WO2020244501A1 - 一种用于预防/治疗代谢综合征和其并发症的中药增减方 - Google Patents

一种用于预防/治疗代谢综合征和其并发症的中药增减方 Download PDF

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WO2020244501A1
WO2020244501A1 PCT/CN2020/093911 CN2020093911W WO2020244501A1 WO 2020244501 A1 WO2020244501 A1 WO 2020244501A1 CN 2020093911 W CN2020093911 W CN 2020093911W WO 2020244501 A1 WO2020244501 A1 WO 2020244501A1
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complications
chinese medicine
traditional chinese
diabetes
prescription
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PCT/CN2020/093911
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English (en)
French (fr)
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杨根喜
何荣荣
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何荣荣
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Priority to EP20817770.9A priority Critical patent/EP3978009A4/en
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Priority to US17/515,574 priority patent/US20220047658A1/en

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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)
    • A61K36/899—Poaceae or Gramineae (Grass family), e.g. bamboo, corn or sugar cane
    • A61K36/8994—Coix (Job's tears)
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • 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
    • A61K35/56—Materials from animals other than mammals
    • A61K35/57—Birds; Materials from birds, e.g. eggs, feathers, egg white, egg yolk or endothelium corneum gigeriae galli
    • 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
    • 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)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/488—Pueraria (kudzu)
    • 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)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/54—Lauraceae (Laurel family), e.g. cinnamon or sassafras
    • 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)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/62—Nymphaeaceae (Water-lily family)
    • 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)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/65—Paeoniaceae (Peony family), e.g. Chinese peony
    • 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)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/71—Ranunculaceae (Buttercup family), e.g. larkspur, hepatica, hydrastis, columbine or goldenseal
    • 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)
    • A61K36/894—Dioscoreaceae (Yam family)
    • A61K36/8945—Dioscorea, e.g. yam, Chinese yam or water yam
    • 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
    • A61P3/08—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
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/50—Methods involving additional extraction steps
    • A61K2236/51—Concentration or drying of the extract, e.g. Lyophilisation, freeze-drying or spray-drying

Definitions

  • the present invention relates to the field of biomedicine, in particular to a traditional Chinese medicine increase or decrease formula that can be used to prevent and/or treat metabolic syndrome and its complications and a product using the traditional Chinese medicine increase or decrease formula as a raw material.
  • the invention also relates to the preparation of the product method.
  • Metabolic syndrome refers to the pathological state in which the body's protein, fat, carbohydrates and other substances are metabolically disordered. It is a complex of metabolic disorder syndromes and is a risk factor for diabetic cardiovascular and cerebrovascular diseases. It has the following characteristics: 1 A variety of metabolic disorders are integrated, including obesity, hyperglycemia, hypertension, dyslipidemia, hyperviscosity, hyperuric acid, high fatty liver incidence, and hyperinsulinemia. These metabolic disorders are the heart, The pathological basis of cerebrovascular disease and diabetes. It can be seen that diabetes is not an isolated disease, but one of the components of metabolic syndrome. 2They have a common pathological basis. At present, it is believed that their common cause is insulin resistance and hyperinsulinemia caused by obesity, especially central obesity.
  • 3It can cause a variety of diseases, such as high blood pressure, coronary heart disease, stroke, and even certain cancers, including breast cancer, endometrial cancer, prostate cancer, and pancreatic cancer, liver and gallbladder cancer related to sex hormones. , Colon cancer, etc. 4
  • diseases such as high blood pressure, coronary heart disease, stroke, and even certain cancers, including breast cancer, endometrial cancer, prostate cancer, and pancreatic cancer, liver and gallbladder cancer related to sex hormones. , Colon cancer, etc. 4
  • There are common prevention and treatment measures to prevent and treat one metabolic disorder which is also conducive to the prevention and treatment of other metabolic disorders (taken from Baidu Encyclopedia Metabolic Syndrome entry).
  • glucose metabolism disorders such as diabetes and diabetic complications are an important cause of human death.
  • IDF International Diabetes Federation
  • the number of adults with diabetes (20-79 years old) worldwide has increased from 151 million in 2000 to 425 million in 2017, an increase of nearly two times. It is estimated that by 2045, diabetes patients may reach 629 million. my country is a big country with diabetes.
  • IDF International Diabetes Federation
  • my country is a big country with diabetes.
  • type II diabetes patients account for 90%.
  • diabetic patients are prone to complications including damage to the large blood vessels and capillaries and endanger the heart, brain, kidneys, peripheral nerves, eyes, and feet.
  • diabetes complications have the function of mutual prediction.
  • urinary creatinine, urinary microalbumin, and urinary albumin are risk factors and markers of retinopathy.
  • the effects of drugs on omental microangiopathy can be inferred from these test results.
  • every 6 people may have proteinuria.
  • Subjects with microalbuminuria are about twice as likely to develop diabetic eye disease as subjects without microalbuminuria.
  • albuminuria occurs, the risk of diabetic eye disease increases to 6 Times.
  • body weight is also a representative indicator of metabolic syndrome. Weight loss can reduce other indicators of metabolic syndrome, including hyperlipoproteinemia, hypertension, fatty liver disease, arteriosclerosis, atherosclerosis, obesity, and essential hypertension.
  • a follow-up test of 1653 non-obese adult employees showed that the more weight gain in one year, the worse the metabolic syndrome index (Toga et al., 2016).
  • Another health check-up data for 307 20-90 years old (average 45 years old) men and 295 healthy women in Thailand showed that obesity is the main component of metabolic syndrome (Pongchaiyakul et al., 2007).
  • Hyperlipoproteinemia that is, hyperlipoproteinemia, is a manifestation of elevated levels of a certain class or classes of lipoproteins in plasma. Hyperlipidemia plays a very important role in the occurrence and development of atherosclerosis and the cardiovascular events caused by it. It is one of the main risk factors for coronary artery disease, stroke and peripheral vascular disease. The most common complication of abnormal lipoprotein metabolism is atherosclerosis; hypertriglycerides and chylomicronemia are often complicated by fatal diseases such as acute pancreatitis.
  • metabolic syndrome or insulin resistance syndrome is usually accompanied by symptoms such as fatty liver disease, arteriosclerosis, atherosclerosis, obesity, and essential hypertension.
  • Fatty liver disease, including metabolic syndrome or insulin resistance syndrome may develop into chronic inflammation, liver fibrosis and cirrhosis, so the treatment of fatty liver is also very important; while atherosclerosis, arteriosclerosis and primary hyperplasia Blood pressure also accounts for a high rate of chronic diseases.
  • 1Adlay seed is the dry mature seed kernel of Coix lacryma-jobi L., a gramineous plant. It belongs to the classification of diuresis and detumescence drugs; it belongs to the spleen, stomach and lung meridian; it can divert water and soak dampness, invigorate the spleen and relieve diarrhea, eliminate arthralgia, drain pus, detoxify and dispel stagnation.
  • 2Poria cocos is the dried sclerotia of Poria cocos (Schw.), a fungus of the family Polyporiaceae. It belongs to the classification of diuresis and swelling drugs; to the heart, lung, spleen and kidney meridian; diuresis and dampness, invigorating the spleen, calming the heart and tranquilizing the mind.
  • 3Yam (Dioscorea oppositifolia L.) is the dry rhizome of Dioscorea zingiberensis. It belongs to the classification of qi-tonifying drugs; it belongs to the spleen, lung and kidney meridian; it replenishes qi and nourishes yin, replenishes the spleen, lung and kidney, and astringents the essence.
  • Gorgon is the dry mature seed kernel of Euryale ferox Salisb. It belongs to the classification of solid essence, shrinking urine and stop band medicine; belongs to the spleen and kidney heart meridian; can nourish the spleen and stop diarrhea, stop band, nourish the heart and calm the mind.
  • 5Nelumbinis Plumula is the mature seed of the lotus plant of the Nymphaeaceae family. It belongs to the medicine for strengthening essence and reducing urine; returning to the spleen and kidney heart meridian; replenishing the spleen and stopping diarrhea, stopping the belt, replenishing the kidney and astringent essence, nourishing the heart and calming the nerves.
  • 6Endothelium corneum is the inner wall of the dry sand sac of Gallus gallus domesticus Brisson. It belongs to the classification of digestive medicines; sweet returns to the spleen, stomach, small intestine, and bladder meridian; can invigorate the stomach and digest, relieve the essence and stop the congestion, and clear the fossils.
  • Pueraria lobata the dried root of the leguminous plant Pueraria lobata. It belongs to the classification of antiseptic drugs; it belongs to the spleen, stomach and lung meridian; it can relieve muscles and reduce fever, promote body fluids to quench thirst, permeate rash, promote yang and relieve diarrhea, clear meridians, activate collaterals, relieve alcohol and poison.
  • 8Cinnamomum cassia is the dried bark of Lauraceae plant cinnamon. It has the effects of invigorating the fire and assisting the yang, guiding the fire and returning to the yuan, dispelling cold and relieving pain, and warming the meridians. It is used for impotence, uterine cold, cold pain in waist and knees, kidney deficiency as asthma, floating yang, dizziness, redness of the eyes, cold pain in the heart and abdomen, vomiting and diarrhea, cold hernia, abdominal pain, dysmenorrhea and amenorrhea.
  • 9Medicated Leaven is a mixture of flour or bran, almond paste, red bean flour, and natural juice of fresh artemisia annua, fresh cocklebur, and fresh spicy Polygonum vulgare. Mix well to make it dry and wet.
  • hemp leaves or chub leaves keep warm and ferment for a week, take out when yellow mycelium grows, cut into small pieces, and dry in the sun.
  • Raw or stir-fried Digestion and stomach. Indications of food stagnation, abdominal distension, less food and anorexia.
  • 10Paeonia lactiflora is the root of the ranunculaceae plant Paeonia lactiflora. It belongs to the classification of yang medicine; belongs to the liver and spleen meridian; it can nourish blood and regulate menstruation, suppress yin and stop sweating, soften the liver and relieve pain, and suppress liver yang.
  • the ancient medicine white peony and red peony are collectively referred to as peony, which nourishes yin, nourishes blood, softens the liver, and uses raw white peony; stir-fried white peony with wine for moderate and emergency; stir-fried white peony with soil for spleen and antidiarrheal. Therefore, peony, especially Radix Paeoniae Alba, can induce qi and blood downward and supplement Yin and blood, which is the first choice for lowering blood sugar.
  • the traditional Chinese medicine increase and decrease prescription disclosed in the present invention is used to prevent or treat metabolic syndrome disease and its complications, has no toxic side effects, is safe and effective.
  • the inventor has completed the present invention by verifying the following contents through perennial clinical applications and rigorous animal experiments:
  • the formula has the effects of reducing weight, lowering blood sugar, and kidney and eye treatment; at the same time, in clinical application, clinical results also confirmed that this formula can successfully prevent or treat metabolic syndrome and its complications. Including insulin resistance syndrome, diabetes and diabetic complications, hyperlipidemia, fatty liver disease, obesity, atherosclerosis, arteriosclerosis and hypertension and other metabolic disorders and their complications.
  • the purpose of the present invention is to provide effective prevention or treatment of various metabolic disorders and their complications such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, obesity, atherosclerosis, arteriosclerosis, and hypertension.
  • the product contains the traditional Chinese medicine increasing or decreasing prescription as the main ingredient.
  • the present invention provides the prevention or treatment of various metabolic disorders and their complications such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, obesity, atherosclerosis, arteriosclerosis and hypertension.
  • An effective pharmaceutical composition is provided.
  • the present invention provides preparations of effective pharmaceutical compositions for various metabolic disorders such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, obesity, atherosclerosis, arteriosclerosis and hypertension, and their complications Methods, including the preparation of several dosage forms.
  • the present invention also provides effective drugs for preventing or treating various metabolic disorders and their complications such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, obesity, atherosclerosis, arteriosclerosis, and hypertension.
  • various metabolic disorders and their complications such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, obesity, atherosclerosis, arteriosclerosis, and hypertension.
  • the purpose of the combination is not limited to, diabetes, hyperlipidemia, fatty liver disease, obesity, atherosclerosis, arteriosclerosis, and hypertension.
  • the present invention also provides effective functions for preventing or treating various metabolic disorders such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, obesity, atherosclerosis, arteriosclerosis and hypertension, and their complications. Food or health product composition.
  • the present invention also provides effective functions for preventing or treating various metabolic disorders such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, obesity, atherosclerosis, arteriosclerosis and hypertension, and their complications.
  • Method for preparing food or health product composition is also provided.
  • the present invention also provides effective functions for preventing or treating various metabolic disorders such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, obesity, atherosclerosis, arteriosclerosis and hypertension, and their complications. Use of food or health product combinations.
  • the present invention also provides a veterinary medicine effective in preventing or treating various metabolic disorders such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, obesity, atherosclerosis, arteriosclerosis and hypertension, and their complications , Animal health products, feed or feed additives.
  • various metabolic disorders such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, obesity, atherosclerosis, arteriosclerosis and hypertension, and their complications , Animal health products, feed or feed additives.
  • the present invention also provides a veterinary medicine effective in preventing or treating various metabolic disorders such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, obesity, atherosclerosis, arteriosclerosis and hypertension, and their complications , Preparation method of animal health products, feed or feed additive composition.
  • various metabolic disorders such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, obesity, atherosclerosis, arteriosclerosis and hypertension, and their complications , Preparation method of animal health products, feed or feed additive composition.
  • the present invention also provides a veterinary medicine effective in preventing or treating various metabolic disorders such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, obesity, atherosclerosis, arteriosclerosis and hypertension, and their complications , Animal health products, feed or feed additives.
