WO2021013270A1 - 一种治疗息肉的药物组合物 - Google Patents

一种治疗息肉的药物组合物 Download PDF

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WO2021013270A1
WO2021013270A1 PCT/CN2020/104912 CN2020104912W WO2021013270A1 WO 2021013270 A1 WO2021013270 A1 WO 2021013270A1 CN 2020104912 W CN2020104912 W CN 2020104912W WO 2021013270 A1 WO2021013270 A1 WO 2021013270A1
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polyps
chinese medicine
traditional chinese
dosage
medicine composition
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PCT/CN2020/104912
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English (en)
French (fr)
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刘万里
郑艳辉
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南京三同医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/90—Smilacaceae (Catbrier family), e.g. greenbrier or sarsaparilla
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06—Fungi, e.g. yeasts
    • A61K36/07—Basidiomycota, e.g. Cryptococcus
    • A61K36/076—Poria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/11—Pteridophyta or Filicophyta (ferns)
    • A61K36/12—Filicopsida or Pteridopsida
    • A—HUMAN NECESSITIES
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    • A61K36/18—Magnoliophyta (angiosperms)
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    • A61K36/18—Magnoliophyta (angiosperms)
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Definitions

  • the invention relates to the field of natural medicines, in particular to a traditional Chinese medicine composition for treating polyps.
  • Polyp refers to the neoplasms that grow on the surface of human or mammalian tissues.
  • the neoplasms that grow on the mucosal surface are usually collectively called polyps, including proliferative, inflammatory, hamartoma, adenoma and other tumors, etc. .
  • Polyps are a kind of benign tumors. The clinical manifestations are mostly inflammatory polyps, adenomatous polyps and certain gastrointestinal polyposis syndromes. Although these lesions are benign, some of them have a tendency to become malignant.
  • common intestinal polyps According to the location of the disease, common intestinal polyps, uterine polyps, cervical polyps, throat polyps, nasal polyps, large intestine polyps, gastric polyps, colon polyps, gallbladder polyps, etc. are common.
  • Inflammatory polyps refer to chronic inflammation of mucosal tissues, excessive proliferation of mucosal tissues and hyperplasia of granulation tissues protruding to the mucosal surface to form pedicled masses. There are two possibilities for its formation: one is the protruding residual mucosa in the center of the ulcer surface; the other is the proliferation of granulation tissue on the ulcer surface and the adjacent mucosa is covered.
  • Adenomatous polyp (adenomatous polyp) is also called "polypoidal adenoma”.
  • Mucosal adenomas are mostly polypoid, common in the gastrointestinal mucosa, and more often in the colon. Single or multiple, with or without pedicle. In patients with familial polyposis, there are multiple polypoid adenomas of varying sizes in the colonic mucosa, the number can be as many as hundreds or even thousands, making the entire colon and rectal mucosa covered with polyps, prone to malignant changes.
  • Gastrointestinal polyps generally refer to neoplasms derived from the mucosal epithelium of the digestive tract, protruding from the mucosal surface and protruding into the digestive tract cavity. According to the growth position of polyps, they are called esophageal polyps, stomach polyps, small intestine polyps, large intestine polyps (colon and rectum) polyps, and gallbladder polyps.
  • Gastrointestinal polyposis syndrome is a multiple polyposis mainly involving the colon, most of which are accompanied by extraintestinal manifestations. According to the degree of gastrointestinal involvement, the accompanying extraintestinal manifestations, whether there is a genetic predisposition and different genetic methods, and the general and histological manifestations of polyps. Generally can be divided into two categories: adenomatous and hamartomatic polyposis syndrome.
  • Juvenile polyposis syndrome polyps are most common in the rectum, but can occur in the entire colon, occasionally in the stomach and small intestine;
  • Cronkhite-Canada syndrome This disease is a group of clinical syndromes first reported by Cronkhite and Canada in 1955. The disease was first reported in China in 1985 and is usually called gastrointestinal polyps in China- Pigmentation-baldness-nail atrophy syndrome. CCS is a rare acquired disease. The etiology and pathogenesis of the disease are still unclear. Most studies believe that it may be related to infection, mental stress, overwork, lack of growth factors, and arsenic poisoning. Studies by foreign scholars have shown that it is mostly related to hypothyroidism and autoimmune diseases. At present, there is no specific treatment plan, and symptomatic treatment, nutritional support and hormone therapy are mainly adopted.
  • the purpose of the present invention is to provide a traditional Chinese medicine composition for the treatment of polyps, which is composed of Smilax glabra, Lonicera japonica, Forsythia suspensa and Baiwei.
  • the dosage of Smilax glabra, Lonicera japonicus, Forsythia suspense, and Bai Wei can be used clinically, for example, the dosage of Smilax glabra is 3-100g, the dosage of Lonicera japonica is 3-100g, and the dosage of Forsythia is 3-100g. , Baiwei dosage is 2-50g.
  • the dosage of Smilax glabra is 10-60g
  • the dosage of honeysuckle is 10-60g
  • the dosage of forsythia is 5-30g
  • the dosage of Baiwei is 5-30g.
  • the dosage of Smilax glabra is 15-30g
  • the dosage of honeysuckle is 15-30g
  • the dosage of forsythia is 10-15g
  • the dosage of Baiwei is 10-15g.
  • the dosage ratio of Smilax glabra, Lonicera japonica, Forsythia suspense, and Bai Wei can be 3-100:3-100:3-100:2-50, and more preferably 10-60:10- 60:5-30:5-30, most preferably 15-30:15-30:10-15:10-15.
