Protective agent for preventing and / or treating damage to the digestive tract by chemotherapy drugs and use thereof

Abstract

This invention relates to protective agents for preventing and / or treating gastrointestinal damage caused by chemotherapy drugs and their applications. More specifically, it relates to the use of fullerene materials in the preparation of medicaments for preventing and / or treating gastrointestinal damage caused by chemotherapy drugs, wherein the medicament is a formulation suitable for gastrointestinal administration, and the fullerene in the fullerene material includes one or more of prototype fullerenes and fullerene derivatives, wherein the prototype fullerene includes one or more of hollow fullerenes and metallofullerenes. Application of the fullerene material can significantly improve gastrointestinal damage caused after administration of chemotherapy drugs.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, specifically to a protective agent for preventing and / or treating gastrointestinal damage in patients with chemotherapy drugs, and its application in preventing and / or treating gastrointestinal damage. Background Technology

[0002] Chemotherapy, as the main treatment for tumors that have already metastasized clinically, is a systemic treatment. Chemotherapy drugs circulate throughout the body's organs and tissues via the bloodstream, so their toxicity mainly affects rapidly growing tissues. Cancer cells, due to their rapid growth, are most sensitive to chemotherapy drugs. Gastrointestinal mucosal cells are proliferative cells with high growth capacity and a lifespan of only 3-5 days. Therefore, while chemotherapy drugs kill cancer cells, they also cause significant damage to gastrointestinal mucosal cells, destroying normal intestinal epithelial cells and immune cells, causing severe intestinal dysfunction, and even intestinal obstruction.

[0003] Chemotherapy-induced colitis, distinct from food contamination (e.g., deoxynivalenol, DON) infection, chemical or physical irritation-induced inflammation, is a major dose-limiting adverse reaction to chemotherapy, particularly in regimens containing irinotecan (CPT) (Cancer. 2014; 120:1453-1461; Ann Oncol. 2015; 26(Suppl 5):v139-v151.), with a clinical incidence as high as 83% (Curr Oncol. 2007; 14:13-20.). It hinders the effective use of chemotherapy and reduces patients' quality of life. Although the European Society for Medical Oncology (ESMO) clinical guidelines recommend several adjuvant drugs (such as ranitidine, omeprazole, and octreotide), their efficacy is unsatisfactory (Curr Oncol Rep. 2015; 17:50.). In recent years, due to the prominent role of intestinal ischemia-induced colitis in clinical chemotherapy, research on its related mechanisms has increased significantly. Chemotherapy drugs, including CPT, paclitaxel, cisplatin, carboplatin, 5-fluorouracil, and etoposide, have been reported to cause ischemic injury, with histological examination revealing extensive ischemic injury accompanied by vasodilation and revascularization after colonoscopy and hemicolectomy. However, the precipitating factors for ischemic injury in chemotherapy-induced colitis remain unclear.

[0004] Chemotherapy drugs generally have poor selectivity for normal human cells. While killing tumor cells, they inevitably damage normal cells as well. The adverse reactions of chemotherapy can affect a patient's quality of life, either temporarily or long-term, and may limit the dosage and duration of treatment. In severe cases, they can even be life-threatening. In recent years, the development of adjuvant chemotherapy drugs has made a significant contribution to improving the efficacy of chemotherapy and reducing adverse reactions. Existing adjuvant drugs mainly include:

[0005] 5-HT3 (5-HT3) receptor antagonists: Nausea and vomiting caused by cytotoxic chemotherapy drugs are mainly due to damage to the gastrointestinal mucosa, especially the ileum, caused by these drugs. Mucosal damage leads to the release of 5-HT from chromaffin cells in the intestinal epithelium, which stimulates 5-HT3 receptors on the vagus nerve, thereby exciting the vomiting center and inducing a vomiting response, or transmitting the signal to the vomiting center through excitation of chemoreceptors. 5-HT3 receptor antagonists mainly exert their antiemetic effect by competitively blocking the binding of 5-HT released from the gastrointestinal mucosa to 5-HT3 receptors. Adverse reactions include headache, constipation, diarrhea, sedation, and mild elevation of transaminase levels. Overdose may cause visual hallucinations and elevated blood pressure. There are also reports of transient electrocardiographic changes. In addition, 5-HT3 receptor antagonists only act on 5-HT3 receptors to inhibit the vomiting response and cannot prevent or protect the intestinal mucosa. Although they relieve the patient's vomiting response, the continuous damage to the intestinal mucosa caused by chemotherapy drugs does not stop.

[0006] Hematopoietic cell colony-stimulating factors (CSFs): CSFs are glycoproteins that act on hematopoietic cells. They bind to specific cell surface receptors, stimulating cell proliferation, promoting differentiation, and activating some terminal cell functions. The CSFs used in tumor chemotherapy are mainly granulocyte and granulocyte-macrophage colony-stimulating factors (G-CSF, GM-CSF), which are widely used in routine tumor treatment. The main cells producing G-CSF are monocytes / macrophages, endothelial cells, and fibroblasts, while the cells producing GM-CSF are T cells, monocytes / macrophages, endothelial cells, and fibroblasts. These cells can be induced to produce G-CSF and GM-CSF by antigen stimulation such as bacterial infection. G-CSF specifically acts on precursor cells of granulocytes / macrophages (CFU-GM), promoting their proliferation and differentiation. It not only increases the number of neutrophils but also acts on mature neutrophils, promoting their release from the bone marrow to the periphery and enhancing their migration, phagocytosis, and bactericidal abilities. In addition to having a similar effect on neutrophils as G-CSF, GM-CSF can also enhance the phagocytic capacity of eosinophils. The main side effect of G-CSF is bone pain, and adverse reactions include fever, nausea, fatigue, headache, bone pain, chills, loss of appetite, and pain at the injection site.

[0007] Amifostine (Ethyol) is an organothiophosphate. In vivo, amifostine is activated by alkaline phosphatase (AKP) and loses its phosphorylated group, becoming the active metabolite WR1605, which contains free sulfhydryl groups. WR1605 can scavenge oxygen free radicals, thereby repairing damaged molecules. Amifostine's selective protective effect on normal tissues is mainly due to the higher concentration of free sulfhydryl groups that normal tissues can take up. Clinically, it is used to reduce chemotherapy-induced nephrotoxicity, hematological toxicity, neurotoxicity, and ototoxicity. The main adverse reaction is hypotension. Other adverse reactions include nausea, vomiting, dizziness, hot flashes, mild drowsiness, a metallic taste in the mouth, and occasionally allergic reactions. Transient hypocalcemia has also been reported.

