WO2019205943A1 - 一种改善胰岛素抵抗的复合制剂及制备方法与应用 - Google Patents

一种改善胰岛素抵抗的复合制剂及制备方法与应用 Download PDF

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Publication number
WO2019205943A1
WO2019205943A1 PCT/CN2019/082127 CN2019082127W WO2019205943A1 WO 2019205943 A1 WO2019205943 A1 WO 2019205943A1 CN 2019082127 W CN2019082127 W CN 2019082127W WO 2019205943 A1 WO2019205943 A1 WO 2019205943A1
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Prior art keywords
extract
insulin resistance
composite preparation
preparation
improving insulin
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PCT/CN2019/082127
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English (en)
French (fr)
Inventor
沈鹤霄
李国龙
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美益添生物医药(武汉)有限公司
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Priority claimed from CN201810395759.2A external-priority patent/CN108403930B/zh
Priority claimed from CN201810393624.2A external-priority patent/CN108478633B/zh
Priority claimed from CN201810394911.5A external-priority patent/CN108576821A/zh
Priority claimed from CN201810395768.1A external-priority patent/CN108567901B/zh
Application filed by 美益添生物医药(武汉)有限公司 filed Critical 美益添生物医药(武汉)有限公司
Publication of WO2019205943A1 publication Critical patent/WO2019205943A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/733—Fructosans, e.g. inulin
    • 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
    • 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
    • A61K36/481—Astragalus (milkvetch)
    • 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)
    • A61K36/64—Orobanchaceae (Broom-rape 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)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
    • A61K36/8969—Polygonatum (Solomon's seal)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

Definitions

  • the present disclosure relates to the field of oral preparations, and in particular to a composite preparation for improving insulin resistance, a preparation method and application thereof.
  • the object of the present disclosure includes, for example, providing a composite preparation for improving insulin resistance which is safe and effective in improving insulin resistance.
  • the object of the present disclosure also includes, for example, a method for preparing a composite preparation for improving insulin resistance, which is simple in process and easy to industrially produce.
  • the object of the present disclosure also includes, for example, the use of a composite preparation for improving insulin resistance for the preparation of an oral preparation for improving insulin resistance.
  • the present disclosure provides a composite preparation for improving insulin resistance, which is prepared from the following raw materials, and the raw materials include:
  • the oligosaccharide is selected from the group consisting of inulin, oligofructose, xylooligosaccharide, galactooligosaccharide, oligo-isomaltose, polydextrose, resistant dextrin, L-arabinose, and konjac At least one of a combination of glucomannan compositions.
  • the plant extract is selected from the group consisting of seaweed extract, kelp extract, yellow essence extract, alfalfa extract, alfalfa extract, puerarin and ginseng extract, and psyllium husk At least one of the combinations.
  • the fungal extract is selected from at least one of the group consisting of a mushroom extract, a cordyceps extract, a ganoderma lucidum extract, a Hericium erinaceus extract, and a yeast extract.
  • the raw material further comprises Tremella extract, and the Tremella extract is used in an amount of from 1% to 5% by mass of the fungal extract.
  • the feedstock further comprises Dendrobium candidum extract, the Dendrobium candidum extract being from 1% to 5% by mass of the plant extract.
  • the present disclosure provides a method for preparing the above-described composite preparation for improving insulin resistance, which comprises the following steps:
  • the oligosaccharide, the plant extract, the fungal extract, the sodium taurine and the Cistanche extract are mixed and ground.
  • the plant extract is prepared as follows:
  • the selected plant raw materials are washed, pulverized and mixed, and added with 4-6 times weight and 60 ° C-80 ° C hot water extraction for 3-4 hours, and filtered to obtain an extract; after the extract is concentrated, ethanol precipitation is carried out to obtain a crude polysaccharide.
  • the crude polysaccharide is separated by chromatography and eluted with distilled water to obtain a polysaccharide liquid; after the polysaccharide liquid is concentrated, it is precipitated with ethanol and dried to obtain a powdery plant extract.
  • the fungal extract is prepared as follows:
  • the fungal raw material is dried and fully ground, and then added with 10-20 volumes of pure water, extracted at 70-80 ° C for 3-4 hours, and filtered to obtain an extract; the extract is centrifuged at 3000-5000 r/min for 10-15 minutes. The supernatant was taken; the supernatant was concentrated, and precipitated with ethanol; the precipitate was taken and dried to obtain a powdery fungal extract.
  • the present disclosure provides the use of the above-described composite preparation for improving insulin resistance, which is used for preparing an oral preparation for reducing the ratio of the thick-walled mycelium/Bacteroides in the intestinal tract and increasing the specific gravity of the SCFA-producing bacteria.
  • Embodiments of the present disclosure provide the use of a composite preparation for improving insulin resistance according to the present disclosure for improving insulin resistance or treating or preventing a disease or condition associated with insulin resistance.
  • Embodiments of the present disclosure provide a method of treating or preventing a disease or condition associated with insulin resistance or insulin resistance, comprising administering to a subject in need thereof a composite preparation for improving insulin resistance as described in the present disclosure, or an improvement as described in the present disclosure A combination of insulin resistance and a pharmaceutically acceptable carrier.
  • the insulin resistance-related disease or condition is metabolic syndrome, obesity, type 2 diabetes, hyperinsulinemia, polycystic ovary syndrome, hyperglycemia, hypertension, or dyslipidemia .
  • the composite preparation that improves insulin resistance is an oral powder formulation.
  • the beneficial effects of the composite preparation for improving insulin resistance and the preparation method and application thereof of the embodiments of the present disclosure include at least: a composite preparation for improving insulin resistance according to an embodiment of the present disclosure, which is prepared from the following raw materials in mass percentage: 20% -65% oligosaccharides; 21%-44% plant extract; 10%-30% fungal extract; 0.5%-5% sodium taurate; and 0.5%-5% Cistanche extract, the safety of the composite preparation Good sex, can effectively regulate the intestinal flora.
