Traditional Chinese medicine composition, traditional Chinese medicine preparation and application thereof

Abstract

The invention belongs to the technical field of medicine, and provides a traditional Chinese medicine composition, a traditional Chinese medicine preparation and application thereof, and the traditional Chinese medicine composition is prepared from the following raw materials in parts by weight: 20-30 parts of astragalus membranaceus, 20-30 parts of phaseolus calcaratus, 5-10 parts of radix rehmanniae, 10-20 parts of endothelium corneum gigeriae galli, 10-15 parts of hawthorn and 5-20 parts of fingered citron. The traditional Chinese medicine composition disclosed by the invention has an exact curative effect on improving the liver function, total bile acid metabolism and the like of intrahepatic cholestasis in the gestation period. Clinical, animal and cell test results show that the traditional Chinese medicine composition can effectively improve symptoms and signs of intrahepatic cholestasis in the gestation period.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and specifically relates to a Chinese medicine composition, a Chinese medicine preparation and applications thereof. Background Art

[0002] Intrahepatic cholestasis of pregnancy (ICP) is a common complication of pregnancy in the middle and late stages caused by a combination of endocrine hormones, environment and genes, characterized by significantly elevated serum total bile acid (TBA) levels and skin itching. It is worth noting that there are obvious racial and regional differences in the incidence of ICP. It is highly prevalent in southwest my country (Sichuan, Chongqing, etc.), with an incidence rate as high as 5%-15%. Therefore, there is an urgent regional demand for drug development of ICP in Sichuan and Chongqing. Multiple survey data show that the incidence of ICP is higher in multiple pregnancies, 14-22% in twins and 43% in triplets. With the widespread use of assisted reproductive technology, especially the use of in vitro fertilization (IVF) technology, the incidence of ICP has increased significantly (21.7% vs 13.2%): the incidence of ICP in IVF twin pregnancies is characterized by an earlier onset window, increased severity, and increased stillbirth rate.

[0003] ICP not only has a great impact on the quality of life of pregnant women, but also excessive TBA can harm the health of the fetus and newborn by destroying fetal pulmonary surfactant or inducing vasoconstriction of the placental chorionic veins and reducing placental blood supply. It has been confirmed that ICP is closely related to complications such as premature birth, stillbirth, fetal distress and neonatal asphyxia, and the stillbirth rate can reach 10% to 15% in severe cases. Because the pathogenesis of ICP is complex and has not yet been fully elucidated, the current treatment options are very limited, with only ursodeoxycholic acid (UDCA) as the only drug recommended by the guidelines.

[0004] As a first-line drug recommended by domestic and international guidelines for the treatment of ICP, UDCA has the following mechanisms of action: protecting liver cell membranes from the toxic effects of hydrophobic bile acids, promoting bile secretion and excretion, and resisting hepatocyte apoptosis. However, UDCA has obvious limitations: it cannot improve maternal and child outcomes (including reducing adverse perinatal outcomes of pregnant women with ICP and reducing stillbirth rates), and mainly improves pruritus and liver function symptomatically. Moreover, for patients with severe ICP, the efficacy is significantly worse than that of mild ICP (33.96% vs 83.11%), and may be completely ineffective in patients with severe or complex ICP, such as those with significantly elevated liver enzymes, severe hyperlipidemia, and TBA ≥ 40 μmol / L. The above defects and deficiencies of UDCA have forced scientists around the world to increase the development of safe and effective drugs to improve maternal and child outcomes during the perinatal period of ICP. Traditional Chinese medicine has good potential and broad prospects in this field. There is no name for ICP in ancient Chinese medical books. According to its clinical symptoms, it can be classified into the categories of "pregnancy body itching", "fetal toxicity", and "yellow uterus". The pathogenesis is mostly due to the interweaving of dampness, heat and fetal toxins, evaporation into blood stasis, obstruction of bile excretion and its overflow, and liver and gallbladder dampness and heat syndrome is the most common clinical syndrome. Based on the summary of many years of clinical practice experience under the guidance of the above theory, the present invention proposes a Chinese medicine composition, a Chinese medicine preparation and its application. Summary of the invention

[0005] The technical problem to be solved by the present invention is to provide a Chinese medicine composition for treating intrahepatic cholestasis of pregnancy.

