RU2235483C2 - Composition, pharmaceutical preparation, and method for prophylaxis and/or treatment and/or attenuation of cardiovascular diseases - Google Patents

Abstract

FIELD: medicinal biotechnology, medicine, cardiology.

SUBSTANCE: invention relates to a soybean-base composition that comprises additionally phytoestrogenic compound and food cellular tissue. Composition can be used for preparing a pharmaceutical preparation and prophylaxis and/or treatment, and/or attenuation of multiple cardiovascular diseases. Composition is used in the dose providing reduction of serum blood cholesterol content, and/or serum blood LDLP-cholesterol content, and/or serum blood triglycerides content, and/or serum blood homocysteine content, and/or increase of the ratio HDLP-cholesterol to the content LDLP-cholesterol, and/or to the content of serum blood HDLP-cholesterol content, and/or reducing the deposition of cholesterol and/or triglycerides in artery walls, and/or prophylaxis, reducing or elimination of formation of lipid bands, and/or prophylaxis, reducing or elimination of formation of fibrous plaques, and/or reducing or elimination of formation of the complicated damage, and/or prophylaxis, reducing or elimination of risk in development of stenocardia, and/or prophylaxis, reducing or elimination risk in development of myocardium infarction. Invention promotes to normalization of lipid metabolism in humans.

EFFECT: improved method for prophylaxis and treatment.

58 cl, 5 dwg, 4 tbl, 2 ex

Description

FIELD OF THE INVENTION

The present invention relates to soy protein, a phytoestrogen compound and dietary fiber and compositions thereof suitable for the prevention, amelioration and / or treatment of cardiovascular diseases such as arteriosclerosis, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hypertension and related cardiovascular diseases. In particular, the composition in accordance with the present invention has an improved effect in reducing serum total cholesterol and LDL cholesterol. The composition of the present invention is also particularly useful for reducing cholesterol accumulation in artery walls in patients at high risk of developing a cardiovascular disease or already suffering from a cardiovascular disease such as atherosclerosis. The composition in accordance with the present invention is also applicable to reduce the content of total cholesterol and / or LDL cholesterol and / or triglycerides and / or homocysteine in serum and / or increase the content of HDL cholesterol in serum and / or improve the ratio HDL cholesterol to LDL cholesterol in subjects at risk of developing cardiovascular disease and in subjects already suffering from an atherosclerotic condition, such as, for example, atherosclerosis or a related cardiovascular diseases. The present invention also relates to the use of these compositions in the manufacture of a medicament for the treatment of patients with cardiovascular diseases, especially arteriosclerosis, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hypertension and / or related cardiovascular diseases. The present invention also relates to the use of the composition in accordance with the present invention in the prevention and / or treatment of the above diseases and disorders and for reducing total cholesterol and / or LDL cholesterol and / or triglycerides and / or homocysteine in serum in subjects. In addition, the present invention also relates to methods of prophylaxis and / or treatment and / or prophylactic treatment and / or attenuation as a result of treatment of the above diseases and disorders.

BACKGROUND OF THE INVENTION

Lipid metabolism includes the processes of biosynthesis and breakdown of, for example, fatty acids, triglycerides and cholesterol. Absorbed triglycerides are hydrolyzed in the small intestine and the hydrolysis products are absorbed by the intestinal mucosa. As a result of the relative insolubility of food lipids in water, the action of detergents such as bile acids secreted by the gallbladder promotes the digestion and absorption of lipids. Bile acids are essential for digestion and absorption of lipids by the intestinal mucosa.

Triglycerides and cholesterol are synthesized in the liver and transported through the bloodstream to peripheral tissues by transport proteins called lipoproteins. Lipoproteins are very small vesicles coated with apoproteins, phospholipids and free cholesterol, with an inner part consisting of more hydrophobic lipids, cholesterol esters and triglycerides. Apoproteins and lipoproteins are synthesized mainly in the liver. Lipoproteins are capable of representing apoprotein, which mediates binding to a receptor on the surface of a cell into which a whole particle of lipoprotein is absorbed and subsequently metabolized.

Several different families of lipoproteins are characterized and traditionally classified according to their density determined by centrifugation. The standard classification scheme for lipoproteins can include, by increasing the density, very low density lipoproteins (VLDL), intermediate density lipoproteins (VLDL), low density lipoproteins (LDL) and high density lipoproteins (HDL).

VLDL contains approximately 60-65 percent triglycerides and 5-10 percent cholesterol, lecithin and protein. They are relatively large and are involved in the transport of triglycerides from the liver to the tissue. LDL contains approximately 40-50 percent of cholesterol and 10-15 percent of triglycerides, lecithin and protein. They are slightly smaller than VLDL and are also involved in the transport of cholesterol from the liver to the tissue. HDL contains roughly 75 percent lecithin and protein, while the remainder consists of cholesterol and a small amount of triglycerides. They participate in the transport of cholesterol from tissue to the liver, thereby possessing a function inverse to LDL. Cholesterol esters cannot freely penetrate cell membranes and are absorbed by cells by a receptor-mediated mechanism. Upon binding to the LDL receptor, the LDL particle is internalized by endocytosis, cholesterol and fatty acids are released and metabolized.

Ongoing studies of LDL-receptor-mediated internalization of cholesterol have formed a better understanding of the relationship between food cholesterol, serum cholesterol and atherosclerosis. It is believed that white blood cells that accumulate cholesterol in the foci of damage to the arteries contain a receptor called a phagocytic receptor. Like the LDL receptor, the phagocytic receptor acts by the mechanism of endocytosis and mediates the internalization of various extracellular materials. However, the phagocytic receptor is non-selective and absorbs many different types of extracellular materials, including oxidized LDL particles containing cholesterol. In contrast to the LDL receptor, the phagocytic receptor is not a down-regulated high concentration of cholesterol in the cell.

In addition to the aforementioned lipoproteins, the body also contains a type of lipoprotein called chylomicrons. Chylomicrons contain 90-95 percent triglycerides and only a small amount of cholesterol, lecithin and protein, and they are involved in the transport of triglycerides from the small intestine, for example, to the muscles, liver and heart.

Cholesterol metabolism in the human body is closely associated with the synthesis, transport and breakdown of triglycerides. Cholesterol is an essential component of all mammalian cells. It is used to regulate the fluidity of cell membranes and serves as a precursor for certain hormones, vitamin D and bile acids. Cholesterol is synthesized in the liver and transported with blood to peripheral tissues by lipoproteins. The liver has a double function in cholesterol metabolism, as it is capable of synthesizing cholesterol and converting excess cholesterol into bile acids. The liver is also able to secrete cholesterol in bile.

Bile acids have the properties of an amphoteric electrolyte and contain both hydrophobic and hydrophilic surfaces. This property of amphoteric electrolyte helps mediate the emulsification of lipids into micelles by bile acids. The formation of micelles makes possible the attack of water-soluble digestive enzymes and facilitates the absorption of lipids by the cells of the intestinal mucosa. Bile acids are secreted by the liver and stored in the gall bladder until they pass through the bile duct into the intestine. Bile acid biosynthesis is a method of utilizing cholesterol and makes up more than half of the approximately 800 mg of cholesterol normally metabolized per day by a normal adult. Even though bile acids in an amount of 400 mg are synthesized every day, a significantly larger amount is secreted into the intestines. Most of the bile acids are secreted into the upper part of the small intestine, absorbed in the lower part of the small intestine and processed in the liver. The process of enterohepatic circulation can be 20-30 g of bile acids per day. In contrast, the daily loss of bile acids with feces is only 0.5 g or less.

Cholesterol has an effect on three different levels of regulation of its own synthesis. First, it inhibits the synthesis of endogenous cholesterol by inhibiting hydroxymethylglutaryl CoA reductase. Secondly, it activates acyl-CoA: cholesterol-acyltransferase, which is involved in the synthesis of cholesterol esters from cholesterol and fatty acids associated with acyl-CoA. Third, cholesterol regulates the synthesis of LDL receptor. A correspondingly reduced synthesis of LDL receptors ensures that a cell with an already sufficient cholesterol content will not absorb cholesterol. This may explain the fact that excess cholesterol in food causes a rapid increase in blood cholesterol.

It is known that high blood cholesterol positively correlates with arteriosclerosis, a condition characterized by deposition of plaque and fat in the inner lining of the artery wall of the artery. One of the most common arterial conditions is atherosclerotic cardiovascular disease. The condition can develop over time through several stages. The normal structure of the artery is characterized by discrete numbers of foci of adherent monocytes, several foamy intimal cells and several smooth muscle intimal cells, or clusters of intimal cells in bifurcations. Fat strips may form asymptomatically and involve a layer of foam cells. With the progression of arteriosclerosis, the cells that make up the inner wall of the artery begin to solidify as a result of plaque deposition, and the cells can degenerate over time. While the artery wall thickens, hardens and loses its elasticity during arteriosclerosis, the blood vessel ducts can form bends and turns and become narrow to such an extent that the heart needs to work harder to pump normal volume of blood through the arteries. The condition may regress or may develop with the formation, for example, of a fibrous plaque. A fibrous plaque is a slowly reversible condition that can develop with the formation of complicated damage.