  • various metabolic disorders such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, obesity, atherosclerosis, arteriosclerosis and hypertension, and their complications , Animal health products, feed or feed additives.
  • the present invention also provides effective methods for preventing or treating various metabolic disorders such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, obesity, atherosclerosis, arteriosclerosis and hypertension, and their complications
  • the method is as follows: administering a pharmaceutically effective dose of the composition to an animal suffering from diabetes or obesity.
  • the present invention also provides effective methods for preventing or treating various metabolic disorders such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, obesity, atherosclerosis, arteriosclerosis and hypertension, and their complications
  • the method includes the following steps: to prevent or suffer from various metabolic disorders such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, obesity, atherosclerosis, arteriosclerosis and hypertension and other Subjects with complications are given a pharmaceutically effective dose of the composition.
  • the invention discloses a traditional Chinese medicine increase and decrease prescription for preventing and/or treating metabolic disorder syndrome and its complications, including: Poria coix, Coix seed, Chinese yam, Gorgon and lotus seed.
  • the traditional Chinese medicine increase or decrease prescription includes any one or any combination of Gallus gallus domesticus, Cinnamon, Shenqu, Pueraria lobata or Peony;
  • the paeoniflorin may contain paeoniflorin, paeoniflorin, hydroxypaeoniflorin, oxypaeoniflorin, benzoylpaeoniflorin, new paeoniflorin, paeonol, paeonol protoglycoside, paeonol glycoside Or replaced by any one or combination of paeoniflorin plants;
  • the Gallus gallus domesticus can be replaced by one or a combination of hawthorn, raspberry seeds, malt, rice sprouts, divine yeast, protease, or other components that can help digestion or enrich blood;
  • the protease includes but is not limited to pepsin and trypsin;
  • the protease includes, but is not limited to, protease hydrolysate, protease polypeptide, or other enzymes or polypeptides that can help digestion or enrich blood.
  • the weight of any one of the ingredients is 1-100g;
  • the weight of any one component is 1-20 g.
  • each dose of the traditional Chinese medicine increase or decrease prescription includes 10 g each of Chinese yam, Gorgon, Poria cocos, lotus seed, coix seed, cinnamon and kudzu root, and 15 g of Gallus gallus domesticus.
  • each dose of the traditional Chinese medicine increase or decrease prescription includes 10 g each of Chinese yam, Gorgon, Poria cocos, lotus seed, Coix seed and Gallus gallus domesticus.
  • the traditional Chinese medicine increase or decrease prescription further includes auxiliary materials
  • the auxiliary material includes sugar and dextrin.
  • the weight ratio of the sugar and dextrin is 2:1.
  • adjuvants of the present invention are not limited to sugars and dextrins, and those skilled in the art can choose any suitable adjuvants to complete the present invention, and they are all within the protection scope of the present invention.
  • the weight ratio of the Poria, Coix Seed, Chinese Yam, Gorgon and Lotus Seed is 1:1:1:1:1.
  • the weight ratio of the Poria, Coix Seed, Yam, Gorgon, and Lotus Seed is not limited to 1:1:1:1:1:1, and those skilled in the art can choose any suitable ratio to complete the present invention, and all of them are in the present invention. Within the scope of protection of the invention.
  • the second aspect of the present invention discloses a product, which includes the above-mentioned traditional Chinese medicine increase or decrease prescription;
  • the product is medicine, health care product, food, feed or feed additive.
  • the medicines and health products are applied to humans.
  • the dosage form of the product includes: powder, paste, granule, pill, tablet, capsule, granule, ointment, decoction or injection.
  • the product includes: pulverized raw material components, water extract, organic solvent extract, and raw material extraction residue; the pulverized raw material components include active monomers or monomer mixtures in plant components.
  • the third aspect of the present invention provides a method for preparing the above-mentioned product.
  • the preparation method of the powder is as follows: all the ingredients in the product are processed, pulverized, and mixed to obtain a powder; wherein, the processing steps, The order of the pulverization process and the mixing process can be interchanged arbitrarily.
  • the decoction is prepared by a conventional preparation method, and the preparation method of the ointment is: after the decoction is obtained, the decoction is concentrated into an extract to prepare the ointment.
  • the decoction is heated to evaporate and concentrated to form an extract.
  • the decoction is concentrated into an extract, dried and crushed, and any one of the following steps is selected:
  • Granules and granules are obtained by granulation.
  • the composition of veterinary drugs, animal health products, feed or feed additives can be extracted from raw materials such as human drugs, human health products, food, etc.
  • the residue after the production and extraction is reprocessed, extracted or fermented Become.
  • the fourth aspect of the present invention discloses the following applications:
  • the metabolic disorder syndrome includes insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, obesity, atherosclerosis, arteriosclerosis and hypertension.
  • the present invention has the following significant advantages and effects:
  • the present invention discloses a method that can be used to prevent or treat various metabolic disorders and their complications such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, obesity, atherosclerosis, arteriosclerosis and hypertension
  • various metabolic disorders and their complications such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, obesity, atherosclerosis, arteriosclerosis and hypertension
  • the effective traditional Chinese medicine increase and decrease prescriptions are confirmed by animal experiments and clinical experiment results that the medicine of the present invention has the following advantages:
  • the drug of the present invention can effectively alleviate various metabolic disorders and their complications such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, obesity, atherosclerosis, arteriosclerosis and hypertension, and diabetes Complications include diabetic nephropathy, eye disease, liver disease, peripheral neuropathy and other related complications.
  • the composition of the present invention has a significant synergistic effect in the treatment of diabetes, not only can significantly improve the symptoms of diabetes and its complications, but also delay the development of diabetes, reduce the occurrence of complications, and can Prevent, improve or treat metabolic syndrome and other indicators of its complications.
  • the composition of the present invention is a food-derived ingredient, with simple additions and reductions in ingredients and no toxic side effects, intolerance, adverse reactions and side effects to the human body Significantly reduced.
  • the traditional Chinese medicine can be taken for a long time, depending on the condition of the disease. It can have different effects. It will not cause blood sugar, blood pressure or other indicators to drop below the normal value or toxic reaction due to excessive doses, which is for patients with metabolic syndrome. Brought the gospel.
  • the traditional Chinese medicine composition of the present invention contains a variety of drug components, has many targets, has better therapeutic effect, prevents, improves and treats various indicators of patients with metabolic syndrome, improves the medication compliance of patients with metabolic syndrome, and Improve the quality of life of patients.
  • Figure 1 is a comparison diagram of the effect on the body weight of the diabetic animal model in the embodiment of the present invention.
  • Fig. 2 is a comparative diagram of the influence of the invention on the glycosylated hemoglobin HbA1c (%) in a diabetic animal model.
  • Fig. 3 is a comparative diagram of the influence of the invention on the 24-hour urine albumin quantification (mg/DL) of a diabetes animal model UTP.
  • Fig. 4 is a comparative diagram of the invention's influence on ALB urine albumin (g/L) in an animal model of diabetes.
  • Figure 5 is a comparative diagram of the invention's effect on mALB urine albumin (g/L) in an animal model of diabetes.
  • Fig. 6 is a comparative diagram of the invention's effect on CRE*20 urine creatinine ( ⁇ mol/L) in a diabetic animal model.
  • the present invention provides effective prevention and/or treatment of various metabolic disorders and their complications such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, obesity, atherosclerosis, arteriosclerosis, and hypertension.
  • a pharmaceutical composition which is an increase or decrease formula of several drugs.
  • the present invention also provides effective prevention and/or treatment of various metabolic disorders and their complications such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, obesity, atherosclerosis, arteriosclerosis and hypertension.
  • the pharmaceutical composition is a method for extracting several medicines.
  • the present invention also provides effective prevention and/or treatment of various metabolic disorders and their complications such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, obesity, atherosclerosis, arteriosclerosis and hypertension.
  • the pharmaceutical composition is the use of the increase or decrease of several drugs.
  • the diabetic complications are preferably a combination of the following complications, but not limited to: diabetic retinopathy, diabetic cataract, diabetic liver disease, diabetic nephropathy, diabetic neuropathy, heart disease, cancer, bone Porosity, atherosclerosis, and Alzheimer's disease.
  • Diabetes complications are symptoms that develop when diabetes lasts for a long time.
  • the drugs used in this formula to treat diabetic complications are the same as diabetes.
  • the order of the processing step, the crushing step and the mixing step may not be limited. Among them, all the ingredients in the product are processed.
  • the filtered extract obtained in step 2 is concentrated and then dried.
  • the dry extract in step 3 is a granular preparation or tablet preparation.
  • step 1 the traditional Chinese medicine ingredients in step 1 are purchased in Tongrentang pharmacy.
  • the extraction solvent herein is water, alcohol or a mixture thereof.
  • the alcohol is preferably a C1-C4 lower alcohol.
  • the extraction method herein is one of the conventional methods accepted in the art, such as filtration, cold soak extraction, hot water extraction, reflux extraction and ultrasonic extraction. Hot water extraction is preferred herein.
  • the extraction is preferably repeated 1-5 times, more preferably twice, but is not limited thereto.
  • the extraction solvent is added to the dried medicinal materials at a ratio of 1-10 times, more preferably 3 times the volume of the dried medicinal material mixture.
  • the extraction temperature is preferably but not limited to boiling water extraction.
  • the extraction time is preferably but not limited to 1 h to 4 h.
  • test animal herein is a vertebrate, preferably a mammal, more preferably a test animal (e.g., mouse, rat, rabbit, guinea pig, hamster, dog, and cat), and most preferably ape (e.g., chimpanzee and gorilla).
  • a test animal e.g., mouse, rat, rabbit, guinea pig, hamster, dog, and cat
  • ape e.g., chimpanzee and gorilla
  • test animal herein is a mouse, preferably a BKS.Cg-Dock7m+/+Leprdb/J mouse (abbreviated as db/db mouse) of SPF grade for the prevention and treatment of type II diabetes animal model.
  • db/db mouse BKS.Cg-Dock7m+/+Leprdb/J mouse
  • the pharmaceutical composition of the present invention may contain the Chinese medicine mixture extract or its part as an active ingredient at a concentration of 0.1 wt% to 99.9 wt%. Any pharmaceutically acceptable carrier, excipient or diluent can be added to the composition.
  • the composition of the present invention can be prepared for oral administration or parenteral administration, such as fillers and extenders. , Binders, wetting agents, disintegrating agents and surfactants.
  • Solid preparations for oral administration are tablets, pills, powders, granules and capsules. These solid preparations are prepared by mixing the pharmaceutical ingredients with one or more suitable excipients, such as starch, calcium carbonate, sucrose or lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate, talc and the like can also be used.
  • Liquid preparations for oral administration are suspensions, solutions, emulsions, syrups; in addition to commonly used simple diluents, such as water and liquid paraffin, the above-mentioned preparations can contain various excipients, such as wetting agents, sweeteners, Fragrances and preservatives.
  • the preparations for parenteral administration are sterile aqueous solutions, water-insoluble excipients, suspensions, emulsions, freeze-dried preparations and suppositories.
  • water-insoluble excipients and suspending agents may include propylene glycol, polyethylene glycol, vegetable oils (such as olive oil), injectable esters (such as ethyl oleate), and the like.
  • suppositories may contain Witepsol, macrogol (macrogo1), tween, cocoa butter, laurin butter, glycerin gelatin, and the like.
  • composition of the present invention can be administered orally or parenterally.
  • the composition of the present invention can be administered by means of external application, intraperitoneal injection, intrarectal injection, intravenous injection, intramuscular injection, subcutaneous injection, intrauterine injection or intracerebroventricular injection. More preferably, the composition is administered by external application.
  • the effective dose of the composition of the present invention can be determined according to body weight, age, sex, health status, diet, frequency of administration, method of administration, excretion and severity of disease.
  • the dosage of the Chinese medicine composition extract is 0.01 mg/kg to 2000 mg/kg, preferably 30 mg/kg to 1000 mg/kg per day.
  • the frequency of administration is once a day, or preferably 1-6 times a day.
  • composition of the present invention can be administered alone or used in combination with other methods such as surgery, radiation therapy, hormone therapy, chemotherapy, and biological modulators.
  • Fasting blood glucose refers to the blood glucose level in the basal state. It is an important criterion for diagnosing diabetes and reflects the basic function of pancreatic islet B cells. Oral glucose tolerance test is to test the fasting blood glucose of the animal after fasting, then give the drug, give the glucose solution by gavage at the corresponding time point, and measure the blood glucose before and 30min, 60min and 120min after glucose.
  • the blood glucose test value 2 hours after a meal is the most valuable and can reflect the reserve function of pancreatic islet B cells. Choose to measure blood glucose after the animal has eaten.
  • Glycated hemoglobin is the product of the combination of hemoglobin in red blood cells and sugars in serum. It is formed by a slow, continuous and irreversible glycation reaction, and its content depends on the blood glucose concentration and the contact time between blood glucose and hemoglobin, and has nothing to do with the time of blood draw, whether the patient is fasting, whether to use insulin or other factors. Therefore, GHb can effectively reflect the blood sugar control of diabetic patients in the past 1-2 months.
  • Detection method After the animal is fasted, 20 ⁇ L of whole blood is collected and placed in an EP tube containing HbA1c diluent, and the HbA1c content is detected by an automatic analyzer.
  • the specific method refers to the kit instructions.
  • the present invention also provides a combination of drugs for the prevention and/or treatment of metabolic syndrome and its complications and a preparation method, the method including the preparation of the drug and administering pharmacologically to subjects suffering from metabolic syndrome and its complications.
