose of this test is to test the ability of the test subject to cause changes in chick embryo chorioallantoic membrane toxicity, and the criteria describe the elements and processes for evaluating the potential ocular irritation of the substance being evaluated to evaluate the safety and irritation of the product.

2. Experimental method

2.1 preparation of chick embryo

2.1.1 lines and sources

The SPF eggs of Bai Laihang chickens are selected, the quality of the eggs meets the requirements of related standards, and suppliers have the qualification of experimental animal production licenses, animal epidemic prevention condition qualifications and SPF egg out-of-range inedible animal products production, processing and storage enterprises for inspection, quarantine and registration qualifications.

2.1.2 preparation of chick embryo

9-day-old chick embryo with the relative humidity of 45-70 percent at the room temperature of 20-25 ℃. The incubation temperature is 37.8+/-0.3 ℃, the relative humidity is 55% -70%, and the eggs are turned by rotating the rod for 1/2 h.

2.1.3CAM preparation

Checking 9-day-old chick embryos by irradiating eggs, and marking the positions of air chambers on the surfaces of the eggshells; the marked eggshell portion was stripped with dental saw tooth forceps to expose the white eggshell membrane, taking care not to disrupt the eggshell membrane integrity. A few mL of 0.9% sodium chloride (NaCl) solution is dripped into the incubator by a straw to moisten the egg membrane, and the next operation can be immediately performed, otherwise, the chick embryo is placed under an incubator or light (preventing the temperature of the chick embryo from being reduced) and the placing time is not longer than 20min. The 0.9% sodium chloride solution was poured out. The intima was carefully removed with forceps, ensuring that the vessel membrane was not damaged. At this point the structure of the vascular system should be reviewed and a determination made as to its integrity and suitability for testing.

2.2 materials and apparatus deionized water, glassware, pH paper, forceps, microscale sample applicator, and Disposable adapter tip, stereomicroscope

2.3 test pieces and preparation thereof

2.4 control and preparation

2.4.1 negative control

Sodium chloride solution with the mass concentration of 0.9% is selected for washing and negative control after the test object acts.

2.4.2 solvent control

Deionized water was used as a control substance.

2.4.3 Positive control

Sodium lauryl sulfate 2%, sodium hydroxide 0.2%, sodium hydroxide 0.3%, acetic acid 0.3% and acetic acid 3% were used as positive controls.

3. Test procedure

3.1 Pre-test

Pre-test 3 chick embryos were used, 0.3mL undiluted liquid test pieces were taken, and solid test pieces were used in an amount to ensure coverage of at least 50% of the CAM surface. Immediately after the test substance was applied, the CAM reaction was observed for 5min, and the observation was recorded. If the sample is a solid or turbid liquid, the sample is washed with physiological saline after a certain period of time (e.g., 3 min), and the observation result is recorded. The reactivity of each batch of chick embryos should be checked before the pre-test, at least 2 chick embryos should be tested at a time, and the action time should be limited to 5 minutes.

3.2 formal test

3.2.1 test group

Each group had 6 embryos, and if necessary, 1 chicken embryo each should be additionally provided with positive material (reference material) and solvent control.

3.2.2 reaction time method

For transparent liquid test subjects. The detection of turbid solutions or solid test substances can be carried out by selecting the highest concentration transparent solution dissolved/diluted by a proper solvent. And (3) taking 0.3mL of the transparent liquid, directly dripping the transparent liquid on the surface of the CAM, observing the condition of CAM reaction, and recording the occurrence time of each toxic effect within 5 minutes of action.

4. Results and evaluation

4.1 stimulation scoring method

The test performed using the reaction time method, the stimulus score (IS) was calculated using formula (1), and the results remained two bits after the decimal point:

wherein: sec H (time to bleed) -the average time in seconds (S) at which bleeding is observed to begin on the CAM film; sec L (vascular thawing time) -the average time in seconds (S) at which onset of vascular thawing is observed on the CAM membrane; the average time in seconds (S) for the onset of clotting was observed on the Sec C (clotting time) -CAM membrane.

The subject eye irritation IS classified according to table 13 based on the calculated IS values.

TABLE 13 evaluation of results of stimulation scoring

Stimulation scoring	Irritation classification
		IS＜1	No irritation
1≤IS＜5	Light irritation
		5≤IS＜9	Moderate irritation
IS≥10	Strong irritation/corrosiveness

4.2 test acceptability criteria

Test results are considered acceptable if the negative and positive controls set up by the test produce a response well within the classification of non-irritating and strongly irritating, respectively.

4.3 test results

According to the method, 17 test pieces were tested, and the test results were evaluated by a reaction time method, and the results are shown in the following table.

TABLE 14 results of examination of chick embryo chorioallantoic membrane test

As can be seen from Table 14, the solvent control and the negative control were not stimulated (see FIGS. 2-5). Sodium lauryl sulfate (SDS) at 2%, sodium hydroxide at 0.2%, sodium hydroxide at 0.3%, acetic acid at 0.3% and acetic acid at 3% were used as positive control solutions, wherein SDS at 2% was strongly stimulated and resulted in vascular bleeding and vascular lysis of CAM (see FIGS. 6-7), sodium hydroxide at 0.3% resulted in vascular bleeding and clotting of CAM (see FIG. 8), and acetic acid at 3% resulted in cloudiness of CAM membrane (see FIG. 9).

