WO2020200212A1 - 用于预防和治疗代谢类疾病的土壤制剂及其制备方法与应用 - Google Patents

用于预防和治疗代谢类疾病的土壤制剂及其制备方法与应用 Download PDF

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WO2020200212A1
WO2020200212A1 PCT/CN2020/082556 CN2020082556W WO2020200212A1 WO 2020200212 A1 WO2020200212 A1 WO 2020200212A1 CN 2020082556 W CN2020082556 W CN 2020082556W WO 2020200212 A1 WO2020200212 A1 WO 2020200212A1
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soil
preparation
preventing
metabolic diseases
treating metabolic
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周东蕊
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Southeast University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/02—Medicinal preparations containing materials or reaction products thereof with undetermined constitution from inanimate materials
    • A61K35/10—Peat; Amber; Turf; Humus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/745—Bifidobacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the invention relates to a soil preparation, in particular to a soil preparation for preventing and treating metabolic diseases, and a preparation method and application thereof.
  • the prepared soil preparation can further regulate human metabolic activities by adjusting the intestinal microbial structure and composition, thereby achieving the effect of treating and preventing the occurrence of metabolic diseases.
  • the objective of the present invention is to provide a soil preparation with the effects of preventing and treating metabolic diseases, and its preparation method and application.
  • the technical solution adopted by the present invention is:
  • a soil preparation with the effect of preventing/treating metabolic diseases which is prepared from sterilized soil and oral probiotics or auxiliary materials.
  • the soil is red soil, loess, black soil or cinnamon soil that is not polluted.
  • the soil preparation with the effect of preventing/treating metabolic diseases include Bifidobacterium, Lactobacillus, Streptococcus, Propionibacterium, Lactococcus lactis or Leuconostoc bacteria.
  • the auxiliary materials include protein, fat, sugar, starch or cellulose food materials.
  • the metabolic diseases include hypertension, hyperlipidemia, diabetes, obesity, cardiovascular disease, cerebrovascular disease, high uric acid and fatty liver.
  • a preparation method for preparing the above soil preparation includes the following steps:
  • the soil contains the following elements in mass percentages: Na 0.5-1%, Mg 1-3%, Al 5-10%, Si 20-35%, K 1-5%, Ca 0.5-10%, Ti 0-5%, Fe 2-10%, O 40-50%.
  • the heavy metals include Hg, Pb, As, Cd and Cu; wherein Hg ⁇ 0.2mg/kg, Pb ⁇ 5.0mg/kg, Cd ⁇ 0.3mg/kg, As ⁇ 2.0mg /kg, Cu ⁇ 20.0mg/kg.
  • the soil preparation is made into a solid or fluid form that can be taken orally.
  • the mass ratio of the soil to the probiotics or auxiliary materials is 1 to 5:1.
  • the soil contained in the present invention has the function of regulating the structure and composition of the intestinal microecology: studies have found that soil has a huge impact on the structure and type of intestinal microecological, second only to diet, and interacts with diet, which has a significant impact on the intestinal microbiota. The impact is irreplaceable; this invention uses soil as medicine and eats it into the body, and by regulating the structure and composition of intestinal microorganisms, it can prevent and treat diseases from the surface.
  • the soil preparation of the present invention has the function of further regulating human metabolic activity by regulating the intestinal microecology: A number of studies have shown that intestinal microbes can help the host ferment the carbohydrates in the food that the host cannot metabolize, and convert cellulose into short Chain fatty acids (SCFA), such as n-butyric acid, acetic acid and propionic acid, are delivered through the G-coupled proteins GPR41 and GPR43 produced by intestinal epithelial expression to provide energy for the host.
  • SCFA short Chain fatty acids
  • GPR41 and GPR43 produced by intestinal epithelial expression to provide energy for the host.
  • Clostridia, Eubacteria and Roseburia are the main intestinal bacteria that produce butyric acid.
  • the invention can adjust the structure and composition of human intestinal microbes, thereby regulating human metabolic activities, and further achieving the effect of preventing and treating diseases.