  • the metabolic syndrome is preferably selected from a combination of the following complications, but is not limited to these: such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, obesity, atherosclerosis, arteriosclerosis And hypertension and other metabolic disorders.
  • the present invention can also be used as a health product or food to prevent and improve metabolic syndrome and its complications.
  • the patent includes drug combinations and preparation methods, which include product preparation and The step of administering a pharmaceutically effective dose of a composition containing a Chinese medicine extract or its part as an active ingredient to a subject suffering from metabolic syndrome and its complications.
  • the metabolic syndrome is preferably selected from the group consisting of, but not limited to, the following complications: such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver disease, obesity, atherosclerosis, arteriosclerosis and Various metabolic disorders such as hypertension.
  • the health functional food of the present invention may additionally contain various flavoring agents, additives or excipients.
  • the food can be in the form of bread, biscuits, noodles, chewing sticks and other daily foods.
  • the invention also provides veterinary drugs, animal health products, feeds and feed additives for preventing and improving metabolic syndrome and its complications.
  • the animal experiments and clinical experiments carried out by the present invention have effectively proved its curative effect on metabolic syndrome and its complications. Therefore, the present invention can be effectively used to produce products for preventing and treating metabolic syndrome and its complications.
  • the dosage can be selected from the human body dose to 6-12 times the human body dose.
  • the feed additive of the present invention may additionally include carriers generally accepted in this field for pets, poultry and livestock.
  • feed additives can be used alone or together with other acceptable carriers and stabilizers. If necessary, nutrients (such as vitamins, amino acids and minerals) or other additives (such as antioxidants, antibiotics, Antimicrobial agents, etc.).
  • nutrients such as vitamins, amino acids and minerals
  • other additives such as antioxidants, antibiotics, Antimicrobial agents, etc.
  • the feed additive can be formulated into powder, granule, pill and suspension form. When supplied to poultry and livestock, the feed additive of the present invention can be administered alone or mixed with feed.
  • the Chinese medicine materials were all purchased from Tongrentang Pharmacy. The materials were processed and proportioned. They were crushed with a Chinese medicine grinder. The particles were passed through a steel sieve with a diameter of 160 microns. The particles that were not sufficiently fine were repeatedly sieved until the particle sizes were all consistent.
  • Chinese medicine materials are all purchased from Tongrentang Pharmacy. The materials are prepared according to the proportions, and excess cold water is added to them. After boiling, they continue to decoct on a low fire. The two decoction methods are used to mix the two decoctions to obtain the water for Chinese medicine. Extraction solution.
  • the Chinese medicine materials were all purchased from Tongrentang Pharmacy, and the materials were prepared according to the proportion after being processed, and crushed with a Chinese medicine pulverizer, and 80% ethanol was added to them. Put the prepared sample into an extraction container, and repeat the extraction at room temperature. The extract was filtered and concentrated under reduced pressure. The operating temperature is maintained at 40°C to 45°C to prevent decomposition and hydrolysis of ingredients.
  • the extract preparation was performed in the same manner as described in 3) above, except that methanol was used instead of ethanol.
  • mice SPF-level BKS.Cg-Dock7m+/+Leprdb/J mice (db/db mice for short) were selected for hypoglycemic experiment verification. Free feed and water supply. The mice were divided into 4 groups (4 mice in each group), and the mice were given oral gavage once a day. The experiment included the control group NOR, the metformin group (350mg/kg) treated diabetes group MET, the low dose (6mg/kg) drug group of the present invention drug treated diabetes group RX-6 and the present invention drug high dose (12mg/kg) kg) RX-12 in the diabetes group treated by the drug group. The test samples were orally administered to each group once a day until the 4th week. After 4 weeks, urine was collected and blood was taken.
  • the drugs in the drug group include Poria, Coix Seed, Chinese Yam, Gorgon, Lotus Seed, Gallus gallus, and Peony.
  • the preparation method is Poria, Coix Seed, Yam, Gorgon, Lotus Seed, Gallus gallus, and Peony.
  • the ratio is 1:1:1:1:1:1:1:2 to prepare the powder.
  • the obtained powder is diluted in a certain proportion to obtain the low-dose (6mg/kg) drug group RX-6 and the high-dose (12mg/kg) drug group RX-12.
  • Animals are kept in breeding boxes of suitable specifications and kept in single cages. In the SPF animal room, the environmental conditions are controlled at room temperature 20-26°C, relative humidity 40%-70%, light and dark alternately for 12 hours.
  • a qualified testing unit will determine the nutrient components (main testing components: crude protein, crude fat, crude fiber, moisture, calcium, total phosphorus, crude ash) and physical and chemical indicators (main testing indicators: arsenic, lead, Mercury, cadmium, BHC, DDT, and aflatoxin B1) were tested.
  • the person in charge of the animal experiment department or the designated person shall ensure that there are no pollutants that affect or interfere with the test results.
  • the evaluation of test results refers to the national standards GB14924.2-2001 and GB14924.3-2010.
  • the litter is made of wood shavings and is specially tested for autoclaving.
  • Pollutants main testing indicators: arsenic, lead, mercury, cadmium, BHC, DDT, aflatoxin B1 are tested once a year, and a qualified unit is entrusted to conduct testing.
  • Microbiological inspection main test indicators: total number of colonies, visible objects is carried out once a month.
  • Dosing volume 10mL/kg. Determine the dosing volume of each animal based on the last weighed weight of each animal.
  • Dosing frequency once a day for 4 weeks (fasting for about 4 hours before dosing).
  • Observation content including animal mental state, behavioral activities, food intake, etc.
  • the body weight was measured twice a week after the drug.
  • the postprandial blood glucose level of the positive control group MET was lower than the negative control group NOR after taking the drug for 2 days; the blood glucose level of the high-dose group RX-12 and the low-dose group RX-6 gradually decreased, and It was lower than the NOR of the negative control group on the 15th day of dosing (data not shown).
  • the glycated hemoglobin value of NOR in the negative control group is 8.85%, and the positive control group MET (6%) and the high-dose group RX-12 (6.43%) compared with the negative control group NOR (8.85%) Significant difference; while the low-dose group RX-6 (7.50%) is 1.35% lower than the negative control group, there is no significant difference.
  • This part of the experiment confirmed the hypoglycemic effect of the invention through the detection of three indicators (fasting blood glucose level, non-fasting blood glucose level and glycosylated hemoglobin).
  • the fasting blood glucose level and the non-fasting blood glucose level were measured at different time points (fasting blood glucose level: D2, D7, D15 before grouping and after administration; non-fasting blood glucose level: 24h, D4, D4, D4, D4, D4, D7, D15, D21), the fasting blood glucose level of the invention drug on the 15th day and the non-fasting level on the 7th day were lower than the negative control value, and gradually decreased; and after 29 days of administration, the high dose
  • the glycosylated hemoglobin value of group RX-12 (6.43%) was significantly lower than that of the negative control group NOR (8.85%).
  • the overnight urine was collected in a metabolic cage, placed on crushed ice, and tested for urine total protein, urine albumin, urine microalbumin, and urine creatinine.
  • the detection time is the 29th day after administration.
  • the 24-hour urine protein quantitative test refers to a urine test method that collects all urine excreted within 24 hours for qualitative testing.
  • Albumin is a normal protein in the blood, accounting for 60% of the total plasma protein, negatively charged, with a molecular weight of 69KD and a radius of 3.6nm.
  • Normal glomerular basement membrane has a filtering function, with an average pore size of 5.5nm, and a uniform layer of negative charge on the surface.
  • ALB Albuminuria
  • albuminuria is a pathological condition in which serum albumin is present in urine. It is one of the types of proteinuria.
  • the value of ALB urine albumin content is shown in Figure 4.
  • the ALB urine albumin content (0.1g/L) of the high-dose group RX-12 was significantly lower than that of the negative control group NOR (0.3g/L) and the positive control group MET (0.25g /L) and RX-6 (0.33g/L) ALB urine albumin content.
  • the results show that the drug of the present invention can significantly reduce the ALB urine albumin of mice after 29 days of breeding.
  • Microalbuminuria refers to the appearance of microalbumin in the urine.
  • Microalbumin microalbunminuria, mAlb
  • mAlb urine microalbumin refers to the presence of microalbumin in urine. It is currently believed that the measurement of urine microalbumin can reflect early kidney disease and kidney damage.
  • the value of mAlb urine microalbumin content is shown in Figure 5.
  • the mAlb urine microalbumin content (7.37 mg/L) of the high-dose drug group RX-12 is lower than the negative control group NOR (20.10 mg/L) and the positive control group MET ( 8.50mg/L) and RX-6 (15.70mg/L).
  • the results show that the medicament of the present invention can reduce the urine microalbumin content of mAlb in mice after 29 days of breeding.
  • Urinary creatinine mainly comes from the creatinine excreted in urine after blood is filtered by the glomerulus.
  • the urinary creatinine in the urine of the high-dose group RX-12 was 5.5 ⁇ moI/L lower than the negative control group NOR mice, while the positive control group MET was lower than the negative control group NOR Increase by 10.5 ⁇ moI/L.
  • the results of the urine creatinine experiment part proved that the drug of the present invention can significantly reduce the urine creatinine value of mice after 29 days of feeding.
  • This part of the experiment designed a comparative experiment of the invention drug in mouse body weight, blood sugar, kidney index and positive control drug and negative control.
  • the experimental results confirmed that compared with the positive control drug metformin: the drug of the present invention can significantly reduce the weight of mice, mildly and significantly reduce the blood glucose index, and reduce the series of kidney detection indexes through 4 weeks of feeding. From the results, it can be judged that the present invention has the therapeutic effects of lowering blood lipids, lowering blood sugar, and restoring kidney damage, and it can be inferred that the present invention can prevent, improve or treat complications such as retinal microangiopathy, and can prevent, improve or treat metabolic syndrome and Other indicators of its complications.
  • Indexes included in the group include: age, time of illness, medication history, blood sugar level, vision, diabetic foot, kidney disease, fatty liver, blood pressure and other indicators.
  • the entry age should be ⁇ 18 years old and ⁇ 75 years old.
  • hypoglycemia ⁇ 3.9mmol /L
  • hyperglycemia ⁇ 16.7mmol/L
  • Severe hypertension patients who cannot be controlled/untreated after treatment (systolic blood pressure ⁇ 180mmHg and/or diastolic blood pressure ⁇ 110mmHg) need to be combined with other traditional Chinese medicine treatments and are temporarily not included in the statistical group;
  • diabetic patients were screened out, of which 51 patients who continued to take medication were followed up. Among them, 32 were male patients and 20 were female patients; they were 20-75 years old, with an average of 52.17 years old. There were 20 patients with hypertension; 19 patients with nephropathy; 20 patients with hyperlipidemia; 18 patients with diabetic eye disease; 14 patients with diabetic peripheral neuropathy.
  • Patients in the treatment group took the traditional Chinese medicine preparation of the present invention, and adults took orally twice a day, 10-30g each time, 90 days as a course of treatment.
  • ADA American Diabetes Association
  • FPG fasting blood glucose
  • OGTT 75g oral glucose tolerance test
  • random blood glucose 200mg/DL (11.1mmol/L) or higher
  • glycosylated hemoglobin The (HbA1c) level is 6.5% or higher.
  • the guidelines for high blood pressure are as follows: clinic blood pressure measurement value 140/90mmHg, family blood pressure measurement value HBPM135/85mmHg, daytime ambulatory blood pressure monitoring value ABPM135/85mmHg, Night ambulatory blood pressure monitoring value ABPM120/70mmHg and 24-hour ambulatory blood pressure monitoring value ABPM130/80mmHg (Melvyn Rubenfire, MD, FACC, 2018).
  • the diagnostic criteria for nephropathy are as follows:
  • Persistent proteinuria (>300mg/24h or >200 ⁇ g/min) is a clinical syndrome characterized by at least 2 diagnoses with an interval of 3-6 months (Vecihi Batuman, MD, 2019).
  • the urinary protein excretion rate does not reach the effective standard or has increased inversely, and the TCM symptom grading score and the treatment decrease are less than 1/3.
  • Diabetic peripheral neuropathy (diabetic peripheral neuropathy, DPN) is highly insidious. More than 50% of patients have no clinical symptoms. The degree of pathology is often inconsistent with the appearance and severity of symptoms. It is a high risk factor for amputation caused by foot ulcers and gangrene. The Michigan Diabetic Neuropathy Score (MD) was used to score peripheral neuropathy.
  • MD Diabetic Neuropathy Score
  • Medication and duration of illness In 2017, he was diagnosed with diabetes, and his pre-meal blood sugar was 17mmol/L. No other treatment was taken, and the formula disclosed in this example was taken in February 2017.
  • Medication record The patient's blood sugar dropped to normal after taking it for more than one month. After 6 months of intermittent medication for consolidation. The condition has not been repeated for 2 years.
  • Subject B Male (44 years old)
  • Medication and time of illness Diabetes was diagnosed in 2016, blood sugar before meals was 12mmol/L, metformin was taken 2 times a day, 1 tablet (0.5g) each time, and many times of Chinese medicine treatments were not effective.
  • the formula disclosed in this example was started in December 2017.
  • Medication record The patient's symptoms improved ten days after taking the medicine, and his blood sugar dropped to 5.7mmol/L one month later. The condition has not been repeated so far.
  • Subject C Female (66 years old)
  • Dosage 30g each on an empty stomach before breakfast and dinner.