[0006] In order to solve the above technical problems, the technical solution adopted by the present invention is as follows: A traditional Chinese medicine composition is composed of the following raw materials in parts by weight: 20-30 parts of astragalus, 20-30 parts of red beans, 5-10 parts of raw rehmannia, 10-20 parts of chicken gizzard lining, 10-15 parts of hawthorn, and 5-20 parts of bergamot.

[0007] Optionally, the Chinese medicine composition is composed of the following raw materials in parts by weight: 25-30 parts of astragalus, 25-30 parts of red beans, 9-10 parts of raw rehmannia, 10-12 parts of chicken gizzard lining, 12-15 parts of hawthorn, and 15-17 parts of citron.

[0008] Optionally, the Chinese medicine composition is composed of the following raw materials in parts by weight: 30 parts of astragalus, 30 parts of red beans, 9 parts of raw rehmannia, 12 parts of chicken gizzard lining, 12 parts of hawthorn, and 15 parts of bergamot.

[0009] A traditional Chinese medicine preparation is prepared using the above-mentioned traditional Chinese medicine composition as a raw material.

[0010] Optionally, the Chinese medicine preparation is selected from at least one of decoction, granules, tablets, oral liquid and capsules.

[0011] Optionally, the Chinese medicine preparation also includes excipients, which are selected from at least one of pharmaceutically acceptable solvents, solubilizers, cosolvents, emulsifiers, colorants, adhesives, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integrators, penetration enhancers, pH regulators, buffers, plasticizers, surfactants, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculating agents, filter aids, release retardants and film-forming materials.

[0012] The preparation method of the Chinese medicine preparation comprises the following steps: The traditional Chinese medicine composition is extracted by water extraction to obtain an extract.

[0013] Optionally, the water extraction method adopts at least one of water decoction, maceration extraction, percolation extraction, reflux extraction, ultrasonic extraction and steam distillation extraction; Optionally, the water extraction method performs 2 to 4 water immersion extractions on the traditional Chinese medicine composition, and the mass ratio of the traditional Chinese medicine composition to water in each water immersion extraction is 1:2.5 to 3.5.

[0014] A pharmaceutical composition comprising the above-mentioned traditional Chinese medicine preparation and ursodeoxycholic acid (UDCA); Wherein, the weight ratio of the traditional Chinese medicine composition for preparing the traditional Chinese medicine preparation to ursodeoxycholic acid is 90-110 g:700-800 mg.

[0015] Use of the above-mentioned traditional Chinese medicine composition, traditional Chinese medicine preparation or pharmaceutical composition in the preparation of a medicine for treating intrahepatic cholestasis of pregnancy.

[0016] Use of the above-mentioned traditional Chinese medicine composition, traditional Chinese medicine preparation or pharmaceutical composition in the preparation of a drug for reducing alanine aminotransferase, aspartate aminotransferase and total bile acid indicators.

[0017] Compared with the prior art, the present invention has the following beneficial effects: The pharmaceutical composition of the present invention is a pure Chinese medicine preparation, which is a Chinese herbal medicine with the same origin as medicine and food, and no adverse reactions and toxic side effects have been reported. Among them: Chicken gizzard lining is good at eliminating stones, and animal experiments have confirmed that it can significantly improve the blood viscosity of hyperlipidemic rats, the characteristics of red blood cell degeneration, and the antioxidant defense system in the body and liver; red bean tastes sweet and sour, is flat in nature, and is non-toxic. It has the effects of diuresis and swelling, detoxification and pus discharge, and is commonly used for edema, beriberi edema, jaundice and red urine, etc.; my country is the country with the largest production of red bean in the world and is also a major exporter. Its diuretic, stranguria, dehumidification and jaundice have a long history of application. Modern research has found that the main components are pentacyclic triterpenoid saponins, flavonoids, tannins and other compounds, and it has good effects in treating diseases such as liver cirrhosis ascites, chickenpox, mumps, and inflammatory external hemorrhoids. Buddha's hand is one of the commonly used Chinese medicines that are both medicinal and edible in clinical practice. It has the effects of soothing the liver and regulating qi, harmonizing the stomach and relieving pain, drying dampness and resolving phlegm. Because it contains volatile oils, flavonoids and coumarins, it has antibacterial, anti-inflammatory, and digestion-promoting effects. Its main chemical components are volatile mixtures, polyphenols, terpenes, flavonoids, phenolic acids, etc. The main active ingredients of raw rehmannia include iridoids, iridoid glycosides, amino acids, ionones, trace elements, phenylethanoid glycosides, sugars, etc. Among them, catalpol belongs to a small molecule iridoid compound and is the main component and active ingredient in raw rehmannia. Rehmannia polysaccharides can inhibit the production of inflammatory factors IL-6 and transforming growth factor-β (TGF-β) by macrophages induced by bacterial lipopolysaccharide (LPS). Its mechanism is related to the downregulation of inflammation-related AKT / ERK / JNK signaling pathways. Astragalus has the effects of replenishing qi, strengthening the spleen, benefiting the lungs, consolidating the exterior, and enhancing immunity. Modern pharmacology believes that it has the effects of antibacterial, promoting metabolism, and regulating immune function.

