KR20140008452A - Combination for treatment of diabetes mellitus - Google Patents

Abstract

The present invention provides a combination for treating diabetes mellitus, which may be formulated in a pharmaceutical composition or pharmaceutical set form. The combinations include antihyperglycemic agents and natural phenolic compounds capable of releasing oxidative phosphorylation. The combination offers the possibility to reduce the occurrence of side effects resulting from the use of antihyperglycemic agents, in particular the risk of lactoacidosis.

Description

Combination for treatment of diabetes mellitus

The present invention relates to the pharmaceutical industry and in particular to medicaments for treating diabetes mellitus.

Diabetes mellitus remains a significant problem for national health and health services in virtually every country of the world. It has been evident that the prevalence and incidence of diabetes mellitus has increased significantly worldwide over the past 30 to 40 years, especially in developed countries, where 6 to 10% of the population suffers from and suffers from diabetes. The morbidity rate is a clear upward trend, mainly in the age group over 40.

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

Chronic hyperglycemia is not only the main symptom of diabetes, which provides the basis for diagnosing the disease, but in fact is the most important factor in the development of all complications: microangiosis and macrovascular disease, neuropathy, nephropathy and the like.

Prolonged hyperglycemia leads to increased stimulation of the beta-cells of the pancreas, which then exhaust their functional capacity, contributing to the progression of the disease.

The goal of treating diabetes mellitus is to achieve a reward of carbohydrate metabolism for a long time, ie to ensure an indication of blood sugar content substantially the same as observed in healthy people during the day. Treatment of diabetes mellitus begins with prescribing diet and regular exercise but requires significant effort on the part of the patient to achieve the target carbohydrate metabolism index, which is typically maintained to an insignificant extent for patients with diabetes mellitus. This is why a major role in the treatment of diabetes mellitus is in drug treatment.

Anti-hyperglycemic drug treatment regimens not only reduce the glycemic index but also eliminate the clinical symptoms of disease causes by hyperglycemia. It also blocks "malignant circles" formed by increasing insulin deficiency due to exhaustion of insulin secreting cells and increasing hyperglycemia due to increasing insulin deficiency. The positive action of antihyperglycemic drugs under insulin deficiency described herein is to a greater extent related to the early stages of type 2 diabetes and type 1 diabetes.

Currently, antihyperglycemic oral drug treatments of the following groups are used for the treatment of type 2 diabetes:

Slowing the digestion of carbohydrates and the absorption of sugars in the gastrointestinal tract (alpha-glucosidase inhibitors sugar, acarbose, miglitol, etc.);

Promoting insulin production by the pancreas (sulfonylurea derivatives glybenclamide, glipizide, glyclazide, glyquidone and glymepiride);

Stimulating post-prandial insulin secretion (glinide, incretin mimetics, DPP-4 inhibitors, amylin and glucagon-type peptide 1 analogs);

Stimulating the uptake of glucose into the cell and inhibiting its release by the cell (biguanides, now-especially metformin);

Agents that promote insulin sensitivity in tissues, or insulin sensitizers thiazolidinedione (glitazone) —pioglitazone, rosiglitazone;

● insulin.

A-glucosidase inhibitors (acarbose) reduce intestinal glucose absorption and are generally effective in the early stages of the disease. Their side effects are associated with symptoms of flatulence and diarrhea. In most patients, the need to stop drug administration occurs within three years of its start date.

Sulfonylurea derivatives stimulate insulin secretion by b-cells of the pancreas. The most commonly used sulfonylureas are currently glyclazide, glybenclamide, glyphizide and glyquidone. Treatment with sulfonylureas may include the risk of type 1 diabetes mellitus or secondary (pancreatic) diabetes mellitus, pregnancy and lactation, surgery, severe infections, injuries, allergies or severe hypoglycemia to similar medications in sulfonyl urea drugs or medical history. Use is prohibited in the case of existence.

Glinides (meglitinides) are characterized by fast onset of action and short duration, which on the one hand can effectively inhibit postprandial hyperglycemia and on the other hand not increase the risk of hypoglycemia.

Agents specifically intended to affect postprandial sugar levels are incretin mimetics, DPP-4 inhibitors, amylin analogues and glucagon-type peptide 1 analogues. These drugs compensate for the existing deficiency in hormone secretion of the pancreas and gastrointestinal tract, which affects insulin and glucagon secretion, satiety and fasting. They are characterized by very rapid onset of action and short antihyperglycemic effects, so their use does not involve any side effects caused by their influence on sugar metabolism. Rapid and short action makes the drug treatment useful only as a postprandial antidiabetic drug.

Purified antihyperglycemic biguanide groups are now mostly represented by metformin. Biguanides do not enhance insulin secretion. Their antihyperglycemic action only occurs when there is enough insulin in the blood. Biguanides promote their action on peripheral tissues, reducing insulin resistance. Biguanides increase sugar uptake by muscle and adipose tissue. They reduce liver sugar production, intestinal sugar absorption and increase sugar use, thereby reducing appetite. The prescription of biguanides is prohibited if there is renal failure, any etiological hypoxia (heart failure, lung disease, anemia, emotional disorders), acute complications of diabetes mellitus, alcohol abuse, lactic acidosis. Among the side effects of metformin are dyspepsia when high doses of the drug are administered. Cases are known in which patients develop lactoacidosis, which reflects the drug's ability to increase glycolysis and inhibit glycosynthesis in the liver.

