WO2021180293A1 - A composition for normalizing blood lipid level - Google Patents
A composition for normalizing blood lipid level Download PDFInfo
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- WO2021180293A1 WO2021180293A1 PCT/EA2021/000001 EA2021000001W WO2021180293A1 WO 2021180293 A1 WO2021180293 A1 WO 2021180293A1 EA 2021000001 W EA2021000001 W EA 2021000001W WO 2021180293 A1 WO2021180293 A1 WO 2021180293A1
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Definitions
- the invention relates to medicine and concerns a composition suitable for normalizing blood lipid level, including low-density lipoproteins, cholesterol and triglycerides, a composition containing glycyrrhizic acid in the form of pharmaceutically acceptable salt combined with effective amounts of lignin that provide for a therapeutically effective daily dose of the composition.
- This present invention also relates to the use of the said composition for the prevention of diseases mediated by an increased content of lipids in blood, including low-density lipoproteins, cholesterol, triglycerides.
- diseases include hypercholesterolemia, the onset and development of atherosclerosis, and lipid metabolism disorders.
- the invention can also be embodied as a biologically active food supplement that contains the said composition and various additives.
- a product for effective therapeutic and prophylactic dietary nutrition, which contains the specified composition and acceptable additives.
- lipid metabolism in the human body are known to play a key role in the development of cardiovascular diseases (CVD).
- CVD cardiovascular diseases
- Disorders of lipid metabolism are characterized by pathological changes in the levels of cholesterol (CS), low and high density lipoproteins (LDL, HDL), triglycerides (TG), blood apolipoprotems.
- CS cholesterol
- LDL low and high density lipoproteins
- TG triglycerides
- Cholesterol is an indispensable and constitutive element of normal body functioning. It is required for the synthesis of sex hormones and proper functioning of the nervous system, takes part in the digestion process and antioxidant mechanisms [Ya. Kolman, K.G. Rem. Visual biochemistry. Moscow: Mir, 2000. 470 p.]. Cholesterol is a component of all cell membranes, without it a full-quality life is impossible.
- lipid metabolism disorders are caused by many factors, including heredity, diet, sedentary lifestyle, overweight, excessive alcohol consumption, smoking, concomitant diseases, etc.
- the correction of lipid metabolism is one of the main methods for the prevention and treatment of CVD.
- the currently used drug products are focused on normalizing CS and TG levels in blood using various action mechanisms, such as statins, bile acid sequestrants, cholesterol-binding agents, PCSK9 inhibitors, fibrates, etc.
- Correction of diet and change of lifestyle is an integral part of CVD prevention and treatment, and greatly contributes to the improvement of treatment efficacy and rise in the standard of patients’ living.
- a common approach is the introduction of specialized food components into the daily diet, including biologically active additives, therapeutic or prophylactic dietary food products that have a lipid-lowering effect.
- the object of the present invention was to create a new composition for normalizing lipid levels in blood, containing a combination of lignin and glycyrrhizic acid and/or its derivatives, having high stability, without limitations on use in all age groups and specific groups of patients, due to the synergistic effect of effective amounts of active components present in the composition.
- the composition can be used as an oral dosage form, and can also be included in the composition of a biologically active food supplement, as well as in the composition of medical or preventive dietary food products.
- lignin in particular, hydrolytic lignin, which is a natural polymer forming part of plant cells and exhibiting its unique adsorption and antioxidant properties.
- hydrolytic lignin can represent a natural lignocellulose complex containing from 55 to 85 wt% of lignin and 15-45 wt% of cellulose.
- the properties of lignin are conditioned by the presence of a developed porous structure dominated by pores with a radius of more than 50 nm (up to 90% of the total porosimetric volume). However, the effective radii of pores in the preparation are in the range of 100-1000 nm, which characterizes lignin as a macroporous sorbent.
- the variety of polar and non-polar functional groups increases the sorption activity of lignin.
- the porous structure and functional groups are responsible for the ability of lignin to adsorb hydrophilic and hydrophobic compounds, as well as microorganisms, using the mechanisms of chemisorption, adsorption, and absorption [ ⁇ .A. ⁇ . ⁇ ntended recipients convinced tone torque ⁇ Mé ⁇ . 1991.].
- the second component of the claimed composition is glycyrrhizic acid (GA) and/or its acceptable salts, which are one of the main components of the licorice root ( Glycyrrhizaglabra ).
- GA glycyrrhizic acid
- Glycyrrhizaglabra The glycyrrhizic acid and/or its derivatives are included in the claimed composition due to their hypolipidemic and anti-inflammatory activity, as well as the hepatoprotective properties of GA, which prevent apoptosis of liver cells.
- the hypolipidemic effect of GA is based on the inhibition of the activity of phospholipase A2 (ensures the cleavage of fatty acid residues from phospholipids) and activation of bile acid synthesis, the precursor of which is cholesterol [Inoue N., Saito N., KoshiharaY., MurotaS. // Chem. Pharm. Bull. 1986. V. 34(2). P. 897-901; Yano Sh., Harada M., Watanabe K., Nakamura K., Hatakeyama Y., Shibata Sh., Takahashi K, Mori T., HirabayashiK., Takeda M., Nagata N. // Chem. Pharm. Bull. 1989. V. 37(9). P. 2500-2504; Farina C, Pinza M., PifferiG. // IL Farmaco. 1998. V. 53. P. 22-32].
- GA exerts anti-inflammatory and anti-apoptotic effects by inhibiting TNF-a and caspase-3
- Patent RU 2308947 Cl describes a drug with a hypolipidemic effect, comprising a molecular complex of simvastatin with b-glycyrrhizic acid at a molar ratio of simvastatin: b- glycyrrhizic acid of l:(l-4).
- the patent document discloses a hypolipidemic property of a composition containing b-glyeyrrhizic acid along with the active component of simvastatin.
- Patent RU 2396079 Cl describes a drug with a hypolipidemic effect, comprising a molecular complex of atorvastatin with b-glycyrrhizic acid at a molar ratio of atorvastatin ⁇ - glycyrrhizic acid of 1 :(l-4).
- Patent RXJ 2683641 C2 describes a pharmaceutical composition for the treatment of hyperlipidemia, containing a mixture of: (a) a glycyrrhizinic derivative selected from the group consisting of glycyrrhizie acid and its pharmaceutically acceptable salt; (b) a lipidlowering drag, wherein the lipid-lowering drug is a statin selected from the group comprising atorvastatin, lovastatin, rosuvastatin, simvastatin, pravastatin, pitavastatin, fluvastatin, or a pharmaceutical salt thereof, or a mixture thereof.
- a statin selected from the group comprising atorvastatin, lovastatin, rosuvastatin, simvastatin, pravastatin, pitavastatin, fluvastatin, or a pharmaceutical salt thereof, or a mixture thereof.
- Patent RU 2549966 C2 describes a composition comprising: a) at least one phospholipid; b) at least one glycyrrhizic acid; or c) salt of glycyrrhizie acid for the manufacture of a medicinal product for the remo val of subcutaneous fat accumulations.
- Application US20190124958 A1 describes an antimicrobial composition of hydrolysis lignin for inhibiting the growth of microorganisms in food, which contains enriched lignin with a molecular weight of >10,000 daltons; carbohydrates; and water.
- Patent RU 2623876 C2 (the closest analogue) describes a pharmaceutical composition for the treatment of hyperlipidemia, comprising a mixture of a glycyrrhizin derivative selected from the group consisting of glycyrrhizie acid and its pharmaceutically acceptable salt; and a hypolipidemic drug, wherein the lipid-lowering agent is a statin selected from the group comprising atorvastatin, lovastatin, rosuvastatin, simvastatin, pravastatin, pitavastatin, fluvastatin, a pharmaceutically acceptable salt thereof or a mixture thereof, and auxiliary substances.
- the patent document discloses a hypolipidic property of a composition containing b-glycyrrhizic acid along with an active statin component.
- the disadvantage of the above composition for the treatment of hyperlipidemia is the use of a lipid-lowering agent containing statin derivatives, the long-term use of which causes serious side effects.
- the object of the present invention was to create a new composition without side effects suitable for normalizing the level of blood lipids, including low density lipoproteins, cholesterol and triglycerides, which can be used in a biologically active food supplement or a product for therapeutic and/or prophylactic dietary nutrition in combination with various additional components that can be selected, for example, from prebiotics.