  • the preparation method of the composite preparation is that the oligosaccharide, the plant extract, the fungal extract, the sodium taurine and the Cistanche extract are mixed and ground, and the process is simple and easy to industrialize.
  • the use of the composite preparation for improving insulin resistance of the embodiments of the present disclosure is a composite preparation for preparing an oral preparation for improving insulin resistance.
  • the embodiments of the present disclosure provide a composite preparation for improving insulin resistance, which is prepared from the following raw materials, and the raw materials include: 20%-65% oligosaccharides; 21%-44% plant extracts; %-30% fungal extract; 0.5%-5% sodium taurate; and 0.5%-5% Cistanche extract.
  • the raw material comprises: 33% - 52% oligosaccharide; 29% - 36% plant extract; 15% - 25% fungal extract; 2% - 5% sodium taurate; and 1% - 4% Cistanche Extract.
  • the oligosaccharide is selected from the group consisting of inulin, oligofructose, xylooligosaccharide, galactooligosaccharide, oligo-isomaltose, polydextrose, resistant dextrin, L-arabinose, and konjac At least one of a combination of glucomannan compositions.
  • the raw materials include 1%-10% inulin, 1%-5% xylooligosaccharide, 1.5%-10% galacto-oligosaccharide, 1%-5% oligo-isomaltose, 5%-by mass percent. 10% polydextrose, 5%-10% resistant dextrin, 5%-10% L arabinose and 0.5%-5% konjac glucomannan.
  • the plant extract is obtained by plant extraction, mostly plant polysaccharides.
  • the plant extract is selected from the group consisting of seaweed extract, kelp extract, extract of Rhizoma Polygonati, extract of Lycium barbarum, extract of Lycium barbarum L., extract of Radix Puerariae (ie, Pueraria lobata extract), and ginseng extract, and composition of psyllium psyllium. At least one of the combinations.
  • the front hull of the round shovel is the outer shell of the seed of the planted psyllium (Llant name: Plantago ovata), which can be directly ground.
  • the raw materials include 5%-10% seaweed extract, 3%-5% kelp extract, 1.5%-5% yellow essence extract, 3%-5% quince extract, 5%-10% by mass percentage.
  • the fungal extract is obtained by fungal extraction, mostly fungal polysaccharides.
  • the fungal extract is at least one selected from the group consisting of a mushroom extract, a cordyceps extract, a ganoderma lucidum extract, a Hericium erinaceus extract, and a yeast extract.
  • the raw materials include 5%-10% shiitake mushroom extract, 0.5%-5% Cordyceps extract, 0.5%-5% Hericium erinaceus extract, and 4%-10% yeast extract by mass percentage.
  • the raw material may further comprise Tremella extract, and the Tremella extract is used in an amount of from 1% to 5% by mass of the fungal extract.
  • the feedstock further comprises Dendrobium candidum extract, the Dendrobium candidum extract being from 1% to 5% by mass of the plant extract.
  • the raw material further comprises a flower extract
  • the flower extract is used in an amount of from 2% to 10% by mass of the plant extract.
  • the flower extract is selected from at least one of a combination of a peony flower extract, a honeysuckle extract, and a dandelion extract.
  • the composite formulation is made using oligosaccharides, plant extracts, fungal extracts, sodium taurate, and Cistanche extract, wherein oligosaccharides, plant extracts, fungal extracts, cattle Sodium sulfonate synergistically improves insulin resistance.
  • Embodiments of the present disclosure provide a method of preparing the above-described composite preparation for improving insulin resistance, comprising the steps of:
  • the oligosaccharide, the plant extract, the fungal extract, the sodium taurine and the Cistanche extract are mixed and ground.
  • the plant extract can be purchased as a high purity extract, or can be prepared according to the following preparation methods:
  • the selected plant raw materials are washed, pulverized and mixed, and added with 4-6 times weight and 60 ° C-80 ° C hot water extraction for 3-4 hours, and filtered to obtain an extract; after the extract is concentrated, ethanol precipitation is carried out to obtain a crude polysaccharide.
  • the crude polysaccharide is separated by chromatography and eluted with distilled water to obtain a polysaccharide liquid; after the polysaccharide liquid is concentrated, it is precipitated with ethanol and dried to obtain a powdery plant extract.
  • the fungal extract can be purchased as a high purity extract, or can be prepared according to the following preparation methods:
  • the fungal raw material is dried and fully ground, and then added with 10-20 volumes of pure water, extracted at 70-80 ° C for 3-4 hours, and filtered to obtain an extract; the extract is centrifuged at 3000-5000 r/min for 10-15 minutes. The supernatant was taken; the supernatant was concentrated, and precipitated with ethanol; the precipitate was taken and dried to obtain a powdery fungal extract.
  • the flower extract is commercially available or can be prepared according to the following preparation methods:
  • the flower raw material is added to the yeast for fermentation, filtered, matured, and clarified to obtain a flower and fruit fermentation liquid; the fermentation liquid is filtered and concentrated to obtain a powdery flower extract.
  • the Cistanche extract is commercially available or can be prepared according to the following preparation methods:
  • Cistanche deserticola microwave extraction device microwave power 500W-900W, temperature 70 °C, a total of 3 extractions, the first addition of 50%-90% ethanol, extraction 10min-30min; the second addition 50%-90% Ethanol, extraction for 10min-30min; the third addition of distilled water, extraction 20min-40min.
  • the first and second ethanol extracts were concentrated to remove ethanol, and the third aqueous extract was added thereto, mixed, and concentrated to obtain a powdery Cistanche extract.
  • Embodiments of the present disclosure provide an application of the above-described composite preparation for improving insulin resistance.
  • the composite preparation has a function of improving insulin resistance, thereby increasing sensitivity to insulin. Accordingly, the composite preparation can be used to prepare an oral preparation for improving insulin resistance. More specifically, the composite preparation is used for the preparation of an oral preparation for improving the symptoms of obesity in obese people.
