Traditional Chinese medicine composition for preventing and treating new-generation targeting and immunotherapy-related adverse reactions of tumors and preparation method of traditional Chinese medicine composition

Abstract

The rapid development of tumor molecular targeting drugs and immunotherapy promotes the progress in the field of tumor treatment, but the treatment means of related adverse reactions are very single, so that the invention discloses a traditional Chinese medicine composition for preventing and treating new-generation targeting and immunotherapy related adverse reactions of tumors and a preparation method of the traditional Chinese medicine composition. The composition is prepared from the following traditional Chinese medicinal materials in parts by mass: 3 to 20 parts of radix astragali seu hedysari, 3 to 18 parts of radix rehmanniae recen, 3 to 15 parts of radix arnebiae seu lithospermi, 3 to 20 parts of herba hedyotidis diffusae, 3 to 20 parts of fructus tribuli, 3 to 18 parts of herba geranii, 3 to 12 parts of gallnut, 3 to 20 parts of fried medicated leaven and 3 to 10 parts of radix glycyrrhizae. The traditional Chinese medicine composition disclosed by the invention has the effects of nourishing yin and tonifying qi, promoting blood circulation and dispelling wind, and detoxifying and dissolving turbidity, and has good effects on preventing and treating rash, gastroenteritis, diarrhea, hypothyroidism, proteinuria, hypertension, pneumonia, myocarditis and the like. The preparation method comprises decoction, granules, pills and capsule preparations. The traditional Chinese medicine composition is simple, convenient, low in cost, free of toxic and side effects and beneficial to prolonging the tolerance period of targeting and immunotherapy and improving the life quality of patients.

Description

Technical Field

[0001] The present invention belongs to the technical field of traditional Chinese medicine, and particularly relates to a traditional Chinese medicine composition for preventing and treating adverse reactions related to a new generation of tumor targeted and immunotherapy and a preparation method thereof.

[0002] Malignant tumors are a global problem that seriously threatens human life and health. According to statistics released by the National Cancer Center where the patent applicant is located, there will be 4.8247 million new cases of cancer and 2.5742 million deaths in my country in 2022, with an average annual increase of 1.4%. With the rapid development of molecular biology technology and cytogenetics, tumor molecular targeted drugs represented by epidermal growth factor receptor (EGFR) inhibitors, human epidermal growth factor receptor-2 (HER-2) inhibitors, anti-vascular endothelial growth factor antibodies, antibody-drug conjugates (ADCs), etc., and tumor immunotherapy represented by anti-programmed cell death receptor-1 (PD-1) / programmed cell death ligand-1 (PD-L1) monoclonal antibodies, anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) monoclonal antibodies, and chimeric antigen receptor T cell (CAR-T) immunotherapy are rapidly expanding the field of tumor treatment and promoting the development of tumor treatment concepts and theories.

[0003] However, common adverse reactions related to tumor targeted and immunotherapy: rash, gastroenteritis and diarrhea, proteinuria, hypertension, hypothyroidism, pneumonia and myocarditis, seriously affect the treatment effect and quality of life of patients. In general, rash is the earliest and most common adverse reaction during targeted therapy and immunotherapy, with an incidence of targeted therapy-related rash as high as 79% to 88%, and an incidence of immunotherapy-related rash of 30% to 60%. Gastroenteritis with diarrhea as the main manifestation is one of the main adverse reactions of many targeted drugs, with an incidence as high as 50%. The incidence of immunotherapy-related gastroenteritis is 8% to 27%, and in severe cases, the drug is forced to be discontinued. In clinical trials of targeted drugs, the incidence of hypertension was observed to be about 30%, most of which were grade 3 hypertension, and 6% to 26% of patients also experienced varying degrees of increased blood pressure during immunotherapy. Myocarditis is a rare immune-related adverse reaction. A large-scale retrospective survey conducted abroad showed that the incidence of myocarditis was 1.14%, but the mortality rate was as high as 39.7% to 50%. Hypothyroidism is a manifestation of the impact of targeted and immune drugs on the endocrine system. If patients experience unexplained fatigue, weight gain, hair loss, Chills, constipation, depression and other symptoms, you need to consider the possibility of hypothyroidism. Studies have shown that the incidence of hypothyroidism caused by targeted drugs is about 11%, and the incidence of hypothyroidism caused by immunotherapy is 5%-10%; pneumonia is mainly manifested as dyspnea, cough, chest pain and fever, the incidence of immunotherapy-related pneumonia is 3%-5%, of which 72% of patients are grade 1-2 and require further treatment with hormones or immunosuppressants. Reports of pneumonia caused by targeted therapy are also increasing. For example, interstitial pneumonia is the most serious adverse reaction of erlotinib, with an incidence of 0.4% to 5.8%, of which about 0.6% are fatal; studies have shown that the incidence of proteinuria caused by targeted therapy combined with chemotherapy is 5% higher than that of chemotherapy alone. Most patients have grade 1 or 2 proteinuria, and grade 3 or severe nephrotic syndrome (grade 4) is very rare. The incidence of acute kidney injury during immunotherapy is 2.2%-5%, and immune checkpoint inhibitors need to be permanently discontinued, and creatinine and urine protein should be monitored every 24 hours.

[0004] The above-mentioned adverse reactions not only occur in targeted and immunotherapy drugs that have been used clinically, but also restrict the development of the new generation of ADC targeted drugs and the new generation of CAR-T immunotherapy.

