RU2435593C2 - Pharmaceutical composition for treatment of type 2 diabetes mellitus and medicine on its basis - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry and can be applied for treatment of type 2 diabetes mellitus. Composition containa as active substances N-(β-oxyethyl)-4,6-dimethyldihydropyrimedone-2 (xymedon) and inulin in ratio (2.5-5):(1-3). Composition can additionally contain magnesium, zinc, chromium asparaginates and can be made in form of capsules or pills.

EFFECT: effect from application of pharmaceutical composition for treatment of type 2 diabetes mellitus consists in continuous reduction of glucose level in blood and normalisation of lipid metabolism parameters.

13 ex, 3 tbl

Description

The invention relates to medicine and can be used for soft correction of metabolic systems and the treatment of type 2 diabetes.

Type 2 diabetes mellitus (DM) is one of the urgent problems, the significance of which is determined by its high prevalence (up to 90%) among diabetic pathology with late vascular complications. According to the WHO definition, diabetes is a group of metabolic diseases, manifested by hyperglycemia as a result of impaired insulin secretion. The pathogenesis of type 2 diabetes is still not fully understood.

The main pathogenetic mechanisms of the disease are a decrease in the sensitivity of tissues to the action of insulin (insulin resistance), as well as insufficient pancreatic β-cell function of varying severity [1]. In addition, it is known that type 2 diabetes is a heterogeneous and polygenic disease, in the pathogenesis of which several genetic factors and processes of free radical oxidation are complexly involved, which cause such complications as micro- and macroangiopathy, nephro- and neuropathy, retinopathy, and diabetic foot syndrome ", and others. In general, the course of type 2 diabetes is determined by the state of the metabolic systems of acetylation, microsomal oxidation, serum cholinesterase activity, antioxidant protection.

For the treatment of type 2 diabetes, various medications are used. First of all, these are drugs that contribute to achieving good compensation of carbohydrate and lipid metabolism [2]. In the treatment of this pathology, mild correction of metabolic systems of acetylation, microsomal oxidation, serum cholinesterase activity, antioxidant protection is desirable.

There are several groups of synthetic compounds that have a hypoglycemic effect when taken orally and are used to treat diabetes. These are sulfonylurea derivatives, biguanides, alpha-glycosidase inhibitors and others.

The action of sulfonylurea derivatives (PSM) is associated with stimulation of pancreatic beta cells and increased release of endogenous insulin produced by them. In addition, sulfonylurea preparations have an extrapancreatic effect:

they contribute to an increase in the number of insulin-sensitive receptors on target cells, thereby increasing the sensitivity of tissues and organs to insulin. Currently, in the world for the treatment of type 2 diabetes mellitus, second and third generation sulfonylureas are used (Glibenclamide, Gliclazide, Glycvidon, Glimepiride). In their activity, they exceed the first (Carbutamide, Chlorpropramide) by 50-100 times in terms of sugar-reducing effect and the risk of undesirable effects. Side effects when using sulfonylurea derivatives are most often mild. As a rule, they appear in the first two months from the start of therapy and are manifested by dyspeptic disorders. Side effects of PSM include weight gain, but this effect can be minimized or prevented by proper diet.

Biguanides - representatives of antihyperglycemic drugs - have a significant effect not only on the normalization of carbohydrate metabolism, but also improve the state of lipid metabolism and have antiatherogenic properties. Drugs of this group (Metformin, Buformin) do not alter the secretion of insulin, however, in the presence of the latter, peripheral utilization of glucose by tissues is increased. The second important mechanism of action of biguanides is a decrease in gluconeogenesis and a decrease in glucose production by the liver. Currently, the only drug in this group that is approved for use is metformin, which is inexpensive, safe and effective. Along with the effect of metformin on carbohydrate metabolism, it should be emphasized its positive effect on lipid metabolism, which is no less important for type 2 diabetes. Metformin is almost the only sugar-lowering drug, the treatment of which can lead to a decrease in the patient’s body weight [3, 4]. Side effects of biguanides are noted more often than in PSM (20% versus 4%). First of all, these are adverse reactions from the gastrointestinal tract, lactic acidosis.