- the problem was being solved by means of the qualitative and quantitative composition of the components representing hydrolysis lignin and glycyrrhizic acid in the form of its pharmaceutically acceptable salt in the claimed effective amounts.
- the invention relates to a composition based on a natural lignoeellulose complex, a source of dietary fiber exhibiting antioxidant and adsorption properties and a natural component of glycyrrhizic acid, which has hepatoprotective activity when used together due to multidirectional action.
- the claimed composition has an unexpected synergistic effect aimed at normalizing the levels of blood lipids, including low-density lipoproteins, cholesterol and triglycerides.
- the object of the present invention was to create a new composition for normalizing the level of blood lipids, comprising a composition of a lignoeellulose complex and glycyrrhizic acid and/or its derivatives, which has high stability, without limitations on use in all age groups and specific groups of patients due to the synergistic effect of the active components of the composition, as an oral dosage form, as a biologically active food supplement, as well as a therapeutic or prophylactic dietary food product.
- One of the embodiments of the invention disclosed herein is an oral dosage form of tablets, powder, gel or suspension and other dosage forms containing a lignoeellulose complex and glycyrrhizic acid, including acceptable salts thereof.
- a dietary supplement which is used for the prevention of hypercholesterolemia, the onset and development of atherosclerosis, lipid metabolism disorders, dyslipidemia, which contains a lignoeellulose complex and glycyrrhizic acid, including acceptable salts thereof.
- a product for therapeutic nutrition which is used for the prevention of hypercholesterolemia, the onset and development of atherosclerosis, lipid metabolism disorders, dyslipidemia, which contains a lignocellulose complex and glycyrrhizic acid, including its acceptable salts in combination with various acceptable additives.
- the components in the composition have different mechanisms of action on blood lipids, in particular, due to the normalization of liver and intestinal function, which in the aggregate has unexpectedly led to the possibility to effectively correct the observed disorders.
- the invention relates to a composition in the form of an oral dosage form for normalizing the level of lipids in blood, including low-density lipoproteins, cholesterol and triglycerides, which contains a hydrolytic lignin, in particular, a lignocellulose complex in the amount of 84.5 to 99.9 wt% and glycyrrhizic acid in the form of an acceptable salt in the amount of 0.1 to 15.5 wt%, wherein the weight of the specified composition provides for an effective dosage of 10 to 5000 mg per day.
- the most preferred embodiment of the invention is that the weight of the said composition provides for an effective dosage of 50 to 500 mg per day.
- the invention relates to using the specified composition in the form of an oral dosage form in effective amounts for the prevention of the onset and development of atherosclerosis, lipid metabolism disorders, hypercholesterolemia, and dyslipidemia.
- a biologically active food supplement is also provided, containing the specified composition and various acceptable additives.
- the mass of the composition provides for a dosage of 10 to 5,000 rag per day.
- the most preferred embodiment of the invention is that the weight of the said composition provides for an effective dosage of 50 to 500 mg per day.
- the invention relates to using a dietary supplement for the prevention of the onset and development of atherosclerosis, lipid metabolism disorders, hypercholesterolemia, and dyslipidemia.
- a product is provided for effective therapeutic and prophylactic dietary nutrition, which contains the specified composition and acceptable additives.
- the invention also relates to using a product for therapeutic and prophylactic dietary nutrition, which contains the specified composition in effective amounts for the treatment and acceptable additives for the prevention of lipid metabolism disorders, hypercholesterolemia, and dyslipidemia.
- the mass of the composition provides for a dosage of 10 to 5,000 mg per day.
- the most preferred embodiment of the invention is that the weight of the said composition provides for an effective dosage of 50 to 500 mg per day.
- the ratio of the components included in the above composition helps reduce (normalize) the level of total cholesterol, LDL cholesterol, TG in the blood of experimental animals, slows down the progression of dyslipidemia during simulation process. The most significant effects of therapy begin to appear 60 days after starting the administration of the combination.
- GA added to the composition implements its own mechanism of action aimed at normalizing lipid levels by influencing cholesterol synthesis, reducing general inflammation in liver tissues and restoring its function.
- the inclusion of the lignocellulose complex makes it possible to adsorb fat and bile acids in the intestine, preventing their absorption into the bloodstream.
- the lignocellulose complex apparently reduces lipid peroxidation in intestinal cells, which leads to a decrease in the permeability of the intestinal wall for bacterial lipopolysaccharides and toxins that induce liver inflammatory reactions.
- the effect of the claimed composition intended for normalizing the lipid level in blood consists in achieving an unexpected synergistic effect due to the implementation of the mechanism of simultaneous action on the functions of the liver and intestines from the side of glycyrrhizic acid in the claimed effective amounts in combination with pronounced adsorption and antioxidant activity of hydrolysis lignin in the form of a ligninocellulose complex in the stated effective amounts.
- the adsorption activity of the lignocellulose complex in relation to bile salts A lignocellulose complex (manufactured by AVVA RUS JSC) was studied as a test sorbent. As tested sorbates, we studied sodium salt of cholic acid (primary bile acid), sodium salt of ehenodeoxycholic acid (primary bile acid), sodium salt of deoxycholic acid (secondary bile acid), since these acids constitute the main pool of bile acids in the human body.
- lignocellulose complex 500 mg was transferred into a flat-bottomed flask, then a phosphate buffer solution, pH 7.0, was poured in and incubated on a shaker at 37 °C for 2 hours to completely wet the lignocellulose complex. Then, solutions of sodium bile salts were added (the final concentration of 2 mmol/L), The total volume of the mixture was 50 mL. The mixtures were incubated on a shaker for 4 hours at a temperature of 37 °C, the supernatant was obtained after centrifugation, and the residual concentration of bile salts was investigated using the method of gas-liquid chromatography.
- Solutions of the lignocellulose complex and ascorbic acid were prepared in dimethyl sulfoxide. 3 mL of 0.02 M ammonium molybdate solution, 1 mL of 3% hydrogen peroxide solution, and 0.1 gram of sulfuric acid equivalent were transferred to a 25 mL volumetric flask, 0.1 or 0.2 mL of a 1% solution of the test substance were added, and the solution was diluted to volume with water. The solution was kept for 20 min at a temperature of 25 °C.
- the substance concentrations of 100, 1000, 10000 pg/mL were studied.
- the optical density of the resulting solutions was measured at a wavelength of 410 nm using an EpochBiotek plate reader.
- Antioxidant (antiperoxide) activity of the lignocellulose complex versus ascorbic acid the decrease in the concentration of peroxide (assessed by optical density) versus the control on the concentration of the lignocellulose complex: with an increase in the concentration, a decrease in the residual peroxide in the reaction medium was observed, that is, the interaction of the substance with peroxide increases.
- the stability of combinations of the lignocellulose complex and glycyrrhizic acid, in particular, ammonium glycyrrhizinate, during storage was assessed by changes in the adsorption capacity of the lignocellulose complex, the content of ammonium glycyrrhizinate in the mixture, and microbiological characteristics.
- the checkpoints were 1 month, 3 months and 6 months.
- the combinations were stored in a climatic chamber at a temperature of 25 °C and a relative humidity of 60%.
- AGC ammonium glycyrrhizinate
- LCC lignocellulose complex
- the content of ammonium glycyrrhizinate in the mixture was determined by HPLC.
- the test solution was prepared by introducing an accurately weighed portion of the AGC mixture diluted with an aqueous solution of acetonitrile (1:1), followed by sonication for 10 minutes.
- the resulting AGC suspension was thoroughly mixed, cooled to room temperature, and passed through a 0.45 pm pore size membrane filter. The measurements were made at a wavelength of 254 nm.
- a solution prepared with a standard sample of ammonium glycyrrhizinate manufactured by Sigma- Aldrich
- the result of measuring the content of ammonium glycyrrhizinate was expressed as a % of the calculated value for each mixture of LCC + AGC.
- a model of hypercholesterolemia, lipid metabolism disorders and atherosclerosis in California rabbits was used as a test system to assess the specific pharmacological activity of combinations of the lignoceilulose complex and ammonium glycyrrhizinate in various mass ratios versus monotherapy with the lignoceilulose complex and ammonium glycyrrhizinate.