By examining the irritation of sodium chloride with different concentrations, the result shows that when the concentration of sodium chloride is lower than 2%, the sodium chloride is light-irritation, and the local coagulation in the CAM capillary and small blood vessels is embodied, namely, the hypertonic saline with proper concentration can shrink the capillary and cause the local coagulation of the capillary and small blood vessels, but the medium blood vessels and the large blood vessels are not influenced (see figures 12-13); in addition, the hypertonic saline can dehydrate cells, is favorable for recovering the function of a sodium pump of a cell membrane and balancing the concentration of ions inside and outside the cells, so that the edema pain caused by hemorrhoids can be relieved to a certain extent; whereas when the sodium chloride concentration was 5%, it was a moderate stimulus, and when the sodium chloride concentration was higher than 15%, it was a strong stimulus (see fig. 12-15).

At an extract concentration below 2.4%, the solution was non-irritating. The mass concentration of the disintegrating agent is lower than 1.5%, so that the disintegrating agent is non-irritating. The solution had light irritation at chlorhexidine acetate concentrations above 0.05% and strong irritation at solutions above 0.1% (see figures 18-20).

Chlorhexidine acetate is a common additive used as a bacteriostatic component of external lotions, and the additive amount is higher than 0.05% of the use concentration, so that extravascular blood coagulation (which is manifested as turbidity of CAM membrane and dissolution of blood vessel) is easy to occur. The chlorhexidine acetate has strong irritation and is a chemically synthesized bactericidal component, so the chlorhexidine acetate is not added into the product.

The tablet has no stimulus at a concentration of less than 5g-200mL, light stimulus at a concentration of 5g-100mL, and moderate stimulus at a concentration of 5g-50mL, so it is recommended that the tablet has a concentration of not more than 5g-100mL (see FIGS. 10-11, 16-17). The main antibacterial components of the product adopt natural plant extracts and natural mineral salts, and under proper use concentration, the product can furthest reduce the injury and the irritation of the product to a user, and has better effects of relieving and nursing edema pain caused by hemorrhoids and pruritus vulvae of men and women.

Example 14

The application method of the private external effervescent tablet comprises the following steps: for external use, the effervescent tablet is taken and dissolved in warm water (5-10 tablets are dissolved in 1L of warm water, 5 g/tablet). Hip bath, or washing anus or vulva. Can be used for cleaning and nursing during the onset of hemorrhoids; or for vulvar cleaning care.

Claims

1. The private effervescent tablet for external use is characterized in that the formula raw materials comprise, by mass, 45% -55% of salt, 21% -25% of traditional Chinese medicine extract, 8% -12% of citric acid, 8% -10% of sodium bicarbonate, 1% -3% of polyethylene glycol and 3% -6% of boric acid; the Chinese medicinal extract is cortex Phellodendri extract, radix Sophorae Flavescentis extract, fructus Cnidii extract, flos Chrysanthemi Indici extract, and herba Menthae extract; the preparation method comprises the following steps:

s1: weighing salt, chinese medicinal extract, citric acid, sodium bicarbonate, polyethylene glycol and boric acid according to the formula, and respectively keeping for later use; wherein, the granularity of the salt is controlled to be 0.55 mm-0.83 mm, and the granularity of the traditional Chinese medicine extract, the citric acid, the sodium bicarbonate and the boric acid is controlled to be 0.15 mm-0.18 mm;

s2: uniformly mixing salt, a traditional Chinese medicine extract and boric acid, and dividing a main material mixture into two parts of a main material mixture A and a main material mixture B; dissolving polyethylene glycol with 80% ethanol to obtain a lubricant, and dividing the lubricant into a lubricant C and a lubricant D according to the mass ratio of the main material mixture A to the main material mixture B;

s3: adding citric acid and lubricant C into the main material mixture A, uniformly mixing to prepare a soft material, sieving, granulating and drying to prepare acid mixture particles; adding sodium bicarbonate and lubricant D into the main material mixture B, uniformly mixing to prepare a soft material, sieving, granulating and drying to prepare alkali mixture particles; wherein the drying parameter is temperature 45-55 ℃ and time 2.5-4 h;

s4: the acid mixture particles and the alkali mixture particles are uniformly mixed, and then the mixture is tabletted, wherein the pressure controlled by the tableting is 0.7-0.11 Mpa.

2. The private effervescent tablet for external use according to claim 1, wherein the formula comprises, by mass, 50% of table salt, 23% of a traditional Chinese medicine extract, 10% of citric acid, 10% of sodium bicarbonate, 2% of polyethylene glycol and 5% of boric acid.

3. The private effervescent tablet for external use according to claim 2, wherein the formula raw materials of the effervescent tablet comprise, by mass, 50% of table salt, 6% of phellodendron bark extract, 6% of kuh-seng extract, 4% of cnidium fruit extract, 4% of wild chrysanthemum flower extract, 3% of peppermint extract, 10% of citric acid, 10% of sodium bicarbonate, 2% of polyethylene glycol and 5% of boric acid.

4. A private topical effervescent tablet as claimed in claim 1, wherein in step S2 the mass ratio of the main ingredient mixture a to the main ingredient mixture B is 0.8-1.2:1.