RU2451506C1 - Combination for treatment of diabetes and complications thereof - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry, particularly - to composition for diabetes treatment. The diabetes treatment combination includes at least one antidiabetic medication and a natural phenol compound or mixture of such compounds capable of oxidative phosphorylation interruption. The pharmaceutical composition for diabetes treatment includes the combination and a pharmaceutically acceptable carrier. The pharmaceutical set for diabetes treatment includes the combination. The complex diabetes therapy method involves prescription of the combination to the patient. Natural phenol compounds capable of oxidative phosphorylation interruption of such compounds mixture are used for diabetes treatment with antidiabetic preparations as the acidosis suppressing medication.

EFFECT: above combination is effective for diabetes treatment, reduces the possibility occurrence of side effects of antihyperglycemic preparations applications, in particular - lactate acidosis risk.

22 cl, 3 tbl, 12 ex

Description

The present invention relates to the field of pharmaceutical industry and relates, first of all, to the treatment of diabetes.

Diabetes continues to be a significant problem for national health services in virtually every country in the world. Over the past 30-40 years, there has been a significant increase in the prevalence and incidence of diabetes mellitus worldwide and especially in industrialized countries, where 6-10% of the population suffer from diabetes and its prevalence has a clear tendency to increase, primarily in age groups older 40 years.

As you know, the main tasks that need to be addressed in the treatment of diabetes are to alleviate the symptoms of diabetes, improve the quality of life and prevent both acute (hyperosmotic coma and ketoacidosis) and chronic complications, such as diabetic neuropathy, diabetic nephropathy and premature atherosclerosis (Diabetes Control and Complications Trial Research Group; N. Engl. J. Med., 329, 977-986 (1993)).

Chronic hyperglycemia is not only the main manifestation of diabetes, which forms the basis for diagnosis, but also represents the most important pathogenetic factor in the development of almost all complications: micro and macroangiopathies, neuropathies, nephropathies, etc.

Prolonged hyperglycemia leads to increased stimulation of pancreatic beta cells, which leads to depletion of their functional capabilities, thereby contributing to the progression of the disease.

The goal of diabetes treatment is to achieve compensation for carbohydrate metabolism over a long time, i.e. the presence of indicators of glucose in blood plasma, which practically do not differ from those observed in a healthy person throughout the day. Treatment of diabetes begins with the appointment of a diet and dosed physical activity, but in order to achieve the target indicators of the state of carbohydrate metabolism, considerable efforts on the part of the patient are required, which, as a rule, patients with diabetes have little. Therefore, the main place in the treatment of diabetes is given to drug therapy.

At the same time, sugar-lowering drug therapy not only reduces glycemia and thereby eliminates the clinical manifestations of the disease due to hyperglycemia. She also breaks the "vicious circle" formed by increasing insulin deficiency due to depletion of insulin-synthesizing cells and increasing hyperglycemia with increasing insulin deficiency. The described positive effect of hypoglycemic agents for insulin deficiency is more related to type 2 diabetes and to the initial stages of type 1 diabetes.

Currently, oral sugar-lowering drugs of the following groups are used to treat type 2 diabetes:

- reducing the absorption of carbohydrates and the absorption of glucose in the gastrointestinal tract (alpha-glucosidase inhibitors, guar, acarbose, meglitol, etc.);

- increasing the production of insulin by the pancreas (sulfonylureas, glibenclamide, glipizide, glyclazide, glycidone and glimepiride);

- stimulating the secretion of insulin by the postprandial type (clayides, incretin mimetics, DPP-4 inhibitors, analogues of amylin and glucagon-like peptide 1);

- stimulating the absorption of glucose by cells and inhibiting its exit from cells (biguanides, currently metformin);

- drugs that increase the sensitivity of tissues to insulin or sensitizers thiazolidinediones (glitazones) - pioglitazone, rosiglitazone;

- insulin.

Inhibitors of a-glucosidases (acarbose) reduce the absorption of glucose in the intestine and are usually effective in the early stages of the disease. Side effects are associated with manifestations of flatulence and diarrhea. In most patients, it becomes necessary to cancel the drug within 3 years from the start of treatment.

Derivatives of sulfonylureas stimulate the secretion of insulin by b-cells of the pancreas. The most commonly used are gliclazide, glibenclamide, glipizide, glycidone. Treatment with sulfonylurea derivatives is contraindicated in type 1 diabetes mellitus or secondary (pancreatic) diabetes mellitus, pregnancy and lactation, surgical interventions, severe infections, injuries, allergies to sulfonylureas or similar drugs in history, the risk of severe hypoglycemia.

Glinids (meglitinides) have a fast onset and short duration of action, which allows, on the one hand, to effectively control postprandial hyperglycemia, on the other hand, does not increase the risk of hypoglycemia.

Drugs designed specifically to influence the level of postprandial glucose are incretin mimetics, DPP-4 inhibitors, analogues of amylin and glucagon-like peptide 1. These drugs make up for the deficiency in the secretion of pancreatic hormones and the digestive tract, affecting the secretion of insulin and glucagon, feeling and gastric emptying. They are characterized by high speed and a short sugar-lowering effect, so their use is not accompanied by any noticeable adverse effects due to the effect on glucose metabolism. A quick and short action limits the use of these drugs only as postprandial hypoglycemic agents.

