WO2014090122A1 - Compositions pharmaceutiques pour réduire le niveau de sucre, leurs procédés de préparation et leurs applications - Google Patents

Compositions pharmaceutiques pour réduire le niveau de sucre, leurs procédés de préparation et leurs applications Download PDF

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WO2014090122A1
WO2014090122A1 PCT/CN2013/088841 CN2013088841W WO2014090122A1 WO 2014090122 A1 WO2014090122 A1 WO 2014090122A1 CN 2013088841 W CN2013088841 W CN 2013088841W WO 2014090122 A1 WO2014090122 A1 WO 2014090122A1
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parts
pharmaceutical composition
water
spray
portions
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PCT/CN2013/088841
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English (en)
Chinese (zh)
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吴以岭
田书彦
赵韶华
高学东
李向军
刘敏彦
董超
秦拢
王宏涛
唐思文
徐登峰
安军永
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石家庄以岭药业股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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)
    • 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)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A61K36/284—Atractylodes
    • 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)
    • A61K36/42—Cucurbitaceae (Cucumber family)
    • A61K36/424—Gynostemma
    • 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)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • A61K36/537—Salvia (sage)
    • 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)
    • A61K36/60—Moraceae (Mulberry family), e.g. breadfruit or fig
    • A61K36/605—Morus (mulberry)
    • 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)
    • A61K36/77—Sapindaceae (Soapberry family), e.g. lychee or soapberry
    • 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)
    • A61K36/80—Scrophulariaceae (Figwort family)
    • A61K36/808—Scrophularia (figwort)
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • 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

Definitions

  • the invention belongs to the field of pharmaceutical technology.
  • the present invention relates to a medicament for treating diabetes, a preparation method thereof and a pharmaceutical use. Background technique
  • Diabetes mellitus is an endocrine and metabolic disease characterized by chronic hyperglycemia caused by various causes. It is a common and frequently-occurring disease that seriously endangers human health and has become a global health concern. Among them, type I type I diabetes is also called adult-onset diabetes, and it usually occurs after 35-40 years old, accounting for more than 90% of diabetic patients. According to the 2002 epidemiological survey of diabetes, the prevalence of urban diabetes in China was 4.5%, and that in rural areas was 1.8%. In 2007-2008, the Diabetes Association of China Medical Association was held in nearly 50,000 people in 14 provinces and cities nationwide. According to the epidemiological survey, the prevalence rate of diabetes in China was over 9.7%, and the pre-diabetes prevalence rate was 15.5%.
  • hypoglycemic drugs used for the treatment of diabetes mainly include sulfonylureas and glinides which promote insulin secretion, and biguanides, ⁇ -glucosidase inhibitors and insulin sensitizers which increase insulin sensitivity, etc.
  • People with diabetes need to take medication for life. Long-term use of the above hypoglycemic agents can cause many side effects and adverse reactions.
  • sulfonylureas and glinides are mainly hypoglycemic. After taking the medicine, there will be palpitation, sweating and hunger. In severe cases, there may even be disturbances of consciousness, and sometimes allergic reactions such as rash and liver and kidney damage may occur.
  • the biguanides are mainly gastrointestinal reactions (nausea, loss of appetite) and lactic acidosis (weakness, disturbance of consciousness, and even coma).
  • Some patients have liver and kidney dysfunction and allergic reactions as well as large cell anemia reactions; the main side effect of ⁇ -glycosidase inhibitors is gastrointestinal reactions; the biggest side effect of insulin sensitizers is liver damage and increased blood. Capacity, which increases the burden on the heart.
  • side effects such as hypoglycemia, subcutaneous lipodystrophy, insulin allergy, hyperinsulinemia, insulin resistance, insulin edema, refractive error, and weight gain.
  • Traditional Chinese medicine has accumulated rich theoretical and practical experience in the prevention and treatment of diabetes.
  • Traditional Chinese medicine preparations have comprehensive conditioning advantages, and have a significant role in improving clinical symptoms, lowering blood sugar, urine sugar, improving blood circulation, delaying and reducing chronic complications such as blood vessels and neuropathy, and improving quality of life. highly valued.
  • Yuquan Pill, Jiangtang Capsule, Diabetes Tablet for Yin Deficiency and Heat Syndrome Xiaoke Ping Tablet for Yin Deficiency, Qi and Yin Deficiency Syndrome
  • Jinqi Jiangtang Tablet for Internal Heat Qi Deficiency Shenjing Zhike Pills for Qiyin deficiency and internal heat and zinc injury syndrome
  • Jiangtangshu Capsule, Shenqi Jiangtang Capsule, Maiqi Jiangtang Capsule, Shiwei Yuquan Capsule, Diabetes for Qi and Yin Deficiency Syndrome Le capsule, Xiaokeling tablets, hypoglycemic tablets, thirsty Lening capsules, etc.