[0018] The present invention can improve the liver function and total bile acid metabolism of ICP and has a definite curative effect. The results of clinical, animal and cell studies all support that the present invention can effectively improve the symptoms and signs of ICP.

[0019] The setting of the prescription of the present invention takes into account the safety of the mother and the factors of the initiation of labor. The compatibility principle of the Chinese medicine prescription is as described above, which is conducive to the smooth initiation of labor by the mother to a certain extent. At present, the team continues to track 30 patients who took the Chinese medicine prescription of the present invention, of which 18 patients had full-term normal delivery, 12 had caesarean sections, and the mother and the fetus were safe, and no case of fetal distress occurred.

[0020] The present invention has a very broad and good application prospect, and can be prepared into various Chinese patent medicines in different dosage forms by conventional methods, which is not only convenient for patients, but also the raw materials are all Chinese medicines that are both medicine and food, and the overall cost is low, which can greatly reduce the economic burden of such patients. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1Comparison of serum results of 38 ICP patients before and after UDCA+TCM treatment. A, B, and C are comparisons of fasting ALT, AST, and TBA levels in each group, respectively. D is the age and gestational baseline data of each group. Blank group: normal pregnant women; ICP+U: mild ICP patients treated with UDCA; ICP+U+S: mild ICP patients treated with UDCA+TCM treatment; "Before" indicates baseline level, and "after" indicates re-examination data after 12 weeks.

[0022] Figure 2 OPLS-DA diagram of plasma metabolites of 38 patients; red: after UDCA treatment; blue: after UDCA + Chinese medicine combination treatment.

[0023] Figure 3 This is the differential metabolite analysis of plasma metabolomics between UDCA+TCM and UDCA groups. A. Anion mode. B. Cationic mode. Red indicates upregulation, and blue indicates downregulation.

[0024] Figure 4 Metabolomics function prediction results for 38 patients, focusing on metabolic pathways and biosynthesis of unsaturated fatty acids.

[0025] Figure 5 The network pharmacology analysis of the core target Hub gene screening for the treatment of ICP of the present invention. A is the network diagram of the common target of the drug of the present invention and the disease (ICP). B is the cluster analysis diagram of the mcode of the common target of the present invention and intrahepatic cholestasis of pregnancy.

[0026] Figure 6 Predicted molecular mechanism diagram for KEGG enrichment analysis of network pharmacology.

[0027] Figure 7 The molecular docking model diagram of the key components and key genes for treating ICP in the network pharmacology invention. A. Docking model of quercetin and NF-kB (6y1j); B. Docking model of kaempferol and PI3K (1e8y).

[0028] Figure 8 Comparison of serum transaminase, TSA and liver IL6 levels in each group of mice in the animal experiment. A is a comparison of liver IL6 levels, B is a comparison of plasma TBA levels, C is a comparison of plasma ALT levels, D is a comparison of plasma AST levels, and the model in the figure is the model group of intrahepatic cholestasis of pregnancy.

[0029] Fig. 9This is a diagram showing the effect of the drug-containing serum of the present invention on TBA metabolism and transaminase in a HepG2 cholestasis cell model in a cell experiment. DETAILED DESCRIPTION

[0030] To better illustrate the purpose, technical solutions and advantages of the present invention, the present invention will be further described below in conjunction with specific embodiments. It should be understood by those skilled in the art that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention.

[0031] Unless otherwise specified, the experimental methods used in the examples are all conventional methods; the materials, reagents, etc. used, unless otherwise specified, can be obtained from commercial channels.