The group of tableted sugar-lowering preparations of biguanides is currently represented mainly by metformin. Biguanides do not enhance insulin secretion. Their sugar-lowering effect is manifested only if there is a sufficient amount of insulin in the blood. Biguanides enhance its effect on peripheral tissues, reducing insulin resistance. Biguanides increase glucose uptake by muscle and adipose tissue. They reduce the production of glucose by the liver, the absorption of glucose in the intestine, enhance its utilization, and reduce appetite. Their purpose is contraindicated in cases of impaired renal function, hypoxic conditions of any etiology (cardiovascular failure, lung disease, anemia, infectious diseases), acute complications of diabetes, alcohol abuse, a history of lactic acidosis. Among the side effects of metformin, dyspeptic symptoms when using high doses of the drug should be noted. As a reflection of the ability of the drug to enhance anaerobic glycolysis and inhibit gluconeogenesis in the liver, cases of the development of lactic acidosis are known.

The use of sugar-lowering sulfanilamide drugs and biguanides causes side effects in the form of gastrointestinal disorders, skin allergic reactions, hypoglycemic conditions due to the proximity of the therapeutic and toxic doses of these drugs.

Thiazolidinediones affect glycemic control, reducing the insulin resistance of peripheral tissues and especially adipose tissue, and also reduce the production of glucose by the liver. Drugs in this group do not cause the development of hypoglycemia, but can contribute to weight gain. These drugs are contraindicated in patients with symptoms of heart failure and manifestations of the preproliferative and proliferative stages of diabetic retinopathy.

If sugar-lowering monotherapy is ineffective, the desired effect is sometimes achieved by combining sugar-lowering drugs. The following combinations of oral hypoglycemic drugs are possible: sulfonylureas and thiazolidinediones, metformin and meglitinides, metformin and thiazolidinediones, sulfonylureas and a-glucosidase inhibitors. If glycemic control is not achieved by a combination of oral hypoglycemic drugs, combination therapy with biguanides and insulin or insulin monotherapy is prescribed.

Sulfonylurea preparations and metformin affect the compensation of carbohydrate metabolism, but the mechanisms of their hypoglycemic effect are different. It is these aspects that allow them to be used as combination therapy.

Combined-action oral hypoglycemic drug - Glibomet consists of 2.5 mg glibenclamide and 400 mg metformin. The glibenclamide contained in the preparation stimulates the secretion of insulin by pancreatic b-cells, and metformin reduces insulin resistance mainly in the liver, which is accompanied by inhibition of gluconeogenesis, a decrease in the rate of glucose formation in the liver and its entry into central blood circulation. The use of a combination of drugs increases the hypoglycemic effect, but retains the threat of lactic acidosis accompanying the use of metformin.

A combination is known for the treatment of metabolic disorders, especially diabetes and diseases associated with diabetes, including nateglinide and antidiabetic glitazone in a pharmaceutically acceptable carrier. Glitazone is pioglitazone, rosiglitazone or troglitazone (RU No. 2280447, September 15, 2000).

The combination may be in the form of a combined preparation or pharmaceutical composition. The pharmaceutical composition may contain, as a third antidiabetic agent, metformin in a pharmaceutical carrier. The combined use of nateglinide with another antidiabetic agent provides a synergistic therapeutic effect on type 2 diabetes, as well as an increase in the duration of action of the drug, as a result of which the possible use of insulin is delayed. The disadvantage of the described combinations is the use of glitazones and metformin in them, which contribute to the development of lactic acidosis.

Known drug for the treatment of diabetes, containing a combination of exenatide and dalargin in effective amounts (RU 2413528, 01/18/2007). This combination is a combined drug and provides effective treatment for diabetes by potentiating the hypoglycemic and hypocholesterolemic effects of exenatide. The disadvantage of the proposed combination is the preferred use of the injection method of administration.

Known drug for the treatment of non-insulin-dependent diabetes mellitus type 2, containing a combination of metformin and glibenclamide in effective doses, as well as a method of treating non-insulin-dependent diabetes or hyperglycemia, while glibenclamide included in the combination for oral administration has a particle powder surface area of from 1.7 to 2 , 2 m ² / g (RU No. 2286788, 07/12/1999).

EFFECT: invention provides bioavailability of glibenclamide in the composition of dosage forms combined with metformin, comparable with bioavailability of glibenclamide monostructures. However, the use of metformin in the proposed drug leads to the need to take into account the increased likelihood of developing lactic acidosis when used.

Thus, the currently used sugar-lowering drugs for oral use solve the problem of reducing blood sugar levels by various mechanisms and therefore are effective only under certain conditions. A fuzzy manifestation of the symptoms of the underlying and concomitant diseases, which determine the presence of contraindications in some subgroups of patients, leads to undesirable side effects. One of the most significant contraindications is a predisposition to lactic acidosis.

A decrease in blood glucose when using the vast majority of drugs used for this purpose (sulfonylureas, clayides, biguanides, thiazolidinediones, insulin) and almost all of their known combinations is characterized by a pronounced accumulation of glucose in the cells of the body tissues. Excess glucose arising inside the cells leads to an increased formation of glycolysis products, their further transformation with insufficient intensity of their use in oxidative energy metabolism and lead to a number of undesirable side effects, the most dangerous of which is lactic acidosis.

