CN101152165A - An anti-tumor isoliquiritigenin tablet - Google Patents

Abstract

The invention discloses an anti-tumor isoliquiritigenin tablet. The isoliquiritigenin is used as an active ingredient to prepare anti-tumor tablets. It is composed of isoliquiritigenin, filler, binder, disintegrant, wetting agent and lubricant in a certain proportion, and has a reasonable formula and is convenient to use. The obtained pharmaceutical composition has good antitumor effect, and the formula is reasonable, the effect is good, and the toxic and side effects are few.

Description

An anti-tumor isoliquiritigenin tablet

technical field

The invention relates to the field of pharmacy, in particular to an anti-tumor isoliquiritigenin tablet. Suitable for human cervical cancer cells, prostate cancer cells, S ₁₈₀ tumor line, Ehrlich ascites cancer cells, human A549 lung cancer cells, oral epidermal cancer KB cells, KM-12 colon cancer cells, BEL-7402 liver cancer cells and MCF-7 breast cancer cells cancer cell.

Background technique

1. Tumor has become the number one killer threatening human health

Tumor is one of the common and frequently-occurring diseases that seriously threaten human life, and its incidence rate is increasing year by year. According to the survey of the World Health Organization, nearly 10 million cancer patients are newly discovered every year in the world. Nearly 7 million people die from cancer every year. Recent statistics show that about 20 million cancer patients are newly discovered in my country every year, and nearly 1.5 million people die of cancer. Cancer deaths account for 1/5 of all deaths. Therefore, cancer prevention and treatment have become an urgent and arduous task.

2. Currently, there are many methods for treating tumors, but all of them have certain limitations

Traditional methods of treating tumors include surgical resection, radiation therapy, and chemotherapy. However, for many patients, they may have lost the chance of surgical resection when they are diagnosed as tumors; while radiotherapy has local limitations and damage to normal tissues; chemicals (drugs) generally have cytotoxic effects, especially Serious side effects on liver, kidney, bone marrow and digestive system, therefore, greatly restricting their clinical use. Emerging interventional therapy has a certain effect on the primary tumor, but it is difficult to deal with the constantly sporadic metastases; modern molecular targeted (gene) therapy has brought hope to cancer patients, but the vector construction, cross-linking of the vector and the warhead and the Many issues such as its distribution in the body and changes in the metabolic process are still under discussion.

3. Antitumor effect of flavonoids

Flavonoids are a class of polyphenolic compounds that are widely found in a variety of green vegetables, fruits and medicinal plants. In recent years, the role of flavonoids in maintaining normal physiological functions of the human body and preventing and treating diseases has received extensive attention. Epidemiological surveys have shown that regular intake of vegetables and fruits rich in flavonoids can reduce the incidence of cancers such as lung cancer, colorectal cancer and breast cancer (Armstrong B, Doll R. Environmental factors and cancer incidence and mortality in different countries, With special reference to dietary practices [J]. Int J Cancer. 1975, 15(4): 617-631.). Because the anti-tumor activity of flavonoids often has the characteristics of high efficiency and low toxicity, many developed countries such as the United States are constantly screening for the anti-tumor effects of flavonoids.

The discovery that flavonoids have anti-tumor effects has prompted people to try to prepare tumor chemical drugs from natural plants. So far, the research results are encouraging: (1) flavonoids inhibit cell proliferation, mainly stop the cell cycle, and have cytotoxic effect on tumor cells, but have no toxic and sudden-induced effects on normal cells, but have Antioxidant and positive immune regulation; (2) flavonoids promote tumor cell apoptosis; (3) flavonoids can inhibit tyrosine protein kinase, protein kinase C, phosphatidylinositol in the process of cell signal transduction -3 kinase activity; (4) flavonoids have anti-inflammatory, anti-oxidative stress and promote the expression of tumor suppressor genes and inhibit the expression of oncogenes. At present, the screening of flavonoids for anti-tumor effect is still going on. my country is a country with rich resources of Chinese herbal medicines. It is our advantage to fully develop flavonoids to serve human health.