[0032] The inventor team is a team of Chinese medicine and obstetricians and gynecologists and nurses who have been working in the front line of clinical practice in the southwest region for a long time. Based on the summary of many years of clinical practice experience under the guidance of Chinese medicine theory, a Chinese medicine composition, a Chinese medicine preparation and its application are proposed. Pharmacological analysis of the present invention: Chinese medicine believes that ICP is mostly pregnant women in the middle and late stages, and its bile acid metabolism abnormalities mainly present a complex state of deficiency and excess, liver and gallbladder dampness and heat, and fetal toxicity stagnation in the liver meridian and gallbladder. Starting from this pathogenesis, the theory, method and prescription need to take into account the confusion of deficiency and excess, and the rise and fall of positive and negative forces. After nearly 10 years of practice and summary, this research team has accumulated rich experience in the treatment of ICP. Aiming at the characteristics of ICP onset, the new characteristics of ICP in the new era (high incidence of patients with artificial assisted reproductive technology), and the defects of drugs recommended by the existing guidelines for ICP, the Chinese medicine composition of the present invention is proposed: Aiming at the pathological characteristics of ICP deficiency and excess, we use Astragalus as the main medicine, replenishing the middle and replenishing qi, and supporting the positive qi to facilitate the exorcism of evil spirits, and taking into account that patients in the middle and late stages are about to face the start of labor, consuming qi and blood, and helping the positive qi to use for smooth delivery. On the other hand, for the evil of damp-heat in the liver and gallbladder (abnormal accumulation of bile acid in the liver meridian and gallbladder), chicken gizzard lining is added, which is good at dispersing stones, strengthening the spleen and digesting food, and clearing the stomach, etc. Hawthorn is added to digest food and resolve stagnation, promote qi and disperse blood stasis and resolve turbidity. Chicken gizzard lining and hawthorn are both ministerial drugs, which play the role of promoting blood circulation, promoting qi and dispersing stagnation, and assist the monarch drug in playing the role of unblocking the gallbladder and dredging the liver meridian. Red bean tastes sweet and sour, is flat in nature, has the effects of diuresis and swelling, detoxification and pus discharge, and is widely used for jaundice, red urine, rheumatism, heat arthralgia, carbuncle, intestinal carbuncle and abdominal pain. In this prescription, its diuresis, swelling and detoxification effects are used to not only eliminate the evil of damp-heat and blood stasis in the liver and gallbladder, but also can reduce swelling, promote diuresis and relieve itching for the symptoms of increased blood volume, swelling and discomfort of the extremities and itching in pregnant women in the middle and late stages of ICP, and treat both the symptoms and the root causes, so it is a ministerial drug. The circulating body fluids of pregnant women in the middle and late stages need additional supply of amniotic fluid for fluid exchange. In addition, some body fluids penetrate into the interstitial space of peripheral cells, which can easily cause dry mouth, deficiency of yin fluid, and yin deficiency and heat. Adding raw rehmannia can timely nourish yin fluid, moisten dryness and relieve itching, and nourish yin and reduce fire. It is combined with astragalus to play the role of replenishing yin and yang, and is a ministerial drug. Finally, add bergamot. "Bencao Zaixin" records: bergamot can regulate qi and soothe the liver, harmonize the stomach and resolve phlegm, break up accumulation, treat choking and nausea, and eliminate symptoms of lumps and scrofula. It tastes pungent, bitter, and sour, and is warm in nature. It enters the liver, spleen, stomach, and lung meridians, and has the effect of soothing the liver and regulating qi. In the present invention, the pathogenic factors formed by bile acid metabolism disorders block the liver and gallbladder meridians, thereby affecting the adverse qi movement of the uterus and threatening the safety of the mother and the fetus, and plays the effect of soothing the liver and gallbladder qi movement. It is combined with hawthorn to assist astragalus in playing the role of strengthening the body, expelling evil, saving the mother and protecting the fetus. At the same time, because bergamot enters the liver meridian, it can help lead the monarch drug and the minister drug into the liver and gallbladder meridians to improve bile acid metabolism.

[0033] Example 1 Weigh the Chinese medicine raw materials according to the following weight ratio: 30g of Astragalus, 30g of Red Bean, 9g of Rehmannia, 12g of Chicken Gizzard Stone, 12g of Hawthorn, and 15g of Citron.

[0034] First, take the Chinese medicinal raw materials according to the weight ratio mentioned above, add 300g of water to soak and extract 2-3 times, each extraction time is 2-3 hours, filter, and combine the filtrate to obtain the medicinal solution.

[0035] Example 2 The weights of the weighed Chinese medicinal raw materials are as follows: 20 g of Astragalus, 20 g of Red Bean, 5 g of Rehmannia, 10 g of Chicken's Gizzard Stone, 10 g of Hawthorn, and 5 g of Citron. The others are the same as in Example 1.

