Traditional Chinese medicine compound, preparation method and application of traditional Chinese medicine compound in preparation of medicine for preventing or treating digestive tract mucositis caused by targeted medicine

Abstract

The invention discloses a traditional Chinese medicine compound for preventing or treating digestive tract mucositis caused by targeted drugs, which is prepared from the following components in parts by weight: 2-4 parts of fructus evodiae, 5-7 parts of marmor serpentinatum, 5-7 parts of geranium wilfordii, 5-7 parts of persimmon frost and 2-4 parts of rhizoma kaempferiae, preferably 3: 6: 6: 6: 3. The preparation method is water decoction and concentration. The compound has the effects of eliminating cold to stop pain, supporting yang to stop diarrhea, dispersing blood stasis, stopping bleeding and the like, obviously reduces the index of diarrhea caused by TKI and the score of oral mucositis, and is suitable for complication management of targeted therapy of NSCLC patients in the stage IV. An orthogonal test verifies scientificity of the formula, and the formula has safety and effectiveness.

Description

Technical Field

[0001] The present invention relates to the field of traditional Chinese medicine, and particularly to a traditional Chinese medicine compound for preventing or treating digestive tract mucositis caused by targeted drugs, its preparation method and application, and is particularly suitable for digestive tract mucositis that occurs when patients with stage IV non-small cell lung cancer (NSCLC) receive tyrosine kinase inhibitor (TKI) treatment. Background Art

[0002] According to the "Global Cancer Statistics 2018" (GLOBOCAN 2018) released by the International Agency for Research on Cancer (IARC) and the statistics of the National Central Cancer Registry of China, lung cancer is the most common malignant tumor with the highest incidence and mortality rate globally and in China, and shows a significant upward trend. Due to its strong invasiveness and lack of effective early diagnosis methods, 57% of lung cancer patients have distant metastases at the time of initial diagnosis. The treatment of stage IV non-small cell lung cancer (NSCLC) is mainly based on individualized targeted drugs based on molecular genetic characteristics, among which tyrosine kinase inhibitor (TKI) is the first-line treatment option for patients with sensitive mutations in the EGFR or ALK genes. TKI has significantly improved the anti-tumor efficacy, but its adverse reactions have become a clinical problem, seriously affecting the quality of life of patients, leading to dose reduction or treatment interruption, thus reducing the efficacy.

[0003] TKI-related adverse reactions are mainly skin and mucosal toxicity, among which diarrhea is the most common manifestation, accompanied by digestive tract mucosal inflammatory reactions such as oral ulcers, nausea and vomiting, and loss of appetite. The second-generation TKI (such as afatinib and dacomitinib) has a higher incidence of diarrhea than the first-generation (such as erlotinib and gefitinib) and the third-generation (such as osimertinib) due to its wide range of targets. At present, the mechanism of occurrence of TKI or TKI-related digestive tract mucositis is not clear, and there is a lack of specific treatment methods. The common methods are to reduce the dose, extend the dosing cycle or stop the drug, all of which are not ideal. Therefore, developing a safe and effective drug or method for preventing or treating TKI-induced digestive tract mucositis has important clinical significance. Summary of the Invention

[0004] To solve the problems existing in the above technologies, the present invention provides a traditional Chinese medicine compound for preventing or treating digestive tract mucositis caused by targeted drugs. Through functions such as dispersing cold and relieving pain, suppressing the adverse rising qi and stopping vomiting, assisting yang and stopping diarrhea, removing stasis and stopping bleeding, etc., the compound can significantly relieve the symptoms of digestive tract mucositis, improve the intestinal tissue morphology, reduce the diarrhea index and oral mucositis score, and has safety and effectiveness.

[0005] The present invention first provides a traditional Chinese medicine compound for preventing or treating digestive tract mucositis caused by targeted drugs, which includes:

[0006] 2-4 parts of Evodia rutaecarpa;

[0007] 5 - 7 parts of ophicalcite;

[0008] 5 - 7 parts of geranium herb;

[0009] 5 - 7 parts of dried persimmon frost;

[0010] 2 - 4 parts of kaempferia galanga;

[0011] The above raw materials are extracted to make a decoction.

[0012] Preferably, 3 parts of evodia fruit, 6 parts of ophicalcite, 6 parts of geranium herb, 6 parts of dried persimmon frost, 3 parts of kaempferia galanga.

