RU2661622C1 - Solidphase composition of natural bioactive ingredients for correction of metabolic disturbances in diabetes mellitus type ii - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to the pharmaceutical industry, in particular to a solidphase composition having the property of correcting metabolic disorders in diabetes mellitus type 2. Solidphase composition having the property of correcting metabolic disorders in diabetes mellitus type 2, is an ultradisperse powder of a mixture (mechanochemically activated in the presence of 0.7–0.9 wt% of the plant raw material of sodium bicarbonate) of lichens blastemas of Cladonia genus and Jerusalem artichoke tubers (Helidnthus tuberosus) in a weight ratio of 9:1, which contains lichen β-oligosaccharides, fructose oligosaccharides, fructose in a certain concentration.

EFFECT: above-described composition effectively corrects metabolic disorders in diabetes mellitus type 2.

1 cl, 2 tbl

Description

The invention relates to the field of medicine and pharmacology, in particular to endocrinology, and can be used to correct metabolic disorders in type 2 diabetes mellitus (T2DM). Diabetes mellitus (DM) is a metabolic disease associated with impaired glucose metabolism due to absolute or relative insulin deficiency, as well as impaired transmission of the insulin signaling cascade in target tissues of insulin. At the same time, the key to the pathogenesis of T2DM, especially in its early stages, is not a violation of insulin synthesis in β-cells of the pancreatic Langerhans islets, but inhibition of its secretion as a result of disturbances in bioenergetic processes in these cells and changes in the structure and properties of cell membranes leading to to the formation of a number of defects associated with “distortions” of the process of “recognition” of glucose or glucose sensitivity of receptors on the membrane of pancreatic β-cells, or a violation of the transport function of ionic analov. As a result of a decrease in blood insulin level or impaired transmission of the insulin signaling cascade in target cells, glucose transport to the target cells of insulin is impaired, hyperglycemia and glucosuria form, while the target cells themselves experience glucose deficiency; as a result, the whole complex of bioenergetic processes in the corresponding tissues is disrupted [1-3]. The most common cardiovascular complications of diabetes: arterial hypertension, diabetic angio- and retinopathy, coronary heart disease and a number of other complications. These complications are considered to be the cause of premature disability and high mortality from diabetes.

Traditional hypoglycemic therapy includes hypoglycemic and antihyperglycemic agents. At the same time, hypoglycemic agents (sulfonylurea derivatives, meglitinides, etc.) stimulate the secretion of endogenous insulin (this is accompanied by an increase in body weight) and can cause hypoglycemic conditions, and antihyperglycemic agents (alpha-glucosidase blockers, biguanides (metformin), improve thiazolidinediones) peripheral utilization of glucose, but do not have a stimulating effect on pancreatic β-cells. Therefore, they do not increase insulin levels in the blood and do not cause hypoglycemic conditions. The use of the above methods of glucose-normalizing drug therapy does not allow for accurate regulation of glycemia, has a number of side effects and contraindications for concomitant diseases, therefore, new developments in this area are aimed at studying a fundamentally new mechanism for regulating glucose homeostasis through incretins, peptide hormones of the gastrointestinal tract, produced in response to food intake and causing glucose-dependent stimulation of insulin secretion, as well as the creation of preparations comrade, reducing the intactness of the membrane of the pancreas β-cells, bioenergetic homeostasis and functional activity of ion channels involved in glyukozostimulirovannoy insulin secretion.

A wide range of pharmacological preparations with various mechanisms of action aimed at normalizing glucose homeostasis is used to treat patients with T2DM. For many years, these drugs, targeted by β-cells and peripheral tissues, have dominated the pharmaceutical market [4]. At the same time, it was found that, despite a large assortment of various groups of oral hypoglycemic drugs, it is rarely possible to achieve and maintain targets for glycated hemoglobin for a long time. In addition, prolonged use of sugar-lowering pharmaceutical preparations per os often leads to side effects and has severe contraindications for exacerbation of complications [4].