[0036] Example 3 The weights of the weighed Chinese medicinal raw materials are as follows: 30 g of Astragalus, 25 g of Red Bean, 10 g of Rehmannia, 20 g of Chicken's Gizzard Stone, 15 g of Hawthorn, and 20 g of Citron. The others are the same as in Example 1.

[0037] Example 4 Weigh the following weights of Chinese medicinal pieces: 30 g of Astragalus, 30 g of Red Bean, 9 g of Rehmannia, 12 g of Chicken Gizzard Stone, 12 g of Hawthorn, and 15 g of Citron; add 500 ml of water and boil for 40 min to obtain a decoction.

[0038] The liquid medicine and decoction prepared in the above embodiments can be used directly, or the liquid medicine can be concentrated and prepared into any Chinese medicine preparation such as capsule, granule, oral solution or tablet according to conventional methods. Excipients can be added to the Chinese medicine preparation, and the excipients are selected from at least one of pharmaceutically acceptable solvents, solubilizers, cosolvents, emulsifiers, colorants, adhesives, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, aromatics, anti-adhesives, integrators, penetration enhancers, pH regulators, buffers, plasticizers, surfactants, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculating agents, filter aids, release retardants and film-forming materials.

[0039] Clinical observation: From October 2022 to August 2024, a small sample clinical study (n=38) was conducted to observe the use of the present invention (the decoction in Example 4, twice a day) combined with UCDA (250 mg orally, three times a day) to treat mild ICP. The results are as follows Figure 1 As shown, Figure 1A, B, and C are comparisons of fasting alanine transaminase (ALT), aspartate transaminase (AST), and total bile acid (TBA) levels in each group. D is the age and gestational baseline data of each group. Blank group: normal pregnant women; ICP+U: mild ICP patients intervened with UDCA; ICP+U+S: mild ICP patients intervened with UDCA+traditional Chinese medicine combination; "before" indicates baseline level, and "after" indicates reexamination data after 12 weeks. It can be seen that the combined treatment regimen can quickly reduce TBA levels and improve liver enzyme indicators, and the effect is better than UDCA monotherapy, and no adverse reactions were observed.

[0040] Plasma metabolomics analysis: The results of plasma metabolomics suggest that omega-3 unsaturated fatty acids (mainly EPA, DHA, etc.) and quercetin are the main pharmacodynamic material basis, and functional prediction is related to metabolic pathways ( Figure 2 , Figure 3 , Figure 4 ), among the six Chinese medicines of the present invention, astragalus, hawthorn, red bean and bergamot all contain quercetin. And astragalus, hawthorn and chicken gizzard lining are also confirmed to contain relatively rich unsaturated fatty acids.

[0041] Further network pharmacology predictions suggest that the mechanism of action of the present invention in treating ICP is related to the classic autophagy pathway PI3K / Akt / mTOR signaling pathway ( Figure 6-Figure 7 ).

[0042] Plasma metabolomics suggests that omega-3 unsaturated fatty acids (mainly DHA and EPA) are differential metabolites related to the present invention ( Figure 2 , Figure 3 ), functional prediction is related to metabolic pathways ( Figure 4 ). The network pharmacology results suggest that the key ICP genes of the present invention focus on the PI3K / Akt signaling pathway and its downstream molecules (NF-kB, CASP3, GSK3β, etc., Figure 5 ). KEGG enrichment analysis focused on apoptosis signaling pathways ( Figure 6 In addition, the key ingredient of the present invention, quercetin, has good docking with NF-kB, and kaempferol has good docking with PI3K molecules ( Figure 7 ).

[0043] Animal experiments Based on previous clinical research and network predictions, further experiments were conducted on animal models.

[0044] Model establishment: SPF-grade 6-8-week-old BALC female mice were selected and given 17α-ethinylestradiol at a dose of 5 mg / kg by oral gavage for 5 consecutive days on the 10th to 12th day of pregnancy to induce intrahepatic cholestasis of pregnancy. The successful modeling was confirmed by collecting mouse serum and detecting TBA, alanine transaminase (ALT), and aspartate transaminase (AST) levels.