Excessive accumulation of lactic acid in the body and subsequent lactic acidosis are most clearly observed as a side effect when using biguanides. The same metabolic shift underlies the restriction on the use of hypoglycemic agents (sulfonylureas, thiazolidines, clayides) if the patient has signs of lactic acidosis and ketoacidosis. In addition, a high level of glycolysis products leads to activation of the synthesis of fatty acids, which underlies the weight gain observed with a number of sugar-lowering drugs (sulfonylureas, thiazolidines, clayides).

As already noted, the described disadvantage of hypoglycemic agents is not eliminated when used in combination with each other.

Thus, the development of antidiabetic drugs, the use of which will be accompanied by less accumulation of glycolysis products in the cells, is highly relevant. This will reduce the likelihood of developing unwanted side effects.

As is known, the metabolism of pyruvic acid formed during glycolysis is associated with its oxidation in the Krebs cycle with the formation of reduced cofactors in addition to those synthesized during glycolysis. The main consumption of these factors occurs during the synthesis of ATP in the oxidative phosphorylation chain in mitochondria. Under conditions of increased formation of pyruvic acid, the natural consumption of ATP is insufficient for the effective outflow of reduced cofactors. This leads to the formation of excessive amounts of lactic acid from pyruvic acid in cells with a high glucose content. To increase the consumption of reduced cofactors of other glycolysis products, in practice in the treatment of diabetes, higher levels of physical activity are used to create an increased background consumption of ATP in energy-dependent processes.

At the same time, the task of increasing the consumption of restored cofactors could be solved by using components that provide an increase in the consumption of restored cofactors in intracellular processes as part of antidiabetic agents.

In this regard, the authors drew attention to a number of substances capable of uncoupling oxidative phosphorylation in mitochondria, which leads to an increased use of reduced cofactors to restore oxygen to water in the chain of mitochondrial cytochromes without the formation of ATP, i.e., idle.

Subsequent studies by the authors showed that in order to suppress the development of acidosis associated with the accumulation of glycolysis products during treatment with hypoglycemic agents, natural phenolic compounds capable of dissociating oxidative phosphorylation in mitochondria can be successfully used.

There are proposals for the use of natural phenolic compounds capable of dissociating oxidative phosphorylation of natural phenolic compounds and their products to enhance thermogenesis in adipose tissue in order to treat lipid metabolism disorders (US 20100215782). However, the authors are not aware of the use of natural phenolic compounds to dissociate oxidative phosphorylation in order to suppress the development of acidosis associated with the accumulation of glycolysis products during treatment with hypoglycemic agents.

In addition, as shown by the studies of the authors, the additional introduction of ascorbic acid into the body together with natural phenolic compounds enhances the above effect by maintaining the latter in phenolic form. This makes it possible to obtain a stable effect of separation due to the ability of reduced NADI cofactors (NADPH) to directly or with the participation of ascorbic acid and its derivatives to restore natural phenolic compounds.

Thus, the formation of the described redox cycles in the body cells with the participation of natural polyphenolic compounds creates an additional way of spending the excess of recovered cofactors.

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

It should be noted that it is known to use a pharmaceutical composition containing green coffee berry extract for the treatment and prevention of diseases associated with impaired antioxidant protection (RU 2378003, 06.06.2008).

The effect of the use of this composition is expressed in a decrease in blood levels of glucose, glycosylated hemoglobin, cholesterol and triglycerides.

A known method for treating a patient with diabetes or diabetes-related disorders by administering to the patient a composition containing coffee berry (US 2009017597).

The effect of using this composition in the treatment of diabetes and diabetes-related disorders in patients is described as stabilization of blood sugar levels, glycosylated hemoglobin A1C, triglycerides and low density lipoproteins, or as normalization of blood sugar levels.

In all these cases, the goal is to obtain a direct therapeutic effect in diabetes due to the antioxidant effect of the composition.

All known sources do not describe, imply or prejudice the effect discovered by the authors of using natural phenolic compounds to dissociate oxidative phosphorylation in order to suppress the development of acidosis associated with the accumulation of glycolysis products in the treatment of hypoglycemic drugs for diabetes.

Closest to the proposed invention are pharmaceutical compositions containing antidiabetic agents, in particular metformin, and methods for treating diabetes, including the administration of antidiabetic drugs to a patient. (Balabolkin MI Diabetology. M., Medicine, 2000; Ametov A.S. Type 2 diabetes mellitus. Fundamentals of pathogenesis and therapy. M., 2003).

However, as noted earlier, the decrease in blood glucose when using the vast majority of antidiabetic drugs used for this purpose (sulfonylureas, clayides, biguanides, thiazolidinediones, insulin) and almost all of their known combinations is characterized by a pronounced accumulation of glucose in the cells of the body tissues. Excess glucose arising inside the cells leads to increased formation of glycolysis products, their further transformations, with insufficient intensity of their use in oxidative energy metabolism, lead to a number of undesirable side effects, the most dangerous of which is lactic acidosis.