[0008] Bisphosphonates: Bisphosphonates have a high affinity for bone and are preferentially transported to sites of accelerated bone formation or resorption. Once deposited on the bone surface, they are taken up by osteoclasts, which have osteoclast-like activity. They inhibit the dissolution and destruction of bone trabeculae by osteoclasts, thus preventing osteolytic lesions caused by tumors, reducing bone resorption, alleviating pain, and reducing hypercalcemia and other complications caused by bone metastases. It is also believed that tumor cells cause bone destruction, and the cytokines or growth factors released from the destroyed bone can stimulate the activity and growth of tumor cells. Bisphosphonates can block this effect, slowing the occurrence and development of bone metastases, and can lead to the death of some tumor cells. Bisphosphonates also have some therapeutic effect on osteoporosis. The main side effects are increased body temperature, flu-like symptoms, transient pain, gastrointestinal reactions, transient myopathy, and arthropathy; mild reactions at the injection site are occasionally observed. Bisphosphonates have no effect on the overall survival of cancer patients; all studies have failed to find any improvement in survival. The main purpose is to reduce skeletal complications such as pathological fractures, fractures or spinal cord compression, and hypercalcemia.

[0009] Mesna: It can prevent urinary tract epithelial toxicity such as hemorrhagic cystitis caused by high-dose ifosfamide or cyclophosphamide chemotherapy for tumors. It can also be used in combination with antitumor chemotherapy drugs ifosfamide or cyclophosphamide as a urinary tract protectant.

[0010] Interleukin-11 (IL-11): In the human body, IL-11 is produced by primitive bone marrow stromal cells. It stimulates the growth of primitive hematopoietic stem cells and promotes the differentiation and maturation of macrophage precursor cells. Animal experiments have shown that IL-11 can promote the recovery of platelet count and alleviate thrombocytopenia in animals with bone marrow suppression. The main adverse reaction is water and sodium retention, which may cause peripheral edema, dyspnea, and fatigue. In severe cases, pleural effusion, ascites, and pericardial effusion may occur. Water and sodium retention can lead to a decrease in hemoglobin and red blood cell count, and sometimes patients need red blood cell transfusions. Local pain and swelling may occur at the injection site. A few patients may also experience rash, anorexia, temporary blurred vision (caused by papilledema), antibody formation, and allergies.

[0011] Calcium leucovorin (CF): It serves as an antidote for folic acid antagonists such as methotrexate, pyrimethamine, or trimethoprim, and can also be used as adjuvant therapy for colorectal cancer. Combined use with fluorouracil can prolong patient survival. Adverse reactions include gastrointestinal disturbances, insomnia, depression, or irritability after high doses.

[0012] Although existing chemotherapy adjuvant drugs can alleviate the side effects of chemotherapy, each adjuvant drug addresses only a single side effect and does not protect the digestive tract from chemotherapy damage. Moreover, there are currently no drugs on the market that can protect or prevent chemotherapy drugs from damaging the digestive tract.

[0013] Fullerene (C 60 Carbon is the third allotrope of carbon. Internally, it is a hollow, soccer ball-shaped molecule composed of 60 carbon atoms forming 60 vertices, 32 faces (including 12 regular pentagons and 20 regular hexagons, where the pentagons are not connected to each other but only adjacent to the hexagons), and 30 carbon-carbon double bonds. Each carbon atom is connected to three adjacent carbon atoms via sp2 hybrid orbitals, and the remaining p orbitals are in the C... 60 π bonds are formed between the outer periphery and the inner cavity of the molecule. Fullerenes are known as "free radical sponges," and studies have shown that they possess a variety of biological functions, including antioxidant activity, broad-spectrum cell protection, radiation protection, and relief of gastric ulcers. Therefore, fullerenes have great potential in preventing / treating gastrointestinal damage in chemotherapy patients. Summary of the Invention

[0014] The purpose of this invention is to provide the use of a fullerene material in the preparation of a medicament for preventing and / or treating gastrointestinal damage caused by chemotherapy drugs, particularly the application of the fullerene material before administering chemotherapy drugs to a patient, which can significantly improve gastrointestinal damage caused by chemotherapy drugs.

[0015] Specifically, the present invention aims to provide the use of fullerene materials in the preparation of medicaments for the prevention and / or treatment of gastrointestinal damage caused by chemotherapy drugs, wherein the medicaments are formulations suitable for administration via the gastrointestinal tract, and the fullerenes in the fullerene materials include one or more of prototype fullerenes and derivatives of fullerenes, wherein the prototype fullerenes include one or more of hollow fullerenes and metallofullerenes.

[0016] In one embodiment, the prototype fullerene is C 60 C 70 C 82 Or a mixture thereof.

[0017] In one embodiment, the fullerene is a water-insoluble fullerene.

[0018] In one embodiment, the water-insoluble fullerene is selected from one or more of water-insoluble hollow fullerenes and water-insoluble metal fullerenes.

[0019] In one embodiment, the water-insoluble fullerene is selected from C 60 C 70 C 82 and one or more of their derivatives.

[0020] In one embodiment, the water-insoluble hollow fullerene is one or more of the general formula C 2m The cage-like structure composed of carbon atoms, 30≤m≤60; preferably, 30≤m≤45; more preferably, m is 30, 35 or 41;

[0021] In one embodiment, the water-insoluble metal fullerene comprises M@C 2n M2@C 2n MA@C 2n M3N@C 2n M2C2@C 2n M2S@C 2n M2O@C 2n and M x A 3-x N@C 2n One or more of the following, wherein: M and A both represent metallic elements and M and A are selected from any one of Sc, Y and lanthanide metals, 30≤n≤60, 0≤x≤3; preferably, the metal fullerene is a C-type metal with embedded Gd, Ca, Sr, Ba, Sc, Y, La and lanthanide metals (Ce~Lu) and some actinide metals (Th~Am). 60 C 70 C 82 Or a combination thereof; preferably, the metallofullerene is Gd@C 82 .

[0022] In one embodiment, the chemotherapy drug is selected from chemotherapy drugs that can cause damage to the gastrointestinal tract.

