WO2020211571A1 - 具有防治神经内分泌失调相关疾病的土壤制剂及其制备方法与应用 - Google Patents

具有防治神经内分泌失调相关疾病的土壤制剂及其制备方法与应用 Download PDF

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WO2020211571A1
WO2020211571A1 PCT/CN2020/078491 CN2020078491W WO2020211571A1 WO 2020211571 A1 WO2020211571 A1 WO 2020211571A1 CN 2020078491 W CN2020078491 W CN 2020078491W WO 2020211571 A1 WO2020211571 A1 WO 2020211571A1
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soil
treatment
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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
    • 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
    • A61P1/10—Laxatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system

Definitions

  • the invention relates to a soil preparation, in particular to a soil preparation that can be used to prevent and treat neuroendocrine disorders related diseases and a preparation method thereof.
  • Interstitial cystitis refers to a disease with urinary discomfort, manifested by varying degrees of frequency, urgency, and often accompanied by varying degrees of pain in the bladder area, upper or lower abdomen, and other symptoms.
  • the medical history exceeds 6 weeks, and infection and other diseases must be ruled out before the diagnosis of interstitial cystitis can be made.
  • Interstitial cystitis is often associated with lower urinary tract symptoms.
  • the two main symptoms of the disease are frequent urination and pain, which seriously affect the quality of life of patients. More than 80% of patients have different degrees of sleep disturbance, depression and anxiety, and the prevalence is increasing year by year.
  • interstitial cystitis currently mainly uses tricyclic antidepressants to antagonize the effects of some neurotransmitters, and has certain therapeutic effects in clinical applications; antihistamines are used to reduce mast cell activation and infiltration , And then achieve the effect of relieving pain; Sodium pentamethylene sulfide can form a protective film on the surface of the bladder to reduce the damage of toxins to the bladder nerve. Patients with more severe symptoms are often treated with bladder perfusion, cystectomy, and urinary diversion.
  • Trigeminal neuralgia is a common clinical refractory disease. The pain is unbearable at the onset of onset. It is mainly manifested as paroxysmal rapid electric shock-like, knife-cut-like and tear-like pain, which often stops suddenly, and the course of the disease is longer and serious. It affects the patient's normal life and work, reduces the patient's quality of life, and is known as "the first pain in the world".
  • trigeminal neuralgia refers to the facial pain of patients innervated by the trigeminal nerve due to the stimulation and compression of tumors and vascular diseases.
  • trigeminal neuralgia The pathogenesis of primary trigeminal neuralgia is not yet clear. Most people think that trigeminal neuralgia is caused by multiple factors. Among them, central disease and peripheral disease, as well as changes in immune factors and neurotransmitters are important causes of trigeminal neuralgia.
  • the treatment methods for trigeminal neuralgia include Western medicine treatment, combined Chinese and Western medicine treatment, and surgical treatment (such as microvascular decompression, radiofrequency thermocoagulation, stereotactic radiotherapy, etc.).
  • Western medicine treatment as the patient's drug resistance increases, the factors of more drug response will lead to the further development of the disease.
  • the repetition of TCM treatment is poor, and surgical treatment is more commonly used clinically, but the side effects of surgical treatment are often more serious. Therefore, the current treatment of this disease is more difficult.
  • the present invention can regulate the structure and composition of intestinal microbes, and further regulate neuroendocrine activities, thereby achieving the treatment and prevention of the occurrence of the aforementioned diseases.
  • the main technical problem solved by the present invention is to overcome the shortcomings of the prior art, provide a good safety, low side effects, and have better prevention and treatment of qualitative cystitis, primary trigeminal neuralgia, depression, sleep disorders, youth A soil preparation for acne or constipation.
  • a soil preparation is provided, which is prepared from sterilized soil and oral probiotics or auxiliary materials.
  • the soil is uncontaminated soil, including red soil, loess, black soil and cinnamon soil.
  • the probiotics include Bifidobacterium, Lactobacillus, Streptococcus, Propionibacterium, Lactococcus lactis, or Leuconostoc mesenteroides.
  • the auxiliary materials are edible materials, including protein, starch or cellulose food materials.
  • the soil preparation is used to prepare the prevention and/or treatment of human neuroendocrine disorders, including primary interstitial cystitis, interstitial pneumonia, primary trigeminal neuralgia, Drugs for multiple sclerosis, alopecia areata, psoriasis, depression, sleep disorders, acne, or constipation.
  • human neuroendocrine disorders including primary interstitial cystitis, interstitial pneumonia, primary trigeminal neuralgia, Drugs for multiple sclerosis, alopecia areata, psoriasis, depression, sleep disorders, acne, or constipation.
  • 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 toxic trace elements 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.
  • step (1) no toxic organic matter can be detected in the conventional soil method.
  • the soil preparation is made into a solid or fluid form that can be taken orally.
  • the soil preparation of the present invention can further regulate neuroendocrine function by regulating the intestinal microecology: a number of studies have shown that intestinal microbes and their metabolites can stimulate the intestinal epithelial cells to produce serotonin (more than 95% of the human body The serotonin comes from the intestine). Serotonin is an important neurotransmitter in neuroendocrine, which is closely related to the occurrence of depression and many other diseases. Therefore, the present invention can adjust the structure and composition of human intestinal microbes, thereby regulating human neuroendocrine activities, and further achieve the prevention and treatment of interstitial cystitis, primary trigeminal neuralgia, multiple sclerosis, depression, sleep The effect of diseases such as obstacles.
  • Example 1 Black clay preparation for preventing and treating interstitial cystitis.
  • Preparation of preparation select black loam soil, sample sample element average content (mass percentage): Na 0.95%, Mg 2.03%, Al 8.28%, Si 27.19%, K 2.56%, Ca 6.45%, Ti 0.58%, Fe 5.57 %, O 46.39%, 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 1.7% of the dry weight of the soil.
  • the high-pressure fire fungus is reserved for use.
  • the auxiliary materials are high-quality dry-fried peanut powder and sucrose.
  • the soil after the high-pressure fire fungus is mixed with dry-fried peanut powder and sucrose.
  • the mixing ratio is soil: peanut powder: sucrose. 1:1:0.5 (mass ratio) to obtain a black clay preparation.
  • Interstitial cystitis research subjects 40 patients were selected as the experimental subjects, the age range was 20-85 years old, and the average age was 50.1 ⁇ 14.1 years, including 15 male patients and 25 female patients.
  • the patient's course of illness was 10 to 70 months, with a course interval of 30.1 ⁇ 11.7 months. Among them, 10 cases were first diagnosed and 30 cases were revisited.