Cell degeneration usually leads to a violation of the integrity of the artery wall, which in turn leads to the deposition of calcium, the formation of a blood plate and the gradual formation of scar tissue, which subsequently participates in cell degeneration, and a significant decrease in the elasticity of the artery wall. Atherosclerosis, characterized by a restriction of blood flow through the coronary artery, can lead to coronary heart disease. Complicated artery damage is usually symptomatic, difficult to reverse, and can lead to death in severe cases, such as with thrombosis. Decreased blood flow through the artery can lead to the formation of blood clots, and this can lead to thrombosis over time. If a blood clot forms in the coronary artery, the cessation of blood flow can lead to the death of part of the heart muscle and cause extremely severe chest pain associated with a heart attack.

Symptoms of arteriosclerosis are largely dependent on which arteries and tissues are affected. When arteriosclerosis leading to the brain arteries arises, a decrease in blood flow and oxygen content can lead to confusion and personality disorder. In the event that the blood flow to the brain stops flowing through the artery of the brain, weakened by a rupture or blood clot, a stroke can occur. This can lead to partial paralysis, loss of speech, or sometimes even death. Reduced blood flow in the coronary arteries leads to a lack of oxygen in the heart muscle and causes pain in the chest area and a painful condition called angina pectoris.

Angina pectoris is usually caused by narrowing or obstruction of the coronary artery. An attack of angina pectoris can be caused by stress or be the result of physical exertion, requiring increased blood flow to the heart.

Thus, even though it is well known that cholesterol, lipids and lipoproteins contribute to the progression of various arteriosclerotic conditions in patients with diabetes mellitus, little is known about the causes of arteriosclerosis. In some cases, hereditary factors play a clear role, and socioeconomic factors and lifestyle-related factors such as smoking, hypertension, eating habits, and prolonged stress also determine the development of arteriosclerosis.

Currently, there is no simple method of treatment and therapeutic effect on arteriosclerosis, and doctors usually recommend that patients follow a low-fat diet, stop smoking, and exercise regularly. Patients with high blood cholesterol can be classified into four risk groups: (1) overt coronary heart disease; (2) other forms of atherosclerotic vascular disease; (3) other risk factors for coronary heart disease in the absence of an established atherosclerotic cardiovascular disease; and (4) an isolated increased blood cholesterol in the absence of other risk factors. The recommended treatment regimen for the risk group (4) is general advice along with laboratory tests for patients with total cholesterol in the range of 5.0-6.4 mmol / l without any further control. Only non-drug treatment is indicated for patients with a cholesterol content in the range of 6.5-7.9 mmol / L and an LDL content> 5.0 mmol / L or a ratio of the LDL content to the HDL content> 5.0.

Drug treatment for cardiovascular diseases may include the use of calcium channel blockers to expand the arteries in order to allow blood to flow more freely and anticoagulants to prevent the formation of blood clots in the affected arteries. Some studies have shown that compounds such as acetylsalicylic acid and sulfinpyrazone, which can reduce and / or inhibit blood clot formation by reducing platelet reactivity, can also prevent blood clot formation. With advanced disease, surgery may be required to replace the affected blood vessels with healthy arteries.

The use of various lipid lowering drugs is also being promoted, as some studies have shown or noted that even for otherwise healthy patients with moderately or medium high cholesterol blood levels, treatment with these lipid lowering drugs reduces morbidity and mortality from coronary artery disease. The most commonly used lipid lowering drugs in recent years have been statins, such as hydroxymethylglutaryl-CoA reductase inhibitors, bile acid resins, fibrates, nicotinic acid derivatives and various fish oil concentrates with a high content of ω-3 fatty acids.

Elevated serum triglycerides are currently regarded as a known risk factor for the development of cardiovascular disease. Importantly, recent studies have shown that serum triglycerides, which are currently considered normal — 200 mg per deciliter of serum — may actually be too high. It has been proposed to reduce by 50 percent the normal range for triglycerides compared to what is currently considered normal (Yahoo News, I May 1998). In the group of patients observed for almost 20 years, with an increase in serum triglycerides of more than 100 mg per serum deciliter, the relative risk of developing cardiovascular disease actually increased by 50 percent and the chance of survival in this case was reduced. It was emphasized that a long time ago no clinical studies were conducted on whether reduced triglycerides affect the frequency of subsequent cardiovascular events, and studies on the effect of serum triglycerides on the frequency of acute cardiovascular disorders lagged far behind the study aimed at clarifying the effect of increased serum cholesterol for the subsequent development of cardiovascular disease.

Adiercreutz (Finnish Medical Society, Ann. Med. 29, 95-120 (1997)) reviewed the classes of lignans and isoflavones and described their effects on a number of manifestations of cellular activity and a number of metabolic processes. Soy intake has been reported to prevent LDL oxidation, but an antioxidant mechanism has not yet been established. Although isoflavones can prevent the development of atherosclerosis, it seems very difficult to separate the effect of phytoestrogen from the effect of other components in food. It is emphasized that phytoestrogens, especially in combination with soy, may have great potential in the prevention of cardiovascular diseases, but since this area is actually in the early stages of development, further established beneficial effect of soy and isoflavonoids should be followed by research. It is further argued that despite the large amount of literature at this early stage in the study of food phytoestrogens, more work is required before any recommendations can be made regarding the consumption of phytoestrogens. Nevertheless, the experimental and epidemiological data do confirm the point of view that these compounds do not have any negative effects and that they can form a group of substances with high potential in preventive medicine. It is noted that at the present time certain recommendations cannot be given regarding the amounts in the diet necessary for the prevention of the disease. References to the composition, including a combination of soy protein, a high content of phytoestrogen compounds and dietary fiber, were not made.

Anderson (N. Eng. J. Med. 333. 276-282 (1995)) analyzed a total of 38 clinical cases and concluded that consumption of soy protein significantly lowers total cholesterol, LDL cholesterol, and serum triglycerides. It was found that consumption of soy protein-containing food compared to control food was accompanied by a significant decrease in serum cholesterol, LDL-cholesterol and triglycerides. However, soy protein intake did not significantly affect serum HDL cholesterol concentrations. The effect of soy protein intake depended on the initial cholesterol concentration. Subjects with normal cholesterol showed a slight decrease of 3.3 percent, and subjects with a moderately elevated blood cholesterol showed a slight decrease of 4.4 percent. Only in subjects with medium or severely high blood cholesterol there was a significant decrease in cholesterol by 7.4 percent and 19.6 percent, respectively. The nature of changes in serum LDL cholesterol concentrations was similar to the nature of changes in total cholesterol concentrations. Also, changes in serum triglyceride concentrations strongly depended on the initial serum triglyceride concentrations. Various types of soy proteins were studied, such as isolated soy protein, structured soy protein, or a combination thereof, and it was found that the type of soy protein does not significantly affect the change in serum cholesterol. The study did not consider the simultaneous administration of various types of soy proteins separately with dietary fiber. References to the composition, including a combination of soy protein, a high content of phytoestrogen compounds and dietary fiber, were not made.

Bakhit (J. Nutr. 124, 213-222 (1993)) studied men with moderately high blood cholesterol who were on the main diet and reported that adding 25 g of soy protein to a diet low in fat and cholesterol reduced total cholesterol concentrations in men with high blood lipids. In subjects with lower blood cholesterol concentrations (<5.7 mmol / L), this level of soy protein intake did not affect blood lipids, and it was suggested that plasma lipids may even be increased in some subjects following eating soybeans. Other studies have also shown that, in general, subjects with pre-existing high cholesterol levels in the blood respond to soy protein intake, while subjects with normal blood cholesterol levels do not. Bakhit et al. no additional effect of competitive use of soybean protein and soybean fiber was observed. References to the composition, including a combination of soy protein, a high content of phytoestrogen compounds and dietary fiber, were not made.

Faggiotto (Athrosclerosis Reviews 21, 187-194 (1990)) claims that atherosclerosis is a very complex disease that involves various pathological processes, such as inflammation and degeneration. The onset of atherosclerosis and its progression are difficult to perceive, slow and asymptomatic processes, partially coinciding with the normal aging process. It is emphasized that despite the enormous amount of accumulated information, it is not possible to explain why atherosclerosis is so common in the Western civilized world, how fat strips are formed in young people, how fat strips turn into fibrous plaques, and what is the role of inflammation, for example, with atherosclerosis. It is argued that even if atherosclerosis becomes symptomatic, the choice of treatment usually comes down to surgery, since drug treatment has little short-term benefit or is useless, except when patients undergo relatively long-term and aggressive therapy. References to the composition, including a combination of soy protein, a high content of phytoestrogen compounds and dietary fiber, were not made.