- the age of animals at the beginning of the study was 8 weeks, the weight varied in the range of 2.5-3.0 kg, there were 4 animals in each group.
- the model of hypercholesterolemia and atherosclerosis was induced as follows:
- Exogenous cholesterol was administered orally on a daily basis to form the state of hypercholesterolemia in animals, leading to the development of dyslipoproteinemia.
- Vitamin D 3 (cholecalciferol) was administered to animals from time to time in order to stimulate the occurrence of atherocalcinosis, which aggravates the development of atherosclerosis. Metabolites of vitamin D 3 cause the disruption of the integrity of the arterial wall and provoke necrosis of smooth muscle arterial fibers (media) to a certain extent, thus increasing the integration of lipid particles into the arterial wall.
- Cholesterol was dissolved in superheated vegetable oil and administered at a dosage of 0.3 g/kg of animal weight, once a day, intragastrically through a tube. The duration of cholesterol administration was 90 days. After 30 days from the beginning of cholesterol administration, vitamin D3 (cholecalciferol) was added to the diet of animals at a dose of 0.256 mL/kg to enhance aortic lipidosis. Cholecalciferol was administered intragastrically from day 31 to day 60 of the experiment. During the same period, in order to enhance atherosclerotic changes in the aorta, the animals were injected with adrenaline at a dose of 0.04 mg per 1 kg of body weight intravenously every 5 days.
- compositions containing ammonium glycyrrhizinate (AGC) and a lignocellulose complex (LCC) were subjected to study:
- the parameters of the blood lipid spectrum were assessed on the A-25 RandomAccess open-type biochemical analyzer (Spain) using reagents manufactured by BioSystems (Spain).
- FOS fluetooligosaccharides
- GOS galactooligosaceharides
- lactitol used in an amount from 0.5 to 3,000 mg.
- LCC and AGC have a significant effect on LDL cholesterol, total cholesterol, and TG.
- LH at a dose of 5,000 mg reduces TG levels significantly more pronouncedly than AGC at a dose of 50 mg.
- AI (cholesterol - HDL cholesterol) / HDL cholesterol).
- the combination of AGC 50 mg + LCC 5,000 mg caused the most pronounced decrease in cholesterol, LDL, TG and IA versus other groups, except for the intact group.
- the AGC 30 mg + LCC 2,600 mg group reduced the TG level to a degree similar to that of the AGC 50 mg + LCC 5,000 mg group, and their indicators did not differ significantly.
- the indicator of the TG level in the AGC 50 mg + LCC 5,000 mg and AGC 50 mg + LCC 5,000 mg + prebiotic groups was significantly lower than in other groups.
- the AGC 200 mg + LCC 1,090 mg and AGC 30 mg + LCC 1,000 mg groups reduced LDL-C and CS levels significantly more pronouncedly versus the pathology + LCC 5,000 mg and pathology + AGC 50 mg groups.
- groups can be divided according to the strength of influence on the normalization of lipid metabolism as follows, from the most effective group to the least effective one:
- the introduced scoring system was used, namely:
- the degree of atherosclerotic damage to the aortic wall was assessed according to the relevant stages of atherogenesis (no signs of pathology - 0 points; pre-lipid stage - 1 point, lipoidosis - 2 points, calcification - 3 points), to identify the early stages of atherosclerosis - pre-lipid, the toluidine blue dye was used, which, due to the metachromasia reaction, allows visualizing dystrophic changes in the connective tissue; to isolate accumulations of lipids in the tissues, the oil red O dye was used, the maximum score was 5 (when simultaneously observing calcification and lipoidosis);
- the degree of atherosclerotic damage to the heart valves was assessed according to the same criteria as the degree of damage to the aorta.
- Prebiotics are selected from FQS, GOS, lactitol and used in an amount from 0.5 to 3,000 mg.
- the combination of AGC 50 mg + LCC 5,000 mg has the most pronounced effect aimed at reducing the negative effect of atherogenic factors on the studied organs of rabbits with induced dyslipidemia.
- the effect of AGC at a dose of 50 mg was mainly associated with a significant decrease in the severity of pathological changes in the structure of the liver in rabbits.
- the ligninocellulose complex at a dose of 5,000 mg had a significant positive effect (a decrease in the severity of pathological changes) on all examined organs versus the pathology control group.
- Group AGC 30 mg + LCC 2,600 mg was close in its therapeutic and prophylactic activity to the groups that received the combination of AGC 50 mg + LCC 5,000 mg and
- AGC 50 mg + LCC 5,000 mg + prebiotics however, it was significantly inferior to them in the effect observed in the aorta and li ver of rabbits.
- the group receiving the combination of AGC 30 mg + LCC 1000 mg showed tire least activity in terms of prevention and elimination of pathological changes in the examined organs.
- results obtained indicate the presence of a synergistic effect when using a combination containing a lignocellulose complex in the amount of 84.5 to 99.9 wt% and glycyrrhizic acid in the form of acceptable salt in the amount of 0,1 to 15.5 wt%.
- hypolipidemic, hepatoprotective and other effects revealed were less pronounced than in the case of using the composition.
- Synergism was provided by means of the combined (joint) implementation of various action mechanisms characteristic of each component of the combination.
- AGC powder in the amount of 10 to 200 mg and a lignocellulose complex in the amount of 50 to 5,000 mg, they were ground to a powdery condition using laboratory glassware for grinding solid substances.
- ACG tablet 10 to 200 mg and a 50 to 5,000 mg lignocellulose complex they were ground to a powdery condition using laboratory glassware for grinding solid substances, then povidone K17 (PVP) from 1 mg to 65 mg; calcium stearate from 1 mg to 10 mg; croscarmellose sodium from 1 mg to 10 mg were added to the resulting mixture and tableted using special equipment.
- PVP povidone K17
- capsules of AGA from 10 to 200 mg and a lignocellulose complex from 50 to 5,000 mg they were ground to a powdery condition using laboratory glassware for grinding solid substances, and auxiliary substances were added, such as microcrystalline cellulose from 0.5 mg to 80 mg, low molecular weight povidone from 0, 5 mg to 10 mg, potato starch from 0.5 mg to 10 mg, magnesium stearate from 0.5 mg to 5 mg, lactose monohydrate from 0.5 mg to 175 mg.
- auxiliary substances such as microcrystalline cellulose from 0.5 mg to 80 mg, low molecular weight povidone from 0, 5 mg to 10 mg, potato starch from 0.5 mg to 10 mg, magnesium stearate from 0.5 mg to 5 mg, lactose monohydrate from 0.5 mg to 175 mg.
- the resulting mixture was encapsulated using special equipment.
- a biologically active additive for example, in the form of a bar, AGC from 10 to 200 mg and a lignocellulose complex from 50 to 5,000 mg were ground to a powdery condition using laboratory glassware for grinding solids, then fruit puree or berry puree from 1 mg to 10,000 mg, inulin from 1 mg to 8,000 mg, beta-glucan from 1 mg to 5,000 mg, an additional source of dietary fiber, for example, oligoffuctose syrup from 1 mg to 2,000 mg, a source of vitamins to support the immune system (vitamin E* ascorbic acid) from 1 mg up to 2,500 mg, potassium sorbate from 1 mg to 1,000 mg, stabilizer from 1 mg to 1,000 mg, flavoring agent from 1 mg to 1,000 mg, baking powder from 1 mg to 1,000 mg were added, and the necessary shape was given to the product using special equipment.
- vitamins to support the immune system vitamin E* ascorbic acid
- potassium sorbate from 1 mg to 1,000 mg
- stabilizer from 1 mg to 1,000 mg
- flavoring agent from 1 mg to 1,000 mg
- AGC from 10 to 200 mg and a lignocellulose complex from 50 to 5,000 mg were ground to a powdery state using laboratory glassware for grinding solid substances, then fruit puree or berry puree from 1 mg to 10,000 mg, an additional source of dietary fiber, ixiulin from 1 mg to 8,000 mg, beta-glucan from 1 mg to 5,000 mg, a source of vitamins to support the immune system (vitamin E, ascorbic acid) from 1 mg to 2,500 mg, potassium sorbate from 1 mg to 1,000 mg, stabilizer from 1 mg to 1,000 mg, flavoring agent from 1 mg to 1,000 mg, baking powder from 1 mg to 1,000 mg were added.