An object of the present invention is to provide a combination agent for treating diabetes, reducing the possibility of side effects from the use of sugar-lowering drugs by accelerating the utilization of glycolysis products and reducing the formation of lactic acid, and the possibility of using such an agent in the treatment of diabetes.

The technical effect of the invention is to reduce the risk of lactic acidosis using known hypoglycemic agents.

The invention consists in the use of combinations of known sugar-lowering agents with natural phenolic compounds capable of uncoupling oxidative phosphorylation, and additionally with ascorbic acid, which improves the bioavailability of natural phenolic compounds, maintaining them in an active phenolic form.

To solve this problem, the authors proposed a combination for the treatment of diabetes, comprising at least one antidiabetic agent and a natural phenolic compound or a mixture of such compounds.

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

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

Preferably, for use in combination, the natural phenolic compound capable of uncoupling oxidative phosphorylation is selected from the group consisting of chlorogenic acid, or epigallocatechin-3-gallate, or epicatechin-3-gallate, or ellagic acid, or quercetin, or dehydroquercetin, or fisetin, or curcumin, or resveratrol, or capsaicin, or caffeic acid phenylethyl ether.

Such compounds are part of extracts of green coffee berries, green tea, pomegranate, acacia catechu, turmeric, Japanese highlander, hot pepper, propolis, as well as a number of other products of plant or animal origin. These natural phenolic compounds can be isolated from products containing them by known methods or obtained synthetically, or used in the form of enriched extracts. As the authors showed, an effective amount of natural phenolic compounds (single dose) is 10-200 mg.

Preferably, the combination contains a plant extract as a mixture of natural phenolic compounds.

Preferably, the combination contains metformin as an antidiabetic agent, and coffee berry extract as a plant extract.

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

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

The authors also proposed a pharmaceutical composition for the treatment of diabetes and its complications, which is a combined preparation and comprising a combination of at least one antidiabetic agent and a natural phenolic compound or a mixture of such compounds and a pharmaceutically acceptable carrier.

Moreover, it is preferable that when it contains therapeutically effective amounts of metformin, green coffee extract and ascorbic acid as an antidiabetic agent.

The amount by weight of metformin, green coffee extract and ascorbic acid is preferably in a ratio of from 100: 20: 10 to 100: 40: 30.

In this case, the composition can be made in the form of a powder, granules, tablets, dragees, capsules, caramel, suspension, emulsion, solubilizate and contain auxiliary substances, in particular fillers (silicon dioxide, microcrystalline cellulose, croscarmellose sodium, etc.), binders ( polyvinylpyrrolidone, a copolymer of vinylpyrrolidone and vinyl acetate, etc.), tabletting agents (magnesium stearate, etc.), emulsifiers (ethoxylated hydrogenated castor oil, lecithin, etc.), solubilizers (polysorbates, poloxamers, etc.), prolon gators (behenic acid glycerides, hydroxypropyl methylcellulose, etc.), flavoring agents (fructose, lactose, sorbitol, etc.).

Antidiabetic agents in the composition are used in doses recommended for their independent use. The frequency of administration of the claimed composition coincides with the frequency of administration of its antidiabetic agents. Duration of administration - until the patient has no signs of lactic acidosis, but at least two weeks. It is preferable that the patient continues to take the claimed composition after restoring the pH and blood lactate levels, since this helps to reduce the risk of re-development of lactic acidosis.

The authors also proposed a pharmaceutical kit effective in treating diabetes, comprising a combination of at least one antidiabetic agent and a natural phenolic compound or a mixture of such compounds.

Such a kit is a separately manufactured preparation of antidiabetic agents and a preparation of agents containing natural phenolic compounds or mixtures thereof. Such agents may include ascorbic acid or pharmaceutically acceptable derivatives thereof.

An antidiabetic preparation may contain, for example, metformin hydrochloride and excipients (hydroxypropyl methyl cellulose, microcrystalline cellulose, povidone, magnesium stearate) and be in tablet form.

An agent containing a natural phenolic compound may contain, for example, an extract of green coffee berries (50-55% polyphenols), ascorbic acid, and microcrystalline cellulose as an auxiliary substance. Such a composition can be placed in a hard gelatin capsule.

Tablets and capsules can be packaged in blisters or bottles with the appropriate labeling and placed in a common box based on the same number of tablets and capsules.

Depending on the composition, one, two and three tablets and capsules can be prescribed.

Also provided is a method for the complex treatment of diabetes, comprising administering to a patient a combination consisting of at least one antidiabetic agent and a natural phenolic compound or a mixture of such compounds.

Moreover, a pharmaceutical composition may be used as a combination.

The pharmaceutical composition is used in the treatment of diabetes when the patient shows signs of lactic acidosis or at the beginning of the treatment of diabetes, if the patient has a history of indications of a predisposition to acidosis. The composition is prescribed in an amount corresponding to a therapeutically effective dose of an antidiabetic hypoglycemic agent included in it, with a daily dose divided into 2-3 doses. This corresponds to taking 2-3 capsules or tablets containing the claimed composition, 2-3 times a day during or after meals. The patient takes the composition until the signs of acidosis disappear, but not less than two weeks. After restoration of normal blood pH and the content of lactate in it, it is possible to switch to treatment using a preparation containing only an antidiabetic hypoglycemic agent without adding natural phenolic compounds according to the claimed invention. However, it is preferable that the patient continues to take the claimed combination, as this helps to reduce the risk of developing lactic acidosis in him.