  • Medication and duration of illness 25 years of diabetes history, daily injection of 32 units of insulin, 3 tablets of metformin (0.5g each); blood sugar maintained at 8-12mmol/L.
  • Medication record 2 months before taking the medicine, the patient's physical conditions such as blurred vision, poor sleep, and lower limb inconvenience alleviated, but there was basically no change in blood sugar.
  • blood sugar began to drop steadily to 6mmol/L.
  • reduce insulin by two units per day, and then reduce by one unit per day until all of them are stopped, and the blood sugar value is 14mmol/L. Continue taking until the blood sugar gradually drops to normal.
  • Subject D Female (57 years old)
  • Dosage 30g each on an empty stomach before breakfast and dinner.
  • Medication and duration of illness Hypertension has been ill for more than 30 years, taking 1 tablet (80mg) of mecaxine a day; and in 2016, the pre-meal blood glucose was 7.0 mmol/L, post-meal blood glucose 9.6 mmol/L, and glycosylated hemoglobin 6.7 %; For patients with pre-diabetes with double high type. No other treatment was taken, and the formula disclosed in this example was taken.
  • Medication record One week after taking the Chinese medicine formula in this example, the eye discomfort disappeared, the food intake was normal, and the sleep was normal. After taking it for 1 month, the pre-meal blood sugar dropped to 5.9mmol/L. After taking the traditional Chinese medicine formula in this example for 3 months, it was changed to take one after another. The condition has not been repeated for 3 years. The blood pressure dropped to a normal value and no blood pressure lowering drugs were taken.
  • Subject E Female (42 years old)
  • Dosage 30g each on an empty stomach before breakfast and dinner.
  • Medication and duration of illness Diabetes has been diagnosed for 10 years, and metformin is taken twice a day, one tablet (0.5g) once, and urine protein is 150mg/DL. Take the formula disclosed in this example.
  • Medication record 1 month after taking the traditional Chinese medicine formula in this example, urine protein dropped to 11 mg/DL, and the amount of western medicine was halved. After that, he continued to take Chinese medicine for 6 months, until all western medicine was cancelled and blood sugar returned to normal.
  • Dosage 30g each on an empty stomach before breakfast and dinner.
  • Medication and duration of illness Diabetes has been diagnosed for 15 years. Metformin was taken twice a day, 2 tablets (0.5g) at a time, acarbose 3 times, one tablet (50mg) at a time; urine protein was 100mg/DL.
  • Medication record 2 months after taking the traditional Chinese medicine formula in this example, urine protein dropped to 20 mg/DL, no foaming during urination, and the dosage of western medicine was halved. Continue to take Chinese medicine for 3 months until the blood sugar returns to normal.
  • Dosage 30g each on an empty stomach before breakfast and dinner.
  • Medication and duration of illness Diabetes for more than 20 years, daily insulin injection, pre-meal blood sugar 10.1mmol/L, cold feet and calves, dark spots, Michigan diabetic peripheral neuropathy score of 25, will be notified by the hospital Amputated half a year later. No other treatment was taken, and the formula disclosed in this example was taken in February 2017. .
  • Medication record After taking the Chinese medicine formula in this example for 3 months, the symptoms of diabetic foot disappeared, and continued taking it for 6 months until the color of the legs and feet recovered and the feeling of wearing boots disappeared.
  • the drug of the present invention can effectively relieve related complications including diabetic nephropathy, eye disease, liver disease, peripheral neuropathy and the like.
  • the composition of the present invention has a significant synergistic effect in the treatment of diabetes, not only can significantly improve the symptoms of diabetes, but also delay the development of diabetes and reduce the occurrence of complications.
  • the composition of the present invention is a food-derived ingredient, which significantly reduces adverse reactions and side effects, improves the medication compliance of diabetic patients, and improves the quality of life of patients .
  • Existing diabetes treatment drugs have a good therapeutic effect in the initial stage of diabetes, but with the extension of the treatment time, obvious drug tolerance problems appear, and the treatment effect of diabetes decreases.
  • the traditional Chinese medicine composition of the present invention contains a variety of drug components, has many targets, and the composition of the present invention has a comprehensive effect and a better therapeutic effect. It prevents, improves and treats various indicators of patients with metabolic syndrome and its complications. It effectively solves the tolerance problem of diabetes treatment drugs, and its treatment effect on diabetes does not decrease due to prolonged treatment time.
  • a tablet is prepared by mixing all the above-mentioned components.
  • a pill is prepared by mixing all the above components.
  • the food containing the extract of the present invention is prepared as described below.
  • flour mixtures are used to prepare pasta foods, such as bread, cakes, biscuits, crepes, noodles, chewing sticks, and the like.
  • milk mixtures are used to prepare health-promoting dairy products such as butter and ice cream.
  • Coarse grains such as quinoa, barley, glutinous rice, black sesame seeds are fried, gelatinized, dried and crushed to obtain 60 mesh powder in accordance with conventional methods.
  • Example ⁇ 1-2> The water extract of Example ⁇ 1-2> was concentrated under reduced pressure, spray-dried and pulverized to obtain 60 mesh dry powder. The coarse grains and the dry powder of the water extract of Example ⁇ 1-2> were mixed to prepare supplementary food.