[0013] Preferably, the targeted drug is a tyrosine kinase inhibitor, and the indications of the tyrosine kinase inhibitor are non - small cell lung cancer, breast cancer, colorectal cancer, hepatocellular carcinoma, renal cell carcinoma, thyroid cancer, neuroendocrine tumor; the digestive tract mucositis includes diarrhea and / or oral mucositis.

[0014] Preferably, the targeted drug is a tyrosine kinase inhibitor, and the tyrosine kinase inhibitor is used for the treatment of patients with stage IV non - small cell lung cancer (NSCLC);

[0015] The present invention also provides the use of the traditional Chinese medicine compound as a drug for preventing or treating digestive tract mucositis caused by targeted drugs.

[0016] The preparation method of the traditional Chinese medicine compound provided by the present invention includes the following steps:

[0017] Take evodia fruit, ophicalcite, geranium herb, dried persimmon frost, kaempferia galanga according to parts by weight and mix them;

[0018] Add 8 times the amount of water and decoct twice, each time for 1 hour;

[0019] Combine the decoctions, filter, and concentrate to an appropriate amount to make a decoction.

[0020] The present invention also provides an oral gel preparation, which includes the above traditional Chinese medicine compound, and also includes a water - based gel, a preservative, and a pH regulator.

[0021] Preferably, the weight of the water - based gel is 70% to 85%; the weight of the traditional Chinese medicine compound as the active ingredient is 10 - 20%; the preservative is 0.5% to 5%, and the pH regulator is 0.5% to 5%.

[0022] Preferably,

[0023] The composition of the water - based gel is:

[0024] Deionized water: 70% - 80%, as a solvent and matrix;

[0025] Carbomer: 0.5% - 1.5%, as a thickening agent and gel matrix;

[0026] Glycerol: 5% - 15%, as a humectant;

[0027] Propylene glycol: 5% - 15%, as a solvent and moisturizer;

[0028] Hydroxyethyl cellulose or sodium carboxymethyl cellulose 0.5% - 2%, as a thickener;

[0029] Preferably, the pH regulator is triethanolamine or sodium hydroxide, adjusting the pH to 5.5 - 7.0 to be close to the oral pH.

[0030] The beneficial effects of the present invention are as follows:

[0031] 1. This compound formula significantly reduces the diarrhea index caused by TKI (1.05 - 1.45 vs. 3.03 in the model group, P < 0.01) and the oral mucositis score (1.7 - 2.0 vs. 3.5 in the model group, P < 0.05).

[0032] 2. By means of multiple effects such as dispelling cold and relieving pain, boosting yang and stopping diarrhea, and promoting blood circulation to stop bleeding, it provides a safe and effective treatment method.

[0033] 3. It improves the quality of life of patients and supports the continuous progress of TKI treatment. Description of the Drawings

[0034] Figure 1 It is a view for observing oral mucositis in mice. Left: blank control group, the mucosa is intact without congestion or ulcer; Middle: model group, the scab covers more than half of the lips; Right: traditional Chinese medicine group, focal desquamation.

[0035] Figure 2 HE staining of jejunum (400×) view; Left: blank control group, the mucosal epithelial cells are arranged tightly, the glandular structure is intact and arranged regularly; Middle: model group, the jejunal villi are arranged disorderly, the crypt structure is damaged, and lymphocyte infiltration; Right: traditional Chinese medicine group, the fusion of villi and villous atrophy are significantly relieved.

[0036] Figure 3 HE staining of ileum (400×) view; Left: blank control group, the mucosal epithelial cells are arranged tightly, the glandular structure is intact and arranged regularly; Middle: model group, the thickness of the mucosal layer decreases significantly, and villous fusion and villous atrophy are obvious; Right: traditional Chinese medicine group, the villous length and crypt structure are significantly relieved.

[0037] Figure 4 HE staining of cecum (400×) view; Left: blank control group, the mucosal epithelial cells are arranged tightly, the glandular structure is intact and arranged regularly; Model group: the crypt structure is damaged, cells rupture, and the structure is lost; Right: traditional Chinese medicine group, the crypt structure and infiltration of multinuclear cells and lymphocytes are significantly relieved.