[0045] After the modeling is successful, an animal experiment is carried out, and a control group and two test groups are set, with 6 mice in each group. The two test groups are tested using the two prescriptions of Example 1 and Example 2 respectively. Specific gavage dose: The two prescriptions of Example 1 and Example 2 of the present invention are concentrated into 0.2g / ml (0.2g of crude drug per milliliter) according to the optimal dose water decoction observed in clinical practice, and then according to the "Equivalent Dose Ratio Table between Humans and Animals Calculated by Body Surface Area", the gavage dose of mice is 0.015ml / g.day. The mice in the two test groups were gavaged continuously for 12 weeks.

[0046] After 12 weeks, serum and liver tissues of mice in each group were taken to measure serum TSA, AST, ALT levels and liver IL6 levels. The results showed that both Example 1 and Example 2 could effectively improve serum transaminase indexes (AST, ALT), reduce serum TSA levels, and down-regulate liver IL6 levels, and the differences were statistically significant. Compared with Example 1 and Example 2, Example 1 had a better improvement effect on the above indicators than Example 2, and there was a significant difference between the two groups ( Figure 8 ), these results suggest that both Example 1 and Example 2 can effectively improve liver function, TSA metabolism, and improve the inflammatory damage to liver cells caused by cholestasis of pregnancy modeling, and the improvement effect of Example 1 may be better than that of Example 2.

[0047] After the mice went into labor on days 19-21 of gestation, 2 mice in the control group (n=6) had intrauterine distress, 1 stillbirth, and 1 live birth, but the Apgar score was 4, which was considered to be intrauterine asphyxia. Both group 1 and group 2 mice gave birth live.

[0048] The above animal experiments show that the Chinese medicine composition of the present invention has good safety and effectiveness in treating ICP and can be used for treating ICP.

[0049] The drug-containing serum of the present invention improves the bile acid level and liver injury test of the cholestatic hepatocyte injury model To further find evidence that the present invention improves bile acid metabolism in a cell model, we first prepared the drug-containing serum of the present invention: the decoction in Example 1 of the present invention was concentrated to 0.2g / ml (0.2g of crude drug per ml), and then according to the "Equivalent Dose Ratio Table between Humans and Animals Calculated by Body Surface Area", the oral dose for mice was 0.015ml / g day. Six 12-week-old BALC female mice were gavaged daily for 1 week. After 1 week, whole blood was collected and centrifuged to obtain the drug-containing serum of the present invention.

[0050] In a cholestasis cell model established by inducing taurocholic acid (TCA) in HepG2 hepatocytes, the following culture medium treatments were performed: the drug-containing serum of the present invention was mixed with a conventional culture medium, the drug-containing serum was intervened at a volume fraction of 5%, 10%, and 20%, and the culture medium containing 20 µmol / L UDCA was used as a positive control, such as Fig. 9 As shown, normal represents normal cell indicators, model represents model cell indicators, UDCA represents model cell indicators treated with UDCA, 5%, 10%, and 20%, respectively, represent model cell indicators treated with different concentrations of medicated serum. The results show that the medicated serum of the present invention can effectively improve the levels of TBA, AST, and ALT, and there is a dose-effect relationship.

[0051] The following provides examples of using the Chinese medicine composition of the present invention to treat ICP: Example 1 The patient, 27 years old, had regular menstruation and no dysmenorrhea. Before pregnancy, color Doppler ultrasonography of liver, kidney function, liver, gallbladder, spleen and pancreas showed no abnormalities. The last menstrual period was on May 21, 2022, and the menstruation was amenorrhea for 40 days. Ultrasound confirmed intrauterine early pregnancy, mild early pregnancy reaction, no history of exposure to toxic substances and radiation, and normal prenatal examinations at 8-10 weeks of pregnancy. Examination of liver indicators A, B, C, D, E, and G was normal, and there was no recent history of medication and abnormal eating history. Color Doppler ultrasonography showed that there were no abnormalities in the liver, spleen, pancreas, and kidneys. At 28 weeks of pregnancy, systemic itching occurred, especially at night. The total bile acid was 98.52 μmol / L, ALT 62.9 U / L, and AST 56.7 U / L. Color Doppler ultrasonography showed: breech presentation, single live fetus, and umbilical cord around the neck for 1 week. Ursodeoxycholic acid capsules 250 mg were given twice a day. During this period, liver function was regularly tested at 90-104 U / L, and bile acid was 56-168 μmol / L. The pruritus symptoms were better than before. At 32 weeks of pregnancy, she was hospitalized again in the Provincial People's Hospital due to severe skin itching. The bile acid level was increased again to 47.0-131.33 μmol / L. Ursodeoxycholic acid tablets 250 mg were taken orally, 3 times a day (the dose was increased compared with the previous one). After one week of oral administration, the bile acid and liver function were rechecked and no significant decrease was found, and the systemic itching was not significantly relieved. After consultation with the Department of Traditional Chinese Medicine, the obstetrics department gave the present invention (30 grams of Astragalus, 30 grams of red beans, 9 grams of raw earth, 12 grams of chicken gizzards, 12 grams of hawthorn, and 15 grams of bergamot, boiled in water for 1 week, and 2 times a day) decocted in water for 1 week, combined with ursodeoxycholic acid tablets for oral administration. One week later, the bile acid level dropped to 13.50 μmol / L, liver function returned to normal, and the itching was significantly relieved before discharge. Ursodeoxycholic acid tablets and the combined oral medication of the present invention were continued and the patient was discharged. ＋2 Week 1, the patient was admitted to the hospital with vaginal bleeding. The abdomen showed mild uterine contractions and the fetal heart rate was normal. For personal reasons, a cesarean section was requested, and a single live fetus was delivered, with good scores in all aspects.