  • the present inventors have explored the pathogenesis and pathological mechanism of diabetes (diabetes), and after a lot of research and experiments, proposed a new drug, which is a pure Chinese medicine compound preparation, which can restore the spleen.
  • the normal function of the water-feeding solution is to correct the imbalance in the use of the water and the metabolic process of the water, and to eliminate the symptoms of stagnation and thirst.
  • the present invention provides a pharmaceutical composition for hypoglycemic, the raw material of the pharmaceutical composition comprising, by weight: 4 to 12 parts of Atractylodes Rhizome, 5 to 15 parts of Polygonatum, and 5 to 15 parts of Scrophularia 15 parts, 5 to 15 parts of pueraria, 5 to 15 parts of Gynostemma pentaphyllum; preferably, the drug substance of the pharmaceutical composition of the present invention is in parts by weight from the atractylodes 4 to 12 parts, 5 to 15 parts of Polygonatum, 5 to 15 parts of Scrophularia, 5 to 15 parts of Pueraria, 5 to 15 parts of Gynostemma pentaphyllum; Preferably, the drug substance of the pharmaceutical composition is 4 parts by weight of amaranth 15 parts of Huangjing, 5 parts of Scrophulariae, 15 parts of Radix Puerariae, 5 parts of Gynostemma pentaphyllum, or preferably 12 parts of Atractylodes Rh
  • the drug substance of the pharmaceutical composition comprises, in parts by weight: 6 to 10 parts of Atractylodes Rhizome, 8 to 12 parts of Polygonatum, 8 to 12 parts of Scrophulariae, 8 to 12 parts of Radix Puerariae, and 8 to 12 parts of Gynostemma pentaphyllum;
  • the drug substance of the pharmaceutical composition of the present invention comprises 6 to 10 parts by weight of amaranth, 8 to 12 parts of yellow essence, 8 to 12 parts of scrophularia, 8 to 12 parts of pueraria, and 8 to 12 parts of gynostemma in parts by weight. ;
  • the drug substance of the pharmaceutical composition is composed of 6 parts of fried atractylodes, 12 parts of scutellaria, 8 parts of scrophularia, 12 parts of puerarin, 8 parts of gynostemma, or preferably 10 parts of fried atractylodes, in parts by weight, 8 parts, 12 parts of Scrophularia, 8 parts of Pueraria, 12 parts of Gynostemma.
  • the raw material medicine of the pharmaceutical composition further comprises: salvia miltiorrhiza, mulberry leaf, anemarrhena, ghost arrow feather, litchi core.
  • the composition of the present invention consists of Atractylodes macrocephala, Rhizoma Polygonati, Radix Salviae Miltiorrhizae, Radix Scrophulariae, Radix Puerariae, Mulberry Leaf, Anemarrhenae, ghost Arrow, Gynostemma, and Litchi.
  • the pharmaceutical composition is made up of the following bulk drugs in parts by weight:
  • the pharmaceutical composition is prepared from the following raw materials: 12 parts of Atractylodes Rhizome, 5 parts of Polygonatum, 30 parts of Salvia miltiorrhiza, 5 parts of Scrophularia, 15 parts of Pueraria, 5 parts of Mulberry, 15 parts of Anemarrhena, 15 parts of Ghost Arrow 5 servings, 15 parts of Gynostemma pentaphyllum, 7 parts of litchi core;
  • the pharmaceutical composition is prepared from the following raw materials: 4 parts of Atractylodes Rhizome, 15 parts of Polygonatum, 10 parts of Salvia miltiorrhiza, 15 parts of Scrophularia, 5 parts of Radix Puerariae, 15 parts of Mulberry leaves, 5 parts of Anemarrhenae, and 5 Parts, 5 parts of Gynostemma pentaphyllum, 22 parts of litchi core;
  • the pharmaceutical composition is prepared from the following raw materials: 12 parts of Atractylodes Rhizome, 15 parts of Polygonatum, 30 parts of Salvia miltiorrhiza, 15 parts of Scrophularia, 15 parts of Pueraria, 15 parts of Mulberry, 15 parts of Anemarrhena, 15 parts of Ghost Arrow 15 Parts, 15 parts of Gynostemma pentaphyllum, 22 parts of litchi core.