[0023] In one embodiment, the chemotherapeutic agent is selected from one or more of microtubule activity inhibitors, dihydrofolate reductase inhibitors, platinum complexes, DNA topoisomerase inhibitors, and uracil derivatives.

[0024] In one embodiment, the DNA topoisomerase inhibitor includes one or more of camptothecin, hydroxycamptothecin, irinotecan, and topotecan.

[0025] In one embodiment, the uracil derivative includes one or more of 5-fluorouracil, difluorouracil, deoxyfluorouridine, and carmofluorine.

[0026] In one implementation, the prevention and / or treatment of gastrointestinal damage caused by chemotherapy drugs includes gastric damage or disease caused by chemotherapy drugs, and intestinal damage or disease caused by chemotherapy drugs.

[0027] In one embodiment, the gastrointestinal injury includes inflammatory diseases of the gastrointestinal tract, ischemic gastrointestinal injury, intestinal obstruction, diarrhea, constipation, and fecal occult blood; preferably, the gastrointestinal disease is selected from gastrointestinal mucosal inflammation.

[0028] In one embodiment, the formulation suitable for gastrointestinal administration comprises a fullerene material and a pharmaceutically acceptable carrier; preferably, the formulation suitable for gastrointestinal administration is selected from tablets, pills, powders, lozenges, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, capsules, or sterile packaged powders for injection.

[0029] The inventors of this invention have discovered that administering fullerene preparations via the gastrointestinal tract (e.g., orally or via enema) can effectively protect against damage caused by chemotherapy drugs, especially damage to the digestive tract.

[0030] The inventors of this invention have further discovered that administering a fullerene preparation with the prototype fullerene as the active ingredient via the gastrointestinal tract can effectively protect against damage caused by chemotherapy drugs, especially damage to the digestive tract.

[0031] Specifically, the fullerene formulation of the present invention can be taken before taking chemotherapy drugs, taken simultaneously with chemotherapy drugs, or taken after taking chemotherapy drugs. For example, it can be taken the day before taking chemotherapy drugs.

[0032] The fullerene formulation comprises 0.1-50% by weight of fullerene material and excipients; preferably, the fullerene formulation comprises 0.1-33.5% by weight of fullerene material and excipients; more preferably, the fullerene material comprises 0.1-20% by weight of fullerene material and excipients; even more preferably, the fullerene formulation comprises 0.1-1% by weight of fullerene material and excipients.

[0033] Preferably, the excipient is an inert excipient, more preferably an inert excipient.

[0034] Preferably, the excipients are selected from one or more of the following: sodium carboxymethyl cellulose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, tragacanth gum, xanthan gum, gum arabic, sodium alginate, starch paste, pregelatinized starch, talc, copovidone, poloxamer, glycerin, gelatin, olive oil, propylene glycol, potassium sorbate, disodium edetate, vitamin C, methylparaben, ethylparaben, propylparaben, phenoxyethanol, glyceryl monooctanoate, thimerosal, colloidal silica, and polyethylene glycol.

[0035] The drugs that prevent and / or treat gastrointestinal damage caused by chemotherapy drugs exert their effects through one or more of the following pathways: promoting cell proliferation, increasing white blood cell levels, increasing platelet levels, protecting the gastrointestinal mucosa, reducing mesenteric vasoconstriction, and preventing ischemic damage to the gastrointestinal tract.

[0036] The present invention also aims to provide a protective agent for preventing and / or treating gastrointestinal damage caused by chemotherapy drugs, said protective agent being a formulation suitable for administration via the gastrointestinal tract, said protective agent comprising 0.1-50% by weight of fullerene material and excipients; preferably, said protective agent exerts its effect through one or more of the following pathways: promoting cell proliferation, increasing white blood cell levels, increasing platelet levels, protecting the gastrointestinal mucosa, reducing mesenteric vasoconstriction, and preventing ischemic damage to the gastrointestinal tract.

[0037] In one embodiment, the fullerene formulation or protectant comprises 0.1-50% by weight of fullerene material, 0-10% sodium carboxymethyl cellulose and / or 0-60% microcrystalline cellulose.

[0038] In one embodiment, the fullerene formulation or protectant is a fullerene suspension comprising 0.1-20% by weight of fullerene, 1.2-5% by weight of sodium carboxymethyl cellulose, 0.1-0.62% by weight of microcrystalline cellulose, and 0.01-0.5% by weight of poloxamer. Optionally, it also comprises 0.01-0.2% by weight of methylparaben and / or 0.01-0.1% by weight of propylparaben.

[0039] In one embodiment, the fullerene formulation or protectant is a fullerene powder comprising 0.1-50% by weight of fullerene, 1-5% by weight of pregelatinized starch, and 1-60% by weight of microcrystalline cellulose. Optionally, it also comprises 1-10% by weight of colloidal silica and / or 0.1-2% by weight of disodium edetate.

[0040] In one embodiment, the fullerene formulation or protectant is a fullerene granule comprising 0.1-50% by weight of fullerene, 1-5% by weight of sodium carboxymethyl cellulose, 1-60% by weight of pregelatinized starch, and 1-10% by weight of copovidone. Optionally, it also comprises 1-5% by weight of talc and / or 0.1-2% by weight of disodium edetate.

[0041] In one embodiment, the fullerene formulation or protectant is a fullerene hard capsule comprising 0.1-50% by weight of fullerene, 1-10% by weight of sodium carboxymethyl cellulose, 1-60% by weight of microcrystalline cellulose, and 1-10% by weight of copovidone. Optionally, it also comprises 1-10% by weight of colloidal silica, 1-5% by weight of low-substituted hydroxypropyl cellulose, and / or 0.1-2% by weight of vitamin C.

[0042] In one embodiment, the fullerene formulation or protectant is a fullerene tablet comprising 0.1-50% by weight (preferably, optionally from 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%) of fullerene, 1-10% by weight (preferably, optionally from 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%) of sodium carboxymethyl cellulose, 1-70% by weight (preferably, optionally from 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%) of microcrystalline cellulose, and 1-10% by weight (preferably, optionally from 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%) of copovidone. Optionally, it also comprises 0.1-5% by weight (preferably, optional from 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%) of xanthan gum, 1-10% by weight (preferably, optional from 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%) of colloidal silica, 1-25% by weight (preferably, optional from 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%) of low-substituted hydroxypropyl cellulose, and 0.1-2% by weight (preferably, optional from 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%) of disodium edetate. Optionally, it also contains 0.1-5% vitamin C, 0.1-1% butylated hydroxyanisole, 0.1-5% tocopherol, 0.1-2% propyl gallate, 0.1-4% ascorbyl palmitate, arginine, and / or 0.1-3% citric acid.