Isoliquiritigenin is an effective monomer in licorice, which belongs to flavonoids, and has biological activities such as anti-tumor, anti-virus, anti-free radical, and inhibition of lipid peroxidation (Ii T, Satomi Y, Katoh D, et al. Induction of cell cycle arrest and p21CIP1/WAF1 expression in human lung cancer cells by isoliquiritigenin[J]. Cancer Lett, 2004, 207(1): 27-35; Haraguchi H, Ishikawa H, Mizutani K, et al. Antioxidative and superoxide activating its scavengies of retrochalcones in Glycyrrhiza inflata. [J]. Bioorg Med Chem, 1998, 6(3): 339-347). In recent years, foreign literature has reported that isoliquiritigenin can inhibit the proliferation of various tumor cells such as lung cancer, breast cancer and prostate cancer (Kanazawa M, Satomi Y, Mizutani Y, et al. Isoliquiritigenin inhibits the growth of prostate cancer[J]. Eur Urol, 2003, 43(5): 580-586; Hsu YL, Kuo PL, Chiang LC, et al. Isoliquiritigenin inhibits the proliferation and induces the apoptosis of humannon-small cell lung cancer A549 cells[J]. Clin Exp Pharmacol Physiol, 2004, 31(7):414-418). In addition, our research also shows that ISL can inhibit the proliferation of cervical cancer cells (Zhang Jing, et al. The inhibitory effect of isoliquiritigenin on the proliferation of human cervical cancer cells. Chinese Journal of Pharmacology and Toxicology, 2005, 19 (6): 436 -442).

However, so far, no preparation methods of oral preparations such as isoliquiritigenin anti-tumor tablets or capsules have been disclosed or used.

Contents of the invention

The object of the present invention is to provide an anti-tumor isoliquiritigenin tablet, which is composed of isoliquiritigenin, fillers, binders, disintegrating agents, wetting agents, lubricants in a certain proportion, the formula is reasonable, and it is easy to use Convenient, non-toxic to human body, non-irritating, safe to use and good effect.

Isoliquiritigenin (ISL), whose chemical structure is 2', 4', 4'-trihydroxychalcone, is an effective monomer in licorice, and belongs to flavonoids (see I for the chemical structure formula), It has biological activities such as anti-tumor, anti-virus, anti-free radical, and inhibition of lipid peroxidation. In recent years, it has been reported in the literature that ISL can inhibit the proliferation of various tumor cells such as lung cancer, breast cancer, prostate cancer and cervical cancer. However, so far, no preparation method of isoliquiritigenin anti-tumor tablet has been disclosed or used.

The molecular structure of isoliquiritigenin is:

Sources of isoliquiritigenin: Isoliquiritigenin has a wide range of sources, which can be chemically synthesized or isolated and extracted from licorice, and can be purchased in the market.

The invention uses isoliquiritigenin to prepare anti-tumor tablets. Adopt following technical scheme in order to realize the present invention: this tablet is made by weight percentage of following raw material;

Raw material % by weight (%)

Isoliquiritigenin 10～15

Filler 71～85

Adhesive 1～8

Disintegrant 1～8

Wetting agent 1～6

Lubricant 1～2

Its preparation steps are as follows:

① Add excipients: add filler, binder and disintegrant respectively to isoliquiritigenin, then add wetting agent and mix well to make soft material;

② Granulation: Pass the mixed soft material through a 50-200 mesh nylon sieve to granulate, dry at 70-80°C for 30 minutes, pass through a 50-200 mesh iron sieve for granulation;

③ Tablet compression: adding a lubricant to compress the tablet to make a tablet.

The filler is one of starch, dextrin, powdered sugar, pregelatinized starch, lactose, glucose, microcrystalline cellulose, calcium carbonate, calcium sulfate, calcium bicarbonate or other pharmaceutically acceptable fillers Or two to ten of them or any combination;

The binder is one of liquid glucose, gum arabic, gelatin, hydroxymethylcellulose, low-substituted hydroxypropylcellulose or other pharmaceutically acceptable binders or two to five of them or any combination;

The disintegrating agent is croscarmellose sodium, crospovidone, sodium carboxymethyl starch, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, citric acid, tartaric acid, acid anhydride, bicarbonate One of sodium, sodium carbonate or other pharmaceutically acceptable disintegrants or any combination of two to nine of them;

Described wetting agent is water, ethanol or its combination;

The lubricant is one of magnesium stearate, talcum powder, liquid paraffin, polyethylene glycol or other pharmaceutically acceptable lubricants or any combination of two to four of them.