  • the quality control of the soil preparation of the invention is simple and easy: the detection of soil elements is currently very mature, and there are many methods. The detection of various soil components can be performed with modern equipment such as atomic absorption spectrometers;
  • Preparation preparation select red loam soil, and sample the average element content (mass percentage) of the sample by X-ray spectrometer: Na 0.68%, Mg 1.66%, Al 7.38%, Si 29.58%, K 3.03%, Ca 4.56%, Ti 0.47%, Fe 7.03%, 045.61%, of which heavy metal content Hg ⁇ 0.2mg/kg, Pb ⁇ 5.0mg/kg, Cd ⁇ 0.3mg/kg, As ⁇ 2.0mg/kg, Cu ⁇ 20.0mg/kg, and No toxic organic matter can be detected by conventional methods.
  • Organic matter components accounted for 1.9% of the dry weight of the soil, autoclaved for later use.
  • the auxiliary materials were peanut powder and sucrose, the soil after autoclaving, dry-fried peanut powder and sucrose, the mixing ratio was soil: peanut powder: sucrose was 1:1 :1 (mass ratio) to obtain red clay preparation. Prepare it for later use.
  • the selected cases all meet the diagnostic criteria of TCM symptoms (the main symptoms of Yin deficiency and Yang hyperactivity designated by the Drug Administration of the People's Republic of China (2002) "Guiding Principles for Clinical Research on New Chinese Medicines"), and meet the 1999 WHO/SH four-time guidelines for hypertension diagnosis : Average value obtained from repeated blood pressure measurements on non-medicinal conditions 2 or more times on different days: systolic blood pressure 140mmHg and/or diastolic blood pressure 90mmHg, first-level hypertension 140-159/90-99, medical treatment is required according to hypertension guidelines of.
  • Exclusion criteria 1Acute Coronary Syndrome (ACS); 2Acute stroke event within 1 month; 3Secondary hypertension, hypertensive crisis; 4Patients with secondary dyslipidemia; 5High level II and above Patients with blood pressure; 6Type I diabetes and type II diabetes with acute metabolic disorders; 7Within 3 months of trauma or surgery; 8Within 1 month of acute infectious diseases; 9Patients who have obvious reasons and cannot cooperate with the completion.
  • ACS acute Coronary Syndrome
  • 2Acute stroke event within 1 month 3Secondary hypertension, hypertensive crisis
  • 4Patients with secondary dyslipidemia 5High level II and above Patients with blood pressure
  • 6Type I diabetes and type II diabetes with acute metabolic disorders 7Within 3 months of trauma or surgery; 8Within 1 month of acute infectious diseases; 9Patients who have obvious reasons and cannot cooperate with the completion.
  • Treatment method The treatment group took orally the red clay preparation of step (1) 3 times a day, 5 grams each time.
  • the control group was a placebo made of peanut powder: sucrose with a mass ratio of 1:1, and the dose was the same as the treatment group (3 times a day, 5 grams each time).
  • the treatment effect was evaluated after 12 weeks of medication.
  • the treatment time is 12 weeks, and the treatment effect is evaluated 4 weeks after stopping the drug. Observation of signs: 1 d before treatment and 1, 4, 7 d after the start of treatment, 2 times/week thereafter, at a fixed time (8:00-10:00 in the morning; 15:00-15:00 in the afternoon) to monitor blood pressure, weekly Take the average of the two times, and the subject rests quietly for 10 minutes, and the blood pressure of the right upper limb in the sitting position is taken.
  • Symptom observation Observe dizziness, headache, palpitations, insomnia, tinnitus.
  • Curative effect standard is significant: after treatment, diastolic blood pressure drops by 10mmHg and drops to normal or drops above 20mmHg, systolic blood pressure drops to normal. Effective: After treatment, the diastolic blood pressure has not dropped to 10mmHg, but it has dropped to the normal range, or it has dropped by 10-19mmHg. For systolic hypertension, the systolic blood pressure will drop by 30mmHg. Ineffective: The blood pressure drop after treatment did not reach the effective standard.
  • Criteria for determining the efficacy of symptoms 1 Significantly effective: clinical symptoms are significantly improved and the score is reduced by ⁇ 70%; 2 Effective: clinically improved, and the symptom score is reduced by ⁇ 30%; 3 Ineffective: the clinical symptoms are not significantly improved, or even worsened, and the symptom score is reduced by ⁇ 30 %.
  • Results show the effective rate of treatment, see Table 1. According to statistical analysis, there is a significant difference in clinical efficacy between the treatment group and the control group (P ⁇ 0.001). No adverse reactions.