Drugs with an antihyperglycemic effect achieved by inhibition of α-glucosidases (Acarbose, Miglitol) inhibit the breakdown of poly- and oligosaccharides, reducing the formation and absorption of glucose in the intestine and thereby preventing the development of postprandial hyperglycemia. Drugs in this group can cause side effects from the gastrointestinal tract. In real clinical practice, the effectiveness of acarbose monotherapy is not large enough and is manifested mainly in patients with newly diagnosed type 2 diabetes.

Thiazolidinedione drugs entered the clinical practice only in recent years. Currently, two drugs of this group are allowed for use - pioglitazone and rosiglitazone. Like biguanides, drugs of this group do not stimulate insulin secretion, but improve the sensitivity of peripheral tissues to it.

Prandial regulators (glinides) are short-acting drugs that realize their sugar-lowering properties by acute stimulation of insulin secretion. Repaglinide is the first drug in this group. It refers to carbamoylmethyl-benzoic acid derivatives. The drug stimulates the secretion of insulin by binding to its own specific site (molecular weight 36 kDa), which is part of the ATP-dependent K-channel. All this determines the specific pharmacological properties of the drug.

Nateglinide is another representative of the prandial glycemic regulators. It is a derivative of the amino acid D-phenylalanine. The mechanism of action and all the main pharmacokinetic and pharmacodynamic properties are similar to repaglinide.

Thus, the group of hypoglycemic agents includes a number of effective drugs. They have a different mechanism of action, differ in pharmacokinetic and pharmacodynamic parameters.

Currently, there are practically no combined drugs on the pharmaceutical market, as well as drugs that gently correct metabolic systems, which is especially important in the initial stages of the disease. A prerequisite for the successful treatment of type 2 diabetes mellitus as a heterogeneous disease is the impact on all links of its pathogenesis. It is necessary to achieve hypoglycemic and antihyperglycemic (hypoglycemic) and hypocholesterolemic effects, improve biochemical and metabolic processes in enzyme systems, as well as reduce processes occurring via free radical mechanisms and lead to increased lipid peroxidation (POL) in the membranes of tissues and organs, worsening the state of the membranes.

One of the main tasks in the treatment of diabetes is the fight against oxidative stress. Therefore, the search for new drugs that reduce the intensity of free radical oxidation, having a positive effect on tissue metabolism, is very relevant.

Also known is the drug N- (β-hydroxyethyl) -4,6-dimethyldihydropyrimedone-2 (xymedon).

Xymedon - a domestic drug developed by the Institute of Organic and Physical Chemistry. A.E. Arbuzov of the Kazan Scientific Center of the Russian Academy of Sciences (IOFH) and Kazan State Medical University (KSMU). Xymedon is one of the simplest non-glycoside analogues of pyrimidine nucleosides [5]. In the registry of state drugs, Xymedon belongs to the group of reparants and regenerants, which allows it to be effectively used in the treatment of many diseases.

The currently detected spectrum of xymedon action in clinical practice is extremely wide: antiviral, antiatherosclerotic, anti-inflammatory effects, inhibition of apoptosis, stimulation of N-acetyltransferase induction, tissue regeneration, immunostimulant for chronic obstructive pulmonary disease and tuberculosis, immunosuppressant for treatment of rheumatism and systems, chronic osteomyelitis, long non-healing wounds and trophic ulcers, burns of various etiologies [6, 7, 8].

Closest to the invention is the use of Xymedon for the treatment of patients with type 2 diabetes [9]. The pharmacological activity of xymedon is manifested in the possibility of its effect on certain enzymes and enzyme complexes of complex systems. When studying the effect of xymedon in vitro on the respiration of mitochondria during the oxidation of various substrates (malic, succinic, ascorbic and glutamic acids) by the method of inhibited analysis, it was found that xymedon is not toxic. Even in very high doses, there was no inhibition of the activity of NADH dehydrogenase, succinate oxidase and cytochrome oxidase, as well as mitochondrial ATP synthetase [10].

A number of authors have shown for the first time the possibility of pharmacological correction by Ximedon of human metabolic enzyme systems in patients with type 2 diabetes [11, 12]. The general mechanism of action of xymedon in this disease is fundamentally different from the above medicinal substances.