Advantages of the present invention:

1. Isoliquiritigenin has a wide range of sources. It can be chemically synthesized or isolated and extracted from licorice, and it is available in the market.

2. The present invention adopts a conventional oral dosage form, has mature technology, and simple and easy production process.

3. The present invention adopts an oral administration mode, which is convenient and painless.

4. The isoliquiritigenin tablet has little toxic and side effects on the human body and is safe to use. The tumor inhibition rate can reach 47.3-74.9%, and the effect is good.

5. The isoliquiritigenin tablet used in the present invention not only has obvious anti-tumor effect but also has obvious detoxification and synergistic effect.

Detailed ways

Embodiments of the present invention will be described below, but the content of the present invention is not limited thereto at all.

Isoliquiritigenin filler Adhesive disintegrant D lubricant Example 1 10.0% Starch 85.0% Gum Arabic 2.0% croscarmellose sodium 1.0% Ethanol 1.0% Magnesium Stearate 1.0% Example 2 10.5% Dextrin 84.0% Hydroxymethylcellulose 2.0% Sodium Carboxymethyl Starch 1.5% Ethanol 1.0%  Polyethylene glycol 1.0% Example 3 11.0% Starch 83.0% Gum Arabic 3.0% Hydroxypropyl starch 1.0% Ethanol 1.0%  Polyethylene glycol 1.0% Example 4 11.5% Dextrin 81.0% Gelatin 1.0% Sodium carboxymethyl starch 3.0% Ethanol 2.5% Magnesium Stearate 1.0% Example 5 12.0% Dextrin 78.0% Hydroxymethylcellulose 2.0% Hydroxypropyl starch 4.0% Ethanol 2.0%  Polyethylene glycol 2.0% Example 6 12.5% Starch 77.0% Gum Arabic 1.0% Hydroxypropyl starch 4.5% Ethanol 2.0% Magnesium Stearate 1.0% Example 7 13.0% Dextrin 76.0% Hydroxymethylcellulose 3.0% Sodium bicarbonate 3.0% Ethanol 3.0% Talc 2.0% Example 8 13.5% Dextrin 75.0% Gelatin 4.0% Sodium bicarbonate 3.5% Ethanol 2.0% Magnesium Stearate 2.0% Example 9 14.0% Starch 73.0% Hydroxymethylcellulose 2.5% Sodium bicarbonate 6.0% Ethanol 2.5% Talc 2.0% Example 10 15.0% Dextrin 71.0% Gelatin 3.0% croscarmellose sodium 5.0% Ethanol 5.0% Magnesium Stearate 1.0%

Its preparation steps are as follows:

① Add excipients: add filler, binder and disintegrant respectively to isoliquiritigenin, then add wetting agent and mix well to make soft material;

② Granulation: Pass the mixed soft material through a 50-200 mesh nylon sieve to granulate, dry at 70-80°C for 30 minutes, pass through a 50-200 mesh iron sieve for granulation;

③ Tablet compression: adding a lubricant to compress the tablet to make a tablet.

The filler is one of starch, dextrin, powdered sugar, pregelatinized starch, lactose, glucose, microcrystalline cellulose, calcium carbonate, calcium sulfate, calcium bicarbonate or other pharmaceutically acceptable fillers Or two to ten of them or any combination;

The binder is one of liquid glucose, gum arabic, gelatin, hydroxymethylcellulose, low-substituted hydroxypropylcellulose or other pharmaceutically acceptable binders or two to five of them or any combination;

Described disintegrant is croscarmellose sodium, crospovidone, sodium carboxymethyl starch, hydroxypropyl starch, low-substituted hydroxypropyl cellulose citric acid, tartaric acid, acid anhydride, sodium bicarbonate , sodium carbonate or other pharmaceutically acceptable fillers or any combination of two to nine of them;

Described wetting agent is water, ethanol or its combination;

The lubricant is one of magnesium stearate, talcum powder, liquid paraffin, polyethylene glycol or other pharmaceutically acceptable fillers or any combination of two to four of them.