[0052] Example 2 The patient, a 32-year-old female, had been married for 7 years and had had one abortion during early pregnancy. She had not been pregnant for 5 years without contraception. Her menstrual cycle was 40-60 days. Hysterosalpingography showed adhesions at the ends of the fallopian tubes on both sides. She underwent IVF assisted reproductive technology. On the 14th day after the transplantation, ultrasound showed intrauterine twins and triplets. The patient complained of skin itching at 7 weeks of pregnancy, which was obvious at night. After 1 week, the itching was significantly aggravated, and the skin and mucous membranes were slightly yellowed. The aspartate aminotransferase was 122U / L, the alanine aminotransferase was 218U / L, and the total bilirubin was 40.1μmol / L. She was diagnosed with "pregnancy complicated with intrahepatic cholestasis". Considering that the patient was in the early pregnancy period, the present invention (30 grams of astragalus, 30 grams of red beans, 9 grams of raw earth, 12 grams of chicken gizzard, 12 grams of hawthorn, and 15 grams of bergamot) was given to her for review after 1 week. The itching symptoms were alleviated. The results showed that the aspartate aminotransferase was 52U / L, the alanine aminotransferase was 53U / L, and the total bilirubin was 10.1μmol / L. After continuing to take the present invention orally for 2 weeks, the above indicators returned to normal. Follow-up of a single live fetus at full term was performed, weighing 2780g and developing well.

[0053] Use Case 3 The patient was 36 years old and came to the hospital 35+1 weeks after amenorrhea. Half a month ago, she developed skin itching all over her body, without rash, mild during the day and severe at night, and had not been diagnosed or treated. Four days ago, her skin turned yellow all over her body, and she was admitted to the hospital for 1 day of progressive worsening. Physical examination: T 36.6℃, P 83 times / min, R 20 times / min, BP 130 / 70mmHg. Mild yellowing of the skin and sclera all over the body. Obstetric signs: uterine height 36cm, abdominal circumference 98cm, no regular uterine contractions palpable. Anal examination showed that the cervix was soft and could accommodate one finger, and the fetal head was floating. Fetal heart monitoring showed that the fetal heart rate was normal and the NST was reactive. Liver function: AST77U / L, TBA 145umol / L, albumin 35.1g / L. Hepatitis negative. Diagnosis: ① 35+3 weeks of pregnancy threatened premature labor G1 P0, ② LOT, ③ ICP. After admission, the patient was given tocolysis, liver protection and oral ursodeoxycholic acid capsule 250mg 1 day 4 times, decocted with the medicine of the present invention (30 grams of astragalus, 30 grams of red bean, 9 grams of raw rehmannia, 12 grams of chicken gizzard lining, 12 grams of hawthorn, 15 grams of bergamot, 1 day 3 times), and reexamination after 1 week: AST 32U / L, TBA 23umol / L, a single live fetus was delivered by cesarean section at 36+2 weeks, and the score was good.

[0054] In summary, the present invention is composed of 6 Chinese herbal medicines that are both medicinal and edible: Astragalus, Radix Rehmanniae, Gallus gallus tuber, Crataegus, Citron, and Adzuki Bean. A small sample clinical observation of the present invention combined with UCDA to treat ICP found that the combined treatment regimen can quickly reduce TBA levels and improve liver enzyme indicators, and the effect is better than UDCA monotherapy, and no adverse reactions are observed. It can be seen that the present invention can effectively treat ICP clinically.