  • Preparation preparation select yellow loam soil, and use X-ray energy spectrometer to sample the average element content (mass percentage) of the sample: Na 0.58%, Mg 1.76%, Al 6.38%, Si 29.03%, K 3.58%, Ca 5.56%, Ti 0.61%, Fe 7.47%, O 45.03%, of which heavy metal content Hg ⁇ 0.2mg/kg, Pb ⁇ 5.0mg/kg, Cd ⁇ 0.3mg/kg, As ⁇ 2.0mg/kg, Cu ⁇ 20.0mg/kg, And conventional methods cannot detect toxic organic matter.
  • the organic matter component accounts for 2.0% of the dry weight of the soil, autoclaved for later use.
  • the auxiliary materials are high-quality dry-fried peanut flour and sucrose.
  • the soil after autoclaving, wheat flour and cellulose, the mixing ratio is soil: wheat flour: cellulose 1: 1:1 (mass ratio) to obtain a loess preparation. Prepare it for later use.
  • Participant selection 80 patients were randomly divided into treatment group and control group. There were 40 patients in the treatment group, 20 males and 20 females, aged 41-69 years old, with an average of (44.7 ⁇ 11.1) years old. The course of illness was 1-16 years, with an average of (7.1 ⁇ 4.2) years; the control group had 40 cases, 20 males and 20 females, aged 40-68 years, with an average of (45.1 ⁇ 10.5) years; the course of illness was 1-15 years, with an average of (7.3 ⁇ 5.1) years. There was no statistical difference in gender, age, and course of disease between the two groups.
  • the selected cases all meet the criteria for the diagnosis of diabetes (refer to the 1998 ADA criteria for the diagnosis of diabetes) and the diagnosis criteria for non-alcoholic fatty liver (refer to the revision of the fatty liver and alcoholic liver disease group of the Chinese Medical Association Hepatology Branch in February 2006 "Guidelines for the Diagnosis and Treatment of Non-alcoholic Fatty Liver Disease"), diagnosed as a patient with type 2 diabetes and non-alcoholic fatty liver.
  • Treatment method 80 outpatients keep the original treatment plan and diet exercise plan unchanged. From the day of observation, the treatment group took orally the loess preparation of step (1) 3 times a day, 10 grams each time.
  • the control group was a placebo made of wheat flour: cellulose with a mass ratio of 1:1, and the dosage and frequency were the same as those in the treatment group (3 times a day, 10 grams each time). The medication was stopped for 10 days after 180 days, and then the treatment effect was evaluated.
  • the curative effect standard is markedly effective: fasting blood glucose after treatment ⁇ 7.0mmol/L, or 2h blood glucose after meal ⁇ 7.8mmol/L, or the blood sugar reduction rate is reduced by more than 30% compared with before treatment; effective: fasting blood glucose after treatment ⁇ 8.3mmol/L Or 2h blood glucose ⁇ 11.0mmol/L after a meal, or a decrease in blood glucose reduction by 10%-30% compared to before treatment; invalid: blood glucose drop after treatment does not reach the above standard.
  • the effective rate is calculated based on the total number of markedly effective and effective cases.
  • liver function indexes aspartate aminotransferase (AST) and alanine aminotransferase (ALT).
  • Preparation preparation select yellow loam soil, and use X-ray energy spectrometer to sample the average element content (mass percentage) of the sample: Na 0.65%, Mg 1.83%, Al 5.39%, Si 29.46%, K 4.57%, Ca 5.13%, Ti 0.31%, Fe 7.37%, O45.43%, of which heavy metal content Hg ⁇ 0.2mg/kg, Pb ⁇ 5.0mg/kg, Cd ⁇ 0.3mg/kg, As ⁇ 2.0mg/kg, Cu ⁇ 20.0mg/kg , And conventional methods cannot detect toxic organic matter.
  • the organic matter component accounts for 2.4% of the dry weight of the soil, autoclaved for later use.
  • the auxiliary materials are wheat flour and corn flour.
  • the soil after autoclaving is mixed with wheat flour and corn flour.
  • the mixing ratio is soil: wheat flour: corn flour 1:1: 1 (mass ratio) to obtain a loess preparation. Prepare it for later use.