- Vitamin E ascorbic acid
- potassium sorbate from 1 mg to 1,000 mg
- stabilizer from 1 mg to 1,000 mg
- flavoring agent from 1 mg to 1,000 mg
- baking powder from 1 mg to 1,000 mg were added.
- the necessary shape was provided to the product using special equipment.
- Male outbred rats were used as a test system to determine the effect of the combination of AGC and LCC, including when combined with prebiotics, on the functioning of the gastrointestinal tract. Healthy animals aged 6-7 weeks were used.
- the studied combinations were administered to animals intragastrically in the form of a suspension in 1% starch solution. Animals of the intact group received only starch solution. The administration was carried out for 14 days. The animals were kept individually. During the study, the number of bowel movements per day was studied (defecations were counted every 2 hours during the day and in the morning of the next day).
- Table 6 shows measurement results of the number of boluses per day in animals of different groups.
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Abstract
The invention relates to a composition suitable for normalizing the lipid level in blood, including low-density lipoproteins, cholesterol and triglycerides, comprising glycyrrhizic acid in the form of its pharmaceutically acceptable salt in combination with hydrolysis lignin in effective amounts that provide for a therapeutically effective daily dose of the composition, and also to a dietary supplement and a product for therapeutic and preventive dietary nutrition. The effect consists in achieving an unexpected synergistic effect by implementing the mechanism of simultaneous action on the functions of the liver and intestines from the side of glycyrrhizic acid in the claimed effective amounts in combination with the pronounced adsorption and antioxidant activity of hydrolytic lignin in the form of a ligninocellulose complex in the claimed effective amounts.
Description
A COMPOSITION FOR NORMALIZING BLOOD LIPID LEVEL
Description
The invention relates to medicine and concerns a composition suitable for normalizing blood lipid level, including low-density lipoproteins, cholesterol and triglycerides, a composition containing glycyrrhizic acid in the form of pharmaceutically acceptable salt combined with effective amounts of lignin that provide for a therapeutically effective daily dose of the composition.
This present invention also relates to the use of the said composition for the prevention of diseases mediated by an increased content of lipids in blood, including low-density lipoproteins, cholesterol, triglycerides. Such diseases include hypercholesterolemia, the onset and development of atherosclerosis, and lipid metabolism disorders.
The invention can also be embodied as a biologically active food supplement that contains the said composition and various additives.
In yet another embodiment of the invention, a product is provided for effective therapeutic and prophylactic dietary nutrition, which contains the specified composition and acceptable additives.
Background
Disorders of lipid metabolism in the human body are known to play a key role in the development of cardiovascular diseases (CVD). Disorders of lipid metabolism are characterized by pathological changes in the levels of cholesterol (CS), low and high density lipoproteins (LDL, HDL), triglycerides (TG), blood apolipoprotems. Cholesterol is an indispensable and constitutive element of normal body functioning. It is required for the synthesis of sex hormones and proper functioning of the nervous system, takes part in the digestion process and antioxidant mechanisms [Ya. Kolman, K.G. Rem. Visual biochemistry. Moscow: Mir, 2000. 470 p.]. Cholesterol is a component of all cell membranes, without it a full-quality life is impossible.
However, excess cholesterol content in blood is one of the main risk factors for the development of complications of cardiovascular diseases and premature death. Apart from high-density lipoproteins that mobilize cholesterol from tissues (including from the walls of blood vessels), this is conditioned by the presence of low and very low density lipoproteins in blood, which transfer cholesterol to peripheral tissues, thus contributing to the formation of atherosclerotic plaques on the walls of blood vessels, and the development of atherosclerosis.
Pathological changes in the structure and functioning of various organs and tissues caused by lipid metabolism disorders and its consequences, including vascular atherosclerosis, are one of the main causes of high CVD mortality. A direct relationship has been established between an increase in CS levels, especially DDL cholesterol, and the risk of CVD and death. Relationships have also been observed between increased TG levels combined with non-HDL cholesterol and the risk of atherosclerosis.
Disorders in lipid metabolism are caused by many factors, including heredity, diet, sedentary lifestyle, overweight, excessive alcohol consumption, smoking, concomitant diseases, etc.
The correction of lipid metabolism is one of the main methods for the prevention and treatment of CVD. The currently used drug products are focused on normalizing CS and TG levels in blood using various action mechanisms, such as statins, bile acid sequestrants, cholesterol-binding agents, PCSK9 inhibitors, fibrates, etc.
Correction of diet and change of lifestyle is an integral part of CVD prevention and treatment, and greatly contributes to the improvement of treatment efficacy and rise in the standard of patients’ living. A common approach is the introduction of specialized food components into the daily diet, including biologically active additives, therapeutic or prophylactic dietary food products that have a lipid-lowering effect.
Thus, the object of the present invention was to create a new composition for normalizing lipid levels in blood, containing a combination of lignin and glycyrrhizic acid and/or its derivatives, having high stability, without limitations on use in all age groups and specific groups of patients, due to the synergistic effect of effective amounts of active
components present in the composition. The composition can be used as an oral dosage form, and can also be included in the composition of a biologically active food supplement, as well as in the composition of medical or preventive dietary food products.
One of the components included in the claimed composition is lignin, in particular, hydrolytic lignin, which is a natural polymer forming part of plant cells and exhibiting its unique adsorption and antioxidant properties.
In one embodiment of the invention, hydrolytic lignin can represent a natural lignocellulose complex containing from 55 to 85 wt% of lignin and 15-45 wt% of cellulose.
The properties of lignin are conditioned by the presence of a developed porous structure dominated by pores with a radius of more than 50 nm (up to 90% of the total porosimetric volume). However, the effective radii of pores in the preparation are in the range of 100-1000 nm, which characterizes lignin as a macroporous sorbent. The variety of polar and non-polar functional groups increases the sorption activity of lignin. The porous structure and functional groups are responsible for the ability of lignin to adsorb hydrophilic and hydrophobic compounds, as well as microorganisms, using the mechanisms of chemisorption, adsorption, and absorption [Н.A. Б. Энтеросорбция. 1991.]. For lignin and preparations based on it, the ability to sorb organic molecules of protein and lipopolysaccharide nature was also shown, which makes it possible to use it for the sorption of microbial toxins and toxic substances of endogenous origin, average weight molecules, allergens and xenobiotics. [Leskinen T. et al. Adsorption of Proteins on Colloidal Lignin Particles for Advanced Biomaterials. // Biomacromolecules. 2017. Vol. 18, N° 9. p. 2767- 2776][Смирнова О.И. Фармакологические свойства энтероката. Санкт-Петербургская гос. академии ветеринарной медицины , 2007] [Решетнико В.И. Оценка адсорбционной способности энтеросорбентов и их лекарственных форм // Химико-терапевтический журнал. 2003. Vol. 37, N° 5. P. 28-32]. The sorption activity of LH in relation to heavy metals, radioactive isotopes, ammonia, divalent cations, etc., is also known [rlsnet.ru - Hydrolytic lignin, Electronicresource] .
The second component of the claimed composition is glycyrrhizic acid (GA) and/or its acceptable salts, which are one of the main components of the licorice root ( Glycyrrhizaglabra ). The glycyrrhizic acid and/or its derivatives are included in the claimed
composition due to their hypolipidemic and anti-inflammatory activity, as well as the hepatoprotective properties of GA, which prevent apoptosis of liver cells.
The hypolipidemic effect of GA is based on the inhibition of the activity of phospholipase A2 (ensures the cleavage of fatty acid residues from phospholipids) and activation of bile acid synthesis, the precursor of which is cholesterol [Inoue N., Saito N., KoshiharaY., MurotaS. // Chem. Pharm. Bull. 1986. V. 34(2). P. 897-901; Yano Sh., Harada M., Watanabe K., Nakamura K., Hatakeyama Y., Shibata Sh., Takahashi K, Mori T., HirabayashiK., Takeda M., Nagata N. // Chem. Pharm. Bull. 1989. V. 37(9). P. 2500-2504; Farina C, Pinza M., PifferiG. // IL Farmaco. 1998. V. 53. P. 22-32].