  • the tea leaves are leached at high temperature, filtered and then mixed with the following ingredients, canned, sealed, and sterilized.
  • Vitamin C 0.5g
  • Soy protein 10g Soy protein 10g
  • the extract or its part of the present invention is a natural product, and is effective in preventing, treating or delaying metabolic syndrome and its complications; therefore, the present invention can be used in medicine to prevent or delay metabolic syndrome. , Improve the body's immunity, and be used in the production of health products, health functional foods or as functional feeds or feed additives.

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Abstract

一种可用于预防/治疗代谢综合征和其并发症的中药增减方。该中药增减方包括：茯苓、薏苡仁、山药、芡实和莲子，其可用于预防和/或治疗诸如胰岛素抵抗综合征、糖尿病、高脂血症、脂肪性肝病、肥胖症、动脉粥样硬化、动脉硬化和高血压等各种代谢紊乱综合征和其并发症，该中药增减方成分简单且对人体无毒副作用，无耐受性。该中药增减方可长期服用，根据病情酌情加减，可以起到不同的效果，不会因为剂量过大而导致血糖、血压等降低至正常值以下或中毒反应，为代谢综合征和其并发症患者带来了福音。

Description

一种用于预防/治疗代谢综合征和其并发症的中药增减方 技术领域
本发明涉及生物医药领域，尤其涉及一种可用于预防和/或治疗代谢综合征和其并发症的中药增减方和以该中药增减方为原料的产品，本发明还涉及该产品的制备方法。
背景技术
代谢综合征(metabolic syndrome，MS)是指人体的蛋白质、脂肪、碳水化合物等物质发生代谢紊乱的病理状态，是一组复杂的代谢紊乱症候群，是导致糖尿病心脑血管疾病的危险因素。其具有以下特点：①多种代谢紊乱集于一身，包括肥胖、高血糖、高血压、血脂异常、高血黏、高尿酸、高脂肪肝发生率和高胰岛素血症，这些代谢紊乱是心、脑血管病变以及糖尿病的病理基础。可见糖尿病不是一个孤立的病，而是代谢综合征的组成部分之一。②有共同的病理基础，目前多认为它们的共同原因就是肥胖尤其是中心性肥胖所造成的胰岛素抵抗和高胰岛素血症。③可造成多种疾病的发生几率，如高血压、冠心病、脑卒中、甚至某些癌症，包括与性激素有关的乳腺癌、子宫内膜癌、前列腺癌，以及消化系统的胰腺癌、肝胆癌、结肠癌等。④有共同的预防及治疗措施，防治住一种代谢紊乱，也就有利于其他代谢紊乱的防治(摘自百度百科代谢综合征词条)。
其中糖代谢紊乱如糖尿病和糖尿病并发症是人类致死的一个重要原因。根据国际糖尿病联盟(International Diabetes Federation，IDF)的统计数据，全球糖尿病成人患者(20-79岁)从2000年的1.51亿，到2017年已达到4.25亿，增加近2倍。预计到2045年，糖尿病患者可能达到6.29亿。我国是糖尿病大国，根据2017年IDF发布的最新糖尿病地图显示，中国糖尿病人群已达1.14亿，居世界首位。其中II型糖尿病患者占90％。随着病程增加，糖尿病患者容易出现并发症包括大血管、微血管受损并危及心、脑、肾、周围神经、眼睛、足等。
据世界卫生组织统计，糖尿病并发症高达100多种，是目前已知并发症最多的一种疾病。在已确诊糖尿病患者中，有57％的患者患有并发症，且随着病程的增加，糖尿病患者患有并发症的比率逐步提高(中国糖尿病及并发症发病风险数据分析报告)。糖尿病各种慢性并发症是影响糖尿病患者生存率和生活质量的重要因素，因此积极防治各种糖尿病并发症已迫在眉捷。
其中，糖尿病并发症有相互预测的功能。例如尿肌酐、尿微量白蛋白、尿白蛋白是视网膜病变的风险因子和标记物，通过这些检测结果可以推断药物对网膜微血管病变的影响。根据Rani等人(2011)统计的1414例II型糖尿病患者的临 床数据显示，在II型糖尿病人群中，每6个人就可能有蛋白尿。有微量白蛋白尿的受试者患糖尿病眼病的可能性是没有微量白蛋白尿的受试者的2倍左右，而同时当白蛋白尿出现时，受试者患糖尿病眼病的风险增加到了6倍。同时也有文献证实(Estacio等人，1998)，在西班牙裔病患群体中，白蛋白尿被认为是糖尿病视网膜病的一种强大预测(OR＝2.13，95％CI＝1.34，3.37，P＝0.0013)。除了以上相互预测的指标之外，体重也是代谢综合征的代表性指标。体重的减轻，可以降低代谢综合征其他各项指标，包括高脂蛋白血症、高血压、脂肪性肝病、动脉硬化症、动脉粥样硬化症、肥胖症和原发性高血压等症状。通过对1653名非肥胖成年员工的跟踪试验表明，1年内体重的增加值越多，代谢综合征的指标越差(Toga等人，2016)。而另外一个针对在泰国307名20-90岁(平均45岁)男性和295名健康女性的健康体检数据显示，肥胖是代谢综合征的主要组成部分(Pongchaiyakul等人，2007)。
高脂蛋白血症，即高脂血症(hyperlipoproteinemia)是血浆中某一类或某几类脂蛋白水平升高的表现。高脂血症在动脉粥样硬化的发生和发展及其引起的心血管事件中起到非常重要的作用，是冠状动脉疾病、卒中和外周血管疾病的主要危险因素之一。脂蛋白代谢异常最常见的并发症是动脉粥样硬化；高三酰甘油及乳糜微粒血症，常可并发急性胰腺炎等致命性疾病。
除了糖尿病和高脂血症之外，代谢综合征或胰岛素抵抗综合征还通常伴有脂肪性肝病、动脉硬化症、动脉粥样硬化症、肥胖症和原发性高血压等症状。代谢综合征或胰岛素抵抗综合征包括的脂肪性肝病，可能会发展成慢性炎症、肝纤维化和肝硬化，因此脂肪肝的治疗也非常重要；而动脉粥样硬化、动脉硬化和原发性高血压也占有高比率的慢性病发病率。
由上述可见糖尿病或代谢综合征的治疗不是针对单一脏腑、单一代谢途径或单一靶点的治疗，而是需要根据整体考虑用药，进行各个器官功能的恢复，多靶点用药将代谢途径打通，使机体恢复正常功能；同时单一药物成分易于出现药物耐受问题。我们的配方主要包括下几个成分，针对代谢失常分别进行预防和修复。成分包括：
①薏苡仁(Adlay seed)是禾本科植物薏苡Coix lacryma-jobi L.的干燥成熟种仁。归属利水消肿药分类；归脾胃肺经；能够利水渗湿，健脾止泻，除痹，排脓，解毒散结。
②茯苓为多孔菌科真菌茯苓Poria cocos(Schw.)的干燥菌核。归属利水消肿药分类；归心肺脾肾经；利水渗湿，健脾，宁心安神。
③山药(Dioscorea oppositifolia L.)是薯蓣科植物薯蓣的干燥根茎。归属补气药分类；归脾肺肾经；益气养阴，补脾肺肾，涩精止带。
④芡实，为睡莲科植物芡Euryale ferox Salisb.的干燥成熟种仁。归属固精缩尿止 带药分类；归脾肾心经；可补脾止泻，止带，益肾涩精，养心安神。
⑤莲子(Nelumbinis Plumula)，为睡莲科植物莲的成熟种子。归属固精缩尿止带药；归脾肾心经；补脾止泻，止带，益肾涩精，养心安神。
⑥鸡内金(Endothelium corneum)为雉科动物家鸡Gallusgallusdomesticus Brisson的干燥沙囊内壁。归属消食药分类；甘归脾胃小肠膀胱经；可健胃消食、涩精止遗、通淋化石。
⑦葛根(Pueraria lobata)，为豆科植物野葛的干燥根。归属解表药分类；归脾胃肺经；可解肌退热，生津止渴，透疹，升阳止泻，通经活络，解酒毒。
⑧肉桂(Cinnamomum cassia)，为樟科植物肉桂的干燥树皮。有补火助阳，引火归元，散寒止痛，温通经脉的功效。用于阳痿宫冷，腰膝冷痛，肾虚作喘，虚阳上浮，眩晕目赤，心腹冷痛，虚寒吐泻，寒疝腹痛，痛经经闭。
⑨神曲(Medicated Leaven)是以面粉或麸皮与杏仁泥、赤小豆粉，以及鲜青蒿、鲜苍耳、鲜辣蓼自然汁，混合拌匀，使干湿适宜，做成小块，放入筐内，复以麻叶或楮叶，保温发酵一周，长出黄菌丝时取出，切成小块，晒干即成。生用或炒用。消食和胃。主治饮食积滞，脘腹胀满，食少纳呆。
⑩芍药，为毛茛科植物芍药(Paeonia lactiflora)的根。归属补阳药分类；归肝脾经；可养血调经、敛阴止汗，柔肝止痛，平抑肝阳。古代药方白芍赤芍统称芍药，养阴、补血、柔肝、用生白芍；和中缓急用酒炒白芍；安脾止泻用土炒白芍。因此芍药，尤其白芍，可引气血下行，补充阴血，为降糖首选。
以上综述的代谢综合征和其并发症的治疗费用，占有用了大量的国家医保资源，并大大降低了百姓的生活质量，因此，能够找到一组药物能够有效的预防和治疗此类病症，将会是国家医药计划的重中之重，也是利国利民的善举。
发明内容
本发明公开的中药增减方用于预防或治疗代谢综合征疾病和其并发症，无毒副作用且安全有效。发明人通过常年的临床应用和严谨的动物实验证实了以下内容而完成了本发明：
在动物试验中证实了配方具有可减轻体重、降低血糖、以及肾眼部的治疗作用；同时在临床应用中，临床结果也证实了此配方可以成功的预防或治疗代谢综合征和其并发症，包括胰岛素抵抗综合征、糖尿病和糖尿病并发症、高脂血症、脂肪性肝病、肥胖症、动脉粥样硬化、动脉硬化和高血压等各种代谢紊乱和其并发症。
本发明的目的是提供预防或治疗诸如胰岛素抵抗综合征、糖尿病、高脂血症、脂肪性肝病、肥胖症、动脉粥样硬化、动脉硬化和高血压等各种代谢紊乱和其并发症有效的产品，所述产品含有所述中药增减方作为主要成分。
为实现上述目的，本发明提供了预防或治疗诸如胰岛素抵抗综合征、糖尿病、高脂血症、脂肪性肝病、肥胖症、动脉粥样硬化、动脉硬化和高血压等各种代谢紊乱和其并发症有效的药物组合物。
本发明提供了诸如胰岛素抵抗综合征、糖尿病、高脂血症、脂肪性肝病、肥胖症、动脉粥样硬化、动脉硬化和高血压等各种代谢紊乱和其并发症有效的药物组合物的制备方法，包括几种剂型的制备方法。
本发明还提供了预防或治疗诸如胰岛素抵抗综合征、糖尿病、高脂血症、脂肪性肝病、肥胖症、动脉粥样硬化、动脉硬化和高血压等各种代谢紊乱和其并发症有效的药物组合的用途。
本发明还提供了预防或治疗诸如胰岛素抵抗综合征、糖尿病、高脂血症、脂肪性肝病、肥胖症、动脉粥样硬化、动脉硬化和高血压等各种代谢紊乱和其并发症有效的功能食品或保健品的组合物。
本发明还提供了预防或治疗诸如胰岛素抵抗综合征、糖尿病、高脂血症、脂肪性肝病、肥胖症、动脉粥样硬化、动脉硬化和高血压等各种代谢紊乱和其并发症有效的功能食品或保健品的组合物的制备方法。
本发明还提供了预防或治疗诸如胰岛素抵抗综合征、糖尿病、高脂血症、脂肪性肝病、肥胖症、动脉粥样硬化、动脉硬化和高血压等各种代谢紊乱和其并发症有效的功能食品或保健品组合的用途。
本发明还提供了预防或治疗诸如胰岛素抵抗综合征、糖尿病、高脂血症、脂肪性肝病、肥胖症、动脉粥样硬化、动脉硬化和高血压等各种代谢紊乱和其并发症有效的兽药、动物保健品、饲料或饲料添加剂的组合物。
本发明还提供了预防或治疗诸如胰岛素抵抗综合征、糖尿病、高脂血症、脂肪性肝病、肥胖症、动脉粥样硬化、动脉硬化和高血压等各种代谢紊乱和其并发症有效的兽药、动物保健品、饲料或饲料添加剂的组合物的制备方法。
本发明还提供了预防或治疗诸如胰岛素抵抗综合征、糖尿病、高脂血症、脂肪性肝病、肥胖症、动脉粥样硬化、动脉硬化和高血压等各种代谢紊乱和其并发症有效的兽药、动物保健品、饲料或饲料添加剂的用途。
本发明还提供了预防或治疗诸如胰岛素抵抗综合征、糖尿病、高脂血症、脂肪性肝病、肥胖症、动脉粥样硬化、动脉硬化和高血压等各种代谢紊乱和其并发症有效的方法，所述方法如下骤：向患有糖尿病、肥胖症的动物给予药学上有效剂量的组合物。
本发明还提供了预防或治疗诸如胰岛素抵抗综合征、糖尿病、高脂血症、脂肪性肝病、肥胖症、动脉粥样硬化、动脉硬化和高血压等各种代谢紊乱和其并发症有效的方法，所述方法包括如下步骤：向预防或患有诸如胰岛素抵抗综合征、 糖尿病、高脂血症、脂肪性肝病、肥胖症、动脉粥样硬化、动脉硬化和高血压等各种代谢紊乱和其并发症的受试者给予药学上有效剂量的组合物。
具体的，本发明的技术方案如下：
本发明公开了一种用于预防和/或治疗代谢紊乱综合征和其并发症的中药增减方，包括：茯苓、薏苡仁、山药、芡实和莲子。
优选的，所述中药增减方包括鸡内金、肉桂、神曲、葛根或芍药中的任意一种或任何组合；
更优选的，所述芍药可以被含有芍药苷、芍药内酯苷、羟基芍药苷、氧化芍药苷、苯甲酰芍药苷、芍药新苷、丹皮酚、丹皮酚原苷、丹皮酚苷或芍药苷元的植物中的任意一种或者组合所替代；
更优选的，所述鸡内金可被山楂、莱菔子、麦芽、稻芽、神曲、蛋白酶或其他具有帮助消化或补血功能的成分中的一种或者组合所替代；
更优选的，蛋白酶包括但不局限于胃蛋白酶、胰蛋白酶；
更优选的，蛋白酶包括但不局限于蛋白酶水解物、蛋白酶多肽或其他具有帮助消化或补血功能的酶或多肽。
优选的，其中任意一项成分的重量为1-100g；
更优选的，其中任意一项成分的重量为1-20g。
在本发明的一些具体实施例中，每剂所述中药增减方中包括山药、芡实、茯苓、莲子、薏苡仁、肉桂、葛根各10g，鸡内金15g。