  • CUA Canadian Urological Association
  • Exclusion criteria 1) The patient's maximum bladder function capacity in the awake state> 350ml; 2) No urgency sensation when filling the bladder with 150ml of fluid; 3) Symptom duration ⁇ 6 weeks; 4) Symptoms relieved after antibiotics or antispasmodics; 5) The frequency of urination during the day is less than 8 times, and nocturia is less than 2 times. 6) Complicated with urethral or vaginal infections, bacterial cystitis, tuberculous cystitis, radiation cystitis, chemical cystitis, pelvic inflammatory disease, endometriosis, sexually transmitted diseases, urinary calculi, bladder tumors Wait.
  • Treatment method The black clay preparation of step (1) in the treatment group was taken orally, twice a day, with a dosage of 5g/time, and it could be mixed with food. The treatment effect was evaluated after 3 months of medication. The curative effect was evaluated after taking it for three months.
  • Example 2 A preparation of Bifidobacterium loessum used for the prevention and treatment of primary trigeminal neuralgia.
  • the diagnostic criteria refer to the diagnostic criteria of primary trigeminal neuralgia in the 2004 International Classification of Headaches (Second Edition) of the International Headache Society Classification Committee. 1) Sudden onset pain on the face, generally less than 2 minutes in duration, invading one or several branches of the trigeminal nerve distribution area; 2) The pain has at least one of the following symptoms: severe, acupuncture-like, burning-like or even knife Cut sample; can be triggered by trigger point or related trigger factors and cause sudden attack; 3) clinically no positive signs of nervous system; 4) cannot be attributed to other diseases and dysfunction.
  • Inclusion criteria 1) Meet the relevant diagnostic criteria of Chinese and Western medicine; 2) Men or women aged 15 years or older but less than 80 years old, the two groups of observation subjects in the course of disease, age and various indicators before and after treatment, after statistical processing There is no obvious difference, and it is comparable; 3) A week before the observation, it is necessary to stop taking various Chinese and Western medicines and stop other treatment methods; 4) The condition is stable and the consciousness is clear; 5) The frequency of attacks is greater than or equal to 1 time per day. 6) The patient understands the trial process and participates voluntarily, and signs an informed consent form;
  • Exclusion criteria 1) Those who do not meet the above diagnostic criteria; 2) Patients with secondary trigeminal neuralgia; 3) Women who are breast-feeding or pregnant; 4) Those with other primary diseases such as severe cardio-cerebrovascular and coagulopathy; 5) Those who are participating in other medical trials; 6) Those who have severe nerve damage and cognitive impairment that affect pain assessment.
  • Grouping Randomly divided into treatment group of 20 cases and conventional treatment group of 20 cases. There was no statistical difference in gender, age, and course of disease between the two groups.
  • the treatment group takes the loess preparation of step (1), 3 times a day, the dosage is 3-6g/time, and can be mixed with food.
  • the control group was a placebo made of cellulose: Bifidobacterium longum dry powder with a mass ratio of 1:1, and the dose was the same as the treatment group. The treatment effect was evaluated after 2 months of medication.
  • Effective rate (number of cures + number of significant effects + effective number) X 100% / total number
  • Control group 20 19.11 ⁇ 4.03 13.42 ⁇ 4.16 5.69 ⁇ 3.68 therapy group 20 19.14 ⁇ 4.48 2.98 ⁇ 1.99 14.66 ⁇ 5.39
  • Curative effect N get well Markedly effective effective invalid Efficient therapy group 20 12 3 2 3 85% Control group 20 3 3 1 13 35%
  • Example 3 A red clay preparation for the prevention and treatment of multiple sclerosis.
  • Treatment method The treatment group took the red clay preparation of step (1) twice a day, 5g each time, which can be mixed with food.
  • the control group took starch as a placebo, and the dosage was the same as the treatment group.
  • the treatment effect was evaluated after 3 months of medication.
  • preparation select yellow loam soil, sample sample element average content (mass percentage): Na 0.84%, Mg 1.42%, Al 9.17%, Si 30%, K 2.37%, Ca 1.48%, Ti 0.67%, Fe 6.94 %, O 47.11%, where the 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 2.1% of the dry weight of the soil, autoclaved for later use.
  • the auxiliary materials are high-quality dry-fried peanut powder and starch. The soil after autoclaving and dry-fried peanut powder and starch are mixed in a ratio of soil: peanut powder: starch 1:1:1 (mass ratio) to obtain a loess preparation.
  • Treatment method The treatment group takes orally every day. Step (1) Loess preparation, 3 times a day, 5 grams each time. The control group took peanut powder with a mass ratio of 1:1: starch as a placebo, and the dosage was the same as that in the treatment group. The treatment effect was evaluated after 4 weeks of medication.
  • Results show the effective rate of treatment, see Table 11. 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.
  • Treatment method Before administration, the treatment group and the control group were set to wash out for 2 weeks to avoid the influence of other depression drugs on this study.
  • the observation group took the red clay preparation of step (1) every day, 3 times a day, 4 grams each time.
  • the control group took the same proportion of auxiliary materials (quality ratio 1:1 bran and corn flour) as a placebo, and the dosage was the same as that of the treatment group.
  • the treatment effect was evaluated after 6 months of medication.
  • the Hamilton Depression Scale (HAMD) score and comparative analysis were used for different treatment periods. Before treatment, the HAMD scores of the two groups were basically the same, and there was no statistically significant difference between the groups . At 6 weeks and 12 weeks after treatment, the HAMD score of the observation group was significantly improved compared with the control group, and the difference between the groups was statistically significant (P ⁇ 0.05), as shown in Table 13.
  • Preparation of preparation select black loam soil, sample sample element average content (mass percentage): Na 1.13%, Mg 0.87%, Al 7.24%, Si 32.7%, K 1.99%, Ca 1.39%, Ti 0.63%, Fe 6.22 %, O 47.83%, 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, and the mixing ratio is soil: wheat flour: corn flour 1:1:1 (Mass ratio) to obtain a black soil preparation.
  • Treatment method The treatment group takes orally every day Step (1) Black soil preparation, 3 times a day, 5 grams each time.
  • the control group took wheat flour: corn flour with the same mass ratio of 1:1 as placebo, and the dosage was the same as that of the treatment group.
  • the treatment effect was evaluated 14 days after the medication.