Phytopreparations with the ability to reduce the concentration of glucose in the blood and urine, these disadvantages are not characteristic. They include various medicinal plants with a hypoglycemic (antidiabetic) effect, primarily due to increased insulin secretion by pancreatic β-cells, as the main or additional treatment, as well as by stopping the deficiency of bioenergetic monosaccharides in cells. Plants with hypoglycemic properties have long been used in folk medicine. And they are the source of the active substances of a number of antidiabetic pharmaceuticals. For example, goat's medicinal (lat. Galega officinalis), containing alkaleid galegin with antihyperglycemic properties. Galegin is a structural analogue of metformin, a drug widely used in the treatment of type 2 diabetes. Currently, it is becoming urgent to search for new, previously unused natural compounds or their mixtures in the prevention of T2DM, which boils down to the creation of compositions of bioactive substances of hypoglycemic purpose and used together or in combination with standard hypoglycemic therapy.

Known liquid-phase biological product "Yagel" obtained by water-alcohol extraction of thalli of the lichens of the genus Cladonia, pre-treated with carbon dioxide in a supercritical fluid (one of the main active substances is lichen β-oligosaccharides) [5], which has the effect of stimulating insulin secretion by insulin cells in 1.8-2.0 times when added to the medium of their incubation for 3-4 weeks due to the restoration of insulin secretory ability, due to the modification of cell and mitochondrial membranes of lichen β cells nicks β-oligosaccharides [6]. Further, the level of transmembrane transfer of glucose into the cell increases, the intensity of cellular respiration and mitochondrial activity in muscle cells increase [6]. Clinical studies of the effectiveness of dietary supplements "Yagel" conducted for the prevention of T2DM showed that after a 3-week intake of the drug, the proportion of people with high glucose decreased by 3.0 times (up to 14.3%), cholesterol - 1.6 times (up to 33.3%), the atherogenic coefficient - 2.6 times, and with the combined elevated levels of glucose and cholesterol - more than 5 times [7]. As a result, the dietary supplement "Yagel" was recommended for the prevention of the development of cardiovascular diseases and metabolic disorders caused by hyperglycemia.

Clinical studies of the effectiveness of another biological product, the active substance of which are lichen β-oligosaccharides - dietary supplement Jagel-Detox [8], obtained by mechanochemical activation of coarsely ground thalli of the genus Cladonia in order to correct metabolic disorders in patients with type 2 diabetes, showed that admission for 3 months leads to a persistent decrease in blood glucose by 20%, glycated hemoglobin - by 12%, total cholesterol - by 7%, with an increase in the content of high density lipoproteins by 18%, as a result oeffitsient atherogenic decreased by 24% [9, 10].

Lichen β-oligosaccharides also have other important properties that are significant for achieving the goal of correcting metabolic disorders in T2DM. They:

- do not hydrolyze in the gastrointestinal tract (GIT), because contain strong β-glycosidic bonds and cellulases that can hydrolyze them enzymatically are not produced in the human intestines;

- contain a large number of hydrophilic functional groups (—OH, —NH ₂ , = CO, etc.) and hydrophobic fragments providing the formation of supramolecular complexes (SMC) with low molecular weight and / or oligomeric compounds in contact with them, both hydrophilic and hydrophobic in nature, in which β-oligosaccharides act as an “active carrier”, and the low molecular weight compounds contained in the composition (or introduced into it) are “pharmacons”;

- SMC is well absorbed from the gastrointestinal tract into the blood, due to the biphilic structure and size of the “active carrier”, it is easily transported through cell membranes due to the small size and biphilic nature of lichen β-oligosaccharides, which are close to the oligoglycoside fragments of glycocalyx of cell membranes, providing increased bioavailability of the “pharmacon” ;

- in the internal environments of the body, after the decomposition of the supramolecular complex, lichen β-oligosaccharides bind in the internal environments (cytoplasm, intercellular fluids, blood, lymph) the end products of metabolism - endotoxins (lactic and uric acid, urea, inflammatory mediators - small and medium molecular endotoxins masses, etc.), as well as exotoxins (heavy metal cations, radionuclides, carbon and sulfur oxides, organic toxic compounds, including phenols, alcoholic toxins: acetaldehyde, acetone, bacterial and viral toxins, etc.) and remove them from the body.

Due to these properties of lichen β-oligosaccharides, firstly, an increased digestibility and bioactivity of the "pharmacon" is achieved regardless of its degree of hydrophobicity / hydrophilicity. Secondly, the manifestation of detoxification activity against the internal environment of the body is provided.