The use of antihyperglycemic sulfanylamide preparations and biguanides can cause side effects with gastrointestinal disorders, skin allergies and hypoglycemic conditions due to discontinuation of the drug in therapeutic and toxic doses.

Thiazolidinedione affects blood sugar control by reducing insulin resistance in peripheral tissues, particularly adipose tissue, and also reduces hepatic glucose production. Agents of this group do not cause hypoglycemia but may contribute to weight gain. These drugs are prohibited for use in patients with symptoms of heart failure and pre-proliferative and proliferative stages of diabetic retinopathy.

If antihyperglycemic monotherapy proves ineffective, the desired effect can sometimes be achieved by using an antihyperglycemic agent. Combinations of the following oral antihyperglycemic agents are possible: sulfonylurea preparations with thiazolididinedione, metformin and meglitinide, metformin and thiazolidinedione, sulfonylurea preparations and a-glucosidase inhibitors. If glycemic control is not achieved by the combination of oral antihyperglycemic agents, a combination therapy of insulin and biguanide or monotherapy with insulin is prescribed.

Both sulfonylurea preparations and metformin affect the compensation of carbohydrate metabolism but their antihyperglycemic mechanisms differ. In these aspects the drug can be used for combination therapy.

Glybometh, a combined action oral antihyperglycemic agent, consists of 2.5 mg of glybenclamide and 400 mg of metformin. Glybenclamide contained in the drug stimulates insulin secretion by b-cells of the pancreas, and metformin mainly decreases insulin resistance in the liver and entails suppression of sugar synthesis, leading to the formation of glucose in the liver and its entry into the circulation. Decrease. The use of concomitant drugs enhances the antihyperglycemic effect, but the threat of lactoacidosis accompanying the use of metformin remains complete.

Combination drug treatments comprising nateglinide and antidiabetic glitazone in pharmaceutically acceptable carriers are known for the treatment of metabolic disorders, mainly diabetes and disorders associated with diabetes. Glitazones may be represented by pioglitazone, rosiglitazone or troglitazone (RU No. 2280447, 15.09.2000).

The combination drug treatment may take the form of a combination formulation or a pharmaceutical composition. The pharmaceutical composition may comprise metformin as the third antidiabetic agent in a pharmaceutical carrier. Combination of nateglinide with another antidiabetic agent ensures a synergistic therapeutic effect on type 2 diabetes and long-term continuation of the drug action, thus delaying insulin use until later. A disadvantage of the combination is the use of glitazones and metformin, both of which may contribute to the development of lactoacidosis.

Drug treatment is known for the treatment of diabetes mellitus, including a combination of an effective amount of exenatide and dalargine (RU 2413528 18.01.2007). The combination is a combination drug and ensures effective treatment of diabetes mellitus by enhancing the hypoglycemic and hypocholesterolemic effects of exenatide. A disadvantage of the combination is that the preferred use is administration in the form of injections.

Treatment of insulin-independent diabetes or hyperglycemia with a combination of an effective amount of metformin and glybenclamide, and glybenclamide, which forms part of a combination drug treatment for oral administration with a powder particle surface area of 1.7 to 2.2 m ² / g. Drug treatment, including the method, is known for the treatment of insulin independent type 2 diabetes mellitus (RU No. 2286788 12.07.1999).

The present invention ensures the bioavailability of glybenclamide in compositions of metformin-comprising drug therapy comparable to the bioavailability of glybenclamide monoforms. However, the use of metformin in the proposed formulation raises the need to consider the increased likelihood of lactoacidosis.

Thus, currently used antihyperglycemic drugs for oral administration solve the problem of reducing blood glucose by different mechanisms and therefore they are effective only under certain conditions. The appearance of ambiguous symptoms of major diseases and coexisting conditions that cause contraindications in some patient subgroups leads to undesired side effects. One of the most significantly prohibited uses is the tendency to lactoacidosis.

During the administration of the overwhelming majority of agents (sulfonylurea derivatives, glinides, biguanides, thiazolidinediones and insulins) and indeed all combinations thereof used for blood sugar reduction, a decrease in blood sugar content is apparent in the body tissue cells. Characterized by accumulation. Subsequent conversion of excess sugar is enhanced inside the cell, increases the production of glycolysis products, and results in insufficient strength used in oxidative energy metabolism, causing a number of undesired side effects, and lactoacidosis is the most dangerous of them. .

Excess accumulation of lactosan in the body and subsequent lactoacidosis are most clearly observed as a side effect of biguanide intake. The same metabolic shift forms the basis for limited use of antihyperglycemic means (sulfonylurea derivatives, thiazolidines and glinides), where the patient exhibits lactoacidosis and ketoacidosis. In addition, high levels of glycolysis products activate fatty acid synthesis and thus form the basis for weight gain observed during the administration of many antihyperglycemic agents (sulfonylurea derivatives, thiazolidine, glinides).

As already noted above, the described problem of antihyperglycemic drugs persists when the drugs are used in combination.

Thus, the development of antidiabetic agents whose use involves less accumulation of intracellular glycolysis products appears to be very relevant at the present time. This may reduce the likelihood of undesired side effects.