  • Another object of the present invention is to provide the application of the traditional Chinese medicine composition and its oral preparation in the treatment of polyps in humans or mammals, preferably in the treatment of polyps in humans.
  • the polyps in the present invention refer to neoplasms that grow on the mucosal surface of humans or mammals. According to their histopathology, they include proliferative, inflammatory, hamartoma, and adenoma.
  • the polyps of the present invention belong to a kind of benign tumors, and inflammatory polyps, adenomatous polyps and certain gastrointestinal polyposis syndromes are common in clinical manifestations, but some of them have a tendency to become malignant.
  • the polyps of the present invention are classified according to their onset locations, and common ones include digestive tract polyps, endometrial polyps, cervical polyps, throat polyps, nasal polyps and the like.
  • the polyp in the present invention refers to gastrointestinal polyposis syndrome.
  • the gastrointestinal polyposis syndrome in the present invention refers to Cronkhite-Canada syndrome.
  • the polyps of the present invention are preferably digestive tract polyps, cervical polyps, and throat polyps.
  • the digestive tract polyps in the present invention refer to single or multiple polyps that occur in the entire digestive tract, including: esophageal polyps, gastric polyps, small intestine polyps, large intestine polyps (colon polyps, rectal polyps), anal polyps, gallbladder polyps
  • the digestive tract polyps of the present invention can also be multiple polyps that occur simultaneously in the stomach and small intestine and or large intestine (including colorectal and anus), and such polyps are also referred to as gastrointestinal polyps in this application.
  • the Chinese medicinal composition provided by the present invention can also be used in combination with other drugs for symptomatic use according to the patient's disease.
  • it can be used in combination with one or more of the following Chinese medicines, including pinellia, tangerine peel, tuckahoe, licorice, ginseng, atractylodes, yam, Liu Shenqu, Jiao Hawthorn, woody, coptis, white fresh peel, Kochia scoparia, phoenix Tail grass, Danpi, Jiaoshan Zhi.
  • the traditional Chinese medicine composition of the present invention is used in combination with one or more of the following pharmaceutical compositions, such as a pharmaceutical composition composed of pinellia, tangerine peel, tuckahoe, licorice, ginseng, and Atractylodes macrocephala; a pharmaceutical composition composed of Chinese yam, Liushenqu, and Jiao Hawthorn Composition; medicinal composition composed of woody and coptis; medicinal composition composed of white fresh peel and Kochia scoparia; medicinal composition composed of paeonol and Jiaoshanzhi.
  • the traditional Chinese medicine and traditional Chinese medicine composition used in combination with the composition of the present invention all adopt clinical routine dosages.
  • the traditional Chinese medicine composition provided by the present invention can also be used in combination with one or more of glucocorticoids, immunosuppressive agents, antibiotics, and acid suppressants.
  • Another object of the present invention is to provide oral preparations of the above-mentioned traditional Chinese medicine composition, including capsules, tablets, granules, and oral liquids.
  • Capsules include hard capsules, soft capsules, sustained-release capsules, etc.; tablets include ordinary tablets, buccal tablets, sustained-release tablets, and the like.
  • the pharmaceutical composition of the present invention can be extracted by conventional methods in the art, and the obtained extract (liquid) is used to prepare a suitable oral preparation.
  • the pharmaceutical composition of the present invention can be separately extracted and combined extracts (liquids), or can be combined and extracted together to obtain extracts (liquids).
  • Conventional extraction methods in this field include water decoction, dipping, percolation, modified gelatin, reflux, solvent extraction, steam distillation, sublimation, supercritical fluid extraction, membrane separation technology, ultramicro Crushing technology, traditional Chinese medicine flocculation separation technology, semi-bionic extraction method, ultrasonic extraction method, cyclone extraction method, pressure countercurrent extraction method, enzymatic method, macroporous resin adsorption method, ultrafiltration method, molecular distillation method, etc., preferably water decoction Method, dipping method, percolation method, solvent extraction method, ultrasonic extraction method, supercritical fluid extraction method.
  • auxiliary materials such as powdered sugar, magnesium stearate, lactose, sodium bicarbonate, starch, dextrin, etc.
  • the Smilax glabra in the present invention refers to the dried rhizome of the Liliaceae plant Smilax glabra Roxb., also known as Smilax glabra Roxb.; Smilax glabra; Smilax glabra; Smilax glabra; Vajra vine; Vajra japonicus; pointed tail leaf; flower vine; scorpion scorpion; serrata vine; horseshoe crab vine; hard rice ball; smooth smilax; cold rice head; soil stilt; red smilax; mountain chestnut; smilax; grass Yu Yuliang; Smilax glabra; Nine Niu Li; Thousand Tail Root; Yu Yuliang; Soil Fuling; Mountain Tail Potato; Xiaobai Soil Poria; Sheep Tongue Vine; Hard Board Head; Cold Rice Vine; Mountain Remnant Quantity; Cold rice ball; Yu surplus food; Cold rice tuo; Longxucai; Vest-supper; hairy tail potato; cotton nose vine; Qianjinl
  • the honeysuckle vines are the dried stalks of Lonicera japonica Thunb (Lonicera japonica Thunb), which are also known as old man's beard, golden hairpin, large pumila, salicula vine, Qianjin vine ("Su Chen Liang Fang”), and Mandarin duck grass (“ ⁇ ), Heron Vine (“Lugan Rock Materia Medica”), Honeysuckle ("Keys for Syndrome and Treatment”), Zuo Zang Teng ("Yu Ju Shi Selected Prescriptions"), Lonicerae ("Hong's Collection of Prescriptions"), psychic Grass, honeybucket vine ("Tu Su Materia Medica”), honeysuckle vine (“Danxi Heart Method”), gold and silver vine (“Qiankun Business Secret Yun”), honeysuckle stem (“Southern Yunnan Materia Medica”), sweet vine (“Materia Medica”) "), Right Seal Teng ("Classification of Herbal Properties”), Right Rotating Teng ("Guizhou Folk Recipe Collection”)
  • the forsythia in the invention is the fruit of Forsythia suspensa (Thunb.) Vahl.
