CN103402506A - Combination for treatment of diabetes mellitus - Google Patents
Combination for treatment of diabetes mellitus Download PDFInfo
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- CN103402506A CN103402506A CN2012800085850A CN201280008585A CN103402506A CN 103402506 A CN103402506 A CN 103402506A CN 2012800085850 A CN2012800085850 A CN 2012800085850A CN 201280008585 A CN201280008585 A CN 201280008585A CN 103402506 A CN103402506 A CN 103402506A
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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
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
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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
- A61K31/12—Ketones
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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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
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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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
- A61K31/37—Coumarins, e.g. psoralen
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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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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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)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/74—Rubiaceae (Madder family)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
A combination is claimed for treating diabetes mellitus and can be executed in the form of a pharmaceutical composition or a pharmaceutical set. The combination comprises antihyperglycemic agents and natural phenolic compounds capable of uncoupling oxidative phosphorylation. The said combination provides the possibility to reduce the incidence of side effects resulting from the use of antihyperglycemic preparations, in particular the risk of lactacidosis.
Description
Technical field
The present invention relates to pharmaceuticals industry and especially for the treatment diabetes medicine.
Background technology
Diabetes remain the prominent question for the national public health service of in fact in the world All Countries.Between in the past 30 to 40 years, the unprecedentedly soaring of the prevalence of diabetes and sickness rate worldwide clearly appears, especially in industrially developed country, wherein the crowd of 6-10% suffer from diabetes and wherein its prevalence obvious ascendant trend is arranged, be mainly in the crowd at the age more than 40 years old.
As everyone knows, the main target for the treatment of diabetes scheme is to reduce diabetic symptom, the quality of making the life better and prophylaxis of acute complication (hyperosmolar coma and ketoacidosis) and chronic complicating diseases, for example diabetic neuropathy, diabetic nephropathy and early atherosclerosis (Diabetes Control and Complications Trial Research Group; N.Engl.J.Med., 329,977-986 (1993)).
Chronic hyperglycemia is not only the main manifestations of the diabetes that form diagnosis described disease basis, and is a most important factor of the development of nearly all complication: microangiopathies and macroangiopathy, neurotrophic pathological changes, nephropathy etc.
Long-standing hyperglycemia can cause the β cell of stimulating pancreas, and this causes again the exhausting of ability of its function conversely, facilitates thus the progress of disease.
The target for the treatment of diabetes is to realize the metabolism compensation of carbohydrate within a very long time,, guarantees that the index of the glucose content in blood plasma in a day is with observed basic identical in Healthy People that is.Treating diabetes starts from the prescription of opening diet and regularly moving, but, in order to realize target carbohydrate metabolism index, need significant effort for some patients were, and as convention, diabetics has only been made the effort of minimum degree.Here it is, and pharmacotherapy plays the reason of Main Function in treating diabetes.
Hyperglycemia medicine therapy not only reduces blood glucose target and eliminates thus the clinical manifestation of the disease that is caused by hyperglycemia.It also can interrupt by increasing insulin defect formed " vicious cycle " (this is because the exhausting and the growth of the hyperglycemia that the increase of insulin defect causes of insulin secretory cell).The described hyperglycemia medicine of the application is relating to type ii diabetes and type i diabetes initial stage to a greater extent to the positive role of insulin defect.
At present, use the hyperglycemia oral drugs of following each group for the treatment type ii diabetes:
Slow down the absorption (Alpha-glucosidase inhibitor guar gum, acarbose, miglitol etc.) of glucose in the digestion of carbohydrate and gastrointestinal tract;
Promote the insulin of pancreas to produce (sulphanylureas derivant glibenclamide, glipizide, gliclazide, gliquidone and glimepiride);
Stimulate insulin secretion (meglitinide (glinides), incretin analogies, DPP-4 inhibitor, amylopectin and glucagon-like peptide 1 analog) after the meal;
Stimulate the picked-up of glucose to enter cell and suppress and discharge glucose (biguanide, at present particularly metformin) by cell;
Improve the preparation of insulin sensitivity in tissue, perhaps insulin sensitizer thiazolidinedione (glitazone)-pioglitazone, rosiglitazone;
Insulin.
Alpha-glucosidase inhibitor (acarbose) reduces the absorption of glucose in intestinal, and usually disease early stage effectively.Their side effect is relevant to the performance of abdominal distention and diarrhoea.In Most patients, increase gradually for the demand that stops described drug administration in start from drug administration 3 years.
Sulfonylurea derivative stimulating pancreas B emiocytosis insulin.The most frequently used sulfonylurea drugs is gliclazide, glibenclamide, glipizide and gliquidone at present.Use the treatment of sulfonylurea drugs to avoid in following situation: type i diabetes or Secondary cases (pancreas) diabetes, pregnancy and suckling, operation, severe infections, injured, irritated or have a serious risk of hypoglycemia to sulfonylurea drugs or similar medicine in anamnesis.
Meglitinide (meglitinides) be characterised in that rapid-action and action time short, this makes, and effectively controls on the one hand postprandial hyperglycemia, and does not increase on the other hand risk of hypoglycemia.
The preparation that is intended to especially to affect the GLPP level is incretin analogies, DPP-4 inhibitor, amylopectin and glucagon-like peptide 1 analog.These medicines make up the deficiency that exists in the secretion of pancreas and gastrointestinal hormone, affect secretion, satiety and the gastric emptying of insulin and glucagon.They are characterised in that onset is exceedingly fast and the anti-high-blood-sugar function time is short, thus its use without any by them on the caused bad development of the impact of glucose metabolism.Rapid-action and action time is short makes aforementioned medicine only be used as hyperglycemia medicine after the meal.