Pharmacodynamic experiment

In order to disclose the essence of the present invention, in combination with the present invention, pharmacodynamic studies on isoliquiritigenin preparations are carried out from the aspects of tumor inhibition, toxicity reduction and efficiency enhancement:

(1) Experimental materials

1. Drugs: Isoliquiritigenin Tablets were provided by the Non-clinical Drug Research Center of Wuhan University, batch number: 030401; furan fluorouracil (FT207) was produced by Jinan Pharmaceutical Factory, batch number: 031003; cyclophosphamide was provided by Jiangxi Hengrui Pharmaceutical Co., Ltd. Produced by the company, batch number: 21156-21160; compound donkey-hide gelatin pulp is produced by Shandong Ejiao Co., Ltd., batch number: 040672.

2. Animals: Kunming mice, BALB/c mice, SD rats, both male and female, provided by the Experimental Animal Center of Wuhan University, license number: SCXK (E) 2003-0004.

3. Cancer cell lines and target cells: S ₁₈₀ tumor line, Ehrlich ascites cancer cells, A ₅₄₉ lung cancer cells, oral epidermal cancer KB cells, KM-12 colon cancer cells, BEL-7402 liver cancer cells and MCF-7 breast cancer cells strain, introduced and passed down by the Institute of Materia Medica, Chinese Academy of Medical Sciences.

4. Reagents and instruments: MTT is provided by Sigma; 450 microplate reader is produced by American BioRad.

(2) Experimental methods and results

1. Tumor inhibition test

1.1 In vitro inhibitory effect on various cancer cell lines

Mice were treated with isoliquiritigenin tablets 20, 100, 500 mg.kg ^-1 to prepare drug-containing serum; cells were digested with 0.25% trypsin and passaged. Adjust the cell concentration to 2×10 ⁴ .ml ^-1 with RPMI-1 640 culture medium containing 10% fetal bovine serum, add 100 μl to each well of a 96-well culture plate, incubate at 37°C, 5% CO ₂ for 24 hours, discard the culture medium , add 10% filter-sterilized medicated serum, incubate at 37°C, 5% CO ₂ for 18h, and use MTT method to detect cell proliferation.

The results are shown in Table 1.

Table 1. The effect of isoliquiritigenin on the growth of different cancer cell lines

group Dose (mg/kg) Inhibition rate(%) A549 KB KM-12 BEL-7402 MCF-7 Blank control group isoglycyrrhizal group -20100500 1.3±0.325.9±4.1**55.6±3.8**74.9±3.4** 1.2±0.414.8±3.1 ^* 27.6±3.2 ^** 47.3±4.3 ^** 1.4±0.415.7±2.7 ^* 44.5±3.9 ^** 74.8±2.6 ^** 0.9±0.215.9±2.8 ^* 39.7±4.1 ^** 60.9±3.2 ^** 12±0.227.9±3.0 ^** 39.9±3.7 ^** 54.88±3.2 ^**

Compared with the blank control group, **P<0.01

The results in Table 1 show that compared with the blank control group, three dose groups of isoliquiritigenin, large, medium, and small, have significant effects on human A549 lung cancer cells, oral epidermal cancer KB cells, KM-12 colon cancer cells, BEL-7402 liver cancer cells, and MCF-7 cells. The growth of breast cancer cells has obvious inhibitory effect, and there is a certain dose-effect relationship.

1.2 Inhibitory effect on S ₁₈₀ sarcoma strain

Tumor cells (S ₁₈₀ sarcoma cells in the peritoneal cavity of tumor-bearing mice 2 × 10 ⁶ were inoculated in the armpit of male healthy BALB/c nude mice, and randomly divided into groups. On the second day after inoculation, intragastric administration of isoliquiritigenin was started, 1 time/ day, the doses were 20mg.kg ^-1 , 100mg.kg ^-1 , and 500mg.kg ^-1 respectively. The control group was given the corresponding volume of vehicle, which was administered by gavage continuously for 10 days. At the end of the experiment, blood was collected from the orbit, and the tumor was removed and weighed. .

The results are shown in Table 2. The tumor inhibition rates of three isoliquiritigenin groups of large, medium and small doses were 53.6%, 45.7% and 36.2%, respectively, and there was a certain dose-effect relationship.

Table 2. Effect of isoliquiritigenin on tumor growth in S ₁₈₀ tumor-bearing mice

Compared with blank control group, *P<0.05, **P<0.01

1.3 Effect on the survival period of Ehrlich ascites carcinoma mice

The results in Table 3 show that both the large and medium dose groups of isoliquiritigenin prolong the survival period of Ehrlich ascites carcinoma mice, and there is a significant difference compared with the tumor-bearing group; the effect of the low dose group is not obvious. The results of the three experiments all showed that isoliquiritigenin can prolong the survival period of tumor-bearing mice.