  • the Baiwei described in the present invention is the root and rhizome of Cynanchum atratum Bge. and the trailing Baiwei Cynanchum versicolor Bge., also known as Zhiwei Lao; Half-pull scoop; White curtain; White horsetail; White horsewei; Bailongxu; Laogua calabash; Shanyangenzi; Samara Baiwei; calabash a few melons; Jiulongxu; Zhiweilao; Zhiweicao; sewing kit; Yima dry-huhe; Gumei; Laojianjiao; Yang Horn willow; old calabash; big calabash melon; cowhide disappear; horn wind; hornbill grass; big squash; old scorpion clip; spring grass; tiger calabash; old calabash root; old melon calabash root; calabash melon; Lavender root; Dabaiwei; Asarum asarum; Nenbaiwei; Baiqian
  • Figure 1 shows the effect of the tested drug on the number of colorectal adenomas in mice
  • Figure 2 is a photo of mouse colorectal adenoma.
  • the main complaint of the patient diarrhea, skin pigmentation, soft nails for more than half a year.
  • the patient was treated at the Spleen and Gastroenterology Clinic of our hospital (Nanjing Hospital of Integrated Traditional Chinese and Western Medicine) on June 11, 2011 due to "diarrhea with low fever for more than 1 month, worsening for 3 days”.
  • the patient underwent colonoscopy (2011-06-16): the nature of multiple polyp lesions in the colon is to be determined (Cronvicte-Canada to be confirmed); colonoscopy pathology (2011-06-23): (ascending colon, 25cm from the anus) Villous tubular adenoma with mild dysplasia of glandular epithelium, (50cm from the anus) villous tubular adenoma with moderate dysplasia of glandular epithelium.
  • the outpatient doctor recommends that the patient go to a superior hospital for treatment.
  • the patient has diarrhea intercropping, walking 2 to 3 times a day, forming a shapeless, sticky feeling, loss of appetite, and obvious fatigue.
  • Physical examination look, mental atrophy, skin pigmentation on the fingertips, softening and peeling of the distal nails, scattered pigmentation spots on the face, obvious hair loss, no other positive signs.
  • Colonoscopy was performed after admission (2011-09-16): There were hundreds of polypoid swellings in the entire colon, with a size of 0.4cm ⁇ 0.4cm to 1.0cm ⁇ 1.5cm, with a papillary surface and hyperemia on the surface of the colon.
  • Colonoscopy showed that there were a dozen polypoid swellings in the entire colon, and the number was significantly reduced compared to the previous one, indicating that it was papillary and indicating mucosal congestion. Two colons were taken for biopsy (not seen in the report). Significant improvement before. After that, the patient insisted on applying traditional Chinese medicine, and did not use hormones, immunosuppressants, antibiotics and other western medicine during the period.
  • the patient's condition is stable, bowel movement is performed 1 to 2 times a day, excessive formation, no abdominal distension, no abdominal pain, no aversion to cold and fever, appetite gradually normal, taste gradually returned to normal, but eating cold food and stomach discomfort, fatigue is significantly improved, and night sleep is normal , Urine is normal, weight rises about 5kg.
  • Colonoscopy in September 2014 no polyps and no biopsy.
  • Colonoscopy in October 2017 no polyps and no biopsy.
  • Gastroscopy in October 2017 duodenal bulb ulcer (stage S1), descending duodenal polyp.
  • Gastroscopy pathology no polyps (descending duodenum), chronic active enteritis, and (large) mild chronic atrophic gastritis.
  • Main prescription Smilax glabra 30g, Lonicera japonica 30g, Forsythia 15g, Bai Wei 15g; 1 dose/day, decocted in water, divided into morning and evening.
  • the original Fang Baiwei was reduced to 10g
  • the honeysuckle vine was reduced to 15g
  • the forsythia was reduced to 10g.
  • the original Fang Baiwei was reduced to 10g
  • the honeysuckle vine was reduced to 15g
  • the forsythia was reduced to 10g.
  • the original Fang Baiwei was reduced to 10g
  • the honeysuckle vine was reduced to 15g
  • the forsythia was reduced to 10g.
  • the original Fang Baiwei was reduced to 10g
  • the honeysuckle vine was reduced to 15g
  • the forsythia was reduced to 10g.
  • Example 3 Establishing a mouse model of adenomatous polyps and evaluating the efficacy of the test drug compound
  • mice Balb/c mouse, SPF grade, weight 18-22g, male, Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd., license number: SCXK ( ⁇ )2016-0003.
  • the mice were raised in separate cages in the Animal Experiment Center of Nanjing University of Traditional Chinese Medicine, with a breeding license: SYXK2018-0049, moderate light, room temperature 22-25°C, humidity 50-60%.
  • Test drug 1 Pseudoginsenopsis 15g Atractylodes macrocephala (stir-fried) 10g Bai Fuling 15g Coix seed (raw) 30g Smilax glabra 30g Honeysuckle 30g Forsythia 15g Baiwei 10g.
  • Total crude drug quantity 155g/person/day.
  • Test drug 2 Smilax glabra 30g Lonicera japonica 30g Forsythia 15g Bai Wei 10g.
  • Total crude drug 85g/person/day.