  • Subject selection 83 patients participated in the experiment and were randomly divided into treatment group and control group. There were 43 cases in the treatment group, including 20 males and 23 females, aged 37-68 years, with an average of (42.3 ⁇ 7.7) years old. There were 40 cases in the control group, 20 males and 20 females, aged 36-69 years old, with an average of (43.2 ⁇ 8.7) years old. There was no statistical difference in gender, age, and course of disease between the two groups. Participants signed the informed consent form one week after taking no medication or stopping antihypertensive drugs.
  • Selection and exclusion criteria are: serum triglyceride (TG) ⁇ 2.3mmol/L, serum uric acid, male>420 ⁇ mol/L, female>360 ⁇ mol/L. Exclude secondary hypertension, diabetes, thyroid disease, liver and kidney dysfunction, and take other drugs that affect the metabolism of blood lipids and uric acid.
  • TG serum triglyceride
  • serum uric acid male>420 ⁇ mol/L
  • female>360 ⁇ mol/L Exclude secondary hypertension, diabetes, thyroid disease, liver and kidney dysfunction, and take other drugs that affect the metabolism of blood lipids and uric acid.
  • Treatment method 83 outpatients kept the original treatment plan and diet exercise plan unchanged. From the date of observation, the treatment group took the step (1) loess preparation 3 times a day, 5 grams each time.
  • the control group was a placebo made of wheat flour: corn flour with a mass ratio of 1:1, and the dosage and frequency were the same as the treatment group (3 times a day, 5 grams each time). The medication was stopped for 10 days after 90 days, and then the treatment effect was evaluated.

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Abstract

一种具有预防和/或治疗代谢性疾病的土壤制剂，由经灭菌处理后的土壤与可以口服的益生菌或辅料制备而成。所述土壤制剂的制备方法包括采集无污染土壤，高压灭菌，冷却后按照比例与益生菌或辅料混合均匀，制备成胶囊或粉剂。所述的代谢性疾病包括高血压、高血脂、糖尿病等。