In the experiment [9], it was shown that xymedon, along with hypoglycemic and hypocholinergic effects, exhibits antioxidant activity [2, 13]. These works reliably show an increase in blood plasma AOE in patients with type 2 diabetes when treated with an immunomodulator and a reporter, xymedon, at a dose of 0.5 g 3 times daily per os. It can be assumed that the antioxidant effect is achieved not from the direct effect of xymedon on lipid peroxidation, but from the activating effect of enzyme systems (for example, N-acetyltransferase and P-450 cytochromes) with xymedon.

The disadvantage of using Xymedon mono drug for the treatment of patients with type 2 diabetes is its lack of effectiveness in regulating carbohydrate and lipid metabolism, and reducing elevated blood glucose levels.

The problem to which the invention is directed, is to create a pharmaceutical composition of combined action for the treatment of type 2 diabetes mellitus based on the active substance - xymedon, which has hypoglycemic properties and is a “soft” regulator of enzymatic systems of acetylation, microsomal oxidation, serum cholinesterase activity, antioxidant protection .

The problem is solved in that the pharmaceutical composition for the treatment of type 2 diabetes is characterized in that it contains N- (β-hydroxyethyl) -4,6-dimethyldihydropyrimedone-2 (xymedon) and inulin in the ratio (2.5 -5) :( 1-3).

Also, according to the invention, the composition further comprises magnesium, zinc, chromium asparaginates in the following ratio, mg:

Xymedon - 250-500

Inulin - 100-300

Magnesium Asparaginate - 10-100

Zinc Asparaginate - 1-10

Chromium Asparaginate - 0.01-0.1

Also, according to the invention, the composition may be in the form of capsules or tablets.

A drug based on the proposed composition is characterized in that it is made in the form of gelatin capsules in the following ratio of components per capsule, mg:

Xymedon - 125-250

Inulin - 50-150

Magnesium Asparaginate - 5-50

Zinc asparaginate - 0.5-5

Chromium Asparaginate - 0.005-0.5

The essence of the proposed invention lies in the fact that it is proposed to use a combined preparation containing xymedon and inulin as the main active substances, which is a “soft” corrector and activator of the immune and enzyme systems with an indirect antioxidant effect. The estimated single dose of Ximedon in the dosage form should be 0.25-0.5 g. It was shown in [11] that a dose of less than 0.25 g 3 times a day is ineffective. A dose of more than 0.5 g does not significantly affect the antioxidant status of the body compared to a dose of 0.5 g, while drug stress increases with drug treatment, in addition, it is not economically feasible to offer a dosage form with a higher concentration.

As the second component (active substance), we proposed the use of a polysaccharide - inulin, which can also serve as an auxiliary substance and provide a transport function for other components, for example, zinc, chromium, copper, magnesium ions, due to sorption of ions by inulin polymer chains.

Inulin is a polysaccharide formed by D-fructose residues. Inulin regulates carbohydrate metabolism: in the acidic environment of gastric juice, inulin, under the influence of the inulase enzyme, hydrolyzes with the formation of fructose, which is absorbed by the body without insulin, thereby preventing energy hunger in the tissues of patients with diabetes, while reducing hunger. Inulin is an additional tool in the treatment of diabetes mellitus, supplementing the intake of hypoglycemic drugs (sulfa, biguanides), preventing the development of diabetic coma and prolonging the life of the patient. However, inulin does not prevent the development of diabetic neuro-, nephro-, retino- and encephalopathy.

Inulin is involved in the same metabolic processes as glucose, and replaces it in situations where glucose is not absorbed by cells; only reduces elevated blood glucose and does not affect normal glycemia; improves lipid metabolism, positively affects the intestinal flora, being an effective means of detoxifying the body, accelerates the cleansing of the body from toxins and harmful substances, has an immunomodulating and hepatoprotective effect. The physiological effects of inulin are the result of the effects of inulin metabolism products on cellular proteins, which has an effect on diseases associated with diabetes, such as atherosclerosis, diabetic neuropathy, impotence, retinopathy, etc.

The amount of inulin in the dosage form can be estimated based on known data. So, the drug "Inulin Forte", containing up to 65% inulin, is recommended at a dose of 1 g 3 times a day, which corresponds to a dose of inulin of 0.65 g 3 times a day. In a complex preparation where inulin plays a supporting role, the indicated dose is greatly overestimated, since part of inulin is intended for preventive nutrition in diabetes and is used as an energy reserve (fructose) and sorbent.