  • Results show the effective rate of treatment, see Table 16. 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 of preparation select black loam soil, sample average element content (mass white content ratio): Na 0.58%, Mg 1.31%, Al 8.71%, Si 29.07%, K 2.22%, Ca 2.69%, Ti 0.54%, Fe 7.56%, O 47.32%, 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 2.5% of the dry weight of the soil, autoclaved for later use.
  • the auxiliary materials are red bean flour and corn flour.
  • the soil after autoclaving is mixed with red bean flour and corn flour.
  • the mixing ratio is soil: red bean flour: corn flour is 1 :1:1 (mass ratio) to obtain a black clay preparation.
  • Treatment method The treatment group was taken orally every day. Step (1) Black soil preparation, 2 times a day, 12 grams each time. The control group took red bean flour: corn flour with the same mass ratio of 1:1 as placebo, and the dosage was the same as that of the treatment group. The treatment effect was evaluated after 180 days of medication.
  • Observation index Observe the patient's hair loss area and range before and after treatment, as well as the scalp hair regrowth, hair pulling experiment and other results, and record these results. Then, according to the skin lesion scoring standard, the scores of the above observation items before and after the treatment of the subject's skin lesion were calculated. According to the observational indicators of hair loss in the third series of "Guiding Principles for Clinical Research of New Chinese Medicines", the specific scoring standards are as follows:
  • A. Hair loss area and location 0 points: no obvious hair loss areas; 1 point: limited to flaky hair loss on the head epidermis, and the area of hair loss is less than or equal to 10% of the total scalp area; 2 points: only on the head epidermis Patchy hair loss occurs, the area of hair loss is greater than 10% of the total scalp area, but less than 20%; 3 points: the area of hair loss is greater than or equal to 20%
  • Hair growth (according to four-level scoring method) 1 Hair regeneration in the lesion area: 3 points: ⁇ 30% or still falling; 2 points: >30% and ⁇ 70%, no shedding; 1 point: >70 % And ⁇ 95%, no off; 0 points: 100%, no off.
  • 2New-born hair density 3 points: the healthy hair area is sparse; 2 points: the healthy hair area is sparse; 1 point: the healthy hair area is sparse; 0 points: no difference from the healthy hair area.
  • 3 New-born hair thickness 3 points: obviously softer than healthy hair area; 2 points: softer hair area; 1 point: slightly softer hair area; 0 point: no difference from healthy hair area.
  • 4 Newborn hair color 3 points: white color; 2 points: gray or yellow color; 1 point: brown color; 0 point: black color.
  • Total effective rate (number of cured cases + number of markedly effective cases + number of effective cases) / total number of cases in this group ⁇ 100%
  • Results show the effective rate of treatment, see Tables 18 and 19. 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 of preparation select black loam soil, sample sample element average content (mass percentage): Na 0.56%, Mg 1.34%, Al 8.01%, Si 28.03%, K 2.21%, Ca 4.11%, Ti 0.34%, Fe 7.85 %, O 47.55%, 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 2.7% of the dry weight of the soil.
  • the auxiliary materials are peanut flour and wheat flour.
  • the soil after autoclaving is mixed with wheat flour and corn flour.
  • the mixing ratio is soil: peanut flour: wheat flour 1:1:1 (Mass ratio) to obtain red clay preparation.
  • Psoriasis vulgaris participant selection 80 patients were randomly divided into treatment group and control group. There were 40 patients in the treatment group, 25 males and 15 females, aged 40-69 years old, with an average of (54.5 ⁇ 7.8) years old. The course of disease was 2-16 years, with an average of (8.5 ⁇ 3.6) years; the control group had 40 cases, 28 males and 12 females, aged 41-69 years, with an average of (57.5 ⁇ 7.9) years; the course of disease was 2-17 years, with an average of (8.1 ⁇ 4.2) years. There was no statistical difference in gender, age, and course of disease between the two groups.
  • the treatment group takes orally every day Step (1) Black soil preparation, 3 times a day, 10 grams each time.
  • the control group took peanut flour: wheat flour with the same mass ratio of 1:1 as the placebo, and the dosage was the same as that of the treatment group.
  • the treatment effect was evaluated after 180 days of medication.
  • the lesion area and severity index of patients with psoriasis refer to the PASI score: the lesion area and severity index of patients with psoriasis refer to the Global PASI (Psoriasis area and severity index, PASI) scoring standard. Before treatment for the two groups of patients Record the PASI points after treatment.
  • 2Scoring of the degree of pruritus Score the pruritus of the three groups of patients before and after treatment, observe the improvement of the degree of pruritus before and after treatment, using a four-level scoring method of 0, 3, 6, and 9 points. 0 points: no itching; 3 points: slight itching, but does not affect sleep and work; 6 points: paroxysmal itching, which affects sleep and work, requires medication; 9 points: severe itching, which seriously affects sleep and work.
  • Efficacy index (integral before treatment-integral after treatment)/integral before treatment ⁇ 100%.
  • Results show the effective rate of treatment, see Tables 21 to 23. 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.