[0043] In one embodiment, the fullerene formulation or protectant is a fullerene soft capsule comprising 0.1-1% by weight of fullerene, 60-80% by weight of olive oil, 2-4% by weight of glycerin, and 6-13% by weight of gelatin. Optionally, it also comprises 0.5-5% by weight of polyethylene glycol (e.g., PEG200, PEG400).

[0044] The present invention also aims to provide a method for preventing and / or treating gastrointestinal damage caused by chemotherapy drugs using fullerene materials in the above-mentioned applications, the method comprising: administering an effective dose of the fullerene material into an organism requiring prevention and / or treatment of gastrointestinal damage caused by chemotherapy drugs; preferably, the fullerene material acts directly on the gastrointestinal tract to exert a protective effect on the gastrointestinal tract.

[0045] The fullerene materials involved in this invention have the following advantages in the application, protective agent, and method of preparing drugs for preventing and / or treating gastrointestinal damage caused by chemotherapy drugs:

[0046] The fullerene material involved in this invention can promote cell proliferation, increase white blood cell levels, increase platelet levels, protect the digestive tract mucosa, reduce intestinal vasoconstriction, and prevent ischemic damage to the gastrointestinal tract caused by chemotherapy drugs, thereby improving intestinal function and enhancing patients' quality of life. In particular, it can be administered via the gastrointestinal tract to directly protect the digestive tract mucosa from chemotherapy damage, thus better preventing digestive tract damage caused by chemotherapy drugs. Attached Figure Description

[0047] Figure 1 The results of histopathological sections in Example 7 are shown.

[0048] Figure 2 The effect of fullerene on the state of fluorouracil-induced gastrointestinal damage in mice is shown in Example 8.

[0049] Figure 3 The effect of fullerene on disease activity (DAI) in mice with fluorouracil-induced gastrointestinal injury is shown in Example 8.

[0050] Figure 4 The effect of fullerene on blood counts (WBC: white blood cells; Neu: neutrophils; Lym: lymphocytes) in mice with fluorouracil-induced gastrointestinal injury is shown in Example 8.

[0051] Figure 5 The effect of fullerene on fecal occult blood in mice with CTP-induced gastrointestinal damage is shown in Example 9.

[0052] Figure 6 The effect of fullerene on the state of CTP-induced gastrointestinal damage in mice is shown in Example 9.

[0053] Figure 7 The effect of fullerene on blood counts in mice with CTP-induced gastrointestinal injury, as shown in Example 9 (40 mg / (kg·d) group), is illustrated.

[0054] WBC: white blood cells; Neu: neutrophils; Lym: lymphocytes.

[0055] Figure 8 The effect of fullerene on platelet count in mice with CTP-induced gastrointestinal injury is shown in Example 9 (40 mg / (kg·d) group).

[0056] Figure 9 An anatomical diagram of the mouse digestive tract in Example 9 is shown, where the arrow indicates large intestine obstruction (40 mg / (kg·d) group).

[0057] Figure 10The histopathological images of mouse colorectal tissue in Example 9 are shown (40 mg / (kg·d) group).

[0058] Figure 11 An anatomical diagram of the mouse digestive tract in Example 10 is shown.

[0059] Figure 12 The results of the antioxidant capacity test of the fullerene material in Example 12 are shown. Detailed Implementation

[0060] Based on the above description of the present invention, and in accordance with common technical knowledge and conventional methods in the field, various other modifications, substitutions, or alterations can be made without departing from the basic technical concept of the present invention.

[0061] I. Definition

[0062] Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "comprising" shall be understood to include the stated elements or components without excluding other elements or other components.

[0063] As used in this article, the terms "gastrointestinal damage caused by chemotherapy drugs" and "chemotherapy-induced enteritis" include gastrointestinal damage caused by chemotherapy drugs and the diseases resulting from this damage, such as nausea, vomiting, intestinal obstruction, diarrhea, fecal occult blood, and anemia. Gastrointestinal damage caused by chemotherapy differs from gastrointestinal damage caused by food contamination, chemical or physical irritation, and can directly impair intestinal function, leading to intestinal adhesions, tissue edema, and fecal impaction. The term "gastrointestinal damage caused by food contamination, chemical or physical irritation" includes inflammation caused by bacteria, pathogens, fungi, and parasites, which is often relieved by adjusting diet, rest, or administering medications such as mesalazine and glucocorticoids to control inflammation.

[0064] As used herein, the term "fullerene" is a series of spherical cluster molecules composed of an even number of carbon atoms, consisting of 12 five-membered rings and the rest six-membered rings; it is a cage-like structure composed of carbon atoms. Fullerenes include hollow fullerenes and metallofullerenes, wherein the hollow fullerene is a cage-like structure composed of a single carbon atom.

[0065] The term "metal fullerene" refers to a class of compounds with unique structures and properties formed by incorporating various atoms, ions, or atomic clusters within the carbon cage structure of fullerenes. These compounds are commonly referred to as endohedral fullerenes, typically denoted by M@C. 2n The form is represented as M, where M represents a metallic element.

[0066] The term "water-insoluble fullerene" mainly refers to fullerene materials such as hollow fullerenes and metal fullerene particles that are basically insoluble in water. When these materials are used to prepare drugs or health foods, they can only be administered through the gastrointestinal route.

[0067] The term "water-soluble fullerene," also known as "water-soluble fullerene modifier" or "water-soluble fullerene derivative," refers to the water-soluble modification of fullerene particles, such as hollow fullerenes and metallofullerenes. The modified fullerene particles are externally modified with multiple water-soluble functional groups. These chemical functional groups contain one or more hydrophilic groups, such as hydroxyl, carboxyl, thiol, or amino groups, or combinations thereof, making the fullerene particles soluble in water. Alternatively, metallofullerenes or their derivatives can be directly modified with hydrophilic small biomolecules such as amino acids or peptide chains. Fullerenes or their derivatives can also be loaded onto biocompatible carrier materials, such as liposomes or cell membrane carriers, or formed through self-assembly into water-soluble supramolecular systems. All of the above modification methods can be performed according to methods disclosed in the prior art.

