Traditional Chinese medicine composition with yang warming effect for treating irinotecan delayed diarrhea

Abstract

The invention discloses a traditional Chinese medicine composition with a yang warming effect for treating irinotecan delayed diarrhea, and belongs to the technical field of traditional Chinese medicines. The traditional Chinese medicine composition comprises the following components in parts by weight: 6-12 parts of ginseng, 3-9 parts of dried ginger, 9-15 parts of bighead atractylodes rhizome, 3-6 parts of honey-fried licorice root, 6-12 parts of fructus psoraleae, 3-9 parts of myristica fragrans, 1-3 parts of fructus evodiae, 3-6 parts of schisandra chinensis, 9-15 parts of poria cocos, 12-18 parts of Chinese yam, 6-12 parts of lotus seed and 6-12 parts of white hyacinth bean. The traditional Chinese medicine composition with the yang warming effect for treating irinotecan delayed diarrhea focuses on the pathogenesis of spleen-kidney yang deficiency and water-dampness downward flow, can cover 1-4 levels of diarrhea, is free of western medicine side effects, can improve accompanying symptoms such as intolerance of cold and abdominal distension, meets the requirements of different patients, and improves chemotherapy compliance.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of traditional Chinese medicine, in particular to a traditional Chinese medicine composition for treating delayed diarrhea caused by irinotecan chemotherapy, which has the core functions of warming yang, invigorating the spleen, and tonifying the kidney to stop diarrhea, and is especially based on the improved formula of Li Zhong Sishen Decoction. BACKGROUND

[0002] Irinotecan is a commonly used topoisomerase I inhibitor in clinical practice, and is widely used in the chemotherapy of malignant tumors such as colorectal cancer, gastric cancer, and lung cancer. However, this drug is prone to cause delayed diarrhea (DD), with an incidence rate of 60%-80%, and the incidence rate of severe diarrhea (grades 3-4) is as high as 15%-40%. Delayed diarrhea usually occurs 24 hours after administration, and is characterized by frequent watery stools, abdominal pain, and electrolyte imbalance. In severe cases, it can lead to interruption of chemotherapy, dehydration, and even shock, significantly affecting the quality of life and treatment compliance of patients.

[0003] Currently, the commonly used treatment options in clinical practice include western medicines such as loperamide and octreotide. Although these drugs can provide short-term relief from symptoms, they have side effects such as abdominal distension, constipation, and arrhythmia, high recurrence rates, and limited efficacy for severe diarrhea. According to traditional Chinese medicine theory, irinotecan, as a "foreign toxic evil", can easily damage the yang qi of the spleen and stomach, and over time, it can affect the kidney, leading to deficiency of the spleen and kidney yang, dysfunction of transportation and transformation, and downward flow of water and dampness, ultimately causing diarrhea. This is the core pathogenesis of irinotecan-induced delayed diarrhea, so the fundamental principle of treatment should be to warm yang, invigorate the spleen, and tonify the kidney to stop diarrhea.

[0004] Lizhong Decoction (Radix Ginseng, Rhizoma Zingiberis, Rhizoma Atractylodis Macrocephalae, and Radix Glycyrrhizae) is a classic formula for warming the middle and invigorating the spleen in traditional Chinese medicine, and is used to treat spleen-stomach deficiency syndrome. Sishen Decoction (Fructus Aurantii Immaturus, Myristicae Semen, Fructus Evodiae, and Fructus Schisandrae Chinensis) is a representative formula for warming the kidney and stopping diarrhea, and is suitable for treating five-early diarrhea caused by deficiency of the spleen and kidney yang. Although existing studies have confirmed that the two formulas, alone or in combination, are effective for ordinary cold and deficiency diarrhea, there are still deficiencies in the special formula for irinotecan-induced delayed diarrhea: first, the original formula does not optimize the compatibility of the drugs in response to the damage of chemotherapy drugs to the intestinal mucosa, and the effect of stopping diarrhea is slow; second, it does not consider the deficiency of qi and blood in chemotherapy patients, and is prone to appear fatigue, poor appetite, and other accompanying symptoms; third, the dosage form is single, mostly in the form of decoction, which is not convenient for long-term use by chemotherapy patients.