We have proposed a dose of 0.05-0.15 g in a capsule or tablet, for example, a daily dose of 2 capsules (0.1-0.3 g) 3 times a day. A single dose of less than 0.1 g does not provide a positive pharmacological effect, based on literature data. A single dose above 0.3 g is not economically feasible.

The introduction of a number of microelements, such as magnesium, zinc, and chromium, into the drug promotes optimal correction of hypoglycemic status and a decrease in the risk of complications of type 2 diabetes [1, 23]. The most commonly used for correction are magnesium sulfates (20 mg), and zinc (8 mg), and chromium picolinate (0.08 mg).

Magnesium is an activator of more than 300 enzymes, mainly carbohydrate metabolism [15]. Magnesium is involved in the production, binding, and activation of insulin, which is required for glucose uptake.

Magnesium deficiency is a significant factor in diabetic organ damage and is a predictor of the greater severity of diabetes, in addition, without an adequate level of magnesium, glucose control is not possible. It has been established that in diabetes mellitus, regardless of the level of insulin production, normal magnesium content increases the sensitivity of tissues (cells) to insulin and improves glucose utilization, moreover, when compensating for the lack of magnesium, the state of the cardiovascular system, which is so vulnerable in diabetes mellitus, improves.

The introduction of magnesium in the dosage form is more preferably in the form of magnesium L-asparaginate, while a single dose reaches 200 mg. Accordingly, it is more expedient to introduce magnesium in the form of L-asparaginate into the developed dosage form. The recommended single dose is from 10 to 100 mg. Small doses of less than 10 mg are of prophylactic value only and practically do not correct indicators of diabetes mellitus 2. Doses of 100 mg are pharmacologically and technologically impractical.

Zinc as a coenzyme is involved in more than 70 enzymatic reactions in the body, including it being a cofactor of insulin. The function of zinc is to normalize blood sugar levels - zinc regulates the production and functioning of insulin, and thereby affects the entire spectrum of insulin-dependent processes. It regulates the balance of blood sugar, as it is one of the components of insulin [15].

Zinc is involved in almost all parts of the immune system: in the process of maturation of lymphocytes and reactions of cellular immunity, it increases the level of thymine and thymosin produced by the central body of the immune system - the thymus; increases the protective antimicrobial activity of neutrophils and macrophages; increases the production of protective antibodies. Improving the immune properties of the human body is a very important factor in the treatment of any systemic diseases, including diabetes.

Zinc is an important substance for maintaining and improving vision, especially a lot of zinc is contained in the retina of the eye, therefore it is important for the prevention of myopia, increases the ability to adapt to the dark, in the treatment of concomitant diabetes, such as diabetic retinopathy.

Zinc plays a key role in the synthesis of the most important digestive enzymes, including the pancreas, and also participates in the formation of special transport particles (chylomicrons), in which edible fats enter the blood and lymph.

The antioxidant protection of the body's zinc occurs due to the active center of one of the important enzymes - superoxide dismutase. The trace element zinc in the form of zinc sulfate is introduced in a dose of 5 to 50 mg. The most optimal is the introduction of zinc in the form of salts of organic acids, for example, in the form of zinc L-asparaginate, a single dose of 2.5-5.0 mg [21].

The recommended dose of zinc asparaginate for the treatment of type 2 diabetes is 1-10 mg. A single dose of less than 1 mg does not have the necessary pharmacological effect, and a dose of more than 10 mg is not pharmacologically and economically feasible.

The trace element chromium is usually introduced in the form of salts (or complexes) of organic acids. These compounds enhance the action of insulin. Chromium demand is approximately 1 mcg / day. Given the fact that trivalent chromium is very poorly absorbed from the digestive tract (1-3%), adult consumption is considered to be 50-200 mcg / day. Chromium deficiency is manifested by a decrease in glucose tolerance and the development of peripheral neuropathy, including in patients who have been on parenteral nutrition for a long time. The administration of trivalent chromium to such patients at a dose of 150-250 mcg / day was accompanied by an increase in glucose tolerance and a reduction in the manifestations of peripheral neuropathy. In experimental animals, the signs of trivalent chromium deficiency are eliminated when brewing yeast containing a “glucose tolerance factor” is included in the diet (trivalent chromium CrCl _{3 was} subsequently established as a biologically active brewing yeast factor).