As is known, the metabolism of pyruvic acid formed during glycolysis is associated with its oxidation in the Krebs cycle, with which additional cofactors are recovered from those synthesized during glycolysis. The main consumption of the aforementioned cofactors occurs during ATP synthesis in chain oxidative phosphorylation in mitochondria. Under conditions of increased pyruvic acid formation, natural ATP consumption proves to be insufficient to ensure an effective outflow of reduced cofactors. This induces intracellular formation with increased sugar content of excess lactoic acid from the pyruvic acid in the cell. In order to increase the release of reduced cofactors of other glycolysis products, higher levels of exercise are used to treat diabetes and produce increased background ATP consumption in energy dependent processes.

At the same time, increasing the release of reduced cofactors can be solved by the use of these ingredients to ensure reduced consumption of cofactors in intracellular processes in the composition of antidiabetic drugs.

In this regard, the author's interest is to uncouple oxidative phosphorylation in mitochondria, leading to increased use of reduced cofactors to reduce oxygen to water in the chain mitochondrial cytochromes without the formation of ATP, i.e. in immature ways. Drawn to as many substances as possible.

Subsequent studies conducted by the authors showed that during the administration of antihyperglycemic agents, natural phenolic compounds can be successfully used to release oxidative phosphorylation coupling in mitochondria to suppress the development of acidosis associated with the accumulation of glycolysis products. .

For the purpose of treating lipid metabolism disorders, the use of natural phenolic compounds capable of releasing oxidative phosphorylation coupling and products containing them has been proposed to promote heat generation in adipose tissue (US 20100215782). However, the authors did not recognize the random use of natural phenolic compounds for the purpose of releasing oxidative phosphorylation coupling to inhibit the development of acidosis associated with accumulation of glycolysis products during administration of antihyperglycemic agents.

In addition, according to a study conducted by the authors, further administration of ascorbic acid into the body together with natural phenolic compounds enhances the above-mentioned effects due to the latter retention of the phenolic form. This offers the possibility of obtaining a stable decoupling effect either directly or due to the ability of the reduced cofactor NADH (NADPH) to reduce natural phenolic compounds with the involvement of ascorbic acid and derivatives thereof.

Thus, the intracellular formation of the above-mentioned redox cycles with the participation of natural polyphenolic compounds creates additional pathways to consume excess reduced cofactors.

In addition, the use of ascorbic acid and derivatives thereof improves the bioavailability of natural phenolic compounds.

It is worth mentioning that the use of pharmaceutical compositions comprising green coffee bean extracts for the treatment and prevention of diseases associated with antioxidant defense disorders is known (RU 2378003 06.06.2008).

The effect of applying the composition is to reduce blood sugar levels, glycated hemoglobin, cholesterol and triglycerides.

Methods of treating diabetes or diabetes induced disorders in patients are known to be carried out by injecting a composition comprising coffee beans (US 2009017597).

The effect of applying the composition to treat diabetes or diabetes induced disorders in patients is defined as stabilization of blood glucose, glycated hemoglobin AIC, triglycerides and low density lipoprotein levels or normalization of blood glucose levels.

In all the above mentioned cases, the target purpose is to achieve a direct therapeutic effect on diabetes by the antioxidant action of a given composition.

None of the known data reports or implies the use of natural phenolic compounds to release oxidative phosphorylation coupling for the purpose of inhibiting the development of acidosis associated with the accumulation of glycolysis products in treating diabetes with antihyperglycemic agents. Or unexpected.

The invention most similar to the above proposed invention is a method of treating diabetes comprising a pharmaceutical composition comprising an antidiabetic agent, in particular metformin, and a prescription of an antidiabetic agent 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 noted above, the overwhelming majority of antidiabetic agents used for this purpose (sulfonylurea derivatives, thiazolidines, glinides, biguanides, thiazolidinediones, insulins) and practically all known The reduction of blood glucose under the administration of a combination thereof is characterized by the apparent accumulation of sugar in body tissue cells. Increased excess of sugar inside the cell increases the production of glycolysis products, and its post-transposition is insufficient strength to use them for oxidative energy metabolism, induces many undesired side effects, and lactoacidosis is the most dangerous of these. Do.

It is an object of the present invention to provide for the treatment of diabetes and the treatment of diabetes in a wide variety of diabetes treatment regimens, which, due to the accelerated utilization of glycolytic products, reduce the incidence of side effects due to the application of antihyperglycemic agents and also reduce the production of lactosan. Developing concomitant medications to create opportunities for use.

The therapeutic effect of the present invention is to reduce the risk of developing lactoacidosis using known antihyperglycemic agents.

Summary of the Invention

The basis of the present invention is a combination of natural phenolic compounds capable of releasing oxidative phosphorylation and ascorbic acid and known antihyperglycemic substances which further improve the bioavailability of natural phenolic compounds by keeping them in an active phenolic state. It is to use.

To achieve the above object, the authors proposed a combination for treating diabetes, comprising at least one antidiabetic agent capable of releasing oxidative phosphorylation and a natural phenolic compound or a mixture of said compounds.

Preferably the combination comprises a natural phenolic compound or a mixture of these 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 capable of releasing oxidative phosphorylation coupling to be used in the combination is chlorogenic acid or epigallocatechin-3-gallate or epicatechin-3-gallate or elginic acid or quercetin or dihydro. Quercetin or picetin or curcumin or resveratrol or capsaicin or caffeic acid phenethyl ester.