  • the pharmaceutical composition is made of the following drug substance:
  • the pharmaceutical composition is made of the following bulk drugs: 6 parts of fried atractylodes, 12 parts of yellow essence, salvia miltiorrhiza 12 Serve, 12 parts of Scrophularia, 8 parts of Pueraria, 12 parts of mulberry leaves, 8 parts of Zhimu, 12 pieces of ghost arrow feather, 8 parts of Gynostemma pentaphyllum, 18 parts of lychee core;
  • the pharmaceutical composition is prepared from the following raw materials: 10 parts of Atractylodes Rhizome, 8 parts of Polygonatum, 24 parts of Salvia miltiorrhiza, 8 parts of Scrophularia, 12 parts of Pueraria, 8 parts of Mulberry, 12 parts of Anemarrhena, 12 parts of Anemarrhena, ghost Feather 8 Parts, 12 parts of Gynostemma pentaphyllum, 12 parts of litchi core;
  • the pharmaceutical composition is made from the following bulk drugs:
  • the pharmaceutical composition of the present invention can be used as a medicine after being simply processed by a conventional pharmaceutical method in the field of traditional Chinese medicine, and has a good hypoglycemic effect on diabetes, particularly type I diabetes.
  • each of the drug substances of the pharmaceutical composition of the present invention can be directly decocted and used as a decoction. Therefore, the composition of the present invention can be obtained by a method comprising the steps of: weighing the drug substance in proportion, adding water to decoction and filtering, and then taking the boiling solution.
  • the method of preparing the pharmaceutical composition comprises the steps of:
  • the decoction liquid obtained in the step 1) is concentrated under reduced pressure to a chemical solution having a relative density of 1.05-1.
  • step 3 Spray the solution obtained in step 2) to obtain a spray-dried powder.
  • the pharmaceutical composition of the present invention can be treated to obtain its active ingredient in combination with the medicinal properties of the present invention.
  • the present invention provides a method of preparing an active ingredient of the above pharmaceutical composition, the method comprising:
  • the decoction liquid obtained in the step 1) is concentrated under reduced pressure to a chemical solution having a relative density of 1.05-1.
  • step 3 Spray the solution obtained in step 2) to obtain a spray-dried powder.
  • the pharmaceutical composition may also be reprocessed into pharmaceutical preparations such as tablets, capsules, powders or granules for clinical use.
  • a tablet may be selected as the dosage form for this formulation.
  • the tablet is made by the following steps:
  • the spray-dried powder obtained in the step 3) is subjected to dry granulation, granulated, added with magnesium stearate, mixed, compressed, and then coated with a film.
  • the tablet of the present invention is prepared by the following steps: 1) weighing the drug substance in proportion, wherein the litchi core is broken, and then boiling water three times, adding 9 times for the first time Decoction for 2 hours, the second time with 9 times the amount of water to cook for 1.5 hours, the third time with 7 times the amount of water for 1 hour, the decoction is filtered and combined;
  • the decoction liquid obtained in the step 1) is concentrated under reduced pressure to a liquid having a relative density of 1. 15-1.20 at 60 ° C;
  • step 2) spray drying the liquid obtained in step 2) to obtain a spray-dried powder
  • the present invention provides the use of the above pharmaceutical composition for the preparation of a medicament for treating diabetes and a related disease thereof; preferably, the diabetes is type I diabetes.
  • the present invention provides a pure Chinese medicine preparation which is effective and has no toxic side effects, and the medicine of the present invention has the following advantages as compared with the prior art medicines in the art:
  • the raw materials for the pharmaceutical composition of the present invention include atractylodes, yellow essence, scrophularia, puerarin, and gynostemma, or the components thereof are composed of fried atractylodes, huangjing, scrophularia, puerarin, and gynostemma. Its prescription has a good hypoglycemic effect on diabetes, especially type I diabetes.
  • the raw material medicine of the pharmaceutical composition of the present invention may further comprise salvia miltiorrhiza, mulberry leaf, Zhimu, ghost arrow feather, litchi nucleus, or the group thereof consisting of fried atractylodes, huangjing, salvia miltiorrhiza, scrophularia, puerarin, mulberry leaf, and known Mother, ghost arrow feather, Gynostemma pentaphyllum, litchi core.
  • the prescription of these 10 herbs has a better hypoglycemic effect on diabetes, especially type I diabetes.