We proposed the use of a single dose of chromium in the dosage form, in the treatment of type 2 diabetes, 10-100 mcg. Using a dose of less than 10 μg has a weak effect on the course of the disease, and a dose above 100 μg is associated with a greater risk of side effects.

We have chosen a dosage form - gelatin capsules. A single dose is 2 capsules per dose.

Composition per 1 capsule:

Xymedon - 125-250 mg

Inulin - 50-150 mg

Magnesium Asparaginate - 5-50 mg

Zinc asparaginate - 0.5-5 mg

Chromium asparaginate - 5-50 mcg

The maximum mass of the average capsule is 511 mg.

Additionally, each capsule, if necessary, may contain stabilizers and preservatives used in traditional pharmacopeia.

In dry form (in the absence of water), there are no interactions of the studied components with each other in the pharmaceutical composition. It is supposed to be stored in a dry, dark place at a temperature of 15-25 ° C. Inulin is very hygroscopic and in the pharmaceutical composition it is capable of swelling under the action of moisture, and the contents of the capsule lose flowability. Xymedon under the influence of light is able to oxidize to the corresponding derivatives, for example,

и

and

In the human body in the gastrointestinal tract, inulin is capable of sorbing metal cations (trace elements), holding them on the surface of polymer chains and, thereby, performing a transport function. In addition, in the acidic environment of the stomach, xymedon passes into the protonated (cationoid) form and is able to form associates with active oxygen-containing groups of inulin. The resulting associates will interact more selectively with biotargets in the human body. Given the fact that 50% of xymedon is excreted by the kidneys in an unchanged state, the inclusion of xymedon in associates can slow the elimination process and thereby reduce the dose of xymedon in a dosage form.

To confirm the effectiveness of the drug proposed according to the invention, an experimental study of its specific pharmacological activity (antidiabetic effect) was carried out.

For testing, 4 experimental formulations of the following compositions were proposed:

Composition No. 1 (per 1 capsule):

Xymedon - 200 mg, Inulin - 100 mg, Magnesium asparaginate - 20 mg, Zinc asparaginate - 2.5 mg, Chromium asparaginate - 30 μg, Nipagin - 5 mg.

Composition No. 2 (per 1 capsule):

Lactose - 200 mg, Inulin - 100 mg, Magnesium asparaginate - 20 mg, Zinc asparaginate - 2.5 mg, Chromium asparaginate - 30 μg, Nipagin - 5 mg.

Composition No. 3 (per 1 capsule):

Xymedon - 200 mg, Lactose - 100 mg, Magnesium Asparaginate - 20 mg, Zinc Asparaginate - 2.5 mg, Chromium Asparaginate - 30 μg, Nipagin - 5 mg.

Composition No. 4 (per 1 capsule):

Xymedon - 200 mg, Inulin - 100 mg, Lactose - 22.5 mg, Nipagin - 5 mg.

The study of the hypoglycemic effect and possible antidiabetic activity of the preparations was carried out in laboratory animals with the intragastric route of administration in comparison with the drug Metformin, traditionally used to treat type 2 diabetes.

Example 1. The study of the hypoglycemic effect of experimental drugs in the hypoglycemic test in mice

To study the hypoglycemic effect, the preparations were administered to mice (groups of 6 male animals weighing 18-20 g) intragastrically at a dose of 50 mg / kg for 5 days. Animals were freely available for food and water. Blood sampling was carried out on day 5 1 hour after the last injection of drugs, the level of glucose in serum was determined by the ortotoluidine method. The results are presented in table 1.

Table 1 The blood glucose level of mice after drug administration, mmol / l, M ± s No. p / p A drug Dose mg / kg Glucose level, mmol / l one Control, intact - 6.8 ± 0.1 2 Metformin one hundred 4.5 ± 0.2 * 3 Composition No. 1 fifty 4.6 ± 0.2 * four Composition No. 2 fifty 5.2 ± 0.3 * 5 Composition No. 3 fifty 4.9 ± 0.1 * 6 Composition No. 4 fifty 4.3 ± 0.2 * * - significant differences from control

The results indicate that the drugs have a hypoglycemic effect. The most active were compounds No. 1 and No. 4.