Such compounds are known to be present in the composition of green coffee bean extract, green tea, pomegranate, catechu acacia, curcuma, Japanese bark, red pepper powder, propolis and many other products of plant or animal origin. The natural phenolic compounds can be separated from the products containing them by known methods or obtained synthetically or used in the form of concentrated extracts. According to a study conducted by the author, the effective amount (single dose) of the natural phenolic compound is 10 to 200 mg.

Preferably, the mixture of natural phenolic compounds in the combination comprises a vegetable extract.

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

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

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

The authors also provide pharmaceutical compositions for the treatment of diabetes mellitus and its complications comprising a composition comprising a combination of one or more antidiabetic agents and a combination of natural phenolic compounds or mixtures thereof, and a pharmaceutically acceptable carrier. Suggested.

In this case, a preferred embodiment is a composition comprising metformin, green coffee bean extract and ascorbic acid in a therapeutically effective amount as an antidiabetic agent.

In this case, the mass of metformin, green coffee bean extract and ascorbic acid preferably has a ratio thereof between 100: 20: 10 and 100: 40: 30.

In such cases, the composition may be formulated in the form of powders, granules, tablets, pellets, capsules, candy, suspensions, emulsions or lysates and auxiliary materials, in particular fillers (silicon dioxide, microcrystalline cellulose, croscarmell) Sodium sodium, etc.), binders (such as polyvinylpyrrolidone, vinylpyrrolidone, and vinyl acetate polymers), lubricants (such as magnesium stearate), emulsifiers (oxyethylated castor wax, lecithin, etc.), solubilizers (poly Sorbate, poloxamer, and the like), prolonator (glycerides of behenic acid, hydroxypropylmethylcellulose, and the like), and emollients (fructose, lactose, sorbet, and the like).

The antidiabetic agents in the compositions are used in doses recommended for their individual administration. The frequency of administration of the claimed composition is consistent with the frequency of administration of the antidiabetic agent-its component. The administration period should be at least 2 weeks as long as any lactoacidosis persists. It may be desirable for the patient to continue taking the claimed composition after the recovery of the pH value and lactate blood content because this will lower the risk of recurrence of lactoacidosis.

The author also proposed an effective pharmaceutical set for treating diabetes, comprising a combination of one or more antidiabetic agents and one natural phenolic compound or a mixture of the compounds.

The set consists of separately prepared formulations of antidiabetic agents and another separately prepared formulation comprising a natural phenolic compound or mixtures thereof. The formulation may comprise ascorbic acid or a pharmaceutically acceptable derivative thereof.

Such formulations, consisting of antidiabetic agents, may contain, for example, metformin hydrochloride and auxiliary substances (hydroxypropylmethylcellulose, microcrystalline cellulose, povidone, magnesium stearate) and may be in tablet form.

Formulations comprising natural phenolic compounds may contain, for example, green coffee bean extract (50-55% polyphenols), ascorbic acid and microcrystalline cellulose as auxiliary substances. The composition may be located in a hard gelatin capsule.

Tablets and capsules can be packaged in blisters or flasks with appropriate marking and placed in a conventional box with the same number of tablets and capsules in duplicate.

Depending on the composition, one, two and three tablets and capsules may be prescribed in a single dose.

Also proposed is a method of treating concomitant diabetes comprising prescribing to a patient a combination comprising one or more antidiabetic agents and natural phenolic compounds or mixtures thereof.

Without limiting prior universality, the claimed pharmaceutical compositions can be used as a combination.

The pharmaceutical composition is used to treat diabetes mellitus at the onset of diabetes mellitus treatment when there is information on the occurrence of lactoacidosis in the patient or on patients with acid tendency in history. The composition is prescribed in an amount corresponding to a therapeutically effective amount of the specific antidiabetic antihyperglycemic agent comprising the daily dose divided into two or three single doses. This corresponds to the intake of 2-3 capsules or tablets containing the claimed composition, two or three times daily after or at mealtime. The patient takes the composition for at least two weeks until the acidosis is eliminated. Upon recovery of blood pH values and lactate blood content, one can switch to treatment with only one antidiabetic antihyperglycemic agent without the addition of natural phenolic compounds according to the claimed invention. However, the preferred option is to keep the patient taking the claimed combination because this lowers the risk of developing lactoacidosis.

In the proposed combination diabetes treatment method, the claimed combinations can be used in the form of pharmaceutical sets.

The pharmaceutical set according to the invention is used when instructed by a patient to use the claimed combination in the form of a pharmaceutical composition. As in the case of pharmaceutical compositions, the amount of concomitant drug therapy in the pharmaceutical set form is determined by the therapeutically effective amount of the particular antidiabetic antihyperglycemic agent it contains. The combination is prescribed in one or two sets when taken two or three times a day at meal or after meal. Administration of the pharmaceutical set continues for at least two weeks until the acidosis is removed from the patient. The preferred choice is to continue administering the claimed set in subsequent treatment of diabetes mellitus. In this period, according to clinical laboratory investigation studies, appropriate types of individual components may be added to a single dose set for the purpose of enhancing antihyperglycemic or antidiabetic effects.

The Applicant seeks to protect the application of natural phenolic compounds or mixtures of such compounds capable of releasing oxidative phosphorylation coupling to the treatment of diabetes with the use of antihyperglycemic agents as agents that inhibit the development of lactoacidosis.

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

Example 1

A combination for treating diabetes according to the invention represented by a pharmaceutical composition encapsulated in a hard gelatin capsule.