Gooderham (J. Nutr. 126 (8), 2000-2006 (1996)) suggested that although the addition of soy protein to a typical western diet could certainly increase the concentration of isoflavones in the blood plasma, this would not necessarily be significant in confronting the risk factors for developing the disease heart, such as high serum cholesterol and triglycerides and platelet aggregation. It has been found that any increase in serum isoflavones following ingestion of soy-rich foods varies among subjects analyzed. It is assumed that the reason for this may be, for example, the choice of a certain time of consumption of soy protein or the composition of the intestinal flora. The intestinal metabolism of isoflavones varies in subjects, and remains to be seen. It is noted that the content of isoflavones present in human plasma is most likely not significant for mediating significant inhibition of platelet aggregation. It is emphasized that isoflavones are found in human blood plasma predominantly in an inactive glucuronide conjugated form and only a small amount, such as about 10 percent, are in active free and sulfate conjugated forms. It was reported that the lack of the effect of isoflavones on total cholesterol in serum in one study is in good agreement with other studies, which also showed that soy has a weak effect in subjects with normal cholesterol in the blood, while in subjects with elevated cholesterol blood cholesterol generally shows a lower total and LDL cholesterol compared to subjects with normal blood cholesterol. It is emphasized that only a few studies have shown the effect of increasing HDL cholesterol due to consumption of soy protein, and that most studies have shown little or no effect on HDL cholesterol. Reported data show a similar lack of soy protein effect on HDL cholesterol in subjects with normal blood cholesterol. It was emphasized that in order to determine the ability of these compounds to have the effect of lowering the lipid content associated with the intake of soy protein, separately isoflavones were only recently studied. The introduction of purified isoflavones to animals showed different results on the content of lipids in the blood. The results of one study conducted in subjects with high blood cholesterol could not show the effect of purified isoflavones on plasma lipids. References to the composition, including a combination of soy protein, a high content of phytoestrogen compounds and dietary fiber, were not made.

Hendrich (J. Nutr. 124 (9 Suppi.), 1789S-1792S (1994)) reported that isoflavones can potentially be highly beneficial for maintaining human health and that isoflavones may have a health-protecting effect in amounts that are potentially acceptable to humans. daily containing soy products. The content of isoflavones in soy products varies from 0.1 to 1 mg / g. Some factors, such as the appearance of soybeans, the processing and addition of other ingredients to food, affect the isoflavone content in food. It has been argued that human intestinal bacteria can significantly destroy isoflavones taken internally, and that this may be an explanation for the fact that only 15-20 percent of isoflavones are reported to be removed unchanged from urine and feces. It is argued that a large amount of work is required to determine the relationship between the concentration of isoflavones in urine and human blood plasma and the biological effects of isoflavones. It is noted that although more data on health effects are needed on animals, the time is approaching when permission can be given to study the health effects of long-term studies of adding purified isoflavones and isoflavones-containing foods to human food. References to the composition, including a combination of soy protein, a high content of phytoestrogen compounds and dietary fiber, were not made.

Hunninghake (Am. J. Med. 97, 504-508 (1994)) evaluated the effects of lowering blood cholesterol as a result of long-term treatment with a dietary fiber mixture administered twice daily. 59 subjects with average blood cholesterol who completed a 15-week placebo-controlled study with dietary fiber received 20 g / day of fiber for an additional 36 weeks. Significant effects on the content of both triglycerides and HDL were not obtained. The content of total cholesterol and LDL cholesterol and the ratio of HDL cholesterol to LDL cholesterol significantly decreased during treatment. The average percentage reduction compared to control after 51 weeks of treatment was approximately 8 percent for total cholesterol, 9 percent for LDL cholesterol, and 11 percent for the ratio of LDL cholesterol to HDL cholesterol. References to the composition, including a combination of soy protein, a high content of phytoestrogen compounds and dietary fiber, were not made.

Knight (Maturitas 22, 167-175 (1995)) provides a brief review of the literature, mainly related to the clinical effects of phytoestrogens in relation to diseases associated with aging. A literature review related to cardiovascular disease states that the protective effect of phytoestrogens is manifested through changes in lipids, lower LDL cholesterol, and higher HDL cholesterol and vascular effects that affect both vascular tone and vascular wall elasticity. It is reported that the use of soy protein changes the lipid content, and it turns out that food soy protein has an anti-atherogenic effect compared to various animal proteins. It is concluded that isoflavones represent a large and interesting group of compounds with potential benefits in relation to many diseases. It is emphasized that current data confirm the conclusion that phytoestrogens may be among nutritional factors that have a protective effect against heart disease. However, further clinical studies are required to more accurately explain these effects. References to the composition, including a combination of soy protein, a high content of phytoestrogen compounds and dietary fiber, were not made.

Knight (Obstet. Gynecol. 87, 897-904 (1996)) reviewed the sources, metabolism, efficacy, and clinical effects of phytoestrogens in relation to humans. The review suggests that phytoestrogens are among the nutritional factors that have a protective effect against heart disease in vegetarians. Based on epidemiological studies and cell line studies, it is argued that invasive studies are currently suitable for achieving the clinical effects of phytoestrogens due to their potentially significant health benefits associated with eating these compounds containing food. It is concluded that the clinical applications of phytoestrogens are still at an initial stage. References to the composition, including a combination of soy protein, a high content of phytoestrogen compounds and dietary fiber, were not made.

Packard (Arterioscler. Thromb. Vasc. Biol. 17, 3542-3556 (1997)) reviewed the heterogeneity of the classes of lipoprotein containing apolipoprotein B and proposed an interpretation of kinetic studies of the metabolism of apolipoprotein B in the light of fundamental structural and functional abnormalities. The review is based on the fact that lipoprotein classes consist of a limited number of components with individual properties. However, the cause of this heterogeneity and importance for the disease is not well understood. The LDL fraction consists of a small number of subtypes of particles with a relatively discrete size and density. People with a predominant small LDL content have a three-fold increased risk of developing myocardial infarction, regardless of the total LDL concentration. References to the composition, including a combination of soy protein, a high content of phytoestrogen compounds and dietary fiber, were not made.

Potter (Am. J. Clin. Nutr. 58, 501-506 (1993)) studied the effects of soy protein with or without soy fiber on plasma lipids in men with moderately high blood cholesterol. It is reported that the total concentration and concentration of LDL cholesterol can be significantly reduced in men with a moderately increased blood cholesterol, as shown by replacing 50 percent of the protein diet with soy protein. Similar decreases in blood lipids were observed for isolated soy protein, regardless of whether it was consumed with soy cotyledon fiber or cellulose fiber. Plasma triglyceride concentrations were not affected by the various food exposures described in the article. The study did not reveal any additional effect of lowering cholesterol by competitively administering soybean cotyledon fiber with isolated soy protein, and it was found that it is not known whether or not there is an additional benefit to lowering plasma cholesterol concentrations from increased competitive administration of soybean protein and fiber in humans. References to the composition, including a combination of soy protein, a high content of phytoestrogen compounds and dietary fiber, were not made.

Reinli (Nutr. Cancer 26, 123-148 (1996)) reviewed the literature on quantitative data on the content of known phytoestrogens (daidzein, genistein, cumestrol, formononetin and biochanin A) in edible plants. It is reported that isoflavones daidzein and genistein can exist in four related types of chemical structure, i.e. in the aglyconic structure (daidzein and genistein), in the 7-ortho-glucoside structure (daidzein and genistein), in the 6'-ortho-acetylglucoside structure (6'-ortho-acetyldaidzein and 6'-ortho-acetylgenistein) and in 6'- ortho-malonylglucoside structure (6'-ortho-malonyldaidzein and 6'-ortho-malonylgenistein). Conjugates (7-ortho-glucosides, 6’-ortho-acetyl glucosides and 6’-ortho-malonyl glucosides) are transformed into aglycones, sometimes called free isoflavones, by hydrolysis of the intestinal bacteria with the enzyme β-glucosidase. Acid hydrolysis in the stomach can also contribute to the formation of free isoflavones. It is unclear how readily the conjugates undergo hydrolysis and subsequent absorption. It is emphasized that isoflavones in various animals and humans are metabolized differently. References to the composition, including a combination of soy protein, a high content of phytoestrogen compounds and dietary fiber, were not made.

Sniderman (Am J. Cardiol. 79, 64-67 (1997)) presented a risk factor hypothesis with an emphasis on the integral role of LDL in atherogenesis. It was emphasized that measuring LDL cholesterol is not enough to assess the risk inherent in LDL, and that other classic risk factors, such as hypertension, diabetes, and smoking, show their atherogenic potential to a greater extent or solely by enhancing the harmful effects of LDL on arterial wall. It has been confirmed that the content of small, dense LDL particles is one of the most traditional dyslipoproteinemias associated with coronary artery disease. It is reported that an increased content of lipoprotein (a) is associated with an increased risk of developing ischemia, but the reason for this fact is still unclear. References to the composition, including a combination of soy protein, a high content of phytoestrogen compounds and dietary fiber, were not made.

WO 95/10512 relates to a method for producing agluconic isoflavone enriched with plant-derived whey protein, and relates, in one embodiment, to serum with a genistein solids content of from about 2.6 to about 8.7 mg / g and a daidzein content in solids from about 2.5 to about 6.0 mg / g. References to the composition, including a combination of soy protein, a high content of phytoestrogen compounds and dietary fiber, were not made.

WO 95/10529 relates to a method for producing agluconic isoflavone enriched with a protein concentrate, and relates, in one embodiment, to a concentrate with a genistein solids content of from about 1.0 to about 2.0 mg / g and a daidzein content of from about 0.7 up to approximately 1.5 mg / g. References to the composition, including a combination of soy protein, a high content of phytoestrogen compounds and dietary fiber, were not made.