  • Modeling reagent AOM (Azomethane Oxide), sigma, batch number: SLCC0424. DSS (dextran sodium sulfate), MP biomedicals, batch number: Q1723.
  • mice After being adaptively reared, the mice are randomly divided into two groups: blank group, model group, test drug 1, and test drug according to their weight.
  • mice in each group were given intraperitoneal injection of AOM 10mg/kg on the first day of the first week, and were given 2.5% DSS drinking water for one week. The mice were free to drink, and then given Ordinary drinking water is free to drink for 2 weeks, a total of 3 weeks as a cycle. Same as the first cycle, intraperitoneal injection of 10mg/kg of AOM on the first day of the 4th week and the 7th week, and the administration of 2.5% DSS for 2 weeks, and ordinary drinking water for the rest of the time, a total of 9 weeks and 3 cycles.
  • the mice in the blank group were intraperitoneally injected with physiological saline on the same day as the intraperitoneal injection of the model group. From the beginning of the experiment to the end of the experiment, they were given ordinary drinking water for free.
  • mice in the positive drug group were given the test drug 1 or 2 by gavage, once a day, the gavage was continued for 9 weeks during the model building, and the gavage was continued after the model was completed 1 week, a total of 10 weeks of administration.
  • mice were sacrificed by cervical dislocation and the large intestine (from the end of the cecum to the entire colorectal section of the anus) was cut out longitudinally along the intestine. Open, rinse with normal saline to clean the intestinal feces, place the intestinal mucosa face up on the dissection table, take pictures and observe the performance of the intestinal mucosal tissue, inflammatory reaction and the occurrence of tumors with the naked eye. If tumors occur, record the tumors Number of occurrences, location, size, etc. (Attached pictures of intestinal polyps at the back).

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Abstract

一种治疗息肉的药物组合物及其应用，该组合物包括土茯苓、忍冬藤、连翘、白薇，还包括半夏、陈皮、茯苓、甘草、人参、白术、山药、六神曲、焦山楂、木香、黄连、白鲜皮、地肤子、凤尾草、丹皮、焦山栀中的一种或多种。

Description

一种治疗息肉的药物组合物 技术领域
本发明涉及天然药物领域，具体而言涉及一种治疗息肉的中药组合物。
背景技术