GA exerts anti-inflammatory and anti-apoptotic effects by inhibiting TNF-a and caspase-3 [N. F EI-Tahawy, A. H. Ali, S. R. Saied, and Z. A. Wahab, «Effect of glycyrrhizin on lipopolysaccharide/D-galactosamine-induced acute hepatitis in albino rats: a histological and immunohistochemical study», The Egyptian Journal of Histology, vol. 34, no. 3, pp. 518— 527, 2011], It significantly inhibits the release of cytochrome C from mitochondria into the cytoplasm, and exerts myeloperoxidase activity and translocation of nuclear factor-B (NF-B) into the nucleus, which may contribute to the regeneration of the liver damage [B. Tang, H. Qiao, F. Meng, and X. Sun, «Glycyrrhizin attenuates endotoxin-induced acute liver injury after partial hepatectemy in rats», Brazilian Journal of Medical and Biological Research, vol. 40, no. 12, pp. 1637-1646, 2007]. GA conjugates free radicals, which may serve as one of the mechanisms of the protective action of GA [M. Ogiku, H. Kono, M. Kara, M. Tsuchiya, and H. Fujii, «Glycyrrhizin prevents liver injury by inhibition of high-mobility group box 1 production by kupffer cells after ischemia-reperfusion in rats», Journal of Pharmacology and Experimental Therapeutics, vol. 339, no. 1, pp. 93-98, 2011.].
Patent RU 2308947 Cl describes a drug with a hypolipidemic effect, comprising a molecular complex of simvastatin with b-glycyrrhizic acid at a molar ratio of simvastatin: b- glycyrrhizic acid of l:(l-4). The patent document discloses a hypolipidemic property of a composition containing b-glyeyrrhizic acid along with the active component of simvastatin.
Patent RU 2396079 Cl describes a drug with a hypolipidemic effect, comprising a molecular complex of atorvastatin with b-glycyrrhizic acid at a molar ratio of atorvastatinβ- glycyrrhizic acid of 1 :(l-4).
Patent RXJ 2683641 C2 describes a pharmaceutical composition for the treatment of hyperlipidemia, containing a mixture of: (a) a glycyrrhizinic derivative selected from the group consisting of glycyrrhizie acid and its pharmaceutically acceptable salt; (b) a lipidlowering drag, wherein the lipid-lowering drug is a statin selected from the group comprising atorvastatin, lovastatin, rosuvastatin, simvastatin, pravastatin, pitavastatin, fluvastatin, or a pharmaceutical salt thereof, or a mixture thereof.
Patent RU 2549966 C2 describes a composition comprising: a) at least one phospholipid; b) at least one glycyrrhizic acid; or c) salt of glycyrrhizie acid for the manufacture of a medicinal product for the remo val of subcutaneous fat accumulations.
Application US20190124958 A1 describes an antimicrobial composition of hydrolysis lignin for inhibiting the growth of microorganisms in food, which contains enriched lignin with a molecular weight of >10,000 daltons; carbohydrates; and water.
Patent RU 2623876 C2 (the closest analogue) describes a pharmaceutical composition for the treatment of hyperlipidemia, comprising a mixture of a glycyrrhizin derivative selected from the group consisting of glycyrrhizie acid and its pharmaceutically acceptable salt; and a hypolipidemic drug, wherein the lipid-lowering agent is a statin selected from the group comprising atorvastatin, lovastatin, rosuvastatin, simvastatin, pravastatin, pitavastatin, fluvastatin, a pharmaceutically acceptable salt thereof or a mixture thereof, and auxiliary substances. The patent document discloses a hypolipidic property of a composition containing b-glycyrrhizic acid along with an active statin component.
The disadvantage of the above composition for the treatment of hyperlipidemia is the use of a lipid-lowering agent containing statin derivatives, the long-term use of which causes serious side effects.
The object of the present invention was to create a new composition without side effects suitable for normalizing the level of blood lipids, including low density lipoproteins, cholesterol and triglycerides, which can be used in a biologically active food supplement or a product for therapeutic and/or prophylactic dietary nutrition in combination with various additional components that can be selected, for example, from prebiotics.
The problem was being solved by means of the qualitative and quantitative composition of the components representing hydrolysis lignin and glycyrrhizic acid in the form of its pharmaceutically acceptable salt in the claimed effective amounts.
SUMMARY OF THE INVENTION
The invention relates to a composition based on a natural lignoeellulose complex, a source of dietary fiber exhibiting antioxidant and adsorption properties and a natural component of glycyrrhizic acid, which has hepatoprotective activity when used together due to multidirectional action. The claimed composition has an unexpected synergistic effect aimed at normalizing the levels of blood lipids, including low-density lipoproteins, cholesterol and triglycerides.
The object of the present invention was to create a new composition for normalizing the level of blood lipids, comprising a composition of a lignoeellulose complex and glycyrrhizic acid and/or its derivatives, which has high stability, without limitations on use in all age groups and specific groups of patients due to the synergistic effect of the active components of the composition, as an oral dosage form, as a biologically active food supplement, as well as a therapeutic or prophylactic dietary food product.
One of the embodiments of the invention disclosed herein is an oral dosage form of tablets, powder, gel or suspension and other dosage forms containing a lignoeellulose complex and glycyrrhizic acid, including acceptable salts thereof.
In another embodiment of the present invention, a dietary supplement is provided, which is used for the prevention of hypercholesterolemia, the onset and development of atherosclerosis, lipid metabolism disorders, dyslipidemia, which contains a lignoeellulose complex and glycyrrhizic acid, including acceptable salts thereof.
In yet another embodiment of the present invention, a product for therapeutic nutrition is provided, which is used for the prevention of hypercholesterolemia, the onset and
development of atherosclerosis, lipid metabolism disorders, dyslipidemia, which contains a lignocellulose complex and glycyrrhizic acid, including its acceptable salts in combination with various acceptable additives.
The components in the composition have different mechanisms of action on blood lipids, in particular, due to the normalization of liver and intestinal function, which in the aggregate has unexpectedly led to the possibility to effectively correct the observed disorders.
In a preferred embodiment, the invention relates to a composition in the form of an oral dosage form for normalizing the level of lipids in blood, including low-density lipoproteins, cholesterol and triglycerides, which contains a hydrolytic lignin, in particular, a lignocellulose complex in the amount of 84.5 to 99.9 wt% and glycyrrhizic acid in the form of an acceptable salt in the amount of 0.1 to 15.5 wt%, wherein the weight of the specified composition provides for an effective dosage of 10 to 5000 mg per day. The most preferred embodiment of the invention is that the weight of the said composition provides for an effective dosage of 50 to 500 mg per day.
Further, the invention relates to using the specified composition in the form of an oral dosage form in effective amounts for the prevention of the onset and development of atherosclerosis, lipid metabolism disorders, hypercholesterolemia, and dyslipidemia.
In one of the embodiments of the invention, a biologically active food supplement is also provided, containing the specified composition and various acceptable additives. In this case, the mass of the composition provides for a dosage of 10 to 5,000 rag per day. The most preferred embodiment of the invention is that the weight of the said composition provides for an effective dosage of 50 to 500 mg per day.
Further, the invention relates to using a dietary supplement for the prevention of the onset and development of atherosclerosis, lipid metabolism disorders, hypercholesterolemia, and dyslipidemia.
In yet another embodiment of the invention, a product is provided for effective therapeutic and prophylactic dietary nutrition, which contains the specified composition and acceptable additives.
The invention also relates to using a product for therapeutic and prophylactic dietary nutrition, which contains the specified composition in effective amounts for the treatment and acceptable additives for the prevention of lipid metabolism disorders, hypercholesterolemia, and dyslipidemia. In this case, the mass of the composition provides for a dosage of 10 to 5,000 mg per day. The most preferred embodiment of the invention is that the weight of the said composition provides for an effective dosage of 50 to 500 mg per day.
It was unexpectedly found that the ratio of the components included in the above composition helps reduce (normalize) the level of total cholesterol, LDL cholesterol, TG in the blood of experimental animals, slows down the progression of dyslipidemia during simulation process. The most significant effects of therapy begin to appear 60 days after starting the administration of the combination.
At the same time, GA added to the composition implements its own mechanism of action aimed at normalizing lipid levels by influencing cholesterol synthesis, reducing general inflammation in liver tissues and restoring its function.