WO 95/10530 relates to a method for preparing a protein-containing aqueous extract and gluconic isoflavone and discloses, in one embodiment, a vegetable protein isolate with a genistein solids content of from about 1.5 to about 3.5 mg / g and a daidzein content in solids from about 1.0 to about 3.0 mg / g. References to the composition, including a combination of soy protein, a high content of phytoestrogen compounds and dietary fiber, were not made.

WO 97/31546 refers to data from general substitution programs (over 6 weeks) in weight loss studies conducted at Karolinska Hospital in Sweden. It was shown that products including isolated soy protein and soybean cotyledon fiber reduce serum cholesterol by a maximum of 27 percent and serum triglycerides by a maximum of 44 percent for a sample of patients with an average initial cholesterol of 5.6 mmol / L. An average value of 6.25 mmol / L was determined for all patients with a serum cholesterol content of more than 6 mmol / L, and a decrease in serum cholesterol by 33 percent was observed for this group of patients. Since the reported data was part of a weight loss program, the effect of diet and / or the effect associated with weight loss should have influenced the observed decrease in cholesterol and / or triglycerides. References to the composition, including a combination of soy protein, a high content of phytoestrogen compounds and dietary fiber, were not made.

WO 97/37547 relates to an isoflavone-enriched product based on soy protein with a protein content of more than 60 percent of the total dry matter, with a total fiber content of less than 4 percent of the total dry matter, with a sucrose content of more than 10 percent of the total dry matter , with a total sulfur-containing amino acid content of more than 2.2 percent of the total amino acid content, with a stachyose content of less than 1.5 percent of the total dry matter, with a total isoflavone content of more than 2.5 mg / g, equivalent to 0, 25 percent. The use of fiber of soybean cotyledon cannot be opposed and the claimed claims are used as an ingredient in the preparation of a food-grade product, and not for the treatment of diabetes mellitus. The product also differs from the composition of the present invention by the inclusion of total dietary fiber in an amount of less than 4 percent of the total dry matter and an unusually low amount of stachyose and a high amount of sulfur-containing amino acids.

US Patent No. 5,320,949 relates to a method for preparing a fiber-based agluconic isoflavone-rich product from protein material of vegetable origin in suspension form and relates, in one embodiment, to a fiber-based aglucone-rich product obtained directly using the process with a genistein content of about 1.0 -2.0 mg / g and with a daidzein content of from about 0.7 to 1.7 mg / g. References to the composition, including a combination of soy protein, a high content of phytoestrogen compounds and dietary fiber, were not made. No references were made to the treatment of diabetes mellitus using a composition comprising a combination of soybean cotyledon fiber and a phytoestrogen compound.

US Patent No. 5,353,384 relates to an aglucon-rich fiber-based product with a genistein content of from about 1.0 to 2.0 mg / g and a daidzein content of from about 0.7 to 1.7 mg / g. References to the composition, including a combination of soy protein, a high content of phytoestrogen compounds and dietary fiber, were not made.

EP 827698 A2 and EP 827698 A3 relate to a method for producing agluconic isoflavone-enriched extract from plant material containing isoflavone conjugates and protein. References to the composition, including a combination of soy protein, a high content of phytoestrogen compounds and dietary fiber, were not made.

Abstract presented at a March 1998 goda American Heart Association's 38 ^{th Annual Conference on Cardiovascular Disease Epidemiology and} Prevention, refers to a reduction of total and LDL-cholesterol in a patient after a meal with addition of 25 g of soybean protein, containing 4, 25, 42 mg and 58 mg of isoflavones, respectively. A dose-dependent effect is reported in such a way that an increase in isoflavones is associated with an increase in lower cholesterol. A maximum decrease in serum total and LDL cholesterol levels of 4 and 7 percent has been reported, respectively, for a product containing 58 mg of isoflavone. References to the composition, including a combination of soy protein, a high content of phytoestrogen compounds and dietary fiber, were not made.

SUMMARY OF THE INVENTION

The present invention relates to a nutritional composition with a stably high content of phytoestrogenic substances, such as, for example, natural isoflavones. More specifically, the present invention relates to a nutritional composition of ingredients derived from soybeans with a stably high content of phytoestrogenic substances, such as, for example, natural isoflavones.

The present invention represents a possible breakthrough in the treatment of diabetes mellitus and, more specifically, the present invention relates to a combination comprising a) soy protein, preferably isolated soy protein, b) a consistently high content of plant hormone in the form of a phytoestrogen compound, preferably natural isoflavones, and ) nutritional fiber, preferably soybean fiber, particularly preferably soybean fiber derived from the cotyledon of soybeans, hereinafter referred to as fiber coy cotyledons of soy.

The present invention is used for the treatment, including prophylactic, treatment of cardiovascular diseases, such as hypercholesterolemia, hypertriglyceridemia, hyperlipidemia and other cardiovascular diseases, such as, for example, arteriosclerosis. One objective of the present invention is to substantially reduce serum cholesterol, LDL cholesterol and triglycerides in a subject with a moderately elevated blood cholesterol level. Another objective of the present invention is a significant reduction in total cholesterol, LDL cholesterol and triglycerides in serum in a subject with a high blood cholesterol and / or high blood lipids. Another objective of the present invention is to bring the artery wall into a state more resistant to the accumulation of lipoproteins. A further object of the present invention is to provide a composition effective in the treatment and / or prophylactic treatment and / or prophylaxis and / or attenuation of an arteriosclerotic state by reducing deposition of cholesterol and / or triglycerides in the endothelium of an artery wall. Another objective of the present invention is to reduce the formation of lipid plaques. The composition in accordance with the present invention can be included in a micropreparation, as described hereinafter.

Phytoestrogen compounds are natural plant hormones with structural similarities to 17β-estradiol. Phytoestrogens consist of several classes, including isoflavones, cumestans, lignans and resorcylic acid lactones. The class of isoflavones includes, among others, genistein, daidzein, equol, glycetin, biochanin A, formononetin and ortho-desmethylangolezine. It was found that isoflavones genistein and daidzein are found almost exclusively in soybeans. When present in a plant, isoflavones are mainly in glucoside form, i.e. linked to a sugar molecule. Isoflavones in glucoside form can deconjugate with the release of isoflavones in the so-called aglyconic form, which is a biologically more active form of isoflavones and which is absorbed faster and to a greater extent in the human intestine than isoflavones in glucoside form. In vitro studies have examined the relative estrogen effect exhibited by various phytoestrogens, including isoflavones. Knight (Maturitas 22, 167-175 (1995)) reported efficiencies compared to estradiol (having a relative potency of 100), among others for genistein (0.084) and daidzein (0.013). However, the results also showed that estrogen receptor complexes formed by estradiol and isoflavones, such as genistein and daidzein, are functionally equivalent. It was shown that the relative dissociation constant of genistein with an estrogen receptor, as shown by competitive binding methods, is 100-10000 times greater than the dissociation constant of estradiol.

The term "natural" substance, as used in the present description of the invention and the accompanying claims, refers to a substance originally isolated from a natural source, animal or vegetable origin, such as soy, or a modified form of such a substance. A natural substance for use in a composition in accordance with the present invention may be included in the composition in accordance with the present invention as part of a natural source or in any type of extract, isolate or the like, or it may be isolated from a source of plant origin or synthesized biologically, microbiologically either chemically or by any other means.

Soy proteins are involved in lowering cholesterol and triglycerides, they are easily digested, and they are the only effective source of protein to maintain nitrogen balance. The intake of soy isoflavones in large quantities further enhances this effect. It has been shown that dietary fiber, such as fiber of soybeans, especially fiber of soybean cotyledon, lowers total serum cholesterol, normalizes the activity of the gastrointestinal tract and does not affect the absorption of essential minerals.

Thus, one aspect of the present invention relates to a composition comprising:

(a) a soy protein source selected from isolated soy protein, soy protein concentrate, or soy flour, said soy protein source providing a protein content that is at least 45 weight percent of the total protein content in the composition and said total protein content provides at least 15 percent of the total energy in the composition,

(b) at least one phytoestrogen compound in an amount of more than 0.16 weight percent of the soy protein content in the composition, and

(c) dietary fiber in an amount of more than 6 weight percent of the total weight of the composition in dry residue.

A more preferred aspect of the present invention relates to a composition comprising:

(a) isolated soy protein in an amount of not less than 50 weight percent of the total protein content in the composition, said total protein content providing at least 15 percent of the total energy content in the composition,

(b) at least one phytoestrogen compound in an amount of more than 0.16 weight percent of the soy protein content in the composition, and

(c) soybean fiber in an amount of more than 6 weight percent of the total weight of the composition in dry residue.

The most preferred aspect of the present invention relates to a composition comprising:

(a) isolated soy protein in an amount of not less than 50 weight percent of the total protein content in the composition, said total protein content providing at least 15 percent of the total energy content in the composition,

(b) at least one phytoestrogen compound in an amount of more than 0.16 weight percent of the soy protein content in the composition, and

(c) fiber soybean cotyledon in an amount of more than 6 weight percent of the total weight of the composition in the dry residue.

