JP2014527506A - Combinations for diabetes treatment - Google Patents

Abstract

Combinations for the treatment of diabetes are claimed which can be made in the form of pharmaceutical compositions or pharmaceutical sets. Such combinations include hypoglycemic drugs and natural phenolic compounds that can uncouple oxidative phosphorylation. Such a combination offers the possibility of reducing the incidence of side effects caused by the use of hypoglycemic preparations, more particularly the risk of lactic acidosis.

Description

  The present invention relates to the pharmaceutical industry, and in particular to pharmaceuticals for the treatment of diabetes.

  Diabetes remains a significant problem in national public health practice in almost every country in the world. Over the past 30 to 40 years, a significant increase in the prevalence and incidence of diabetes has become evident around the world, and this trend indicates that 6-10% of the population suffers from diabetes and its prevalence However, this is particularly noticeable in industrialized countries, where there is a clear upward trend mainly in the age group of 40 years and older.

  As is known, the main objectives of diabetes treatment plans are to reduce diabetes symptoms, improve quality of life, and acute complications (hyperosmotic coma and ketoacidosis) and eg diabetic neuropathy, diabetic nephropathy, It is prevention of both chronic complications such as early atherosclerosis (Diabetes Control and Complications Trial Research Group; N. Engl. J. Med., 329, 977-986 (1993)).

  Chronic hyperglycemia is not only the main sign of diabetes, which is the basis for the diagnosis of the disease, but also the most important in the development of almost all complications such as microvascular and macrovascular disorders, neurological disorders, renal disorders It is also a major factor.

  Long-term hyperglycemia leads to increased stimulation of the pancreatic beta cells, which in turn leads to a depletion of their functional capacity and consequently contributes to disease progression.

  The goal of diabetes treatment is to achieve enhanced carbohydrate metabolism over time, i.e. to reliably achieve an indication of plasma glucose levels that would be substantially the same as that observed in the daytime in healthy individuals It is to be. Treatment of diabetes begins with prescribing diet and exercise therapy. However, a great deal of patient effort is required to achieve the target carbohydrate metabolism index, but such efforts are usually practiced to a limited extent in diabetic patients. This is why drug therapy plays a major role in the treatment of diabetes.

  Hypoglycemic drug therapy does not simply reduce the glycemia indicator, thereby eliminating the clinical symptoms of the disease caused by hyperglycemia. Hypoglycemic drug therapy also eliminates the “vicious circle” formed by the increase in insulin deficiency due to the depletion of insulin secreting cells and the progression of hyperglycemia given the increase in insulin deficiency. The positive effects of hypoglycemic drugs under insulin deficiency as described herein are more closely related to type 2 diabetes and the early stages of type 1 diabetes.

Currently, the following groups of oral hypoglycemic drugs are used in the treatment of type 2 diabetes:
Delays carbohydrate digestion and glucose absorption in the gastrointestinal tract (alpha-glucosidase inhibitors guar, acarbose, miglitol, etc.);
Enhances insulin production by the pancreas (sulfonylurea derivatives glibenclamide, glipizide, gliclazide, glyquidone and glimepiride);
Promotes postprandial insulin secretion (glinide drugs, incretin mimetics, DPP-4 inhibitors, amylin and glucagon-like peptide 1 analogs);
Promotes glucose uptake into cells and inhibits glucose release by cells (biguanides, now in particular metformin);
Formulations that enhance the insulin sensitivity of tissues, or thiazolidinedione drugs (glitazones) that are insulin sensitizers-pioglitazone, rosiglitazone;
・ Insulin.

  A-glucosidase inhibitors (Acarbose) reduce glucose absorption in the intestine and are usually effective early in the disease. Side effects of the inhibitor are associated with symptoms of flatulence and diarrhea. In most patients, administration of the drug will need to be discontinued within 3 years from the start of administration.

  Sulfonylurea derivatives stimulate insulin secretion by pancreatic B cells. The currently most commonly used sulfonylureas are gliclazide, glibenclamide, glipizide and glyquidone. Treatment with sulfonylureas is at risk for type 1 or secondary (pancreatic) diabetes, pregnancy and breastfeeding, surgery, severe infections, trauma, history of allergy to sulfonylureas or similar drugs, or severe hypoglycemia. If present, it is contraindicated.

  Glinide drugs (meglitinides) are characterized by rapid onset of action and short duration of action, which, on the one hand, allows effective control of postprandial hyperglycemia while not increasing the risk of hypoglycemia. Also make it possible.

  Formulations specifically intended to affect postprandial glucose levels are incretin mimetics, DPP-4 inhibitors, amylin analogs and glucagon-like peptide 1 analogs. These drugs compensate for existing deficiencies in pancreatic and gastrointestinal hormonal secretion and act on insulin and glucagon secretion, satiety, and gastric emptying. They are characterized by very rapid onset and short-term hypoglycemic action, and therefore their use does not involve any adverse development due to their influence on glucose metabolism. The rapid and short acting action makes the drug useful only as a postprandial hypoglycemic agent.

  The group of tablet-type biguanide antihyperglycemic drugs is currently represented mainly by metformin. Biguanides do not promote insulin secretion. Their hypoglycemic effect appears only when sufficient insulin is present in the blood. Biguanide drugs enhance their action on peripheral tissues and decrease insulin resistance. Biguanide drugs increase glucose uptake by muscle and adipose tissue. They reduce hepatic glucose production, intestinal glucose absorption, increase glucose utilization, and decrease appetite. It is contraindicated to prescribe biguanides if you have renal dysfunction, hypoxia due to any etiology (heart failure, lung disease, anemia, infection), acute complications of diabetes, alcoholism, or a history of lactic acidemia It is. Among the side effects of metformin, notable are the symptoms of dyspepsia when administering high doses of drugs. Cases of patients who develop lactic acidosis are known, which reflects the ability of the drug to increase anaerobic glycolysis in the liver and inhibit gluconeogenesis.