  • the pharmaceutical composition of the present invention can be used as a medicine after being simply processed by a conventional pharmaceutical method in the field of traditional Chinese medicine, and has a good hypoglycemic effect on diabetes, particularly type I diabetes.
  • clinical use of this group as a decoction can improve clinical symptoms, lower blood sugar, urine sugar, improve blood circulation, delay and reduce chronic complications such as blood vessels and neuropathy, and have no side effects of western medicine commonly used in the field.
  • the traditional decoction is relatively troublesome in frying, it is not convenient for the patient to carry and take. Therefore, in combination with the medicinal properties of the prescription, the pharmaceutical composition of the present invention can be further processed and processed into other dosage forms.
  • the present invention selects a tablet as a preferred dosage form of the pharmaceutical composition.
  • the invention provides that the dosage of the auxiliary materials of the tablet is small, and the experiment proves that it is easy to form, the dissolution rate and the bioavailability are good, the volume is small, the dosage is accurate, and the difference in the drug content is small, carrying, It is convenient to transport and take.
  • the present invention also provides methods for their preparation as well as specially optimized preparation steps and conditions.
  • the experiment proves that the preparation method of the invention has a reasonable route and the process parameters are clear, after three batches.
  • Test certificate the quality of the finished product has been inspected according to the regulations, and the transfer rate of salvianolic acid B is basically stable, indicating that the method is stable and reliable.
  • the pharmaceutical compositions provided by the present invention are also useful in the preparation of a medicament for the treatment of diabetes, particularly type II diabetes, which composition or medicament can be used to treat diabetes and its related conditions. Diabetes is a lifelong disease, and in order to consolidate the curative effect, the medication is generally longer. Animal model experiments have shown that the pharmaceutical composition of the present invention has significant improvement effects on blood sugar, blood lipids, endothelial function, insulin resistance index and insulin receptor in type II diabetic rats, and acute and long-toxic experiments show that The drug is safe and has no obvious side effects.
  • the drug can regulate the expression of insulin receptors, inhibit oxidative stress caused by high glucose and high fat, and vascular endothelial injury, and play a role in the treatment of type 2 diabetes, concurrent with diabetes and hyperlipidemia. It also has a potential preventive and therapeutic effect, and can be used as a new type of traditional Chinese medicine preparation with clinical curative effect and little toxic side effects.
  • the drug of the present invention has a similar or better effect than the positive drug metformin in terms of clinical total efficacy, biochemical indicators, and improvement in clinical symptoms.
  • Fried atractylodes It has the functions of strengthening the spleen and replenishing qi, dampness and dampness, antiperspirant, and anti-fetal. It mainly contains polysaccharides and amino acids. Modern pharmacological experiments show that Baizhu extract decoction has hypoglycemic effect, so it is decoction in this side.
  • Huang Jing It has the effects of tonifying qi and nourishing yin, strengthening the spleen, moistening the lungs and benefiting the kidney. It mainly contains components such as saponins, starches, polysaccharides and amino acids. Modern pharmacological experimental studies have shown that Polysaccharide from Polygonatum is an effective component in the treatment of diabetes, which can significantly reduce hyperglycemia, so the water is decoction.
  • Salvia miltiorrhiza It has the effects of relieving pain, promoting blood circulation and clearing the heart, clearing the heart and removing troubles.
  • the Chinese Danshen takes its role in promoting blood circulation and removing blood stasis. Modern pharmacological research shows that its water-soluble ingredients have the effect of promoting blood circulation and removing blood stasis. Therefore, water is used in this prescription. decoction.
  • Scrophularia sinensis It has the effects of cooling blood and nourishing yin, purging fire and detoxification, and mainly contains iridoids. Pharmacological studies have shown that Scrophularia sinensis extract has a mild hypoglycemic effect, so the water is boiled.
  • Pueraria It has the effect of raising the spleen and stomach, and the main ingredient is flavonoids such as puerarin.
  • Pharmacological experiments show that puerarin has the effect of lowering blood sugar, and it is proposed to use different solvents to investigate the extraction process of puerarin.
  • Mulberry leaves It has the functions of evacuating wind and heat, clearing the lungs and moistening the dryness, clearing the liver and improving eyesight, and mainly contains flavonoids and alkaloids.
  • Pharmacological experiments show that the active components of mulberry blood glucose and anti-diabetes are mainly polysaccharides, total flavonoids and polyhydroxy alkaloids. Since these components are all soluble in hot water, they are decoctioned with water.