[0068] As used herein, the term "water-insoluble fullerene" refers to hollow fullerenes, metallofullerenes, or their derivatives that have not undergone water-solubility modification. In particular, it includes, for example, fullerenes that are practically insoluble in water. Furthermore, the water-insoluble fullerene may be a water-insoluble hollow fullerene, which can be defined as one or more substances of the general formula C1. 2m A cage-like structure composed of carbon atoms, 30≤m≤60 or 30≤m≤45; preferably, m is 30, 35 or 41. Examples of water-insoluble hollow fullerenes include C1. 60 C 70 C 82 Or combinations thereof. For example, insoluble fullerenes can also be defined as those selected from the formula M@C. 2n M2@C 2n MA@C 2n M3N@C 2n M2C2@C 2n M2S@C 2n M2O@C 2n and M x A 3-x N@C 2n The metallofullerene is a fullerene derivative composed of one or more elements from the group consisting of Sc, Y, and lanthanides. M and A represent metallic elements, and both M and A are selected from any one of Sc, Y, and lanthanides, where 30 ≤ n ≤ 60 and 0 ≤ x ≤ 3. For example, M and A can be Gd, Ca, Sr, Ba, Sc, Y, La, as well as lanthanides (Ce-Lu) and some actinides (Th-Am). Specifically, the metallofullerene is a C-type metallofullerene with embedded Gd metal. 60 C 70 C 82Or a combination thereof.

[0069] Correspondingly, the term "water-soluble fullerene" refers to the water-soluble modification of fullerene particles such as hollow fullerenes and metallofullerenes. The modified fullerene particles are externally modified with multiple water-soluble functional groups, such as hydrophilic groups or combinations thereof, such as hydroxyl, carboxyl, mercapto, or amino groups, which make the fullerene particles soluble in water.

[0070] In this invention, all disclosures of ranges should be considered as disclosures of all sub-ranges and all point values ​​within the range. For example, a disclosure of 1-50% should be considered as also disclosing ranges such as 10-40%, 10-50%, and 30-50%, as well as point values ​​such as 20%, 30%, and 33.5%.

[0071] The term "treatment" includes suppressing, alleviating, or eliminating one or more symptoms or side effects associated with the disease, condition, or disorder being treated.

[0072] The terms “reduction,” “inhibition,” “mitigation,” or “reduction” are used relative to a control. Those skilled in the art will readily determine the appropriate control for each experiment. For example, a reduced response in a subject or cell treated with the compound is compared to a response in a subject or cell not treated with the compound.

[0073] As used herein, the term "effective dose" or "therapeutic effective dose" refers to a dose sufficient to treat, suppress, or alleviate one or more symptoms of the treated disease state or otherwise provide the desired pharmacological and / or physiological effect. The precise dose will vary depending on a variety of factors, such as subject-dependent variables (e.g., age, immune system health, etc.), the disease or illness, and the treatment administered. The effect of an effective dose can be relative to a control. These controls are known in the art and discussed herein, and can be, for example, the condition of the subject before or without administration of the drug or combination of drugs, or, in the case of a combination of drugs, the combined effect can be compared to the effect of administration of only one drug.

[0074] As used in this article, the term "preparation for gastrointestinal administration" refers to a dosage form in which a drug preparation enters the gastrointestinal tract and is absorbed through the gastrointestinal tract or exerts its therapeutic effect directly in the gastrointestinal tract without being absorbed through the gastrointestinal tract. Its administration method is relatively simple, such as commonly used powders, tablets, granules, capsules, solutions, emulsions, suspensions, etc. Drugs that are easily destroyed by acids (or enzymes) in the gastrointestinal tract generally cannot be simply administered using this type of dosage form.

[0075] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following embodiments. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention.

[0076] II. Examples

[0077] The present invention is further illustrated below with reference to embodiments. The description of specific exemplary embodiments of the invention is for illustrative and explanatory purposes. These descriptions are not intended to limit the invention to the precise forms disclosed, and it will be apparent that many changes and variations can be made in accordance with the teachings of this specification. The exemplary embodiments were chosen and described in order to explain the specific principles of the invention and its practical application, thereby enabling those skilled in the art to implement and utilize various different exemplary embodiments of the invention, as well as various different choices and variations.

[0078] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0079] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0080] Example 1: Fullerene suspension

[0081] <![CDATA[Fullerene C 60 > 0.1-20 Sodium carboxymethyl cellulose 1.2-5 microcrystalline cellulose 0.1-0.62 Polosham 407 (F127) 0.01-0.5 Methylparaben 0.01-0.2 Propylparaben 0.01-0.1 Purified water Supplement to 100

[0082] Preparation method: Weigh each component according to the above formula and prepare the suspension using conventional methods.

[0083] Example 2: Fullerene Powder

[0084] <![CDATA[Fullerene C 60 > 33.5 Pregelatinized starch 5 microcrystalline cellulose 51 colloidal silica 1.5 Sodium edetate 0.5 Made 1000g

[0085] Preparation method: Weigh each component according to the above formula and prepare the powder using conventional methods.

[0086] Example 3: Fullerene Granules

[0087] <![CDATA[Fullerene C 60 > 33.5 Sodium carboxymethyl cellulose 3 Pregelatinized starch 50 Copolyvinylpyrrolidone 5 talcum powder 2 Sodium edetate 0.5 Purified water Supplement to 100 Granulation 1000g

[0088] Preparation method: Weigh each component according to the above formula and prepare granules using conventional methods.

[0089] Example 4: Fullerene Hard Capsules

[0090] Fullerenes 33.5 Sodium carboxymethyl cellulose 5 Microcrystalline fiber 102 51 Copolyvinylpyrrolidone 5 colloidal silica 1.5 Low-substituted hydroxypropyl cellulose 4 Vitamin C 0.1 Empty capsule shell 1000 pills Made 1000 pills

[0091] Preparation method: Weigh each component according to the above formula and prepare hard capsules using conventional methods.

[0092] Example 5: Fullerene Tablets

[0093]

[0094]

[0095] Preparation method: Weigh each component according to the above formula and prepare tablets using conventional methods.