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

The combination is prescribed in a single dose of two or three capsules.

Example 2.

A combination for treating diabetes according to the invention represented by a pharmaceutical composition encapsulated in a hard gelatin capsule.

The capsule comprises a mixture of 250 mg metformin hydrochloride, 60 mg green coffee bean extract (50-55% polyphenols), 36.5 mg ascorbic acid and 3.5 mg silicon dioxide.

The combination is prescribed to take two or three capsules at a time.

Example 3.

A combination for treating diabetes according to the invention represented by a pharmaceutical composition encapsulated in a hard gelatin capsule.

The capsules comprise 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 prescribed to take two or three capsules at a time.

Example 4.

Combination for treating diabetes according to the present invention represented by the pharmaceutical composition in the form of a tablet.

The tablet contains 250 mg of metformin hydrochloride, 60 mg of chlorogenic acid and auxiliary substances (microcrystalline cellulose, croscarmellose sodium, polyvinylpyrrolidone, magnesium stearate, hydroxypropylmethylcellulose, polyethylene glycol, titanium dioxide). .

The tablets are prepared by means of wet granulation of a mixture of metformin and chlorogenic acid with the addition of a binder, followed by mixing the granules with a solubilizer and a lubricant and tableting the mixture and coating the obtained tablets with a hydrophilic polymer film. It manufactures by the method including making it make.

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

Example 5.

Combination for treating diabetes according to the present invention represented by the pharmaceutical composition in the form of a tablet.

The tablet contains 250 mg metformin hydrochloride, 1.25 mg glybenclamide, 30 mg chlorogenic acid, 40 mg ascorbic acid and auxiliary substances (microcrystalline cellulose, croscarmellose sodium, polyvinylpyrrolidone, magnesium stearate, hydroxy Propylmethylcellulose, polyethylene glycol, titanium dioxide).

The tablets produce granules by means of wet granulation of a mixture of metformin, glybenclamide, chlorogenic acid and ascorbic acid with the addition of a binder, and then the granules are mixed with a solubilizer and a lubricant and the mixture is compressed into a hydrophilic polymer It is prepared by a method comprising coating the obtained tablet with a film.

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

Example 6.

A combination for treating diabetes according to the invention represented by a pharmaceutical set consisting of separately prepared tablets comprising an antidiabetic antihyperglycemic agent and a tablet containing a natural phenolic compound.

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

The tablets are prepared by means of wet granulation of a mixture of metformin and pioglitazone with the addition of a binder, followed by mixing the granules with a solubilizer and a lubricant and tableting the mixture and coating the obtained tablets with a hydrophilic polymer film. It manufactures by the method including making it make.

Tablets containing polyphenolic compounds contain 100 mg of chlorogenic acid and auxiliary substances (hydroxypropylmethylcellulose, microcrystalline cellulose, povidone, magnesium stearate).

The tablets are prepared by a method comprising preparing granules by means of wet granulation of a mixture of chlorogenic acid and binder, mixing the granules with a solubilizer and a lubricant and tableting the mixture.

Tablets containing antihyperglycemic agents on the one hand and tablets containing natural phenolic compounds on the other hand are packaged in blisters or flasks with different labels and the same number of each type of tablet in the box is placed in a conventional box. .

The combination is prescribed to take one or two tablets of each type at a time.

Example 7.

A combination for treating diabetes according to the invention represented by a pharmaceutical set consisting of separately prepared tablets comprising an antidiabetic antihyperglycemic agent and a capsule containing a mixture of natural phenolic compounds and ascorbic acid.

Tablets contain 500 mg of metformin hydrochloride and auxiliary substances (hydroxypropylmethylcellulose, microcrystalline cellulose, povidone, magnesium stearate).

The tablets are prepared by a method comprising preparing granules by means of wet granulation of a mixture of metformin with the addition of a binder and then mixing the granules with a solubilizer and a lubricant and tableting the mixture.

The capsules comprise a mixture of 100 mg green coffee bean extract (50-55% polyphenol), 75 mg ascorbic acid and 25 mg microcrystalline cellulose.

Tablets and capsules are packaged in blisters or flasks with respective markings and placed in conventional boxes with the same number of tablets and capsules in the box.

The combination is prescribed to take one set (one tablet and one capsule) or two sets (two tablets and two capsules) at a time.

Example 8

A combination for treating diabetes according to the invention represented by a pharmaceutical set consisting of a separately prepared tablet comprising an antidiabetic antihyperglycemic agent and a tablet containing a mixture of ascorbic acid and a natural phenolic compound.

Tablets containing an antihyperglycemic agent include 500 mg of metformin hydrochloride, 5 mg of glybenclamide and auxiliary substances (crosamelose sodium, magnesium stearate, starch, microcrystalline cellulose, povidone, lactose monohydrate).

The tablets are prepared by a method comprising preparing granules by means of wet granulation of a mixture of metformin and glybenclamide with the addition of a binder and then mixing the granules with a solubilizer and a lubricant and tableting the mixture. .

The tablets are for long-term release of the active substance, including 200 mg of green coffee bean extract, 50 mg of ascorbic acid and auxiliary substances (compritol 888 ATO, collidone VA64, collidone 17PF, magnesium stearate).

The tablets are prepared by direct compression of the tablet mass in the form of granules obtained by the disintegration of a direct-compression cake of a mixture of the active substance and auxiliary components.