  The use of sulfanilamide hypoglycemic preparations and biguanides can cause side effects in the form of gastrointestinal disorders, skin allergies, and hypoglycemia resulting from the close therapeutic and toxic doses of these drugs.

  Thiazolidinedione drugs act on glycemic control by reducing insulin resistance in peripheral tissues, particularly adipose tissue, and also reduce hepatic glucose production. This group of formulations does not cause hypoglycemia but can contribute to weight gain. These drugs are contraindicated in patients with symptoms of heart failure and signs of pre- and proliferative stage diabetic retinopathy.

  If it turns out that monotherapy of hypoglycemic drugs is not effective, sometimes the desired effect may be achieved by combining hypoglycemic preparations. The following combinations of oral hypoglycemic preparations are possible: sulfonylurea preparations and thiazolidinedione drugs, metformin and meglitinide drugs, metformin and thiazolidinedione drugs, sulfonylurea preparations and a-glucosidase inhibitors. If glycemic control is not achieved by a combination of oral hypoglycemic preparations, combination therapy with insulin and biguanide drugs, or monotherapy with insulin will be prescribed.

  Both sulfonylurea preparations and metformin act to reinforce carbohydrate metabolism, but their mechanisms of hypoglycemic action are different. These aspects allow these drugs to be used in combination therapy.

  Glibomet, an oral hypoglycemic preparation with combined action, consists of 2.5 mg glibenclamide and 400 mg metformin. Glybenclamide contained in the drug stimulates insulin secretion by pancreatic B cells, while metformin reduces insulin resistance primarily in the liver, including inhibition of gluconeogenesis, decreased glucose formation rate in the liver, and Accompanied by their acceptance into the circulatory system. The use of concomitant drugs promotes the hypoglycemic effect, but the threat of lactic acidosis associated with the use of metformin remains.

  Combination drugs for the treatment of metabolic disorders, mainly diabetes and disorders related to diabetes, comprising nateglinide and the antidiabetic drug glitazone in a pharmaceutically acceptable carrier are known. The glitazone can be represented by pioglitazone, rosiglitazone or troglitazone (Russian Patent No. 2280447, September 15, 2000).

  The combination drug may take the form of a combined preparation or a pharmaceutical composition. Such a pharmaceutical composition may comprise metformin in a pharmaceutical carrier as a third antidiabetic agent. The combination of nateglinide and another anti-diabetic drug ensures a synergistic therapeutic effect on type 2 diabetes and a long duration of drug action, resulting in a later extension of insulin use. The disadvantage of this combination is the use of glitazone and metformin, both of which can contribute to the development of lactic acidosis.

  Drugs for the treatment of diabetes are known (Russian Patent No. 2413528, January 18, 2007) comprising an effective amount of a combination of exenatide and dalargin. This combination is a concomitant drug that ensures the effective treatment of diabetes by enhancing the blood glucose and cholesterol lowering effects of exenatide. The disadvantage of this combination is that injection form administration is preferably used.

Drugs for the treatment of non-insulin-dependent type 2 diabetes, comprising an effective amount of metformin and glibenclamide combination, are known and have a powder particle surface area of 1.7-2.2 m ² / g for oral administration combination A method of treating non-insulin dependent diabetes or hyperglycemia using glibenclamide, which is part of the drug, is known (Russian Patent No. 2286788, July 12, 1999).

  The present invention ensures the bioavailability of glibenclamide in the composition of metformin-containing drugs that is comparable to the bioavailability of the glibenclamide single form. However, the use of metformin in the proposed formulation brings about the need to consider the increased likelihood of lactic acidosis.

  Thus, currently used oral hypoglycemic drugs solve the problem of lowering blood glucose by different mechanisms and are therefore effective only under certain conditions. The ambiguous manifestation of the symptoms of the main disease and the combined conditions that result in contraindications in some patient subgroups result in unwanted side effects. One of the most important contraindications is a predisposition to lactic acidosis.

  The reduction in blood glucose during the administration period of the overwhelming number of formulations (sulfonylurea derivatives, glinides, biguanides, thiazolidinediones and insulin) used for that purpose and almost all of their combinations Characterized by a significant accumulation of glucose in the cell. Excess glucose accumulates in the cell leading to an increase in the production of glycolytic products, and subsequent conversions of the product may be desired in some cases when they are not sufficiently used in oxidative energy metabolism. Lactic acidosis is the most dangerous, with no side effects.

  Excessive accumulation of lactic acid in the body and subsequent lactic acidosis is most clearly observed as a side effect of taking biguanide drugs. The same metabolic shift is the basis for limiting the use of hypoglycemic means (sulfonylurea derivatives, thiazolidine drugs, and glinide drugs) when patients have symptoms of lactic acidosis and ketoacidosis. In addition, high levels of glycolysis products lead to activation of fatty acid synthesis, resulting in the weight gain observed during the administration of several hypoglycemic preparations (sulfonylurea derivatives, thiazolidine drugs, glinide drugs) It becomes.

  As stated above, the described problems with hypoglycemic drugs still remain when such drugs are used in combination.