Description

用于预防和治疗代谢类疾病的土壤制剂及其制备方法与应用 技术领域
本发明涉及一种土壤制剂，特别是一种用于预防和治疗代谢类疾病的土壤制剂及其制备方法与应用。
背景技术
近些年来，随着人们生活水平的提高和生活方式的改变，高血压、2型糖尿病和肥胖等代谢类的疾病发病率，全世界都急剧上升。2008年世界患有肥胖症的病人，男性约为2亿，女性约为3亿。美国成年人肥胖的发病率从1960年-1962年的12.8％增长至1999-2000年的30.5％，糖尿病发病率从1990年的4.9％增加到2001年的7.9％。美国成年中约66％体重超重，约33％患有肥胖症。中国近年肥胖与糖尿病都呈快速增长趋势。
肥胖和糖尿病等代谢性疾病的发病机制，虽然全世界进行了大量研究，但依然没有阐明。
本发明通过大量实验筛选，制备得到的土壤制剂可以通过调节肠道微生物结构与组成，进一步调节人体代谢活动，进而达到治疗与预防代谢类疾病发生的效果。
发明内容
发明目的：本发明目的是提供一种具有预防和治疗代谢类疾病功效的土壤制剂及其制备方法与应用。
为解决上述技术问题，本发明采用的技术方案是：
一种具有预防/治疗代谢性疾病功效的上壤制剂，它是由经灭菌处理后的土壤与可以口服的益生菌或辅料制备而成。
作为优选方案，以上所述的具有预防/治疗代谢性疾病功效的土壤制剂，其所述土壤为没有被污染的红土、黄土、黑土或褐土。
作为优选方案，所述的具有预防/治疗代谢性疾病功效的土壤制剂，所述益生菌包括双歧杆菌属、乳杆菌菌属、链球菌属、丙酸杆菌、乳酸乳球菌或肠膜明串珠菌。
作为优选方案，所述的具有预防/治疗代谢性疾病功效的土壤制剂，所述辅料包括蛋白、脂肪、糖、淀粉或纤维素类食材。
本发明所述的具有土壤制剂在制备预防/治疗代谢性疾病的药物或保健品中的应用。
作为优选，所述的代谢类疾病，包括高血压、高血脂、糖尿病、肥胖症、心血管病、脑血管病、高尿酸和脂肪肝等。
一种用于制备上述土壤制剂的制备方法，包括下述步骤：
(1)采集无污染上壤，并做微量元素分析，所述土壤重金属含量须控制在一定范围内，以及常规方法检测中检测不到有毒有机物；
(2)高压灭菌，在水蒸汽121℃条件高压灭菌60分钟；
(3)冷却后按照预定比例与益生菌或辅料混合均匀；
(4)制备成胶囊或冲剂。
在本发明一个较佳实施例中，所述土壤包含下列质量百分比的元素：Na 0.5～1％，Mg 1～3％，Al 5～10％，Si 20～35％，K 1～5％，Ca 0.5～10％，Ti 0～5％，Fe 2～10％，O 40～50％。
在本发明一个较佳实施例中，所述重金属包括Hg、Pb、As、Cd和Cu；其中Hg≤0.2mg/kg，Pb≤5.0mg/kg，Cd≤0.3mg/kg，As≤2.0mg/kg，Cu≤20.0mg/kg。
在本发明一个较佳实施例中，所述土壤制剂被制成可以口服的固体或流体形式。
在本发明一个较佳实施例中，所述土壤与益生菌或辅料的质量比为：1～5∶1。
本发明的有益效果是：
1)本发明含有的土壤，具有调节肠道微生态结构与组成作用：研究发现，土壤对肠道微生态结构与类型影响巨大，仅次于饮食，且与饮食相互作用，对肠道微生物的影响无可替代；该项发明，将土壤入药，并食入体内，通过调节肠道微生物的结构与组成，从面达到预防与治疗疾病的作用。
2)本发明土壤制剂通过调节肠道微生态，有进一步调节人体代谢活动功能：多项研究表明，肠道微生物可以帮助宿主发酵食物中宿主自身不能代谢的碳水化合物，将纤维素等转化为短链脂肪酸(SCFA)，如n-丁酸，乙酸和丙酸等，通过肠道上皮表达产生的G偶联蛋白GPR41和GPR43传递，为宿主提供能量。比如梭菌(Clostridia)、真细菌(Eubacteria)和Roseburia是产生丁酸的主要肠道细菌。由于饮食与现代的生活方式的改变，常常打破肠道微生态的平衡，导致一些益生菌的丢失，最终引起人体代谢紊乱和多种代谢类疾病的发生。本发明可以调节人体肠道微生物的结构与组成，进而来调节人体代谢活动，进一步达到预防与治疗疾病的效果。
3)该项发明保存运送和生产成本相对较低：由于该制剂中有效成分主要是土壤中的无机物和有机物，干燥条件下，土壤中的成分较为稳定，因此，保存运送及生产成本相对较低。