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Abstract

一种土壤制剂，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，以及该土壤制剂在制备防治神经内分泌失调相关疾病药物中的应用。

Description

具有防治神经内分泌失调相关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，特别是涉及一种可用于防治神经内分泌失调相关疾病的土壤制剂及其制备方法。
背景技术
间质性膀胱炎是指一种具有排尿不适感疾病，表现为不同程度的尿频、尿急，同时常常伴有不同程度的膀胱区、耻骨上或者下腹部的疼痛等症状。病史超过6周，并要排除感染和其他疾病，才可诊断为间质性膀胱炎。间质性膀胱炎常常合并下尿路症状。该病的两大主要症状是尿频和疼痛，严重地影响患者生活质量，80％以上患者都有不同程度的睡眠障碍、抑郁和焦虑，而且患病率逐年有增长趋势。
有关间质性膀胱炎发病原因已有大量研究，但仍没有统一的病因标准。神经生物学发病机制认为，感觉神经被激活后，释放P物质、神经激肽A和降钙素等信号分子，易引起神经性炎性反应，进一步引起膀胱粘膜损伤和通透性增加。溃疡型间质性膀胱炎肥大细胞显著增加，由于肥大细胞含有大量的炎性介质，导致疼痛、尿频和水肿等症状。但非溃疡型间质性膀胱炎肥大细胞数量多数情况下正常。
间质性膀胱炎的治疗目前主要采用三环类抗抑郁药，来拮抗一些神经递质的作用，临床上应用有一定的治疗效果；抗组胺类药是用来着减少肥大细胞激活与浸润，进而达到缓解疼痛的效果；戊聚硫钠可以在膀胱表面形成一层保护膜，降低毒素对膀胱神经的侵害。症状进一步严重的患者，常常采用膀胱灌注、膀胱切除及尿流改道等治疗方法。
三叉神经痛是临床常见的顽固性疾病，发病时疼痛较难忍受，主要表现为阵发性快速电击样、刀割样和撕裂样剧痛，常常突发突止，而且病程较长，严重影响了患者正常生活和工作，降低患者的生活质量，号称“天下第一痛”。
该疾病多发于50岁以上的老年人，一般为单侧发作，女性多于男性，发病率大约为1/15000。三叉神经痛主要有原发性和继发性两种，继发性三叉神经痛是指，由于肿瘤、血管病变等的刺激和压迫，导致三叉神经支配的患者面部疼痛。
原发性三叉神经痛发病机制目前尚未十分明确。多数人认为三叉神经痛是多种因素引起的。其中中枢病变和周围病变，以及免疫因子与神经递质发生变化是导致三叉神经痛的重要原因。
目前三叉神经痛的治疗方法有西医治疗、中西医联合治疗，以及外科手术治疗(如微血管减压术、射频热凝术、立体定向放射治疗等)。西医治疗，随着患者耐药性增加，药物反应较多的因素会导致病情进一步发展。中医治疗重复性差，临床上更多采用手术治疗，但手术治疗带来的副作用常常较为严重。因此，目前该病治疗较为因难。
通过实验筛选发现，本发明可以调节肠道微生物结构与组成，进一步调节神经内分泌活动，从而达到治疗与预防上述疾病的发生。
发明内容
本发明主要解决的技术问题是克服现有技术的不足，提供一种安全性好，不良反应低，具有较好的防治质性膀胱炎、原发性三叉神经痛、抑郁症、睡眠障碍、青春痘或便秘功效的土壤制剂。
技术方案，为解决上述技术问题，本发明采用以下技术方案：
提供一种土壤制剂，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。
在本发明一个较佳实施例中，所述土壤为没有被污染的土壤，包括红土、黄土、黑土和褐土。
在本发明一个较佳实施例中，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。
在本发明一个较佳实施例中，所述辅料为食用材料，包括蛋白类、淀粉类或纤维素类食材。
在本发明一个较佳实施例中，所述土壤制剂用于制备预防和/或治疗人体神经内分泌失调症，包括原发性间质性膀胱炎、间质性肺炎、原发性三叉神经痛、多发性硬化症、斑秃、银屑病、抑郁症、睡眠障碍、青春痘或便秘的药物。
一种制备上述土壤制剂的制备方法，包括下述步骤：
(1)采集无污染土壤，并做微量元素分析，筛选土壤重金属含量合格的土壤；(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，所述有毒微量元素包括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。
步骤(1)的土壤常规方法检测中检测不到有毒有机物。
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。
本发明的有益效果是：
1)本发明土壤制剂可通过调节肠道微生态，有进一步调节神经内分泌的功能：多项研究表明，肠道微生物及其代谢产物，可以刺激肠道上皮细胞产生5羟色胺(人体中95％以上的5羟色胺来自于肠道)。5羟色胺是神经内分泌重要的神经递质，与抑郁症等多种疾病的发生密切相关。因此，本发明可以调节人体肠道微生物的结构与组成，进而来调节人体神经内分泌活动，进一步达到预防与治疗间质性膀胱炎、原发性三叉神经痛、多发性硬化症、抑郁症、睡眠障碍等疾病的效果。
2)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。
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用于预防与治疗间质性膀胱炎的黑土制剂。
(1)制剂制备：选取黑色壤土，抽样样本元素平均含量(质量百分比)：Na 0.95％，Mg 2.03％，Al 8.28％，Si 27.19％，K 2.56％，Ca 6.45％，Ti 0.58％，Fe 5.57％，O 46.39％，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1.7％，高压火菌备用，辅料为优质干炒花生粉与蔗糖，高压火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∶0.5(质量比)，得到黑土制剂。
(2)间质性膀胱炎研究对象：选择40例患者作为实验对象，年龄区间为20～85岁，平均年龄50.1±14.1岁，其中男性病人15例，女性病人25例。患者病程10～70个月，病程区间30.1±11.7个月。其中初诊10例，复诊30例。
患者符合加拿大泌尿外科协会(CUA)2016年诊断标准。纳入标准：1)病史6周以上，无尿路感染，超声肾、输尿管、膀胱无异常发现；2)存在尿频，憋尿时下腹不适或胀痛，排尿后下腹不适或胀痛缓解症状；3)麻醉后，80cmH2O(1cmH2O＝0.098kPa)压力下，膀胱持续扩张5min后，膀胱镜发现Hunner溃疡或弥漫性膀胱粘膜出血，即：每视野出现10个及以上出血点，并有3个视野以上。
排除标准：1)清醒状态下患者最大膀胱功能容量＞350ml；2)150ml液体充盈膀胱时无急迫性排尿感；3)症状持续时间＜6周；4)应用抗生素或者解痉药后症状缓解；5)每天清醒情况下白天尿频次数＜8次，夜尿＜2次。6)伴发尿道或阴道感染、细菌性膀胱炎、结核性膀胱炎、放射性膀胱炎、化学性膀胱炎、盆腔炎症性疾病、子宫内膜异位症、性传播疾病、泌尿系结石、膀胱肿瘤等。