在本发明的一些具体实施例中，每剂所述中药增减方中包括山药、芡实、茯苓、莲子、薏苡仁和鸡内金各10g。
优选的，所述中药增减方还包括辅料；
更优选的，所述辅料包括糖分和糊精。在本发明的一些具体实施例中，所述糖分和糊精的重量比为2：1。
应当理解，本发明辅料并不限于糖分和糊精，本领域技术人员可以选择任何合适的辅料来完成本发明，且均在本发明的保护范围之内。
优选的，所述茯苓、薏苡仁、山药、芡实和莲子的重量比为1：1：1：1：1。
应当理解，所述茯苓、薏苡仁、山药、芡实和莲子的重量比并不限于1：1：1：1：1，本领域技术人员可以选择任何合适的比例来完成本发明，且均在本发明的保护范围之内。
本发明第二个方面公开了一种产品，所述产品包括上述的中药增减方；
优选的，所述产品为药品、保健品、食品、饲料或饲料添加剂。
更优选的，所述药品和保健品应用于人。
优选的，所述产品的剂型包括：散剂、糊剂、颗粒剂、丸剂、片剂、胶囊剂、冲剂、膏滋、汤剂或注射剂。
优选的，所述产品包括：原料成分粉碎物、水提物、有机溶剂提取物和原料提取剩余物；所述原料成分粉碎物包括植物成分中活性单体或单体的混合物。
本发明第三个方面提供了一种制备上述产品的方法，所述散剂的制备方法为：将产品中的所有成分进行加工工序、粉碎工序和混合工序，得到散剂；其中，所述加工工序、粉碎工序和混合工序三者的顺序可以任意互换。
优选的，所述汤剂采用常规的制备方法制得，所述膏滋的制备方法为：得到汤剂后，将所述汤剂浓缩成浸膏后制成膏滋。
在本发明的一些较佳实施例中，将所述汤剂加热蒸发浓缩成浸膏后制成膏滋。
更优选的，将汤剂浓缩成浸膏，烘干粉碎后选择以下步骤中的任意一种：
a)压片成片剂；
b)制备成胶囊剂、丸剂、糊剂；
c)制粒得到颗粒剂、冲剂。
优选的，为了节约成本，所述兽药、动物保健品、饲料或饲料添加剂的组合物可由原料提取剩余物例如人药、人用保健品、食品等生产提取后的药渣再次加工、提取或发酵而成。
本发明第四个方面公开了如下应用：
(1)上述的中药增减方在预防和/或治疗代谢紊乱综合征和其并发症中的应用；
(2)上述的产品在预防和/或治疗代谢紊乱综合征和其并发症中的应用；
(3)上述的方法在预防和/或治疗代谢紊乱综合征和其并发症中的应用；
优选的，所述代谢紊乱综合征包括胰岛素抵抗综合征、糖尿病、高脂血症、脂肪性肝病、肥胖症、动脉粥样硬化、动脉硬化和高血压等。
在符合本领域常识的基础上，上述各优选条件，可任意组合，而不超出本发明的构思与保护范围。
本发明相对于现有技术具有如下的显著优点及效果：
本发明公开了一种可用于预防或治疗诸如胰岛素抵抗综合征、糖尿病、高脂血症、脂肪性肝病、肥胖症、动脉粥样硬化、动脉硬化和高血压等各种代谢紊乱和其并发症有效的中药增减方，通过动物实验和临床实验结果证实，本发明药物有如下优势：
1)本发明药物可以有效的缓解诸如胰岛素抵抗综合征、糖尿病、高脂血症、脂肪性肝病、肥胖症、动脉粥样硬化、动脉硬化和高血压等各种代谢紊乱和其并发症，糖尿病并发症包括糖尿病肾病、眼病、肝病、周围神经病变等相关并发症等。与现有其他糖尿病药物相比，本发明组合物在糖尿病治疗中具有显著的协同作 用，不仅能够显著改善糖尿病和其并发症的症状，还能延缓糖尿病的发展，减少并发症的发生，且可以预防、改善或治疗代谢综合征和其并发症的其他各项指标。
2)与当前治疗代谢综合征的化学治疗药物和天然纯中药制剂相比，本发明组合物为食品源成分，增减方成分简单且对人体无毒副作用，无耐受性，不良反应和副作用显著降低。该中药增减方可长期服用，根据病情酌情加减，可以起到不同的效果，不会因为剂量过大而导致血糖、血压或其他指标降低至正常值以下或中毒反应，给代谢综合征患者带来了福音。
3)现有的糖尿病治疗药物在糖尿病初期治疗效果尚可，但随着治疗时间的延长均出现明显的药物耐受问题，糖尿病的治疗效果下降。本发明中药组合物中含有多种药物组分，作用靶点众多，治疗效果更佳，预防、改善和治疗了代谢综合征患者的各项指标，提高了代谢综合征患者的用药依从性，并提高了患者的生活质量。
附图说明
图l为本发明实施例中对糖尿病动物模型体重影响对比图。
图2为发明对糖尿病动物模型糖化血红蛋白HbA1c(％)影响对比图。
图3为发明对糖尿病动物模型UTP24小时尿白蛋白定量(mg/DL)影响对比图。
图4为发明对糖尿病动物模型ALB尿白蛋白(g/L)影响对比图。
图5为发明对糖尿病动物模型mALB尿白蛋白(g/L)影响对比图。
图6为发明对糖尿病动物模型CRE*20尿肌酐(μmol/L)影响对比图。
具体实施方式
下面结合附图和实施例对本发明的技术方案进行详细描述，但并不因此将本发明限制在所述的实施例范围之中。
下列实施例中未注明具体条件的实验方法，均按照常规方法和条件，或按照商品说明书选择。
下文中，将对本发明进行详细描述。本发明提供了预防和/或治疗诸如胰岛素抵抗综合征、糖尿病、高脂血症、脂肪性肝病、肥胖症、动脉粥样硬化、动脉硬化和高血压等各种代谢紊乱和其并发症有效的药物组合物，所述药物组合物为几种药物的增减方。
本发明还提供了预防和/或治疗诸如胰岛素抵抗综合征、糖尿病、高脂血症、脂肪性肝病、肥胖症、动脉粥样硬化、动脉硬化和高血压等各种代谢紊乱和其并发症有效的药物组合物，所述药物组合物为几种药物的增减方的提取方法。
本发明还提供了预防和/或治疗诸如胰岛素抵抗综合征、糖尿病、高脂血症、 脂肪性肝病、肥胖症、动脉粥样硬化、动脉硬化和高血压等各种代谢紊乱和其并发症有效的药物组合物，所述药物组合物为几种药物的增减方的用途。
所述糖尿病并发症优选于由下列并发症所组成的组合，但并不局限于此：糖尿病性视网膜病、糖尿病性白内障、糖尿病肝病、糖尿病性肾病、糖尿病性神经病变、心脏病、癌症、骨质疏松症、动脉粥样硬化以及阿尔茨海默病。糖尿病并发症是当糖尿病持续较长时间时发展出的症状，此配方中用于治疗糖尿病并发症的药物与糖尿病相同。
我们对于专利配方的研究包括以下几项：
1.发明的制备工艺
优选通过由下列步骤所组成的制备方法来制备中药制剂，包括但并不局限于以下几种：
1)配方的散剂制剂
①将产品中的所有成分进行炮制工序；炮制方法可以参考中国医药科技出版社出版的《中华人民共和国药典》。
②将药品进行粉碎。
③按照比例将粉碎物进行配比后混合，得到散剂。
其中，所述加工工序、粉碎工序和混合工序三者的顺序可以不限。其中对产品中的所有成分进行加工。
2)配方的有效成分提取
包括水提取方法和溶剂提取方法，后期可进行颗粒剂、汤剂、膏剂、片剂等制剂形式的有效成分提取。
①使用提取溶剂对中药制剂进行提取；
②对步骤①中得到的提取物进行冷却，然后进行过滤；以及
③可选的，对步骤②中得到的经过滤的提取物进行浓缩，然后进行干燥。
④可选的，步骤③中的干燥提取物为颗粒剂制剂或进行压片制备。
在上述方法中，步骤①中的中药成分购置于同仁堂药店。
本文中的提取溶剂是水、醇或它们的混合物。所述醇优选为C1-C4低级醇。本文中的提取方法是本领域所接受的常规方法之一，例如过滤、冷浸提取、热水提取、回流提取和超声提取。本文优选热水提取。提取优选重复1-5次、更优选重复2次，但不局限于此。以相对于干燥药材混合物体积1-10倍、更优选3倍的比例，向干燥的药材中加入提取溶剂。提取温度优选但并不局限于沸水提取。提取时间优选但并不局限于1h至4h。
2.发明的药效试验动物验证
1)试验动物
本文中的受试动物为脊椎动物、优选哺乳动物、更优选试验动物(例如小鼠、 大鼠、兔、豚鼠、仓鼠、狗和猫)、最优选猿(如黑猩猩和大猩猩)。
本文中的受试动物为小鼠，优选为预防和治疗II型糖尿病动物模型SPF级的BKS.Cg-Dock7m+/+Leprdb/J小鼠(简称db/db小鼠)。
2)给药剂量和给药方式
本发明的药物组合物中可以按照0.1wt％-99.9wt％的浓度含有中药混合物提取物或其部位作为活性成分。可向所述组合物中加入任何药学上可接受的载体、赋形剂或稀释剂。
通过与常用的稀释剂或赋形剂进行混合，可将本发明的组合物制成用于口服给予或胃肠外给予，所述稀释剂或赋形剂例如填充剂、增量剂(extenders)、粘合剂、湿润剂、崩解剂和表面活性剂。用于口服给予的固体制剂是片剂、丸剂、粉剂、颗粒剂和胶囊剂。这些固体制剂通过将药用成分与一种或多种合适的赋形剂混合来制备，所述赋形剂例如淀粉、碳酸钙、蔗糖或乳糖、明胶等。除简单的赋形剂外，还可使用润滑剂，例如硬脂酸镁、滑石等。用于口服给予的液体制剂为悬浮剂、溶液剂、乳剂、糖浆剂；除常用的简单稀释剂、如水和液体石蜡外，上述制剂可含有多种赋形剂，例如湿润剂、甜味剂、芳香剂和防腐剂。用于胃肠外给予的制剂为无菌水溶液剂、水不溶性赋形剂、悬浮剂、乳剂、冻干制剂和栓剂。除活性化合物外，水不溶性赋形剂和悬浮剂可包含丙二醇、聚乙二醇、植物油(如橄榄油)、可注射的酯(如油酸乙酯)等。除活性化合物外，栓剂可包含Witepsol、聚乙二醇(macrogo1)、吐温、可可油脂、甘油三月桂酸酯(1aurin butter)、甘油明胶等。
可口服或胃肠外给予本发明的药物组合物。可通过外用、腹膜内注射、直肠内注射、静脉内注射、肌内注射、皮下注射、子宫内注射或脑室内注射的方式给予本发明的组合物。更优选地，通过外用给予所述组合物。
本发明组合物的有效剂量可根据体重、年龄、性别、健康状况、膳食、给药频率、给药方法、排泄情况和疾病严重程度来确定。中药组合物提取物的剂量为每天0.01mg/kg到2000mg/kg、优选30mg/kg到1000mg/kg。给药频率为每天1次、或优选每天1-6次。
本发明的组合物可单独给予，或者与手术、放射疗法、激素疗法、化学疗法和生物调节剂等其他方法组合使用。
3)体重检测
对动物进行体重检测。
4)血糖水平和耐糖量实验
包括空腹血糖水平、口服糖耐量实验、非禁食血糖水平(餐后血糖)和糖化血红蛋白(HbA1c)浓度测定。几个指标测定后对把数据进行记录，和阴性对照、阳性对照进行对比和统计分析。
①空腹血糖水平和口服糖耐量实验(OGTT)
空腹血糖指基础状态下的血糖水平，是诊断糖尿病的重要标准，反应胰岛B细胞的基础功能。口服糖耐量实验是动物禁食后进行空腹血糖测定，然后给予药物，在相应时间点灌胃给予葡萄糖溶液，并在灌糖前及灌糖后的30min、60min和120min进行血糖测定。
②非禁食血糖水平
餐后2小时的血糖检测值最具有价值，可以反映出胰岛B细胞的储备功能。选择在动物进食后进行血糖测定。
③糖化血红蛋白(HbA1c)浓度测定
糖化血红蛋白(GHb)是红细胞中的血红蛋白与血清中的糖类相结合的产物。它是通过缓慢、持续及不可逆的糖化反应形成，其含量的多少取决于血糖浓度以及血糖与血红蛋白接触时间，而与抽血时间、患者是否空腹、是否使用胰岛素等因素无关。因此，GHb可有效地反映糖尿病患者过去1-2个月内血糖控制的情况。
检测方法：动物禁食后，采全血20μL置于含HbA1c稀释液EP管中，使用全自动分析仪检测HbA1c含量，具体方法参照试剂盒说明书进行。
5)糖尿病肾病检测实验
包括尿生化检测(尿总蛋白、尿白蛋白、尿微量白蛋白、尿肌酐)。
取过夜尿液，置于碎冰上，进行尿总蛋白、尿白蛋白、尿微量白蛋白、尿肌酐检测。
3.配方的临床验证
选择符合糖尿病/糖尿病肾病/高血压等诊断标准的病例，服药时间为3-6个月。服药后进行有效率统计。
4.发明的使用覆盖范围
1)预防和治疗代谢综合征和其并发症的药物
本发明还提供了预防和/或治疗代谢综合征和其并发症的药物的组合和制备方法，所述方法包括药物的制备和向患有代谢综合征和其并发症的受试者给予药学上有效剂量的、含有中药提取物或其部位作为活性成分的组合物的步骤。
所述代谢综合征优选选自由下列并发症所组成的组合，但并不局限于此：诸如胰岛素抵抗综合征、糖尿病、高脂血症、脂肪性肝病、肥胖症、动脉粥样硬化、动脉硬化和高血压等各种代谢紊乱。
2)预防和治疗代谢综合征和其并发症的保健品或食品
由于本发明产品全部为药食同源成分，本发明还可作为保健品或食品来进行预防和改善代谢综合征和其并发症，专利包括药物组合和制备方法，所述方法包括产品的制备和向患有代谢综合征和其并发症的受试者给予药学上有效剂量的、含有中药提取物或其部位作为活性成分的组合物的步骤。
所述代谢综合征优选自由下列并发症所组成的组，但并不局限于此：诸如胰岛素抵抗综合征、糖尿病、高脂血症、脂肪性肝病、肥胖症、动脉粥样硬化、动脉硬化和高血压等各种代谢紊乱。
本发明的健康功能食品还可另外包含多种矫味剂、添加剂或赋形剂等。食品可以为面包、饼干、面条、咀嚼棒等日常见到的食品形式。
3)预防和治疗代谢综合征和其并发症的兽药、动物保健品或饲料添加剂
除了人类，动物也会患有代谢综合征和其并发症，这其中包括糖尿病。
本发明还提供了预防和改善代谢综合征和其并发症的兽药、动物保健品、饲料和饲料添加剂。本发明进行的动物实验和临床实验，有效的证明了其对于代谢综合征和其并发症的疗效。因此，可有效地将本发明用于生产预防和治疗代谢综合征和其并发症的产品。
通过持续性地对宠物、家禽和家畜给予所述兽药、动物保健品、饲料和饲料添加剂，可预防代谢综合征和其并发症的发生，并且还可治愈已经发展出的代谢综合征。用量可选用人体剂量至人体剂量的6-12倍用量。
本发明的饲料添加剂可另外包含该领域普遍接受的用于宠物、家禽和家畜的载体。在本发明中，饲料添加剂可单独使用或与其它可接受的载体和稳定剂共同使用，如果需要的话，可加入营养物质(如维生素、氨基酸和矿物质)或者其它添加剂(例如抗氧化剂、抗生素、抗微生物剂等)。可将饲料添加剂配制成粉剂、颗粒剂、丸剂和悬浮剂的形式。当提供给家禽和家畜时，本发明的饲料添加剂可单独给予或与饲料混合给予。
实施例1制备中药复合物
1)中药复合物散剂制备
中药材料全部购自同仁堂药房，将材料炮制后按比例配好，用中药粉碎机粉碎，将颗粒过直径为160微米钢筛，将未足够细的颗粒重复过筛，直至颗粒大小全部符合。
2)中药复合物水提取物
中药材料全部购自同仁堂药房，将材料炮制后按比例配好，向其中加入过量冷水，煮沸后继续小火煎煮，采用两次煎煮法，将两次煎煮液混合后得到中药的水提取液。