[0005] ADC is a type of targeted biological agent that connects cytotoxic drugs to monoclonal antibodies through connectors. It often causes adverse reactions due to toxicity caused by binding to normal cells with low specific expression, premature drug release caused by inappropriate connector selection, and protein aggregation leading to reduced immunogenicity of ADC drugs and increasing drug resistance of tumor cells. There are 8 ADC drugs approved for clinical use worldwide. According to the current expert consensus, the common adverse reactions described in this patent all occur in the clinical use of ADC drugs. For example, gosartuzumab is emetic, with an incidence of nausea of ​​69%, vomiting of 49%, and diarrhea of ​​63%; the incidence of non-infectious pneumonia and radiation pneumonia of emetic trastuzumab is 0.8% to 1.1% and 1.8%, respectively. CAR-T cell therapy is an important treatment for refractory recurrent lymphomas, which is a modification of the patient's own T cells through genetic engineering technology to specifically identify and kill tumor cells. However, it can also cause related adverse reactions due to off-target effects and co-stimulatory molecules that promote the release of a large number of cytokines by immune cells. Cytokine release syndrome is one of the most common acute adverse reactions in CAR-T cell therapy, leading to systemic inflammatory responses, including pneumonia, myocarditis, gastrointestinal reactions, etc., which usually occur in the first week after treatment. Common symptoms include fever, chills, fatigue, headache, nausea and vomiting. In addition, clinical studies have shown that the incidence of rash in CAR-T therapy for B lymphocyte blood tumors is 12%.

[0006] It can be seen that the core pathogenesis of the new generation of targeted and immunotherapy-induced adverse reactions is that while the new method enhances the activity of the immune system and attacks tumor cells, it cannot make normal cells increase their resistance to immune lethality as the activity of the immune system increases, thereby breaking the balance between autoimmunity and immunity to a certain extent, and adverse reactions will follow. After searching a large number of clinical literature, treatments guided by the idea of ​​"strengthening the body and detoxifying" in traditional Chinese medicine often bring good clinical efficacy. "Cancer poison" is the toxicity produced by tumor cells, and "drug poison" is the damage caused by the overactive immune system relative to normal cells. On the one hand, when "cancer poison" breaks the body's neutral and peaceful state, the body's sensitivity to drugs decreases and it is more susceptible to "drug poison". "Cancer poison" and "drug poison" together become the cause of inducing adverse reactions; on the other hand, most tumor patients are weak, which is generally speaking, both yin and yang are weak. If the body is weak, it will not be able to resist "drug poison", causing the poison to spread all over the body and causing adverse reactions in the corresponding weak parts of the body. Therefore, this patent starts from the perspective of strengthening the body and detoxifying, selects clinical experience medication, enhances the adaptability of body cells to new therapies, and enables the treatment to proceed smoothly.

[0007] Although traditional Chinese medicine has become an indispensable part of comprehensive cancer treatment in my country, and its efficacy in treating adverse events of targeted and immunotherapy has been fully verified in a large number of clinical trials and evidence-based studies, the current treatment of adverse reactions related to targeted and immunotherapy is still mainly based on glucocorticoids combined with conventional symptomatic treatment. Since hormone drugs should be used in accordance with the principle of slow reduction, and need to be used for 6-8 weeks or even longer to prevent recurrence, the risk of fungal infection, osteoporosis, and gastrointestinal reactions will be greatly increased. Summary of the invention

[0008] In order to solve the above problems, the applicant of the present invention has invented a Chinese medicine composition and preparation method for preventing and treating adverse reactions related to the new generation of targeted and immunotherapeutic treatments for tumors based on a number of scientific research topics, clinical and basic research. The Chinese medicine composition nourishes yin and replenishes qi, promotes blood circulation and dispels wind, detoxifies and resolves turbidity. The combination of these medicines can nourish yin and supplement yang, harmonize qi and blood, take into account the internal organs, and remove blood stasis and toxins. It has good prevention and / or treatment effects on adverse reactions related to the new generation of targeted and immunotherapeutic treatments, has high efficiency and has no side effects on the human body.

[0009] The present invention is achieved through the following technical scheme: a traditional Chinese medicine composition for preventing and treating adverse reactions related to a new generation of targeted and immunotherapy for tumors and a preparation method thereof, wherein the traditional Chinese medicine composition is prepared from the following raw materials in weight / volume proportions: 3-20 parts of astragalus, 3-18 parts of raw rehmannia, 3-15 parts of lithospermum, 3-20 parts of oldenlandia diffusa, 3-20 parts of white tribulus, 3-18 parts of geranium, 3-12 parts of gallnut, 3-20 parts of stir-fried Shenqu, and 3-10 parts of raw licorice.

[0010] Preferably, the composition comprises the following components in parts by weight: 5-15 parts of astragalus, 5-12 parts of raw rehmannia, 5-10 parts of lithospermum, 5-15 parts of oldenlandia diffusa, 5-15 parts of tribulus terrestris, 5-12 parts of geranium, 3-12 parts of gallnut, 5-12 parts of stir-fried Shenqu, and 3-8 parts of raw licorice.

[0011] More preferably, the composition comprises the following components in parts by weight: 10 parts of astragalus, 10 parts of raw rehmannia, 10 parts of lithospermum, 10 parts of oldenlandia diffusa, 10 parts of tribulus terrestris, 10 parts of geranium, 6 parts of gallnut, 10 parts of stir-fried Shenqu, and 5 parts of raw licorice.