Tablets containing antihyperglycemic agents on the one hand and tablets containing a mixture of natural phenolic compounds and ascorbic acid on the other hand are packaged in blisters or flasks with different labels and the same number of each type of tablet in the box is usually In the box.

The combination is prescribed to take one or two tablets of each type at a time.

Example 9.

A combination for treating diabetes according to the invention represented by a separately prepared tablet containing an antidiabetic antihyperglycemic agent and a pharmaceutical set consisting of a soft gelatin capsule containing a suspension of a mixture of natural phenolic compounds and ascorbic acid.

Purification of Metformin according to Example 7

A soft gelatin capsule comprising a suspension of a mixture of 75 mg green coffee bean extract (50-55% polyphenol) and 50 mg ascorbic acid in 150 mg polysorbate 80 (Tween 80).

The filling suspension of the capsule is prepared in the form of a homogeneous pasty body by gradually mixing the premixed preparation of the green coffee bean extract with ascorbic acid under constant stirring in a vacuum reactor.

Tablets and capsules are packaged in blisters or flasks with respective markings and the same number of tablets and capsules are placed in boxes in conventional boxes.

Example 10.

Inhibition of the decrease in intracellular pH induced in MDCK continuous cell lines (dog liver cells) by means of natural phenolic compounds capable of releasing oxidative phosphorylation coupling in mitochondria was performed by adding metformin and rosiglitazone to the cell culture medium. .

MDCK cell cultures were grown in DMEM medium supplemented with 10% bovine serum at 37 ° C. and 5% CO ₂ pH 7.4. After unblocked monolayer formation, the cells were transferred to suspension using trypsin-EDTA solution. Only when the cells were completely isolated to stop any further action of EDTA-trypsin, fetal bovine serum and DMEM medium were introduced into the culture flask in the same ratio (1: 1). The cells were washed twice with DMEM medium. After the last wash was completed, cell suspensions were prepared in culture flasks at a concentration of 1 10 ⁶ cells / ml in Krebs-Hencelite medium containing 10 _M M of d-glucose added with one of the following antihyperglycemic substances: Metformin hydrochloride (5 _M M) or rosiglitazone maleate (25 μΜ), and one natural phenolic compound (50 μΜ).

The suspension was incubated at 37 ° C. for 60 minutes with stirring every 10 minutes by shaking the test-tubes. Upon completion of the incubation, the cells were precipitated by centrifugation and precipitated with 10 _M M of d-glucose and 5 μΜ of pH-sensitive dye 2 ', 7'-bis- (2-carboxyethyl) -5- (and-6). Resuspend in Krebs-Hencelite medium containing carboxyfluorescein acetoxymethyl ester (BCECF-AM). The obtained suspension was incubated at 37 ° C. for 25 minutes to induce dye adsorption by cells. The suspension was then washed three times in Krebs-Hencelite medium with HEPES replaced with bicarbonate. The obtained cells were suspended in the same buffer at a concentration of 1 · 10 ⁶ cells / ml and introduced into microcuvets for fluorescence measurements, thermostated at 37 ° C. Fluorescence measurements are performed with a Perkin Elmer LS-5 spectrometer, where fluorescence is recorded at 530 nm and excited at two wavelengths: 490 nm (pH sensitive fluorescence) and 440 nm (isotropy point). The ratio of fluorescence at 490 nm to fluorescence at 440 nm is used to calculate intracellular pH, which is different pH values (6.5 to 7.5) containing H + / K + ion carrier nigerisin (10 μg / mL). It is based on calibration correction obtained using 1 · 10 ⁶ cells / ml of cell suspension in Krebs-Hencelite medium with.

The effect of natural phenolic compounds capable of releasing oxidative phosphorylation coupling in mitochondria, which causes changes in intracellular pH of MDCK continuous cell lines by the addition of metformin and rosiglitazone, is shown in Table 1.

The results obtained (Table 1) show a decrease in the intracellular pH induced in MDCK continuous cell lines by adding antihyperglycemic agents from the group of biguanides (methformin) and thiazolidineedione (rosiglitazone) to the cell culture medium. Demonstrate the ability of natural phenolic compounds to release oxidative phosphorylation coupling to prevent

Example 11.

Demonstration of inhibition of the development of lactoacidosis in rats by intravenous administration of high doses of metformin or solutions and dispersions of natural phenolic compounds and ascorbic acid capable of releasing oxidative phosphorylation coupling in the mitochondria.

In the experiments, Sprague Dawley rats of 8 months of age with a body mass of 250-280 g were used. Animals were maintained under a 12-hour light / dark cycle and were given free access to feed for water and rodents. Twelve hours before the start of the experiment, the animals were kept away from food and water remained freely accessible. Metformin was injected directly into the tail vein at a dose of 250 mg / kg in the form of 2.5% solvent in 4 physiological solutions at 1 hour intervals. Thirty minutes before the first injection of metformin, the study animals were orally ingested a solvent or suspension of the natural phenolic compound in water or in an aqueous solution of ascorbic acid. The dose of natural phenolic compounds amounts to 5 mg / kg and the dose of ascorbic acid is 2.5 mg / kg. Controls are intact animals, ie, animals that received only metformin only and those that received metformin and ascorbic acid without natural phenolic compounds.