  • oligosaccharide 100 g inulin, 100 g oligofructose, 100 g xylooligosaccharide, 90 g galactooligosaccharide, 50 g oligo-isomaltose, 50 g polydextrose, 50 g resistant dextrin, 50 g L arabinose and 40 g Konjac glucomannan
  • 230 g plant extract 50 g kelp extract, 80 g scutellaria extract, 50 g sorghum extract, 50 g sorghum extract
  • 120 g fungal extract 60 g mushroom extract, 40 g cordyceps extract, 20 g yeast) Extract
  • 10 g of sodium taurate 60 g mushroom extract, 40 g cordyceps extract, 20 g yeast
  • 220 g oligosaccharide 50 g galactooligosaccharide, 50 g oligo isomaltose, 50 g polydextrose, 50 g L arabinose and 20 g konjac glucomannan
  • 430 g plant extract 100 g kelp extract, 80 g huangjing extract
  • 300 g of fungal extract 100 g of mushroom extract, 50 g of cordyceps extract, 100 g of extract of Hericium erinaceus and 50 g of yeast extract
  • 25 g Sodium taurate and 25 g of Cistanche extract.
  • oligosaccharide 100 g inulin, 100 g oligofructose, 100 g xylooligosaccharide, 100 g galactooligosaccharide, 100 g oligo-isomalt
  • 300 g plant extract 100 g seaweed extract, 100 g yellow essence extract
  • 50g of alfalfa extract, 50g of alfalfa extract 50g of alfalfa extract
  • 150g of fungal extract 50g of mushroom extract, 50g of cordyceps extract, 50g of extract of Hericium erinaceus
  • 25g of sodium taurate 50g of Dendrobium Extract.
  • the oligosaccharide, the plant extract, the fungal extract, the sodium taurine and the Cistanche extract, the Dendrobium candidum extract are mixed and ground.
  • oligosaccharide 50g inulin, 50g oligofructose, 50g xylooligosaccharide, 50g galactooligosaccharide, 50g oligo-isomaltose, 50g polydextrose, 50g resistant dextrin
  • 350g plant extract 50 g seaweed extract, 50 g kelp extract, 100 g scutellaria extract, 50 g sorghum extract, 50 g sorghum extract and 50 g ginseng extract
  • 250 g fungal extract 100 g mushroom extract, 50 g cordyceps extract, 50 g monkey head
  • Mushroom extract and 50 g yeast extract 25 g sodium taurine; and 25 g Cistanche extract
  • 8 g Tremella extract 50g inulin, 50g oligofructose, 50g xylooligosaccharide, 50g galactooligosaccharide, 50g oligo-isomaltose,
  • the oligosaccharide, the plant extract, the fungal extract, the sodium taurine and the Cistanche extract, the white fungus extract are mixed and ground.
  • oligosaccharide 50g inulin, 50g xylooligosaccharide, 50g galacto-oligosaccharide, 30g oligo-isomaltose, 50g polydextrose, 50g resistant dextrin, 100gL arabinose and 40g konjac glucomannan
  • 320g plant extract 50g seaweed extract, 50g kelp extract, 50g scutellaria extract, 30g sorghum extract, 60g sorghum extract and 30g puerarin, 50g psyllium husk
  • 200g fungal extract 40 g of shiitake mushroom extract, 40 g of Cordyceps extract, 40 g of extract of Hericium erinaceus and 40 g of yeast extract
  • 20 g of sodium taurate and 40 g of Cistanche extract.
  • oligosaccharide 50g inulin, 50g xylooligosaccharide, 50g galacto-oligosaccharide, 30g oligo-isomaltose, 50g polydextrose, 50g resistant dextrin, 100gL arabinose and 40g konjac glucomannan
  • 320g plant extract 50g seaweed extract, 50g kelp extract, 50g scutellaria extract, 30g sorghum extract, 60g sorghum extract and 30g puerarin, 50g psyllium husk
  • 200g fungal extract 40 g of mushroom extract, 40 g of Cordyceps extract, 40 g of extract of Hericium erinaceus and 40 g of yeast extract
  • 20 g of sodium taurate and 40 g of Cistanche extract
  • 30 g of peony extract 50g inulin, 50g xylooligosaccharide, 50g galacto-oligosaccharide, 30g
  • mice Female BALb/c mice, 4 weeks old (body weight 20 ⁇ 1g), SPF grade, were purchased from Hubei Experimental Animal Research Center. Raised in the SPF animal room. Oral feed (fat calorie 10%) and high-fat high-protein feed (fat calories 40% or more) fed to mice were purchased from the Hubei Animal Research Center, and mice were given free access to water during feeding.
  • mice After adaptive feeding for 1 week, the mice were randomly divided into 3 groups, 12 in each group:
  • Blank control group continuous feeding of common feed
  • Conditional control group After feeding high-fat feed for 6 weeks, the feed was changed to normal feed for 1 week;
  • Example 5 The compound preparation of Example 5 was changed to 6 weeks after continuous feeding of the high fat diet, and each mouse was perfused for 1 week at a dose of 1 g/kg.
  • mice obesity model The results of induction of mouse obesity model can be seen from the table.
  • the changes in body weight of the high-fat diet (P ⁇ 0.05) in the control group and the experimental group were significantly higher than those in the control group.
  • the weight gain of the comparison group was ⁇ 20%.
  • Mouse obesity model The changes in body weight of the high-fat diet (P ⁇ 0.05) in the control group and the experimental group were significantly higher than those in the control group.
  • the weight gain of the comparison group was ⁇ 20%.
  • mice were fasted for 4 h, and the blood glucose concentration of the tail vein of the mice (Roche blood glucose meter) was measured. All blood samples were tested for blood insulin levels according to the Rat/Mouse Insulin ELISA Kit (Millipore, US) kit operating instructions.
  • mice were fasted for 12 h, and the body weight of the mice and the blood of the tail vein were measured to determine the blood glucose level of the fasting state of the mice;
  • the glucose solution was intragastrically administered with a 50% glucose sugar solution at a dose of 2 g/kg; the blood glucose concentration of the tail vein of the mouse was measured at intervals of 30 min, 60 min, 90 min, and 120 min.