[0005] Therefore, based on the classic compatibility of Lizhong Sishen Decoction, the present application designs a traditional Chinese medicine composition that is more suitable for the pathogenesis of irinotecan-induced delayed diarrhea by adding and subtracting medicinal ingredients and optimizing the dosage ratio, which has the functions of warming yang, stopping diarrhea, protecting the intestinal mucosa, and tonifying qi, and can be made into various convenient dosage forms, filling the clinical gap. SUMMARY

[0006] The application aims to provide a traditional Chinese medicine composition for treating irinotecan-induced delayed diarrhea, which has the effect of warming yang and is safe, targeted and capable of fundamentally improving irinotecan-induced delayed diarrhea.

[0007] To achieve the above-mentioned purpose, in one aspect, the application provides a traditional Chinese medicine composition for treating irinotecan-induced delayed diarrhea, which has the effect of warming yang and comprises, by weight, 6-12 parts of ginseng, 3-9 parts of dried ginger, 9-15 parts of white atractylodes, 3-6 parts of fried licorice, 6-12 parts of psoralea, 3-9 parts of nutmeg, 1-3 parts of evodia, 3-6 parts of schisandra, 9-15 parts of poria, 12-18 parts of yam, 6-12 parts of lotus seed and 6-12 parts of white kidney bean.

[0008] Preferably, the traditional Chinese medicine composition comprises, by weight, 9 parts of ginseng, 6 parts of dried ginger, 12 parts of white atractylodes, 4 parts of fried licorice, 9 parts of psoralea, 6 parts of nutmeg, 2 parts of evodia, 4 parts of schisandra, 12 parts of poria, 15 parts of yam, 9 parts of lotus seed and 9 parts of white kidney bean.

[0009] Preferably, the traditional Chinese medicine composition comprises, by weight, 6 parts of ginseng, 3 parts of dried ginger, 12 parts of white atractylodes, 3 parts of fried licorice, 6 parts of psoralea, 3 parts of nutmeg, 1 part of evodia, 3 parts of schisandra, 15 parts of poria, 12 parts of yam, 6 parts of lotus seed and 15 parts of white kidney bean.

[0010] Preferably, the traditional Chinese medicine composition comprises, by weight, 12 parts of ginseng, 9 parts of dried ginger, 15 parts of white atractylodes, 6 parts of fried licorice, 12 parts of psoralea, 9 parts of nutmeg, 3 parts of evodia, 6 parts of schisandra, 15 parts of poria, 18 parts of yam, 9 parts of lotus seed and 12 parts of white kidney bean.

[0011] In another aspect, the application provides a preparation based on the traditional Chinese medicine composition, which can be prepared into any one of a decoction, a granule and a pill.

[0012] In another aspect, the application provides an application of the traditional Chinese medicine composition in preparing a medicine for treating irinotecan-induced delayed diarrhea caused by chemotherapy, wherein the traditional Chinese medicine composition is used as a raw material, the preparation type is a decoction, a granule or a pill, and the preparation process is as follows. Decoction: the composition is crushed into coarse powder, decocted twice, and the combined decoction is concentrated to 1g of crude drug per 1mL; Granule: the concentrated liquid of the decoction is taken, dextrin and stevioside are added for granulation, and the granules are dried at 65℃ until the moisture content is less than or equal to 5%; Pill: the composition is crushed into fine powder, 1.2 times of refined honey is added for pan-granulation, and the granules are dried at 55℃ until the moisture content is less than or equal to 6%, and then coated with hydroxypropyl methyl cellulose.

[0013] Preferably, in the preparation process of the decoction, the first decoction is added with 10 times of water and heated for 40 minutes on a low fire; the second decoction is added with 8 times of water and heated for 30 minutes on a low fire.