Phytoestrogen compounds are natural substances of plant origin that have either structural or functional similarities with 17β-estradiol or with estrogenic effects. Phytoestrogens consist of several classes, including isoflavones, cumestans, lignans and re-acyl acid lactones. Examples of isoflavones in accordance with the present invention are genistein, daidzein, equol, glycetin, biochanin A, formononetin and ortho-desmethylangolezine. The phytoestrogenic compounds of the composition of the present invention are preferably isoflavones, more preferably genistein, daidzein, glycetin and / or equol, even more preferably genistein and / or daidzein, even more preferably genistein. Genistein and daidzein are found almost exclusively in soybeans. A preferred composition in accordance with the present invention may thus include a separate isoflavone, such as genistein, daidzein, glycetin or equol, or it may include a separate isoflavone selected from the group consisting of at least genistein, daidzein, glycetin or equol.

The composition in accordance with the present invention may be able to prevent and / or attenuate and / or treat and / or prophylactically treat an arteriosclerotic condition by reducing the accumulation of cholesterol in the artery wall. This inhibitory effect can be mediated by binding of natural isoflavones and / or soy proteins to the estrogen receptor or estrogen-like receptor present in the artery endothelium. Soy proteins are preferably obtained by partial hydrolysis of soy protein.

Plasma levels of both triglycerides and lipoproteins are usually increased in patients receiving treatment for cardiovascular disease, and this increased content, provided that it is not reduced during treatment, is likely to cause atherosclerosis and / or coronary heart disease (CHD) . Beta-2 adrenergic receptors are present on many different types of cells, including fat cells. The beta-2 adrenergic receptor is involved in the regulation of triglyceride synthesis in fat cells and, based on the currently preferred hypothesis, the binding of soy proteins and / or a phytoestrogen compound, such as, for example, natural isoflavone, to beta-arteries present on the fat cell or in the artery wall 2-adrenergic receptor, is effective in reducing, for example, the synthesis of triglycerides in the fat cell, and / or the release of triglycerides into the bloodstream, and / or reducing the deposition of triglycerides in the artery wall. Soy proteins are preferably obtained by partial hydrolysis of soy protein.

According to a preferred hypothesis, the composition of the present invention reduces and / or eliminates one or more risk factors for developing cardiovascular diseases. Accordingly, the composition of the present invention can be effective in the prophylaxis and / or prophylactic treatment and / or the alleviation and / or treatment of conditions such as hypercholesterolemia, hypertriglyceridemia, hypertension and hyperglycemia. The composition in accordance with the present invention may also be able to reduce, prevent and / or eliminate the formation of fat strips and / or the formation of fibrous plaques and / or is effective in mediating the regression of one or both of these arteriosclerotic conditions.

According to a preferred hypothesis, the composition of the present invention will reduce serum total cholesterol and / or lower serum LDL cholesterol and / or lower serum triglycerides and / or effectively lower HDL ratio -cholesterol to the content of LDL cholesterol and / or to effectively increase the content of high density lipoprotein (HDL) and / or cause a decrease in the content of low density lipoprotein (LDL) in serum. It is desirable to achieve an increased ratio of HDL cholesterol to LDL cholesterol, as this can lead to increased reverse cholesterol transport and subsequent secretion.

It is also believed that the composition of the present invention acts on the metabolism of apolipoprotein B lipoprotein, including the metabolism of a recently discovered class of apolipoprotein B, comprising lipoprotein particles called small dense LDL particles. The LDL class of lipoproteins actually consists of several components with individual qualities. The basis of this heterogeneity and the consequences for the disease are currently not well understood. An increased content of small, dense LDL particles is one of the most common forms of dyslipoproteinemia associated with coronary heart disease, and serum apolipoprotein B is usually disproportionately higher than LDL cholesterol in patients with dyslipoproteinemia.

The heterogeneity within the classes of lipoproteins may result from varying lipid contents, different apoprotein compositions, altered protein conformation, or yet unidentified structural variation. Subjects with a predominance of small dense LDL particles have an increased risk of developing myocardial infarction, regardless of the total concentration of LDL in serum. Accordingly, the composition in accordance with the present invention can be effective in reducing the increased content of small dense LDL particles.

Hypertriglyceridemia is associated with an increase in the coagulation activity of thrombogenic factors, such as factor VII, and / or factor X, and / or factor XII, and with an increase in the content of tissue plasminogen activator inhibitor, PAI-1. An increase in the inhibitor concentration is expressed in a decrease in the level of plasminogen synthesis, and therefore in a reduced content of plasminogen clot stimulating lysis. These changes in coagulation activity undoubtedly contribute to the observed state, characterized by an increase in blood coagulation. In accordance with one currently preferred hypothesis, the present invention provides a composition that can be effective in normalizing the homocysteine content and / or coagulation activity of at least one of the thrombogenic factors, such as, for example, factor VII and / or factor, X and / or factor XII, for example, by reducing their increased activity. Also, the composition in accordance with the present invention can be effective in increasing a reduced concentration of a tissue plasminogen activator inhibitor PAI-1, which in turn leads to an increase in plasminogen-stimulated clot lysis. The composition in accordance with the present invention can be effective in reducing the increased aggregation ability of platelets and / or mediating, directly or indirectly, reducing the increased content of lipoprotein (a) associated with a condition characterized by increased blood coagulation in arteriosclerotic condition.

Accordingly, in one embodiment, the present invention relates to a composition effective in reducing and / or eliminating risk factors for developing coronary heart disease (CHD) in obese subjects. Therefore, the composition in accordance with the present invention can be able to prevent and / or weaken and / or treat and / or prophylactically treat and / or eliminate hypertriglyceridemia and / or hypercholesterolemia and / or hyperglycemia and / or hypertension and / or is effective in mediating an increase in the ratio of HDL cholesterol to LDL cholesterol.

The composition in accordance with the present invention can be effective in the treatment of dyslipidemia, such as, for example, hypertriglyceridemia and / or hypercholesterolemia due to the increased content of VLDL, reduced and altered HDL and small dense LDL, and hypertension, all of which are risk factors for developing atherosclerosis . Accordingly, in one embodiment, the composition of the present invention may be able to effectively reduce and / or eliminate elevated serum VLDL, effectively increase reduced serum HDL, and effectively lower serum LDL, including low-density, low-density serum LDL. The composition in accordance with the present invention may be able to prevent and / or treat and / or prophylactically treat and / or relieve hypertension.

The composition in accordance with the present invention can be effective in suppressing any effect that could otherwise cause an increase in the turnover of smooth muscle cells of the artery and / or lead to an increase in the accumulation of cholesterol esters in the walls of the artery.

In hypercholesterolemia characterized by increased intracellular cholesterol due to, for example, increased delivery of LDL cholesterol via the LDL receptor, the composition in accordance with the present invention can be effective in reducing the increased activity of LDL receptor. The composition of the present invention may also be capable of attenuating, eliminating and / or treating any decrease in HDL-receptor-mediated cholesterol release. Accordingly, the composition in accordance with the present invention may be able to reduce and / or eliminate any enhanced containment of intracellular cholesterol due to a decrease in HDL-receptor-mediated cholesterol output.

Modifications of lipoproteins are another risk factor for the development of cardiovascular disease. A modification characterized by protein glycosylation is associated, for example, with atherosclerosis, and it is believed that glycosylated lipoproteins, such as, for example, LDL, VLDL, VLDL and HDL, may be functionally abnormal. Thus, the accumulation of glycosylated LDL in plasma can be regarded as an increase in the accumulation of cholesterol ester. It is also believed that HDL glycosylation may decrease the ability of HDL to adhere to the HDL receptor. This weakened binding probably reduces the level of intracellular cholesterol output. Thus, glycosylated HDL can be another powerful factor potentially contributing to the accumulation of cholesterol in the artery cell walls. The composition in accordance with the present invention can be effective in preventing, attenuating, treating, reducing and / or eliminating glycosylation of lipoproteins in the serum of subjects. The composition in accordance with the present invention may also be effective in preventing lipoprotein modification due to, for example, oxidation, chemical modification, such as chemical cross-linking, or modifications due to a change in the lipid composition of the lipoprotein, such as any increase or decrease in the content of triglycerides, esters cholesterol, free cholesterol and apolipoproteins.

It is believed that glycosylated lipoproteins are a substrate for further processing leading to the formation of hyperglycosylated compounds. Glycosylation and hyperglycosylation of proteins, including lipoproteins, both in blood plasma and in the artery wall, can also be a risk factor for the development of cardiovascular disease, including arteriosclerosis. Thus, the composition in accordance with the present invention may be able to prevent, treat, reduce, weaken and / or eliminate the accumulation of hyperglycosylated proteins in both serum and artery wall cells. Thus, the composition reduces the content of LDL, which become "trapped" in the artery wall as a result of a high level of glycosylation of the artery wall proteins. The composition of the present invention can also be effective in attenuating and / or preventing any change in the endothelial cell wall that enhances the LDL trap process and can be effective in restoring the formation of cells with normal permeability and adhesion parameters.