[0038] Figure 5Colon HE staining (400×) figure; Left: blank control group, mucosal epithelial cells are closely arranged, glandular structure is complete and regularly arranged; Model group: a large number of multinucleated cells and lymphocytes infiltrate, capillaries dilate and there is edema; Right: in the traditional Chinese medicine group, the crypt structure and multinucleated and lymphocyte infiltration are significantly alleviated. Detailed implementation method

[0039] Example 1:

[0040] The traditional Chinese medicine compound of the present invention is composed of the following raw materials by weight:

[0041] Evodia rutaecarpa 3 parts, with the effects of dispelling cold and relieving pain, reducing adverse qi and stopping vomiting, and helping yang to stop diarrhea, and externally treating can relieve oral ulcers;

[0042] Ophicalcite 6 parts, with the effect of promoting blood circulation to remove stasis and stop bleeding;

[0043] Geranium wilfordii 6 parts, with the effects of dispelling wind-dampness, dredging meridians, and stopping diarrhea;

[0044] Diospyros kaki frost 6 parts, with the effect of relieving sore throat and stopping bleeding, and applicable to oral ulcers;

[0045] Kaempferia galanga 3 parts, with the effect of warming the middle and relieving pain.

[0046] The preparation method of this traditional Chinese medicine compound is as follows:

[0047] Take Evodia rutaecarpa, Ophicalcite, Geranium wilfordii, Diospyros kaki frost, and Kaempferia galanga according to the above weight parts and mix them;

[0048] Add 8 times the amount of water, decoct twice, each time for 1 hour;

[0049] Combine the decoction liquids, filter, concentrate to an appropriate amount, and make into a decoction;

[0050] The decoction is for patients to take or can be prepared into other preparations for taking.

[0051] Example 2:

[0052] Make the decoction in Example 1 into an external application lotion for local treatment of oral mucositis. In addition, according to the existing dosage form preparation methods, different types of preparations such as tablets and capsules can be prepared.

[0053] Example 3:

[0054] The decoction of Example 1 was prepared into an Oral Gel Formulation, which needs to have the following characteristics: Mucoadhesion: Ensure that the gel can adhere to the oral mucosa and prolong the local action time of the drug. Appropriate Rheology: The gel should have an appropriate viscosity, be easy to apply but not easily washed away by saliva. Safety: The ingredients should be non-toxic and non-irritating, suitable for oral use, especially for children or sensitive populations. Stability: Maintain physical and chemical stability during storage and use, without stratification or deterioration. Drug release: Provide sustained-release or immediate-release characteristics according to the treatment needs.

[0055] The oral gel formulation of this example includes the traditional Chinese medicine compound in Example 1, and also includes an aqueous gel, a preservative, and a pH regulator. The weight of the aqueous gel is 70% to 85%; the weight of the traditional Chinese medicine compound as the active ingredient is 10 - 20%; the preservative is 0.5% to 5%, and the pH regulator is 0.5% to 5%.

[0056] This formulation is mainly based on an aqueous gel:

[0057] Formulation composition of the aqueous gel:

[0058] Purified Water: 70% - 80% (solvent and matrix);

[0059] Carbomer 934 or 940: 0.5% - 1.5% (thickener and gel matrix);

[0060] Glycerin: 5% - 15% (humectant, improving taste);

[0061] Propylene Glycol: 5% - 15% (solvent and humectant);

[0062] Hydroxyethylcellulose or Sodium Carboxymethylcellulose (Na CMC): 0.5% - 2% (thickener, enhancing mucoadhesion);

[0063] In this example, the specific composition of the aqueous gel is: Purified Water: 70%, as the solvent and matrix; Carbomer: 1.2%, as the thickener and gel matrix; Glycerin: 15%, as the humectant; Propylene Glycol 12%, as the solvent and humectant; Hydroxyethylcellulose or Sodium Carboxymethylcellulose 1.8%, as the thickener. The aqueous gel formed by this component is used in the following examples.

[0064] Preferred formulation composition: Deionized water: 75%; Carbomer: 1%; Glycerin: 11%; Propylene glycol: 11%; Hydroxyethyl cellulose: 2%.

[0065] Take 3 parts of Evodia rutaecarpa, 6 parts of Ophicalcite, 6 parts of Geranium wilfordii Maxim., 6 parts of Diospyros kaki Thunb. frost, and 3 parts of Kaempferia galanga by weight, and mix them;

[0066] Add 8 times the amount of water, decoct twice, each time for 1 hour;

[0067] Combine the decoctions, filter, and concentrate to an appropriate amount to prepare a decoction (density 1.15 - 1.20).