  • Zhimu It has the functions of clearing heat and purging fire, and moistening and moistening the skin. It mainly contains saponins, flavonoids and dipyridone. Pharmacological experiments show that mangiferin in dipyridone has the effect of lowering blood sugar, and is the main effective component of Zhimu in the treatment of diabetes. Because it is easily soluble in water, it is decoction in this side.
  • Ghost Arrow Feather It has the functions of breaking blood, passing through, killing insects and relieving pain.
  • the soil should contain active ingredients such as flavonoids and saponins.
  • Pharmacological experiments have shown that the decoction has the effect of lowering blood sugar and is used for the treatment of diabetes. Therefore, water decoction is used in this prescription.
  • Gynostemma pentaphyllum It has the effects of clearing away heat and detoxifying, relieving cough, and lowering fat and losing weight. Modern pharmacology shows that the main active ingredient is saponin, which can lower blood sugar. Since Gynostemma pentaphyllum, the main active ingredient of Gynostemma pentaphyllum, is easily soluble in water, it is decoctioned with water.
  • Litchi core It has the effect of stagnation.
  • the theory of traditional Chinese medicine believes that the spleen transport is long-lasting, the air machine is unsmooth, and the fluid is difficult to be transported.
  • the nucleus of the medlar is used as a medicine, and the stagnation of the gas, the liver stagnation, and the blood in the blood, make the air flow smooth, the blood flow is smooth, The body fluid is easy to lose.
  • Modern pharmacological studies have shown that the lychee core aqueous solution has a hypoglycemic effect, so the process of water extraction is selected. detailed description
  • Example 1 The experimental methods in the following examples are conventional methods unless otherwise specified.
  • the medicinal materials, reagent materials and the like used in the following examples are commercially available products unless otherwise specified.
  • Example 1 The medicinal materials, reagent materials and the like used in the following examples are commercially available products unless otherwise specified.
  • Fried Atractylodes 40g Polygonatum 150g, Scrophulariaceae 50g, Pueraria 150g, Gynostemma 50g;
  • Fried Atractylodes 40g Polygonatum 150g, Salvia miltiorrhiza 100g, Scrophulariaceae 150g, Pueraria 50g, Mulberry Leaf 150g, Zhimu 50g, Ghost Arrow Plume 150g, Gynostemma 50g, Lychee Core 220g
  • Fried Atractylodes 120g Polygonatum 50g, Salvia miltiorrhiza 300g, Scrophulariaceae 50g, Puerariae 150g, Mulberry Leaf 50g, Zhimu 150g, ghost Arrow 50g, Gynostemma 150g, Lychee Core 70g
  • Fried Atractylodes 80g Polygonatum 100g, Salvia miltiorrhiza 200g, Scrophulariaceae 100g, Pueraria 100g, Mulberry Leaf 100g, Zhimu 100g, ghost Arrow 100g, Gynostemma 100g, Lychee Core 150g
  • Fried Atractylodes 60g Polygonatum 120g, Salvia Miltiorrhiza 120g, Scrophulariaceae 120g, Pueraria 80g, Mulberry Leaf 120g, Zhimu 80g, Ghost Arrow Feather 120g, Gynostemma 80g, Lychee Core 180g
  • Fried Atractylodes 120g Polygonatum 150g, Salvia miltiorrhiza 300g, Scrophularia 150g, Pueraria 150g, Mulberry 150g, Zhimu 150g, Ghost Arrow 150g, Gynostemma 150g, Lychee Core 220g
  • Rhizome 116g Rhizome 116g
  • Polygonatum 145g Salvia miltiorrhiza 290g
  • Scrophulariaceae 145g Pueraria 145g
  • Mulberry leaf 145g Zhimu 145g
  • ghost arrow feather 145g Gynostemma 145g, Litchi core 217. 5g
  • Test sample A tablet prepared according to the method of Example 5, batch number 071101, specification 0.53 g/tablet.
  • the inner packaging is medicinal PVC hard sheet and PTP aluminum foil blister
  • the outer packaging is aluminum-plastic composite film.
  • the accelerated test is carried out at a temperature of 40 ° C ⁇ 2 ° C and a relative humidity of 75% ⁇ 5%, and the long-term test is carried out under normal temperature conditions.
  • test basis the relevant provisions of the General Rules for the Preparation of Chinese Pharmacopoeia.
  • This product is a film This product is a film This product is a film clothing This product is a film clothing
  • the tablets are removed, the coated tablets are removed, the coated tablets are removed, the coated tablets are removed, the coated tablets are removed, the coated tablets are removed, the coated tablets are removed, and the coating is removed.