[0096] Example 6: Fullerene soft capsules

[0097] <![CDATA[Fullerene C 60 > 0.1-1 olive oil 60-80 glycerin 2-4 gelatin 6-13 PEG200 0.5-5 water 12-15 Made 1000 pills

[0098] Preparation method: Weigh each component according to the above formula and prepare soft capsules using conventional methods.

[0099] Fullerene C used in the formulations of Examples 1-6 above 60 , can be replaced with C 70 C 82 , or selected from C 60 C 70 C 82 Other fullerene formulations can be obtained by mixing one or more of their derivatives.

[0100] Example 7: Damage to the digestive tract caused by chemotherapy drugs and its evaluation method

[0101] (1) Damage to the digestive tract of animals caused by chemotherapy drugs

[0102] Inflammatory bowel disease modeling method: single enema with 10% DNBS ethanol solution; Chemotherapy-induced enteritis modeling method: intraperitoneal injection of irinotecan; Histopathological section preparation method: conventional paraffin section preparation method.

[0103] Histopathological examination showed ( Figure 1 In the inflammatory bowel disease model group, the colon showed pathological changes such as mucosal ulceration and hyperplasia, with the inflammatory pathological changes limited to the area within the black circle, while no pathological changes were observed in the ileum. In the chemotherapy-induced enteritis model group, the colon showed extensive intestinal tissue edema, submucosal inflammatory cell infiltration, and microthrombus and mixed thrombus formation. At the same time, the ileum also showed changes such as reduced crypts, shortened and sparse intestinal villi.

[0104] (2) Observation indicators: Meetere animal status score, DAI score (weight change, fecal occult blood), WBC (blood cell analyzer test).

[0105] Table 1. Chemotherapy Mouse Status Scoring Table (0-10 points)

[0106]

[0107]

[0108] Table 2 Body Weight and Fecal Occult Blood Score Table

[0109] 0 0 normal negative occult blood 1 1-5 soft stool Weak positive for occult blood 2 6-10 loose stool Occult blood positive 3 11-20 loose stool bloody stool 4 >20 extremely loose stools Severe bloody stools

[0110] Table 3 Pathological Score Table

[0111]

[0112] Example 8: Therapeutic effect of fullerene on digestive tract injury induced by 5-fluorouracil (5-FU)

[0113] Forty adult Balb / c mice, aged 12-14 weeks, male, were purchased from Beijing Huafukang Bioscience Co., Inc.; the experimental animals were raised in the animal room of Institute of Chemistry, Chinese Academy of Sciences, with the feeding certification number: SYXK (Jing) 2018-0033. The tested animals were housed in sterile independent ventilated IVC cages, 5 animals per cage. The bedding was 60 corn cob bedding sterilized by Co radiation, with a particle size of 4-6 mm. The animals were fed with sterilized feed specially prepared for mice, and had free access to purified water. The temperature in the animal laboratory was maintained at about 25°C, the relative humidity was maintained at 40-70%, and the daily light exposure was 12 hours.

[0114] (1) Animal modeling method

[0115] After one week of adaptive feeding, the animals were randomly divided into 5 groups according to body weight, with 8 animals in each group. The experimental groups are shown in Table 4 (one group was set as the normal group).

[0116] Table 4 Experimental groups and administration regimens

[0117]

[0118]

[0119] Note: On the first day of modeling, 5-FU was intraperitoneally injected (i.p), recorded as day 1, and the injection was continued for 5 consecutive days.

[0120] (2) Experimental administration

[0121] Fullerene was administered by intragastric gavage starting from the day before modeling (for example, dispersing the fullerene tablet of Example 5 in water), which was recorded as day 0. Samples were collected on the 6th day of the experiment. During the experiment, fullerene was administered by intragastric gavage (i.g) throughout the process. Specifically, on day 1 to day 5, fullerene was administered by gavage first, and after an interval of a period of time (for example, 2 hours), the modeling drug, that is, the chemotherapeutic drug, was injected.

[0122] (3) End of experiment

[0123] After blood collection from the inner canthal vein for routine blood test, 8 animals in each group were euthanized, and the stomach and entire intestinal tract were dissected out. After rinsing with normal saline, the specimens were fixed with 4% paraformaldehyde for 24 h (the intestinal tract was rolled in a Swiss roll manner).

[0124] (4) Data analysis

[0125] Data are expressed as mean±SEM; statistical test was performed with GraphPad Prism 5 software. Statistical analysis among groups was performed by One-way ANOVA and Tukey's test for pairwise comparison; statistical analysis among groups at different time points was performed by Two-way ANOVA and Bonferroni test for pairwise comparison.

[0126] As shown in Figure 2 for the analysis of status score data, starting from day 4, the score of the treatment group was significantly decreased compared with that of the model group. The fullerene treatment group significantly improved the fur status, mental state, response sensitivity and other status of chemotherapy mice compared with the model group. The 5-FU fullerene treatment group (40 mg / kg) showed a significant difference compared with the 5-FU model group, P<0.01. It can be seen that fullerene can significantly reduce the general score of 5-fluorouracil chemotherapy mice, that is, improve the living status of chemotherapy mice.

[0127] As shown in Figure 3 for the analysis of DAI score data, starting from day 3, the score of the treatment group was significantly decreased compared with that of the model group. The fullerene treatment group significantly improved the body weight change and fecal occult blood of chemotherapy mice compared with the model group. The 5-FU fullerene treatment group (40 mg / kg) showed a significant difference compared with the 5-FU model group, P<0.05. It can be seen that fullerene can significantly reduce the DAI score of 5-fluorouracil chemotherapy mice, that is, significantly improve the fecal occult blood of mice.

[0128] As shown in Figure 4 for the analysis of the effect of fullerene on blood picture in mice with gastrointestinal mucositis induced by 5-fluorouracil, fullerene can increase the white blood cell level in 5-fluorouracil chemotherapy mice.

[0129] Example 9: Therapeutic effect of fullerene on digestive tract injury induced by irinotecan (CTP)

[0130] Thirty-two adult Balb / c mice, aged 6-8 weeks, male, were purchased from Beijing Huafukang Biotechnology Co., Ltd.; experimental animals were housed in the animal room of Institute of Chemistry, Chinese Academy of Sciences, breeding certificate No.: SYXK (Jing) 2018-0033.

[0131] The test animals were housed in sterile independent ventilated IVC cages, 5 animals per cage. The bedding was 60The bedding material, sterilized by Co radiation, has a particle size of 4-6 mm. Mice are fed specially formulated sterilized feed and have free access to purified water. The animal laboratory is maintained at approximately 25°C, with a relative humidity of 40-70%, and 12 hours of light per day.