Example 2. The study of hypoglycemic action in the test glucose load in rats

The experiments were performed on Wistar rats weighing 230-250 g, male (group of 8 animals). On the evening before the experiment, the animals lost their food. In the morning, on an empty stomach, the test preparations were administered to rats, and after an hour, glucose was administered orally at a dose of 3 g / kg. Blood glucose levels were determined every hour for 5 hours. The results of the glucose load test are presented in table 2.

table 2 Rat blood glucose in the glucose load test, M ± s, mmol / L A drug Dose mg / kg Time from the moment of glucose loading, hour -1 (before drug administration) 0 minutes (glucose load) one 2 3 four 5 Control - 6.65 ± 0.29 6.58 ± 0.18 11.76 ± 0.24 11.18 ± 0.30 11.48 ± 0.28 8.33 ± 0.42 7.64 ± 0.38 Metformin one hundred 6.55 ± 0.33 5.29 ± 0.48 * 7.34 ± 0.53 * 7.92 ± 0.57 * 8.39 ± 0.49 * 4.76 ± 0.35 * 4.18 ± 0.84 * Composition No. 1 fifty 6.43 ± 0.30 5.26 ± 0.49 * 7.04 ± 0.54 * 8.22 ± 0.52 * 9.14 ± 0.48 * 4.65 ± 0.36 * 4.11 ± 0.88 * Composition No. 2 fifty 6.19 ± 0.27 6.62 ± 0.18 10.40 ± 0.21 9.49 ± 0.27 11.04 ± 0.25 9.06 ± 0.41 7.41 ± 0.38 Composition No. 3 fifty 6.63 ± 0.26 6.48 ± 0.16 10.10 ± 0.22 9.53 ± 0.29 10.84 ± 0.26 8.69 ± 0.52 7.87 ± 0.36 Composition No. 4 fifty 6.13 ± 0.42 5.65 ± 0.43 * 9.53 ± 0.53 * 8.57 ± 0.51 * 8.36 ± 0.48 * 5.74 ± 0.36 * 5.38 ± 0.86 * * - significant differences from control

As follows from the data presented, in the oral glucose load test (oral glucose tolerance test) formulations No. 1 and No. 4 were effective. They have a pronounced hypoglycemic effect, similar in strength and pharmacodynamic profile to that of Metformin. Formulations No. 2 and No. 3 in comparable doses were ineffective.

Example 3. The study of the antidiabetic effect of drugs on a model of chemically-induced (streptozotocin) diabetes

The experiments included only those animals in which by the seventh day after the administration of streptozotocin there was an increase in the level of glucose in the blood serum not less than twice the average glucose measured in the group of intact animals.

The introduction of the studied drugs began on the 7th day from the moment of diabetes induction and ended on the 28th day. The drugs were administered intragastrically in mild starchy mucus once a day at 11 ⁰⁰ at a dose of 50 mg / kg. During the experiment, the animals consumed food and water ad libitum. During the experiment (on days 14, 21 and 28, respectively), the following conditions were recorded: the general condition of the animals, the number of dead animals, water consumption, body weight, glucose levels, total lipids, triglycerides and serum cholesterol.

The average glycemia levels in the groups before the administration of drugs in animals with diabetes did not differ significantly. The experimental results are presented in table 3.

The results obtained indicate that Metformin and formulations No. 1, No. 3 and No. 4 have a sufficient antidiabetic effect. All animals treated with these drugs showed a decrease in blood glucose and normalization of lipid metabolism, these animals normally gained weight. At the same time, the therapeutic effect of formulation No. 1 did not practically differ from the effect of the positive control drug.

Thus, studies have shown that experimental formulations No. 1, 4 have pronounced hypoglycemic and antidiabetic activity. The drugs have the ability to lower blood glucose levels for a long time in a hypoglycemic test, in a glucose-loaded test, and in experimental diabetes, they normalize fat-carbohydrate

exchange. Experimental formulations exert these effects in doses comparable to the therapeutic dose of Metformin.

The proposed pharmaceutical composition for the treatment of type 2 diabetes in the form of capsules and tablets is illustrated by the following examples.

Example 4. The pharmaceutical composition is obtained by mixing and filling into capsules of the following components, mg:

Xymedon - 125

Inulin - 50

Magnesium Asparaginate - 5

Zinc asparaginate - 0.545

Chromium Asparaginate - 0.005

The result is a pharmaceutical composition containing xymedon and inulin in a ratio of 2.5: 1.