  Therefore, the development of anti-diabetic preparations that will result in less intracellular accumulation of glycolytic products associated with their use appears to be indeed adequate at present. This makes it possible to reduce the possibility of unwanted side effects.

  As is known, the metabolism of pyruvate formed during glycolysis is associated with its oxidation in the Krebs cycle, which involves the restoration of additional cofactors in addition to the cofactors synthesized during glycolysis. . The main consumption of the cofactor occurs during ATP synthesis in the mitochondrial oxidative phosphorylation chain. Under conditions of increased pyruvate formation, natural ATP consumption is insufficient to ensure efficient efflux of reduced cofactors. This leads to excessive lactic acid formation from pyruvate in cells with increased glucose levels. Aimed at increasing background ATP consumption in energy-dependent processes, higher levels of exercise are used in diabetes treatment practices to increase the release of reduced cofactors of other glycolytic products .

  At the same time, the problem of increasing the release of reduced cofactors could be solved by using components in the anti-diabetic drug composition that reliably promote consumption of reduced cofactors in intracellular processes.

  In this regard, the authors have noted several substances that can uncouple oxidative phosphorylation in mitochondria. Such uncoupling increases the use of reduced cofactors to reduce oxygen to water without ATP formation, ie meaningless.

  Subsequent studies by the authors have used natural phenolic compounds that can uncouple mitochondrial oxidative phosphorylation to reduce the incidence of acidosis associated with the accumulation of glycolytic products during the administration of hypoglycemic products. Show you get.

  For the purpose of treating lipid metabolism disorders, it has been proposed to use natural phenolic compounds and products containing them that can uncouple oxidative phosphorylation to promote heat production in adipose tissue (US patent application). Publication No. 201100215782). However, the authors recognize any use of natural phenolic compounds for the purpose of uncoupling oxidative phosphorylation to inhibit the onset of acidosis associated with the accumulation of glycolytic products during the administration of hypoglycemic preparations. Not.

  Furthermore, according to studies conducted by the authors, when ascorbic acid is further administered into the body along with the natural phenolic compound, the aforementioned effects are promoted by maintaining the natural phenolic compound in phenolic form. The ability of the reduced cofactor NADN (NADPH) to reduce natural phenolic compounds directly or through the involvement of ascorbic acid and its derivatives offers the possibility of obtaining a stable uncoupling effect.

  Thus, the formation of the above-described redox cycle in somatic cells with the involvement of natural polyphenolic compounds creates an additional pathway for consuming excess reduced cofactors.

  Furthermore, the use of ascorbic acid and its derivatives improves the bioavailability of natural phenolic compounds.

  It is worth mentioning that the use of pharmaceutical compositions containing unroasted coffee bean extract for the treatment and prevention of diseases associated with antioxidant defense disorders is known (Russian patent) No. 2378003, June 6, 2008).

  The effect of applying the composition is in reducing blood glucose levels, glycated hemoglobin, cholesterol and triglycerides.

  Methods for treating diabetes or diabetes-induced disorders in patients by injection of compositions comprising coffee beans are known (US Patent Application Publication No. 2009017597).

  The effect of applying the composition in treating a patient's diabetes or diabetes-induced disorder is defined as stabilization of blood glucose, glycated hemoglobin A1C, triglycerides and low density lipoprotein levels, or normalization of blood glucose levels.

  In all the above cases, the aim is to achieve a direct therapeutic effect of diabetes due to the antioxidant action of a given composition.

  Describes the effects found by the authors of using natural phenolic compounds for uncoupling of oxidative phosphorylation in the treatment of diabetes with hypoglycemic preparations, in order to suppress acidosis associated with the accumulation of glycolytic products, There is no known material that is implied or predicted.

  Closest to the proposed invention is a pharmaceutical composition comprising an anti-diabetic drug, particularly metformin, and a method for treating diabetes comprising prescribing an anti-diabetic preparation to a patient (Balabolkin MI, Diabetology, Moscow, Meditsina 2000; Ametov AS Type 2 Diabetes mellitus: Basics of Pathogenesis and Therapy. Moscow, 2003).

  However, as already mentioned above, the overwhelming number of antidiabetic preparations used for that purpose (sulfonylurea derivatives, thiazolidine drugs, glinide drugs, biguanide drugs, thiazolidinedione drugs, insulin) and almost all of those known The decrease in blood glucose under combined administration is characterized by a significant accumulation of glucose in body tissue cells. Excess glucose that accumulates in the cell results in increased production of glycolytic products, and subsequent conversion of that product may be desirable in some cases when they are insufficiently used in oxidative energy metabolism. Lactic acidosis is the most dangerous, with no side effects.

  The object of the present invention is to develop a concomitant drug for the treatment of diabetes that will reduce the incidence of side effects of application of hypoglycemic preparations and also reduce the production of lactic acid by promoting the use of glycolytic products. And creating opportunities to use such agents in general diabetes treatment.

  The technical effect of the present invention is to reduce the risk of developing lactic acidosis in the use of known hypoglycemic drugs.

  The essence of the present invention is to increase the bioavailability of known hypoglycemic substances, natural phenolic compounds having the ability to uncouple oxidative phosphorylation, and further maintaining natural phenolic compounds in an active phenol state. In use in combination with ascorbic acid to improve.

  In order to achieve a defined objective, the authors have identified at least one anti-diabetic drug and a natural phenolic compound or mixture of such compounds having the ability to uncouple oxidative phosphorylation, for the treatment of diabetes. Propose a combination.