Glycosylation, hyperglycosylation, oxidation and / or autooxidative glycosylation of lipoproteins are risk factors for the development of a cardiovascular disease such as arteriosclerosis. Thus, the composition in accordance with the present invention can be effective in eliminating, preventing, attenuating, treating and / or reducing any case of glycosylation, hyperglycosylation, oxidation and / or autooxidative glycosylation of lipoproteins. According to one currently preferred hypothesis, the phytoestrogen compound of the composition of the present invention is capable of counteracting these cases. The phytoestrogen compound may also be able to prevent, reduce and / or eliminate the formation of, for example, free radicals that are usually involved in such processes, and the composition in accordance with the present invention can be effective in the presence, stimulation and / or elimination of the formation of an effective antioxidant defense system to counter glycosylation, hyperglycosylation, oxidation and / or autooxidative glycosylation of serum proteins and proteins, including cell wall lipoproteins arteries.

The composition in accordance with the present invention can effectively act as an antioxidant in the prevention of oxidation and / or glycosylation of lipoproteins. The term autooxidative glycosylation, or glycoxidation, means a reaction catalyzed, for example, by a decrease in sugar content, which leads to oxidative modification and / or cross-linking of proteins. The increased formation of free radicals and lipid peroxidation can also contribute to the formation of autooxidatively glycosylated lipoproteins, and the composition in accordance with the present invention can also effectively prevent and / or eliminate this contribution.

According to another currently preferred hypothesis, the binding of a phytoestrogen compound, such as, for example, isoflavones, usually in combination with predominantly obtained by hydrolysis of soy proteins by soy peptides, to a receptor on the artery wall, such as, for example, an estrogen receptor, or an estrogen-like receptor involved or effective in controlling the absorption of cholesterol in the artery wall, possibly by regulating the permeability of the specified wall and / or cholesterol transport mechanism and / or triglyceride across cell membranes. Therefore, the binding of isoflavones, such as, for example, genistein and / or daidzein, to a receptor in the artery wall prevents the penetration of lipoproteins into the artery wall. The binding of isoflavones to a receptor in the artery wall is particularly effective in controlling, preventing and / or eliminating the formation of fatty bands and / or the formation of fibrous plaques and / or is effective in mediating the regression of one or both of these arteriosclerotic conditions.

According to a particularly preferred hypothesis, the binding of isoflavones, such as, for example, genistein and / or daidzein, to a receptor in the artery wall, especially to an estrogen receptor or estrogen-like receptor, leads to increased synthesis of nitric oxide in the wall of the endothelial cells of the artery. Nitric oxide is known to have anti-atherosclerotic effects, including inhibition of platelet adhesion and aggregation and smooth muscle cell proliferation. The soy peptides obtained by hydrolysis of soy protein can take part in the binding of isoflavones to an estrogen receptor or estrogen-like receptor, or soy peptides can themselves bind to the indicated receptor and have an effect leading to increased nitric oxide synthesis.

According to another currently preferred hypothesis, the determination of the oxidative potential, which stimulates the oxidation of lipoproteins and / or autooxidative glycosylation of lipoproteins, follows, and is very likely due to, a decline in the work of cellular antioxidant defense systems. Thus, the composition in accordance with the present invention can effectively act as an antioxidant. This action reduces and / or eliminates the sensitivity of LDL, VLDL, HDL and / or HDL to oxidation.

Moreover, the composition in accordance with the present invention can also be effective in reducing hypersensitivity to endothelial damage and / or in weakening and / or restoration and / or improving an ineffective endothelial cell repair mechanism leading to endothelial dysfunction. One of the effects of such an effect, which is affected by the composition in accordance with the present invention, is the direction of the formation of macrophages away from the site of formation of spongy cells and in increasing the potential for the formation of smooth muscle cells of the artery.

In accordance with another preferred hypothesis, the composition in accordance with the present invention contributes to and / or mediates a decrease in the thickness of the artery wall and leads to a decrease in the number of LDL entering the wall. It is believed that the increased thickness of the artery wall is undoubtedly associated with increased absorption of LDL particles, which usually either aggregate or oxidize inside the cells of the artery wall.

Also, the composition in accordance with the present invention may be able to reduce, eliminate and / or prevent the formation of increased serum lipoprotein (a). The content of lipoprotein (a) can be mainly genetically determined, and therefore, to reduce the content of lipoprotein (a) in serum, there are no effective cardiovascular drugs.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the total cholesterol content (in mm) for the four groups of Example 2 (A: patients of group I; B: patients receiving placebo with the same protein and fiber intake as in group I; C: patients of group II ; D: patients receiving placebo with the same protein and fiber intake as in group II) at each of 8 visits. Total cholesterol = total cholesterol; TS = total cholesterol; Visit = visit.

Figure 2 shows the LDL cholesterol content (in mm) for the four groups of Example 2 (A: patients of group I; B: patients receiving placebo with the same protein and fiber intake as in group I; C: patients of group II; D: patients receiving placebo with the same protein and fiber intake as in group II) in each of 8 visits. LDL-cholesterol = LDL-cholesterol; LDL-chol = LDL-cholesterol; Visit = visit.

Figure 3 shows the HDL cholesterol content (in mm) for the four groups of Example 2 (A: patients of group I; B: patients receiving placebo with the same protein and fiber intake as in group I; C: patients of group II; D: patients receiving placebo with the same protein and fiber intake as in group II) in each of 8 visits. HDL-cholesterol = HDL cholesterol; HDL-chol = HDL cholesterol; Visit = visit.

Figure 4 shows the triglyceride content (in mm) for the four groups of Example 2 (A: patients of group I; B: patients receiving placebo with the same protein and fiber intake as in group I; C: patients of group II; D: patients receiving placebo with the same protein and fiber intake as in group II) at each of 8 visits. Triglycerides = triglycerides; Visit = visit.

Figure 5 shows the average ratio of HDL cholesterol to LDL cholesterol for the four groups of Example 2 (A: patients of group I; B: patients receiving placebo with the same protein and fiber intake as in group I; C : patients of group II; D: patients receiving placebo with the same protein and fiber intake as in group II) in each of 8 visits. Mean ratio HDL / LDL = average ratio of HDL cholesterol to LDL cholesterol; Visit = visit.

DETAILED DESCRIPTION OF THE INVENTION

The composition of the present invention is a new combination of soy protein, preferably isolated soy protein, a phytoestrogen compound, preferably natural isoflavones, and dietary fiber, preferably soybean fiber, more preferably soybean cotyledon fiber.

The soy protein source can be isolated soy protein, soy protein concentrate, soy flour, and the like. or any combination thereof. Isolated soy protein is preferred.

Isolated soy protein is the main protein fraction of soybeans. It is obtained from high-quality, peeled, fat-free soybeans by eliminating the predominance of non-protein components, resulting in a fraction of the isolated soy protein, which should contain at least 90 percent protein (N × 6.25) in solids. Obtaining occurs through a series of steps in which the protein portion of the soybeans is separated from the remainder of the soybeans. Carbohydrate removal results in a product that is essentially tasteless and odorless and therefore particularly suitable for a nutritional composition for humans.

Soy protein concentrates are obtained by removing most of the oil and water-soluble non-protein constituents from fat-free and husk-free soybeans. In the current context, the soy protein concentrate should preferably contain at least 65 percent of the protein solids.

Soya protein can also be a source of soya protein, which can be full fat powder or low fat soya flour. Full-fat soy flour is obtained from whole, husk-free soybeans that have been ground to a fine powder and, as the name implies, still contains fat found in nature in soybeans. Fat-free soy flour is obtained from whole, peeled, fat-free soybeans, which were ground to a state of fine powder. Soybean flour contains approximately 50 percent soy protein solids in the present context.

The soy protein used in the composition of the present invention should preferably contain all the necessary amino acids in the amounts required for humans. Preferably, soy protein should also meet or exceed the required amino acid structure requirements for children and adults, as approved by the Food and Agricultural Organization, World Health Organization and United Nations University (FAO / WHO, UNU). Moreover, the preferred soy protein should be digestible compatible with the protein of milk, meat, fish and eggs. In conclusion, the preferred soy protein should be effective in maintaining nitrogen balance when consumed at the recommended level of protein intake.

Preferred isolated soy protein products meeting the above requirements are offered by Protein Technologies international. Inc. under the brand name SUPRO ^® . Isolated SUPRO ^® soy proteins come in many different qualities and SUPRO ^® XT 12C is particularly preferred quality. Currently, the most preferred quality is designated SUPRO ^® FXP-HO159.

Soy protein is preferably the main or sole source of protein in the nutritional composition of the present invention. However, other proteins, such as skim milk, preferably in the form of a powder, and other proteins of plant and animal origin, including milk proteins, can serve as sources of a portion of the protein. Preferably at least 45 weight percent, such as 50 weight percent, for example at least 60 weight percent, such as at least 70 weight percent, for example at least 75 weight percent, such as at least 80 weight percent, for example, at least 85 weight percent, such as at least 90 weight percent, for example at least 95 weight percent, such as at least 98 weight percent of the total protein content of the composition is soy protein ohm and more preferably, substantially all of the protein is soy protein.

In a preferred embodiment of the invention, the soy protein source is isolated soy protein. In this embodiment, preferably at least 50 weight percent, for example at least 60 weight percent, such as at least 70 weight percent, for example at least 75 weight percent, such as at least 80 weight percent, for example at least 85 weight percent, such as at least 90 weight percent, for example at least 95 weight percent, such as at least 98 weight percent of the total protein in the composition, is isolated soy protein and b Lee preferred that substantially all of the protein was isolated soy protein.