[0014] Preferably, in the preparation process of the granules, the amount of dextrin added is 1 times of the solid content of the decoction concentrate, and the amount of stevioside added is 0.02 times of the solid content of the decoction concentrate.

[0015] Preferably, the coating weight is increased by 3%-5%.

[0016] Ginseng can tonify the primordial qi, invigorate the spleen and stomach, dried ginger can warm the middle and dispel cold, and return yang and unblock the collaterals, both of which can play the effect of "warming yang and invigorating the spleen", and target the root of the deficiency of the spleen and stomach; Psoralea can warm the kidney and assist yang, and astringe the intestines to stop diarrhea, Myristica can warm the middle and move qi, and astringe the intestines to stop diarrhea, Evodia can warm the middle and dispel cold, and stop pain and diarrhea, Schisandra can astringe and astringe, and benefit qi and produce saliva, all of which can play the effect of "warming the kidney and astringing", and target the symptoms of the deficiency of the kidney yang and the downward flow of water and dampness; Atractylodes can invigorate the spleen and benefit qi, and dry dampness and drain water, and Radix Glycyrrhizae can tonify the spleen and benefit qi, and harmonize various drugs, and enhance the effect of "invigorating the spleen and stopping diarrhea" of the core combination.

[0017] Poria can invigorate the spleen and drain dampness, and assist Atractylodes to enhance the effect of draining dampness, and prevent the warm-drying nature of dried ginger and Psoralea from damaging yin; Chinese yam can tonify the spleen and stomach, and benefit the kidney and astringe, and is neutral in nature and sweet in taste, and can benefit qi and saliva, and is suitable for patients with deficiency of qi and blood; Lotus seed can tonify the spleen and stop diarrhea, and benefit the kidney and astringe, and can enhance the effect of astringing the intestines, and can also nourish the heart and calm the mind, and improve the anxiety of patients with chemotherapy; White kidney bean can invigorate the spleen and drain dampness, and target the "dampness stagnation" syndrome accompanied by diarrhea, and reduce the symptoms of abdominal distension, diarrhea and sticky stool.

[0018] Therefore, the present application has the following beneficial effects: (1) Strong pathogenesis targeting: closely related to the core pathogenesis of irinotecan-induced delayed diarrhea "spleen and kidney yang deficiency, downward flow of water and dampness", based on the Lizhong Sishen Decoction, and taking into account the four effects of "warming yang, invigorating the spleen, tonifying the kidney and stopping diarrhea", fundamentally improving the intestinal function, rather than simply stopping diarrhea; (2) Synergistic effect: the modified components (Poria, Chinese yam, lotus seed and white kidney bean) can not only enhance the effect of stopping diarrhea and benefiting qi, but also can alleviate the warm-drying nature of dried ginger and Psoralea, avoid the "heat" or intestinal mucosa irritation symptoms of patients with chemotherapy, and have no side effects such as arrhythmia and constipation of western medicine loperamide; (3) It is used for each grade of irinotecan-induced delayed diarrhea after chemotherapy, especially for 2-3 grade diarrhea with poor western medicine effect, and can also improve the symptoms of fatigue, poor appetite and cold of patients with chemotherapy.

[0019] The technical solutions of the present application will be further described in detail through the following examples. DETAILED DESCRIPTION

[0020] The technical solutions of the present application will be further described in detail through the following examples.

[0021] In order to make the purpose, technical scheme and advantages of the present application more clear, thorough and complete, the technical scheme of the present application is described clearly and completely by examples below. The following detailed description is the description of examples, which aims to provide further detailed description of the present application. Unless otherwise specified, all technical terms used in the present application have the same meaning as generally understood by the general technical personnel in the field to which the present application belongs.

[0022] The instrument equipment and reagent materials used in the examples are obtained through commercial channels.

[0023] Example 1 A traditional Chinese medicine composition for treating irinotecan-induced delayed diarrhea with the effect of warming yang, comprising, by weight, 9 parts of ginseng, 6 parts of dried ginger, 12 parts of white atractylodes, 4 parts of prepared licorice, 9 parts of psoralea, 6 parts of mace, 2 parts of evodia, 4 parts of schisandra, 12 parts of poria, 15 parts of yam, 9 parts of lotus seed, and 9 parts of white kidney bean.