3)中药复合物乙醇提取物
中药材料全部购自同仁堂药房，将材料炮制后按比例配好，用中药粉碎机粉碎，向其中加入80％乙醇。将所制备的样品装入提取容器中，在室温下重复提取。将提取物过滤，并在减压下进行浓缩。操作温度保持在40℃至45℃，以防止成分的分解和水解。
4)中药复合物甲醇提取物
除使用甲醇替代乙醇外，以与上述3)所述的相同方式进行提取物制备。
实施例2中药复合物的实验验证
一、动物模型的饲养并给予发明药物
为了研究中药复合物对预防和治疗II型糖尿病动物模型，选用SPF级的BKS.Cg-Dock7m+/+Leprdb/J小鼠(简称db/db小鼠)进行降糖实验验证。饲料和水自由供给。将小鼠分入4组(每组4只)，每天一次向小鼠口服灌胃药物。实验共包括对照组NOR、二甲双胍组(350mg/kg)治疗的糖尿病组MET、本发明药物的低剂量(6mg/kg)药物组治疗的糖尿病组RX-6和本发明药物的高剂量(12mg/kg)药物组治疗的糖尿病组RX-12。每天一次向各组口服给予测试样品至第4周。4周后，收集尿液，取血。
其中，药物组中的药物包括茯苓、薏苡仁、山药、芡实、莲子、鸡内金、芍药，其制备方法为将茯苓、薏苡仁、山药、芡实、莲子、鸡内金、芍药炮制后按重量比为1：1：1：1：1：1：2的比例配好，进行散剂制备。将得到的散剂进行一定比例的稀释，得到低剂量(6mg/kg)药物组RX-6和高剂量(12mg/kg)药物组RX-12。
1.动物模型
种属&品系：BKS.Cg-Dock7m+/+Leprdb/J小鼠(简称db/db小鼠)
等级：SPF级
性别：雌性
2.饲养环境
动物饲养于合适规格的饲养盒中，单笼饲养。SPF级动物房，环境条件控制在室温20-26℃，相对湿度40％-70％，光照12小时明暗交替。
3.饲料
动物给予合格的鼠料，自由摄食。由具有资质的检测单位对每批正常饲料的营养成分(主要检测成分：粗蛋白、粗脂肪、粗纤维、水分、钙、总磷、粗灰分)和理化指标(主要检测指标：砷、铅、汞、镉、六六六、滴滴涕、黄曲霉毒素B1)进行检测。由动物实验部负责人或指定人员确保没有影响或干扰试验结果的污染物存在。检测结果评价参照国标GB14924.2-2001和GB14924.3-2010。
4.饮水
动物给予纯化水，二级反渗透RO膜过滤水。用饮水瓶供应，自由摄水。饮水瓶、瓶塞用前高压消毒。饮水的外观和微生物指标(主要检测指标：菌落总数、臭和味、肉眼可见物)每月检测一次，包括各项污染物在内的毒理学指标(砷、铅、汞、镉、肉眼可见物)检测每年一次，并由动物实验部负责人或指定人员确保没有对试验结果造成干扰或影响的污染物存在。参照国标GB5749-2006对饮 水的分析结果进行评价。
5.垫料
垫料使用的是刨花材质的经高压灭菌专用试验垫料。污染物(主要检测指标：砷、铅、汞、镉、六六六、滴滴涕、黄曲霉毒素B1)每年检测一次，委托有资质的单位进行检测。微生物检验(主要检测指标：菌落总数、肉眼可见物)每月进行一次。
二、试验设计
1.动物分组和给药剂量
依据体重大小随机分为4组。各组给药剂量如下表1所示：
表1
Figure PCTCN2020093911-appb-000001
2.给药信息
给药途径：灌胃
给药容量：10mL/kg，根据每只动物最近一次称量的体重，确定每只动物的给药容量。
给药频率：每天1次，给药4周(给药前禁食4h左右)。
3.一般临床观察
观察频率：试验期间，所有动物每天进行两次大体观察(上下午各一次)。
观察内容：包括动物精神状态、行为活动、摄食情况等。
三、发明的动物实验降脂效果
包括体重测量实验和尿液指标检测实验。指标测定后把数据进行记录，将发明药物组和阴性对照组NOR、阳性对照组MET进行对比和统计分析。
1.体重检测
动物接收时、药前、首次给药当天各1次，药后每周2次进行体重测量。
实验结果(见图1)显示随着给药时间的增加，和阴性对照组NOR和阳性对照组MET相比，我们发明的高低剂量组均具有降低小鼠体重的功效。
结果表明高剂量的发明药物可以显著性的降低小鼠体重，而肥胖正是导致代谢综合征的直接诱因。很多实验结果证实，体重与代谢综合征指标有显著性的关联，这些指标包括血压和甘油三酯(TG)、BMI等(Toga等人，2015；Pongchaiyakul等人，2007)。通过动物实验显著性的降低体重的效果，可以推测我们的发明药 物对于代谢综合征和其并发症的各项指标具有疗效。
四、发明的动物实验降糖效果
包括空腹血糖水平、非禁食血糖水平(餐后血糖)和糖化血红蛋白(HbA1c)浓度测定。
几个指标测定后把数据进行记录，和阴性对照组NOR和阳性对照组MET进行对比和统计分析。
1.空腹血糖水平测定
动物禁食4-6h后尾尖采血进行空腹血糖测定。共4次进行空腹血糖测定，分别为：分组前和给药后D2、D7、D15。
根据空腹血糖水平的测定结果显示，阳性对照组MET在服药2天后的餐后血糖值低于阴性对照组NOR；而高剂量组RX-12与低剂量组RX-6的血糖水平逐渐降低，并在服药第15天低于阴性对照组NOR(数据未展示)。
2.非禁食血糖水平
动物在随机进食后尾尖采血进行非禁食血糖水平血糖测定。共6次进行空腹血糖测定，分别为：分组前和给药后24h、D4、D7、D15、D21、D27。
非禁食血糖水平测定结果显示，阳性对照组MET在给药第4天低于阳性对照，而高剂量组RX-12和低剂量组RX-6在第7天开始低于阳性对照并有逐渐降低的趋势。
3.糖化血红蛋白(HbA1c)浓度测定
在给药第29天检测。动物禁食4-6h后，异氟烷吸入麻醉，眼眶静脉丛采全血20L置于含HbA1c稀释液的EP管中，使用全自动分析仪检测HbA1c含量，具体方法参照试剂盒说明书进行。统计分析采用Duncan's multiple range test进行多组样本间差异显著性分析(P<0.05)。
根据图2中数据可见，阴性对照组NOR的糖化血红蛋白值为8.85％，阳性对照组MET(6％)和高剂量组RX-12(6.43％)与阴性对照组NOR(8.85％)相比有显著性差异；而低剂量组RX-6(7.50％)比阴性对照组降低1.35％，没有显著性差异。
4.小结与讨论
本部分实验通过三个指标(空腹血糖水平、非禁食血糖水平和糖化血红蛋白)的检测来证实发明的降糖效果。其中空腹血糖水平和非禁食血糖水平分别在不同的时间点测定(空腹血糖水平：分组前和给药后D2、D7、D15；非禁食血糖水平：分组前和给药后24h、D4、D7、D15、D21)，发明药物分别在第15天的空腹血糖水平和第7天的非禁食水平开始低于阴性对照值，并有逐渐降低的趋势；而在给药29天后，高剂量组RX-12的糖化血红蛋白值(6.43％)显著性的低于阴性对照组NOR(8.85％)。
降糖实验部分的结果证明，本发明药物可以缓慢、温和且显著性的降低小鼠的血糖值。
五、糖尿病肾病检测实验
代谢笼收集过夜尿液，置于碎冰上，进行尿总蛋白、尿白蛋白、尿微量白蛋白、尿肌酐的检测。检测时间为给药后第29天。
1.U TP24小时尿蛋白定量检测
24小时尿蛋白定量检测(UTP24)是指收集24小时内的排出的所有尿液来做定性试验的一种尿液检测方法。
U TP24小时尿蛋白定量结果显示(图3)，在给药29天后，高剂量组RX-12(18.97mg/DL)的U TP24小时尿蛋白低于阴性对照组NOR(39.30mg/DL)、阳性对照组MET(39.65mg/DL)和RX-6(43.33mg/DL)的检测值。结果表明，在给药29天后本发明药物可以显著性降低小鼠的U TP24小时尿蛋白。
2.ALB尿白蛋白检测
白蛋白(albumin，ALB)是血液中的正常蛋白质，占血浆总蛋白的60％，带负电荷，分子量69KD，半径为3.6nm。正常肾小球基底膜具有滤过功能，平均孔径为5.5nm，表面均匀地带一层负电荷。正常情况下ALB很难通过肾小球基底膜，只有少量ALB可以被滤过，但95％的ALB又在近曲小管被重吸收，所以在生理条件下尿液中仅出现极少量白蛋白。白蛋白尿(Albuminuria)是一种病理状态，其中血清白蛋白是存在于尿中。它是蛋白尿的类型之一。
本实验中ALB尿白蛋白含量数值显示如图4。根据结果显示，在给药29天后，高剂量组RX-12的ALB尿白蛋白含量(0.1g/L)显著性低于阴性对照组NOR(0.3g/L)、阳性对照组MET(0.25g/L)和RX-6(0.33g/L)的ALB尿白蛋白含量。结果表明，在饲养29天后本发明药物可以显著性降低小鼠的ALB尿白蛋白。
3.mAlb尿微量白蛋白检测
微量白蛋白尿是指在尿中出现微量白蛋白。微量白蛋白(microalbunminuria，mAlb)是指尿白蛋白的排泄率超过正常范围，但低于常规方法可检测到的尿蛋白水平。mAlb尿微量白蛋白是指在尿中出现微量白蛋白。目前认为尿微量白蛋白测定可以反映出早期肾病、肾损伤情况。
mAlb尿微量白蛋白含量数值显示于图5，高剂量药物组RX-12的mAlb尿微量白蛋白含量(7.37mg/L)低于阴性对照组NOR(20.10mg/L)、阳性对照组MET(8.50mg/L)和RX-6(15.70mg/L)。结果表明，在饲养29天后本发明药物可以降低小鼠的mAlb尿微量白蛋白含量。
4.尿肌酐检测
尿肌酐主要来自血液经过肾小球过滤后随尿液排出的肌酐。
根据图6尿肌酐检测结果显示，通过29天饲养后，高剂量组RX-12比阴性对照组NOR小鼠尿液中的尿肌酐降低5.5μmoI/L，而阳性对照组MET比阴性对照组NOR升高10.5μmoI/L。尿液中尿肌酐实验部分的结果证明，在饲养29天后本发明药物可以显著性降低小鼠的尿肌酐值。
5.小结与讨论
尿总蛋白、尿白蛋白、尿微量白蛋白和尿肌酐检测结果均显示，高剂量组RX-12的肾脏治疗效果优于阳性对照组和阴性对照组。证明本发明高剂量组对肾病具有有效的治疗效果。不仅如此，诸多研究表明，尿肌酐、尿微量白蛋白、尿白蛋白还是视网膜病变的风险因子和标记物，从我们尿液检测结果可以推断本发明可以预防、改善或治疗视网膜微血管病变。
六、动物实验部分小结与结论
本部分实验设计了发明药物在小鼠体重、血糖、肾脏指标与阳性对照药物和阴性对照的对比实验。通过实验结果证实，与阳性对照药二甲双胍相比：本发明药物通过4周的饲养可以显著性的降低小鼠体重、温和并显著性的降低血糖指标，降低肾脏检测系列指标。通过结果可以判断本发明具有降脂、降糖、恢复肾脏损伤的治疗效果，并可以推测本发明具有可以预防、改善或治疗视网膜微血管病变等并发症，且可以预防、改善或治疗代谢综合征和其并发症的其他各项指标。
实施例3中药复合物的临床实验验证
为了研究组合物在人体内的临床使用效果，进行糖尿病患者招募。用药前我们将患者进行如下指标的不完全统计，并在用药3-6个月后进行指标统计。
一、实验内容
1.入组标准
入组指标包括：年龄、患病时间、用药史、血糖值、视力、糖尿病病足、肾病、脂肪肝、血压等指标。
入组年龄应≥18岁，≤75岁。
下列情况的患者不在入组范围内：
1)活动性肝病患者，包括酒精性肝炎、非酒精性脂肪肝、乙型病毒性肝炎、丙型病毒性肝炎、慢性病毒性肝炎患者，需结合其他中药治疗，暂不包括在统计组内；
2)已有晚期严重并发症的患者，由于治疗时间长，暂不包括在统计组内；
3)有缩短预期寿命的疾病或医疗情况者；
4)前3个月内曾使用过噻唑烷二酮类(TZD)、人胰高血糖素样肽-1(GLP-1)类药物或二肽基肽酶IV抑制剂(DPP-4)治疗者；
5)经判断无法控制的低血糖或高血糖者(曾通过剂量调整无法产生适当的治疗 效果，低血糖或高血糖反复出现；根据I型和II型糖尿病指南，低血糖参考值为≤3.9mmol/L，高血糖参考值建议为≥16.7mmol/L，谨供参考)；
6)前2个月内使用全身类固醇药物治疗，或筛选时正在使用全身类固醇药物(包括糖皮质激素，但局部使用在7天之内者可以入选)、免疫抑制剂或细胞毒治疗者；
7)前12个月内曾患有下列心脏疾病者，需结合其他中药治疗，暂不包括在统计组内：
a.失代偿性心功能不全
b.不稳定型心绞痛
c.心肌梗死
8)经治疗无法控制/未经治疗的重度高血压者(收缩压≥180mmHg和/或舒张压≥110mmHg)，需结合其他中药治疗，暂不包括在统计组内；
9)前5年内有药物滥用史者；
10)有中重度贫血(血红蛋白≤90g/L)者，需结合其他中药治疗，暂不包括在统计组内；
2.病例
筛选出糖尿病患者100例，其中对51例持续服药的患者进行追踪访问。其中男性患者32人，女性患者20人；年龄20-75岁，平均52.17岁。合并高血压患者20例；合并肾病患者19例；合并高脂血症患者20例；合并糖尿病眼病患者18例；合并糖尿病周围神经病变患者14例。
3.治疗方案
治疗组患者服用本发明的中药制剂，成人每日口服2次，每次10-30g，90天为一个疗程。
4.诊断标准
1)高血糖患者判断标准
根据美国糖尿病协会(ADA)的诊断标准包括：空腹血糖(FPG)水平为126mg/DL(7.0mmol/L)或更高，或；在75g口服葡萄糖耐量试验(OGTT)期间，2小时的血糖水平为200mg/DL(11.1mmol/L)或更高，或；在典型的高血糖或高血糖危象的患者中，随机血糖为200mg/DL(11.1mmol/L)或更高，或；糖化血红蛋白(HbA1c)水平为6.5％或更高。
有效：FBG＜8.3mmol/L，2小时的血糖水平＜10mmol/L，或血糖较治疗前下降10％-29％；
无效：血糖下降未达到标准(庞国明等人，2017)。
2)高血压患者判断标准
根据成年人高血压2017指南(2017 Guideline for High Blood Pressure in Adults)中指导高血压为如下情况：诊所血压测量值140/90mmHg、家庭血压测量值HBPM135/85mmHg、白天动态血压监测值ABPM135/85mmHg、夜间动态血压监测值ABPM120/70mmHg和24小时动态血压监测值ABPM130/80mmHg(Melvyn Rubenfire,MD,FACC,2018)。