A present class tablet hyperglycemia biguanide mainly be represented as metformin.Biguanide does not strengthen insulin secretion.Their anti-high-blood-sugar function is only in the situation that exist enough insulins just self to show in blood.Biguanide improves its effect in peripheral tissues, and this has reduced insulin resistant.Biguanide increases the glucose uptake of muscle and fatty tissue.They have reduced Hepatic glucose production, enteral glucose absorption, increased glucose utilization and have reduced appetite.Taboo be the prescription of opening biguanide for acute complications, alcohol abuse, lacticemia for the renal insufficiency in anamnesis, any etiologic etiological hypoxic disease (heart failure, pneumonopathy, anemia, infectious disease), diabetes.In the side effect of metformin, it should be noted dyspeptic performance when giving the medicine of high dose.This case is known as patient's development hyperlactacidemia, and it reflects the ability that medicine increases anaerobic glycolysis and suppresses the glyconeogenesis of liver.
The use of hyperglycemia sulfa drug and biguanide can cause the side effect of following form: disorder of gastrointestinal tract, skin allergy and glycopenia state, this is the intimate degree due to the therapeutic dose of these medicines and toxicity dose.
Thiazolidinedione by reduce peripheral tissues particularly the insulin resistant of fatty tissue affect glycemic control, and also reduce Hepatic glucose production.Such preparation does not cause hypoglycemia but has impelled the body weight increase.These medicines are avoided for the patient with heart failure symptom and diabetic retinopathy propagation early stage and proliferation period performance.
If it is invalid that the monotherapy of hyperglycemia is proved to be, sometimes can be by in conjunction with the hyperglycemia preparation, realizing Expected Results.The following combination of oral hyperglycemia preparation is possible: sulphanylureas preparation and thiazolidinedione, metformin and meglitinides, metformin and thiazolidinedione, sulphanylureas preparation and alpha-glucosidase inhibitor.If glycemic control can not realize by making up oral hyperglycemia preparation, can give the combination treatment of insulin and biguanide or the monotherapy of insulin.
Sulfonylurea drugs preparation and metformin all affect the metabolism compensation of carbohydrate, but their anti-high-blood-sugar function mechanism is different.These aspects make uses them to become possibility in combination treatment.
The oral hyperglycemia preparation Glibomet of compound action is comprised of 2.5mg glibenclamide and 400mg metformin.In medicine, contained glibenclamide has stimulated the secretion of insulin by the pancreas beta cell, and metformin mainly reduces the tolerance of insulin in liver, it is with the inhibition of glyconeogenesis, this reduced the formation of glucose in liver with and enter the ratio of blood circulation.The use of composition of medicine has strengthened anti-high-blood-sugar function, but keep to use metformin with the sign of hyperlactacidemia complete.
Composition of medicine is known for the treatment metabolic disease is mainly diabetes and diabetes associated conditions, be included in Nateglinide and diabetes glitazone medicine in pharmaceutical carrier.The representative of glitazone medicine can be pioglitazone, rosiglitazone or troglitazone (RU2280447,15.09.2000).
Composition of medicine can adopt the form of combination preparation or pharmaceutical composition.Described pharmaceutical composition can be included in the metformin of conduct the 3rd antidiabetic medicine in pharmaceutical carrier.Nateglinide and other being used in combination of antidiabetic medicine guaranteed for the synergistic therapeutic effect of type ii diabetes and the persistent period of pharmaceutically-active prolongation, and this causes the use of insulin was postponed to the date after.The unfavorable aspect of this combination is to use lattice row ketone and metformin, and it all can cause developing hyperlactacidemia.
Medicine for the treatment diabetes is known, and it comprises the combination (RU 2413528 18.01.2007) of Exenatide and the Dalargin (Dalargin) of effective dose.This is combined as composition of medicine and by the blood sugar lowering that strengthens Exenatide and effective treatment that the cholesterol reducing effect has guaranteed diabetes.The unfavorable aspect of this combination is preferably to use the administration of injection form.
The medicine that does not rely on the type ii diabetes of insulin for treatment is known, it comprises the combination of metformin and the glibenclamide of effective dose, and treatment does not rely on the diabetes of insulin or the method for hyperglycemia adopts the glibenclamide that has formed for the composition of medicine of oral administration, and described composition of medicine has 1.7 to 2.2m
2The powder particle surface of/g amasss (RU 2286788 12.07.1999).
The present invention has guaranteed the bioavailability of the glibenclamide in the compositions of the medicine that comprises metformin suitable with the bioavailability of glibenclamide monotype (monoform).Yet the use of the metformin in the suggestion preparation causes needs to consider the probability of the increase of hyperlactacidemia.
Therefore, the hyperglycemia medicine that is used for oral administration that uses has at present solved through different mechanisms and has fallen hypoglycemic problem, so they are only effective under certain conditions.The fuzzy performance that causes the symptom of the principal disease of contraindication and concurrent disease in some patient subgroups causes the side effect of not expecting.A kind of in the most significant contraindication is the inducement of hyperlactacidemia.
Glucose content is characterised in that the obvious accumulation of glucose in the bodily tissue cell in the process reduction blood of the administration overwhelming majority's the preparation (sulphanylureas derivant, meglitinide, biguanides, Thiazolidinediones and insulin) that is used for this purpose and all its combinations basically.Excessive glucose is in the cell inner accumulated, and cause the generation of glycolysis product to increase, its conversion has subsequently caused numerous side effect of not expecting, wherein the most dangerous is hyperlactacidemia (considering the insufficient intensity that they are utilized in the oxidation energy metabolism).
Lactic acid excessive accumulation and hyperlactacidemia subsequently in vivo is the most obviously to observe as the side effect of absorbing biguanide.Identical metabolic alterations has formed the basis of the restriction use of hyperglycemia method (sulphanylureas derivant, Thiazolidine and meglitinide) (wherein the patient has the performance of hyperlactacidemia and ketoacidosis).In addition, high-caliber glycolysis product causes the synthetic activation of fatty acid, is formed in thus the basis that in the process that gives numerous hyperglycemia preparations (sulphanylureas derivant, Thiazolidine, meglitinide), viewed body weight increases.