4)该发明土壤制剂质量控制简单易行：目前土壤元素的检测极为成熟，方法较多，各种土壤成分检测可采用现代如原子吸收分光度计等设备进行检测；
具体实施方式
下面对本发明的较佳实施例进行详细阐述，以使本发明的优点和特征能更易于被本领域技术人员理解，从而对本发明的保护范围做出更为清楚明确的界定。
实施例1红土制剂降血压功能实验研究
(1)制剂制备：选取红色壤土，按X射线能谱仪抽样样本元素平均含量(质量百分比)：Na 0.68％，Mg 1.66％，Al 7.38％，Si 29.58％，K 3.03％，Ca 4.56％，Ti 0.47％，Fe 7.03％，045.61％，其中重金属含量Hg≤0.2mg/kg，Pb≤5.0mg/kg，Cd≤0.3mg/kg，As≤2.0mg/kg，Cu≤20.0mg/kg，以及常规方法检测不到有毒的有机物。有机质组分占土壤干重的1.9％，高压灭菌备用，辅料为花生粉与蔗糖，高压灭菌后的土壤与干炒花生粉与蔗糖，混合比例为土壤∶花生粉∶蔗糖为1∶1∶1(质量比)，得到红土制剂。制好后备用。
(2)高血压病人选择：80例符合I级高血压患者，随机分成治疗组和对照组。治疗组40例，男20例，女20例，年龄40～67岁，平均(45.5±8.7)岁。对照组40例，男20例，女20例，年 龄39～65岁，平均(46.6±9.7)岁。两组被试患者性别、年龄、病程无统计学差异。被试未用药物或者停用降压药1周后，签署知情同意书。
入选病例均符合中医症候诊断标准(中华人民共和国药品监督局(2002)指定《中药新药临床研究指导原则》阴虚阳亢型主症)，并符合1999年WHO/SH四次高血压指南诊断标准：非药物状态下2次或2次以上非同日重复血压测定所得平均值：收缩压140mmHg和/或舒张压90mmHg，一级高血压140～159/90～99，根据高血压指南要求需要药物治疗的。
排除标准：①急性冠脉综合征(ACS)；②急性脑卒中事件1个月内；③继发性高血压，高血压危象；④继发性血脂异常患者；⑤II级及II级以上高血压患者；⑥I型糖尿病和II型糖尿病合并急性代谢紊乱；⑦外伤或手术3个月内；⑧急性感染性疾病1个月内；⑨患者有明显的原因，不能配合完成者。
(3)治疗方法：治疗组每天口服上述步骤(1)的红土制剂3次，每次5克。对照组以质量比例1∶1的花生粉∶蔗糖制成的安慰剂，服用剂量同治疗组(每天3次，每次5克)。用药12周后进行治疗效果评测。
(4)治疗效果评价：治疗时间为12周，停药后4周，评价治疗效果。体征观察：治疗前l d及治疗开始后1、4、7d，以后2次/周，固定时间(上午8：00-10：00；下午15：00-17：00)监测血压，每周测两次取平均值，被测者安静休息10分钟，取坐位右上肢血压。
症状观察：观察眩晕、头痛、心悸、失眠、耳鸣。
疗效标准显效：治疗后舒张压下降10mmHg并下降到正常或下降20mmHg以上，收缩压降到正常。有效：治疗后舒张压下降未达到10mmHg，但己降到正常范围，或下降10-19mmHg，如为收缩期高血压，收缩压下降30mmHg。无效：治疗后血压下降未达到有效标准。
症状疗效判定标准：①显效：临床症状明显改善积分减少≥70％；②有效：临床有所好转，症状积分减少≥30％；③无效：临床症状无明显改善，甚或加重，症状积分减少≤30％。
(5)结果：结果显示治疗有效率，见表1。根据统计分析，治疗组和对照组的临床疗效有显著差异(P＜0.001)。无不良反应。
(6)肠道微生物变化：采用高通量测序仪测序分析16s rRNA，结果显示治疗组肠道微生物的多样性显著增加(P＜0.01)，随机森林(Random Forests)分析显示(表2)，放线菌门细菌种类与数量显著增加(P＜0.01)。
表1两组患者治疗1个月后疗效比较(n，％)
组别 N 显效 有效 无效 有效例数 有效率
治疗组 40 25 12 3 37 92.5％
对照组 40 4 4 32 8 20％
注：经卡方检验：df＝1，X 2＝42.717，P＜0.001。
表2随机森林分析治疗组肠道细菌含量显著增加的类型
Figure PCTCN2020082556-appb-000001
实施例2黄土制剂治疗2型糖尿病伴非酒精性脂肪肝的临床效果分析