[0132] (1) Animal modeling methods

[0133] After one week of acclimatization, the animals were randomly divided into 4 groups of 8 animals each according to their body weight. The experimental groups are shown in Table 5 (one of the groups was designated as the normal group).

[0134] Table 5 Experimental Groups and Dosing Regimens

[0135]

[0136] Note: On the first day of modeling, CTP was injected intraperitoneally, which is recorded as day 1.

[0137] (2) Experimental drug administration

[0138] Fullerene (the fullerene tablets from Example 5 were dispersed in water) was administered by gavage starting one day before modeling, designated as day 0. Samples were collected on the fourth day after administration. During the experiment, fullerene was administered by gavage throughout the entire process. Specifically, from day 1 to 4, fullerene was administered by gavage first, followed by injection of the modeling drug, i.e., the chemotherapy drug, after a certain interval (e.g., 2 hours).

[0139] (3) End of experiment

[0140] Eight animals in each group were sacrificed, and their stomachs and entire intestines were dissected. After rinsing with physiological saline, the specimens were fixed with 4% paraformaldehyde for 24 hours (the intestines were wrapped in a Swiss roll).

[0141] (4) Data Analysis

[0142] Data are expressed as mean ± SEM. Statistical tests were performed using GraphPad Prism 5 software. The statistical analysis between groups was performed using one-way ANOVA and Tukey's test for pairwise comparisons. The statistical analysis between groups at different time points was performed using two-way ANOVA and Bonferroni test for pairwise comparisons.

[0143] like Figure 5 Analysis of fecal occult blood data showed that the fullerene treatment group (40 mg / kg) was significantly different from the irinotecan model group (P < 0.05). This indicates that fullerene can significantly reduce the fecal occult blood score in irinotecan-treated mice, thus significantly improving the fecal occult blood status in these mice.

[0144] like Figure 6The effect of fullerene on the gross mesothelial pharmacokinetic (Meetere) score in mice with CTP-induced gastrointestinal mucositis was shown. From day 2 onwards, the treatment group showed a significant decrease in scores compared to the model group. The fullerene treatment group significantly improved the coat condition, demeanor, and responsiveness of the chemotherapeutic mice compared to the model group. The fullerene treatment group (40 mg / kg) showed a significant difference compared to the irinotecan model group (P < 0.0001). Therefore, fullerene can significantly reduce the Meetere gross mesothelial pharmacokinetic score in irinotecan-treated mice, thus improving their quality of life.

[0145] like Figure 7 Analysis of the effects of fullerene on white blood cells in mice with CTP-induced gastrointestinal mucositis showed that fullerene could increase the white blood cell count in mice treated with irinotecan.

[0146] like Figure 8 Analysis of the effect of fullerene on platelet count in mice with CTP-induced gastrointestinal mucositis showed that fullerene could increase platelet count in mice treated with irinotecan.

[0147] like Figure 9 As shown in the anatomical diagram of the mouse digestive tract, all mice in the irinotecan model group developed severe intestinal obstruction, while no intestinal obstruction was observed in the fullerene treatment group. This indicates that fullerene significantly improved the intestinal function of mice treated with irinotecan, and the mice's defecation was no different from that of normal mice.

[0148] like Figure 10 The histopathological images of the mouse colorectal tissue show that the irinotecan model group animals all exhibited extensive inflammatory cell infiltration, mucosal ulceration, and severe submucosal edema with abundant inflammatory cell infiltration in their colorectal tissue. The fullerene treatment group showed no significant difference in colorectal tissue compared to the normal group, and no pathological changes were observed. This indicates that fullerene significantly improved the intestinal mucosal structure of chemotherapy-treated mice and maintained stable intestinal function.

[0149] Example 10: The therapeutic effects of different fullerene formulations on irinotecan (CTP)-induced gastrointestinal damage

[0150] Thirty-two adult Balb / c mice, 6-8 weeks old, were used, and their specific sources, feeding methods, and feeding environments were the same as in Example 9.

[0151] (1) Animal modeling methods

[0152] After one week of acclimatization, the animals were randomly divided into 4 groups of 8 animals each, according to their weight. The experimental groups are shown in Table 6.

[0153] Table 6 Experimental Groups and Dosing Regimens

[0154]

[0155] Note: On the first day of modeling, intraperitoneal injection of CPT was administered, which was recorded as day 1.

[0156] (2) Experimental drug administration

[0157] One day before modeling, fullerene (the fullerene tablets of Example 5 were dispersed in water) was administered by gavage, which was recorded as day 0. Samples were collected on the 5th day of the experiment. During the experiment, the fullerene preparation was administered to the experimental group by gavage (ig). Specifically, fullerene was administered by gavage first, and the modeling drug, i.e., the chemotherapy drug, was injected after a certain interval (e.g., 2 hours).

[0158] (3) End of experiment

[0159] Eight animals in each group were sacrificed, and their stomachs and entire intestines were dissected. After rinsing with physiological saline, the specimens were fixed with 4% paraformaldehyde for 24 hours (the intestines were wrapped in a Swiss roll).

[0160] like Figure 11 As shown in the anatomical diagram of the mouse digestive tract, animals treated with fullerene prophylaxis and induced by CTP did not develop large intestinal obstruction, while most animals in the model group developed severe intestinal obstruction. The efficacy of fullerene suspensions, capsules, and other dosage forms was compared to that of fullerene tablets.

[0161] Example 11: The therapeutic effect of fullerene on gastrointestinal damage caused by chemotherapy in cancer patients

[0162] Volunteer Case 1 (who underwent radical resection for recurrent colon cancer) received bevacizumab + CELOX chemotherapy after surgery and developed anemia, thrombocytopenia, and colitis symptoms.

[0163] Volunteer Case 2 (colon cancer with liver metastasis) underwent chemotherapy with irinotecan + FOLFOX4 regimen after surgery.

[0164] Table 7. Therapeutic effects of fullerenes on gastrointestinal damage caused by chemotherapy in cancer patients.

[0165]

[0166] As shown in Table 3, fullerenes helped increase platelet levels in cancer chemotherapy case 1. They were also effective in treating diarrhea in case 2 caused by chemotherapy-induced gastrointestinal damage.