As previously having pointed out, when described drug regimen used, the described problem that the hyperglycemia medicine has still existed.
Therefore, the exploitation of antidiabetic agent preparation (its use will be followed the less accumulation of endocellular sugar zymolysis product) is seemingly very appropriate from present's view.This can reduce the probability of the side effect of not expecting.
Oxidation in the metabolism of the acetone acid that produces in glycolytic cycle as known, and the circulation of its kerbs (recovery of the extra cofactor except synthetic those in glycolytic cycle) is relevant.The main consumption of aforementioned cofactor occurs in the ATP building-up process in mitochondrial oxidative phosphorylation chain.Form under the condition that increases at acetone acid, confirmed that the underconsumption of natural A TP is to guarantee effective outflow of the cofactor of reducing.This causes intracellular formation, and its glucose content with lactic acid excessive in acetone acid increases., for the discharge of the cofactor of the reduction that increases other glycolysis product, adopt high-caliber motion to consume to produce the background ATP that increases in the energy dependence process in the treating diabetes practice.
The task of simultaneously, increasing the cofactor of discharging reduction can solve by the described composition in the compositions of using antidiabetic medicine (its consumption that guarantees the cofactor of the reduction in the cell internal procedure strengthens).
Aspect this, inventor's attention has attracted to numerous materials that can uncoupling oxidative phosphorylation (uncoupling oxidative phosphorylation) in the mitochondrion, this causes the use to the cofactor of the reduction of water (and do not form ATP, namely adopt invalid mode) reduction for the oxygen in the mitochondrial cytochrome chain to increase.
The research subsequently of being undertaken by the inventor has shown in order to suppress in giving hyperglycemia preparation process accumulates relevant acidosic development with the glycolysis product, can successfully use can be in mitochondrion the natural phenolic compound of uncoupling oxidative phosphorylation.
Existence can the uncoupling oxidative phosphorylation natural phenolic compound and the operational version that comprises the product of described compound, strengthen the heat production (US 20100215782) in fatty tissue with the purpose for treatment lipid metabolism obstacle.Yet the inventor does not recognize and uses any natural phenolic compound to suppress accumulating relevant acidosic development with the glycolysis product in giving hyperglycemia preparation process for the purpose of uncoupling oxidative phosphorylation.
In addition, the research according to the inventor carries out, be administered to other ascorbic acid in body and strengthened aforementioned effect together with natural phenolic compound, and this is because natural phenolic compound remains the phenol form.It provides the probability that obtains the stable solution coupling effect, and this is because the cofactor NADN (NADPH) of reduction is direct or in the situation that ascorbic acid and derivant thereof participate in the ability of reduction natural phenolic compound.
Therefore, the formation in the somatic cell in redox cycle as mentioned above (in the presence of natural polyphenol compounds) has produced extra approach and has consumed the cofactor of excessive reduction.
In addition, the use of ascorbic acid and derivant thereof has improved the bioavailability of natural phenolic compound.
It is worth mentioning that for treatment and the prevention disease relevant to antioxidant defence obstacle and be known that and use the pharmaceutical composition (RU 2378003 06.06.2008) that comprises raw coffee bean extract.
The effect of said composition is to reduce glucose level, glycolated hemoglobin, cholesterol and the triglyceride in blood.
Diabetes or the method for the disease of diabetes-induced for the treatment of in the patient is known as the compositions that comprises coffee bean by injection and realizes (US 2009017597).
Effect in the disease of the said composition diabetes in the patient or diabetes-induced in treatment is defined as stabilizing blood sugar, glycosated Hb A IC, triglyceride and low-density lipoprotein white level, perhaps is defined as blood sugar level normalization.
In all above mentioned situations, the antioxidation that the target purpose is based on given compositions realizes the direct therapeutic effect to diabetes.
The inventor finds, describes, hints or predict the effect of using the natural phenolic compound of uncoupling oxidative phosphorylation for the purpose of the acidosis development that inhibition is relevant to the accumulation of glycolysis product in using hyperglycemia preparation for treating diabetes process without any known source.
Immediate with the present invention program is to comprise the antidiabetic medicine particularly pharmaceutical composition of metformin and the method for the treatment of diabetes, the method comprises prescription (Balabolkin M.I., Diabetology, the Moscow that opens antidiabetic agent preparation to the patient, Meditsina, 2000; Ametov A.S.Type 2 Diabetes Mellitus:Basics of Pathogenesis and Therapy.Moscow, 2003).
Yet, as previously having pointed out, the administration overwhelming majority's the antidiabetic agent preparation (sulphanylureas derivant, thiazolidines, meglitinide, biguanides, Thiazolidinediones and insulin) that is used for this purpose and basically the process of all its known combination the hypoglycemic obvious accumulation of glucose in the bodily tissue cell that be characterised in that fallen.Excessive glucose has caused the generation of glycolysis product to increase in the cell inner accumulated, its conversion has subsequently caused numerous side effect of not expecting, wherein the most dangerous is hyperlactacidemia (considering the insufficient intensity that they are utilized in the oxidation energy metabolism).
The objective of the invention is to develop the composition of medicine that is used for the treatment of diabetes, it will reduce the side effect incidence rate of hyperglycemia formulation application, this is because the acceleration utilization of glycolysis product, and it also reduces the generation of lactic acid, and is created in the chance of using described medicine in comprehensive diabetotherapy.
The technology of the present invention effect is to reduce the risk of using development hyperlactacidemia in known hyperglycemia medicine.
Summary of the invention
Essence of the present invention is to use the combination of known hyperglycemia material and natural phenolic compound that can the uncoupling oxidative phosphorylation and extra ascorbic acid, and described ascorbic acid has improved its bioavailability by described natural phenolic compound being remained on active phenol state.