(3)研究内容：①年龄、性别、病程、就诊主要症状等；②排尿日记(Urinary Diary)；③O’Leary Sant评分表，包括症状指数(ICSI)和问题指数(ICPI)两部分；④盆腔疼痛和尿频/尿急症状评分表(PUF)；⑤视觉模拟评分(Visual Analogue Scale/Score，VAS)；⑥阿森斯失眠量表(Athens insomnia scale，AIS)；⑦焦虑自评量表(Self-rating Anxiety scale，SAS)、抑郁自评量表(Se]f-rating Depression scale，SDS)。记录治疗前所有IC/BPS患者初始情况及治疗后3月、6月时随访情况，所有问卷(除排尿日记)均由调查人员在场填写并收回，排尿日记2～3天后收回。
(3)治疗方法：治疗组口服步骤(1)的黑土制剂，每天2次，用量5g/次，可与食物混合一起服用。用药3个月后进行治疗效果评测。服用三个月后进行疗效评价。
(4)治疗效果评价：采集的数据采用SPSS 18.0软件进行统计分析。以IC症状评分下降＞5分，或＞25％为有效。
(5)结果：根据统计分析，治疗组治疗前后有显著差异(P＜0.001)。无不良反应。如表1和表2。
(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3)，放线菌门细菌种类与数量显著增加(P＜0.01)。
表1.治疗前后患者24h排尿次数、ICSI、ICPI、PUF、VAS评分比较
时间 N 24h排尿次数 ICSI ICPI PUF VAS
治疗前 40 26.60±12.35 14.28±4.78 9.56±2.43 14.66±4.19 6.11±2.22
Figure PCTCN2020078491-appb-000001
表2.IC病人焦虑、抑郁评分
  N SAS SDS AIS
IC患者治疗前 40 45.67±6.77 52.46±11.31 5.68±3.32
IC患者治疗后 40 32.23±5.69 45.32±8.12 2.14±1.02
中国常模 1628/1158 29.87±10.07 41.88±10.57  
注：治疗前后相比，P＜0.001
表3随机森林分析治疗组肠道细菌含量显著增加的类型
Figure PCTCN2020078491-appb-000002
实施例2用于预防与治疗原发性三叉神经痛的黄土双歧杆菌制剂。
(1)制剂制备：选取黄色壤土，抽样样本元素平均含量：Na 0.36％，Mg 1.49％，Al 9.26％，Si 28.3％，K 2.29％，Ca 4.22％，Ti 0.73％，Fe 7.95％，O 45.4％，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1.2％，高压灭菌备用，同时添加纤维素作为辅料，和长双岐杆菌(Bifidobacterium longum subsp.infantis ATCC 15697)作为益生菌。高压灭菌后的土壤与纤维素与长双岐杆菌干粉，混合比例为土壤∶纤维素∶长双 岐杆菌干粉为1∶1∶1(质量比)制备成黄土制剂。
(2)原发性三叉神经痛被试选择：40例患者随机分成治疗组和对照组。治疗组20例，男8例，女12例，年龄15-80岁，平均(51.8±18.2)岁。病程5天～16年，平均(3.5±1.6)年；对照组20例，男9例，女11例，年龄16～78岁，平均(55.3±14.8)岁；病程5天～20年，平均(4.04±1.8)年。两组被试患者性别、年龄、病程无统计学差异。入选病例均符合原发性三叉神经痛诊断标准。
诊断标准参照2004年国际头痛学会分类委员会《头痛的国际分类(第二版)》中关于原发性三叉神经痛的诊断标准。1)面额部突然发作性的疼痛，持续时间一般不足2分钟，侵犯三叉神经分布区的一支或几支；2)疼痛至少具备下列持征之一：剧烈的、针刺样、烧灼样甚至刀割样；可由扳机点或相关扳机因素诱发而突然发作；3)临床上神经系统无阳性体征；4)不能归于其他疾病和机能紊乱。
纳入标准：1)符合相关中西医诊断标准；2)年龄大于或等于15岁、小于80岁的男性或女性，两组观察对象在病程、年龄以及治疗前后的各项指标，经统计学处理后未见明显的差异，具有可比性；3)观察前一周即需停服各种中、西药物并且停止其它治疗方法；4)病情稳定，意识清楚；5)日发作频率大于等于1次者。6)患者了解试骀流程并自愿参加，签署知情同意书；
排除标准：1)不符合上述诊断标准者；2)继发性三叉神经痛患者；3)哺乳、妊娠期妇女；4)合并其它严重心脑血管、凝血障碍等原发性疾病者；5)正在参加其他医疗试验者；6)严重神经损伤及认知障碍影响疼痛评估者。
分组：随机分为处理组20例，常规治疗组20例，两组患者性别、年龄、病程无统计学差异。
(3)治疗方法：治疗组服用步骤(1)的黄土制剂，每天3次，用量3-6g/次，可与食物混合一起服用。对照组以质量比例1∶1的纤维素∶长双岐杆菌干粉制成的安慰剂，服用剂量同治疗组。用药2个月后进行治疗效果评测。
(4)治疗效果评价：治疗2个月后，观察治疗效果参考2002年颁布的《中医新药治疗三叉神经痛的临床指导原则》所确定疗效标准，并配合临床治疗经验，进行疗效评定。
①随访痊愈：从治疗日起，12月内疼痛症状完全消失；
②随访显效：从治疗日起，12月内疼痛大部分消失；
③随访有效：从治疗日起，12月内疼痛有所减轻；
④随访无效：从治疗日起，12月内疼痛无明显减轻。
有效率＝(痊愈数+显效数+有效数)X100％/总数量
(5)结果：根据统计分析，治疗组的临床疗效有显著差异(P＜0.001)。无不良反应。见表4和表5.
(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6)，放线菌门细菌种类与数量显著增加(P＜0.01)。
表4两组治疗前与治疗后疼痛积分
组别 N 治疗前 治疗后 差值
对照组 20 19.11±4.03 13.42±4.16 5.69±3.68
治疗组 20 19.14±4.48 2.98±1.99 14.66±5.39
注：两组患者治疗前后差值均符合正态分布，经配对样本t检验，治疗组t＝14.66，P＜0.001
表5两组治疗前后疗效比较
疗效 N 痊愈 显效 有效 无效 有效率
治疗组 20 12 3 2 3 85％
对照组 20 3 3 1 13 35％
注：经卡方检验：df＝3，X 2＝11.98，P＝0.007。
表6随机森林分析治疗组肠道细菌含量显著增加的类型
Figure PCTCN2020078491-appb-000003
Figure PCTCN2020078491-appb-000004
实施例3用于预防与治疗多发性硬化症的红土制剂。
(1)制剂制备：选取红色壤土，抽样样本元素平均含量：Na 0.48％，Mg 1.37％，Al 8.93％，Si 30.69％，K 2.87％，Ca 1.68％，Ti 0.04％，Fe 6.18％，O 47.76％，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2.1％。高压灭菌备用。辅料为淀粉。高压灭菌后的土壤与淀粉混合，混合比例为土壤∶淀粉为1∶1(质量比)制得红土制剂。