In the proposed method for the complex treatment of diabetes, the claimed combination can be used in the form of a pharmaceutical kit.

The pharmaceutical kit of the present invention is used if the patient has the indications described for the use of the claimed combination in the form of a pharmaceutical composition. As in the case of the pharmaceutical composition, the amount of the combination in the form of a pharmaceutical kit is determined by a therapeutically effective dose of the antidiabetic hypoglycemic agent included in its composition. The combination is prescribed for 1 or 2 sets per reception 2-3 times a day during or after meals. The pharmaceutical kit is administered until the patient has no signs of acidosis, but for at least two weeks. At the same time, it is preferable to continue taking the inventive kit during the further treatment of diabetes. During this period, depending on the data of the clinical and laboratory examination, one component of the corresponding type of admission may be added to the kit to enhance the sugar-lowering effect or anti-acidosis effect.

The applicant also protects the use of natural phenolic compounds or mixtures thereof in the treatment of diabetes using sugar-lowering drugs as a means of suppressing the development of lactic acidosis.

The following examples demonstrate the application and effectiveness of the invention, without limiting it in essence.

Example 1

The combination for the treatment of diabetes of the present invention, in the form of a pharmaceutical composition comprising a hard gelatin capsule.

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

The combination is prescribed for two to three capsules per reception.

Example 2

The combination for the treatment of diabetes of the present invention, in the form of a pharmaceutical composition comprising a hard gelatin capsule.

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

The combination is prescribed for two to three capsules per reception.

Example 3

The combination for the treatment of diabetes of the present invention, in the form of a pharmaceutical composition, which is a hard gelatin capsule.

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

The combination is prescribed for two to three capsules per reception.

Example 4

The combination for the treatment of diabetes of the present invention, in the form of a pharmaceutical composition, which is a tablet.

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

A tablet is made by a process involving the preparation of granules by wet granulation of a mixture of metformin and chlorogenic acid with the addition of a binder, subsequent mixing of the granules with a diluent and a tabletting additive, tabletting the mixture and coating the obtained tablets with a film of a hydrophilic polymer.

The combination is prescribed for two to three tablets per reception.

Example 5

The combination for the treatment of diabetes of the present invention, in the form of a pharmaceutical composition, which is a tablet.

The tablet contains 250 mg of metformin hydrochloride, 1.25 mg of gibenclamide, 30 mg of chlorogenic acid, 40 mg of ascorbic acid and excipients (microcrystalline cellulose, croscarmellose sodium, polyvinylpyrrolidone, magnesium stearate, hydroxymethylpropyl cellulose, polyethylene glycol) and dioxide.

A tablet is made by a method involving the preparation of granules by wet granulation of a mixture of metformin, glibenclamide, chlorogenic and ascorbic acids with the addition of a binder, subsequent mixing of the granules with a diluent and tabletting additive, tabletting the mixture and coating the obtained tablets with a film of a hydrophilic polymer.

The combination is prescribed for two to three tablets per reception.

Example 6

The combination for the treatment of diabetes of the present invention in the form of a pharmaceutical kit from separately manufactured tablets containing antidiabetic antidiabetic drugs and tablets containing a natural phenolic compound.

A tablet containing sugar-lowering agents includes 500 mg of metformin hydrochloride, 15 mg of pioglitazone hydrochloride and auxiliary substances (microcrystalline cellulose, croscarmellose sodium, polyvinylpyrrolidone, magnesium stearate, hydroxymethyl propyl cellulose, polyethylene glycol, titanium dioxide,

A tablet is prepared by a method including the production of granules by wet granulation of a mixture of metformin and pioglitazone with the addition of a binder, subsequent mixing of the granules with a diluent and a tabletting additive, tabletting the mixture and coating the obtained tablets with a film of a hydrophilic polymer.

A tablet containing a polyphenolic compound includes 100 mg of chlorogenic acid and excipients (hydroxypropyl methylcellulose, microcrystalline cellulose; povidone, magnesium stearate).

A tablet is prepared by a process involving the production of granules by wet granulation of a mixture of chlorogenic acid and a binder, subsequent mixing of the granules with a diluent and a tabletting additive, and tabletting the mixture to obtain tablets.

Tablets containing sugar-lowering agents and a natural phenolic compound are packed in blisters or bottles with different labels and placed in a common box based on the same number of tablets of each type.

The combination is prescribed one or two tablets of each type for admission.

Example 7

The combination for the treatment of diabetes of the present invention is in the form of a pharmaceutical kit of separately manufactured antidiabetic tablets and capsules containing a mixture of a natural phenolic compound with ascorbic acid.

The tablet contains 500 mg of metformin hydrochloride and auxiliary substances (hydroxypropyl methylcellulose, microcrystalline cellulose; povidone, magnesium stearate).

A tablet is prepared by a process involving the production of granules by wet granulation of a metformin mixture with the addition of a binder, subsequent mixing of the granules with a diluent and a tabletting additive, and tabletting the mixture to obtain tablets.