The inclusion of the lignocellulose complex makes it possible to adsorb fat and bile acids in the intestine, preventing their absorption into the bloodstream. In addition, due to its antioxidant effect, the lignocellulose complex apparently reduces lipid peroxidation in intestinal cells, which leads to a decrease in the permeability of the intestinal wall for bacterial lipopolysaccharides and toxins that induce liver inflammatory reactions.
Thus, the effect of the claimed composition intended for normalizing the lipid level in blood, including low-density lipoproteins, cholesterol and triglycerides, consists in achieving an unexpected synergistic effect due to the implementation of the mechanism of simultaneous action on the functions of the liver and intestines from the side of glycyrrhizic acid in the claimed effective amounts in combination with pronounced
adsorption and antioxidant activity of hydrolysis lignin in the form of a ligninocellulose complex in the stated effective amounts.
Exemplary embodiments
Example 1.
Sorption activity of hydrolytic lignin, in particular, lignocellulose complex in relation to lipids.
To study the sorption activity of the lignocellulose complex in relation to lipids, we conducted in vitro experiments.
For this, 50 g of the lignocellulose complex (manufactured by ABVA RUS) was mixed with solid saturated fat (Witepsol H32) in an amount of 50 g and phosphate buffer solution (pH 5.5) in an amount of 50 mL using a stirrer. Stirring was carried out for 2 hours at 37 °C, with samples taken after 30, 60 and 120 minutes during stirring. Next, the samples were left for natural sedimentation for 8 hours at 37 °C to separate fractions. In this case, the samples were divided into three fractions: sediment - at the bottom, liquid - in the center, fatty fraction - at the top. The lipid concentration in the sediment fractions from the obtained samples was determined using the HPLC method. For determination, lipids were converted into methyl esters of higher fatty acids using standard chemical analytical techniques. The results of the sorption activity of the lignocellulose complex in relation to lipids depending on the duration of incubation are presented in Fig. 1.
It was revealed that from 47.3 to 56.5 wt% of lipids were sorbed by the lignocellulose complex during the experiment, with an incubation time from 30 to 120 minutes.
Example 2
The adsorption activity of the lignocellulose complex in relation to bile salts
A lignocellulose complex (manufactured by AVVA RUS JSC) was studied as a test sorbent. As tested sorbates, we studied sodium salt of cholic acid (primary bile acid), sodium salt of ehenodeoxycholic acid (primary bile acid), sodium salt of deoxycholic acid (secondary bile acid), since these acids constitute the main pool of bile acids in the human body.
For this, 500 mg of the lignocellulose complex was transferred into a flat-bottomed flask, then a phosphate buffer solution, pH 7.0, was poured in and incubated on a shaker at 37 °C for 2 hours to completely wet the lignocellulose complex. Then, solutions of sodium bile salts were added (the final concentration of 2 mmol/L), The total volume of the mixture was 50 mL. The mixtures were incubated on a shaker for 4 hours at a temperature of 37 °C, the supernatant was obtained after centrifugation, and the residual concentration of bile salts was investigated using the method of gas-liquid chromatography.
During the experiment, 51.2 ± 1.8% cholic acid, 20.4 ± 3.7% deoxycholic acid and 26.3 ± 2.1% ehenodeoxycholic acid were sorbed for 4 hours.
Example 3
Antioxidant activity of the lignocellulose complex
To assess the antioxidant potential of the lignocellulose complex, we used the molybdate method based on the ability of peroxide to form a colored complex with ammonium molybdate. We used a lignocellulose complex (produced by AVVA RUS JSC) and ascorbic acid produced by Tatkhimfarmpreparaty JSC as a comparison substance with known antioxidant properties.
Solutions of the lignocellulose complex and ascorbic acid were prepared in dimethyl sulfoxide. 3 mL of 0.02 M ammonium molybdate solution, 1 mL of 3% hydrogen peroxide solution, and 0.1 gram of sulfuric acid equivalent were transferred to a 25 mL volumetric flask, 0.1 or 0.2 mL of a 1% solution of the test substance were added, and the solution was diluted to volume with water. The solution was kept for 20 min at a temperature of 25 °C.
The substance concentrations of 100, 1000, 10000 pg/mL were studied. The optical density of the resulting solutions was measured at a wavelength of 410 nm using an EpochBiotek plate reader.
Results: a decrease in the optical density of solutions upon the introduction of a lignocellulose complex or ascorbic acid into the reaction mixture indicated the manifestation of the tested substances’ ability to interact with peroxide and their antioxidant properties. The
lignocellulose complex showed a pronounced activity in all studied concentrations by decreasing the optical density of solutions (Table 1). The lignocellulose complex exhibited the ability to interact with hydrogen peroxide comparable to the known antioxidant of the ascorbic acid.
Table 1
Antioxidant (antiperoxide) activity of the lignocellulose complex versus ascorbic acid
the decrease in the concentration of peroxide (assessed by optical density) versus the control on the concentration of the lignocellulose complex: with an increase in the concentration, a decrease in the residual peroxide in the reaction medium was observed, that is, the interaction of the substance with peroxide increases.
Example 4
Stability of the combination of lignocellulose complex and glycyrrhizic acid (using an example of the ammonium glycyrrhizinate salt, but not limited to this salt)
The stability of combinations of the lignocellulose complex and glycyrrhizic acid, in particular, ammonium glycyrrhizinate, during storage was assessed by changes in the adsorption capacity of the lignocellulose complex, the content of ammonium glycyrrhizinate in the mixture, and microbiological characteristics. The checkpoints were 1 month, 3 months and 6 months. The combinations were stored in a climatic chamber at a temperature of 25 °C and a relative humidity of 60%.
Compositions containing ammonium glycyrrhizinate (hereinafter AGC) and a lignocellulose complex (hereinafter LCC) in the mixtures:
1) AGC 50 mg + LCC 5,000 mg or AGC 1.0 wt%: LCC 99.0 wt%;
2) AGC 30mg + LCC 1,000 mg or AGC 2.9 wt%: LCC 97.1 wt%;
3) AGC 30 mg + LCC 2,600 mg or AGC 1.1 wt%: LCC 98.9 wt%;
4) AGC 200 mg + LCC 1,090 mg or AGC 15.5 wt%: LCC 84.5 wt%.
To prepare the mixtures, we used the substance of the lignocellulose complex produced by AVVA RUS JSC, series 6630918, and the substance of ammonium glycyrrhizinate produced by SelectBotanical, series 10000001183-FP. The mixtures were packaged in glass containers made of dark glass with tight lids, 5 containers of each mixture for each checkpoint. The adsorption capacity of the lignocellulose complex was assessed according to the standard method using methylene blue.
The content of ammonium glycyrrhizinate in the mixture was determined by HPLC. The test solution was prepared by introducing an accurately weighed portion of the AGC mixture diluted with an aqueous solution of acetonitrile (1:1), followed by sonication for 10 minutes. The resulting AGC suspension was thoroughly mixed, cooled to room temperature, and passed through a 0.45 pm pore size membrane filter. The measurements were made at a wavelength of 254 nm. A solution prepared with a standard sample of ammonium glycyrrhizinate (manufactured by Sigma- Aldrich) was used as reference solutions. The result of measuring the content of ammonium glycyrrhizinate was expressed as a % of the calculated value for each mixture of LCC + AGC.
When assessing microbiological parameters, we studied the total aerobic microbial count - not more than 5 x 104 CFU in 1 g (mL); total combined yeasts and molds count - not more than 1 x 102 CFU in 1 g (mL); total bacterial count of the Escherichia coli group - not allowed in 0.1 g (mL); Escherichia coli - not allowed in 1 g (mL); Salmonella spp. - not allowed in 25 g (mL); Staphylococcus aureus - not allowed in 1 g (mL). For microbiological analysis, standard procedures were used (GOST 26670-91, GOST 31747-2012, GOST 30726- 2001, GOST 10444.15-94, GOST 31659-2012, GOST 10444.12-2013). The stability results for the AGC + LCC compositions in various mass ratios are summarized in Table 2.
Table 2
Data on the activity and microbiological purity of ammonium glycyrrhizinate and lignocellulose complex in the composition during storage for 6 months
The experimental results indicate that the compositions are stable, the content and activity of the components in the physical mixture did not change significantly during storage for 6 months.