In order to realize described purpose, the inventor has advised being used for the treatment of the combination of diabetes, and it comprises at least a antidiabetic medicine and natural phenolic compound that can the uncoupling oxidative phosphorylation or the mixture of described compound.
Preferably, described combination comprises the natural phenolic compound of at least 2% amount or the mixture of described compound.
Preferably, the described antidiabetic medicine in combination is selected from biguanide, thiazolidinedione or its combination.
Preferably, use in combination can the uncoupling oxidative phosphorylation natural phenolic compound be selected from chlorogenic acid, EGCG (Epigallocatechin-3-gallate), ECG, ellagic acid, Quercetin, dihydroquercetin, fisetin, Rhizoma Curcumae Longae, resveratrol, capsaicin or CAPE.
Described compound is known as and is present in the compositions that comprises following material: other product of raw coffee bean extract, green tea, Punica granatum L., catechu, arabic gum, Rhizoma Curcumae Longae, Japanese Rhizoma Polygoni Cuspidati (Japanese knotweed), hot pepper, propolis and numerous plant or animal origin.Described natural phenolic compound can be by known method by the product separation that contains them, perhaps obtains by synthesizing, and perhaps with the form of concentrated extract, uses.According to the research that the inventor carries out, the effective dose of natural phenolic compound (single administration) is 10 to 200mg.
Preferably, the mixture of the natural phenolic compound in combination consists of plant extract.
Preferably, described combination comprises as the metformin of antidiabetic medicine and as the coffee bean extract of plant extract.
Preferably, described combination comprises as the metformin of antidiabetic medicine and as the raw coffee bean extract of plant extract.
Preferably, described combination is included as ascorbic acid or its medicinal derivative of at least 25% amount of raw coffee bean extract amount extraly.
The inventor has also advised being used for the treatment of the pharmaceutical composition of the formation composition of medicine of diabetes and complication thereof, and it comprises combination and the pharmaceutical carrier of the mixture of at least a antidiabetic medicine and natural phenolic compound or described compound.
For above-mentioned, preferred embodiment is the compositions that comprises as metformin, raw coffee bean extract and the ascorbic acid of the treatment effective dose of antidiabetic medicine.
For above-mentioned, metformin, raw coffee bean extract and ascorbic acid mass ratio relative to each other is 100:20:10 to 100:40:30.
for above-mentioned, described compositions can powder agent, granule, tablet, small pieces, capsule, confection, suspensoid, the form of Emulsion or solution is made, and it comprises auxiliary substance, filler (silicon dioxide particularly, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose etc.), binding agent (polyvinylpyrrolidone, vinyl arsenic pyrrolidone and vinyl acetate copolymer etc.), lubricant (magnesium stearate etc.), emulsifying agent (oxyethylation Oleum Ricini wax, lecithin etc.), solubilizing agent (Polysorbate, poloxamer etc.), extend agent (prolongator) (behenic acid glyceride, hydroxypropyl emthylcellulose etc.) and correctives (fructose, lactose, sorbitol etc.).
Antidiabetic medicine in compositions is to use for their individually dosed dosage of being recommended.The administration frequency of the compositions that requires is identical with the administration frequency of its component antidiabetic medicine.The administration cycle should be the same with the persistent period of any hyperlactacidemia symptom long, but be at least for two weeks.Preferably the patient should continue to take the compositions of requirement after the content recovery in pH value and Lactated blood, and this is because this will reduce the risk of hyperlactacidemia recurrence.
The inventor has also advised being effective to treat the medicine suit of diabetes, and it comprises the combination of the mixture of at least a antidiabetic medicine and a kind of natural phenolic compound or described compound.
Described preparation has formed the preparation of the independent manufacturing that comprises antidiabetic medicine and has comprised natural phenolic compound or the preparation of the other independent manufacturing of its mixture.Described preparation can comprise ascorbic acid or its medicinal derivative.
The described preparation that comprises antidiabetic medicine for example can contain Metformin and auxiliary substance (hydroxypropyl emthylcellulose, microcrystalline Cellulose, polyvidone, magnesium stearate) and be tablet form.
The described preparation that comprises natural phenolic compound can contain raw coffee bean extract (50-55% polyphenol) for example, ascorbic acid and as the microcrystalline Cellulose of auxiliary substance.Described compositions can be placed in hard gelatin capsule.
The Tablet and Capsula agent can be packaged in bubble-cap (blister) with suitable labelling or bottle and with the Tablet and Capsula agent of wherein similar number, together be placed in and share in box.
Depend on compositions, can give one, two and three Tablet and Capsula agent for single dose.
Equally, advised the method for the treating diabetes of combination, it comprises prescription from combination to the patient that open, and described combination consists of the mixture of at least a antidiabetic medicine and natural phenolic compound or described compound.
Do not limiting under aforesaid general principle, desired pharmaceutical composition can be used as combination and uses.
While the hyperlactacidemia symptom occurring in the patient or when treating diabetes starts (existing about the patient in the situation that have the information of acidosis susceptibility in passing case history), described pharmaceutical composition uses in the treatment diabetes.Open the prescription of described compositions with the amount of the treatment effective dose of the specific anti-diabetic hyperglycemia medicine that comprises corresponding to it, every daily dose is divided into 2 or 3 doses.It comprises 2-3 capsule or the tablet of the compositions of requirement corresponding to picked-up, every day on the feed in or administration 2 or 3 times after feed.The patient takes described compositions until acidosis symptom is eliminated, but is no less than at least for two weeks.When in pH value and Lactated blood, content recovered in blood, possible is changed the natural phenolic compound that the present invention of only with a kind of anti-diabetic hyperglycemia medicine, treating and no longer adding requires into.Yet, be the combination that continues to take requirement for patient's preferred selection, this is because it will reduce the risk of hyperlactacidemia recurrence.
In the method for suggestion of the treating diabetes of combination, the form that the combination of requirement can the medicine suit is used.