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

Tablets and capsules are packed in blisters or vials with the appropriate labeling and placed in a common box at the rate of the same number of tablets and capsules.

The combination is prescribed one at a time (1 tablet and 1 capsule) or two (2 tablets and 2 capsules) sets for admission.

Example 8

The combination for the treatment of diabetes of the present invention is in the form of a pharmaceutical kit from separately manufactured tablets containing antidiabetic antidiabetic drugs and tablets containing a mixture of a natural phenolic compound with ascorbic acid.

A tablet containing sugar-lowering agents includes 500 mg of metformin hydrochloride, 5 mg of glibenclamide and excipients (croscarmellose sodium, magnesium stearate, starch, microcrystalline cellulose, povidone, lactose monohydrate).

A tablet is obtained by a method including the production of granules by wet granulation of a mixture of metformin and glibenclamide with the addition of a binder, subsequent mixing of the granules with a diluent and a tabletting additive, tabletting the mixture to obtain tablets.

A tablet for the prolonged release of active substances containing 200 mg of green coffee berry extract, 50 mg of ascorbic acid and excipients (compritol 888 ATO, VA 64 collidone, 17PF collidone, magnesium stearate).

A tablet is obtained by direct compression of tablet masses in the form of granules obtained by grinding from a briquette of direct compression of a mixture of active substances and auxiliary components.

Tablets containing sugar-lowering agents and a mixture of natural phenolic compounds with ascorbic acid are packaged in blisters or bottles with different labels and placed in a common box based on the same number of tablets of each type.

The combination is prescribed one or two tablets of each type for admission.

Example 9

The combination for the treatment of diabetes of the present invention is in the form of a pharmaceutical kit of separately manufactured antidiabetic tablets and a soft gelatin capsule containing a suspension of a mixture of a natural phenolic compound with ascorbic acid.

The metformin tablet of example 7.

The soft gelatin capsule contains a suspension of a mixture of 75 mg of the extract of green coffee berries (50-55% polyphenols) and 50 mg of ascorbic acid in 150 mg of polysorbate 80 (tween 80).

The suspension for filling the capsules is obtained in the form of a homogeneous pasty mass, gradually adding a pre-prepared mixture of the extract of green coffee berries with ascorbic acid to Polysorbate 80 with constant stirring in a vacuum reactor.

Tablets and capsules are packed in blisters or vials with the appropriate labeling and placed in a common box based on the same number of tablets and capsules.

Example 10

The suppression of natural phenolic compounds with a uncoupling effect on oxidative phosphorylation in mitochondria, the decrease in the intracellular pH induced in cells of the transplantable MDCK line (dog kidney cells) was carried out by adding metformin and rosiglitazone to the culture medium.

The MDCK cell culture was grown in DMEM supplemented with 10% calf serum at 37 ° C and 5% CO2 (pH 7.4). After the formation of a continuous monolayer, the cells were transferred into suspension using a trypsin-EDTA solution. When the cells were completely separated to suspend further action of EDTA-trypsin, fetal serum and DMEM medium were added to the culture vial in a 1: 1 ratio. Cells were washed twice with DMEM. After the last wash in culture tubes, samples of a suspension of cells with a concentration of 1 · 10 ⁶ cells / ml in Krebs-Henseleit medium containing 10 mM d-glucose were added with the addition of one of the sugar-reducing substances: metformin hydrochloride (5 mM) or rosiglitazone maleate (25 μM), and one natural phenolic compound (50 μM).

The suspension was incubated 60 minutes at 37 ° C, stirring every 10 minutes by shaking the tubes. At the end of the incubation, the cells were precipitated by centrifugation and resuspended in Krebs-Henseleit medium containing 10 mM d-glucose and 5 μM pH-sensitive dye - acetoxymethyl ether 2 ', 7'-bis (2-carboxyethyl) -5 (6) -carboxy- fluorescein (BCECF-AM). The resulting suspension was incubated 25 minutes at 37 ° C to absorb dye cells. Then the suspension was washed three times with Krebs-Henseleit medium in which HEPES was replaced with bicarbonate. The obtained cells were suspended in the same buffer with a concentration of 1 · 10 ⁶ cells / ml and introduced into a microcuvette, for fluorescence measurements, thermostatically controlled at 37 ° C. Fluorescence measurements were performed on a Perkin Elmer LS 5 spectrofluorimeter with fluorescence recorded at 530 nm and excitation at two wavelengths: 490 nm (pH-sensitive fluorescence) and 440 nm (isobestic point). The ratio of fluorescence at 490 nm to 440 nm was used to calculate the intracellular pH from a calibration curve obtained using a cell suspension of 1 · 10 ⁶ cells / ml in Krebs-Henseleit medium with different pH (from 6.5 to 7.5) containing H + / K + ionophore nigericin (10 μg / ml).

The effect of natural phenolic compounds that have a uncoupling effect on oxidative phosphorylation in mitochondria on the changes in intracellular pH caused in MDCK cells by adding metformin and rosiglitazone to the culture medium is shown in Table 1.

The results obtained (table 1) demonstrate the ability of natural phenolic compounds with a disabling effect on oxidative phosphorylation to prevent the decrease in intracellular pH caused in MDCK cells by adding sugar-lowering agents from biguanide groups (metformin) and thiazolidinodiones (rosiglitazone) to the culture medium.