[0012] The above-mentioned Chinese medicine composition for preventing and treating adverse reactions related to the new generation of tumor targeted and immunotherapy is prepared according to the existing process into any clinically acceptable preparation. The preparation is: decoction, granules, pills and capsules, which comprises the following steps:

[0013] Preparation method of water decoction: (1) Take 10 parts of Astragalus, 10 parts of Radix Rehmanniae, 10 parts of Lithospermum officinale, 10 parts of Hedyotis diffusa, 10 parts of Tribulus terrestris, 10 parts of Geranium, 6 parts of Galla chinensis, 10 parts of stir-fried Shenqu, and 5 parts of raw licorice, mix them, add water and soak for half an hour. Wherein, the ratio of the total weight of the Chinese medicinal materials to the weight of water can be (1-2): (10-15), and the specific amount of water added can be determined according to the weight of the medicinal materials. (2) Add all the medicinal materials and decoct for 40 minutes. Wherein, the ratio of the total weight of the Chinese medicinal materials to the weight of water can be (1-2): (10-15), and the specific amount of water added can be determined according to the weight of the medicinal materials. (3) Filter the medicinal liquid obtained after decoction to obtain filtrate and filter residue, and the first decoction is completed. (4) Take out the filter residue, add water and decoct again for 25 minutes. Wherein, the ratio of the total weight of the Chinese medicinal materials to the weight of water can be (1-2): (5-10), and the specific amount of water added can be determined according to the weight of the medicinal materials. (5) Filter the decoction obtained after decoction to obtain a filtrate and a filter residue, and the second decoction is completed. (6) Mix the filtrate obtained by the first decoction with the filtrate obtained by the second decoction to obtain the water decoction of the Chinese medicinal composition.

[0014] Granule preparation method: (1) Take 10 parts of Astragalus, 10 parts of Radix Rehmanniae, 10 parts of Lithospermum officinale, 10 parts of Hedyotis diffusa, 10 parts of Tribulus terrestris, 10 parts of Geranium, 6 parts of Gallnut, 10 parts of Stir-fried Shenqu, and 5 parts of Licorice, mix them, add water and soak for 30 minutes. Wherein, the ratio of the total weight of the Chinese medicinal materials to the weight of water can be (1-2): (5-10), and the specific amount of water added can be determined according to the weight of the medicinal materials. (2) Add water and boil three times, and boil for 1.5 hours for the first time. Wherein, the ratio of the total weight of the Chinese medicinal materials to the weight of water is 1:10, and the specific amount of water added can be determined according to the weight of the medicinal materials. (3) Add water and boil for 1.5 hours for the second and third times. Wherein, the ratio of the total weight of the Chinese medicinal materials to the weight of water is 1:8, and the specific amount of water added can be determined according to the weight of the medicinal materials. (4) Combine the filtrates obtained by the three filtrations and filter through 200 mesh to obtain the filtrate. (5) Concentrating at a vacuum degree of -0.06 to -0.08 MPa and a temperature of 70-80°C to a relative density of 1.20-1.25 (50°C) to obtain a clear paste. (6) Using a one-step granulation method, using dextrin and mannitol in a ratio of 8:1 as a base material, spraying the clear paste to obtain granules, and then packaging to obtain the Chinese medicine composition granules.

[0015] Preparation method of honey pills: (1) Take 10 parts of Astragalus, 10 parts of Radix Rehmanniae, 10 parts of Lithospermum officinale, 10 parts of Hedyotis diffusa, 10 parts of Tribulus terrestris, 10 parts of Geranium, 6 parts of Gallnut, 10 parts of stir-fried Shenqu, and 5 parts of raw licorice. (2) Mix and crush the above medicinal materials, pass through a 100-mesh or 120-mesh sieve to make extremely fine powder, and mix the powder and honey in a weight ratio of 1:1.2-1.8 to make honey pills. (3) Each pill is 3g, and 6g is taken each time, twice a day.

[0016] Preparation method of capsules: (1) Take 10 parts of Astragalus, 10 parts of Rehmannia root, 10 parts of Lithospermum officinale, 10 parts of Hedyotis diffusa, 10 parts of Tribulus terrestris, 10 parts of Geranium, 6 parts of Galla chinensis, 10 parts of stir-fried Shenqu, and 5 parts of raw licorice. (2) After mixing and grinding the above medicinal materials, pass through a 100-mesh or 120-mesh sieve to make extremely fine powder, and then put the powder into empty capsules. (3) Each capsule is 0.3g, take 6 capsules each time, and take 3 times a day.

[0017] At the same time, a Chinese medicine composition for preventing and treating adverse reactions related to targeted and immunotherapy, which is prepared using the Chinese medicine composition provided by the present invention as an active ingredient, also falls within the protection scope of the present invention.

[0018] The efficacy and pharmacological effects of the Chinese medicinal materials used in the present invention are as follows:

[0019] Astragalus is the dried root of Astragalus mongolica or Astragalus membranaceus, a plant of the Leguminosae family. It has the effects of replenishing qi and raising yang, consolidating the exterior and stopping sweating, promoting diuresis and reducing swelling, promoting fluid and nourishing blood, relieving stagnation and relieving numbness, expelling toxins and draining pus, and healing wounds and promoting tissue regeneration. It is used to treat edema due to qi deficiency, spontaneous sweating due to exterior deficiency, pain and numbness, carbuncle that is difficult to heal, and carbuncle that does not heal for a long time. Modern pharmacology shows that Astragalus mainly contains chemical components such as astragaloside IV and calycosin glucoside, which can enhance immunity, lower blood pressure, improve blood circulation, and resist oxidation.