Example 5
Oral administration of combinations of AGC and a lignocellulose complex for normalizing lipid levels in blood and preventing the onset and development of diseases mediated by pathological changes in blood lipids caused by dyslipidemia, in particular, in atherosclerosis, lipid metabolism disorders, hypercholesterolemia in rabbits with artificially induced dyslipidemia
A model of hypercholesterolemia, lipid metabolism disorders and atherosclerosis in California rabbits was used as a test system to assess the specific pharmacological activity of combinations of the lignoceilulose complex and ammonium glycyrrhizinate in various mass ratios versus monotherapy with the lignoceilulose complex and ammonium glycyrrhizinate. The age of animals at the beginning of the study was 8 weeks, the weight varied in the range of 2.5-3.0 kg, there were 4 animals in each group.
The model of hypercholesterolemia and atherosclerosis was induced as follows:
1 , Exogenous cholesterol was administered orally on a daily basis to form the state of hypercholesterolemia in animals, leading to the development of dyslipoproteinemia.
2. Vitamin D3 (cholecalciferol) was administered to animals from time to time in order to stimulate the occurrence of atherocalcinosis, which aggravates the development of atherosclerosis. Metabolites of vitamin D3 cause the disruption of the integrity of the arterial
wall and provoke necrosis of smooth muscle arterial fibers (media) to a certain extent, thus increasing the integration of lipid particles into the arterial wall.
3. Multiple intravenous administration of adrenaline to experimental animals was carried out, which stimulates the release of catecholamines and simulates periodic psycho- emotional stress.
Cholesterol was dissolved in superheated vegetable oil and administered at a dosage of 0.3 g/kg of animal weight, once a day, intragastrically through a tube. The duration of cholesterol administration was 90 days. After 30 days from the beginning of cholesterol administration, vitamin D3 (cholecalciferol) was added to the diet of animals at a dose of 0.256 mL/kg to enhance aortic lipidosis. Cholecalciferol was administered intragastrically from day 31 to day 60 of the experiment. During the same period, in order to enhance atherosclerotic changes in the aorta, the animals were injected with adrenaline at a dose of 0.04 mg per 1 kg of body weight intravenously every 5 days.
The following formulations of compositions containing ammonium glycyrrhizinate (AGC) and a lignocellulose complex (LCC) were subjected to study:
1) AGC 50 + LCC 5,000 or AGC 1.0%: LCC 99.0%;
2) AGC 30 + LCC 1,000 or AGC 2.9%: LCC 97.1%;
3) AGC 30 + LCC 2,600 or AGC U%: LCC 98.9%;
4) AGC 200 + LCC 1,090 or AGC 15.5%: LCC 84.5%.
The parameters of the blood lipid spectrum were assessed on the A-25 RandomAccess open-type biochemical analyzer (Spain) using reagents manufactured by BioSystems (Spain).
Against the background of introducing pathology inducers, all animals of the experimental groups showed the development of dyslipidemia within 60 days from the beginning of the experiment, while the level of total cholesterol (CS), low-density lipoprotein cholesterol (LDL cholesterol), triglycerides (TG) increased significantly, and the atherogenic index also increased. The totality of signs indicated the development of a stable disorder of lipid metabolism in experimental animals.
The test combinations began to be used on day 31 from the beginning of the pathology induction. The most pronounced effect was observed in animals that received the studied formulations of the compositions. On the 60th day from the beginning of the experiment, a significant decrease in the level of lipids and the atherogenieity index in the groups of therapeutic use of the combinations was observed, which remained until day 90 against the background of the pathology aggravation in the control group. Changes in the lipid spectrum are presented in Table 3.
Table 3
Data on lipid spectrum indices in rabbits with induced dyslipidemia (with dyslipidemia underlying all these diseases) when treated with a composition containing ammonium glycyrrhizinate (AGC) and lignocellulose complex (LCC) in different quantitative ratios.
The prebiotics listed in Table 3 are FOS (fruetooligosaccharides), GOS (galactooligosaceharides), lactitol, used in an amount from 0.5 to 3,000 mg.
It was noted that LCC and AGC have a significant effect on LDL cholesterol, total cholesterol, and TG. LH at a dose of 5,000 mg reduces TG levels significantly more pronouncedly than AGC at a dose of 50 mg.
LCC at a dose of 5,000 mg also significantly reduces the calculated atherogenic index (AI = (cholesterol - HDL cholesterol) / HDL cholesterol). The combination of AGC 50 mg + LCC 5,000 mg caused the most pronounced decrease in cholesterol, LDL, TG and IA versus other groups, except for the intact group. It should be noted that the AGC 30 mg + LCC 2,600 mg group reduced the TG level to a degree similar to that of the AGC 50 mg + LCC 5,000 mg group, and their indicators did not differ significantly. At the same time, the indicator of the TG level in the AGC 50 mg + LCC 5,000 mg and AGC 50 mg + LCC 5,000 mg + prebiotic groups was significantly lower than in other groups.
The AGC 200 mg + LCC 1,090 mg and AGC 30 mg + LCC 1,000 mg groups reduced LDL-C and CS levels significantly more pronouncedly versus the pathology + LCC 5,000 mg and pathology + AGC 50 mg groups. According to the study results, groups can be divided according to the strength of influence on the normalization of lipid metabolism as follows, from the most effective group to the least effective one:
1) AGC 50 mg + LCC 5,000 mg or 1.0%: 99.0%;
2) AGC 30 mg + LCC 2,600 mg or 1.1%: 98.9%;
3) AGC 200 mg + LCC 1 ,090 mg or 15.5%: 84.5%;
4) AGC 30 mg + LCC 1,000 mg or 2.9%: 97.1%;
5) LOG 5,000 mg or 99.0%;
6) AGC 50 mg or 1.0%
When assessing the histological criteria of damage to the liver, aorta, and heart of rabbits with induced dyslipidemia after euthanasia of animals 90 days after the start of the experiment, the introduced scoring system was used, namely:
- the degree of atherosclerotic damage to the aortic wall was assessed according to the relevant stages of atherogenesis (no signs of pathology - 0 points; pre-lipid stage - 1 point, lipoidosis - 2 points, calcification - 3 points), to identify the early stages of atherosclerosis - pre-lipid, the toluidine blue dye was used, which, due to the metachromasia reaction, allows visualizing dystrophic changes in the connective tissue; to isolate accumulations of lipids in the tissues, the oil red O dye was used, the maximum score was 5 (when simultaneously observing calcification and lipoidosis);
- the degree of liver damage was assessed according to the histological criteria presented in Table 4, each morphological sign of liver damage was assessed in points, which were summed up for each animal in the group, the maximum possible score is 6.
Table 4
- the degree of atherosclerotic damage to the heart valves was assessed according to the same criteria as the degree of damage to the aorta.
The results obtained indicate that the combinations of AGO and LCC have a protective effect on the prevention and elimination of damage to the aorta, heart valves and liver in rabbits with artificial dyslipidemia. The results are summarized in Table 5.
Table 5
Data on the degree of damage to the aorta, liver and heart in rabbits with dyslipidemia after therapeutic and prophylactic use of the composition of ammonium glycyrrhizinate (AGC) and lignocellulose complex (LCC)
Prebiotics are selected from FQS, GOS, lactitol and used in an amount from 0.5 to 3,000 mg.
According to the study results, the combination of AGC 50 mg + LCC 5,000 mg has the most pronounced effect aimed at reducing the negative effect of atherogenic factors on the studied organs of rabbits with induced dyslipidemia. It should be noted that the effect of AGC at a dose of 50 mg was mainly associated with a significant decrease in the severity of pathological changes in the structure of the liver in rabbits. At the same time, the ligninocellulose complex at a dose of 5,000 mg had a significant positive effect (a decrease in the severity of pathological changes) on all examined organs versus the pathology control group. Group AGC 30 mg + LCC 2,600 mg was close in its therapeutic and prophylactic activity to the groups that received the combination of AGC 50 mg + LCC 5,000 mg and
AGC 50 mg + LCC 5,000 mg + prebiotics, however, it was significantly inferior to them in the effect observed in the aorta and li ver of rabbits. The group receiving the combination of AGC 30 mg + LCC 1000 mg showed tire least activity in terms of prevention and elimination of pathological changes in the examined organs.