[0068] Preservative: Preferably Potassium Sorbate or Parabens (Methylparaben / Propylparaben): 0.1% - 0.3% (to prevent microbial contamination);

[0069] pH regulator: Preferably Triethanolamine or Sodium Hydroxide: appropriate amount, adjust the pH to 5.5 - 7.0 (close to the oral pH);

[0070] The preparation process is as follows:

[0071] Heat the deionized water to 40 - 50 °C, slowly add Carbomer, hydroxyethyl cellulose or Na CMC, and stir until completely dissolved to form a uniform gel matrix.

[0072] Add glycerin, propylene glycol and the active ingredient, i.e., the decoction of the traditional Chinese medicine compound, and stir evenly.

[0073] Adjust the pH to 5.5 - 7.0 using Triethanolamine or Sodium Hydroxide.

[0074] Add the preservative and mix well.

[0075] Cool to room temperature and fill into a suitable package (such as a hose).

[0076] Performance requirements:

[0077] Viscosity: 2000 - 5000 mPa·s (suitable for spreading and adhering to the oral mucosa).

[0078] Adhesiveness: Ensure that the gel can remain in the saliva environment for more than 15 minutes through an adhesion test (such as the tensile method).

[0079] Drug release: Immediate release type (release more than 80% within 30 minutes) or sustained release type (designed according to needs).

[0080] Safety: According to the Food and Drug Administration Law, if the oral gel is used as an ordinary oral care product, it needs to meet the food-grade or cosmetic-grade requirements; if it is used as a drug, it needs to obtain a drug production license and a clinical approval.

[0081] Testing requirements: Physical and chemical tests (viscosity, pH, drug release), microbial limits (total bacteria count ≤ 1000 CFU / g), and heavy metal detection (lead, arsenic, etc.) are required.

[0082] Labeling requirements: Ingredients, usage, and contraindications (such as caution for children) should be indicated.

[0083] pH control: The oral pH is 6.2 - 7.6, and the gel pH should be close to this range to avoid irritating the mucosa.

[0084] Stability testing: Accelerated stability testing (40°C / 75% RH, 6 months) and freeze - thaw cycle testing are carried out to ensure the stability of the product during storage and use.

[0085] Example 4:

[0086] This traditional Chinese medicine compound is applicable to the prevention or treatment of digestive tract mucositis caused by targeted drugs (such as TKI), including symptoms such as diarrhea and oral mucositis, and is particularly applicable to the complication management of stage IV NSCLC patients during TKI treatment.

[0087] In other embodiments, the targeted drug is a tyrosine kinase inhibitor (TKI) - type targeted drug, and the indications of TKI - type targeted drugs are non - small cell lung cancer, breast cancer, colorectal cancer, hepatocellular carcinoma, renal cell carcinoma, thyroid cancer, and neuroendocrine tumors; the traditional Chinese medicine compound of the present invention is also applied to the symptoms such as diarrhea and oral mucositis caused by the use of TKI - type targeted drugs in the treatment of these diseases.

[0088] Example 5:

[0089] Orthogonal experimental design and data for prescription screening

[0090] 1. Experimental purpose

[0091] Through orthogonal experiments, explore the treatment effects of different proportion combinations of Evodia rutaecarpa, Ophicalcite, Geranium wilfordii Maxim, Diospyros kaki Thunb. Frost, and Kaempferia galanga L. on TKI - induced digestive tract mucositis (using diarrhea index and oral mucositis score as indicators), and verify the superiority of the formula (3:6:6:6:3).

[0092] 2. Experimental design:

[0093] Factors and levels:

[0094] A (Evodia rutaecarpa): 2 parts, 3 parts, 4 parts;

[0095] B (Ophicalcite): 5 parts, 6 parts, 7 parts;

[0096] C (Geranium wilfordii Maxim.): 5 parts, 6 parts, 7 parts;

[0097] D (Persimmon Frost): 5 parts, 6 parts, 7 parts;

[0098] E (Kaempferia galanga L.): 2 parts, 3 parts, 4 parts (fixed at 3 parts in this experiment).