[0055] The results of plasma metabolomics suggest that Ω-3 unsaturated fatty acids (EPA, DHA, quercetin, etc.) are the main pharmacological material basis, and the functional prediction is related to the metabolic pathway. The main active ingredients of astragalus, red bean, hawthorn, and bergamot are quercetin; astragalus, hawthorn, and chicken gizzard also contain relatively rich unsaturated fatty acids. Further network pharmacology prediction suggests that the mechanism of action of the present invention in treating ICP is related to the PI3K / Akt / mTOR signaling pathway of the classic autophagy pathway. Cell studies by our research group have shown that the plasma active ingredients DHA and EPA of the present invention can effectively improve bile acid metabolism and liver function in the cholestatic hepatocyte injury model.

[0056] It can be seen that the results of clinical data, animal experiments, and cell studies all support that the present invention can effectively improve the symptoms and indicators of ICP. And from the above-mentioned related cases, it can be seen that the Chinese medicine composition of the present invention can be used alone or in combination with UDCA to treat ICP and improve related indicators.

[0057] Obviously, the above embodiments are merely examples for the purpose of clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived therefrom are still within the scope of protection of the invention.

Claims

1. A Chinese medicine composition, characterized in that: The Chinese medicine composition is composed of the following raw materials in parts by weight: 20-30 parts of astragalus, 20-30 parts of red beans, 5-10 parts of raw rehmannia, 10-20 parts of chicken gizzard lining, 10-15 parts of hawthorn, and 5-20 parts of bergamot.

2. The Chinese medicine composition according to claim 1, characterized in that: The Chinese medicine composition is composed of the following raw materials in parts by weight: 25-30 parts of astragalus, 25-30 parts of red beans, 9-10 parts of raw rehmannia, 10-12 parts of chicken gizzard lining, 12-15 parts of hawthorn, and 15-17 parts of bergamot.

3. The Chinese medicine composition according to claim 1, characterized in that The Chinese medicine composition is composed of the following raw materials in parts by weight: 30 parts of astragalus, 30 parts of red beans, 9 parts of raw rehmannia, 12 parts of chicken gizzard lining, 12 parts of hawthorn, and 15 parts of bergamot.

4. A Chinese medicine preparation, characterized in that: The Chinese medicine preparation is prepared using the Chinese medicine composition according to any one of claims 1 to 3 as a raw material.

5. The Chinese medicine preparation according to claim 4, characterized in that: The Chinese medicine preparation is selected from at least one of decoction, granules, tablets, oral liquid and capsules; and / or The Chinese medicine preparation also includes excipients, which are selected from at least one of pharmaceutically acceptable solvents, solubilizers, cosolvents, emulsifiers, colorants, adhesives, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integrities, penetration enhancers, pH regulators, buffers, plasticizers, surfactants, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculating agents, filter aids, release retardants and film-forming materials.

6. The method for preparing the Chinese medicine preparation according to claim 4 or 5, characterized in that: The steps include: The traditional Chinese medicine composition is extracted by water extraction to obtain an extract.

7. The preparation method according to claim 6, characterized in that: The water extraction method adopts at least one of water decoction, maceration extraction, percolation extraction, reflux extraction, ultrasonic extraction and steam distillation extraction; and / or The water extraction method performs 2 to 4 water immersion extractions on the traditional Chinese medicine composition, and the mass ratio of the traditional Chinese medicine composition to water in each water immersion extraction is 1:2.5 to 3.

5.

8. A pharmaceutical composition, characterized in that Comprising the traditional Chinese medicine preparation according to claim 4 or 5 and ursodeoxycholic acid; Wherein, the weight ratio of the traditional Chinese medicine composition for preparing the traditional Chinese medicine preparation to ursodeoxycholic acid is 90-110 g:700-800 mg.

9. Use of the Chinese medicine composition according to any one of claims 1 to 3, the Chinese medicine preparation according to claim 4 or 5, or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating intrahepatic cholestasis of pregnancy.

10. Use of the Chinese medicine composition according to any one of claims 1 to 3, the Chinese medicine preparation according to claim 4 or 5, or the pharmaceutical composition according to claim 8 in the preparation of a medicament for reducing alanine aminotransferase, aspartate aminotransferase and total bile acid indices.

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