An increase in the bioavailability and bioactivity of the "pharmacon" act-protective effect during complexation with lichen β-oligosaccharides and the manifestation of their detoxification activity against endotoxins: lactic acid, urea, was found, for example, when testing the biological product "Kladorod" consisting of lichen β-oligosaccharides secreted from the roots and rhizomes of Rhodiola rosea (salidroside, etc.) [11-13].

The use of lichens of the genus Cladonia and Cetraria in antidiabetic practice confirms the recipe for lichen bread, in which the primary lichen metabolite, β-polysaccharide lichenin, is used as an additive. Lichen bread can serve as a substitute for standard diabetic bread, during the baking of which crushed lichen powder was added to flour [14, 15]. Chinese medicine is known for using deer cladonia (Cladina rangiferina (L.) Nyl.) And matte red dermatocarpone soup (Dermatocarpon miniatum (L.) at high blood pressure, as well as a diuretic agent [16]. Naked stereoocaulon (Stereocaulon paschale (L.) Hoffm.) Was used to treat diabetes-related inflammation. In vivo model experiments with mice with alloxan-induced diabetes revealed hypoglycemic properties of Cladonia humilis lichen extracts, which consists in increasing insulin secretion and glycogen synthesis (p <0, 05 and p <0.01 respectively respectively), in a decrease in blood glucose level (p <0.05), and the ability of this extract to inhibit gluconeogenesis (p <0.01) and increase the level of carbohydrate tolerance was revealed [17].

Of the other phytocomposites and phyto-sources of bioactive substances effective in the correction of metabolic disorders in T2DM, the Detsky collection is known, which has hypoglycemic activity and is used in the combined prevention and treatment of T2DM against the background of standard hypoglycemic therapy. It includes cinnamon rose hips, common bean leaves, white mulberry leaves, walnut, blackcurrant, medicinal sage, dioica nettle, medicinal herbal grass, creeping thyme, Chinese magnolia vine and sowing straw oats [18].

Known phytocomposition "Praskovya" intended for oral and phytoparotherapy of diabetes mellitus [19], containing (1) a leaf: lingonberries, bearberry, blackcurrant, blackberry; (2) fruits and root: hawthorn blood red, rose hips; (3) grass: white veronica, birdlance, large-leafed wintergreen, medicinal sweet clover, stinging nettle, common cuff, peppermint, common shoot, common wormwood, lanceolate thermopsis, field horsetail, three-parted larch; (4) inflorescences of Hypericum perforatum; (5) weeping willow leaf and bark; (6) flowers: meadow clover, meadowsweet; (7) root: burdock, safflower lefts, common chicory, wheat grass creeping; (8) fruits: common juniper, Siberian mountain ash; (9) an ear of milk ripeness of sowing oats; (10) root and grass: dandelion officinalis, large plantain; (11) inflorescences: primrose large-cup, yarrow; (12) Jerusalem artichoke tubers; (13) Siberian moss.

Also known antidiabetic phytocomposite containing 11.8 wt. %: goat's herb (galega), dandelion roots, white mulberry leaves, high elecampane roots, common lingonberry leaves, common bean fruit leaves, noble laurel leaves, grass of a drooping string, and 5.6 wt. % heart-shaped linden flowers [20], etc.

At the same time, obtaining well-known phytopreparations, the main action of which is aimed at increasing carbohydrate tolerance, lowering the level of glycated hemoglobin, is distinguished by such technological stages in which the entire complex of physiologically active substances is incompletely released. The therapeutic effect of the use of such compositions is not high enough, because phytosilicon-derived biologics obtained by simple mechanical mixing are characterized by low bioavailability and weak bioactivity. Taking these drugs can cause side effects, such as heartburn, allergic reactions, high blood pressure, ketoacidosis.