(2)被试选择：20例实验组中，8例男性患者，12例女性患者；年龄最小19岁，最大70岁，平均44.23±15.14岁；平均病程2.1±4.4个月。20例对照组中，9例男性患者，11例女性患者；年龄最小18，最大68岁，平均43.35±14.66岁；平均病程2.4±5.1个月。两组的临床表现无统计学差异(P＞0.05)。
(3)治疗方法：治疗组服用步骤(1)的红土制剂，每天2次，每次5g/次，可与食物混合一起服用。对照组以淀粉为安慰剂，服用剂量同治疗组。用药3个月后进行治疗效果评测。
(4)治疗后两组EDSS评分比较
在治疗3月后，实验组和对照组的EDSS评分，在治疗前与治疗后的变化情均有统计学上的显著差异(P＜0.05)。且治疗后，实验组EDSS评分的降低显著多于对照组，有统计学意义(P＝0.000)，具体数值情况见表7。
(5)治疗后1年两组EDSS评分及复发次数比较
在治疗后1年，实验组和对照组相比，治疗前后的EDSS评分的变化情况均有显著差异(P＜0.05)，实验组EDSS评分下降的幅度较对照组有统计学差异，(P＜0.05)。另外，两组患者1年后复发次数，实验组1人次，对照组2人次，无统计学差异(P＞0.05)，具体数值情况见表8。
(6)治疗效果比较
根据统计分析，实验组和对照组的临床疗效有显著差异(P＜0.001)。无不良反应。详见表9。
(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10)，放线菌门细菌种类与数量显著增加(P＜0.01)
表7两组多发性硬化患者治疗3月后EDSS评分比较
组别 治疗前 治疗后 t值 P值
实验组n＝20 5.13±1.09 2.12±1.36 7.723 ＜0.001
对照组n＝20 5.07±2.01 4.44±1.67 1.078 0.288
t值   -4.817    
P值   ＜0.001    
表8两组患者治疗后1年EDSS评分及复发次数比较
组别 治疗前 治疗后1年 t值 P值
实验组n＝20 5.13±1.09 2.19±1.19 8.142 ＜0.001
对照组n＝20 5.07±2.01 4.96±1.96 0.175 0.862
t值   -5.402    
P值   ＜0.001    
表9两组多发性硬化患者治疗效果比较
组别 例数 显效 有效 无效 总有效率
对照组 20 1 5 14 30％
实验组 20 12 6 2 90％
注：经卡方检验：df＝1，X 2＝15.000，P＜0.001
表10随机森林分析治疗组肠道细菌含量显著增加的类型
Figure PCTCN2020078491-appb-000005
Figure PCTCN2020078491-appb-000006
实施例4黄土制剂治疗青春痘疗效研究
(1)制剂制备：选取黄色壤土，抽样样本元素平均含量(质量百分比)：Na 0.84％，Mg 1.42％，Al 9.17％，Si 30％，K 2.37％，Ca 1.48％，Ti 0.67％，Fe 6.94％，O 47.11％，，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2.1％，高压灭菌备用，辅料为优质干炒花生粉与淀粉，高压灭菌后的土壤与干炒花生粉与淀粉，混合比例为土壤∶花生粉∶淀粉为1∶1∶1(质量比)，得到黄土制剂。
(2)青春痘患者被试选择：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10～25岁，平均(15.7±5.1)岁。病程1～7年；对照组40例，男20例，女20例，年龄11～26岁，平均(15.3±6.3)岁；病程1～7年。两组被试患者性别、年龄、病程无统计学差异。入选病例为有经验的皮肤科医师诊断为青春痘。
(3)治疗方法：治疗组每天口服步骤(1)黄土制剂，每天3次，每次5克。对照组以质量比为1∶1的花生粉：淀粉辅料为安慰剂，服用剂量同治疗组。用药4周后进行治疗效果评测。
(4)治疗效果评价：根据《中医病症诊断疗效标准》结合临床拟定。治愈：皮肤损害消退，自觉症状消失好转；好转：自觉症状明显减轻，皮损消退30％以上；未愈：皮损及症状均无变化或消退不及30％。以治愈、好转病例数合计计算有效率。
(5)结果：结果显示治疗有效率，见表11。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12)，放线菌门细菌种类与数量显著增加(P＜0.01)。
表11两组患者治疗4周后疗效比较(n，％)
组别 N 治愈 好转 无效 有效例数 有效率
治疗组 40 21 14 5 35 87.5％
对照组 40 5 5 30 10 25％
注：经卡方检验：df＝1，X 2＝31.746，P＜0.001。
表12.随机森林分析治疗组肠道细菌含量显著增加的类型
Figure PCTCN2020078491-appb-000007
实施例5红土制剂辅助治疗抑郁症功能研究
(1)制剂制备：选取红色壤土，抽样样本元素平均含量(质量百分比)：Na 0.69％，Mg 2.32％，Al 7.34％，Si 28.04％，K 2.54％，Ca 9.17％，Ti 1.51％，Fe 5.78％，O 42.61％，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1.5％，高压灭菌备用，辅料为优质麸皮和玉米粉，高压灭菌后的土壤与麸皮玉米粉混合，混合比例为土壤∶麸皮∶玉米粉为1∶1∶1(质量比)，制备成红土制剂。
(2)抑郁症被试选择：60例患者志愿者均符合抑郁症疾病的诊断标准(《中国精神障碍分类与诊断标准》，第3版)。将被试随机分为治疗组，共30例，男性患者15例，女性患者15例，年龄13～65岁，平均(38.5±9.9)岁，平均病程(17.8±11.7)月；对照组30例，男性患者15例，女性患者15例，年龄14～65岁，平均(39.5±10.8)岁，平均病程(16.4±10.1)月。两组患者在年龄、性别、病程等指标，无统计学差异。
(3)治疗方法：给药前，治疗组与对照组被试均设清洗期2周，避免其他抑郁药物对本研究的影响。观察组每天口服步骤(1)的红土制剂，每天3次，每次4克。对照组以相同比例辅料(质量比1∶1麸皮和玉米粉)为安慰剂，服用剂量同治疗组。用药6个月后进行治疗效果评测。
(4)治疗效果评价：治疗不同时段，采用汉密顿抑郁量表(Hamilton Depression Scale，HAMD)评分和比较分析，治疗前，两组患者的HAMD评分均基本相当，组间差异无统计学意义。而治疗后6周、12周，观察组较对照组患者的HAMD评分出现了明显改善，组间差异具有统计学意义(P＜0.05)，见表13。
表13两组患者的HAMD指标评分情况
Figure PCTCN2020078491-appb-000008
组别 被试数量 治疗前 治疗6周 治疗12周
观察组 28 28.69±7.97 10.45±4.36 11.22±4.63
对照组 28 28.54±6.85 14.22±5.74 15.44±6.36