息肉(polyp)，是指人或哺乳动物组织表面长出的赘生物，通常把生长在黏膜表面上的赘生物统称为息肉，包括增生性、炎症性、错构瘤、腺瘤及其他肿瘤等。息肉属于良性肿瘤的一种，临床表现多见炎性息肉、腺瘤性息肉和某些胃肠道息肉病综合征，这些病变虽属良性，但其中一部分有恶变倾向。按其发病部位分，常见的有肠道息肉病、子宫息肉、宫颈息肉、喉息肉、鼻息肉、大肠息肉、胃息肉、结肠息肉、胆囊息肉等。
炎性息肉是指粘膜组织的慢性炎症，粘膜组织过度增生及肉芽组织增生向粘膜表面突出形成带蒂的肿物。其形成有两种可能：一是溃疡面中央残留黏膜突出；二是溃疡面肉芽组织增生凸起，邻近黏膜覆盖。
腺瘤性息肉(adenomatous polyp)又称“息肉状腺瘤”。黏膜的腺瘤多呈息肉状，常见于胃肠黏膜，更多在结肠。单发性或多发性，有蒂或无蒂。家族性息肉病患者，结肠黏膜有多个大小不等的息肉状腺瘤，数目可多达数百甚至数千，使整个结肠和直肠黏膜布满息肉，易发生恶性变。
消化道息肉泛指来源于消化道黏膜上皮、隆起于粘膜表面，向消化道腔内突起的赘生物。根据息肉生长的位置分别称之为食管息肉、胃息肉、小肠息肉、大肠息肉(结肠及直肠)息肉、胆囊息肉。
胃肠道息肉病综合征是以累及结肠为主的多发性息肉病，大部分伴有肠道外表现。按照胃肠道累及的程度、伴随的肠外表现、有无遗传倾向及其不同的遗传方式和息肉的大体与组织学表现而分类。一般可分为腺瘤性与错构瘤性息肉病综合征两大类。
(一)腺瘤性息肉病综合征
特点是多发性腺瘤伴有结肠癌的高发率。主要有以下三种：
1.家族性结肠息肉病
2.Gardner综合征
3.Turcot综合征
(二)错构瘤息肉综合征
包含一组疾病，其特点是某些肠段被一些组织的无规律地混合体所累及，具有非肿瘤性 但有肿瘤样增殖的特征。
1.Peutz-Jeghers综合征(黑色素斑-胃肠多发性息肉综合征)；
2.幼年性息肉病综合征：息肉最常见于直肠，但可发生于整个结肠，偶见于胃和小肠；
3.Cronkhite-Canada综合征(CCS)：该病是由Cronkhite和Canada于1955年首先报道的一组临床综合征，该病于1985年在国内首次报道，国内通常称之为胃肠道息肉-色素沉着-秃发-指(趾)甲萎缩综合征。CCS是一种罕见的后天获得性疾病，该病的病因及发病机制至今尚不明确，大多数研究认为可能与感染、精神紧张、过度劳累、缺乏生长因子、砷中毒有关。国外学者有研究表明其多与甲状腺机能减退、自身免疫疾病等相关。目前缺乏特异性治疗方案，主要采取对症治疗、营养支持和激素治疗。
目前，临床针对息肉的治疗手段有限，以各种方式的手术切除为主。但是对于多发性的息肉以及息肉本身易复发的特点，手术切除并不能满足临床需求。
发明内容
本发明的目的是提供一种治疗息肉的中药组合物，该组合物由土茯苓、忍冬藤、连翘、白薇组成。本发明中药组合物，其中土茯苓、忍冬藤、连翘、白薇的用量可以采用临床常用量，例如土茯苓用量为3-100g，忍冬藤用量为3-100g，连翘用量为3-100g，白薇用量为2-50g。优选土茯苓用量为10-60g，忍冬藤用量为10-60g，连翘用量为5-30g，白薇用量为5-30g。进一步优选土茯苓用量为15-30g，忍冬藤用量为15-30g，连翘用量为10-15g，白薇用量为10-15g。本发明提供的中药组合物，其中土茯苓、忍冬藤、连翘、白薇的用量比例可以为3-100:3-100:3-100:2-50，进一步优选为10-60:10-60:5-30:5-30，最优选为15-30:15-30:10-15:10-15。
本发明的再一个目的是提供所述中药组合物及其口服制剂在治疗人或哺乳动物息肉中的应用，优选为治疗人类息肉中的应用。
本发明所述的息肉是指生长在人体或哺乳动物黏膜表面上的赘生物，按其组织病理学分包括增生性、炎症性、错构瘤、腺瘤性等。本发明所述的息肉属于良性肿瘤的一种，临床表现多见炎性息肉、腺瘤性息肉和某些胃肠道息肉病综合征，但其中一部分有恶变倾向。本发明所述的息肉按其发病部位分，常见的有消化道息肉、子宫内膜息肉、宫颈息肉、喉息肉、鼻息肉等。本发明所述的息肉是指胃肠道息肉病综合征。本发明所述的胃肠道息肉病综合征是指Cronkhite-Canada综合征。
本发明所述的息肉优选消化道息肉、宫颈息肉、喉息肉。本发明所述的消化道息肉是指发生在消化道全段的单发或者多发性息肉，包括：食管息肉、胃息肉、小肠息肉、大肠息肉 (结肠息肉、直肠息肉)、肛门息肉、胆囊息肉；本发明所述消化道息肉亦可以为同时发生在胃和小肠和或大肠(含结直肠、肛门)的多发性息肉，此类息肉在本申请中亦称为胃肠道息肉。
特别有益的是，本发明所提供的中药组合物还可以根据患者病症的不同联合其他药物对症使用。例如可以联合以下中药中的一种或多种使用，包括半夏、陈皮、茯苓、甘草、人参、白术、山药、六神曲、焦山楂、木香、黄连、白鲜皮、地肤子、凤尾草、丹皮、焦山栀。或者本发明中药组合物与以下药物组合物中的一种或多种联合使用，如半夏、陈皮、茯苓、甘草、人参、白术组成的药物组合物；山药、六神曲、焦山楂组成的药物组合物；木香、黄连组成的药物组合物；白鲜皮、地肤子组成的药物组合物；丹皮、焦山栀组成的药物组合物。与本发明组合物所联合使用的中药及中药组合物均采用临床常规剂量。
本发明所提供的中药组合物还可以联合包括糖皮质激素、免疫抑制剂、抗生素、抑酸药中的一种或多种使用。