  Preferably, the combination comprises a natural phenolic compound or a mixture of such compounds in an amount of at least 2%.

  Preferably, the antidiabetic agent in the combination is selected from the group comprising biguanides, thiazolidinediones or compositions thereof.

  Preferably, the natural phenolic compound used in the above combination with the ability to uncouple oxidative phosphorylation is chlorogenic acid or epigallocatechin-3-gallic acid or epicatechin-3-gallic acid or ellagic acid or quercetin Or selected from the group consisting of dihydroquercetin or fisetin or curcumin or resveratrol or capsaicin or caffeic acid phenethyl ester.

  Such compounds may be present in the composition of unroasted coffee bean extract, green tea, pomegranate, acacia catechu, turmeric, itadori, chili, propolis, and some other products of plant or animal origin Are known. The natural phenol compounds may be isolated from the products containing them by known methods, or may be obtained synthetically, or may be used in the form of a concentrated extract. According to studies conducted by the authors, the effective amount of natural phenolic compound (single dose) is 10-200 mg.

  Preferably, the mixture of natural phenolic compounds in the combination consists of a plant extract.

  Preferably, the combination comprises metformin as an antidiabetic agent and coffee bean extract as a plant extract.

  Preferably, the combination comprises metformin as an antidiabetic agent and unroasted coffee bean extract as the plant extract.

  Preferably, the combination further comprises ascorbic acid or a pharmaceutically acceptable derivative thereof in an amount of at least 25% of the amount of unroasted coffee bean extract.

  The authors also describe diabetes and its complications comprising a composition drug comprising a combination of at least one anti-diabetic drug, a natural phenolic compound or a mixture of such compounds, and a pharmaceutically acceptable carrier. A pharmaceutical composition for treatment is also proposed.

  Given the above, a preferred embodiment is a composition comprising metformin, unroasted coffee bean extract and ascorbic acid in a therapeutically effective amount as an antidiabetic agent.

  Based on the above, the masses of metformin, unroasted coffee bean extract and ascorbic acid are preferably related to each other in a ratio of 100: 20: 10 to 100: 40: 30.

  Given the above, the compositions may be made in the form of powders, granules, tablets, pellets, capsules, glazes, suspensions, emulsions or solubilites, and supplements In particular, fillers (such as silicon dioxide, microcrystalline cellulose, croscarmellose sodium), binders (such as polyvinyl pyrrolidone, vinyl pyrrolidone and vinyl acetate copolymers), lubricants (such as magnesium stearate), emulsifiers (oxyethylated) Castor wax, lecithin, etc.), solubilizers (polysorbate, poloxamer, etc.), prolongators (glyceryl behenate, hydroxypropylmethylcellulose, etc.), and correctives (fructose, lactose, sorbite, etc.).

  The antidiabetic agents in the composition are used at the recommended dosage for their individual administration. The frequency of administration of the composition of the present application coincides with the frequency of administration of its component antidiabetic drug. The duration of administration should be continued as long as any lactic acidosis symptoms persist, but should be at least 2 weeks. Since the risk of recurrence of lactic acidosis is reduced, it is preferable that the patient continues to take the composition of the present application even after recovery of the pH value and blood lactic acid level.

  The authors have also proposed a pharmaceutical set effective for the treatment of diabetes comprising a combination of at least one anti-diabetic drug and one natural phenolic compound or a mixture of such compounds.

  Such a set constitutes an individually manufactured formulation consisting of an antidiabetic drug and another manufactured formulation containing a natural phenolic compound or mixtures thereof. Such formulations can include ascorbic acid or a pharmaceutically acceptable derivative thereof.

  The preparation comprising an antidiabetic agent may contain, for example, metformin hydrochloride and adjuvants (hydroxypropylmethylcellulose, microcrystalline cellulose, povidone, magnesium stearate), and may be in tablet form.

  Formulations containing natural phenolic compounds can include, for example, unroasted coffee bean extract (50-55% polyphenols), ascorbic acid, and microcrystalline cellulose as an adjuvant. Such a composition may be placed in a hard gelatin capsule.

  Tablets and capsules may be packaged in blister packs or flasks with appropriate markings and the same number of tablets and capsules placed in the same box.

  Depending on the composition, 1, 2 and 3 tablets and capsules may be formulated as a single dose.

  Also proposed is a method of combination therapy comprising prescribing a patient a combination of at least one anti-diabetic drug and a natural phenolic compound or a mixture of such compounds.

  Without limiting the foregoing generality, the pharmaceutical composition of the present application may be used in combination.

  The pharmaceutical composition is used in the treatment of diabetes when lactic acidosis symptoms occur in a patient or at the start of diabetes treatment when there is patient information that has a predisposition to acidosis. The composition is formulated by dividing the daily dose into two or three single doses in an amount corresponding to the therapeutically effective amount of the particular antidiabetic hypoglycemic agent contained in the composition. This corresponds to taking 2 to 3 capsules or tablets containing the composition of the present application 2 or 3 times a day during or after a meal. Patients take the composition until the symptoms of acidosis disappear, but for a minimum of two weeks. After recovery of the blood pH value and blood lactate level, it is possible to switch to treatment with only one anti-diabetic hypoglycemic agent without adding the natural phenolic compound according to the present invention. However, because the present combination reduces the risk of lactic acidosis recurrence, a preferred option for patients is to continue taking the combination.

  In the proposed method of diabetes combination therapy, the present combination can be used in the form of a pharmaceutical set.