t   0.076 -2.768 -2.838
P   0.940 0.008 0.006
(5)两组患者的不良反应发生情况比较：治疗期间，两组患者均出现了口干、出汗、 恶心、呕吐、体重增加、食物模糊等不良反应，但是，观察组不良反应发生率均明显低于对照组患者，其中，出汗、口干、恶心呕吐、体重增加、视物模糊、头疼等不良反应的发生率组间具有统计学差异，见表14。
(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15)，放线菌门细菌种类与数量显著增加(P＜0.01)。
表14两组患者治疗期间发生不良反应情况对比
组别 出汗 口干 恶心呕吐 体重增加 视物模糊 头晕 便秘/腹泻 头疼
观察组 2 3 5 1 2 0 2 1
对照组 7 12 11 8 4 4 3 7
P 0.069 0.007 0.076 0.011 0.388 0.120 1.000 0.056
表15.随机森林分析治疗组肠道细菌含量显著增加的类型
Figure PCTCN2020078491-appb-000009
Figure PCTCN2020078491-appb-000010
实施例6黑土制剂治疗功能性便秘研究
(1)制剂制备：选取黑色壤土，抽样样本元素平均含量(质量百分比)：Na 1.13％，Mg 0.87％，Al 7.24％，Si 32.7％，K 1.99％，Ca 1.39％，Ti 0.63％，Fe 6.22％，O 47.83％，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)，得到黑土制剂。
(2)功能性便秘被试选择：70例患者随机分成治疗组和对照组。治疗组35例，男17例，女18例，年龄30～66岁，平均(41.9±7.5)岁。病程1～8年，平均(3.5±2.3)年；对照组35例，男18例，女17例，年龄31～67岁，平均(42.1±8.5)岁；病程1～8年，平均(4.1±3.2)年。两组被试患者性别、年龄、病程无统计学差异。入选病例均符合功能性便秘诊断标准(罗马II标准)。
(3)治疗方法：治疗组每天口服步骤(1)黑土制剂，每天3次，每次5克。对照组以相同质量比1∶1的小麦粉∶玉米粉为安慰剂，服用剂量同治疗组。用药14天后进行治疗效果评 测。
(4)治疗效果评价：参照《中医病症诊断疗效标准》中的成人便秘疗效标准制定。(1)治愈：1天内排便1次，便质正常，排便通畅，1个月内无复发；(2)显效：2天内排便1次，便质趋于正常，排便通畅，1个月内无复发；(3)有效：3天内排便1次，便质转润，排便欠畅；(4)无效：临床症状无明显改善。以治愈、显效病例数合计计算有效率。
(5)结果：结果显示治疗有效率，见表16。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17)，放线菌门细菌种类与数量显著增加(P＜0.01)。
表16两组患者治疗14天后疗效比较(n，％)
组别 N 治愈 显效 有效 无效 有效例数 有效率
治疗组 35 20 8 3 4 31 88.5％
对照组 35 3 2 8 22 13 37.1％
注：经卡方检验：df＝1，X 2＝19.82，P＜0.001
表17随机森林分析治疗组肠道细菌含量显著增加的类型
Figure PCTCN2020078491-appb-000011
实施例7黑土制剂治疗斑秃研究
(1)制剂制备：选取黑色壤土，抽样样本元素平均含量(质量白分比)：Na 0.58％，Mg 1.31％，Al 8.71％，Si 29.07％，K 2.22％，Ca 2.69％，Ti 0.54％，Fe 7.56％，O 47.32％，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2.5％，高压灭菌备用，辅料为红豆粉和玉米粉，高压灭菌后的土壤与红豆粉和玉米粉混合，混合比例为土壤∶红豆粉∶玉米粉为1∶1∶1(质量比)，得到黑土制剂。
(2)斑秃患者选择：70例患者随机分成治疗组和对照组。治疗组35例，男18例，女17例，年龄16～55岁，平均(28.5±10.4)岁。病程3～10周，平均(7.5±4.5)周；对照组35例，男18例，女17例，年龄17～57岁，平均(26.5±9.8)岁；病程4～10周，平均(8.1±4.7)周。两组 被试患者性别、年龄、病程无统计学差异。
(3)斑秃诊断标准参考《临床皮肤病学》及《中西医结合皮肤性病手册》拟定：
①该疾病在任意年龄阶段皆可出现发病，但以青壮年发病者更多。
②患者头皮突然出现大小不一的圆形或椭圆形、1-10cm直径、数目不等、边界清楚的脱发区。单发或多发，严重者甚至呈现为整个头皮头发全部脱落即“全秃”，或身体其他部位毛发，如眉毛、腋毛、阴毛等脱落即“普秃”。
③在疾病进展期，脱发区边缘头发松动，头发极易拔出，拔发实验(+)，患处脱落的头发放在显微镜下观察，可见毛干近端萎缩，表现为上粗下细的“惊叹号”现象。
④皮损处皮肤光滑，无炎症，未见萎缩及疤痕。
(4)治疗方法：治疗组每天口服步骤(1)黑土制剂，每天2次，每次12克。对照组以相同质量比1∶1的红豆粉∶玉米粉为安慰剂，服用剂量同治疗组。用药180天后进行治疗效果评测。
(5)观察指标：观察患者在治疗前、治疗后脱发面积及范围，以及头皮部的头发再生状况、拔发实验等结果，将这些结果记录下来。然后再按照皮损评分标准分别计算出受试者皮损部位治疗前后的上述观察项目的评分情况。根据《中药新药临床研究指导原则》第3辑中关于脱发的观测性指标，拟定具体评分标准如下：
A、脱发面积及部位：0分：无明显脱发区；1分：仅限于头部表皮出现的片状脱发，脱发面积少于或等于全部头皮面积的10％；2分：仅限于头部表皮出现的斑片状脱发，脱发面积大于全部头皮面积的10％，但小于20％；3分：脱发面积大于或等于20％
B：拔发试验：0分：阴性；1分：阳性。
C：毛发生长情况：(按四级评分法)①皮损区毛发再生情况：3分：＜30％或仍脱落；2分：＞30％且＜70％，不脱；1分：＞70％且＜95％，不脱；0分：100％，不脱。②新生毛发密度：3分：明显较健发区稀疏；2分：较健发区稀疏；1分：稍较健发区稀疏；0分：与健发区无差别。③新生毛发粗细：3分：明显较健发区细软；2分：较健发区细软；1分：稍较健发区细软；0分：与健发区无差别。④新生毛发色泽：3分：色白；2分：色灰或黄；1分：色褐；0分：色黑。
(6)治疗效果评价：疗效的评定标准参照《中药新药临床研究指导原则》。临床痊愈：患者头部头发终止脱落，头皮部脱落的头发完全恢复生长，其新长出头发的密度、色泽与正常头皮部头发相同；疗效指数≥95％。显效：患者头部头发终止脱落，新长出的头皮部头发≥70％，其密度、色泽接近正常头皮部头发；60％≤疗效指数＜95％。有效：患者头部头发终止脱落，30％≤新长出的头皮部头发＜70％，皮损区可见稀疏耄毛及白发生长；30％≤疗效指数＜60％。无效：新长出的头皮部头发＜30％或继续脱落；疗效指数＜30％。
总有效率＝(痊愈例数+显效例数+有效例数)/本组总病例人数×100％
(7)结果：结果显示治疗有效率，见表18和19。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。