本发明的另一个目的是提供上述中药组合物的口服制剂，包括胶囊剂、片剂、颗粒剂、口服液。胶囊剂包括硬胶囊、软胶囊、缓释胶囊等；片剂包括普通片、口含片、缓释片等。为制备上述药物制剂，本发明的药物组合物可以采取本领域常规的方法提取，以所得提取物(液)制备适宜的口服制剂。本发明的药物组合物可以分别提取合并提取物(液)，也可以混合后共同提取获得提取物(液)。
本领域常规的提取方法包括水煎煮法、浸渍法、渗漉法、改良明胶法、回流法、溶剂提取法、水蒸气蒸馏法、升华法、超临界流体萃取法、膜分离技术、超微粉碎技术、中药絮凝分离技术、半仿生提取法、超声提取法、旋流提取法、加压逆流提取法、酶法、大孔树脂吸附法、超滤法、分子蒸馏法等，优选水煎煮法、浸渍法、渗漉法、溶剂提取法、超声提取法、超临界流体萃取法。
按照制剂需要加入医药可接受的辅料以及保健食品可接受的辅料，例如糖粉、硬脂酸镁、乳糖、碳酸氢钠、淀粉、糊精等。
本发明所述的土茯苓是指为百合科植物光叶菝葜(Smilax glabra Roxb.)的干燥根茎，别名光叶菝葜；光菝葜；蓝果土茯芩；久老薯；进山虎；金刚藤；金刚豆藤；尖尾叶；花藤；花萆薢；花萆藤；鲎壳藤；硬饭团；光滑菝葜；冷饭头；土伏茯；红萆薢；山地栗；菝葜；草禹馀粮；光叶葜菝；九牛力；千尾根；禹馀粮；土伏苓；山尾薯；小白土茯苓；羊舌藤；硬板头；冷饭藤；山遗量；狗佬薯；冷饭团；禹余粮；冷饭陀；龙须菜；马甲簕；毛尾薯；绵鼻子藤；千斤力；山归来；山奇量；山猪粪；十八陀；土萆薢；萆薢藤；狗朗头；饭团根； 山奇良；草禹余粮；土茯芩；白余粮；白茯苓；红土苓；狗郎头；土苓；硬饭头；刺猪苓；仙遗粮；仙人换；山遗粮。
所述的忍冬藤为忍冬科植物忍冬(Lonicera japonica Thunb)干燥藤茎，别名老翁须、金钗股、大薜荔、水杨藤、千金藤(《苏沈良方》)、鸳鸯草(《墨庄漫录》)、鹭鸶藤(《履巉岩本草》)、忍冬草(《证治要诀》)、左缠藤(《余居士选奇方》)、忍寒草(《洪氏集验方》)、通灵草、蜜桶藤(《土宿本草》)、金银花藤(《丹溪心法》)、金银藤(《乾坤生意秘韫》)、金银花杆(《滇南本草》)、甜藤(《本草述》)、右篆藤(《分类草药性》)、右旋藤(《贵州民间方药集》)、二花秧、银花秧(《河南中药手册》)。
本发明所述的连翘为木犀科落叶灌木连翘Forsythia suspensa(Thunb.)Vahl.的果实,别名黄寿丹、黄缓丹、缓带。
本发明所述的白薇为萝藦科多年生草本植物白薇Cynanchum atratum Bge.和蔓生白薇Cynanchum versicolor Bge.的根和根茎，别名知薇老；半拉瓢；白幕；白马尾；白马薇；白龙须；老瓜瓢；山烟根子；翅果白薇；瓢几瓜；九龙须；知微老；知微草；针线包；伊麻干-呼和；骨美；老尖角；杨角柳；老鸹瓢；大瓢儿瓜；牛皮消；牛角风；牛角胆草；大瓜蒌；老犍子夹；春草；老虎瓢；老鸹瓢根；老瓜瓢根；瓢儿瓜；拉瓜瓢根；大白薇；马耳细辛；嫩白薇；白前；芒草；百条根；隔心苕；土白前；苦胆草；龙胆白薇；老龙角；老君须；白微；香白薇；羊角柳；羊角细辛；直生白薇；老和尚帽子；羊奶子；山蛤蜊瓢；薇草；微草；山烟；山瓜拉瓢；婆婆针线包；软白薇；百荡草；直立白薇；山鹤瓢；山黄瓜；山黄瓜瓢；山老瓜瓢；山老鸹瓢；三百根；荞麦细辛。
附图说明
图1为受试药对小鼠大肠腺瘤个数的影响；
图2为小鼠大肠腺瘤照片。
具体实施方式
以下通过实施例形式再对本发明的内容作进一步的详细说明，但不应就此理解为本发明上述主题的范围仅限于以下实施例。在不脱离本发明上述技术措施前提下，根据本领域普通技术知识和惯用手段做出的相应替换或变更的修改，均包括在本发明的范围内。
实施例1
患者，女，47岁，教师，2011年11月3日初诊。
患者主诉：腹泻、皮肤色素沉着、指甲变软半年余。
患者自诉：2011年5月下旬开始出现水样腹泻，日行3～5次，常伴有低热，自服“日夜百服咛、黄连素”等对症治疗后低热有好转，但仍有间断性解不成形黄色便，6月初患者自觉双手指甲变软、剥脱，面部及手指皮肤色素沉着，曾至江苏省某中医院就诊，拟诊“更年期综合征”，具体治疗不详，病情未见好转。患者因“腹泻伴低热1月余，加重3d”于2011年6月11日于我院(南京市中西医结合医院)脾胃病科门诊就诊。此次门诊就诊患者行肠镜检查(2011-06-16)：结肠多发息肉病变性质待定(Cronkhite-Canada待确诊)；肠镜病理(2011-06-23)：(升结肠、距肛门25cm)绒毛管状腺瘤，伴腺上皮轻度不典型增生，(距肛门50cm)绒毛管状腺瘤，伴腺上皮中度不典型增生。门诊医师建议患者至上级医院就诊。
2011年7月初，患者开始出现脱发，消瘦明显，且合并乏力、纳差、食之无味，患者至江苏省某人民医院住院诊疗，诊断考虑多发性消化道息肉综合征(CCS)，并予相关血清生化学等检查未见明显异常，此次入院主要以对症、营养支持治疗为主，病情不详。2011年9月12日患者于南京市某医院就诊，以“腹泻、皮肤色素沉着、指甲变软4月余”为主诉，诊断为“Cronkhite-Canada综合征”，并住院治疗。患者腹泻间作，日行2～3次，不成形、黏腻感，食欲不振，乏力明显。查体：神情，精神萎，十指指端皮肤可见色素沉着，远端指甲软化、剥脱，面部可见散在色素沉着斑，头发脱落明显，无其他阳性体征。入院后行肠镜检查(2011-09-16)：内镜下见全结肠有数百枚息肉样隆起，大小约0.4cm×0.4cm到1.0cm×1.5cm，表面呈乳头状，表面黏膜充血、个别有糜烂，内镜下选取较大的息肉切除6枚；患者胃镜检查(2011-09-18)：食管、贲门未见异常，胃底、胃体、胃角、胃窦见弥漫性分布数十枚大小不等息肉样隆起，较大约0.8cm×1.0cm，表面充血，取胃体大弯7块行活检。治疗上内镜下切除小部分息肉，其余无特殊，予营养支持，经请示上级医师予出院，告知患者其病情疑难、危重，无特效药物及治疗方法，建议患者可寻求中医药等方法保守治疗。