The total protein content in the composition in accordance with the present invention is a source of at least 15 percent of the total energy content of the composition, for example 18 percent, such as at least 20 percent, for example at least 22 percent, such as at least 25 percent, for example at least 28 percent, such as at least 30 percent, for example at least 32 percent, such as at least 35 percent, for example at least 38 percent, such as at least at least 40% nt, for example at least 42 percent, such as at least 45 percent, for example at least 48 percent, such as at least 50 percent of the total energy content of the composition, and preferably less than 90 percent of the total energy composition.

Phytoestrogen compounds in accordance with the present invention are defined as natural substances of plant origin, and these substances are structurally or functionally similar to 17β-estradiol or cause estrogen effects. Phytoestrogens consist of several classes, including isoflavones, cumestans, lignans and resorcylic acid lactones. Examples of isoflavones in accordance with the present invention are genistein, daidzein, equol, glycetin, biochanin A, formononetin and ortho-desmethylangolezine. The phytoestrogenic compounds of the composition of the present invention are preferably isoflavones, more preferably genistein, daidzein, glycetin and / or equol, even more preferably genistein and / or daidzein, even more preferably genistein. A preferred composition in accordance with the present invention may thus include a separate isoflavone, such as genistein, daidzein, glycetin or equol, or it may include at least a separate isoflavone selected from the group consisting of at least genistein, daidzein, glycetin and equola. When present in a plant, isoflavones are mainly in glucoside form, i.e. linked to a sugar molecule. The glucoside form can deconjugate with the release of the so-called aglyconic form, which is a biologically active particles. The composition in accordance with the present invention may include isoflavones in glucoside and / or aglyconic form, depending on where the deconjugation of the aglyconic form occurs biologically, in vitro or in any other way, where the isoflavones are included in the composition in accordance with the present invention or if agluconic forms are native forms of isoflavones.

The phytoestrogen compound is preferably present in an amount of at least about 0.16 weight percent, such as at least about 0.18 weight percent, for example at least about 0.20 weight percent, such as at least about 0, 22 weight percent, for example at least about 0.24 weight percent, such as at least about 0.25 weight percent, for example more than about 0.25 weight percent, such as at least re about 0.26 weight percent, for example at least about 0.28 weight percent, such as at least about 0.30 weight percent, for example at least about 0.32 weight percent, such as at least at least about 0.33 weight percent, for example, more than about 0.33 weight percent, such as at least about 0.35 weight percent, for example at least about 0.40 weight percent, such as at least about 0.45 weight percent, for example at least about 0.50 weight percent, such as at least about 0.55 weight percent, for example at least about 0.60 weight percent, such as at least about 0.65 weight percent, for example, at least about 0.70 weight percent, such as at least about 0.75 weight percent, for example at least about 0.80 weight percent, such as at least about 0.85 mass process nta, for example, at least about 0.90 weight percent, such as at least about 1.0 weight percent of the soy protein content, and preferably less than 2.50 weight percent of the soy protein content.

In the past, processing techniques used to produce soy proteins included steps that removed and / or destroyed isoflavones. Currently used methods provide products based on soy protein with a stably high content of natural isoflavones. Isoflavones in accordance with the present invention in glucoside and / or aglyconic form can be included in the composition in accordance with the present invention as such products based on soy protein and / or themselves and / or as part of any other isoflavone-containing composition.

Dietary fiber used in the present invention should preferably include a mixture of insoluble fiber and water-soluble fiber, also called soluble fiber. Soluble fiber has a decreasing effect on blood cholesterol. Examples of dietary fiber containing soluble fiber are fiber from apples, bananas, oranges, carrots, oats, and soybeans. Dietary fiber preferably includes soluble fiber in an amount of about 5 weight percent, such as about 10 weight percent, for example, about 15 weight percent, such as about 20 weight percent, for example, about 25 weight percent, such as about 30 weight percent for example, about 35 weight percent, such as about 40 weight percent, for example, about 45 weight percent, such as about 50 m weight percent, for example, about 55 weight percent, such as about 60 weight percent, for example, about 65 weight percent, such as about 70 weight percent, for example, about 75 weight percent, such as about 80 weight percent, for example, about 85 weight percent, such as about 90 weight percent, for example, about 95 weight percent. The dietary fiber used in the present invention is mainly soybean fiber, more preferably soybean cotyledon fiber. Such fiber is obtained from peeled soybean husk and fat-free cotyledon, and it consists of a mixture of soluble and insoluble fiber. Soybean cotyledon fiber is markedly different from soybean fiber obtained from soybean husk, as well as other sources of fiber. Soya cotyledon fiber is tasteless, cholesterol-free, low in fat and sodium, highly soluble in water and low in calories.

Fiber of soybean cotyledon, added to foods with modified fats and foods that are low in cholesterol, is known to further reduce serum cholesterol in subjects with high to low blood cholesterol levels. The effect is a decrease in serum total cholesterol, including a decrease in LDL cholesterol. Nevertheless, the content of HDL cholesterol and the content of total triglycerides in soybean cotyledon fiber is not significantly affected. It is believed that fiber of soybeans, especially fiber of soybean cotyledon, provides a synergistic effect in combination with a soy protein and / or phytoestrogen compound, such as natural isoflavones, or has a potentiating effect on soy protein and / or phytoestrogen compound, wherein said synergistic and potentiating effects are effective in reducing serum lipids and cholesterol in subjects with both normal and high serum total cholesterol and total triglycerides.

Not limited to any particular theory, it is currently believed that both soluble dietary fiber (working as a nutrient) and insoluble dietary fiber (working as a filling agent), especially soybean fiber, more specifically soybean cotyledon fiber , provides favorable conditions for the growth of microflora in the human intestines, which makes microflora more effective in deconjugation of isoflavones in glucoside form to aglycon form. Isoflavones in aglyconic form are absorbed in the human intestine faster and to a greater extent than isoflavones in glucoside form, and isoflavones in aglyconic form are biologically more active particles, with regard to reducing serum lipids and reducing atherosclerosis. In view of this, it should be understood that the introduction of a combination of soy proteins, a consistently high level of isoflavones and a combination of soluble and insoluble fiber is effective in ensuring an increased consumption of isoflavones.

The dietary fiber content of the total weight of the composition in accordance with the present invention in the dry residue is preferably more than 6 weight percent, for example at least 7 weight percent, such as at least 8 weight percent, for example at least 9 weight percent , such as at least 10 weight percent, for example at least 11 weight percent, such as at least 12 weight percent, for example at least 13 weight percent, such as at least 14 weight percent, for example, at least 15 weight percent, such as at least 16 weight percent, for example at least 17 weight percent, such as at least 18 weight percent, for example at least 19 weight percent, such as at least 20 weight percent, and preferably less than 50 weight percent.

The preferred content of dietary fiber in weight percent of the soy protein content should be in the range of about 10 to 100 weight percent, and the preferred content is in the range of 15 to 90 weight percent, such as 20 to 80 weight percent, for example 25 weight percent percent, for example, 30 mass percent, for example, 33 mass percent, such as 35 mass percent, for example, 40 mass percent, such as 50 mass percent, for example, 60 mass percent, such as 70 mass percent, for example, 75 weight percent.

Thus, the weight ratio of soy protein to dietary fiber is from about 1.0 to about 10.0, preferably more than about 1.0, for example, about 1.25, such as at least about 1.5, for example, at least about 1.75, such as at least about 2.0, for example at least about 2.25, such as at least about 2.5, for example, at least about 2.75, such as at least about 3.0, such as at least e about 3.25, such as at least about 3.5, for example at least about 3.75, such as at least about 4.0, for example, at least about 4.25, such as at least about 4.5, for example at least about 4.75, such as at least about 5.0, for example at least about 5.5, such as at least about 6.0 for example at least about 7.5.

A preferred daily dosage of soybean fiber is from at least 1 g to about 100 g of soybean fiber, for example from at least 2 to about 75 g of soybean fiber, such as from at least 3 g to about 50 g, for example from at least 4 g to about 40 g, such as from at least 5 g to about 30 g, such as from at least 10 g to about 20 g of soybean fiber.

Preferred products are soy cotyledon fiber, manufactured by Protein Technologies International, Inc., presented on the market under FIBRIM ^® trademark. Among the different soybean fiber produced under the trademark FIBRIM ^®, FIBRIM ^® 1020 is particularly preferred because of especial pleasantness to the taste and dispersibility for use in beverages of the dry mixtures. FIBRIM ^® 2000 is presently preferred for use in the ready-to-use liquids.

Two compositions of isolated soy protein and soybean cotyledon fiber are preferred in order to maximize the content of soy protein and isoflavones contained therein, namely SUPRO ^® FXP-HO159 and FIBRIM ^® 1020 for use in dry mix drinks and SUPRO ^® FXP-HO159 and FIBRIM ^® 2000 for use in ready-to-use liquids.