  • the traits are brown after the clothes, and the brown color after the clothes is brownish yellow after the clothes. It is brownish yellow after the clothes;
  • This product is a film garment.
  • This product is a film.
  • This product is a film.
  • This product is a film.
  • This product is a film-like film. , removing the coated tablets, removing the coated tablets, removing the coated tablets, removing the tablets, removing the coating and then displaying a brownish yellow color; after coating, the brown coating is brown after coating and then brownish and then brownish yellow; Weiqi, bitter taste. Yellow; gas slightly, yellow; gas micro, yellow; gas micro, gas micro, bitter taste.
  • control group used metformin tablets 0.25 g / time, 3 times / day.
  • the treatment group was administered with the test drug (prepared according to the method of Example 1), 500 ml/time, 2 times/day.
  • the course of treatment is 2 months.
  • Efficacy criteria Refer to the “Guidelines for Clinical Research of New Drugs in Traditional Chinese Medicine” in 1993 for efficacy judgment. Significant effect: Symptoms disappeared after treatment, fasting blood glucose ⁇ 7.2 mmol/L, postprandial 2 h blood glucose ⁇ 8.3 mmol/L; effective: fasting blood glucose ⁇ 8.0 mmol/L, postprandial 2 h blood glucose ⁇ 10.0 mmol/L; Symptoms did not improve after treatment, and fasting blood glucose and postprandial blood glucose did not meet the above criteria. Symptoms were assessed by a four-point scale: 0 (no symptoms), 1 (with symptoms when prompted), 2 (sometimes with symptoms), 3 (significant symptoms), and symptom scores and scores.
  • Example 14 Effect of the pharmaceutical composition of the present invention on type II diabetic rats
  • the pharmaceutical composition prepared in Example 11 of the present invention (hereinafter referred to as the drug of the present invention)
  • Storage conditions sealed, cool, dry, protected from light.
  • Preparation method In the experiment, use purified water to prepare the required concentration for use.
  • Animal drinking water Sterilize and purify water, animals are free to drink.
  • Rosiglitazone tablets each containing rosiglitazone 4 mg
  • Chengdu Hengrui Pharmaceutical Co., Ltd. batch number 080301.
  • Glycosylated hemoglobin kit Glycosylated hemoglobin kit (GHb), product of Nanjing Bioengineering Research Institute; Nitric Oxide (NO) kit, Nanjing Bioengineering Research Institute product; Superoxide dismutase (SOD) kit, Nanjing built bioengineering Research Institute Products; Malondialdehyde (MDA) Kit, Products of Nanjing Jiancheng Bioengineering Research Institute; Total Cholesterol (CH0) Kit, Zhongsheng Beikong Biotechnology Co., Ltd.; Triglyceride (TG) Kit, Medium Shengbei Control Biotechnology Co., Ltd.; iodine [ 125 ⁇ ] insulin radioimmunoassay kit, Beijing Puer Weiye Biotechnology Co.,
  • the normal control group was fed with conventional diet, and the high-glycemic and high-fat group was given high-sugar and high-fat diet (10%).
  • the drug dosage group (0. 7g / kg, equivalent to the crude drug 2. 4g / kg, equivalent to 7 times the clinical drug), the drug high dose group (1. 4g / kg, equivalent to the crude drug 4. 8g / kg , equivalent to 14 times the clinical use of drugs and the positive drug rosiglitazone group (1.8 mg / kg, equivalent to 14 times the clinical use of drugs).
  • the drug-administered group was intragastrically administered once a day, and the volume was 1 ml/lOOg body weight.
  • the normal control group and the model control group were given an equal volume of purified water for 8 weeks. All diabetic rats continued to be fed with high-sugar and high-fat diet during the experiment, and the normal control group continued to be fed with conventional feed.
  • Dynamic blood glucose The blood glucose of each group was measured by Kyoto blood glucose meter before the experiment, before the administration, 4 weeks after the administration, and 8 weeks after the administration.
  • Biochemical indicators Serum total cholesterol (TC), triglyceride (TG), tumor necrosis factor-a (TNF- ⁇ ), glycosylated hemoglobin (GHb), 6-keto-prostaglandin F1 (6) were measured according to the kit instructions.
  • TC total cholesterol
  • TG triglyceride
  • TNF- ⁇ tumor necrosis factor-a
  • Gb glycosylated hemoglobin
  • 6-keto-prostaglandin F1 (6) were measured according to the kit instructions.
  • - Keto- PGF1 ⁇ Serum total cholesterol (TC), triglyceride (TG), tumor necrosis factor-a (TNF- ⁇ ), glycosylated hemoglobin (GHb), 6-keto-prostaglandin F1 (6) were measured according to the kit instructions.