Table 3 The effect of isoliquiritigenin on the survival period of Ehrlich ascites carcinoma mice

Compared with normal saline group, *P<0.05, **P<0.01

2. Toxic reduction and synergistic test

2.1 Attenuation test

The results in Table 4 show that after rats are injected with cyclophosphamide, the number of nucleated cells in the bone marrow can be significantly reduced, which is 48.9% lower than that of the normal control group; The number of nucleated cells in the bone marrow decreased significantly compared with the model group. It shows that large and medium doses of isoliquiritigenin have a certain therapeutic effect on the inhibition of bone marrow hematopoietic function caused by chemotherapeutic drugs.

Table 4 Effects of isoliquiritigenin on the number of nucleated cells in the bone marrow of cyclophosphamide rats

group Dose (mg/kg) Number of nucleated cells in bone marrow (×10 ⁹ /L) Normal control group cyclophosphamide control group cyclophosphamide + isoliquiritigenin small dose group cyclophosphamide + isoliquiritigenin medium dose group cyclophosphamide + isoliquiritigenin high dose group --20100500 10.26±3.296.69±1.18 ^△ 9.10±3.46 10.20±3.62*10.65±3.83*

Compared with the normal control group, ^△ P<0.05; compared with the model control group, *P<0.05

The results in Table 5 showed that the number of white blood cells and platelets decreased significantly after the rats were injected with cyclophosphamide, and the number of white blood cells and platelets in the isoliquiritigenin large and medium dose groups decreased less, compared with the model control group, there was a significant difference. It is suggested that large and medium doses of isoliquiritigenin have a better antagonism effect on leukopenia and thrombocytopenia caused by cyclophosphamide, and can alleviate the toxic and side effects of chemotherapy drugs to a certain extent.

Table 5 Effects of isoliquiritigenin on peripheral blood hematological indicators of cyclophosphamide rats

group Dose (mg/kg) WBC (×10 ⁹ /L) Hb(g/L) RBC (×10 ¹² /L) PLC (×10 ⁹ /L) Normal control group Model control group Isoliquiritigenin group --20100500 9.89±2.095.30±1.50 ^△△ 8.21±1.998.60±1.81 ^* 9.33±1.90 ^** 135.91±5.51122.39±8.50 ^△ 119.82±6.72128.43±6.90124.11±7.65 9.71±1.708.23±1.098.55±0.988.35±0.878.36±1.17 618.51±47.91291.20±52.50 ^△△ 539.01±104.60628.22±97.13 ^** 630.79±124.81 ^**

Compared with the normal control group, ^△ P<0.05, ^△△ P<0.01; compared with the model control group, ^* P<0.05, ^** P<0.05

2.2 Synergy test

The results are shown in Table 6. Cyclophosphamide (25mg/kg) and isoliquiritigenin (20mg/kg) groups were used alone to inhibit tumor rates were 28.3% and 29.8%, while combined use of cyclophosphamide (25mg/kg) + isoliquiritigenin (20mg/kg) kg) tumor inhibition rate reached 72.7%, compared with the single drug group, the tumor inhibition rate was significantly improved. From the above results, it can be seen that the combined use of isoliquiritigenin and low-dose chemotherapeutic drugs can increase the tumor inhibition rate, showing the advantages of combined drug use.

Table 6 Effect of combination of isoliquiritigenin and cyclophosphamide on the growth of S ₁₈₀ tumor strain

group Dose (mg/kg) Tumor weight (g) Tumor inhibition rate (%) Normal saline group cyclophosphamide group isoliquiritigenin group isoliquiritigenin + cyclophosphamide group -252020+25 1.98±0.42 1.42±0.66 ^** 1.39±0.70 ^** 0.54±0.43 ^** -28.329.872.7

Compared with normal saline group, ^** P<0.01;

(3) Conclusion

The above experimental results show that isoliquiritigenin not only has the effect of significantly inhibiting tumor growth, but also has the effect of reducing its toxic side effects and enhancing its tumor inhibitory effect when used in combination with chemotherapeutic drugs.