Example 5. Carried out analogously to example 4 with the following components:

Xymedon - 250

Inulin - 150

Magnesium Asparaginate - 49.95

Zinc asparaginate - 5

Chromium Asparaginate - 0.05

The result is a pharmaceutical composition containing xymedon and inulin in a ratio of 5: 3.

Example 6. Carried out analogously to example 4 with the following components:

Xymedon - 125

Inulin - 150

Magnesium Asparaginate - 5.035

Zinc asparaginate - 5

Chromium Asparaginate - 0.015

The result is a pharmaceutical composition containing xymedon and inulin in a ratio of 2.5: 3.

Example 7. Carried out analogously to example 4 with the following components:

Xymedon - 250

Inulin - 50

Magnesium Asparaginate - 50

Zinc Asparaginate - 0.51

Chromium Asparaginate - 0.04

The result is a pharmaceutical composition containing xymedon and inulin in a ratio of 5: 1.

Example 8. Carried out analogously to example 4 with the following components:

Xymedon - 175

Inulin - 100

Magnesium Asparaginate - 27.7

Zinc Asparaginate - 2.775

Chromium Asparaginate - 0.025

The result is a pharmaceutical composition containing xymedon and inulin in a ratio of 3.5: 2.

A pharmaceutical composition in the form of tablets is obtained by mixing the components with excipients and compressing the resulting mass. As auxiliary substances, sorbitol, isomalt, polyvinylpyrrolidone, silicon dioxide, magnesium or calcium stearate, aspartame, mono- and diglycerides of fatty acids are used.

Example 9. The pharmaceutical composition is obtained by mixing and pressing the following components, mg:

Xymedon - 125

Inulin - 50

Magnesium Asparaginate - 5

Zinc asparaginate - 0.545

Chromium Asparaginate - 0.005

Excipients - before receiving a tablet weighing 200 mg.

Example 10. Carried out analogously to example 9 with the following components:

Xymedon - 250

Inulin - 150

Magnesium Asparaginate - 49.95

Zinc asparaginate - 5

Chromium Asparaginate - 0.05

Excipients - before receiving a tablet weighing 500 mg.

Example 11. Carried out analogously to example 9 with the following components:

Xymedon - 125

Inulin - 150

Magnesium Asparaginate - 5.035

Zinc asparaginate - 5

Chromium Asparaginate - 0.015

Excipients - before receiving a tablet weighing 300 mg.

Example 12. Carried out analogously to example 9 with the following components:

Xymedon - 250

Inulin - 50

Magnesium Asparaginate - 50

Zinc Asparaginate - 0.51

Chromium Asparaginate - 0.04

Excipients - to obtain a tablet weighing 370 mg.

Example 13. Carried out analogously to example 9 with the following components:

Xymedon - 175

Magnesium Asparaginate - 27.7

Zinc Asparaginate - 2.775

Chromium Asparaginate - 0.025

Excipients - before receiving a tablet weighing 350 mg.

Table 3 Integral indices, indicators of carbohydrate and lipid metabolism in Wistar rats with experimental diabetes and treatment with formulations, M ± s Experimental
groups Percentage of living Body weight g Daily water intake, ml Glucose, mmol / L Common lime id, g / l Cholesterol, mol mol / L Triglycerides, mmol / L 14 days Intact one hundred 220 ± 10 15 ± 5 5.9 ± 0.3 10.5 ± 2.5 1.5 ± 0.3 1.7 ± 0.2 Diabetes (negative control) 60 200 ± 15 42 ± 7 30.2 ± 3.1 17.2 ± 2.1 7.5 ± 0.3 3.2 ± 0.3 Diabetes + Metformin, 100 mg / kg one hundred* 221 ± 14 20 ± 5 * 16.5 ± 1.5 * 9.6 ± 1.8 * 2.5 ± 0.3 * 2.4 ± 0.1 * Diabetes + Composition No. 1, 50 mg / kg one hundred* 219 ± 17 19 ± 3 * 16.7 ± 1.2 * 9.7 ± 1.5 * 2.6 ± 0.1 * 2.5 ± 0.2 Diabetes + Composition No. 2, 50 mg / kg 80 * 205 ± 8 27 ± 5 * 26.2 ± 2.3 15.2 ± 1.3 6.3 ± 0.4 2.9 ± 0.2 Diabetes + Composition No. 3, 50 mg / kg 90 * 210 ± 11 22 ± 3 * 16.1 ± 1.5 * 10.2 ± 1.5 * 4.2 ± 0.2 * 2.7 ± 0.1 Diabetes + Composition No. 4, 50 mg / kg one hundred* 222 ± 10 21 ± 4 * 14.7 ± 1.8 * 9.8 ± 1.5 * 2.3 ± 0.3 * 2.4 ± 0.2 *