As a result, it is possible to make a rating of groups by the strength of influence on the prevention and development of pathological processes in organs as follows, from the most effective group to the least effective one:
1) AGC 50 mg + LCC 5,000 mg or 1.0 wt%: 99.0 wt%;
2) AGC 30 mg + LCC 2,600 mg or 1.1 wt%: 98.9 wt%;
3) AGC 200 mg + LCC 1,090 mg or 15.5 wt%: 84.5 wt%;
4) AGC 30 mg + LCC 1,000 mg or 2.9 wt%: 97.1 wt%;
5) LCC 5,000 mg or 99.0 wt%;
6) AGC 50 mg or 1.0 wt%.
The results obtained indicate the presence of a synergistic effect when using a combination containing a lignocellulose complex in the amount of 84.5 to 99.9 wt% and
glycyrrhizic acid in the form of acceptable salt in the amount of 0,1 to 15.5 wt%. When the components were used separately, hypolipidemic, hepatoprotective and other effects revealed were less pronounced than in the case of using the composition. Synergism was provided by means of the combined (joint) implementation of various action mechanisms characteristic of each component of the combination.
Example 6
Obtaining various forms of the composition
To obtain AGC powder in the amount of 10 to 200 mg and a lignocellulose complex in the amount of 50 to 5,000 mg, they were ground to a powdery condition using laboratory glassware for grinding solid substances.
To obtain an ACG tablet 10 to 200 mg and a 50 to 5,000 mg lignocellulose complex, they were ground to a powdery condition using laboratory glassware for grinding solid substances, then povidone K17 (PVP) from 1 mg to 65 mg; calcium stearate from 1 mg to 10 mg; croscarmellose sodium from 1 mg to 10 mg were added to the resulting mixture and tableted using special equipment.
To obtain capsules of AGA from 10 to 200 mg and a lignocellulose complex from 50 to 5,000 mg, they were ground to a powdery condition using laboratory glassware for grinding solid substances, and auxiliary substances were added, such as microcrystalline cellulose from 0.5 mg to 80 mg, low molecular weight povidone from 0, 5 mg to 10 mg, potato starch from 0.5 mg to 10 mg, magnesium stearate from 0.5 mg to 5 mg, lactose monohydrate from 0.5 mg to 175 mg. The resulting mixture was encapsulated using special equipment.
To obtain a biologically active additive, for example, in the form of a bar, AGC from 10 to 200 mg and a lignocellulose complex from 50 to 5,000 mg were ground to a powdery condition using laboratory glassware for grinding solids, then fruit puree or berry puree from 1 mg to 10,000 mg, inulin from 1 mg to 8,000 mg, beta-glucan from 1 mg to 5,000 mg, an additional source of dietary fiber, for example, oligoffuctose syrup from 1 mg to 2,000 mg, a source of vitamins to support the immune system (vitamin E* ascorbic acid) from 1 mg up to 2,500 mg, potassium sorbate from 1 mg to 1,000 mg, stabilizer from 1 mg to 1,000 mg, flavoring agent from 1 mg to 1,000 mg, baking powder from 1 mg to 1,000 mg were added, and the necessary shape was given to the product using special equipment.
To obtain a product for therapeutic and prophylactic dietary nutrition, for example, in the form of a snack or candy, AGC from 10 to 200 mg and a lignocellulose complex from 50
to 5,000 mg were ground to a powdery state using laboratory glassware for grinding solid substances, then fruit puree or berry puree from 1 mg to 10,000 mg, an additional source of dietary fiber, ixiulin from 1 mg to 8,000 mg, beta-glucan from 1 mg to 5,000 mg, a source of vitamins to support the immune system (vitamin E, ascorbic acid) from 1 mg to 2,500 mg, potassium sorbate from 1 mg to 1,000 mg, stabilizer from 1 mg to 1,000 mg, flavoring agent from 1 mg to 1,000 mg, baking powder from 1 mg to 1,000 mg were added. Next, the necessary shape was provided to the product using special equipment.
The study results with regard to the effectiveness of the composition intended for normalizing the lipid level in blood showed that the weight of the investigated composition allows for an effective dosage of at least 10 mg per day and at least up to 500 mg per day.
Example 7
The effect of prebiotics on the functioning of the gastrointestinal tract when taking a combination of AGC and LCC
Male outbred rats were used as a test system to determine the effect of the combination of AGC and LCC, including when combined with prebiotics, on the functioning of the gastrointestinal tract. Healthy animals aged 6-7 weeks were used.
The study involved the following experimental groups (4 animals per group):
1) intact animals,
2) AGC 50 mg + LCC 5,000 mg;
3) AGC 50 mg + LCC 5,000 mg + inulin 3,000 mg;
4) AGC 50 mg + LCC 5,000 mg + lactitol 3,000 mg;
5) AGC 50 mg + LCC 5,000 mg + galactooligosaecharides (GOS) 3,000 mg;
6) AGC 50 mg + LCC 5,000 mg + beta-glucan 3,000 mg.
The studied combinations were administered to animals intragastrically in the form of a suspension in 1% starch solution. Animals of the intact group received only starch solution. The administration was carried out for 14 days. The animals were kept individually. During the study, the number of bowel movements per day was studied (defecations were counted every 2 hours during the day and in the morning of the next day).
Table 6 shows measurement results of the number of boluses per day in animals of different groups.
Table 6
Data on the frequency of defecation in rats after oral administration of a combination of ammonium glycyrrhizinate (AGO) and a lignocellulose complex (LCC), including the addition of various prebiotics.
Long-term use of the combination of AGO and LCC led to a decrease in the frequency of defecations and thickening of feces in experimental animals, which may indicate an increased risk of constipation when using the studied combination. Using prebiotics of various classes, including inulin, lactitol, halo-oligosaccharide and beta-glucan, helps restore the frequency of defecation in rats to values comparable to the control group.
The results obtained suggest that using prebiotics in conjunction with the combination of AGC + LCC may help reduce the risk of constipation with the prolonged administration of the combination.
Claims
1. A composition for normalizing lipid level in blood, including low-density lipoproteins, cholesterol and triglycerides, which contains hydrolytic lignin in the amount of 84.5 to 99.9 wt% and glycyrrhizic acid in the form of an acceptable salt in the amount of 0.1 to 15.5 wt%.
2. A composition according to claim 1 is characterized in that the weight of the said composition provides for an effective dosage of 10 to 5,000 mg per day.
3. A composition according to any one of claims 1 to 2, characterized in that it represents an oral dosage form made in the form of a powder, tablet, capsule, suspension, and gel.
4. The use of the composition according to any one of claims 1 to 3 for the prevention of the onset and development of atherosclerosis, lipid metabolism disorders, hypercholesterolemia, and dyslipidemia.
5. Biologically active food supplement containing the composition according to claim 1 and auxiliary substances.
6. Biologically active food supplement according to claim 5, wherein the excipients are selected from prebiotics.
7. Biologically active food supplement according to claim 5, wherein the weight of the composition according to claim 1 provides for a dosage of 10 to 5,000 mg per day.
8. Biologically active food supplement according to claim 5, characterized in that it is made in the form of a powder, tablet, capsule, bar, and snack.
9. The use of the biologically active food supplement according to any one of claims 5 to 8 for the prevention of the onset and development of atherosclerosis, lipid metabolism disorders, hypercholesterolemia, and dyslipidemia.
10. A product for therapeutic and prophylactic dietary food comprising the composition according to claim 1 and auxiliary substances.
11. The product according to claim 10, wherein the excipients are selected from prebiotics.
12. The product according to claim 10, wherein the weight of the composition according to claim 1 provides for a dosage of 10 to 5,000 mg per day.
13. The product according to claim 10, wherein the weight of the composition according to claim 1 provides for a dosage of 50 to 500 mg per day.
14. The product according to claim 10, characterized in that it is made in the form of a powder, tablet, capsule, bar, snack, and candy.
15. The use of the product according to claim 10 for the prevention of the onset and development of atherosclerosis, lipid metabolism disorders, hypercholesterolemia, and dyslipidemia.
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EA202090511A EA202090511A1 (en) | 2020-03-13 | 2020-03-13 | COMPOSITION FOR NORMALIZING BLOOD LIPID LEVELS |
EA202090511 | 2020-03-13 |
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WO (1) | WO2021180293A1 (en) |
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