  Where there are instructions regarding the patient about the use of the combination in the form of a pharmaceutical composition, the pharmaceutical set of the invention is used. As in the case of the pharmaceutical composition, the amount of the concomitant drug in the pharmaceutical set form is determined by the therapeutically effective amount of the particular antidiabetic hypoglycemic agent contained therein. Combinations are prescribed in one or two sets per dose, 2-3 times a day during or after a meal. Administration of the pharmaceutical set is continued for more than two weeks until the patient's acidosis symptoms disappear, but. Nevertheless, the preferred option is to continue administration of the present set in subsequent diabetes treatment. During that period, an appropriate type of individual component may be added to the single dose of the set, depending on clinical laboratory results, with the aim of enhancing hypoglycemic or anti-acidosis effects.

  The claimant also applies the application of a natural phenolic compound or a mixture of such compounds that has the ability to uncouple oxidative phosphorylation as a drug that suppresses the development of lactic acidosis in the treatment of diabetes using hypoglycemic preparations. Also intended to protect.

  The following examples demonstrate the applicability and effectiveness of the present invention without limiting its scope.

Example 1
The combination for the treatment of diabetes according to the present invention represented by a pharmaceutical composition encapsulated in a hard gelatin capsule

  The capsule contains a mixture of 250 mg metformin hydrochloride, 125 mg unroasted coffee bean extract (50-55% polyphenols) and 25 mg microcrystalline cellulose.

  The combination is formulated in a single dose of 2 or 3 capsules.

Example 2
The combination for the treatment of diabetes according to the present invention represented by a pharmaceutical composition encapsulated in a hard gelatin capsule

  Capsules contain a mixture of 250 mg metformin hydrochloride, 60 mg unroasted coffee bean extract (50-55% polyphenols), 36.5 mg ascorbic acid and 3.5 mg silicon dioxide.

  The combination is formulated to take 2-3 capsules at a time.

Example 3
The combination for the treatment of diabetes according to the present invention represented by a pharmaceutical composition encapsulated in a hard gelatin capsule

  Capsules contain a mixture of 250 mg metformin hydrochloride, 1 mg rosiglitazone maleate, 50 mg chlorogenic acid, 74 mg ascorbic acid and 25 mg microcrystalline cellulose.

  The combination is formulated to take 2-3 capsules at a time.

Example 4
A combination for the treatment of diabetes according to the invention represented by a pharmaceutical composition in tablet form

  Tablets contain 250 mg metformin hydrochloride, 60 mg chlorogenic acid, and adjuvants (microcrystalline cellulose, croscarmellose sodium, polyvinylpyrrolidone, magnesium stearate, hydroxypropylmethylcellulose, polyethylene glycol, titanium dioxide).

  The tablet is prepared by adding a binder to a mixture of metformin and chlorogenic acid and producing granules by wet granulation; then mixing the granules with solubilizers and lubricants; tableting the mixture As well as coating the resulting tablets with a hydrophilic polymer film.

  The combination is formulated to take 2-3 tablets at a time.

Example 5
A combination for the treatment of diabetes according to the invention represented by a pharmaceutical composition in tablet form

  Tablets include 250 mg metformin hydrochloride, 1.25 mg glibenclamide, 30 mg chlorogenic acid, 40 mg ascorbic acid, and adjuvants (microcrystalline cellulose, croscarmellose sodium, polyvinylpyrrolidone, magnesium stearate, hydroxypropylmethylcellulose Polyethylene glycol, titanium dioxide).

  The tablet is prepared by adding a binder to a mixture of metformin, glibenclamide, chlorogenic acid and ascorbic acid to produce granules by wet granulation; then mixing the granules with solubilizers and lubricants; As well as coating the resulting tablet with a hydrophilic polymer film.

  The combination is formulated to take 2-3 capsules at a time.

Example 6
A combination for the treatment of diabetes according to the present invention represented by a pharmaceutical set consisting of tablets containing antidiabetic hypoglycemic drugs and tablets containing natural phenolic compounds produced separately.

  Tablets containing hypoglycemic substances include 500 mg metformin hydrochloride, 15 mg pioglitazone hydrochloride, and adjuvants (microcrystalline cellulose, croscarmellose sodium, polyvinylpyrrolidone, magnesium stearate, hydroxypropylmethylcellulose, polyethylene glycol, dioxide Titanium, talc).

  The tablet is prepared by adding a binder to a mixture of metformin and pioglitazone and producing granules by wet granulation; then mixing the granules with solubilizers and lubricants; tableting the mixture; As well as coating the resulting tablet with a hydrophilic polymer film.

  Tablets containing polyphenol compounds contain 100 mg of chlorogenic acid and adjuvants (hydroxypropyl methylcellulose, microcrystalline cellulose, povidone, magnesium stearate).

  The tablet is prepared by a method comprising: preparing granules of a mixture of chlorogenic acid and binder by wet granulation; then mixing the granules with a solubilizer and lubricant; and tableting the mixture Manufactured.

  Package tablets containing hypoglycemic drugs on the one hand, tablets containing natural phenolic compounds on the other hand, in blister packs or flasks with different markings, containing the same number of each type of tablet in the same box .

  Combinations are formulated to take one or two tablets of each type at a time.

Example 7
Combination for the treatment of diabetes of the present invention represented by a pharmaceutical set consisting of separately manufactured tablets containing antidiabetic hypoglycemic drugs and capsules containing a mixture of natural phenolic compounds and ascorbic acid

  Tablets contain 500 mg metformin hydrochloride and adjuvants (hydroxypropyl methylcellulose, microcrystalline cellulose, povidone, magnesium stearate).