2011年11月3日，患者以“腹泻、皮肤色素沉着、指甲变软半年余”为主诉，至我院脾胃病科刘万里专家门诊就诊，来诊时患者忧虑重重，自知其所患疾病罕见、病因不明，且目前世界范围内无特效药治疗。患者诉大便日行2～3次，时不成形，黏腻不爽，臭秽无比，伴脐周隐痛间作，纳差明显，口淡、口不知味，胃脘嘈杂、泛酸，无恶寒发热，皮肤作痒阵发，夜寐差，常常整夜不能寐，烦躁不安，小便正常，月经已绝。近半年体重下降10kg。查体：消瘦，少神，面色萎黄，未闻及特殊气味，十指指腹及面部色素沉着明显，指甲薄软，见剥脱，头发稀疏，眉毛脱落；舌质红，苔薄，脉细弦。予中药汤剂口服，主方：土茯苓15g，忍冬藤15g，连翘15g，白薇10g，1剂/天，水煎服，分早晚温服，另辅以白鲜皮、地肤子、牡丹皮、焦山栀等中药针对患者肤痒、烦躁、夜寐不宁等症状予以治疗。
2诊：2011年11月10日，腹泻症状改善，日行1～2次，稍成形，纳食渐佳，可进食少 量流质，夜寐渐佳，皮肤瘙痒仍有，此外有口干、眼干症状明显，余较前一般。予前方加白薇至20g，白鲜皮加至15g，地肤子加至15g，另加焦栀子10g，西洋参15g。后患者坚持前来复诊，每次复诊时二便、纳食、夜寐等情况均不断改善，口服以上中药方剂巩固疗效，直至“口干、眼干、皮肤瘙痒”等好转后，予11月3日方减去地肤子、白鲜皮、牡丹皮。患者坚持中医药治疗半年，病情平稳，无明显腹泻，无腹痛腹胀，无恶寒发热，无恶心呕吐等不适。
2012年6月，患者至南京市某医院复查胃肠镜检查(只见出院小结，无胃肠镜报告)。胃镜示：食管、贲门未见异常，胃体下部、胃窦见多个散在大小不等息肉样隆起，数量较前大幅减少，最大约0.8cm×1.0cm，表面充血，取胃窦2块息肉行活检；(胃窦)病理示增生性息肉。肠镜示：全结肠处共有十数枚息肉样隆起，数量较前大幅减少，表明呈乳头状、表明黏膜充血，取结肠2块行活检(报告未见)，此次胃肠镜复查结果较前改善明显。其后患者一直坚持应用中医药治疗，期间未应用激素、免疫抑制剂、抗生素等西药。
中药治疗近1年，患者再次至南京市某医院复查胃肠镜。肠镜(2012-10-15)：结肠镜检查未见息肉，未活检。胃镜(2012-10-15)及胃镜病理(2012-10-16)提示：中度慢性浅表性胃炎伴急性活动及息肉样增生，部分区见多量嗜酸性粒细胞浸润。此次复查结果患者甚是满意，治疗疗效突显。患者病情稳定，大便日行1～2次，成形偏多，无腹胀腹痛，无恶寒发热，纳食渐正常，味觉渐恢复正常，但饮食生冷食物胃脘不适，乏力明显改善，夜寐正常，小便正常，体重上升约5kg。查体：神清，精神渐佳，十指指腹及面部色素沉着较前稍改善，指甲薄软，未再剥脱，新发重生，仍稀疏；舌质淡红，苔薄，脉细弦。尤其是此次复查提示全结肠镜下未见息肉，患者信心倍增，后一直在刘万里主任门诊复诊，服用中药巩固治疗，并每年定期至南京市某医院复查胃镜肠镜。
随诊结果：一方面从临床症状角度分析，患者病情持续好转，平素无明显不适主诉，二便正常，纳食正常，夜寐及一般情况均无不适，且患者十指指腹及面部色素沉着均消失，指甲再生，头发已正常生长如正常人一般。另一方面患者胃镜肠镜随诊情况好转。2014年9月患者胃镜检查：未见息肉，浅表性胃炎伴糜烂；胃镜病理：(窦后)轻度慢性萎缩性胃炎伴肠上皮化生、急性活动，(体小)中度慢性浅表性胃炎伴急性活动。2014年9月肠镜检查：未见息肉，未活检。2017年10月肠镜检查：未见息肉，未活检。2017年10月胃镜检查：十二指肠球部溃疡(S1期)，十二指肠降部息肉。胃镜病理：未见息肉(十二指肠降部)慢性活动性肠炎，(体大)轻度慢性萎缩性胃炎。经中医药治疗后患者病情明显好转，且随诊长达7年多病情稳定，生活质量得到极大提高。
实施例2
患者：女，47岁；
病史：2019年3月20日外院查胃镜示：慢性非萎缩性胃炎、胃息肉(部分夹除)。肠镜示：结肠息肉(部分夹除)；肠镜病理诊断示：横结肠增生性息肉；患者诉无自觉不适。
2019年4月19日刘万里专家门诊初诊：
主方：土茯苓30g、忍冬藤30g、连翘15g、白薇15g；1剂/天，水煎服，分早晚温服。
4月26日二诊：病史同前，无自觉不适。舌质红，苔薄黄，脉弦细。
原方白薇减至10g、忍冬藤减至15g、连翘减至10g。
5月10日三诊：病史同前，大便日解1-2次，尚通畅。舌质红，苔薄，脉弦。
原方白薇减至10g、忍冬藤减至15g、连翘减至10g。
5月24日四诊：病史同前，自觉无不适。大便日解1-2次。舌质红，苔薄，脉弦。
原方白薇减至10g、忍冬藤减至15g、连翘减至10g。
6月7日五诊：病史同前，自觉无明显不适，大便欠通畅。舌质淡，苔薄，脉细弦。
原方白薇减至10g、忍冬藤减至15g、连翘减至10g。
6月21日复查胃镜、肠镜：均未见息肉病变。
实施例3建立腺瘤性息肉小鼠模型并评价受试药复方的药效