[0167] Example 12: Antioxidant capacity test of fullerene materials

[0168] Fullerene C 60 and C 70 Solutions with concentrations of 10 and 20 ppm were prepared. HaCat cells were first incubated with the two fullerene materials for 3 hours, then the original culture medium was discarded, and the cells were incubated with 1 mM hydrogen peroxide for another 3 hours. Finally, cell viability was detected using a CCK-8 assay.

[0169] Experimental groups: Normal group: no fullerene material and no hydrogen peroxide incubation; Model group: no fullerene material incubation and hydrogen peroxide incubation; Experimental group: fullerene material incubation followed by hydrogen peroxide incubation.

[0170] Experimental results: Fullerene C 60 and C 70 Compared to the model group, the pre-incubated experimental group showed a significant increase in cell viability after hydrogen peroxide stimulation. Figure 12 ).

[0171] Comparative Example 1: The therapeutic effects of fullerenes and conventional drugs on chemotherapy-induced damage in cancer patients

[0172] Volunteer Case 3 (female, age 52, disease: lung adenocarcinoma) underwent chemotherapy and was given either conventional adjuvant chemotherapy drugs that increase white blood cell count and platelet count, or fullerene (fullerene tablets from Example 5). Blood tests were performed 5 days later. The results showed that the use of fullerene significantly increased white blood cell and platelet counts compared to conventional adjuvant chemotherapy drugs.

[0173] Volunteer Case 4 (male, age 54, disease: lung cancer) underwent chemotherapy and was given either conventional adjuvant chemotherapy drugs that increase white blood cell count and platelet count, or fullerene (fullerene tablets from Example 5). After 5 days, a complete blood count was performed. The results showed that the fullerene treatment significantly increased white blood cell count, hemoglobin, and platelet count compared to the conventional adjuvant chemotherapy drugs.

[0174] The results of the above cases are shown in Tables 8 and 9 below.

[0175] Table 8 Effects of fullerenes on blood cells in case 3

[0176]

[0177] Note: Common drugs for increasing white blood cell count include human granulocyte-stimulating factor.

[0178] Table 9 Effects of fullerenes on blood cells in Case 4

[0179]

[0180] Note: The usual time for taking the adjuvant drugs and fullerene preparations is 5 days before the test.

[0181] It should be noted that the experimental data of fullerene tablets are shown only by way of example in the above embodiments and comparative examples, but other dosage forms of fullerene of the present invention (e.g., fullerene suspension, fullerene powder, fullerene granules, fullerene hard capsules, fullerene soft capsules) can also achieve the same efficacy.

[0182] The foregoing description of specific exemplary embodiments of the invention is for illustrative and explanatory purposes. These descriptions are not intended to limit the invention to the precise forms disclosed, and it will be apparent that many changes and variations can be made in accordance with the foregoing teachings. The exemplary embodiments were chosen and described in order to explain the specific principles of the invention and its practical application, thereby enabling those skilled in the art to implement and utilize various different exemplary embodiments of the invention, as well as various different choices and variations. The scope of the invention is intended to be defined by the claims and their equivalents.

Claims

1. The application of fullerene materials in the preparation of drugs for preventing and / or treating gastrointestinal damage caused by chemotherapy drugs, characterized in that, The drug is a formulation suitable for administration via the gastrointestinal tract. The fullerene material contains a prototype fullerene, which is a hollow fullerene. The fullerene material is a water-insoluble fullerene selected from C0. 60 C 70 .

2. The application according to claim 1, characterized in that, The chemotherapy drugs are selected from those that can cause damage to the digestive tract.

3. The application according to claim 2, characterized in that, The chemotherapeutic drugs are selected from one or more of the following: microtubule activity inhibitors, dihydrofolate reductase inhibitors, platinum complexes, DNA topoisomerase inhibitors, and uracil derivatives.

4. The application according to claim 3, characterized in that, The DNA topoisomerase inhibitors include one or more of camptothecin, hydroxycamptothecin, irinotecan, and topotecan.

5. The application according to claim 3, characterized in that, The uracil derivatives include one or more of 5-fluorouracil, difluorouracil, deoxyfluorouracil, and carmofluorine.

6. The application according to claim 1, characterized in that, The prevention and / or treatment of gastrointestinal damage caused by chemotherapy drugs includes gastric damage or disease caused by chemotherapy drugs, and intestinal damage or disease caused by chemotherapy drugs.

7. The application according to claim 6, characterized in that, The digestive tract injuries include inflammatory diseases of the digestive tract, ischemic damage to the gastrointestinal tract, intestinal obstruction, diarrhea, constipation, and fecal occult blood.

8. The application according to claim 7, characterized in that, The inflammatory diseases of the digestive tract are selected from digestive tract mucosal inflammation.

9. The application according to claim 1, characterized in that, The formulation suitable for gastrointestinal administration comprises the fullerene material and a pharmaceutically acceptable carrier.

10. The application according to claim 9, characterized in that, The formulation suitable for gastrointestinal administration is selected from one of the following: tablets, pills, powders, lozenges, suspensions, emulsions, solutions, syrups, aerosols, ointments, capsules, or sterile packaged powders for injection; wherein the solution comprises an elixir.

11. The application according to any one of claims 1 to 10, characterized in that, The formulation comprises 0.1-50% by weight of the fullerene material and excipients.

12. The application according to claim 11, characterized in that, The excipients are inert excipients.

13. The application according to claim 12, characterized in that, The excipients are inert excipients.

14. The application according to claim 13, characterized in that, The excipients are selected from one or more of the following: sodium carboxymethyl cellulose, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, tragacanth gum, xanthan gum, gum arabic, sodium alginate, starch paste, pregelatinized starch, talc, copovidone, poloxamer, glycerin, gelatin, olive oil, propylene glycol, potassium sorbate, disodium edetate, vitamin C, methylparaben, ethylparaben, propylparaben, phenoxyethanol, glyceryl monooctanoate, thimerosal, colloidal silica, and polyethylene glycol.

15. The application according to claim 1, characterized in that, The drugs that prevent and / or treat gastrointestinal damage caused by chemotherapy drugs exert their effects through one or more of the following pathways: promoting cell proliferation, increasing white blood cell levels, increasing platelet levels, protecting the gastrointestinal mucosa, reducing mesenteric vasoconstriction, and preventing ischemic damage to the gastrointestinal tract.

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