Claims (10)

1. an antitumor isoliquiritigenin tablet, it is made by following raw material by weight percentage: Raw material % by weight Isoliquiritigenin 10～15% Filler 71～85% Adhesive 1～8% Disintegrant 1～8% Wetting agent 1～6% Lubricant 1~2%; Its preparation steps are: ① Add filler, binder and disintegrant to isoliquiritigenin respectively, then add wetting agent and mix well to make soft material; ② Granulation: Pass the mixed soft material through a 50-200 mesh nylon sieve to granulate, dry at 70-80°C for 30 minutes, pass through a 50-200 mesh iron sieve for granulation; ③ Tablet compression: adding a lubricant to compress the tablet to make a tablet; The filler is one of starch, dextrin, powdered sugar, pregelatinized starch, lactose, glucose, microcrystalline cellulose, calcium carbonate, calcium sulfate, calcium bicarbonate or other pharmaceutically acceptable fillers Or two to ten or any combination; The binder is one or two to five or any combination of liquid glucose, gum arabic, gelatin, hydroxymethylcellulose, low-substituted hydroxypropylcellulose or other pharmaceutically acceptable binders ; The disintegrating agent is croscarmellose sodium, crospovidone, sodium carboxymethyl starch, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, citric acid, tartaric acid, acid anhydride, bicarbonate One or two to nine of sodium, sodium carbonate or other pharmaceutically acceptable disintegrants or any combination; Described wetting agent is water, ethanol or its combination; The lubricant is one or two to four of magnesium stearate, talc, liquid paraffin, polyethylene glycol or other pharmaceutically acceptable lubricants or any combination thereof. 2. a kind of anti-tumor isoliquiritigenin tablet according to claim 1, is characterized in that: it is made by weight percentage by following raw material: isoliquiritigenin 10%, starch 85%, gum arabic 2%, Croscarmellose Sodium 1%, Ethanol 1%, Magnesium Stearate 1%. 3. A kind of anti-tumor isoliquiritigenin tablet according to claim 1, characterized in that: it is made of the following raw materials by weight percentage: 10.5% isoliquiritigenin, 84% dextrin, hydroxymethyl cellulose Sodium starch glycolate 2%, sodium carboxymethyl starch 1%, ethanol 1%, polyethylene glycol 1%. 4. A kind of anti-tumor isoliquiritigenin tablet according to claim 1, characterized in that: it is made of the following raw materials by weight percentage: 11.0% isoliquiritigenin, 83% starch, 3% gum arabic, Hydroxypropyl starch 1%, ethanol 1%, polyethylene glycol 1%. 5. An anti-tumor isoliquiritigenin tablet according to claim 1, characterized in that: it is made of the following raw materials by weight percentage: 11.5% isoliquiritigenin, 81% dextrin, 1% gelatin, Sodium carboxymethyl starch 3%, ethanol 2.5%, magnesium stearate 1%. 6. An anti-tumor isoliquiritigenin tablet according to claim 1, characterized in that: it is made of the following raw materials by weight percentage: 12.0% isoliquiritigenin, 78% dextrin, hydroxymethyl cellulose 2% hydroxypropyl starch 4%, ethanol 2.5%, polyethylene glycol 1%. 7. A kind of anti-tumor isoliquiritigenin tablet according to claim 1, characterized in that: it is made of the following raw materials by weight percentage: 12.5% isoliquiritigenin, 77% starch, 1% gum arabic, Hydroxypropyl starch 4.5%, ethanol 3%, magnesium stearate 2%. 8. An anti-tumor isoliquiritigenin tablet according to claim 1, characterized in that: it is made of the following raw materials by weight percentage: 13.0% isoliquiritigenin, 76% dextrin, hydroxymethyl cellulose Sodium bicarbonate 3%, ethanol 3%, talcum powder 2%. 9. An anti-tumor isoliquiritigenin tablet according to claim 1, characterized in that: it is made of the following raw materials by weight percentage: 13.5% isoliquiritigenin, 75% dextrin, 4% gelatin, Sodium bicarbonate 3.5%, ethanol 2%, magnesium stearate 2%. 10. An anti-tumor isoliquiritigenin tablet according to claim 1, characterized in that: it is made of the following raw materials by weight percentage: 14.0% isoliquiritigenin, 73% starch, 3% gelatin, hydroxyl Methylcellulose 2.5%, Sodium Bicarbonate 6%, Ethanol 2.5%, Talc 2%.