  The tablet comprises a granulation of a mixture of metformin with a binder added by wet granulation; thereafter mixing the granule with a solubilizer and lubricant; and tableting the mixture Manufactured by.

  The capsule contains a mixture of 100 mg unroasted coffee bean extract (50-55% polyphenols), 75 mg ascorbic acid and 25 mg microcrystalline cellulose.

  Tablets and capsules are packaged in blister packs or flasks with respective markings and the same number of tablets and capsules are contained in the same box.

  Combinations are formulated to take one set (one tablet and one capsule) or two sets (two tablets and two capsules) at a time.

Example 8
Combination for the treatment of diabetes of the present invention represented by a pharmaceutical set comprising separately manufactured tablets containing antidiabetic hypoglycemic drugs and tablets containing a mixture of natural phenolic compounds and ascorbic acid

  Tablets containing hypoglycemic drugs include 500 mg metformin hydrochloride, 5 mg glibenclamide, and adjuvants (croscarmellose sodium, magnesium stearate, starch, microcrystalline cellulose, povidone, lactose monohydrate) It is.

  The tablet is prepared by adding a binder to a mixture of metformin and glibenclamide and producing granules by wet granulation; then mixing the granules with solubilizers and lubricants; and tableting the mixture A method comprising:

  Tablets for sustained release of active substance, containing 200 mg unroasted coffee bean extract, 50 mg ascorbic acid, and adjuvants (completer 888 ATO, Kollidon VA64, Kollidon 17PF, magnesium stearate).

  Said tablets are produced by a direct compression method of a tablet mass in the form of granules obtained by grinding a direct compression cake of a mixture of active substance and auxiliary ingredients.

  The tablets containing hypoglycemic drugs on the one hand and the tablets containing a mixture of natural phenolic compounds and ascorbic acid on the other hand are packaged in blister packs or flasks with different markings in the same box in the same number of each. Contains various types of tablets.

  Combinations are formulated to take one or two tablets of each type at a time.

Example 9
Diabetes treatment of the present invention represented by a pharmaceutical set comprising separately manufactured tablets containing antidiabetic hypoglycemic drugs and soft gelatin capsules containing a suspension of a mixture of natural phenolic compound and ascorbic acid Combination for

Metformin tablet of Example 7.
Soft gelatin capsule containing a suspension of 75 mg unroasted coffee bean extract (50-55% polyphenols) and 50 mg ascorbic acid in 150 mg polysorbate 80 (Tween 80).

  The suspension filled into the capsule is made homogeneous by mixing the pre-mixed unroasted coffee bean extract and ascorbic acid formulation into polysorbate 80 with constant stirring in a vacuum reactor. Manufactured in a pasty form.

  Tablets and capsules are packaged in blister packs or flasks with respective markings and the same number of tablets and capsules are contained in the same box.

Example 10
Inhibition of intracellular pH drop induced in MDCK continuous cells (dog hepatocytes) by natural phenolic compounds capable of uncoupling oxidative phosphorylation in mitochondria, and metformin and rosiglitazone in cell culture This was done by adding.

MDCK cell cultures were grown in DMEM medium supplemented with 10% calf serum at 37 ° C., 5% CO 2 (pH 7.4). After formation of a continuous monolayer, the cells were transferred to the suspension using trypsin-EDTA solution. To stop any further action of EDTA-trypsin, fetal calf serum and DMEM medium were introduced into culture flasks in equal proportions (1: 1) when cells were completely detached. Cells were washed twice with DMEM medium. After completion of the last wash, one of the following hypoglycemic substances: metformin hydrochloride (5 _M M) or rosiglitazone maleate (25 μM); and one natural phenolic compound (50 μM) were added. _A cell suspension was prepared in culture flasks at a concentration of 1 · 10 ⁶ cells / mL in Krebs-Henseleit medium containing MM d-glucose.

The suspension was incubated at 37 ° C. for 60 minutes with shaking every 10 minutes by shaking the tube. After completion of the incubation, the cells were pelleted by centrifugation and 10 _M M d-glucose and 5 μΜ pH sensitive dye 2 ′, 7′-bis- (2-carboxyethyl) -5- (and-6) -carboxy. Resuspended in Krebs-Henseleit medium containing fluorescein acetoxymethyl ester (BCECF-AM). The resulting suspension was incubated at 37 ° C. for 25 minutes to allow the cells to absorb the dye. The suspension was then washed three times in Krebs-Henseleit medium, where HEPES was replaced with bicarbonate. The obtained cells were suspended in the same buffer at a concentration of 1 · 10 ⁶ cells / mL and introduced into a micro cuvette for fluorescence measurement while adjusting the temperature to 37 ° C. Using a Perkin Elmer LS-5 spectrofluorometer, the fluorescence wavelength was set to 530 nm and the excitation wavelength was set to two wavelengths: 490 nm (pH-sensitive fluorescence) and 440 nm (iso-absorption point). Obtained using a cell suspension of 1 · 10 ⁶ cells / mL suspended in Krebs-Henseleit medium with different pH values (6.5-7.5) containing the H + / K + ion permeation carrier nigericin (10 μg / mL) Based on the correlation of the calibration curve, the intracellular pH was calculated using the ratio of fluorescence at 490 nm to fluorescence at 440 nm.

  A natural phenolic compound that has the ability to uncouple mitochondrial oxidative phosphorylation by changing the intracellular pH of MDCK continuous line cells using the addition of metformin and rosiglitazone to the cell culture. The effect is shown in Table 1.