(1)制剂制备：选取黄色壤土，采用X射线能谱仪抽样样本元素平均含量(质量百分比)：Na 0.58％，Mg 1.76％，Al 6.38％，Si 29.03％，K 3.58％，Ca 5.56％，Ti 0.61％，Fe 7.47％，O 45.03％，其中重金属含量Hg≤0.2mg/kg，Pb≤5.0mg/kg，Cd≤0.3mg/kg，As≤2.0mg/kg，Cu≤20.0mg/kg，以及常规方法检测不到有毒的有机物。有机质组分占土壤干重的2.0％，高压灭菌备用，辅料为优质干炒花生粉与蔗糖，高压灭菌后的土壤与小麦粉与纤维素，混合比例为土壤∶小麦粉∶纤维素为1∶1∶1(质量比)，得到黄土制剂。制好后备用。
(2)被试选择：80例患者随机分成治疗组和对照组。治疗组40例，男20例，女20例，年龄41～69岁，平均(44.7±11.1)岁。病程1～16年，平均(7.1±4.2)年；对照组40例，男20例，女20例，年龄40～68岁，平均(45.1±10.5)岁；病程1～15年，平均(7.3±5.1)年。两组被试患者性别、年龄、病程无统计学差异。入选病例均符合糖尿病诊断的标准(参照1998年ADA关于糖尿病诊断的标准)，以及非酒精性脂肪肝诊断标准(参考2006年2月中华医学会肝脏病学分会脂肪肝和酒精性肝病学组修订的《非酒精性脂肪性肝病诊疗指南》)，确诊为2型糖尿病合并非酒精性脂肪肝患者。
(3)治疗方法：80例门诊患者保持原治疗方案和饮食运动方案不变。自观察之日起，治疗组每天口服步骤(1)黄土制剂3次，每次10克。对照组以质量比例1∶1的小麦粉∶纤维素制成的安慰剂，服用剂量和次数同治疗组(每天3次，每次10克)。用药180天后停用10天，然后进行治疗效果评测。
(4)降糖疗效评定：治疗180天后，停药后10天观察治疗效果。疗效标准为显效：治疗后空腹血糖＜7.0mmol/L，或餐后2h血糖＜7.8mmol/L，或降糖幅度较治疗前下降30％以上；有效：治疗后空腹血糖＜8.3mmol/L，或餐后2h血糖＜11.0mmol/L，或降糖幅度较治疗前下降10％～30％；无效：治疗后血糖下降未达上述标准者。以显效、有效病例数合计计算有效率。
(5)肝功能疗效分析：测量血糖的同时测量肝功能指标，天门冬酸氨氨基转移酶(AST)、丙氨酸氨基转移酶(ALT)。
(6)结果：结果显示治疗有效率，见表3和表4。根据统计分析，治疗组和对照组的临床疗效有显著差异(P＜0.001)。无不良反应。
(7)肠道微生物变化：采用高通量测序仪测序分析16s rRNA，结果显示治疗组肠道 微生物的多样性显著增加(P＜0.01)，随机森林(Random Forests)分析显示(表5)，放线菌门细菌种类与数量显著增加(P＜0.01)。
表3两组患者治疗180天后疗效比较(n，％)
组别 N 显效 有效 无效 有效例数 有效率
治疗组 40 30 7 3 37 92.5％
对照组 40 2 2 36 4 10.0％
注：经卡方检验：df＝1， 2＝54.48，p＜0.001。
表4两组肝功能对比(±s，U/L)
Figure PCTCN2020082556-appb-000002
Figure PCTCN2020082556-appb-000003
表5随机森林分析治疗组肠道细菌含量显著增加的类型
Figure PCTCN2020082556-appb-000004
实施例3降高尿酸血症和高甘油三酯症的疗效研究
(1)制剂制备：选取黄色壤土，采用X射线能谱仪抽样样本元素平均含量(质量百分比)：Na 0.65％，Mg 1.83％，Al 5.39％，Si 29.46％，K 4.57％，Ca 5.13％，Ti 0.31％，Fe 7.37％，O45.43％，其中重金属含量Hg≤0.2mg/kg，Pb≤5.0mg/kg，Cd≤0.3mg/kg，As≤ 2.0mg/kg，Cu≤20.0mg/kg，以及常规方法检测不到有毒的有机物。有机质组分占土壤干重的2.4％，高压灭菌备用，辅料为小麦粉和玉米粉，高压灭菌后的土壤与小麦粉和玉米粉混合，混合比例为土壤∶小麦粉∶玉米粉为1∶1∶1(质量比)，得到黄土制剂。制好后备用。
(2)被试选择：83例患者参加该项实验，随机分成治疗组和对照组。治疗组43例，男20例，女23例，年龄37～68岁，平均(42.3±7.7)岁。对照组40例，男20例，女20例，年龄36～69岁，平均(43.2±8.7)岁。两组被试患者性别、年龄、病程无统计学差异。被试未用药物或者停用降压药1周后，签署知情同意书。