[0020] Shengdihuang is a tuber of Rehmannia glutinosa, a plant of the Scrophulariaceae family, which is slowly baked until it is about 80% dry. It has the effects of clearing heat and cooling blood, nourishing yin and promoting body fluid, and is used to treat heat entering the blood, fever caused by warm toxins, vomiting blood and bleeding, yin damage caused by febrile diseases, red tongue and thirst, fever caused by yin deficiency, bone steaming and fatigue fever, and internal heat and thirst. Modern pharmacology shows that Shengdihuang mainly contains chemical components such as rehmannia glutinosa glycoside D and catalpol, which can reduce blood pressure, calm, resist inflammation, resist allergies, strengthen the heart, and act as a diuretic.

[0021] Lithospermum officinale is the dried stem of Xinjiang lithospermum officinale or Inner Mongolia lithospermum officinale of the Boraginaceae family. It has the effects of clearing away heat and cooling blood, promoting blood circulation and detoxifying, and clearing rashes and removing spots. It is used to treat blood heat and toxicity, purple and black rashes, measles that do not clear up, sores, eczema, and burns caused by water or fire. Modern pharmacology shows that lithospermum officinale mainly contains chemical components such as naphthoquinones, monoterpene phenols and benzoquinones, phenolic acids and their salts, alkaloids, etc., which can inhibit bacteria, anti-inflammatory, analgesic, anti-tumor, and hemostasis.

[0022] Oldenlandia diffusa is an annual herbaceous plant. It has the effects of clearing away heat and detoxifying, relieving pain and dispersing knots, and promoting diuresis and removing dampness. It is used to treat various types of inflammation, heat toxins, jaundice, dysentery, etc. Modern pharmacology shows that Oldenlandia diffusa mainly contains chemical components such as vitamins, flavonoids, polysaccharides, etc., which can enhance immune function, antibacterial, anti-tumor, protect the liver and promote bile secretion, and enhance adrenal cortex function.

[0023] Tribulus terrestris is the dried mature fruit of the plant Tribulus terrestris, which belongs to the family Tribulus. It has the effects of calming the liver and relieving depression, promoting blood circulation and dispelling wind, improving eyesight and relieving itching. It is used to treat headache and dizziness, chest and flank pain, breast closure and breast abscess, eye redness and cataract, urticaria and itching. Modern pharmacology shows that Tribulus terrestris mainly contains chemical components such as saponins, flavonoids, alkaloids, polysaccharides, etc., which can enhance sexual function, anti-aging, antibacterial, anti-tumor, regulate blood lipids and treat cardiovascular system diseases.

[0024] Geranium is the dried aerial part of Geranium, Geranium or Wild Geranium of the Geranium family. It has the effects of removing rheumatism, unblocking meridians and stopping dysentery, and is used to treat rheumatic pain, numbness and cramps, muscle and bone pain, diarrhea and dysentery, etc. Modern pharmacology shows that Geranium mainly contains chemical components such as tannins, flavonoids, organic acids and volatile oils, which can be antibacterial, anti-inflammatory, antidiarrheal, liver-protecting and antiviral.

[0025] Gallnut is a gall on the leaves of Rhus chinensis or Populus rubra. It has the effects of astringing the lungs and reducing fire, astringing dampness and sores, astringing the intestines, stopping bleeding, consolidating essence, and astringing sweat. It is used to treat carbuncle, sores, wet and rotten skin, chronic cough due to lung deficiency, chronic diarrhea and dysentery, blood in the stool, spermatorrhea, spontaneous sweating and night sweats, etc. Modern pharmacology shows that the tannins in gallnut can combine with proteins to form water-insoluble macromolecular precipitates, forming a layer of film on the skin ulcers and showing astringent effect. At the same time, small blood vessels are also compressed and contracted, causing blood to coagulate and have a hemostatic effect. It can resist ulcers, resist oxidation, detoxify and inhibit cancer, etc.

[0026] Shenqu is a fermented product made by adding flour or bran to Polygonum hydropiper, Artemisia annua, almond paste, red bean, and fresh Xanthium sibiricum. It is produced all over the country. It has the effects of strengthening the spleen and stomach, digesting food and removing accumulation. It is used to treat food stagnation, indigestion, abdominal distension, loss of appetite, vomiting and diarrhea. Modern pharmacology shows that Shenqu is rich in enzyme substances such as yeast and amylase, which can promote the digestion and absorption of food, thereby improving the spleen and stomach function.

[0027] Raw licorice is the dried root and rhizome of the leguminous plants licorice, licorice inflated fruit or licorice glabra. It has the effects of tonifying the spleen and replenishing qi, clearing away heat and detoxifying, removing phlegm and relieving cough, relieving pain, and harmonizing various medicines. It is used to treat spleen and stomach weakness, fatigue, palpitations and shortness of breath, cough and sputum, abdominal and limb cramps and pain, carbuncle, sore, etc. Modern pharmacology shows that licorice mainly contains triterpenes, flavonoids, polysaccharides, coumarins, volatile oils and amino acids, which can resist tumors, bacteria, viruses, inflammation, regulate immunity, resist oxidation, resist aging, and resist fibrosis.