  • mice were fasted for 12 h, and the mice were bled with blood. All blood samples were processed according to the kit instructions; cholesterol and free fatty acids and glycated serum protein kit (Wuhan Shengzhiyuan Biotechnology Co., Ltd.).
  • the results of oral glucose tolerance test showed that the glucose tolerance of the control group was abnormal (P ⁇ 0.01). Compared with the glucose tolerance of the blank group, the glucose tolerance of the experimental group was significantly lower than that of the control group. P ⁇ 0.05). It is indicated that the composite preparation can effectively reduce insulin resistance caused by obesity.
  • the data results involved in this test are all measurement data, and all data are in mean and standard deviation. Said.
  • the composite preparation for improving insulin resistance of the embodiments of the present disclosure has good safety and can effectively improve insulin resistance;
  • the preparation method of the composite preparation is simple in process and easy to industrialize.
  • the use of the composite preparation for improving insulin resistance of the embodiments of the present disclosure is a composite preparation for preparing an oral preparation for improving insulin resistance.
  • the composite preparation of the present disclosure has good safety and can effectively regulate intestinal flora.
  • the preparation preparation of the composite preparation of the present disclosure is simple and easy to industrialize production.
  • the use of the composite preparation for improving insulin resistance of the embodiments of the present disclosure is a composite preparation for preparing an oral preparation for improving insulin resistance.

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Abstract

一种改善胰岛素抵抗的复合制剂，由按质量百分数计的以下原料制备而成：20％-65％低聚糖；21％-44％植物提取物；10％-30％真菌提取物；0.5％-5％牛磺酸钠；以及0.5％-5％肉苁蓉提取物。该复合制剂能有效调节肠道菌群，改善胰岛素抵抗，用于治疗代谢综合征、肥胖症、2型糖尿病、高胰岛素血症、多囊卵巢综合症、高血糖症、高血压或血脂紊乱等症。该复合制剂是将原料混合、研磨即得，工艺简单，易产业化生产。

Description

一种改善胰岛素抵抗的复合制剂及制备方法与应用
相关申请的交叉引用
本申请要求于2018年04月27日提交中国专利局的申请号为201810393624.2、名称为“一种改善胰岛素抵抗的复合制剂及制备方法与应用”的中国专利申请，于2018年04月27日提交中国专利局的申请号为201810395768.1、名称为“一种提高肠道中SCFA产生菌的复合制剂及制备方法与应用”的中国专利申请，于2018年04月27日提交中国专利局的申请号为201810394911.5、名称为“一种调控脂肪代谢基因表达的复合制剂及制备方法与应用”的中国专利申请，以及于2018年04月27日提交中国专利局的申请号为201810395759.2、名称为“一种提高肠道中AKK菌/致病菌比值的复合制剂及制备方法与应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本公开涉及口服制剂领域，且特别涉及一种改善胰岛素抵抗的复合制剂及制备方法与应用。
背景技术