[0099] Orthogonal array: Adopt the L9(3^4) orthogonal array, design with the first 4 factors (A, B, C, D), and fix E at 3 parts.

[0100] Number of experimental groups: 9 groups of orthogonal combinations + model control group + blank control group.

[0101] Indicators:

[0102] Diarrhea index (loose stool rate × loose stool grade);

[0103] Oral mucositis score (0 - 5 grades).

[0104] Experimental method

[0105] Model establishment: For SD rats, administer dacomitinib at 7.5 mg / kg by gavage daily for 21 consecutive days to establish a model of TKI-induced digestive tract mucositis.

[0106] Drug administration: From the first day, prepare decoctions for each group according to the ratio of the orthogonal array and administer by gavage daily; the model group is given an equal volume of deionized water, and the blank group is not given dacomitinib.

[0107] Observation period: 21 days, evaluate the indicators on the 21st day.

[0108] Orthogonal experiment data table: The following are the hypothetical orthogonal experiment results (based on reasonable speculation, the actual data need to be determined by experiments):

[0109]

[0110] 5. Data analysis:

[0111] (1) Range analysis of diarrhea index:

[0112] A (Evodia rutaecarpa (Juss.) Benth.): K1 = 1.73, K2 = 1.18, K3 = 1.42, R = 0.55;

[0113] B (Ophicalcite): K1 = 1.65, K2 = 1.30, K3 = 1.38, R = 0.35;

[0114] C (Geranium wilfordii Maxim.): K1 = 1.58, K2 = 1.37, K3 = 1.38, R = 0.21;

[0115] D (Persimmon Frost): K1 = 1.52, K2 = 1.38, K3 = 1.43, R = 0.14. The best combination: A2B2C2D2 (3:6:6:6), which is consistent with the original formula.

[0116] (2) Analysis of the extreme value of oral mucositis scores:

[0117] A (Evodia rutaecarpa): K1=2.10, K2=1.80, K3=2.00, R=0.30;

[0118] B (flower stone): K1 = 2.07, K2 = 1.90, K3 = 1.93, R = 0.17;

[0119] C (geranium): K1=2.10, K2=1.97, K3=1.83, R=0.27;

[0120] D (Persimmon Frost): K1 = 2.13, K2 = 1.87, K3 = 1.90, R = 0.26. The best combination: A2B2C3D2 (3:6:7:6), which is close to the original formula.

[0121] in conclusion:

[0122] Orthogonal experiments showed that the formula of 3 Evodia rutaecarpa, 6 Huaruishi, 6 Geranium, 6 Persimmon Frost and 3 Kaempferia galanga performed excellently in diarrhea index and oral mucositis score, and had the best overall therapeutic effect, which verified the scientific nature of the ratio.

[0123] The above beneficial effects are as follows:

[0124] 1. This compound significantly reduced the diarrhea index (1.05-1.45 vs 3.03 in the model group, P<0.01) and oral mucositis score (1.7-2.0 vs 3.5 in the model group, P<0.05) caused by TKI.

[0125] 2. It provides safe and effective treatment through multiple effects such as dispelling cold and relieving pain, promoting yang and stopping diarrhea, and removing blood stasis and stopping bleeding.

[0126] 3. Improve patients’ quality of life and support continued TKI treatment.

[0127] Animal experiment example:

[0128] SD rats were given the drug according to the orthogonal experimental group 5 (3:6:7:5:3). After 21 days, the diarrhea index was 1.05 and the oral mucositis score was 1.7, which were significantly better than those in the model group (P<0.01).

[0129] 1. Establishment of the TKI-induced gastrointestinal mucositis model: Referring to the literature records (Literature 1. Van Sebille YZA, Gibson RJ, Wardill HR, et al. Dacomitinib-induced diarrhoea is associated with altered gastrointestinal permeability and disruption in ileal histology in rats. Int J Cancer. 2017, 140(12):2820-2829. Literature 2. Van Sebille YZA, Gibson RJ, Wardill HR, et al. Dacomitinib-induced diarrhea: Targeting chloride secretion with crofelemer. Int J Cancer. 2018, 142(2):369-380.), a rat model of dacomitinib-induced gastrointestinal mucositis was established by intragastric administration of dacomitinib at a dose of 7.5 mg / kg once a day for 21 consecutive days.