1实验材料
1.1动物
Balb/c小鼠，SPF级，体重18-22g，雄性，北京维通利华实验动物技术有限公司，许可证号码：SCXK(苏)2016-0003。小鼠分笼饲养于南京中医药大学动物实验中心，饲养许可证：SYXK2018-0049，光照适度，室温22～25℃，湿度50～60％。
1.2药物与试剂
受试药1：太子参15g白术(炒)10g白茯苓15g薏苡仁(生)30g土茯苓30g忍冬藤30g连翘15g白薇10g。总生药量：155g/人/天。制备：5付(775g)煎至387ml，浓度2g生药/ml，给药体积0.1ml/10g，给药剂量20g/kg。
受试药2：土茯苓30g忍冬藤30g连翘15g白薇10g。总生药量：85g/人/天。制备：5付(425g)煎至387ml，浓度1.1g生药/ml，给药体积0.1ml/10g，给药剂量11g/kg。
造模试剂：AOM(氧化偶氮甲烷)，sigma，批号：SLCC0424。DSS(葡聚糖硫酸钠盐)，MP biomedicals，批号：Q1723。
2实验方法
2.1动物分组、造模及给药
分组：小鼠适应性饲养后，按照体重分层随机分为空白组、模型组、受试药1、受试药2组。
建立AOM联合DSS三循环模型：除空白组外，各组小鼠在第1周第1天给予腹腔注射AOM10mg/kg，并同时连续给予2.5％DSS饮用水1周，小鼠自由饮用，再予普通饮用水自由饮用2周，共3周为一个循环。同第一循环，在第4周、第7周第1天腹腔注射10mg/kg剂量的AOM，并分别给予2周的2.5％DSS饮用，其余时间给予普通饮用水，共9周3个循环。空白组小鼠在模型组腹腔注射的同一天腹腔注射生理盐水，从实验开始至实验结束均给予普通饮用水白由饮用。
给药：从第1周第1天开始，阳性药组小鼠灌胃给予受试药1或2，每日1次，造模期间持续灌胃9周，造模完成后继续灌胃给药1周，共计给药10周。
2.2指标检测
造模期间密切观察记录各组小鼠体重、饮食、排便等情况；于第10周最后一天，颈椎脱臼处死小鼠并剖取大肠(自盲肠末端至肛门整段结直肠)，沿肠管纵向剖开，生理盐水漂洗清理肠道粪便，以肠粘膜面朝上置于解剖台，拍照、肉眼下观察肠粘膜组织的表现，炎症反应情况及有无肿瘤的发生，如有肿瘤发生，则记录肿瘤发生数目、位置、大小等。(附肠息肉照片于后)。
2.3统计学方法
数据结果用均数±标准差(mean±SD)表示，各组间的差异比较采用Graphpad Prism 7软件的one-way ANOVA分析方法，组间比较采用Dunnett’s检验，P<0.05有统计学意义。
3.结果
经过AOM联合DSS造模，模型小鼠大肠部位明显形成一定数量腺瘤，而给予受试药1和受试药2均能显著抑制腺瘤的生成，明显减少腺瘤个数，抑制率分别为47％和46％。(表1和图1、图2)
表1 受试药对小鼠大肠腺瘤个数的影响
Figure PCTCN2020104912-appb-000001
Figure PCTCN2020104912-appb-000002
***P<0.001，与空白组相比； ##P<0.01，与模型组相比。

Claims (14)

  1. 一种中药组合物，特征在于包括土茯苓、忍冬藤、连翘、白薇。
  2. 权利要求1所述的中药组合物，特征在于土茯苓用量为3-100g，忍冬藤用量为3-100g，连翘用量为3-100g，白薇用量为2-50g。
  3. 权利要求1所述的中药组合物，特征在于土茯苓用量为10-60g，忍冬藤用量为10-60g，连翘用量为5-30g，白薇用量为5-30g。
  4. 权利要求1所述的中药组合物，特征在于土茯苓用量为15-30g，忍冬藤用量为15-30g，连翘用量为10-15g，白薇用量为10-15g。
  5. 权利要求1所述的中药组合物，特征在于土茯苓、忍冬藤、连翘、白薇的用量比例为3-100:3-100:3-100:2-50。
  6. 权利要求1所述的中药组合物，特征在于土茯苓、忍冬藤、连翘、白薇的用量比例为10-60:10-60:5-30:5-30。
  7. 权利要求1所述的中药组合物，特征在于土茯苓、忍冬藤、连翘、白薇的用量比例为15-30:15-30:10-15:10-15。
  8. 权利要求1-7任一所述的中药组合物，特征在于还包括半夏、陈皮、茯苓、甘草、人参、白术、山药、六神曲、焦山楂、木香、黄连、白鲜皮、地肤子、凤尾草、丹皮、焦山栀中的一种或多种。
  9. 权利要求1-7任一所述的中药组合物，特征在于还包括以下药物组合物中的一种或多种：半夏、陈皮、茯苓、甘草、人参、白术；山药、六神曲、焦山楂；木香、黄连；白鲜皮、地肤子；丹皮、焦山栀。
  10. 权利要求1-7任一所述的中药组合物在制备治疗人或哺乳动物息肉药物中的应用。
  11. 权利要求1-7任一所述的中药组合物在制备治疗人或哺乳动物消化道息肉、子宫内膜息肉、宫颈息肉、喉息肉、鼻息肉药物中的应用。
  12. 权利要求11所述的应用，特征在于消化道息肉为胃肠道息肉和胆囊息肉。
  13. 权利要求10所述应用，特征在于所述息肉为胃肠道息肉病综合征。
  14. 权利要求13所述应用，特征在于所述胃肠道息肉病综合征为Cronkhite-Canada综合征。
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