经研究表明，人体内的肠道菌群变化会导致肥胖，其产生机制为：高热量食物经过牙齿的咀嚼和胃的初步降解之后进入肠道，寄居在肠道里的微生物负责完成剩下的消化工作；在微生物的发酵过程中，会有大量的乙酸盐产生，这些乙酸盐被肠道吸收，随血液循环穿过血脑屏障，进入大脑；进入大脑的乙酸盐会激活副交感神经系统。被乙酸盐激活的副交感神经会给胰岛发出分泌胰岛素(insulin)的指令，于是β细胞开始大量分泌胰岛素，细胞启动储存能量的程序；于此同时，副交感神经又给胃发出了释放饥饿激素(ghrelin)和胃泌素(gastrin)的指令，饥饿激素大量产生，饥饿感随之而来。
另外，长期摄入高脂肪食物会导致肠道菌群失调，使肠道中存在更高水平的乙酸，这种正向的调节机制使食量越来越大，从而促进肥胖，和产生胰岛素抵抗。目前还没有通过改善胰岛素抵抗来达到治疗肥胖症的口服制剂。
因此，需要一种能有效改善胰岛素抵抗、且安全性高的口服制剂。
发明内容
本公开的目的包括例如提供一种改善胰岛素抵抗的复合制剂，其安全性好，能有效改 善胰岛素抵抗。
本公开的目的还包括例如提供一种改善胰岛素抵抗的复合制剂的制备方法，该工艺简单，易产业化生产。
本公开的目的还包括例如提供一种改善胰岛素抵抗的复合制剂的应用，复合制剂用于制备改善胰岛素抵抗的口服制剂。
本公开提供一种改善胰岛素抵抗的复合制剂，其是由以下原料制备而成，按质量百分数计，原料包括：
Figure PCTCN2019082127-appb-000001
在一种或多种实施方式中，低聚糖选自菊粉、低聚果糖、低聚木糖、低聚半乳糖、低聚异麦芽糖、聚葡萄糖、抗性糊精、L阿拉伯糖和魔芋葡甘聚糖组成的组合中的至少一种。
在一种或多种实施方式中，植物提取物选自海藻提取物、昆布提取物、黄精提取物、茯苓提取物、枸杞提取物、葛根黄酮和人参提取物、圆苞车前子壳组成的组合中的至少一种。
在一种或多种实施方式中，真菌提取物选自香菇提取物、虫草提取物、灵芝提取物、猴头菇提取物和酵母提取物组成的组合中的至少一种。
在一种或多种实施方式中，原料还包括银耳提取物，银耳提取物的使用量为真菌提取物质量的1％-5％。
在一种或多种实施方式中，原料还包括铁皮石斛提取物，铁皮石斛提取物为植物提取物质量的1％-5％。
本公开提供一种上述的改善胰岛素抵抗的复合制剂的制备方法，其包括以下步骤：
将低聚糖、植物提取物、真菌提取物、牛磺酸钠和肉苁蓉提取物混合、研磨即得。
在一种或多种实施方式中，植物提取物的制备方法如下：
将选取的植物原料清洗、粉碎后混合，添加4-6倍重量、60℃-80℃的热水提取3-4小时，过滤得到提取液；将提取液浓缩后，再用乙醇沉淀得到粗品多糖；将粗品多糖经层析分离、蒸馏水洗脱，得到多糖液；将多糖液浓缩后，再用乙醇沉淀，干燥得到粉状的植物提取物。
在一种或多种实施方式中，真菌提取物的制备方法如下：
将真菌原料干燥后充分研磨，再加10-20倍体积纯水，于70-80℃下提取3-4小时，过 滤得到提取液；将提取液经3000-5000r/min离心10-15分钟后取上清液；将上清液浓缩后，用乙醇沉淀；取沉淀，干燥后得到粉状的真菌提取物。
本公开提供一种上述的改善胰岛素抵抗的复合制剂的应用，复合制剂用于制备减少肠道中厚壁菌门/拟杆菌门的比值，增大SCFA产生菌的比重的口服制剂。
本公开实施方式提供本公开所述的改善胰岛素抵抗的复合制剂用于改善胰岛素抵抗或治疗或预防胰岛素抵抗相关疾病或疾患的应用。
本公开实施方式提供一种治疗或预防胰岛素抵抗或胰岛素抵抗相关疾病或疾患的方法，包括向有需要的受试者给予本公开所述的改善胰岛素抵抗的复合制剂，或本公开所述的改善胰岛素抵抗的复合制剂以及药学上可接受的载体。
在一种或多种实施方式中，所述胰岛素抵抗相关疾病或疾患为代谢综合征、肥胖症、2型糖尿病、高胰岛素血症、多囊卵巢综合症、高血糖症、高血压或血脂紊乱。
在一种或多种实施方式中，所述改善胰岛素抵抗的复合制剂为口服粉末制剂。
本公开实施方式的改善胰岛素抵抗的复合制剂及制备方法与应用的有益效果至少包括：本公开实施方式的改善胰岛素抵抗的复合制剂，其是由按质量百分数计的以下原料制备而成：20％-65％低聚糖；21％-44％植物提取物；10％-30％真菌提取物；0.5％-5％牛磺酸钠；以及0.5％-5％肉苁蓉提取物，该复合制剂的安全性好，能有效调节肠道菌群。复合制剂的制备方法是将低聚糖、植物提取物、真菌提取物、牛磺酸钠和肉苁蓉提取物混合、研磨即得，该工艺简单，易产业化生产。本公开实施方式的改善胰岛素抵抗的复合制剂的应用是复合制剂用于制备改善胰岛素抵抗的口服制剂。
具体实施方式
为使本公开实施方式的目的、技术方案和优点更加清楚，下面将对本公开实施方式中的技术方案进行清楚、完整地描述。实施方式中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市售购买获得的常规产品。
下面对本公开实施方式的改善胰岛素抵抗的复合制剂及制备方法与应用进行具体说明。
本公开实施方式提供一种改善胰岛素抵抗的复合制剂，其是由以下原料制备而成，按质量百分数计，原料包括：20％-65％低聚糖；21％-44％植物提取物；10％-30％真菌提取物；0.5％-5％牛磺酸钠；以及0.5％-5％肉苁蓉提取物。优选的，原料包括：33％-52％低聚糖；29％-36％植物提取物；15％-25％真菌提取物；2％-5％牛磺酸钠；以及1％-4％肉苁蓉提取物。
在一种或多种实施方式中，低聚糖选自菊粉、低聚果糖、低聚木糖、低聚半乳糖、低 聚异麦芽糖、聚葡萄糖、抗性糊精、L阿拉伯糖和魔芋葡甘聚糖组成的组合中的至少一种。例如，按质量百分数计，原料包括1％-10％菊粉、1％-5％低聚木糖、1.5％-10％低聚半乳糖、1％-5％低聚异麦芽糖、5％-10％聚葡萄糖、5％-10％抗性糊精、5％-10％L阿拉伯糖和0.5％-5％魔芋葡甘聚糖。