), основным активным веществом в котором является инулин - до 60% содержания в сухом веществе. Инулин - полифруктозан D-фруктозы, единственный природный полисахарид, состоящий на 95% из фруктозы. Инулин не переваривается пищеварительными ферментами желудочно-кишечного тракта человека. Часть его в кислой среде желудочного сока гидролизуется до коротких фруктозных цепочек - фруктозоолигосахаридов (ФОС), выполняющих функции детоксикации в кишечнике, и отдельных молекул фруктозы, которые проникают в кровеносное русло. Всосавшиеся в кишечнике ФОС и в крови продолжают выполнять детоксикационную функцию, связывая, обезвреживая и облегчая выведение из организма эндо- и экзотоксинов [21, 22]. ФОС утилизируются большинством штаммов бифидобактерий, а также некоторыми культурами лактобактерий. При их употреблении в кишечнике происходит нормализация микробной флоры с увеличением абсорбции из кишечника ионов кальция и магния. Они обладают низкой калорийностью и поэтому могут быть рекомендованы пациентам с сахарным диабетом и ожирением.A more pronounced antidiabetic effect, from known phytocompositions, is possessed by a complex of bioactive substances secreted from Jerusalem artichoke tubers (lat.

), the main active substance in which is inulin - up to 60% of the dry matter content. Inulin is a polyfructosan of D-fructose, the only natural polysaccharide consisting of 95% fructose. Inulin is not digested by the digestive enzymes of the human gastrointestinal tract. Part of it in the acidic environment of gastric juice is hydrolyzed to short fructose chains - fructose oligosaccharides (FOS), which perform the functions of detoxification in the intestine, and individual fructose molecules that penetrate the bloodstream. FOS and blood absorbed in the intestines continue to perform a detoxification function, linking, neutralizing and facilitating the elimination of endo- and exotoxins from the body [21, 22]. FOS are utilized by most strains of bifidobacteria, as well as some cultures of lactobacilli. When they are used in the intestine, the microbial flora normalizes with an increase in the absorption of calcium and magnesium ions from the intestine. They have a low calorie content and therefore can be recommended for patients with diabetes and obesity.

The natural fructose that Inulin consists of is a unique monosaccharide, a dietary sugar that is able to participate in the same metabolic processes as glucose and fully replace it in situations where glucose is not absorbed by cells, i.e. in cases of relative or absolute insulin deficiency. This is also why the dietary and therapeutic value of inulin is very high.

It is known that Jerusalem artichoke is unique in the balance of its trace elements. A high content (in mg / g) was noted: iron - up to 0.12, potassium - up to 2.0, calcium - up to 0.4, silicon - up to 0.08, magnesium - up to 0.3, manganese - up to 0, 45, phosphorus and zinc - up to 5.0. This optimal ratio of trace elements significantly enhances the functional activity of the immune, endocrine, nervous systems of the body, and also improves the clinical indicators of blood. A high content of B vitamins (B ₁ B ₂ and B ₆ ), C, PP, carotenoids, carotene (up to 0.06-0.07 mg / g), organic polyacids: citric, malic, maleic, succinic, fumaric was noted. In combination with vitamin C, they have pronounced antioxidant properties. A relatively high protein content (3.2% per dry matter), represented by 16 amino acids, including the essential ones: valine, isoleucine, leucine, lysine, methionine, threonine, tryptophan, phenylalanine, histidine, arginine (for children) was also noted. According to the data of the Novosibirsk Scientific Research Institute of Clinical Immunology SB RAS, Jerusalem artichoke proteins are similar in structure to the thymus proteins and possess the properties of regulators of maturation and protection of the functional activity of the cells of the immune system. Pectin substances (up to 110 mg / g dry weight) have absorbing, astringent and gelling properties, reduce cholesterol in the body, help improve metabolic processes, normalize intestinal motility, improve peripheral blood circulation, and can absorb and excrete endo- and exotoxins from the body. Therefore, Jerusalem artichoke tubers do not accumulate heavy metals (even when grown in areas with an artificially increased content of 10-15 times), radioactive elements (even when the experimental plots are artificially infected with strontium and cesium isotopes above the background content of 10-20 times the content of these elements in tubers increases only by 10-30%). This explains the fact that Jerusalem artichoke has absolutely no toxic and allergenic effect.