[0028] The above medicine compatibility plays the function of nourishing yin and replenishing qi, promoting blood circulation and dispelling wind, and removing toxins and removing turbidity. It can effectively prevent or alleviate the adverse reactions related to all systems of the body that occur after targeted therapy and immunotherapy, mainly rash, gastroenteritis and diarrhea, proteinuria, hypertension, hypothyroidism, pneumonia and myocarditis. Symptoms are skin itching, rash, severe skin blistering, peeling or ulceration, diarrhea, even feces with blood and mucus, constipation, abdominal pain, abdominal distension, nausea, vomiting, fatigue, fear of cold, hair loss, depression, chest tightness and shortness of breath, fever, chest pain, cough, palpitations. The Chinese medicine composition of the present invention is applicable to the adverse reactions such as rash, gastroenteritis and diarrhea, hypothyroidism, pneumonia, hypertension, proteinuria, myocarditis caused after tumor targeted therapy and immunotherapy, and has significant effects in adjusting and restoring the physiological functions of internal organs, extending the tolerance period of immunotherapy to enhance the anti-tumor effect, improving prognosis, improving the quality of life of patients, and extending the survival period.

[0029] Specific implementation method: The technical solution of the present invention is further described in detail below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto. DETAILED DESCRIPTION

[0030] The Chinese medicine composition of the present invention is further described below in conjunction with specific examples so that those skilled in the art can better understand the present invention, but the present invention is not limited thereby.

[0031] The various Chinese medicinal materials used in the following examples all comply with the relevant provisions of the Chinese Pharmacopoeia 2020 edition under the various medicinal materials. Before feeding, it was identified that the actual medicinal materials were consistent with the names and the quality met the pharmacopoeia standards.

[0032] Example 1: Preparation of a Chinese medicine decoction for preventing and treating adverse reactions associated with the new generation of targeted and immunotherapy for tumors

[0033] The composition comprises the following components in parts by weight: 10 parts of Astragalus, 10 parts of Radix Rehmanniae, 10 parts of Lithospermum officinale, 10 parts of Hedyotis diffusa, 10 parts of Tribulus terrestris, 10 parts of Geranium, 6 parts of Galla chinensis, 10 parts of Chao Shenqu, and 5 parts of Licorice. According to the prescription, 81g of the Chinese medicinal pieces of the above twelve medicinal materials are measured, 400ml of water is added to soak for 30 minutes after mixing, and all the medicinal materials are boiled for 40 minutes with 400ml of water. The medicinal liquid obtained after boiling is filtered to obtain a filtrate and a filter residue, and the first boiling is finished. The filter residue is taken out, 600ml of water is added to boil for 25 minutes again, and the medicinal liquid obtained after boiling is filtered to obtain a filtrate and a filter residue, and the second boiling is finished. The filtrate obtained by the first boiling is mixed with the filtrate obtained by the second boiling to obtain the water decoction of the Chinese medicine composition, which is taken warm when used.

[0034] Example 2: Preparation of a Chinese medicine composition granule for preventing and treating adverse reactions related to the new generation of tumor targeted and immunotherapy

[0035] The composition comprises the following components in parts by weight: 10 parts of astragalus, 10 parts of raw rehmannia, 10 parts of lithospermum, 10 parts of oldenlandia diffusa, 10 parts of white tribulus, 10 parts of geranium, 6 parts of gallnut, 10 parts of stir-fried Shenqu, and 5 parts of raw liquorice. According to the prescription, 81g of the Chinese medicinal pieces of the above twelve medicinal materials are measured, mixed and decocted three times with water. 900ml of water is added for the first time and decocted for 1.5 hours, and 700ml of water is added for the second and third times and decocted for 1.5 hours. The filtrates obtained by the three filtrations are combined and filtered through 200 mesh to obtain the filtrate. The mixture is concentrated under a vacuum degree of -0.06 to -0.08MPa and a temperature of 70-80°C to a relative density of 1.20-1.25 (50°C) to obtain a clear paste. A one-step granulation method is adopted, with dextrin and mannitol in a ratio of 8:1 as the base material, and clear paste is sprayed in to obtain granules. After packaging, the Chinese medicine composition granules are obtained, which can be taken with hot water when used.

[0036] Example 3: Preparation of a Chinese medicine composition pill for preventing and treating adverse reactions related to the new generation of tumor targeted and immunotherapy

[0037] The composition comprises the following components in parts by weight: 10 parts of astragalus, 10 parts of raw rehmannia, 10 parts of lithospermum, 10 parts of oldenlandia diffusa, 10 parts of white tribulus, 10 parts of geranium, 6 parts of gallnut, 10 parts of stir-fried Shenqu, and 5 parts of raw liquorice. According to the prescription, 81g of the Chinese medicinal pieces of the above 12 medicinal materials are measured, mixed and crushed, and sieved through a 100-mesh or 120-mesh sieve to form an extremely fine powder, and the powder and honey are prepared into honey pills in a weight ratio of 1:1.2-1.8, each pill is 3g, and 6g is taken each time, twice a day.

[0038] Example 4: Preparation of a Chinese medicine composition capsule preparation for preventing and treating adverse reactions related to the new generation of tumor targeted and immunotherapy

[0039] The composition comprises the following components in parts by weight: 10 parts of astragalus, 10 parts of raw rehmannia, 10 parts of lithospermum, 10 parts of oldenlandia diffusa, 10 parts of white tribulus, 10 parts of geranium, 6 parts of gallnut, 10 parts of stir-fried Shenqu, and 5 parts of raw liquorice. According to the prescription, 81g of the Chinese medicinal pieces of the above 12 medicinal materials are measured, mixed and crushed, and then sieved through a 100-mesh or 120-mesh sieve to form an extremely fine powder, which is filled into hollow capsules, each capsule is 0.3g, 6 capsules are taken each time, and taken three times a day.