在一种或多种实施方式中，植物提取物是采用植物提取得到的，多为植物多糖。本实施方式中，植物提取物选自海藻提取物、昆布提取物、黄精提取物、茯苓提取物、枸杞提取物、葛根黄酮(即葛根提取物)和人参提取物、圆苞车前子壳组成的组合中的至少一种。圆苞车前子壳是人工种植的车前科车前属圆苞车前(拉丁学名：Plantago ovata)种子的外壳，可以直接磨粉使用。例如，按质量百分数计，原料包括5％-10％海藻提取物、3％-5％昆布提取物、1.5％-5％黄精提取物、3％-5％茯苓提取物、5％-10％枸杞提取物、1％-3％葛根黄酮、2.5％-6％圆苞车前子壳。
在一种或多种实施方式中，真菌提取物是采用真菌提取得到的，多为真菌多糖。本实施方式中，真菌提取物选自香菇提取物、虫草提取物、灵芝提取物、猴头菇提取物和酵母提取物组成的组合中的至少一种。例如，按质量百分数计，原料包括5％-10％香菇提取物、0.5％-5％虫草提取物、0.5％-5％猴头菇提取物和4％-10％酵母提取物。
在一种或多种实施方式中，原料还可以包括银耳提取物，银耳提取物的使用量为真菌提取物质量的1％-5％。
在一种或多种实施方式中，原料还包括铁皮石斛提取物，铁皮石斛提取物为植物提取物质量的1％-5％。
在一种或多种实施方式中，原料还包括鲜花提取物，鲜花提取物的使用量为植物提取物质量的2％-10％。鲜花提取物选自牡丹花提取物、金银花提取物和蒲公英提取物组成的组合中的至少一种。
在一种或多种实施方式中，复合制剂采用低聚糖、植物提取物、真菌提取物、牛磺酸钠和肉苁蓉提取物制成，其中低聚糖、植物提取物、真菌提取物、牛磺酸钠协同作用，能够有效改善胰岛素抵抗。
本公开实施方式提供一种上述的改善胰岛素抵抗的复合制剂的制备方法，其包括以下步骤：
将低聚糖、植物提取物、真菌提取物、牛磺酸钠和肉苁蓉提取物混合、研磨即得。
在一种或多种实施方式中，植物提取物可以购买得到的高纯度提取物，也可以按照以下制备方法制备得到：
将选取的植物原料清洗、粉碎后混合，添加4-6倍重量、60℃-80℃的热水提取3-4小时，过滤得到提取液；将提取液浓缩后，再用乙醇沉淀得到粗品多糖；将粗品多糖经层析 分离、蒸馏水洗脱，得到多糖液；将多糖液浓缩后，再用乙醇沉淀，干燥得到粉状的植物提取物。
在一种或多种实施方式中，真菌提取物可以购买得到的高纯度提取物，也可以按照以下制备方法制备得到：
将真菌原料干燥后充分研磨，再加10-20倍体积纯水，于70-80℃下提取3-4小时，过滤得到提取液；将提取液经3000-5000r/min离心10-15分钟后取上清液；将上清液浓缩后，用乙醇沉淀；取沉淀，干燥后得到粉状的真菌提取物。
在一种或多种实施方式中，鲜花提取物可以购买得到，也可以按照以下制备方法制备得到：
将鲜花原料加入酵母进行发酵，过滤、后熟、澄清得到花果发酵液；将发酵液过滤、浓缩，得到粉状的鲜花提取物。
在一种或多种实施方式中，肉苁蓉提取物可以购买得到，也可以按照以下制备方法制备得到：
称取肉苁蓉置微波提取装置中，微波功率500W-900W，温度70℃，共提取3次，第1次加50％-90％的乙醇，提取10min-30min；第2次加50％-90％乙醇，提取10min-30min；第3次加蒸馏水，提取20min-40min。
再将第1、2次的乙醇提取液浓缩，除去乙醇，再加入第3次的水提取液，混合，浓缩，得到粉状的肉苁蓉提取物。
本公开实施方式提供一种上述的改善胰岛素抵抗的复合制剂的应用。复合制剂具有改善胰岛素抵抗的功能，从而提高对胰岛素敏感性。相应的，复合制剂可用于制备改善胰岛素抵抗的口服制剂。更具体的，复合制剂用于制备改善肥胖者肥胖症状的口服制剂。
以下结合实施例对本公开的特征和性能作进一步的详细描述。
实施例1
本实施例提供一种复合制剂，其是采用以下制备方法制得：
准备原料：630g低聚糖(100g菊粉、100g低聚果糖、100g低聚木糖、90g低聚半乳糖、50g低聚异麦芽糖、50g聚葡萄糖、50g抗性糊精、50gL阿拉伯糖和40g魔芋葡甘聚糖)；230g植物提取物(50g昆布提取物、80g黄精提取物、50g茯苓提取物、50g枸杞提取物)；120g真菌提取物(60g香菇提取物、40g虫草提取物、20g酵母提取物)；10g牛磺酸钠；以及10g肉苁蓉提取物。
将上述低聚糖、植物提取物、真菌提取物、牛磺酸钠和肉苁蓉提取物混合、研磨即得。
实施例2
本实施例提供一种复合制剂，其是采用以下制备方法制得：
准备原料：220g低聚糖(50g低聚半乳糖、50g低聚异麦芽糖、50g聚葡萄糖、50gL阿拉伯糖和20g魔芋葡甘聚糖)；430g植物提取物(100g昆布提取物、80g黄精提取物、100g茯苓提取物、100g枸杞提取物、20g葛根黄酮和30g人参提取物)；300g真菌提取物(100g香菇提取物、50g虫草提取物、100g猴头菇提取物和50g酵母提取物)；25g牛磺酸钠；以及25g肉苁蓉提取物。
将上述低聚糖、植物提取物、真菌提取物、牛磺酸钠和肉苁蓉提取物混合、研磨即得。
实施例3
本实施例提供一种复合制剂，其是采用以下制备方法制得：
准备原料：500g低聚糖(100g菊粉、100g低聚果糖、100g低聚木糖、100g低聚半乳糖、100g低聚异麦芽糖)；300g植物提取物(100g海藻提取物、100g黄精提取物、50g茯苓提取物、50g枸杞提取物)；150g真菌提取物(50g香菇提取物、50g虫草提取物、50g猴头菇提取物)；25g牛磺酸钠；以及25g肉苁蓉提取物、10g铁皮石斛提取物。
将上述低聚糖、植物提取物、真菌提取物、牛磺酸钠和肉苁蓉提取物、铁皮石斛提取物混合、研磨即得。
实施例4
本实施例提供一种复合制剂，其是采用以下制备方法制得：
准备原料：350g低聚糖(50g菊粉、50g低聚果糖、50g低聚木糖、50g低聚半乳糖、50g低聚异麦芽糖、50g聚葡萄糖、50g抗性糊精)；350g植物提取物(50g海藻提取物、50g昆布提取物、100g黄精提取物、50g茯苓提取物、50g枸杞提取物和50g人参提取物)；250g真菌提取物(100g香菇提取物、50g虫草提取物、50g猴头菇提取物和50g酵母提取物)；25g牛磺酸钠；以及25g肉苁蓉提取物；8g银耳提取物。