, when existing while for the patient, using the indication of combination of requirement of pharmaceutical compositions, use medicine of the present invention to be set with.In the situation that pharmaceutical composition, the amount of the composition of medicine of medicine nested form is determined by the treatment effective dose of the specific anti-diabetic hyperglycemia medicine that it comprises.With each serving open the prescription of described combination with 1 or 2 preparation, every day on the feed in or administration 2-3 time after feed.Continue to give the medicine suit until the acidosis symptom in the patient disappears, but be no less than for two weeks.That is to say, the preferred selection is the preparation that continues to require in treating diabetes subsequently.During this period, depend on clinical laboratory's check result, the purpose for strengthening hyperglycemia effect or antiacid poisoning effect, can add the one-component of suitable type in the dose of preparation.
The applicant also be intended to protect can the uncoupling oxidative phosphorylation natural phenolic compound or the application of mixture in the treatment diabetes of described compound, it uses hyperglycemia preparation as the medicine that suppresses the hyperlactacidemia development.
The specific embodiment
Following embodiment has confirmed the suitability of the present invention and effectiveness and has not limited its scope.
Embodiment 1.
The combination table of the present invention that is used for the treatment of diabetes is shown the pharmaceutical composition that is encapsulated in hard gelatin capsule.
This capsule comprises the mixture of 250mg Metformin, 125mg raw coffee bean extract (50-55% polyphenol) and 25mg microcrystalline Cellulose.
Open the prescription of described combination with the dose of 2 or 3 capsules.
Embodiment 2.
The combination table of the present invention that is used for the treatment of diabetes is shown the pharmaceutical composition that is encapsulated in hard gelatin capsule.
This capsule comprises the mixture of 250mg Metformin, 60mg raw coffee bean extract (50-55% polyphenol), 36.5mg ascorbic acid and 3.5mg silicon dioxide.
Open the prescription of described combination once to take 2-3 capsule.
Embodiment 3.
The combination table of the present invention that is used for the treatment of diabetes is shown the pharmaceutical composition that is encapsulated in hard gelatin capsule.
This capsule comprises the mixture of 250mg Metformin, 1mg rosiglitazone maleate, 50mg chlorogenic acid, 74mg ascorbic acid and 25mg microcrystalline Cellulose.
Open the prescription of described combination once to take 2-3 capsule.
Embodiment 4.
The combination table of the present invention that is used for the treatment of diabetes is shown the pharmaceutical composition of tablet form.
This tablet comprises 250mg Metformin, 60mg chlorogenic acid and auxiliary substance (microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, polyvinylpyrrolidone, magnesium stearate, hydroxypropyl emthylcellulose, macrogol, titanium dioxide).
This tablet is made by the following method: by adding binding agent that the mixture of metformin and chlorogenic acid is carried out wet granulation, produce granule, make subsequently granule and solubilizing agent and mix lubricant, with the mixture tabletting and with the tablet of gained hydrophilic polymer film coating.
Open the prescription of described combination once to take 2-3 tablet.
Embodiment 5.
The combination table of the present invention that is used for the treatment of diabetes is shown the pharmaceutical composition of tablet form.
This tablet comprises 250mg Metformin, 1.25mg glibenclamide, 30mg chlorogenic acid, 40mg ascorbic acid and auxiliary substance (microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, polyvinylpyrrolidone, magnesium stearate, hydroxypropyl emthylcellulose, macrogol, titanium dioxide).
This tablet is made by the following method: by adding binding agent that the mixture of metformin, glibenclamide, chlorogenic acid and ascorbic acid is carried out wet granulation, produce granule, make subsequently granule and solubilizing agent and mix lubricant, with the mixture tabletting and with the tablet of gained hydrophilic polymer film coating.
Open the prescription of described combination once to take 2-3 tablet.
Embodiment 6.
The combination table of the present invention that is used for the treatment of diabetes is shown the medicine suit (pharmaceutical set) that comprises the tablet of separately making, the tablet that it comprises anti-diabetic hyperglycemia medicine and contains natural phenolic compound.
The tablet that contains the hyperglycemia material comprises 500mg Metformin, 15mg pioglitazone hydrochlorate and auxiliary substance (microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, polyvinylpyrrolidone, magnesium stearate, hydroxypropyl emthylcellulose, macrogol, titanium dioxide, Talcum).
This tablet is made by the following method: by adding binding agent that the mixture of metformin and pioglitazone is carried out wet granulation, produce granule, make subsequently granule and solubilizing agent and mix lubricant, with the mixture tabletting and with the tablet of gained hydrophilic polymer film coating.
The tablet that contains polyphenol compound comprises 100mg chlorogenic acid and auxiliary substance (hydroxypropyl emthylcellulose, microcrystalline Cellulose, polyvidone, magnesium stearate).
This tablet is made by the following method: carries out wet granulation by the mixture with chlorogenic acid and binding agent and produces granule, make subsequently granule and solubilizing agent and mix lubricant, and with the mixture tabletting.
The tablet (on the other hand) that contains the tablet (on the one hand) of hyperglycemia medicine and contain natural phenolic compound is packaged in bubble-cap with isolabeling not or bottle and with the tablet of every type of wherein similar number, together is placed in and shares in box.
Open the prescription of described combination with 1 or 2 tablet once taking every type.
Embodiment 7.
The combination table of the present invention that is used for the treatment of diabetes is shown the medicine suit that comprises the Tablet and Capsula agent of separately making, and described tablet contains anti-diabetic hyperglycemia medicine, and described capsule contains the mixture of natural phenolic compound and ascorbic acid.
This tablet comprises 500mg Metformin and auxiliary substance (hydroxypropyl emthylcellulose, microcrystalline Cellulose, polyvidone, magnesium stearate).
This tablet is made by the following method: produces granule by adding binding agent that the mixture of metformin is carried out wet granulation, makes subsequently granule and solubilizing agent and mix lubricant, and with the mixture tabletting.