The main thing, with regard to the purpose of the present invention, is that prolonged use of Jerusalem artichoke reduces the level of glucose in the blood, and is an effective means of preventing and stopping metabolic disorders in T2DM. The mechanisms of this are as follows: (1) inulin and fiber, which are not cleaved by hydrochloric acid in the stomach, are capable of excreting a significant amount of dietary glucose and inhibiting its absorption in the blood, which helps to reduce the level of glucose in the blood after eating; (2) FOS bind and remove toxic metabolic products from the body: acetone and other ketone bodies; (3) in the blood, FOS and organic polyoxyacids (malic, fumaric, maleic, citric, succinic, etc.) also perform antioxidant and antitoxic functions, reducing the severity of the disease; (4) FOS are able to integrate into the cell wall, facilitating the passage of glucose into the cell, albeit in relatively small amounts compared to normal; (5) fructose, penetrating into the cells of all organs without the participation of insulin, is able to fully replace glucose in metabolic processes, significantly reducing intracellular glucose deficiency in bioenergy processes. All this leads to a significant and persistent decrease in the concentration of glucose in the blood, which is not accompanied by sharp fluctuations in this indicator during the day. A stable decrease in blood glucose leads to an increase in the production of own insulin by β-cells of the pancreas. The high content of zinc, silicon, and potassium in Jerusalem artichoke, necessary for the synthesis of insulin, also contributes to this. At the same time, the patient's daily requirement for insulin administered as injections is reduced. With regular use of Jerusalem artichoke, there is a slowdown or lack of development of diabetic nephropathy, threatening renal failure; diabetic retinopathy leading to blindness; damage to the vessels of the extremities, ending with gangrene, etc.

At the same time, the antidiabetic activity of the complex of bioactive substances of Jerusalem artichoke can be enhanced by the formation of joint mechanochemically activated compositions with the active substances of reindeer moss, primarily with lichen β-oligosaccharides, due to the ability of the latter, firstly, to increase the level of insulin secretion by pancreatic β-cells . Secondly, increase the bioavailability of FOS formed from inulin in the acidic environment of the stomach. Thirdly, with the mechanical activation of coarsely ground tubers of Jerusalem artichoke, the concentration of FOS increases.

и толокнянки

, образующаяся в процессе их совместной механохимической активации в соотношении 18:1:1 [23] - прототип.Closest to the claimed invention in relation to the effectiveness of the correction of metabolic disturbances in T2DM is a composition consisting of bioactive substances of thalli of the lichens of the genus Cladonia, lingonberry leaves

and bearberry

formed in the process of their joint mechanochemical activation in the ratio of 18: 1: 1 [23] is a prototype.

The technical effect (essence) of the claimed invention consists in the correction of metabolic disorders in T2DM when taking the claimed composition, namely, in lowering the level of glucose and glycated hemoglobin (HbA1c) of the blood, as well as in normalizing lipid metabolism, including atherogenicity, up to the stabilization of these indicators in the upper limit of the norm.

The technical effect (essence) of the claimed invention is achieved due to the fact that they carry out a joint mechanochemical activation of dried and previously roughly ground thalli of the lichen of the genus Cladonia and Jerusalem artichoke tubers in a mass ratio of 9: 1, in the presence of 0.7-0.9 wt. % (by weight of plant material) sodium bicarbonate. This leads, in the absence of solvents, to: (1) the cleavage of part of the β-glycosidic bonds in lichen β-polysaccharides with the formation of β-oligosaccharides (active filler); (2) cleavage of a portion of 1-2 glycosidic bonds in inulin with the formation of FOS and fructose; (3) the formation of supramolecular complexes of the “active filler” with FOS, due to which their bioavailability is increased 2.0–2.5 times; (4) lichen β-oligosaccharides and FOS in the internal environments of the body play the role of their detoxicant; (5) fructose, penetrating into the cells of all organs without the participation of insulin, completely replaces glucose in metabolic processes, significantly reducing energy cell hunger, and FOS, integrating into the cell wall, facilitate insulin-independent passage into the cell and glucose itself.

The invention can be implemented as follows.