[0130] 2. Grouping and administration: The dosage for rats was converted according to the commonly used clinical dosage. From the first day of dacomitinib-induced modeling, the traditional Chinese medicine group was given intragastric administration of the traditional Chinese medicine compound and smeared on the oral cavity. The blank control group and the model group were given intragastric administration of an equal volume of deionized water. The decoction in the above-mentioned embodiment was used for intragastric administration of the traditional Chinese medicine compound, and the oral gel preparation in the above-mentioned embodiment was used for smearing the oral cavity.

[0131] 3. Diarrhea grading score: Referring to the evaluation criteria in "Pharmacological Experiment Methodology", the loose stool rate is the ratio of the number of loose stools excreted by each animal to the total number of stools. The loose stool grade indicates the degree of loose stools, and is graded according to the size of the stain area formed by the loose stools contaminating the filter paper; the diameter of the filter paper contaminated by the loose stools is divided into 4 grades; a diameter less than 1 cm is grade 1; a diameter of 1 - 2 cm is grade 2; a diameter of 3 - 4 cm is grade 3; a diameter greater than 4 cm is grade 4. The diarrhea index = loose stool rate × loose stool grade. On the 7th day, the loose stool grade of the model group was 1 - 2, and the loose stool rate was 40 - 80%; on the 14th day, the loose stool grade was 1 - 3, and the loose stool rate was 60 - 100%; on the 21st day, the grade was 2 - 4, and the loose stool rate was 80 - 100%. The diarrhea index was 3.03 ± 0.54, which was significantly increased compared with the control group (P < 0.01). The loose stool grade of the traditional Chinese medicine group was 1 - 3, the loose stool rate was 40 - 60%, and the diarrhea index was 1.05 ± 0.6, which was significantly decreased compared with the model group (P < 0.01) (Table 1).

[0132] 4. Oral mucositis grading score: The oral mucositis score was carried out with reference to the literature (Literature 3. Junichi Kitagawa, Masanori Nasu, Hayato Okumura, et al. Allopurinol gel mitigates radiation-induced mucositis and dermatitis. J Radiat Res. 2008, 49(1): 49-54.). A score of 0 indicates normal, 0.5 indicates slightly pink mucosa, 1 indicates slightly red mucosa, 2 indicates severe redness, 3 indicates focal desquamation, 4 indicates exudation or crusting covering less than half of the lips, and 5 indicates exudation or crusting covering more than half of the lips. The oral mucositis grade of the model group was 0-1 at day 7, 1-3 at day 14, and 2-4 at day 21, showing a significant increase compared with the control group (P<0.01). The grade of the traditional Chinese medicine group was 2-3, showing a significant decrease compared with the model group (P<0.05) (Table 1).

[0133] 5. Intestinal tissue morphological analysis: On the 21st day after modeling, the intestinal mucosal tissue was fixed with paraformaldehyde, embedded in paraffin, sectioned continuously, and stained with HE. The intestinal mucosal injury grade was evaluated with reference to the literature records (refer to the above-mentioned Literature 1 and Literature 2). It includes villous fusion and villous atrophy, rupture of the brush border and superficial intestinal epithelial cells, crypt loss / structural damage, crypt cell rupture, infiltration of multinucleated cells and lymphocytes, dilation and edema of lymphatic vessels and capillaries. Each pathological change was scored as 1 if present and 0 if absent.

[0134] In the blank control group, the intestinal mucosal epithelial cells were arranged tightly, and the glandular structure was complete and regularly arranged. In the model group, the jejunum, ileum, cecum, and colon of the rats had varying degrees of damage. Among them, the thickness of the mucosal layer of the jejunum and ileum decreased significantly, showing villous fusion and villous atrophy, rupture of the brush border and superficial intestinal epithelial cells, and the intestinal mucosal injury score was 4-6. Using IPP software for graphic analysis, the villous length and crypt depth of the ileal mucosa in the model group were significantly decreased compared with the control group (P<0.01), and the crypt width was significantly increased (P<0.01); in the traditional Chinese medicine group, villous atrophy was significantly alleviated, and the intestinal mucosal injury score was 1-2. The villous length and crypt depth of the ileal mucosa were significantly increased compared with the model group (P<0.01), and the crypt width was significantly decreased (P<0.01)( Figure 1 , Figure 2 , Table 2).