Example 11

Demonstration of the suppression of the development of lactic acidosis in rats caused by the intravenous administration of large doses of metformin, the intragastric administration of solutions and dispersions of natural phenolic compounds, which have the uncoupling effect on oxidative phosphorylation in mitochondria, and ascorbic acid.

Sprague Dawley rats, aged 8 months and weighing 250-280 g, were used in the experiments. The animals were kept in a light / dark cycle of 12 hours under free access to water and rodent food. 12 hours before the start of the experiment, the animals were deprived of access to food, while maintaining free access to water. Metformin was administered intravenously into the tail vein at a dose of 250 mg / kg in the form of a 2.5% solution in saline four times with an interval of 1 hour. Half an hour before the first administration of metformin, experimental animals were orally administered a solution or suspension of natural phenolic compounds in water or an aqueous solution of ascorbic acid. The dose of natural phenolic compounds was 5 mg / kg, and ascorbic acid 2.5 mg / kg. The control groups were represented by intact animals, animals that received only metformin, and animals that received metformin and ascorbic acid without natural phenolic compounds.

An hour after the last injection of metformin, animals (about 0.5 ml) were taken from the hyoid vein into tubes without an anticoagulant and left for 30 minutes at room temperature to form a blood clot. Serum was separated by centrifugation for 15 minutes at 2000 g and 0.25 ml was placed in 1.5 ml microcentrifuge tubes. For deproteinization, 0.25 ml of cold 0.5 M metaphosphoric acid solution was added to the resulting serum, mixed and left on ice for 5 minutes. The denatured protein was precipitated by centrifugation for 5 minutes at 10,000 g and 4 ° C. The supernatant (0.4 ml) was taken into new microcentrifuge tubes, the acid was neutralized by adding 25 μl of a 5 M potassium carbonate solution, and the precipitate was separated by centrifugation for 5 minutes at 10,000 g and 4 ° C. The selected supernatant was immediately used to determine the lactate content using a fluorimetric method using a standard reagent kit adapted for use in microcuvettes on a Perkin Elmer LS 5 spectrofluorimeter.

The effect of natural phenolic compounds with a uncoupling effect on oxidative phosphorylation in mitochondria on the development of lactic acidosis caused by metformin in rats is shown in Table 2.

The results obtained (table 2) demonstrate the ability of natural phenolic compounds, which have a uncoupling effect on oxidative phosphorylation in mitochondria, to suppress the accumulation of lactic acid and the development of lactic acidosis, in particular, caused by the introduction of large doses of the sugar-reducing drug metformin. The introduction of these phenolic compounds together with ascorbic acid enhances the recorded anti-acidosis effect, which confirms the advantage of the joint use of these substances in the invention.

Example 12

A clinical case with the removal of signs of lactic acidosis in a patient during the transition from taking metformin monotherapy to taking a combination of metformin tablets and capsules containing green coffee extract and ascorbic acid.

Patient V., 47 years old, with a first diagnosis of type 2 diabetes. When a diagnosis was made, a hypoglycemic therapy was prescribed in the form of a metformin monotherapy, starting with 500 mg per day. Within 7 days, there were no adverse events from the gastrointestinal tract, and the dose of metformin was increased to 500 mg × 2 per day. A clinical laboratory examination carried out a week after this appointment revealed signs of mild lactic acidosis in the patient (see table 3), which is expressed in a slight excess of the upper limit of the norm for blood lactate content and a decrease in blood pH below the lower limit. The tendency to develop acidosis in the patient was associated with liver failure due to previous hepatitis. Taking into account the revealed biochemical changes, the patient was transferred to a daily intake of two combinations of a tablet of a sugar-lowering agent and a capsule containing a mixture of the natural phenolic compound with ascorbic acid in Example 7 for two weeks. An examination after this revealed a normalization of the lactate content and the pH value of the blood. The values of these indicators within the normal range remained after adding to the daily intake of two combinations according to example 7 an additional tablet of 500 mg metformin metformin (for a total of 500 mg × 3 per day) for four weeks and the subsequent transition to taking metformin 500 mg × 3 per day over the next four weeks. However, given the patient’s lack of a tendency to further decrease the lactate content and increase the pH against the background of persistent liver failure, it was considered advisable to use two combinations of Example 7 and an additional tablet of 500 mg metformin monopreparation (total metformin 500 mg × 3 in day) as maintenance therapy. A four-week clinical and laboratory examination of the patient showed a further improvement in blood biochemical parameters characterizing carbohydrate metabolism, which demonstrates the positive therapeutic effect of using a combination of oral sugar-lowering drugs with natural phenolic compounds and ascorbic acid in the treatment of type 2 diabetes mellitus with a tendency for the patient to develop acidosis.

The dynamics of biochemical clinical and laboratory blood parameters characterizing carbohydrate metabolism in patient V. during treatment using a combination of oral sugar-lowering agents with natural phenolic compounds and ascorbic acid are shown in table 3.