This capsule comprises the mixture of 100mg raw coffee bean extract (50-55% polyphenol), 75mg ascorbic acid and 25mg microcrystalline Cellulose.
The Tablet and Capsula agent is packaged in bubble-cap with labelling separately or bottle and with the Tablet and Capsula agent of wherein similar number, together is placed in and shares in box.
Once to take one (1 tablet and 1 capsule) or two (2 tablets and 2 capsules) preparations are opened the prescription of described combination.
Embodiment 8.
The combination table of the present invention that is used for the treatment of diabetes is shown and comprises the tablet that contains anti-diabetic hyperglycemia medicine of separately making and contain natural phenolic compound and the medicine of the tablet of the mixture of ascorbic acid suit.
The tablet that contains the hyperglycemia medicine comprises 500mg Metformin, 5mg glibenclamide and auxiliary substance (cross-linking sodium carboxymethyl cellulose, magnesium stearate, starch, microcrystalline Cellulose, polyvidone, lactose monohydrate).
This tablet is made by the following method: produces granule by adding binding agent that the mixture of metformin and glibenclamide is carried out wet granulation, makes subsequently granule and solubilizing agent and mix lubricant, and with the mixture tabletting.
The tablet that is used for the release of prolongation active substance comprises 200mg raw coffee bean extract, 50mg ascorbic acid and auxiliary substance (Compritol 888 ATO, Kollidon VA64, Kollidon 17PF, magnesium stearate).
Tablet is made by the direct pressing method of the tablet of particle form, and the direct pressing cake of described granule by the mixture with active substance and helper component carries out disintegrate and obtain.
Contain the tablet (on the one hand) of hyperglycemia medicine and contain natural phenolic compound and the tablet of the mixture of ascorbic acid (on the other hand) is packaged in bubble-cap with isolabeling not or bottle and with the tablet of every type of wherein similar number, together be placed in and share in box.
Open the prescription of described combination with 1 or 2 tablet once taking every type.
Embodiment 9.
The combination table of the present invention that is used for the treatment of diabetes is shown and comprises the tablet separately made and the medicine suit of Gelseal, described tablet contains anti-diabetic hyperglycemia medicine, and described capsule contains the suspension of the mixture of natural phenolic compound and ascorbic acid.
The tablet of metformin is based on embodiment 7.
Gelseal comprises the suspension of mixture in 150mg polyoxyethylene sorbitan monoleate (Tween 80) of 75mg raw coffee bean extract (50-55% polyphenol) and 50mg ascorbic acid.
Be used for the form generation of the suspension of filling capsule with even paste, by the premix formulations with raw coffee bean extract and ascorbic acid, mix under constant agitation in vacuum reactor with polyoxyethylene sorbitan monoleate gradually.
The Tablet and Capsula agent is packaged in bubble-cap with labelling separately or bottle and with the Tablet and Capsula agent of wherein similar number, together is placed in and shares in box.
Embodiment 10.
Natural phenolic compound by can the uncoupling oxidative phosphorylation is suppressed at the internal pH of inducing in MDCK continuous cell line in mitochondrion (hepatocyte of Canis familiaris L.) to be reduced, and it is by being added to metformin and rosiglitazone in cell culture medium and carrying out.
The mdck cell culture is growth in 37 ℃ and 5%CO2 (pH7.4) in being added with the DMEM culture medium of 10% calf serum.After forming continuous monolayer, use trypsin-EDTA solution that cell is transferred in suspension., fully separately to stop tryptic any used time of further doing of EDTA-hyclone and DMEM culture medium are introduced in culture bottle with equal proportion (1:1) when cell.With cell DMEM culture medium washed twice.Washing is while completing the last time, in culture bottle with 110
6The concentration of individual cell/mL prepares cell suspension in containing the Krebs-Henseleit culture medium of 10mM dextrose, add simultaneously a kind of in following hyperglycemia material: Metformin (5MM) or rosiglitazone maleate (25 μ Μ), and a kind of natural phenolic compound (50 μ Μ).
Suspension was hatched 60 minutes under 37 ℃ of stirrings (by the jolting test tube) at every 10 minutes.After having hatched, with cell by centrifugation, and again be suspended in contain 10mM dextrose and 5 μ Μ pH-sensitive dyes 2 ', in the Krebs-Henseleit culture medium of 7 '-two-(2-carboxy ethyl)-5-(with-6)-CF 5(6)-Carboxyfluorescein acetoxyl group methyl ester (BCECF-AM).The suspension of gained is hatched 25 minutes to induce dyestuff by Cell uptake at 37 ℃.Then suspension is washed three times in Krebs-Henseleit culture medium (wherein HEPES replaces with bicarbonate).The cell of gained is suspended in and has 110
6In the identical buffer agent of the concentration of individual cell/mL and be introduced in the micro cell of 37 ℃ of constant temperature to be used for fluorescence measurement.Fluorescence measurement carries out on Perkin Elmer LS-5 fluorophotometer (having fluorescence and following two excitation wavelength: 490nm (to the fluorescence of pH sensitivity) and 440nm (isobestic point) in the 530nm registration).The ratio of the fluorescence of 490nm and the fluorescence of 440nm be used for to be calculated internal pH, its according to use in having the Krebs-Henseleit culture medium that contains H+/K+ ionophore nigericin (10 μ g/mL) of different pH value (6.5 to 7.5) 110
6The calibration dependency that the cell suspension of individual cell/mL obtains.
Can be in mitochondrion the impact of the natural phenolic compound of uncoupling oxidative phosphorylation, namely by metformin and rosiglitazone are added in cell culture medium the internal pH that causes the MDCK continuous cell line, change, be shown in table 1.
Acquired results (table 1) has confirmed that natural phenolic compound that can the uncoupling oxidative phosphorylation prevents the ability (by add the hyperglycemia medicine that is selected from biguanide (metformin) and thiazolidinedione (rosiglitazone) in cell culture medium) that the internal pH of inducing in the MDCK continuous cell line reduces.