  • - Keto- PGF1 ⁇ thromboxane
  • ⁇ 2 thromboxane
  • ⁇ nitric oxide
  • S0D superoxide dismutase
  • RNA insulin membrane receptor (InsR) in liver cell membrane:
  • Total RNA was extracted by liver tissue using Trizol method, reverse transcription reaction was performed with total RNA l as template, reverse transcriptase ⁇ total reaction system 20 ⁇ 1 42 °C water bath for 30 min, cDNA synthesis a chain.
  • the PCR reaction parameters were set at 94 ° C for 3 min pre-denaturation. Denaturation at 94 ° C for 50 sec, 54. 8 ° C annealing for 50 sec, 72 ° C extension for 70 sec, a total of 31 cycles.
  • the same method amplifies ⁇ -actin as an internal reference. 5 l PCR products were electrophoresed on a 1% agarose gel, and the relative molecular mass was determined by marker. After electrophoresis, the gel imaging system was used to photograph, and finally the quantitative target image analysis system was used to detect the target genes and ⁇ - The gray value of the actin gene, the ratio of the two represents the relative expression of InsR mRNA
  • the water consumption and urine volume of the rats in the drug group were increased compared with the normal control group (p ⁇ 0.05 or p ⁇ 0.01); the drug of the invention (0.35g/kg, 0.7g/kg, 1.4) was administered 4 weeks after administration and 8 weeks after administration.
  • the water consumption and urine volume of the rats in the g/kg group were lower than those in the model control group (p ⁇ 0.05 or ⁇ 0 ⁇ 01).
  • the pharmaceutical composition of the present invention is a type II diabetic rat
  • the effect of urine volume ( ⁇ S, n 10)
  • the results are shown in Table 10. From the results, it can be seen that the blood glucose level of the rats in the normal control group and the model control group reached the peak after 0.5 hr of intraperitoneal injection of glucose, and then gradually decreased, showing the characteristics of glucose absorption and metabolism.
  • the positive drug rosiglitazone group was The increase of blood glucose level at 0.5hr, lhr and 2hr was lower than that of the model control group (p ⁇ 0.01).
  • the increase of blood glucose level in the rats of the present invention 1.4g/kg was lower than that at 0.5hr, lhr and 2hr.
  • the AUC was lower than the model control group (P ⁇ 0.01).
  • the rats in the present invention (0.35g/kg, 0.7g/kg) had low blood glucose levels at lhr and 2hr ⁇ .
  • AUC was lower than the model control group ( P ⁇ 0.05 or p ⁇ 0.01).
  • the present invention 0.35 8.8 ⁇ 2 ⁇ 16* 13.0 ⁇ 4 ⁇ 52 11.3 ⁇ 3.94* 9.7 ⁇ 2.64* 33.5 ⁇ 10.53*
  • the drug 0.7 8 ⁇ 5 ⁇ 1 ⁇ 59** 12.7 ⁇ 3 ⁇ 69 11.1 ⁇ 1.96** 9.4 ⁇ 1.88** 32.8 ⁇ 6.83** Group 1.4 7.1 ⁇ 1 ⁇ 46** 10.3 ⁇ 2 ⁇ 05** 9 ⁇ 5 ⁇ 1 ⁇ 80** 8.0 ⁇ 1.38** 27.3 ⁇ 4 ⁇ 6 Guangrogg 1.8 mg 6.3 ⁇ 1.50** 8.9 ⁇ 2.45** 7 ⁇ 9 ⁇ 1 ⁇ 58** 6.8 ⁇ 1.48** 23.3 ⁇ 5.38** Ketone
  • the pharmaceutical composition of the present invention can reduce the amount of urine and water, and lower the blood sugar (FPG) by administering the high-fat diet plus low-dose streptozotocin-induced sputum-type diabetic rats for 4 weeks.
  • Glycated hemoglobin GHb
  • FSI serum insulin
  • H0MA-IR insulin resistance index
  • ISI insulin sensitivity index
  • Example 15 Effect of the pharmaceutical composition of the present invention on alloxan-induced diabetes in mice
  • Feeding conditions, animal feed, and animal drinking water were the same as in Example 14.
  • Metformin Hydrochloride Tablets (0.25g), Tianjin Feiying Pharmaceutical Co., Ltd., batch number 0802007. 4, the main reagent
  • Alloxan (ALX), American Sigma product; GLUC0CARD II blood glucose test paper, Japan ARKRAY, Inc.