One hour after the last injection of metformin, blood was drawn from the sublingual vein of the animal (approximately 0.5 ml) and placed in a test tube without anticoagulant and left for 30 minutes at room temperature for blood clot formation. The serum was separated by centrifugation at 2,000 g for 15 minutes and 0.25 ml was placed in a 1.5 mL small centrifuge tube. For protein removal, 0.25 mL of cold 0.5 M metaphosphoric acid solution was added to the obtained serum, shaken and left on ice for 5 minutes. Denatured protein was precipitated by centrifugation at 10,000 g and 4 ° C. for 5 minutes. The supernatant (0.4 mL) was collected in a new small centrifuge tube and the acid was neutralized by addition of 25 μl of 5M potassium carbonate solution and centrifuged at 10,000 g and 4 ° C. for 5 minutes to separate the residue. The collected supernatant was immediately used to determine lactate content according to the fluorescence measurement method using a standard set of reagents adapted for use in small cuvettes on a Perkin Elmer LS-5 spectrofluorometer.

The effect of natural phenolic compounds that can release oxidative phosphorylation coupling in mitochondria on the development of metformin-induced lactoacidosis in rats is shown in Table 2.

The results obtained (Table 2) show the ability of natural phenolic compounds to release oxidative phosphorylation coupling in the mitochondria, thereby inhibiting lactic acid accumulation and onset of lactosan, in particular induced by high doses of the antihyperglycemic agent metformin. Prove it. Administration of the above-mentioned phenolic compounds with ascorbic acid contributes to the enhancement of the reported antioxidative effects and confirms the benefits of the combination of these substances according to the invention.

Example 12.

Clinical Case—Lactocytosis was eliminated after conversion from administration of metformin alone to metformin tablets and a combination of capsules containing green coffee bean extract and ascorbic acid.

Patient V, 47, was first diagnosed with type 2 diabetes. At confirmation of diagnosis, antihyperglycemia therapy was prescribed in the form of metformin alone starting with 500 mg per day. No adverse events were observed at the gastrointestinal tract over the 7-day period and the metformin dose increased to 500 mg twice daily. The clinical study was conducted one week after the detection of lactoacidosis in the patient was weakened (see Table 3), and the weakening of the lactoacidosis decreased below the upper and lower blood lactate content and lower limits. Manifested by blood pH. The tendency to show acidosis is associated with liver failure, which in turn is associated with hepatitis in medical history. In view of the identified biochemical changes, the patient was converted to a daily intake of two combinations of capsules comprising a mixture of ascorbic acid and natural phenolic compounds according to Example 7 and tablets of antihyperglycemic agents for a period of two weeks. . Clinical studies conducted within a designated time period confirmed lactate content and blood pH normalization. The normal value of this indicator remained stable after adding an additional 500 mg tablet of metformin alone formulation (500 mg total three times daily) to the two combinations daily according to Example 7 for a four week period and subsequently the next four weeks. It was converted to administering the metropmin alone formulation at a dose of 500 mg three times daily for a period of time. However, taking into account that there is no tendency for any decrease in lactate content and pH growth against the background of remaining liver failure, two combinations according to Example 7 and 500 mg metformin as an additional supportive therapy Prescription tablets of a single formulation (total of 500 mg metformin three times a day) were considered to be reasonably used for subsequent treatment of the patient. A clinical study of the patients was conducted after 4 weeks and demonstrated a positive therapeutic effect on the combination of natural phenolic compounds and ascorbic acid with oral antihyperglycemic agents in the treatment of type 2 diabetes with predisposition to patients with acidosis. It has been shown to further improve biochemical blood markers characterized by proving hydrocarbon metabolism.

The kinetics of biochemical clinical studies blood indices characterized by hydrocarbon metabolism in Patient V during treatment with oral antihyperglycemic agents and combinations of natural phenolic compounds are shown in Table 3.

Decoupling Agent Intracellular pH when added to culture Metformin Rosiglitazone w / o decoupling agent 7.06 ± 0.04 6.89 ± 0.07 ∏Hφ, 100μM 7.28 ± 0.04 ^* 7.17 ± 0.05 Chlorogenic acid 7.35 ± 0.05 ^* 7.35 ± 0.03 ⁺ Epigallocatechin-3-gallate 7.24 ± 0.07 7.22 ± 0.06 ^* Epicatechin-3-gallate 7.29 ± 0.02 ^* 7.45 ± 0.08 ^* Ellagin acid 7.18 ± 0.07 7.04 ± 0.05 Quercetin 7.20 ± 0.06 7.27 ± 0.03 ^* Physetine 7.33 ± 0.03 ^* 7.38 ± 0.06 ^* Curcumin 7.29 ± 0.08 7.23 ± 0.09 Resveratrol 7.26 ± 0.03 ^* 7.39 ± 0.05 ^* Capsaicin 7.17 ± 0.06 7.29 ± 0.06 ^* Caffeic acid phenethyl ester 7.16 ± 0.03 7.11 ± 0.08

week.

1. Measured in three parallel trials. Data are shown as mean ± mean error.

2. Intracellular pH was equal to 7.43 ± 0.06 under culturing in culture medium in the absence of antihyperglycemic substances and substances capable of decoupling oxidative phosphorylation in mitochondria. The reduction in recorded intracellular pH only upon addition of the antihyperglycemic agent to the culture medium corresponds to P <0.05 according to the Student's t-test.

3. * P <0.05 according to the Student i-test when compared to the pH value in the test in the absence of decoupling agent.