(8)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20)，放线菌门细菌种类与数量显著增加(P＜0.01)。
表18两组治疗前后皮损总评分比较
组别 例数 治疗前总评分 治疗后总评分
治疗组 35 10.00±4.36 2.31±1.43
对照组 35 10.12±3.65 9.56±5.07
P值   P＞0.05 P＜0.001
表19两组患者治疗180天后疗效比较(n，％)
组别 N 治愈 显效 有效 无效 总有效率
治疗组 35 15 8 8 4 88.6％
对照组 35 4 2 8 21 40％
注：经卡方检验：df＝1，x2＝17.98，p＜0.001
表20.随机森林分析治疗组肠道细菌含量显著增加的类型
Figure PCTCN2020078491-appb-000012
实施例8红土制剂治疗寻常型银屑病研究
(1)制剂制备：选取黑色壤土，抽样样本元素平均含量(质量百分比)：Na 0.56％，Mg 1.34％，Al 8.01％，Si 28.03％，K 2.21％，Ca 4.11％，Ti 0.34％，Fe 7.85％，O 47.55％，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2.7％，高压灭菌备用，辅料为花生粉和小麦粉，高压灭菌后的土壤与小麦粉玉米粉混合，混合比例为土壤∶花生粉∶小麦粉为1∶1∶1(质量比)，得到红土制剂。
(2)寻常型银屑病被试选择：80例患者随机分成治疗组和对照组。治疗组40例，男25例，女15例，年龄40～69岁，平均(54.5±7.8)岁。病程2～16年，平均(8.5±3.6)年；对照组40例，男28例，女12例，年龄41～69岁，平均(57.5±7.9)岁；病程2～17年，平均(8.1±4.2)年。两组被试患者性别、年龄、病程无统计学差异。
(3)寻常型银屑病西医诊断标准：寻常型银屑病的西医诊断标准参照《中国临床皮肤病学》(2010版江苏科学技术出版社)：本病皮肤损害以红色炎性丘疹、斑丘疹及大小不等的斑片为主，上覆多层银白色鳞屑，刮除鳞屑可见一层光亮的薄膜，薄膜下可有点状出血现象。皮疹可发生在身体表面各处。发生在头皮者，毛发呈束状；发于甲板(指、趾)者，可有点 状凹坑呈顶针或甲板不平整，变黄增厚。可伴有不同程度的瘙痒。病程慢，易复发。
(4)治疗方法：治疗组每天口服步骤(1)黑土制剂，每天3次，每次10克。对照组以相同质量比1∶1的花生粉∶小麦粉为安慰剂，服用剂量同治疗组。用药180天后进行治疗效果评测。
(5)疗效评分标准
①银屑病患者的皮损面积和严重程度指数参照PASI评分：银屑病患者的皮损面积和严重程度指数参照Global PASI(Psoriasis area and severity index，PASI)积分标准，对两组患者治疗前和治疗后的PASI积分进行记录。
②瘙痒程度评分：对三组患者治疗前和治疗后的瘙痒情况进行评分，观察患者治疗前和治疗后的瘙痒程度改善情况，采用0、3、6、9分的四级评分法。0分：无瘙痒感；3分：轻微瘙痒，但不影响睡眠及工作；6分：阵发性瘙痒，影响睡眠及工作，需用药治疗；9分：瘙痒剧烈，严重影响睡眠及生活工作.
(6)治疗效果评价：疗效评定标准参照《中药新药临床研宄指导原则》
临床痊愈：皮损几乎全部消退，疗效指数＞95％
显效：皮损大部分消退，95％＞疗效指数≤70％
有效：皮损部分消退，70％＞疗效指数≤55％
无效：皮损消退不明显，疗效指数＜55％
疗效指数＝(治疗前积分-治疗后积分)/治疗前积分×100％。
总有效率包括治愈例数、显效例数及有效例数的总和占本组全部病例数的百分率。即总有效率＝[(治愈例数+显效例数+有效例数)/本组总病例数]×100％。
(7)结果：结果显示治疗有效率，见表21至23。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。
(8)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24)，放线菌门细菌种类与数量显著增加(P＜0.01)。
表21两组患者治疗前后PASI评分比较
Figure PCTCN2020078491-appb-000013
组别 例数 治疗前评分 治疗后评分
治疗组 40 15.17±3.72 2.96±1.88
对照组 40 15.81±3.96 14.86±4.73
P值   P＞0.05 P＜0.001
表22两组患者治疗前后瘙痒程度积分比较
Figure PCTCN2020078491-appb-000014
组别 例数 治疗前评分 治疗后评分
治疗组 40 8.29±1.07 1.34±1.46
对照组 40 8.45±1.69 8.11±2.25
P值   P＞0.05 P＜0.001
表23两组患者治疗180天后疗效比较(n，％)
组别 N 治愈 显效 有效 无效 有效率
治疗组 40 10 18 6 6 85％
对照组 40 2 2 8 28 30％
注：经卡方检验：df＝1，X 2＝18.66，P＜0.001
表24随机森林分析治疗组肠道细菌含量显著增加的类型
Figure PCTCN2020078491-appb-000015
Figure PCTCN2020078491-appb-000016
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 (9)

  1. 一种土壤制剂，其特征在于，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所述的土壤制剂，其特征在于，所述土壤包括红土、黄土、黑土和褐土。
  3. 根据权利要求1所述的土壤制剂，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. 根据权利要求1～4任一项所述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，筛选出重金属含量合格的无污染土壤；
    (2)然后高压灭菌，在水蒸汽高温高压下灭菌60～120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。胶囊或冲剂。
  6. 根据权利要求5所述的土壤制剂的制备方法，其特征在于，所述土壤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％。
  7. 根据权利要求5所述的土壤制剂的制备方法，其特征在于，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。
  8. 权利要求1～4任一项所述的土壤制剂在制备防治神经内分泌失调相关疾病药物中的应用。
  9. 权利要求1～4任一项所述的土壤制剂在制备防治原发性间质性膀胱炎、间质性肺炎、原发性三叉神经痛、多发性硬化症、斑秃、银屑病、抑郁症、睡眠障碍、青春痘或便秘的药物中的应用。
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