有效：血压测量值降低10-20％；
无效：血压下降未达到标准。
3)肾病患者判断标准
根据2019年糖尿病肾病指南(Diabetic Nephropathy Guidelines)中的肾病诊断标准如下：
持续性蛋白尿(>300mg/24h或>200μg/min)为特征的临床综合征，间隔3-6个月至少2次确诊(Vecihi Batuman,MD,2019)。
有效：尿蛋白排泄率恢复正常或较治疗前下降30％，中医症状分级积分和治疗后下降≥1/3-2/3；
无效：尿蛋白排泄率达不到有效标准或反见上升，中医症状分级积分和治疗后下降＜1/3。
4)糖尿病眼病患者判断标准
几乎所有的眼病都可能发生在糖尿病患者身上。如眼底血管瘤、眼底出血、泪囊炎、青光眼、白内障、玻璃体浑浊、视神经萎缩、黄斑变性、视网膜脱落。而且糖尿病患者发些眼病的几率明显高于非糖尿病人群。
有效：根据Messidor数据库DR分级有效，包括：①病变等级Retinopathy grade②黄斑水肿风险等级Risk of macular edema；
无效：根据Messidor数据库DR分级无效。
5)周围神经病变患者判断标准
糖尿病周围神经病变(diabetic peripheral neuropathy，DPN)隐匿性强，超过50％的患者没有临床症状，其病理程度与症状出现及其严重性往往不一致，是足部溃疡、坏疽致截肢的高危因素。将密西根糖尿病神经评分(Michigan Diabetic Neuropathy Score，MD)进行周围神经病变评分。
有效：MDNS得分减少≥10分为有效。
无效：MDNS得分减少＜10分为无效。
二、试验结果
将上述病症的患者在治疗前后的效果进行统计对比，如表2所示：
表2
Figure PCTCN2020093911-appb-000002
由表2中数据可以看出，治疗组患者临床疗效显示，糖尿病患者的总有效率为88.24％，这其中数据由于病患过重的并发症如糖尿病肾病、脂肪肝等，导致早期血糖变动较小；高血压的效率为80％，由于高血压分类可分为先天型高血压和后天型高血压，部分顽固压症状的病人在短期服用后没有得到缓解；高脂血症患者的有效率为75％；糖尿眼病患者和肾病患者治愈率较高，这是由于发明早期治疗针对并发症的缓解，肾病眼病的并发症首先被缓解；而糖尿病周围神经病变患者治愈率达到85.71％，其中，2例无效的患者为重症糖尿病足患者，需要长期服药才能见效。
二、病例介绍
[有关糖尿病试验例1]
实施受试者A：女性(43岁)
给药药剂：实施例1的散剂
给药量：早晨空腹服药30g。
服药和患病时间：2017年检查患有糖尿病，餐前血糖17mmol/L。未采取其他治疗方式，于2017年2月服用本实施例公开的配方。
服药记录：患者服用1个多月，血糖降到正常水平。后间断性服药6个月进行巩固。2年病情未反复。
[有关糖尿病试验例2]
受试者B：男性(44岁)
给药药剂：实施例1的散剂
给药量：早晨空腹服药30g。
服药和患病时间：于2016年查出患有糖尿病，餐前血糖12mmol/L，每日服用二甲双胍2次，一次1片(0.5g)，并多次进行中医治疗，效果均不佳。2017年12月开始服用本实施例公开的配方。
服药记录：患者服药十天后症状好转，一个月后血糖降到5.7mmol/L。至今病情未反复。
[有关糖尿病试验3]
受试者C：女性(66岁)
给药量：早餐、晚餐前空腹服药各30g。
服药和患病时间：25年糖尿病病史，每天注射胰岛素32个单位，3片二甲双胍(每片0.5g)；血糖维持在8-12mmol/L。
服药记录：患者服用前2个月，眼睛视物不清、睡眠不好、下肢不便等身体状况缓解，但血糖基本上没有变化。至第三个月，血糖开始平稳下降至6mmol/L。第四个月，每天减胰岛素两个单位，后每天减一个单位，直至全部停用，血糖值为14mmol/L，继续服用直到血糖逐渐降为正常值。
[有关并发糖尿病和高血压的试验例]
受试者D：女性(57岁)
给药药剂：实施例1的散剂
给药量：早餐、晚餐前空腹服药各30g。
服药和患病时间：高血压30余年患病时间，每日服用美卡素1片(80mg)；并于2016年检测餐前血糖7.0mmol/L，餐后血糖9.6mmol/L，糖化血红蛋白6.7％；为双高型糖尿病前期患者。未采取其他治疗方式，服用本实施例公开的配方。
服药记录：服用本实施例中的中药配方1周后眼睛不适消失，食量正常，睡眠正常。服用1个月后，餐前血糖降至5.9mmol/L。服用本实施例中的中药配方3个月后改为陆续服用。3年病情未反复。血压降至正常值，不再服用降血压药。
[有关并发糖尿病和肾病的试验例1]
受试者E：女性(42岁)
给药药剂：实施例1的散剂
给药量：早餐、晚餐前空腹服药各30g。
服药和患病时间：糖尿病患病时间10年，服用二甲双胍每日2次，一次1片(0.5g)，尿液检测尿蛋白150mg/DL。服用本实施例公开的配方。
服药记录：服用本实施例中的中药配方1个月后尿蛋白降至11mg/DL，西药药量减半。后继续服用中药6个月，直至西药全部取消，血糖恢复正常。
[有关并发糖尿病和肾病的试验例2]
受试者H：男性(50岁)
给药药剂：实施例1的散剂
给药量：早餐、晚餐前空腹服药各30g。
服药和患病时间：糖尿病患病时间15年，每日服用二甲双胍2次，一次2片(0.5g)，阿卡波糖3次，一次一片(50mg)；尿液测尿蛋白100mg/DL。
服药记录：服用本实施例中的中药配方2个月后尿蛋白降至20mg/DL，排尿不再起沫，西药药量减半。后继续服用中药3个月，直至血糖恢复正常。
[有关并发糖尿病和周围神经病变的试验例]
受试者I：男性(70岁)
给药药剂：实施例1的散剂
给药量：早餐、晚餐前空腹服药各30g。
服药和患病时间：糖尿病20余年，注射胰岛素每日量，餐前血糖10.1mmol/L，脚和小腿部冰凉，有黑斑，密西根糖尿病周围神经病评分为25分，被医院通知会在半年后截肢。未采取其他治疗方式，于2017年2月服用本实施例公开的配方。。
服药记录：服用本实施例中的中药配方3个月后，糖尿病病足症状消失，陆续服用6个月，直至腿脚部颜色恢复，穿靴感消失。
三、临床实验部分小结与结论
本部分临床实验收入了以糖尿病患者为主的患者，并发症包括糖尿病肾病患者、高脂血症患者、糖尿病眼病患者、糖尿病周围神经病变患者等。通过临床实验结果证实，本药物有如下优势：
1)本发明药物可以临床有效的缓解包括糖尿病肾病、眼病、肝病、周围神经病变等相关并发症。与现有其他糖尿病药物相比，本发明组合物在糖尿病治疗中具有显著的协同作用，不仅能够显著改善糖尿病的症状，还能延缓糖尿病的发展，减少并发症的发生。
2)与当前治疗糖尿病的化学治疗药物和天然纯中药制剂相比，本发明组合物为食品源成分，不良反应和副作用显著降低，提高了糖尿病患者的用药依从性，并提高了患者的生活质量。
3)现有的糖尿病治疗药物在糖尿病初期治疗效果尚可，但随着治疗时间的延长均出现明显的药物耐受问题，糖尿病的治疗效果下降。本发明中药组合物中含有多种药物组分，作用靶点众多，且本发明组合物作用全面，治疗效果更佳，预防、改善和治疗了代谢综合征和其并发症患者的各项指标，有效地解决了糖尿病治疗药物的耐受问题，其对糖尿病的治疗效果不因治疗时间延长而下降。
接下来描述了本发明组合物的制造实施例。
＜制造实施例1＞制备药物制剂
＜1-1＞制备粉剂
将各味中药按照比例称取后混合，按照制备粉剂的常规方法放入打粉机进行打 粉，粉剂。
＜1-2＞制备水提物
将各味中药按照比例称取后混合，按照中药熬制方法进行熬制，浓缩。
＜1-3＞制备片剂100mg
实施例<1-2>的水提物10mg
羧甲基淀粉钠22.2mg
微晶纤维素37mg
预胶化淀粉11.1mg
50％乙醇10％PVPK30 20mg
硬脂酸镁0.37mg
按照制备片剂的常规方法，通过将上述所有组分混合，制备片剂。
＜1-4＞制备丸剂
实施例<1-2>的水提物1g
乳糖1.5g
甘油0.5g
木糖醇0.5g
按照制备丸剂的常规方法，通过将上述所有组分混合，制备丸剂。
＜1-5＞制备颗粒剂
实施例<1-2>的水提物150mg
大豆提取物50mg
葡萄糖200mg
淀粉600mg
将上述所有组分混合，向其中加入100mg30％乙醇。将混合物在60℃下进行干燥，
并将制备的颗粒填充入包装中。
＜制造实施例2＞制备食品
按照如下所述制备含有本发明提取物的食品。
＜2-1＞制备面制食品
向面粉中加入0.5-5.0重量份的实施例<1-2>的水提物。按照常规方法，用面粉混合物制备面制食品，如面包、蛋糕、饼干、薄饼、面条、咀嚼棒等。
＜2-2＞制备乳制品
向牛奶中加入5-10重量份的实施例<1-2>的水提物。按照常规方法，用牛奶混合物制备促进健康的乳制品，如黄油和冰淇淋。
＜2-3＞制备辅食糊糊
将藜麦、大麦、糯米、黑芝麻等粗粮按照常规方法炒制、糊化，干燥并粉碎 以得到60目粉末。
将实施例<1-2>的水提物进行减压浓缩、喷雾干燥以及粉碎，从而得到60目干燥粉末。将粗粮和实施例<1-2>的水提物的干燥粉末混合制备辅食。
＜制造实施例3＞制备饮品
＜3-1＞制备健康茶饮
将茶叶进行高温浸提，过滤后加入如下成分调配，进行罐装、封口、杀菌。
实施例<1-2>的水提物2g
柠檬酸0.5g
维生素C0.5g
果葡糖浆60g
红茶5g
加纯净水至1000g
＜3-2＞制备代餐奶昔
取粉碎好的或提取好的下列成分进行混合，制备促进健康的代餐奶昔。
实施例<1-2>的水提物5g
魔芋粉20g；
复合维生素3g；
复合矿物质1g；
菊粉1g；
低聚木糖10g；
大豆蛋白10g；
乳清蛋白10g。
＜制造实施例4＞制备动物饲料
＜4-1＞制备饲料
按照如下所述制备动物饲料，按照0.3％加入饲料中混匀后，充分干燥，后分装。
＜1-1＞制备粉剂后的药渣混合物95g
纯植物提取防霉剂5g
＜4-2＞制备发酵饲料添加剂
将如下原料混合，装入发酵袋，避光保温，并进行3-4次倒袋，干燥后分装。
＜1-1＞制备粉剂后的药渣混合物50-500g
米糠或麸子1000g
红糖3g
酵素菌4g
贝壳粉50g
水25％
<制造实施例5>制备兽药
将<4-2>腐熟后的混合中药渣放入碱性复合液中，取出上清液，浓缩，干燥，制得腐植酸含量≥50％的成品。
工业实用性
如上文所述，本发明的提取物或其部位是天然产物，在预防、治疗或延缓代谢综合征和其并发症的方面有效；因此，可将本发明用于药品治疗预防或延缓代谢综合征、机体免疫力提高，以及用于生产保健品、健康功能食品或用作功能饲料或饲料添加剂。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (11)

  1. 一种用于预防和/或治疗代谢紊乱综合征和其并发症的中药增减方，其特征在于，包括：茯苓、薏苡仁、山药、芡实和莲子。
  2. 根据权利要求1所述的中药增减方，其特征在于，所述中药增减方包括鸡内金、肉桂、神曲、葛根或芍药中的任意一种或任何组合；
    优选的，所述芍药可以被含有芍药苷、芍药内酯苷、羟基芍药苷、氧化芍药苷、苯甲酰芍药苷、芍药新苷、丹皮酚、丹皮酚原苷、丹皮酚苷或芍药苷元的植物中的任意一种或者组合所替代；
    优选的，所述莲子可被莲子心或其他一种或者组合所替代；
    优选的，所述鸡内金可被山楂、莱菔子、麦芽、稻芽、神曲、蛋白酶或其他具有帮助消化或补血功能成分中的一种或者组合所替代；
    优选的，蛋白酶包括但不局限于胃蛋白酶、胰蛋白酶；
    优选的，蛋白酶包括但不局限于蛋白酶水解物、蛋白酶多肽或其他具有帮助消化或补血功能的酶或多肽。
  3. 根据权利要求1-2中任意一项所述的中药增减方，其特征在于，其中任意一项成分的重量为1-100g；
    优选的，其中任意一项成分的重量为1-20g。
  4. 根据权利要求1所述的中药增减方，其特征在于，优选的，所述中药增减方还包括辅料；
    优选的，所述茯苓、薏苡仁、山药、芡实和莲子的重量比为1：1：1：1：1。
  5. 一种产品，其特征在于，所述产品包括权利要求1-4任一项所述的中药增减方；
    优选的，所述产品为药品、保健品、食品、饲料或饲料添加剂；
    更优选的，所述药品和保健品应用于人。
  6. 根据权利要求5所述的产品，其特征在于，所述产品的剂型包括：散剂、糊剂、颗粒剂、丸剂、片剂、胶囊剂、冲剂、膏滋、汤剂或注射剂。
  7. 根据权利要求5所述的产品，其特征在于，包括：原料成分粉碎物、水提物、有机溶剂提取物和原料提取剩余物；所述原料成分粉碎物包括植物成分中活性单体或单体的混合物。
  8. 一种制备权利要求5-7中任意一项所述的产品的方法，其特征在于，所述散剂的制备方法为：将产品中的所有成分进行加工工序、粉碎工序和混合工序，得到散剂；其中，所述加工工序、粉碎工序和混合工序三者的顺序可以任意互换。
  9. 一种制备权利要求5-7中任意一项所述的产品的方法，其特征在于，所述汤剂采用常规的制备方法制得，所述膏滋的制备方法为：得到汤剂后，将所述汤剂浓缩成浸膏后制成膏滋。
  10. 根据权利要求9所述的方法，其特征在于，将汤剂浓缩成浸膏，烘干粉碎 后选择以下步骤中的任意一种：
    a)压片成片剂；
    b)制备成胶囊剂、丸剂、糊剂；
    c)制粒得到颗粒剂、冲剂。
  11. 如下应用：
    (1)权利要求1-4所述的中药增减方在预防和/或治疗代谢紊乱综合征和其并发症中的应用；
    (2)权利要求5-7所述的产品在预防和/或治疗代谢紊乱综合征和其并发症中的应用；
    (3)权利要求8-10所述的方法在预防和/或治疗代谢紊乱综合征和其并发症中的应用；
    优选的，所述代谢紊乱综合征和其并发症包括胰岛素抵抗综合征、糖尿病、高脂血症、脂肪性肝病、肥胖症、动脉粥样硬化、动脉硬化和高血压和其并发症。
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