A mixture of powders crushed to a particle size of 1-3 mm thalli of the lichens of the genus Cladonia and Jerusalem artichoke tubers in a mass ratio of 9: 1 is subjected to joint mechanochemical activation in the presence of 0.7-0.9 wt. % (by weight of plant materials) of sodium bicarbonate in centrifugal planetary mill-activators of continuous industrial type (for example, CEM 7-80) or discrete, laboratory type (AGO-2) under the following conditions: rotation speed> 1000 rpm and grinding acceleration tel g> 30. The resulting ultrafine powder (particle size 20-60 nm) is encapsulated in hard gelatin capsules with a dosage of 400 ± 20 mg in one capsule for per os administration.

The resulting composition is characterized by the following composition of the main active substances (table. 1).

Confirmation of biological activity

The indication for prescribing the drug was a verified diagnosis of type 2 diabetes mellitus with metabolic disturbances in the setting of tablet glucose-lowering therapy. Correction preceding hypoglycemic therapy was not carried out. When examining patients, characteristic instrumental laboratory criteria indicating metabolic abnormalities were: (1) hyperglycemia (fasting venous plasma glucose> 6.1 mmol / L, HBa1c>6.5%); (2) dyslipidemia (OXC> 4.5 mmol / L, LDL> 2.6 mmol / L, HDL <1.0 mmol / L (male) HDL <1.2 mmol / L (female), TG> 1, 7 mmol / l); (3) arterial hypertension (blood pressure> 130/80 mmHg); (4) overweight and obesity (BMI> 25 kg / m ² ).

The study program included a comprehensive treatment and examination of a sample of 150 patients: group No. 1 (control) - 50 patients who received a placebo; group No. 2 (comparisons) - 50 patients who received the biological product of the prototype; group No. 3 - 50 patients receiving the claimed composition. The appropriate drug was prescribed in addition to the standard tablet hypoglycemic therapy and was taken per os 1 capsule 3 times a day, the course of administration was 3 and 6 months.

Clinical and laboratory control to assess the effectiveness of the claimed composition, compared with the prototype, was carried out after 3 and 6 months. It included: general clinical and instrumental examination, biochemical and clinical blood tests, determination of the content of HBA1c (glycated hemoglobin). All patients participating in the study received informed consent. To process the results, statistical packages were used - Stat Soft Statistica v.6.0, SPSS 9.0.

Dynamic observation showed that biological preparations of the claimed composition and prototype, as well as placebo, patients tolerated well, adverse events, side effects were not observed. The results are shown in table 2.

* ⁾ p <0.05

Control of glycated hemoglobin level showed a decrease in the level in all study groups. However, a statistically significant decrease was noted only in group No. 3, who took the drug for 6 months. Fasting venous blood glucose also showed a statistically significant decrease in group No. 3 already at the 3rd month of the study, and by the 6th month in groups No. 2 and 3. Some improvement in the comparison group receiving placebo can be explained by more frequent patient self-monitoring. lifestyle modification. Significant significant improvement in lipid metabolism was revealed in group No. 2 and especially in group No. 3, which was expressed in a decrease in the atherogenic coefficient primarily due to an increase in the level of high density lipoproteins (HDL). There was also a decrease in the content of low density lipoproteins (LDL), and in group No. 3 by the 6th month of the experiment and very low density lipoproteins (VLDL).

Monitoring the dynamics of blood pressure and body mass index did not reveal significantly significant changes in all three groups during the study period.

Thus, the claimed composition has a significantly 11-23% more significant effect in relation to the correction of carbohydrate-lipid metabolic disorders in T2DM, compared with the prototype, which is manifested in a decrease in the level of glycated hemoglobin (HbA1c) and glucose in the blood of patients with T2DM, an increase in the atherogenic coefficient due primarily to an increase in HDL content, as well as to a decrease in the level of LDL and VLDL in the regime of a steady therapeutic effect.

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Claims (1)

A solid-phase composition having the property of correcting metabolic disorders in type 2 diabetes mellitus, which is an ultrafine powder mechanochemically activated in the presence of 0.7-0.9 wt. % by weight of plant material of sodium bicarbonate of a mixture of thalli of the lichens of the genus Cladonia and Jerusalem artichoke tubers (Helidnthus tuberosus) in a mass ratio of 9: 1 and characterized in that it contains lichen β-oligosaccharides at a concentration of 5.2 ± 0.4 mg / g, fructozooligosaccharides - 30.0 ± 3.0 mg / g, fructose - 12.0 ± 1.1 mg / g.