  The results obtained (Table 1) show that intracellularly induced in MDCK continuous cells by adding hypoglycemic drugs from the group of biguanides (metformin) and thiazolidinedione (rosiglitazone) to the cell culture. It demonstrates the ability of natural phenolic compounds to uncouple oxidative phosphorylation, preventing pH reduction.

Example 11
Demonstration of inhibition of lactic acidosis in rats by intravenous injection of high-dose metformin, intragastric administration of solutions and dispersions of natural phenolic compounds and ascorbic acid that can uncouple mitochondrial oxidative phosphorylation

  In this experiment, 8-month-old Sprague-Dawley rats weighing 250-280 g were used. The animals were placed under a 12 hour light / dark cycle with free access to water and rodent diet. Feed intake was stopped 12 hours before the start of the experiment, but water was still freely available. A dose of 250 mg / kg metformin in the form of a 2.5% solution in physiological solution was injected directly into the tail vein 4 times at 1 hour intervals. 30 minutes before the first metformin injection, a solution or suspension of the natural phenolic compound in water or an aqueous ascorbic acid solution was orally administered to experimental animals. The dose of natural phenolic compound was 5 mg / kg and the dose of ascorbic acid was 2.5 mg / kg. Intact animals; animals to which metformin alone was administered; and animals to which metformin and an ascorbic acid solution containing no natural phenol compound were administered were used as control groups.

  One hour after the last metformin injection, blood is collected from the sublingual vein of the animal (approximately 0.5 mL) and placed in a test tube without anticoagulant for 30 minutes at room temperature to form a clot. did. Serum was separated by centrifugation at 2,000 g for 15 minutes and 0.25 mL was placed in a 1.5 mL microcentrifuge tube. For deproteinization, 0.25 mL of cold 0.5 M metaphosphate solution was added to the obtained serum, stirred and left on ice for 5 minutes. The denatured protein was precipitated by centrifuging at 10,000 g for 5 minutes at 4 ° C. The supernatant (0.4 mL) was collected in a new microcentrifuge tube, acid was neutralized by addition of 25 μL of 5M potassium carbonate solution, and the residue was separated by centrifugation at 10,000 g for 5 minutes at 4 ° C. The collected supernatant was immediately used to measure the amount of lactic acid according to a fluorometric method using a standard set of reagents adapted for use in a Perkin Elmer LS-5 spectrofluorometer micro cuvette. .

  Table 2 shows the effects of natural phenolic compounds that can uncouple mitochondrial oxidative phosphorylation on the development of lactic acidosis caused by metformin in rats.

  The results obtained (Table 2) show that the ability of natural phenolic compounds that can uncouple oxidative phosphorylation in mitochondria to inhibit the accumulation of lactic acid and the development of lactic acidosis, in particular the high-dose hypoglycemic drug metformin Demonstrates the ability to suppress what is induced by administration. Administration of the aforementioned phenolic compounds in combination with ascorbic acid contributes to the acceleration of the recorded antiacidosis action, which supports the benefits of the combined use of these substances according to the present invention.

Example 12
Clinical Example-Elimination of Lactic Acidosis Symptoms in Patients Transitioning from the Administration of Metformin Single Formulation to a Combination of Metformin Tablets and Capsule Forms Containing Unroasted Coffee Bean Extract and Ascorbic Acid

  Patient V, 47 years old, first diagnosed with type 2 diabetes. After the diagnosis was confirmed, hypoglycemic therapy was prescribed in the form of a metformin single formulation starting at 500 mg daily. During the 7 days no undesirable effects were observed in the gastrointestinal tract, and the dose of metformin was increased to 500 mg twice daily. A clinical test conducted one week later detected mild lactic acidosis symptoms in the patient (see Table 3), which was slightly lower than the lower limit and blood lactate level just above the upper limit. Indicated by blood pH. The tendency to develop acidosis was associated with liver dysfunction and with a history of hepatitis. Taking into account the identified biochemical changes, the patient was combined for two weeks on a daily basis of Example 7 consisting of a hypoglycemic tablet and a capsule containing a mixture of a natural phenolic compound and ascorbic acid. Switched to. Laboratory tests performed at appropriate times have demonstrated normalization of lactic acid levels and blood pH. Additional 500 mg tablets of metformin single formulation were added to the two combinations per day according to Example 7 for a total of 4 weeks (total, 500 mg 3 times a day), followed by 500 mg 1 for the next 4 weeks. Even after moving to administration of metformin single formulation at a dose of 3 times a day, the normal value of the index was stable. However, in view of the remaining liver dysfunction background, the patient does not have any further tendency to decrease lactic acid and increase in pH. It seemed reasonable to prescribe additional tablets of 500 mg metformin single formulation (total, 500 mg metformin three times daily) as a combination and supportive therapy. Laboratory tests conducted after 4 weeks showed a further improvement in the biochemical blood index that characterizes the metabolism of hydrocarbons, which is based on a predisposition to the patient's acidosis. Demonstrates the positive therapeutic effect of the combination of oral hypoglycemic drugs with natural phenolic compounds and ascorbic acid in the treatment of

  Table 3 shows the blood index dynamics of biochemical laboratory tests that characterize hydrocarbon metabolism in patient V during treatment with a combination of oral hypoglycemic drugs, natural phenolic compounds and ascorbic acid.