Table 1 Test disconnector Intracellular pH when added to the culture medium metformin rosiglitazone without disconnector 7.06 ± 0.04 6.89 ± 0.07 DNF, 100 µM 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 * ellagic acid 7.18 ± 0.07 7.04 ± 0.05 quercetin 7.20 ± 0.06 7.27 ± 0.03 * fisetin 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 phenylethyl ether 7.16 ± 0.03 7.11 ± 0.08 Notes 1. The measurements were carried out in three parallel samples. Data are presented as mean ± error of the mean. 2. The intracellular pH in the cells during incubation in a culture medium containing no hypoglycemic substances and substances capable of dissociating oxidative phosphorylation in mitochondria was 7.43 ± 0.06. The recorded decrease in intracellular pH when only sugar-lowering agents are added to the incubation medium corresponds to P <0.05 according to Student's t-test. 3. * - P <0.05 when compared with pH values in samples without a disconnector according to Student t-test.

table 2 Group of animals The content of lactate in serum, mm without the use of ascorbic acid with the use of ascorbic acid Metformin only 6.54 ± 0.27 6.61 ± 0.23 The introduction of metformin and natural phenolic 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 *** ellagic acid 5.29 ± 0.35 3.51 ± 0.33 *** quercetin 5.39 ± 0.26 4.15 ± 0.32 * fisetin 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 phenylethyl ether 5.32 ± 0.32 4.44 ± 0.23 * Notes 1. The groups consisted of 3 animals. Data are presented as mean ± error of the mean. 2. The lactate content in the blood serum of intact animals 1.64 ± 0.19 mm. The recorded increase in the lactate content caused by the administration of metformin corresponds to P <0.05 by the t-student criterion. 3. * - P <0.05 when compared with a group without the introduction of a natural phenolic compound according to the t-student criterion. ** - P <0.05 when compared with the group without the use of ascorbic acid.

Claims (22)

1. A combination for the treatment of diabetes, comprising at least one antidiabetic agent and a natural phenolic compound or a mixture of such compounds capable of dissociating oxidative phosphorylation. 2. The combination according to claim 1, characterized in that it contains a natural phenolic compound or a mixture of such compounds in an amount of at least 2%. 3. The combination according to claim 1, characterized in that the antidiabetic agent is selected from the group consisting of biguanides, thiazolidinediones or their compositions. 4. The combination according to claim 1, characterized in that the natural phenolic compound is selected from the group comprising chlorogenic acid, or epigallocatechin-3-gallate, or epicatechin-3-gallate, or ellagic acid, or quercetin, or dehydroquercetin, or fisetin, or curcumin, or resveratrol, or capsaicin, or caffeic acid phenylethyl ether. 5. The combination according to claim 1, characterized in that as a mixture of natural phenolic compounds it contains a plant extract. 6. The combination according to claim 5, characterized in that it contains metformin as an antidiabetic agent, and coffee berry extract as a plant extract. 7. The combination according to claim 5, characterized in that it contains metformin as an antidiabetic agent, and an extract of green coffee berry as a plant extract. 8. The combination according to claim 7, characterized in that it further comprises ascorbic acid or its pharmaceutically acceptable derivatives in an amount of at least 25% of the amount of green coffee berry extract. 9. A pharmaceutical composition for treating diabetes, comprising a combination according to claim 1 and a pharmaceutically acceptable carrier. 10. The pharmaceutical composition according to claim 9, characterized in that it contains therapeutically effective amounts of metformin, green coffee berry extract and ascorbic acid. 11. The pharmaceutical composition of claim 10, wherein the amounts by weight of metformin, green coffee extract and ascorbic acid are in a ratio of from 100: 20: 10 to 100: 40: 30. 12. The pharmaceutical composition according to claim 9, characterized in that it is made in the form of a powder, granules, tablets, dragees, capsules, caramel, suspension, emulsion, solubilizate. 13. A pharmaceutical kit for treating diabetes, comprising the combination of claim 1. 14. The pharmaceutical kit according to claim 13, characterized in that it contains therapeutically effective amounts of metformin, green coffee berry extract and ascorbic acid. 15. The pharmaceutical kit of claim 14, wherein the amounts by weight of metformin, green coffee extract and ascorbic acid are in a ratio of 100: 20: 10 to 100: 40: 30. 16. The pharmaceutical kit according to item 13, characterized in that it is a powder, granules, tablets, dragees, capsules, caramels, suspensions, emulsions, solubilizers. 17. A method for the complex treatment of diabetes, comprising administering to the patient a combination according to claim 1. 18. The method according to 17, characterized in that the combination according to claim 1 is a pharmaceutical composition. 19. The method according to p. 18, characterized in that the pharmaceutical composition is prescribed when the patient shows signs of lactic acidosis and 2-3 capsules, tablets or units of any other dosage form containing the claimed composition are used 2-3 times a day during or after eating. 20. The method according to 17, characterized in that the combination according to claim 1 is a pharmaceutical kit. 21. The method according to claim 20, characterized in that the pharmaceutical kit is prescribed when the patient shows signs of lactic acidosis and is used for 1 or 2 sets to receive 2-3 times a day during or after meals. 22. The use of natural phenolic compounds capable of uncoupling oxidative phosphorylation, or a mixture thereof in the treatment of diabetes with antidiabetic drugs as a means of suppressing the development of acidosis.