将上述低聚糖、植物提取物、真菌提取物、牛磺酸钠和肉苁蓉提取物、银耳提取物混合、研磨即得。
实施例5
本实施例提供一种复合制剂，其是采用以下制备方法制得：
准备原料：420g低聚糖(50g菊粉、50g低聚木糖、50g低聚半乳糖、30g低聚异麦芽糖、50g聚葡萄糖、50g抗性糊精、100gL阿拉伯糖和40g魔芋葡甘聚糖)；320g植物提取物(50g海藻提取物、50g昆布提取物、50g黄精提取物、30g茯苓提取物、60g枸杞提取物和30g葛根黄酮、50g圆苞车前子壳)；200g真菌提取物(40g香菇提取物、40g虫草提取物、40g猴头菇提取物和40g酵母提取物)；20g牛磺酸钠；以及40g肉苁蓉提取物。
将上述低聚糖、植物提取物、真菌提取物、牛磺酸钠和肉苁蓉提取物混合、研磨即得。
实施例6
本实施例提供一种复合制剂，其是采用以下制备方法制得：
准备原料：420g低聚糖(50g菊粉、50g低聚木糖、50g低聚半乳糖、30g低聚异麦芽糖、50g聚葡萄糖、50g抗性糊精、100gL阿拉伯糖和40g魔芋葡甘聚糖)；320g植物提取物(50g海藻提取物、50g昆布提取物、50g黄精提取物、30g茯苓提取物、60g枸杞提取物和30g葛根黄酮、50g圆苞车前子壳)；200g真菌提取物(40g香菇提取物、40g虫草提取物、40g猴头菇提取物和40g酵母提取物)；20g牛磺酸钠；以及40g肉苁蓉提取物；30g牡丹花提取物。
将上述低聚糖、植物提取物、真菌提取物、牛磺酸钠和肉苁蓉提取物、牡丹花提取物混合、研磨即得。
以下通过动物实验对本公开实施例的复合制剂的功效进行验证。
(1)实验动物
雌性BALb/c小鼠，4周龄(体重20±1g)，SPF级，购于湖北省实验动物研究中心。饲养在SPF级动物房。喂养小鼠的普通饲料(脂肪热量10％)和高脂高蛋白饲料(脂肪热量40％以上)均购于湖北省动物研究中心，小鼠在喂养期间自由饮水。
(2)分组与干预
小鼠适应性喂养1周后进行随机分组共分为3组，每组12只：
1、空白对照组：连续喂饲普通饲料；
2、条件对照组：连续喂饲高脂饲料6周后改为喂饲普通饲料1周；
3、实验组：连续喂饲高脂饲料6周后改为喂实施例5的复合制剂，每只小鼠每天以1g/kg的剂量灌喂1周。
(3)肥胖小鼠模型的建立：
表1肥胖小鼠模型
Figure PCTCN2019082127-appb-000002
*P<0.05
小鼠肥胖模型诱导结果从表中可以看出条件对照组和实验组饲喂6周高脂饲料体重变化(P<0.05)显著大于对照组；对比空白组体重增加≥20％可视为典型的小鼠肥胖模型。
(4)实验过程：
血糖与血胰岛素测定：
小鼠禁食4h，测量小鼠尾静脉血液血糖浓度(罗氏血糖仪)，所有血样均按照Rat/MouseInsulinELISAKit(Millipore，US)试剂盒操作说明检测血胰岛素水平。
口服葡糖糖耐受实验(OGTT)：
小鼠禁食12h，称量小鼠体重和取尾静脉血的测定小鼠空腹状态血糖值浓度；
用50％浓度的葡糖糖溶液，以2g/kg的剂量灌胃喂葡萄糖溶液；间隔30min，60min，90min，120min测量小鼠尾静脉的血糖浓度。
血脂、糖化血清蛋白、血胆固醇的测定：
小鼠禁食12h，小鼠眼眶取血，所有血样均按照试剂盒操作说明操作；胆固醇及游离脂肪酸及糖化血清蛋白试剂盒(武汉生之源生物科技股份有限公司)。
(5)结果分析：
本实验所涉及的数据结果均为计量资料，全部数据以均数和标准差
Figure PCTCN2019082127-appb-000003
表示。
表2不同分组小鼠的OGTT结果
Figure PCTCN2019082127-appb-000004
对比空白组**P<0.01，对比条件对照组#P<0.05
高脂饲料饲喂6周后，口服葡萄糖耐量实验结果显示条件对照组的糖耐受异常显著(P<0.01)；对比空白组糖耐量，实验组糖耐量显著低于条件对照组的糖耐量(P<0.05)。说明复合制剂可有效降低肥胖导致的胰岛素抵抗。
表3不同分组小鼠血糖、血胰岛素及血脂水平的变化
Figure PCTCN2019082127-appb-000005
对比空白组*P<0.05，**P<0.01，对比条件对照组#P<0.05
试验至第8周结束时，条件对照组的小鼠空腹血糖、血胰岛素、血脂水平均明显高于空白组(P<0.05)；对比空白组数据实验组小鼠血糖、血胰岛素水平较高但显著低于条件对照组小鼠水平(P<0.05)。说明复合制剂可有效降低肥胖导致的“三高”。
按照上述相同的动物实验方法对本公开其他实施例的复合制剂的功效进行验证，结果显示本公开其他实施例的复合制剂具有相同或类似的功效。由上述不同分组小鼠血糖与血胰岛素测定，口服葡糖糖耐受实验和血糖、血胰岛素及血脂水平的变化可知，本公开实施例的复合菌剂具有改善胰岛素抵抗的作用，因此，本公开实施例的复合菌剂能改善肥胖者的肥胖症状。
以下通过临床实验对本公开实施例的复合制剂的功效进行验证。
(1)实验对象：
研究对象的总体特征：有430名受试者参与，其中男性202名，平均年龄为34.5±11.2岁；女性228名，平均年龄为36.9±12.1岁。本次项目的所有受试者随机选自国内10个不同省份地区。
已有研究表明，男性体脂率(PBF％)平均值为22.7％，低于女性的28.9％，标准体脂率(PBF％))如下：
表4标准体脂率
Figure PCTCN2019082127-appb-000006
表5成年人超重与肥胖评判标准
Figure PCTCN2019082127-appb-000007
表6受试者体型分布
Figure PCTCN2019082127-appb-000008
(2)干预治疗