21 day Intact one hundred .230 ± 15 16 ± 3 5.8 ± 0.2 9.5 ± 1.5 1.5 ± 0.1 1.6 ± 0.1 Diabetes (negative control) fifty 205 ± 10 47 ± 5 32.5 ± 3.5 18.2 ± 2.1 7.7 ± 0.3 3.1 ± 0.2 Diabetes + Metformin, 100 mg / kg one hundred* 219 ± 11 22 ± 3 * 10.5 ± 1.5 * 10.3 ± I.I * 1.5 ± 0.2 * 1.7 ± 0.1 * Diabetes + Composition No. 1, 50 mg / kg one hundred* 220 ± 10 20 ± 3 * 11.1 ± 1.5 * 10.2 ± 1.4 * 1.5 ± 0.1 * 1.6 ± 0.2 * Diabetes + Composition No. 2, 50 mg / kg 80 * 210 ± 10 25 ± 3 * 16.2 ± 2.5 * 13.3 ± 1.5 * 6.0 ± 0.1 2.6 ± 0.2 Diabetes + Composition No. 3, 50 mg / kg 90 * 230 ± 20 21 ± I * 9.8 ± 0.9 * 10.0 ± 0.5 * 1.5 ± 0.2 * 1.7 ± 0.1 * Diabetes + Composition No. 4, 50 mg / kg one hundred* 225 ± 15 21. ± 2 * 11.0 ± 0.9 * 10.1 ± 0.6 * 1.7 ± 0.2 * 1.7 ± 0.1 *

28 day Intact one hundred 240 ± 15 16 ± 2 5.9 ± 0.2 9.5 ± 1.5 1.5 ± 0.1 1.6 ± 0.1 Diabetes (negative control) thirty 195 ± 15 55 ± 15 35.5 ± 6.1 20.1 ± 2.2 8.5 ± 0.5 3.2 ± 0.5 Diabetes + Metformin, 100 mg / kg one hundred* 245 ± 20 16 ± 3 * 6.3 ± 1.5 * 10.3 ± 0.5 * 1.6 ± 0.1 * 1.7 ± 0.3 * Diabetes + Composition No. 1, 50 mg / kg one hundred* 245 ± 15 15 ± 4 * 5.8 ± 1.3 * 9.2 ± 1.2 * 1.5 ± 0.2 * 1.6 ± 0.1 * Diabetes + Composition No. 2, 50 mg / kg 80 * 240 ± 10 17 ± 2 * 7.3 ± 0.2 * 12.6 ± 0.3 * 2.1 ± 0.2 * 2.3 ± 0.1 * Diabetes + Formulation No. 3, 50 mg / kg 80 * 247 ± 13 18 ± 2 * 6.2 ± 0.1 * 9.5 ± 0.5 * 1.6 ± 0.2 * 1.5 ± 0.1 * Diabetes + Formulation No. 4, 50 mg / kg one hundred* 243 ± 12 16 ± 2 * 6.1 ± 1.1 * 9.4 ± 1.5 * 1.4 ± 0.1 * 1.8 ± 0.2 * * - significant differences from negative control of groups with recipes

Information sources

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Claims (3)

1. A pharmaceutical composition for the treatment of type 2 diabetes mellitus, characterized in that it contains N- (β-hydroxyethyl) -4,6-dimethyldihydropyrimedone-2 (xymedon) and inulin in the ratio (2.5-5) as active substances : (1-3). 2. The composition according to claim 1, characterized in that it further comprises asparaginates of magnesium, zinc, chromium in the following ratio of components, mg:
Ximedon 250-500 Inulin 50-150 Magnesium asparaginate 10-100 Zinc Asparaginate 1-10 Chrome asparaginate 0.01-0.1 3. The composition according to any one of claims 1 and 2, characterized in that it is made in the form of capsules or tablets.