[0040] Example 5: Typical case:

[0041] The inventors conducted Chinese medicine treatment on patients with adverse reactions related to tumor targeting and immunotherapy, observed the changes in the classification of adverse reactions related to tumor targeting and immunotherapy before and after the intervention, evaluated the clinical efficacy of Chinese medicine preparations, and monitored the effects of Chinese medicine treatment on the blood, liver and kidney functions of patients. No patient reported the safety of Chinese medicine preparation treatment. Among them, Chinese medicine preventive intervention can significantly reduce the unconventional and adverse reactions caused by immune drugs, effectively avoid the reduction, discontinuation and interruption caused by drug toxicity, improve the compliance of patients with immune drug treatment, and ensure the smooth progress of tumor targeting and immunotherapy drugs, so as to benefit patients.

[0042] Case 1: (ADC targeted therapy) Sun, female, underwent left supraclavicular puncture in our hospital on December 22, 2021. The immunohistochemistry results showed that she was in line with classical Hodgkin's lymphoma, nodular sclerosis type. Immunohistochemistry results: CD30 (1+), CD15 (3+), Pax-5 (2+), MUM1 (2+), otc-2 (-), P53 (+95%), Ki-67 (+>50%), ALK (-), PD-L1 Neg (-), PD-L1 (22C3) (TPS=80%; CPS=100). On December 31, 2021, he was treated with Dumoxicillin + Dacarbazine + Vindesine + Velbutrin in an external hospital. During this period, he underwent PET-CT examination in our hospital. The results showed: multiple lymph nodes in the bilateral deep cervical chain, back of the neck, supraclavicular, left axilla and behind the pectoral muscle, mediastinum 1-6, portal space, and retroperitoneum, some of which had slightly increased uptake, and multiple lymph nodes in the right deep cervical and submandibular with mild uptake. There was an increased subcutaneous uptake foci in the left groin, and multiple tiny nodules in both lungs, with no increased uptake, the larger of which was about 0.4 cm. Current symptoms: rash all over the body, especially severe on the hands and feet, with many blisters; itching was still tolerable; oral mucosal ulceration; dry skin, peeling of hands and feet, and cracked toes / nails; 2-6 stools / day, unformed, normal urination; poor appetite, fear of cold, dry mouth and bitter mouth; pale tongue with white fur, and deep and fine pulse. After evaluation, the patient's rash grade was G2 and the KPS score was 75 points. Syndrome analysis: The patient's vital energy is deficient, the drug poison attacks the internal organs, penetrates into the blood, the blood heat runs wildly, and the skin is exposed to the skin, causing herpes. The evil heat combines and seeks the orifices to run, causing oral mucosal ulceration, dry mouth and bitter mouth. Heat burns the yin, causing dry skin, peeling hands and feet, and cracked toes / nails. Heat disturbs the intestines, and the lack of middle qi leads to frequent and unformed stools. However, the patient was found to be afraid of cold, with a pale tongue and white fur, and a deep and thin pulse. It can be seen that the aforementioned fire evil is all virtual fire, which is actually a sign of deficiency of both qi and yin, and the evil poison is strong inside. Diagnosis: Accumulation, rash Treatment principle: invigorating qi and nourishing yin, clearing away heat and detoxicating medicine: take embodiment 1 decoction: Radix Astragali 10g, Radix Rehmanniae 10g, Radix Lithospermi 10g, Herba Hedyotis Diffusae 10g, Fructus Tribulae 10g, Herba Geraniae 10g, Chinensis Gallae 6g, stir-fried Dioscorea 10g, Radix Glycyrrhizae 5g.After 1 dose per day, morning and evening divided serving, and continuing for 14 days, see that patient's whole body rash is obviously improved, except that the rash of the external position of both hands and feet disappears, without pruritus, and the peeling of hands and feet is alleviated, and stool 2 times / day is formed, and appetite is improved, and there is relative fear of cold, without obvious dry mouth and bitter taste. Rash classification is reduced to G1 by G2, and KPS score is 85 points. Re-examination continues to give front consolidation treatment for 14 days, and all symptoms are removed afterwards.