Animal group Lactate Content in Serum, mM w / o ascorbic acid With ascorbic acid Metropmine alone 6.54 ± 0.27 6.61 + - 0.23 Administration of Metformin and Natural Phenolic Compounds Chlorogenic acid 3.44 ± 0.41 ^* 2.18 ± 0.45 ⁺ Epigallocatechin-3-gallate 5.22 ± 0.35 3.94 ± 0.22 ^* Epicatechin-3-gallate 4.11 ± 0.29 ^* 2.82 ± 0.21 ^{*, **} Ellagin acid 5.29 ± 0.35 3.51 ± 0.33 ^{*, **} Quercetin 5.39 ± 0.26 4.15 ± 0.32 ^* Physetine 3.64 ± 0.29 ^* 2.24 ± 0.18 ^{*, **} Curcumin 4.11 ± 0.18 ^* 2.07 ± 0.21 ^{*, **} Resveratrol 4.66 ± 0.24 ^* 4.20 ± 0.42 ^* Capsaicin 5.40 ± 0.27 3.41 ± 0.32 ^{*, **} Caffeic acid phenethyl ester 5.32 ± 0.32 4.44 ± 0.23

week

Each group included 3 animals. Data is expressed as mean ± mean error.

2. The lactate content in serum of intact animals is 1.64 ± 0.19 mM. The increase in the recorded lactate content caused by metformin administration corresponds to P <0.05 according to the Student test.

3. *-P <O.05 according to the Student i-test when compared to the group without the natural phenolic compound. **-P <0.05 when compared to the group that did not receive ascorbic acid.

Clinical research indicators
Clinical study indicator value At diagnosis 14 days after metformin monotherapy 14 days after treatment with the combination according to Example 2 28 days after treatment with the combination according to Example 2 with an additional dose of metformin 28 days after metformin monotherapy 28 days after treatment with the combination with an additional dose of metformin Fasting blood sugar
Content, _M M 8.72 7.08 6.58 6.41 6.37 6.34 HbA _1C content,% 7.9 7.7 7.3 7.2 7.0 6.8 Lactate Content, _M M 1.65 2.49 1.71 1.67 1.69 1.65 Blood pH 7.36 7.31 7.38 7.41 7.39 7.42

week. Doses of the combination and metformin 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 phenol compound or a mixture of said compounds in an amount of at least 2%. The combination according to claim 1, wherein the antidiabetic agent is selected from the group consisting of biguanides, thiazolidinediones or combinations thereof. The method of claim 1, wherein the natural phenolic compound is chlorogenic acid or epigallocatechin-3-gallate or epicatechin-3-gallate or elginic acid or quercetin or dihydroquercetin or picetin or curcumin or resveratrol or capsaicin Or a combination consisting of caffeic acid phenethyl ester. The combination according to claim 1, comprising a vegetable extract as a mixture of natural phenolic compounds. The combination according to claim 5, comprising metformin as an antidiabetic agent and coffee bean extract as a vegetable extract. The combination according to claim 5, comprising metformin as an antidiabetic agent and green coffee bean extract as a vegetable extract. 8. The combination according to claim 7, further comprising ascorbic acid or a pharmaceutically acceptable derivative thereof in an amount of at least 25% of the amount of green coffee bean extract. A pharmaceutical composition for treating diabetes comprising the combination according to claim 1 and a pharmaceutically acceptable carrier. The pharmaceutical composition of claim 9, comprising a therapeutically effective amount of metformin, green coffee bean extract and ascorbic acid, wherein the ascorbic acid is natural ascorbic acid, synthetic ascorbic acid or a combination thereof. The pharmaceutical composition of claim 10, wherein the mass of metformin, green coffee bean extract and ascorbic acid is in a ratio of 100: 20: 10 to 100: 40: 30. The pharmaceutical composition of claim 9 formulated in the form of a powder, granules, tablets, pellets, gels, capsules, candy, suspensions, emulsions, solubilizers. A pharmaceutical set for treating diabetes, comprising the combination according to any one of claims 1 to 11. The pharmaceutical set of claim 13, comprising a therapeutically effective amount of metformin, green coffee bean extract, and ascorbic acid. The pharmaceutical set of claim 14, wherein the mass of metformin, green coffee bean extract and ascorbic acid is from 100: 20: 10 to 100: 40: 30. The pharmaceutical set according to claim 13, formulated in the form of powders, granules, tablets, pellets, gels, capsules, candy, suspensions, emulsions, solubilizers. A method of treating concomitant diabetes comprising prescribing a combination according to claim 1 to a patient. The method of claim 17, wherein the combination according to claim 1 constitutes a pharmaceutical composition. The pharmaceutical composition of claim 18, wherein the pharmaceutical composition is prescribed in the case of patients with lactoacidosis and contains 2-3 capsules, tablets, or any other composition containing 2-3 capsules daily, at or after meal. Applied in quantities of units. The method of claim 17, wherein the combination according to claim 1 constitutes a pharmaceutical set. The method of claim 20, wherein the pharmaceutical set is prescribed in the case of patients with lactoacidosis and applied in an amount of one to two sets, two to three times a day at meal or after meal. Use of a natural phenolic compound or mixtures thereof capable of releasing oxidative phosphorylation coupling in treating patients using antidiabetic agents as agents that inhibit lactoacidosis.