Embodiment 11.
Metformin, gastric by the intravenous injection high dose give can be in mitochondrion the solution of the natural phenolic compound of uncoupling oxidative phosphorylation and dispersion liquid and ascorbic acid confirm inhibition to the hyperlactacidemia development.
In this test, use 8 months large Sprague Dawley rats, its body weight is 250-280g.Animal is remained in each bright/dark circulation of 12 hours, it is freely intake and for rodentine feedstuff.Before on-test 12 hours, forbid the animal feed but allow continuing freely to intake.With the form of 2.5% physiological solution with the dosage of 250mg/kg with the metformin direct injection to the tail vein, every injection in 1 hour once, inject four times.Injecting the front half an hour of metformin first, the laboratory animal per os is accepted natural phenolic compound at water or the solution in aqueous ascorbic acid or suspension.The dosage of natural phenolic compound adds up to 5mg/kg, and the dosage of ascorbic acid adds up to 2.5mg/kg.Matched group is by following expression: intact animal; Only accept the animal of metformin; And accept metformin and do not contain the animal of the ascorbic acid solution of natural phenolic compound.
Metformin injection is rear one hour the last time, by the sublingual vein of animal, gathers blood (approximately 0.5mL), be placed in the test tube that do not contain anticoagulant and standing 30 minutes of room temperature to form clot.By at 2,000g, carrying out separation of serum in centrifugal 15 minutes, and 0.25mL is placed in the 1.5mL microcentrifugal tube., for deproteinization, the cold 0.5M metaphosphoric acid solution of 0.25mL is added in the serum of gained jolting and at standing 5 minutes on ice.By centrifugal 5 minutes of 10,000g and 4 ℃ with the albumen precipitation of degeneration.Supernatant (0.4mL) is collected in new microcentrifugal tube, by the 5M solution of potassium carbonate that adds 25 μ L, acid is neutralized, and pass through at 10,000g and 4 ℃ of centrifugal 5 minutes separating residues.The supernatant of use collecting immediately, the fluorescent method of the standard reagent group that is suitable for using in micro cell according to use is determined lactate content on Perkin Elmer LS-5 fluorophotometer.
Can be shown in table 2 impact that the hyperlactacidemia that is caused by metformin in rat develops by the natural phenolic compound of uncoupling oxidative phosphorylation in mitochondrion.
The result (table 2) that obtains has confirmed and can suppress the ability that lactic acid is accumulated and hyperlactacidemia develops by the natural phenolic compound of uncoupling oxidative phosphorylation in mitochondrion, particularly suppressed the ability of the hyperlactacidemia of by the hyperglycemia medicine metformin that gives heavy dose, being induced development.Give the enhancing that aforementioned phenolic compound and ascorbic acid help the antiacid poisoning effect that records, this has confirmed the benefit that is used in combination of these materials of the present invention.
Embodiment 12.
Clinical case-by giving the metformin unitary agent to giving dimethyldiguanide tablet and containing raw coffee bean extract and after the combination of the form of the capsule of ascorbic acid changes, eliminate the hyperlactacidemia symptom in the patient.
Patient V., 47 y/o, be diagnosed as type ii diabetes first.When diagnosis was established, the form proposition hyperglycemia therapy with the metformin unitary agent, originated in 500mg every day.Within the time of 7 days, do not observe in the gastrointestinal tract part effect of not expecting, and the dosage of metformin increases to twice 500mg every day.The clinical laboratory that carries out after one week detects in the patient weak hyperlactacidemia symptom (referring to table 3), and this is by with the confirmation of getting off: in blood, lactate content exceeds upper range and blood pH drops to lower than lower range slightly.Develop acidosic trend relevant to hepatic insufficiency, and the latter is relevant to the hepatitis in medical history.Consider the biochemical change of evaluation, the patient is changed two combinations every day of accepting embodiment 7 into and is reached the time in two weeks, and its tablet by the hyperglycemia medicine and the capsule that comprises the mixture of natural phenolic compound and ascorbic acid form.The clinical laboratory that carries out within the time in time limit checks and has established lactate content and blood pH standardization.Add the tablet (reach and amount to 500mg x3 every day) of extra 500mg metformin unitary agent in combination and subsequently ensuing surrounding changes the metformin unitary agent that gives 500mg x3 dosage every day in the time after, it is stable that the normal value of described index keeps lasting in the time of surrounding to two every days of embodiment 7.Yet, consider the trend that any further reduction that do not have lactate content for the background that keeps hepatic insufficiency in the patient and pH increase, think it is reasonably to use the prescription of two combinations of embodiment 7 and the tablet of extra 500mg metformin unitary agent (reach metformin every day amount to 500mg x3) as supporting treatment for patient treatment subsequently.The patient's who carries out after surrounding clinical laboratory checks the further improvement that has shown the biochemistry physiochemical indice that is characterised in that hydrocarbon metabolism, and this has confirmed to use the positive treatment effect (considering that the patient is easy to occur acidosis) for the treatment of in type ii diabetes that is combined in of oral hyperglycemia medicine and natural phenolic compound and ascorbic acid.
In the therapeutic process of the combination of using oral hyperglycemia medicine and natural phenolic compound and ascorbic acid, be characterised in that in patient V. that the kinetics of the biochemistry clinical laboratory physiochemical indice of hydrocarbon metabolism is shown in table 3.
Table 1.
Note
1. measure and carry out with three parallel testings.Data are expressed as meansigma methods ± meansigma methods error.
Do not contain the hyperglycemia material and can be in mitochondrion in the culture medium of the material of uncoupling oxidative phosphorylation under incubation conditions the internal pH in cell equal 7.43 ± 0.06.Meet P according to Student ' s t check＜0.05 in the decline of the internal pH that records when only adding the hyperglycemia medicine in hatching culture medium.