  • mice were fasted for 24 hr, intraperitoneally injected with freshly prepared 1.4% tetrahydropyrimidine physiological saline solution, and administered at a dose of 280 mg/kg twice at 0 ml/lOg body weight. Blood glucose was measured on the third day, and blood glucose levels were selected. > 11. 50 mice of lmmol *L- 1 were used for the experiment. The mice were randomly divided into 5 groups according to the blood glucose level, 10 rats in each group, which were model control group and low-dose group of the present invention (0.45g/kg, equivalent to crude drug 1.5g/kg, equivalent to clinical medication.
  • the medium dose group of the present invention (0.9 g/kg, equivalent to 3.0 g/kg of crude drug, equivalent to 9 times of clinical drug), and the high dose group of the drug of the present invention (1.8 g/kg, equivalent to crude drug 6.0 g/k) g , which is equivalent to 18 times of clinical use) and the positive drug metformin group (0.36 g/kg, which is equivalent to 18 times of clinical use).
  • Another 10 were taken as normal control group.
  • the mice in the administration group were intragastrically administered once a day, and the volume was 10 ml/kg.
  • the normal control group and the model control group were given an equal volume of purified water for 28 consecutive days. Blood glucose was measured 2 hours after the last administration.
  • Glibenclamide (each tablet containing glibenclamide 2.5 mg), Tianjin Lisheng Pharmaceutical Co., Ltd., batch number 0801004. 4, the main reagent
  • 50 rats were randomly divided into 5 groups, 10 in each group, which were blank control group and low dose group of the present invention (0.35 g/kg, equivalent to crude drug 1.2 g/kg, equivalent to 3.5 times of clinical drug).
  • the drug dosage group of the invention (0.7 g/kg, equivalent to 2.4 g/kg of crude drug, which is equivalent to 7 times of clinical drug)
  • the high dose group of the drug of the invention (1.4 g/kg, equivalent to 4.8 g/kg of crude drug, equivalent to clinical 14 times the drug)
  • the positive drug glibenclamide group 2.3 mg/kg, which is equivalent to 14 times the clinical drug).
  • the drug-administered group was intragastrically administered once a day, and the volume was 1 ml/lOOg body weight.
  • the blood glucose level is 0, 0.5, 1, 2 hours).
  • Feeding conditions, animal feed, and animal drinking water were the same as in Example 14.
  • Glyburide (each tablet containing glibenclamide 2.5 mg), Tianjin Lisheng Pharmaceutical Co., Ltd., batch number 0801004. 4, the main reagent
  • mice were divided into 5 groups, 10 in each group, which were blank control group and low-dose group of the present invention (0.45 g/kg, equivalent to crude drug 1.5 g/kg, equivalent to 4.5 times of clinical drug), in the medicament of the present invention.
  • the dosage group (0.9g/kg, equivalent to 3.0g/kg of crude drug, equivalent to 9 times of clinical drug), the high-dose group of the drug of the invention (1.8g/kg, equivalent to 6. Og/kg of crude drug, equivalent to 18 for clinical use) Double) and the positive drug glibenclamide group (3 mg/kg, which is equivalent to 18 times of clinical use).
  • the mice in the administration group were intragastrically administered once a day, and the volume was 0.2 ml/10 g body weight.
  • the blank control group was given an equal volume of purified water for 28 consecutive days, and blood glucose was measured 2 hours after the second administration.

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Abstract

L'invention concerne une composition pharmaceutique pour traiter le diabète, et son procédé de préparation et son application. Des principes actifs de la composition pharmaceutique comprennent du Rhizoma Atractylodis Macrocephalae grillé, du rhizoma polygonati, du scrophularia ningpoensis, des racines de kudzuvine et du Gynostemma pentaphyllum. L'invention concerne une composition pharmaceutique pour traiter le diabète, et son procédé de préparation et son application. La composition pharmaceutique est produite à l'aide des principes actifs suivants : du Rhizoma Atractylodis Macrocephalae grillé, du rhizoma polygonati, des racines de sauge rouge, du scrophularia ningpoensis, des racines de kudzuvine, des feuilles de mûrier, du rhizome d'Anemarrhena, des brindilles d'ébène ailées, du Gynostemma pentaphyllum et une graine de litchi.
PCT/CN2013/088841 2012-12-12 2013-12-09 Compositions pharmaceutiques pour réduire le niveau de sucre, leurs procédés de préparation et leurs applications WO2014090122A1 (fr)

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