(3)入选和排除标准：入选标准为，患者血清甘油三酯(TG)≥2.3mmol/L，血清尿酸，男性＞420μmol/L，女性＞360μmol/L。排除继发性高血压、糖尿病、甲状腺疾病、肝肾功能不全，服用影响血脂和尿酸代谢的其他药物。
(4)治疗方法：83例门诊患者保持原治疗方案和饮食运动方案不变。自观察之日起，治疗组每天口服步骤(1)黄土制剂3次，每次5克。对照组以质量比例1∶1的小麦粉∶玉米粉制成的安慰剂，服用剂量和次数同治疗组(每天3次，每次5克)。用药90天后停用10天，然后进行治疗效果评测。
(5)疗效评定：高血压患者血压控制到小于140/90mmHg后，检测血清甘油三酯及尿酸浓度。患者采血时间是清晨7-8点，采血前受检者禁食12-14小时。
(6)结果：根据统计分析，治疗组和对照组的临床疗效有显著差异(P＜0.001)，如表6和表7。无不良反应。
(7)肠道微生物变化：采用高通量测序仪测序分析16s rRNA，结果显示治疗组肠道微生物的多样性显著增加(P＜0.01)，随机森林(Random Forests)分析显示(表8)，放线菌门细菌种类与数量显著增加(P＜0.01)。
表6血清甘油三酯治疗前后治疗的变化(mmol/L)
项目 对照组(40例) 治疗组(43例) 两组相比
治疗前 4.68±1.33 4.57±1.21 P＝0.700
治疗后 4.03±1.21 2.75±0.91 P＜0.001
治疗前后相比 P＝0.025 P＜0.001  
表7血清尿酸治疗前后的变化(μmol/L)
Figure PCTCN2020082556-appb-000005
表8随机森林分析治疗组肠道细菌含量显著增加的类型
Figure PCTCN2020082556-appb-000006
Figure PCTCN2020082556-appb-000007
以上所述仅为本发明的实施例，并非因此限制本发明的专利范围，凡是利用本发明说明书内容所作的等效结构或等效流程变换，或直接或间接运用在其他相关的技术领域，均同理包括在本发明的专利保护范围内。

Claims (10)

  1. 一种具有预防/治疗代谢性疾病功效的土壤制剂，其特征在于，它是由经灭菌处理后的土壤与可以口服的益生菌或辅料制备而成。
  2. 根据权利要求1所述的具有预防/治疗代谢性疾病功效的土壤制剂，其特征在于，所述土壤为没有被污染的红土、黄土、黑土或褐土。
  3. 根据权利要求1所述的具有预防/治疗代谢性疾病功效的土壤制剂，其特征在于，所述益生菌包括双歧杆菌属、乳杆菌菌属、链球菌属、丙酸杆菌、乳酸乳球菌或肠膜明串珠菌。
  4. 根据权利要求1所述的具有预防/治疗代谢性疾病功效的土壤制剂，其特征在于，所述辅料包括蛋白、脂肪、糖、淀粉或纤维素类食材。
  5. 权利要求1至4任一项所述的具有土壤制剂在制备预防/治疗代谢性疾病的药物或保健品中的应用。
  6. 权利要求1至4任一项所述的土壤制剂在制备预防/治疗高血压、高血脂、糖尿病、肥胖症、心血管病、脑血管病、高尿酸或脂肪肝的药物或保健品中的应用。
  7. 权利要求1～4任一项所述的具有预防/治疗代谢性疾病功效的土壤制剂的制备方法，其特征在于，包括下述步骤：
    (1)采集无污染土壤，并做微量元素分析，并控制土壤重金属含量合格；
    (2)高压灭菌，在水蒸汽121℃条件高压灭菌60分钟；
    (3)冷却后按照预定比例与益生菌或辅料混合均匀；
    (4)制备成口服制剂。
  8. 根据权利要求7所述的具有预防/治疗代谢性疾病功效的土壤制剂的制备方法，其特征在于，所述土壤制剂包含下列质量百分比的元素：Na0.5～1％，Mg1～3％，Al5～10％，Si20～35％，K1～5％，Ca0.5～10％，Ti0～5％，Fe2～10％，040～50％。
  9. 根据权利要求7所述的具有预防/治疗代谢性疾病功效的土壤制剂的制备方法，其特征在于，步骤(1)所述重金属包括Hg、Pb、As、Cd和Cu；其中Hg≤0.2mg/kg，Pb≤5.0mg/kg，Cd≤0.3mg/kg，As≤2.0mg/kg，Cu≤20.0mg/kg。
  10. 根据权利要求7所述的具有预防/治疗代谢性疾病功效的土壤制剂的制备方法，其特征在于，所述土壤与益生菌或辅料的质量比为：1～5∶1。
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