3.* while with the pH value in test not containing uncoupling agents, comparing, according to Student ' s t check-P＜0.05.
Table 2.
Note
1. every group comprises 3 animals.Data are expressed as meansigma methods ± meansigma methods error.
2. the lactate content of the serum of intact animal is 1.64 ± 0.19mM.The increase of the lactate content that records that is caused by the metformin administration meets according to the P of Student ' s t check＜0.05.
3.* while with the group that does not give natural phenolic compound, comparing, according to Student ' s t check-P＜0.05.When * compares with the group that does not give ascorbic acid ,-P＜0.05.
Table 3.
Attention: combination and the dosage of metformin are as described in present specification.
Claims (22)
1. be used for the treatment of the combination of diabetes, it comprises at least a antidiabetic medicine and at least a natural phenolic compound.
2. the combination of claim 1, wherein it comprises the natural phenolic compound of at least 2% amount or the mixture of described compound.
3. the combination of claim 1, wherein said antidiabetic medicine are selected from biguanide, thiazolidinedione or their combination.
4. the combination of claim 1, wherein said natural phenolic compound is selected from chlorogenic acid, EGCG, ECG, ellagic acid, Quercetin, dihydroquercetin, fisetin, Rhizoma Curcumae Longae, resveratrol, capsaicin or CAPE.
5. the combination of claim 1, wherein it comprises the plant extract as the mixture of natural phenolic compound.
6. the combination of claim 5, wherein it comprises as the metformin of antidiabetic medicine with as the coffee bean extract of plant extract.
7. the combination of claim 5, wherein it comprises as the metformin of antidiabetic medicine with as the raw coffee bean extract of plant extract.
8. the combination of claim 7, wherein it also comprises ascorbic acid or its medicinal derivative, and the amount of described ascorbic acid or its medicinal derivative is at least 25% of raw coffee bean extract amount.
9. the pharmaceutical composition that is used for the treatment of diabetes, it comprises combination and the pharmaceutical carrier of claim 1.
10. the pharmaceutical composition of claim 9, wherein it comprises metformin, raw coffee bean extract and the ascorbic acid for the treatment of effective dose, and wherein said ascorbic acid is natural ascorbic acid, synthetic ascorbic acid or their combination.
11. the pharmaceutical composition of claim 10, wherein the ratio of the quality of metformin, raw coffee bean extract and ascorbic acid is 100:20:10 to 100:40:30.
12. the pharmaceutical composition of claim 9, wherein its form with powder agent, granule, tablet, small pieces, gel, capsule, confection, suspensoid, Emulsion, solution is made.
13. be used for the treatment of the medicine suit of diabetes, it comprises the combination of any one in claim 1-11.
14. the medicine of claim 13 suit, wherein it comprises metformin, raw coffee bean extract and the ascorbic acid for the treatment of effective dose.
15. the medicine of claim 14 suit, wherein the ratio of the quality of metformin, raw coffee bean extract and ascorbic acid is 100:20:10 to 100:40:30.
16. the medicine of claim 13 suit, wherein its form with powder agent, granule, tablet, small pieces, capsule, confection, suspensoid, Emulsion, solution is made.
17. the diabetes remedy of combination, comprise prescription from the combination of claim 1 to the patient that open.
18. the method for claim 17, wherein claim 1 has constituted pharmaceutical composition.
19. the method for claim 18; wherein in the situation that the patient shows that the symptom of hyperlactacidemia opens the prescription of pharmaceutical composition; and any other dosage form with the amount of capsule, tablet or other unit number of the amount of the 2-3 that contains claimed compositions is used, every day on the feed in or use 2-3 time after feed.
20. the method for claim 17, wherein claim 1 has constituted the medicine suit.
21. the method for claim 20, wherein in the situation that the patient shows that the symptom of hyperlactacidemia opens the prescription of medicine suit, and use with the amount of 1 or 2 suit, every day on the feed in or use 2-3 time after feed.
22. natural phenolic compound that can the uncoupling oxidative phosphorylation or its mixture are in the purposes of using in treating diabetes as the antidiabetic agent preparation that suppresses the hyperlactacidemia medicine.
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| PCT/RU2012/000254 WO2012166008A1 (en) | 2011-06-02 | 2012-04-05 | Combination for treatment of diabetes mellitus |
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| JP (1) | JP2014527506A (en) |
| KR (1) | KR101567660B1 (en) |
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| CN105902761A (en) * | 2016-06-16 | 2016-08-31 | 河南中医学院 | Application of flos sophorae powder in preparing drugs for treating hyperglycemia and diabetes |
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| CN105263484B (en) * | 2013-05-24 | 2018-08-03 | 株式会社加龄.营养研究所 | Including the pharmaceutical composition of melbine and dihydroquercetin and its purposes for treating cancer |
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| FR3062795B1 (en) * | 2017-02-16 | 2019-06-07 | Valbiotis | PHARMACEUTICAL ACTIVE INGREDIENT AND USE IN PARTICULAR IN THE PREVENTION AND TREATMENT OF METABOLIC DERGLEMENTS IN MAN AND ANIMAL. |
| RU2687256C1 (en) * | 2018-03-26 | 2019-05-08 | Федеральное Государственное бюджетное образовательное учреждение высшего образования Дагестанский государственный медицинский университет Министерства здравоохранения Российской Федерации Даггосмедуниверситет | Method of personalized treatment of chronic renal disease in patients with diabetic nephropathy |
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Also Published As
| Publication number | Publication date |
|---|---|
| EA028394B1 (en) | 2017-11-30 |
| RU2451506C1 (en) | 2012-05-27 |
| KR20140008452A (en) | 2014-01-21 |
| KR101567660B1 (en) | 2015-11-10 |
| WO2012166008A1 (en) | 2012-12-06 |
| EP2714022A1 (en) | 2014-04-09 |
| EA201301308A1 (en) | 2014-03-31 |
| JP2014527506A (en) | 2014-10-16 |
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