[0024] Example 2 A traditional Chinese medicine composition for treating irinotecan-induced delayed diarrhea with the effect of warming yang, comprising, by weight, 6 parts of ginseng, 3 parts of dried ginger, 12 parts of white atractylodes, 3 parts of prepared licorice, 6 parts of psoralea, 3 parts of mace, 1 part of evodia, 3 parts of schisandra, 15 parts of poria, 12 parts of yam, 6 parts of lotus seed, and 15 parts of white kidney bean.

[0025] Example 3 A traditional Chinese medicine composition for treating irinotecan-induced delayed diarrhea with the effect of warming yang, comprising, by weight, 12 parts of ginseng, 9 parts of dried ginger, 15 parts of white atractylodes, 6 parts of prepared licorice, 12 parts of psoralea, 9 parts of mace, 3 parts of evodia, 6 parts of schisandra, 15 parts of poria, 18 parts of yam, 9 parts of lotus seed, and 12 parts of white kidney bean.

[0026] Example 4 A decoction is prepared using the traditional Chinese medicine composition in Example 1 as raw material, comprising the following steps: (1) After screening, washing and drying, each component in Example 1 is crushed into coarse powder with a particle size of 2-4 mm.

[0027] (2) 100 g of the coarse powder is taken, soaked in 10 times the amount of purified water for 30 minutes, and then boiled and simmered for 40 minutes. The first decoction is obtained after filtration. The residue is added with 8 times the amount of purified water, boiled, and then simmered for 30 minutes. The second decoction is obtained after filtration.

[0028] (3) The two decoctions are combined, filtered through a 0.45 μm microporous filter membrane, and concentrated to 1 g of crude drug per 1 mL at 60°C and -0.08 MPa reduced pressure.

[0029] Granules are prepared with the traditional Chinese medicine composition in Example 1 as raw material, including the following steps: (1) Concentrate preparation: Concentrate is prepared according to the steps (1)-(3) of the above decoction (solid content is about 20%).

[0030] (2) Soft material preparation: Add dextrin and stevioside to the concentrate, the amount of dextrin is 1.2 times of the solid, and the amount of stevioside is 0.02 times of the solid, which is suitable for diabetic patients, and stir into a uniform soft material.

[0031] (3) Granulation and drying: 16 mesh sieve granulation, 65°C air drying to moisture ≤5%.

[0032] (4) Granule sizing and packaging: 14 mesh sizing, remove fine powder, and package.

[0033] Pills are prepared with the traditional Chinese medicine composition in Example 1 as raw material, including the following steps: (1) Raw material pretreatment: Dry each component of Example 1 at 50°C, crush into fine powder, pass through a 100 mesh sieve, and the moisture content is ≤8%.

[0034] (2) Drug mixing and balling: Take 100g of drug powder, add 1.2 times of honey (medium honey state: 116-118°C, relative density 1.37), and stir into a uniform drug mass.

[0035] (3) Pan granulation and drying: Pan granulator is used to make 3mm diameter pellets, and 55°C air drying to moisture ≤6%.

[0036] (4) Coating: Coated with hydroxypropyl methylcellulose dissolved in 10% ethanol, weight gain 3%-5%, and obtained (each pill contains 0.5g of crude drug).

[0037] Example 5 Diagnosis criteria: (1) Western medicine diagnosis criteria: Irinotecan delayed diarrhea diagnosis: Within 24 hours to 14 days after using irinotecan chemotherapy, the number of defecation increases (increased by ≥1 times per day compared with baseline), or the stool character changes (watery stool); Diarrhea classification: 1st grade: The number of daily defecation increases by 1-3 times compared with baseline, or the stool is paste-like; 2nd grade: The number of daily defecation increases by 4-6 times compared with baseline, or the stool is watery with mild abdominal pain / abdominal distension; 3rd grade: The number of daily defecation increases by 7-9 times compared with baseline, or the stool is a large amount of watery with obvious abdominal pain, electrolyte disturbance, and need for intravenous fluid infusion; 4th grade: The number of daily defecation increases by ≥10 times compared with baseline, or the stool is jet-like watery with shock and need for intensive care.