不同体型分组的受试者统一剂量服用实施例6的复合制剂；服用复合制剂期间(7天)禁食；禁食前，3天预先调整饮食，清淡素食为主。禁食期：本产品完全代替一日三餐，早中晚各服用15g/袋，粉剂使用37℃温水冲服，每日饮水3-5L。禁食期之后经7天复食期恢复正常饮食。
(3)数据统计：
本试验所涉及的数据结果均为计量资料，全部数据以均数和标准差
Figure PCTCN2019082127-appb-000009
表示。
表7不同分组体脂率变化
Figure PCTCN2019082127-appb-000010
Figure PCTCN2019082127-appb-000011
对比干预前*P＜0.05
结果显示，连续7天使用复合制剂代替正常饮食的干预治疗的减脂效果具有统计学显 著意义(P＜0.05)。
综上所述，本公开实施例的改善胰岛素抵抗的复合制剂，其安全性好，能有效改善胰岛素抵抗；该复合制剂的制备方法的工艺简单，易产业化生产。本公开实施例的改善胰岛素抵抗的复合制剂的应用是复合制剂用于制备改善胰岛素抵抗的口服制剂。
以上所描述的实施例是本公开一部分实施例，而不是全部的实施例。本公开的实施例的详细描述并非旨在限制要求保护的本公开的范围，而是仅仅表示本公开的选定实施例。基于本公开中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本公开保护的范围。
工业实用性
本公开的复合制剂的安全性好，能有效调节肠道菌群。本公开的复合制剂的制备工艺简单，易产业化生产。本公开实施例的改善胰岛素抵抗的复合制剂的应用是复合制剂用于制备改善胰岛素抵抗的口服制剂。

Claims (15)

  1. 一种改善胰岛素抵抗的复合制剂，其特征在于，其是由以下原料制备而成，按质量百分数计，所述原料包括：
    Figure PCTCN2019082127-appb-100001
  2. 根据权利要求1所述的改善胰岛素抵抗的复合制剂，其特征在于，所述低聚糖选自菊粉、低聚果糖、低聚木糖、低聚半乳糖、低聚异麦芽糖、聚葡萄糖、抗性糊精、L阿拉伯糖和魔芋葡甘聚糖组成的组合中的至少一种。
  3. 根据权利要求1或2所述的改善胰岛素抵抗的复合制剂，其特征在于，所述植物提取物选自海藻提取物、昆布提取物、黄精提取物、茯苓提取物、枸杞提取物、葛根黄酮和人参提取物、圆苞车前子壳组成的组合中的至少一种。
  4. 根据权利要求1至3中任一项所述的改善胰岛素抵抗的复合制剂，其特征在于，所述真菌提取物选自香菇提取物、虫草提取物、灵芝提取物、猴头菇提取物和酵母提取物组成的组合中的至少一种。
  5. 根据权利要求1至4中任一项所述的改善胰岛素抵抗的复合制剂，其特征在于，所述原料还包括银耳提取物，所述银耳提取物的使用量为所述真菌提取物质量的1％-5％。
  6. 根据权利要求1至5中任一项所述的改善胰岛素抵抗的复合制剂，其特征在于，所述原料还包括铁皮石斛提取物，所述铁皮石斛提取物为所述植物提取物质量的1％-5％。
  7. 根据权利要求1至4中任一项所述的改善胰岛素抵抗的复合制剂，其特征在于，所述原料包括630g低聚糖；230g植物提取物；120g真菌提取物；10g牛磺酸钠；以及10g肉苁蓉提取物，
    其中，所述低聚糖由100g菊粉、100g低聚果糖、100g低聚木糖、90g低聚半乳糖、50g低聚异麦芽糖、50g聚葡萄糖、50g抗性糊精、50gL阿拉伯糖和40g魔芋葡甘聚糖组成，
    所述植物提取物由50g昆布提取物、80g黄精提取物、50g茯苓提取物和50g枸杞提取物组成，以及
    所述真菌提取物由60g香菇提取物、40g虫草提取物和20g酵母提取物组成。
  8. 一种如权利要求1至7中任一项所述的改善胰岛素抵抗的复合制剂的制备方法，其特征在于，其包括以下步骤：
    将低聚糖、植物提取物、真菌提取物、牛磺酸钠和肉苁蓉提取物混合、研磨即得。
  9. 根据权利要求1至7中任一项所述的改善胰岛素抵抗的复合制剂或根据权利要求8所述的方法，其特征在于，所述植物提取物的制备方法如下：
    将选取的植物原料清洗、粉碎后混合，添加4-6倍重量、60℃-80℃的热水提取3-4小时，过滤得到提取液；将提取液浓缩后，再用乙醇沉淀得到粗品多糖；将粗品多糖经层析分离、蒸馏水洗脱，得到多糖液；将多糖液浓缩后，再用乙醇沉淀，干燥得到粉状的植物提取物。
  10. 根据权利要求1至7中任一项所述的改善胰岛素抵抗的复合制剂或根据权利要求8所述的方法，其特征在于，所述真菌提取物的制备方法如下：
    将真菌原料干燥后充分研磨，再加10-20倍体积纯水，于70-80℃下提取3-4小时，过滤得到提取液；将提取液经3000-5000r/min离心10-15分钟后取上清液；将上清液浓缩后，用乙醇沉淀；取沉淀，干燥后得到粉状的真菌提取物。
  11. 一种如权利要求1至7中任一项所述的改善胰岛素抵抗的复合制剂的应用，其特征在于，所述复合制剂用于制备改善胰岛素抵抗的口服制剂。
  12. 根据权利要求1至7中任一项所述的改善胰岛素抵抗的复合制剂用于改善胰岛素抵抗或治疗或预防胰岛素抵抗相关疾病或疾患的应用。
  13. 一种治疗或预防胰岛素抵抗或胰岛素抵抗相关疾病或疾患的方法，包括向有需要的受试者给予如权利要求1至7中任一项所述的改善胰岛素抵抗的复合制剂，或如权利要求1至7中任一项所述的改善胰岛素抵抗的复合制剂以及药学上可接受的载体。
  14. 根据权利要求12所述的应用或权利要求13所述的方法，其中所述胰岛素抵抗相关疾病或疾患为代谢综合征、肥胖症、2型糖尿病、高胰岛素血症、多囊卵巢综合症、高血糖症、高血压或血脂紊乱。
  15. 根据权利要求11或12所述的应用，或权利要求13所述的方法，所述改善胰岛素抵抗的复合制剂为口服粉末制剂。
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