備考。
１．３つの平行試験において測定を行った。データは平均値±平均誤差として表される。
２．血糖降下物質およびミトコンドリアの酸化的リン酸化を脱共役させ得る物質を含まない培地中でのインキュベーション下の細胞における細胞内ｐＨは、7.43±0.06と等しかった。インキュベーション培地に血糖降下薬のみを添加した時の、細胞内ｐＨの記録された低下は、スチューデントのｔ検定によるP＜0.05に相当する。
３．^＊−脱共役剤を含まない試験におけるｐＨ値と比較してスチューデントのｔ検定でP＜0.05。

Remarks.
1. Measurements were taken in three parallel tests. Data are expressed as mean ± average error.
2. The intracellular pH in cells under incubation in medium without hypoglycemic and mitochondrial oxidative phosphorylation was equal to 7.43 ± 0.06. The recorded decrease in intracellular pH when only the hypoglycemic agent is added to the incubation medium corresponds to P <0.05 by Student's t-test.
3. ^* -P <0.05 by Student's t-test compared to pH value in the test without uncoupler.

備考。
１．各群は３匹の動物を含んだ。データは平均値±平均誤差として表される。
２．インタクトな動物の血清中乳酸量は1.64±0.19mMである。メトホルミン投与により引き起こされる乳酸量の記録された増加は、スチューデントのｔ検定によるP＜0.05に相当する。
３．^＊−天然フェノール化合物を含まない投与を受けた群と比較してスチューデントのｔ検定でP＜0.05。^＊＊−アスコルビン酸を含まない投与を受けた群と比較してP＜0.05。

Remarks.
1. Each group contained 3 animals. Data are expressed as mean ± average error.
2. Intact animals have a serum lactic acid level of 1.64 ± 0.19 mM. The recorded increase in the amount of lactic acid caused by metformin administration corresponds to P <0.05 by Student's t-test.
3. ^* -P <0.05 by Student's t-test compared to the group receiving no natural phenolic compound. ^** — P <0.05 compared to the group receiving ascorbic acid-free administration.

備考。組み合わせおよびメトホルミンの用量は本明細書に記載される通りである。

Remarks. Combinations and metformin doses are as described herein.

Claims (22)

  A combination for treating diabetes comprising at least one antidiabetic agent and at least one natural phenolic compound.   The combination according to claim 1, comprising a natural phenolic compound or a mixture of such compounds in an amount of at least 2%.   The combination according to claim 1, wherein the antidiabetic agent is selected from the group comprising a biguanide drug, a thiazolidinedione drug or a combination thereof.   The group wherein the natural phenolic compound consists of chlorogenic acid or epigallocatechin-3-gallic acid or epicatechin-3-gallic acid or ellagic acid or quercetin or dihydroquercetin or fisetin or curcumin or resveratrol or capsaicin or caffeic acid phenethyl ester The combination according to claim 1, selected from:   The combination according to claim 1 comprising plant extracts as a mixture of natural phenolic compounds.   6. A combination according to claim 5 comprising metformin as an antidiabetic and coffee bean extract as a plant extract.   6. A combination according to claim 5, comprising metformin as an antidiabetic agent and unroasted coffee bean extract as a plant extract.   8. The combination of claim 7, further comprising ascorbic acid or a pharmaceutically acceptable derivative thereof in an amount of at least 25% of the amount of unroasted coffee bean extract.   A pharmaceutical composition for the treatment of diabetes comprising the combination of claim 1 and a pharmaceutically acceptable carrier.   10. The pharmaceutical composition of claim 9, comprising a therapeutically effective amount of metformin, unroasted coffee bean extract and ascorbic acid, wherein the ascorbic acid is natural ascorbic acid, synthetic ascorbic acid, or a combination thereof.   The pharmaceutical composition according to claim 10, wherein the masses of metformin, unroasted coffee bean extract and ascorbic acid are in a ratio of 100: 20: 10 to 100: 40: 30.   The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition is made in the form of powder, granule, tablet, pellet, gel, capsule, glaze, suspension, emulsion, solubilise.   The pharmaceutical set for diabetes treatment containing the combination of any one of Claims 1-11.   14. A pharmaceutical set according to claim 13, comprising a therapeutically effective amount of metformin, unroasted coffee bean extract and ascorbic acid.   The pharmaceutical set according to claim 14, wherein the masses of metformin, unroasted coffee bean extract and ascorbic acid are in a ratio of 100: 20: 10 to 100: 40: 30.   14. A pharmaceutical set according to claim 13, made in the form of a powder, granules, tablets, pellets, capsules, glazes, suspensions, emulsions, solubilites.   A method of combined diabetes therapy comprising prescribing the patient according to claim 1 to the patient.   18. A method according to claim 17, wherein the combination according to claim 1 constitutes a pharmaceutical composition.   The pharmaceutical composition is prescribed in cases where the patient exhibits symptoms of lactic acidosis and 2-3 capsules comprising the claimed composition 2-3 times a day, during or after a meal 19. The method of claim 18, wherein the method is applied in an amount of an agent, a tablet, or other unit of any other dosage form.   18. A method according to claim 17, wherein the combination according to claim 1 comprises a pharmaceutical set.   The pharmaceutical set is prescribed when the patient is symptomatic of lactic acidosis and is applied in an amount of one or two sets at a time, 2-3 times a day, during or after a meal, The method of claim 20.   Use of a natural phenol compound or a mixture thereof having an ability to uncouple oxidative phosphorylation as an agent for suppressing lactic acidosis in the treatment of diabetes using an anti-diabetic preparation.