[0038] (2) TCM syndrome differentiation criteria: Core syndrome: spleen-kidney yang deficiency: main symptoms (diarrhea, chills, soreness of the waist and knees), secondary symptoms (weakness, poor appetite, pale tongue, white fur, and thin pulse), and 2 main symptoms and 1 secondary symptom can be diagnosed; Combined syndrome classification: Dampness and stagnation: on the basis of spleen-kidney yang deficiency, accompanied by abdominal distension, loose and sticky stool (mixed with undigested food), and white and greasy tongue fur; Kidney yang deficiency: on the basis of spleen-kidney yang deficiency, accompanied by cold limbs, morning diarrhea (diarrhea in the morning), and weak and slow pulse.

[0039] Case 1: A 58-year-old male patient with colorectal cancer, after surgery (pathological stage T3N1M0), received irinotecan, leucovorin, and 5-fluorouracil chemotherapy every 2 weeks. 48 hours after the first chemotherapy, grade 2 diarrhea (8-10 times of watery stool per day) occurred, accompanied by abdominal pain and chills. Loperamide was ineffective for 3 days. The soup prepared from the herbal composition of Example 4 was used, 100 mL each time, 3 times a day.

[0040] Efficacy: 4-5 times of defecation per day (paste-like) after 1 day of treatment, and 1-2 times per day (formed) after 3 days; no delayed diarrhea occurred after subsequent chemotherapy.

[0041] Case 2: A 62-year-old female patient with advanced gastric cancer (gastric body adenocarcinoma stage IV with abdominal metastasis), received irinotecan monotherapy every 3 weeks. 72 hours after the second chemotherapy, grade 3 diarrhea (12-15 times of watery stool per day) occurred, accompanied by cold limbs and soreness of the waist and knees. Octreotide was ineffective for 2 days. The soup prepared from the herbal composition of Example 3 was used, 100 mL each time, 3 times a day.

[0042] Efficacy: 5-6 times of defecation per day after 2 days of treatment, and 1-2 times per day after 5 days; only grade 1 diarrhea (3-4 times per day) occurred after subsequent preventive use (6 pills each time, 2 times a day, for 7 consecutive days).

[0043] Case 3: A 65-year-old male patient with advanced gastric cancer (gastric antrum adenocarcinoma, stage IV), received irinotecan and cisplatin chemotherapy every 3 weeks, and had type 2 diabetes with stable blood glucose control (glycated hemoglobin 6.5%). 36 hours after the first chemotherapy, grade 2 delayed diarrhea occurred, with 6-8 times of defecation per day, and the stool was loose and sticky (mixed with undigested food residues), accompanied by obvious abdominal distension and loss of appetite. After taking loperamide for 2 days, the frequency of defecation was slightly reduced (5-6 times per day), but the abdominal distension was not improved, affecting eating.

[0044] The soup prepared from the herbal composition of Example 2 was used, 100 mL each time, 3 times a day. Efficacy: After 1 day of medication, abdominal distension was significantly relieved, and normal semi-liquid food could be eaten; after 2 days of medication, the frequency of defecation decreased to 3-4 times, and the stool became paste-like; after 5 days of medication, the defecation returned to 1-2 times per day (formed stool), and there were no abdominal distension and loss of appetite symptoms; in the subsequent 3 chemotherapy cycles, prophylactic use was performed (24 hours after chemotherapy, 2 times per day, 1 bag each time, for 5 consecutive days), and there was no recurrence of delayed diarrhea, and the blood glucose was stable.

[0045] Finally, it should be noted that: the above examples are only used to illustrate the technical solutions of the present application, but not to limit them, although the present application has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that: it can still modify or equivalently replace the technical solutions of the present application, and these modifications or equivalent replacements also cannot make the modified technical solutions deviate from the spirit and scope of the technical solutions of the present application.