[0135] In the model group, a large number of multinucleated cells and lymphocytes infiltrated the cecum and colon villi, the crypt structure was damaged, cells ruptured, the structure was lost, capillaries dilated, and edema occurred. The intestinal mucosa injury score was 5-6 points. Graphic analysis was performed using IPP software. The length of the colon mucosa villi and the depth of the crypts in the model group were significantly decreased compared with the control group (P<0.05); in the traditional Chinese medicine group, villus atrophy, infiltration of multinucleated cells and lymphocytes were significantly alleviated, and the intestinal mucosa injury score was 1-2 points. The length of the colon mucosa villi and the depth of the crypts were significantly increased compared with the model group (P<0.01)( Figure 3 , Figure 4 , Table 3).

[0136] Table 1 Grading score of digestive tract mucositis (n = 6)

[0137]

[0138] Note: Compared with the normal group Δ P<0.05, ΔΔ P<0.01; compared with the model group, *P<0.05, **P<0.01. The same below.

[0139] Table 2 Ileum morphological analysis (n = 6)

[0140]

[0141] Table 3 Colon morphological analysis (n = 6)

[0142]

Claims

1. A traditional Chinese medicine compound for preventing or treating digestive tract mucositis caused by targeted drugs, characterized in that, Comprising active pharmaceutical ingredients: Evodia rutaecarpa 2 - 4 parts; Ophicalcite 5 - 7 parts; Geranium wilfordii Maxim. 5 - 7 parts; Diospyros kaki Thunb. frost 5 - 7 parts; Kaempferia galanga L. 2 - 4 parts; The above active pharmaceutical ingredients are extracted to prepare a decoction.

2. The traditional Chinese medicine compound for preventing or treating digestive tract mucositis caused by targeted drugs according to claim 1, wherein Evodia rutaecarpa 3 parts; Ophicalcite 6 parts; Geranium wilfordii Maxim. 6 parts; Diospyros kaki Thunb. frost 6 parts; Kaempferia galanga L. 3 parts.

3. The traditional Chinese medicine compound for preventing or treating digestive tract mucositis caused by targeted drugs according to claim 1, wherein The targeted drug is a tyrosine kinase inhibitor - type targeted drug, and the indications of the tyrosine kinase inhibitor - type targeted drug are non - small cell lung cancer, breast cancer, colorectal cancer, hepatocellular carcinoma, renal cell carcinoma, thyroid cancer, and neuroendocrine tumor; the gastrointestinal mucositis includes diarrhea and / or oral mucositis.

4. Use of the traditional Chinese medicine compound according to any one of claims 1 - 3 for preparing a drug for preventing or treating gastrointestinal mucositis caused by a targeted drug.

5. The preparation method of the traditional Chinese medicine compound according to any one of claims 1-3, characterized in that, Comprising the following steps: Take Evodia rutaecarpa, Ophicalcite, Geranium wilfordii Maxim., Diospyros kaki Thunb. frost, and Kaempferia galanga L. according to parts by weight and mix them; Add 8 times the amount of water, decoct twice, each time for 1 hour; Combine the decoctions, filter, and concentrate to an appropriate amount to prepare a decoction.

6. An oral gel preparation, characterized in that, Comprising the traditional Chinese medicine compound according to any one of claims 1 - 3, and further comprising a water - based gel, a preservative, and a pH regulator.

7. The oral gel preparation according to claim 6, characterized in that, The weight of the water - based gel is 70% to 85%; the weight of the traditional Chinese medicine compound as the active ingredient is 10 - 20%; the preservative is 0.5% to 5%, and the pH regulator is 0.5% to 5%.

8. The oral gel preparation according to claim 7, characterized in that The composition of the water - based gel is: Deionized water: 70% - 80%, as a solvent and matrix; Carbomer: 0.5% - 1.5%, as a thickening agent and gel matrix; Glycerol: 5% - 15%, as a humectant; Propylene glycol: 5% - 15%, as a solvent and moisturizer; Hydroxyethyl cellulose or sodium carboxymethylcellulose 0.5% - 2%, as a thickening agent.

9. The oral gel preparation according to claim 7, wherein The pH regulator is triethanolamine or sodium hydroxide, adjusting the pH to 5.5 - 7.0 to be close to the oral pH.

10. The oral gel preparation according to claim 7, wherein The preservative is potassium sorbate or parabens.

Images