[0043] Case 2: (Immunotherapy) Zhao, male, 75 years old, was found to have esophageal lesions by endoscopic examination on February 13, 2024. Pathology showed severe atypical hyperplasia of squamous epithelium and localized cancer. He then underwent radiotherapy for 30 times and ended on April 3, 2024. After 6 treatments of capecitabine + carrelizumab, he was in maintenance treatment of carrelizumab when he came to the clinic on August 12, 2024. Current symptoms: rash on the face, neck, and chest, no itching, fatigue, hoarseness, facial edema, difficulty swallowing, coughing when drinking water, poor appetite, hiccups, poor sleep, difficulty falling asleep and waking up easily, dry stool, dry mouth and bitter mouth in the morning, red tongue with thin white fur, and stringy and slippery pulse. On August 12, a thyroid function test was ordered, and the results showed: T30.53ng / ml↓, T42.04ug / dl↓, FT30.57pmol / L↓, FT40.18pmol / L↓, TSH 72.4mu / L↑. Syndrome differentiation and analysis: Traditional Chinese medicine calls hypothyroidism "goiter deficiency disease". The patient is old and has kidney yang deficiency. Yang deficiency and water overflowing cause facial edema. Kidney deficiency affects spleen, and spleen and stomach qi are not working well, which leads to poor appetite, hiccups, and dry stool. Spleen and kidney yang deficiency is the root cause, so fatigue occurs. In addition, cancer invasion and chemotherapy drug toxicity cause the patient's qi and blood to malfunction, and fire, qi, stasis, and phlegm combine to cause the disease. Invasion of the upper part of the human body manifests as facial, neck, and chest rashes, dry mouth, bitter mouth, and hoarseness. It is a syndrome of both evil and real, and mixed deficiency and real, and the tongue and pulse are supporting evidence. Diagnosis: Accumulation, goiter, rash Treatment principle: Strengthening the body and detoxifying prescription: Taking the decoction of Example 1, adding and subtracting according to syndrome differentiation: Astragalus 12g, Radix Rehmanniae 12g, Radix Lithospermi 10g, Herba Hedyotis Diffusae 12g, Tribulus Terrestris 9g, Geranium 9g, Galla Chinensis 6g, Stir-fried Dioscorea 10g, Radix Glycyrrhizae 6g, Pinellia 9g, Pericarpium Citri Reticulatae 10g, Rhizoma Anemarrhenae 10g, Rhizoma Atractylodis Macrocephalae 12g for clearing away heat, regulating qi and resolving phlegm, Rhizoma Acorus Calamus 10g, Perilla 6g, Herba Zedoariae 6g for aromatic dampness removal and tranquilizing the mind. 1 dose per day, divided into morning and evening, continued for 28 days, the patient's rash subsided, pruritus, fatigue was alleviated, defecation was smooth, appetite increased, the number of awakenings during sleep decreased, facial edema disappeared, and there was no obvious dry mouth and bitter taste. Thyroid function was rechecked on September 15, 2024, and the results showed that all indicators had improved: T30.74ng / ml↓, T48.23ug / dl, FT31.76pmol / L↓, FT41.11pmol / L↓, TSH40.6mu / L↑, and the patient was given the previous removal method of Pinellia, Tangerine Peel, Rhizoma Anemarrhenae, Atractylodes, Acorus Calamus, Cyperus rotundus, and Eupatorium fortunei. After 28 days of treatment, the thyroid function indicators all returned to normal and did not affect the continuation of immunotherapy.

[0044] Case 3: (Targeted therapy) Tian, ​​male, 56 years old, underwent surgical treatment for medullary thyroid cancer. More than 13 years after the surgery, he underwent surgery again for right submandibular recurrence in 2020. In 2022, he underwent right femoral tumor segment resection in our hospital in April 2022 due to metastasis in the middle and upper segments of the right femur. He started to continue treatment with the targeted drug anlotinib in July 2022. Because the patient developed proteinuria after taking anlotinib, he came to the Department of Traditional Chinese Medicine for treatment on February 29, 2024. The results of the patient's urine routine chemical analysis + urine formed element analysis on February 22, 2024 showed that the specific gravity of urine increased to 1.028, urine protein (3+); the results of the micro total protein (mTP) determination (24-hour urine) showed that the micro total protein in urine increased to 2.81g / 24H. Symptoms at the time of consultation: foam in urine, soreness and heaviness in waist and abdomen, unformed stool, 2-3 times / day, slight pain in lower abdomen, good appetite and sleep, regular urination, dark tongue with yellow greasy coating, slippery and rapid pulse. He had a history of hypertension, and his blood pressure was usually 150 / 90 mmHg. Syndrome differentiation analysis: The patient has metastasis of tumor lesions in his body, and the cancer toxins have not been cleared. In addition, the patient has a phlegm-damp constitution and likes to eat fatty and greasy food, which leads to dampness and phlegm, causing qi stagnation and blood stasis. The dampness tends to go down and stays in the waist, causing waist soreness and slight pain in the lower abdomen. The kidney controls excretion and defecation, and the phlegm-damp evil flows to the lower part of the body, which prevents the kidney water from rising and weakens its warming and metabolic capacity. Protein is seen in the urine and the stool is not formed. It can be seen that the patient has the syndrome of phlegm and blood stasis, and the tongue and pulse are supporting evidence. Diagnosis: Accumulation Treatment principle: detoxification and blood stasis, dampness removal and phlegm removal prescription: take embodiment 1 decoction on the basis of differentiation of symptoms and additions: Astragalus 30g, Radix Rehmanniae 18g, Radix Lithospermi 15g, Herba Hedyotis Diffusae 15g, Tribulus Terrestris 12g, Herba Geraniae 10g, Galla Chinensis 10g, stir-fried Divine Comedy 10g, Radix Glycyrrhizae 6g, add bran stir-fried Atractylodes macrocephalae 10g, Pericarpium Citri Reticulatae 10g, Jiao Sanxian each 10g spleen and dampness, Rhizoma Coptidis 3g, Cortex Phellodendri 5g, Prunus Mume 5g, Rhizoma Zingiberis 3g clear upper and warm lower. Every day 1 dose, morning and evening divided serving, continue 14 days later, patient states that foam in urine reduces, waist and abdomen acid and fatigue alleviates, lower abdominal pain disappears, appetite increases, more feel happy to move, but stool is still not formed. Recheck test result shows: patient's urine protein is reduced to (2+), and trace total protein is reduced to 1.12g / 24H in urine. During the follow-up visit, the patient was given "3g of Coptis chinensis, 5g of Phellodendron chinense, 5g of Prunus mume, and 3g of dried ginger" instead of the previous prescription. After 14 days of consolidation treatment, the test indicators returned to normal, the stools became formed, and there was occasional soreness in the waist and abdomen.