Claims

1. A traditional Chinese medicine composition with warming and yang-tonifying effects for treating irinotecan-induced delayed diarrhea, characterized in that, By weight, it includes: ginseng 6-12 parts, dried ginger 3-9 parts, atractylodes macrocephala 9-15 parts, prepared licorice root 3-6 parts, psoralea corylifolia 6-12 parts, nutmeg 3-9 parts, evodia rutaecarpa 1-3 parts, schisandra chinensis 3-6 parts, poria cocos 9-15 parts, dioscorea opposita 12-18 parts, lotus seed 6-12 parts, and white hyacinth bean 6-12 parts.

2. The traditional Chinese medicine composition with warming and yang-tonifying effects for treating irinotecan-induced delayed diarrhea according to claim 1, characterized in that, By weight, it includes: 9 parts ginseng, 6 parts dried ginger, 12 parts Atractylodes macrocephala, 4 parts prepared licorice root, 9 parts Psoralea corylifolia, 6 parts nutmeg, 2 parts Evodia rutaecarpa, 4 parts Schisandra chinensis, 12 parts Poria cocos, 15 parts Dioscorea opposita, 9 parts lotus seeds, and 9 parts white hyacinth bean.

3. A traditional Chinese medicine composition with warming and yang-tonifying effects for treating irinotecan-induced delayed diarrhea according to claim 1, characterized in that, By weight, it includes: 6 parts ginseng, 3 parts dried ginger, 12 parts Atractylodes macrocephala, 3 parts prepared licorice root, 6 parts Psoralea corylifolia, 3 parts nutmeg, 1 part Evodia rutaecarpa, 3 parts Schisandra chinensis, 15 parts Poria cocos, 12 parts Dioscorea opposita, 6 parts lotus seeds, and 15 parts white hyacinth bean.

4. A traditional Chinese medicine composition with warming and yang-tonifying effects for treating irinotecan-induced delayed diarrhea according to claim 1, characterized in that, By weight, it includes: 12 parts ginseng, 9 parts dried ginger, 15 parts atractylodes macrocephala, 6 parts prepared licorice root, 12 parts psoralea corylifolia, 9 parts nutmeg, 3 parts evodia rutaecarpa, 6 parts schisandra chinensis, 15 parts poria cocos, 18 parts dioscorea opposita, 9 parts lotus seeds, and 12 parts white hyacinth bean.

5. A formulation based on the traditional Chinese medicine composition according to any one of claims 1-4, characterized in that: Traditional Chinese medicine compositions can be formulated into any of the following dosage forms: decoction, granules, or pills.

6. The use of the traditional Chinese medicine composition according to any one of claims 1-4 in the preparation of a drug for treating delayed diarrhea induced by irinotecan chemotherapy, characterized in that, Using the traditional Chinese medicine composition according to any one of claims 1-4 as raw material, the preparation type is decoction, granules or pills, and the preparation process is as follows: Decoction: The composition is pulverized into coarse powder, decocted twice, and the decoctions are combined and concentrated to contain 1g of raw herbs per 1mL; Granules: Take the concentrated decoction, add dextrin and steviol glycosides to granulate, and dry at 65℃ until the moisture content is ≤5%; Pills: The composition is pulverized into a fine powder, 1.2 times the amount of refined honey is added to form pills, dried at 55°C until the moisture content is ≤6%, and then coated with hydroxypropyl methylcellulose.

7. The application according to claim 6, characterized in that: During the preparation of the decoction, add 10 times the amount of water for the first decoction and simmer for 40 minutes; add 8 times the amount of water for the second decoction and simmer for 30 minutes.

8. The application according to claim 6, characterized in that: During the preparation of granules, the amount of dextrin added is 1 times the amount of solids in the decoction concentrate, and the amount of steviol glycosides added is 0.02 times the amount of solids in the decoction concentrate.

9. The application according to claim 6, characterized in that: The coating increases weight by 3%-5%.