[0045] Case 4: (Targeted therapy) Liu, female, 48 years old, underwent ovarian cancer, uterine, partial colon and peritonectomy in our hospital in April 2021. Postoperative pathology indicated high-grade serous carcinoma and T53 gene mutation frequency of 21%, so she received niraparib treatment. A follow-up examination in December 2023 revealed local thickening of the abdominal and pelvic peritoneum, and strip shadows in the mesenteric area, some of which were new compared to the previous ones, and metastasis was considered. Thickening of the right pleura, right hilar lymph nodes, and lesser curvature of the gastric body, new metastasis was considered. Subsequently, three bevacizumab targeted therapies were performed, and during the treatment, she came to the Department of Traditional Chinese Medicine for treatment on February 27, 2024. Symptoms: dull pain in the lower abdomen, abdominal bloating, diarrhea and loose stools, 3-4 times a day, yellow urine, frequent urination, urgency, incomplete urination, good appetite and sleep, numbness of the tongue, fear of heat, no abnormal sweating, dry mouth and thirst. The tongue is red with yellow fur, and the pulse is thin and weak. The patient's white blood cell count is 15.08x10 9 / L, the absolute value of neutrophils was 11.94x10 9 / L, both are elevated, gastroenteritis is considered. Syndrome differentiation analysis: The patient's cancer toxins invaded the intestines and viscera, and the targeted drugs were strong and damaged the patient's spleen and stomach qi. If the water and food could not be transported and transformed, there would be diarrhea and flatulence; if the qi was stagnant, there would be obstruction, and if there was obstruction, there would be pain, so the patient had abdominal pain; cancer toxins damaged the yin, and the yin was deficient and the fire was strong, resulting in dry mouth and thirst; the bladder yin fluid was boiled and the urine was yellow, with frequent urination, urgent urination, and incomplete urination. Therefore, the patient had the syndrome of qi deficiency and toxicity, and the tongue and pulse were supporting evidence. Diagnosis: Accumulation, diarrhea Treatment principle: Qi-boosting and detoxifying, tonifying deficiency and nourishing Yin prescription: taking embodiment 1 decoction based on syndrome differentiation and addition and subtraction: Radix Astragali 6g, Radix Rehmanniae 6g, Radix Lithospermi 5g, Herba Hedyotis Diffusae 5g, Radix Tribulae 5g, Herba Geraniae 5g, Chrysanthemum chinense 3g, stir-fried Dioscorea opposita 10g, Radix Glycyrrhizae 3g.Add Cortex Moutan 5g, Fructus Gardeniae 5g to clear the fire of intestinal tract, Radix Angelicae Sinensis 5g, Poria 6g, Rhizoma Atractylodis Macrocephalae 5g, Endothelium Corneum 5g to invigorate spleen and stomach qi and blood, strengthen spleen and stomach transportation and transformation ability, Dalbergia Odorifera 3g to remove blood stasis and stop bleeding, regulate qi and relieve pain.Daily 1 dose, morning and evening serving, continue 7 days later, test result shows that patient's leukocyte, neutrophil count is normal, patient's self-report lower abdominal dull pain is relieved, flatulence disappears, stool is formed, 1-2 times / day, urine is slightly yellow, urine is slightly frequent, urgency, incomplete urination sense disappears, still has dry mouth. During the follow-up visit, the previous prescription of "gardenia, stir-fried Atractylodes macrocephala, chicken gizzard lining, and aloeswood" was removed and "6g of salted fennel and 9g of vinegar turtle shell" was added to promote qi and stomach function, assist yang and reduce urine, nourish yin and clear heat. After 14 days of consolidation treatment, the dull pain in the lower abdomen disappeared, the color of urine returned to normal, the dryness of mouth was relieved, and the appetite was enhanced. The patient can continue chemotherapy combined with targeted therapy.

[0046] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A Chinese medicine composition for preventing and treating adverse reactions related to the new generation of tumor targeted and immunotherapy and a preparation method, characterized in that: The composition is composed of the following components in parts by weight: 3-20 parts of astragalus, 3-18 parts of raw rehmannia, 3-15 parts of lithospermum, 3-20 parts of oldenlandia diffusa, 3-20 parts of white tribulus terrestris, 3-18 parts of geranium, 3-12 parts of gallnut, 3-20 parts of stir-fried Shenqu and 3-10 parts of raw licorice.

2. A Chinese medicine composition for preventing and treating adverse reactions related to the new generation of tumor targeted and immunotherapy and a preparation method, characterized in that: The composition consists of the following components in parts by weight: 5-15 parts of astragalus, 5-12 parts of raw rehmannia, 5-10 parts of lithospermum, 5-15 parts of oldenlandia diffusa, 5-15 parts of white tribulus terrestris, 5-12 parts of geranium, 3-12 parts of gallnut, 3-20 parts of stir-fried Shenqu and 3-8 parts of raw licorice.

3. A Chinese medicine composition for preventing and treating adverse reactions related to the new generation of tumor targeted and immunotherapy and a preparation method thereof as claimed in claim 1, characterized in that: The composition is composed of the following components in parts by weight: 10 parts of astragalus, 10 parts of raw rehmannia, 10 parts of lithospermum, 10 parts of oldenlandia diffusa, 10 parts of white tribulus, 10 parts of geranium, 6 parts of gallnut, 3-20 parts of stir-fried Shenqu and 5 parts of raw licorice.

4. A Chinese medicine composition for preventing and treating adverse reactions related to the new generation of targeted and immunotherapeutic treatments for tumors, wherein the active ingredient is the Chinese medicine composition described in any one of claims 1 to 3.

5. Use of the Chinese medicine composition described in any one of claims 1 to 3 in the preparation of a Chinese medicine decoction / granule / pill / capsule preparation for preventing and treating adverse reactions related to the new generation of targeted and immunotherapy for tumors.