Alternatively, the present invention provides a source of a composition in which soy protein is not provided and where dietary fiber is soybean cotyledon fiber. This composition includes soybean cotyledon fiber in an amount of more than 4 weight percent of the total weight of the composition on a dry residue and at least one phytoestrogen compound in an amount of more than 0.10 weight percent of soybean cotyledon fiber in the composition. The present invention also relates to the use of such a composition as a medicament and / or in the manufacture of a medicament effective in the prophylaxis and / or treatment and / or prophylactic treatment and / or attenuation and / or elimination of a cardiovascular disease in a subject. . The present invention also relates to the use of such a composition as a medicament and / or in the manufacture of a medicament effective in the prophylaxis and / or treatment and / or prophylactic treatment and / or debilitating treatment, amelioration and / or elimination of arteriosclerosis and related cardio vascular disease in a subject. The present invention also relates to the use of such a composition and / or such a composition for the treatment of arteriosclerosis and related cardiovascular disease in a subject.

If soy protein is not present in the composition, the phytoestrogen compound is preferably present in an amount of at least about 0.12 weight percent of the soybean cotyledon fiber, such as at least about 0.14 weight percent, for example at least about 0, 16 weight percent, such as at least about 0.18 weight percent, for example at least about 0.20 weight percent, such as at least about 0.22 weight percent, for example, at least about 0.24 weight percent, such as at least about 0.25 weight percent, for example, more than about 0.25 weight percent, such as at least about 0.26 weight percent, for example at least about 0.28 weight percent, such as at least about 0.30 weight percent, for example at least about 0.32 weight percent, such as at least about 0.33 weight percent, for example more than pr about 0.33 weight percent, such as at least about 0.35 weight percent, for example at least about 0.40 weight percent, such as at least about 0.45 weight percent, for example at least about 0.50 weight percent, such as at least about 0.55 weight percent, for example at least about 0.60 weight percent, such as at least about 0.65 weight percent, for example at least approximately 0.70 weight percent, such as at least about 0.75 weight percent, for example at least about 0.80 weight percent, such as at least about 0.85 weight percent, for example at least about 0.90 weight percent, such as at least about 1.00 weight percent, for example at least about 1.25 weight percent, such as at least about 1.50 weight percent, for example, at least about 1.75 mass percent enta, such as at least about 2.00 mass percent, for example at least about 2.50 mass percent, such as at least about 3.00 mass percent, for example at least about 3.5 mass percent, such as at least about 5.00 weight percent of the soybean cotyledon fiber content in the composition and preferably less than 10.00 weight percent of the soybean cotyledon fiber composition.

The composition in accordance with the present invention may optionally include a source of carbohydrates, a source of fats, flavoring agents, vitamins, minerals, electrolytes, trace elements and other permitted additives. The nutritional composition in accordance with the present invention in one manifestation also includes one or more flavoring agents, such as cocoa, vanillin, lime, strawberries or soup additives, such as mushroom, tomato or broth, and / or sweeteners, such as aspartame, and other additives, such as xanthan gum.

When a source of carbohydrates is present in a composition in accordance with the present invention, it is preferably present in an amount of less than 30 weight percent, such as less than 25 weight percent of the composition. Preferably, the amount of carbohydrate is at least 5 weight percent, more preferably at least 10 weight percent, and most preferably at least 15 weight percent of the composition. Preferred carbohydrates for use in the compositions of the present invention are dextrose, fructose and / or maltodextrin or glucose. Skim milk and cocoa with lecithinized fat removed are other possible sources of carbohydrates.

When a source of fat is present in the composition of the present invention, it is usually present in an amount of from 0.5 to 10 weight percent, preferably 1 to 9 weight percent, such as from 1.5 to 8 weight percent, for example from 2 up to 7 weight percent, such as from 2.5 to 6 weight percent of the composition. The fat source should preferably include polyunsaturated fatty acids or monounsaturated fatty acids as well as, optionally, saturated fatty acids. Soya lecithins and α-linolenic acids are particularly preferred. The amount of polyunsaturated fatty acids and monounsaturated fatty acids, including essential fatty acids, can vary from 35 to 50, preferably 38-44, weight percent of the total source of fat. Essential fatty acids are also called omega-6 and omega-3 fatty acids and include linoleic acid and / or linolenic acid (α-linolenic acid). The saturated fatty acid content may be from 20 to 30 weight percent, preferably 22 to 26 weight percent of the total fat.

Vitamins and mineral compounds may optionally be added to the composition in accordance with the present invention in accordance with the restrictions defined by healthcare institutions. Vitamins usually include A, B1, B2, B12, folic acid, niacin, pantothenic acid, biotin. C, D, E, and K. Mineral compounds typically include iron, zinc, iodine, copper, manganese, chlorine, and selenium. Electrolytes such as sodium, potassium and chloride, trace elements, and other permitted additives can also be added in recommended amounts.

The ingredients of the preferred composition are presented in table 1

The above composition in a preferred amount of approximately 37 g corresponds to a single daily intake. The energy content in the composition is approximately 339 kcal (1437 kJ) per 100 g.

The composition in accordance with the present invention can be used as food for special dietary use, preferably to lower total cholesterol and / or LDL cholesterol and / or triglycerides in serum in patients with high blood lipids or in patients with normal the content of lipids in the blood, suffering from cardiovascular disease. For example, from one to three meals of ordinary food may be supplemented or substituted by the composition in accordance with the present invention. Thus, a significant decrease in the content of total cholesterol and / or LDL cholesterol and / or triglycerides in serum can be obtained, as well as an improvement in the ratio of HDL cholesterol to LDL cholesterol and / or increase in HDL cholesterol . The composition may provide from 50 to 250 calories per dose.

The daily dose of the composition in accordance with the present invention may include an energy content of from 400 to 800 kcal / day, in particular from 450 to 800 kcal / day, which is considered a very low-calorie diet (ONCR), or a daily dose may include an energy content of from 800 to 1200 kcal / day, which is considered a low-calorie diet (NKR). In another drug embodiment of the present invention, the energy content may be the amount of energy required by a normal subject per day.

The present invention also relates to a composition in accordance with the invention in the form of a micronutrient. In this regard, the micronutrient is a nutritional supplement and / or pharmacological composition and / or drug, including i) a synthetic phytoestrogen-like compound capable of binding to an estrogen receptor or estrogen-like receptor, and / or ii) a naturally occurring plant-derived compound in excess by weight of the content of a natural host, such as a plant cell, from which the compound can be extracted and isolated, and optionally iii) soy proteins obtained by partial hydrolysis of soy protein.

A naturally occurring plant derived compound is preferably, but not limited to, a compound capable of binding to an estrogen receptor and an estrogen-like receptor, a beta-2 adrenergic receptor, or a beta-2 adrenergic receptor class receptor. When natural compounds are isolated from plants, such as soybeans, they can be selected from the group of at least phytoestrogens, such as soybean phytoestrogens, such as soybean isoflavones, soy protein or fragments thereof, for example peptides or amino acid sequences, fiber soybeans, lecithin, linolenic acid, antioxidant, saponin, lignan, a protease inhibitor, trypsin inhibitor and tyrosine kinase inhibitor. Additional micronutrient constituents may preferably be selected from a DNA topoisomerase inhibitor, a ribosomal kinase inhibitor, a growth control factor such as, for example, epidermal growth factor, transforming growth factor alpha, platelet growth factor, and preferably any growth-controlling factor controlled by action tyrosine kinases. The micronutrient may also include oromeloxyphene and / or levomeloxyphene, as described among others by Holm et al. (1997) in Arteriosclerosis, Thrombosis, and Vascular Biology 17 (10), 2264-2272, and in Clinical Investigation 100 (4), 821-828. If the natural compound is isoflavone, the isoflavones can be deconjugated into an aglycon form either biologically or in vitro before being combined into a micronutrient.

In one particularly preferred embodiment, the present invention relates to a composition or micronutrient in accordance with the present invention in combination with a sterol-containing functional food ingredient, preferably an ingredient selected from the group consisting of stanol ester, tocotrienol, mevinolin and a phytosterol compound, such as, for example , campesterol, sitosterol or stigmasterol, or a combination thereof.

In accordance with one preferred embodiment, the composition or micronutrient in accordance with the present invention are used as a functional ingredient in food. The composition or micronutrient in accordance with the present invention can also be administered as a probe either by intravenous administration or in the form of tablets or capsules. The present invention also relates to a pharmaceutical preparation comprising a composition or micronutrient in accordance with the present invention, the use of a composition or micronutrient in accordance with the present invention in the therapy and / or diagnostic method carried out on a living human or animal organism, the use of the composition or micronutrient in accordance with the present invention for the manufacture of a medicament and the use of a composition or micronutrient element according to the present invention for the manufacture of a medicament for the treatment of subjects suffering from cardiovascular diseases.

The micronutrient is especially applicable in the prevention and / or treatment and / or weakening of hypercholesterolemia, hypertriglyceridemia, other hyperlipidemia and arteriosclerosis, atherosclerosis and related cardiovascular diseases.

In one embodiment, the present invention relates to a composition in accordance with the present invention for use as a medicament. The composition of the present invention for use as a medicament can preferably be used in the prophylaxis and / or treatment and / or prophylactic treatment and / or the alleviation of cardiovascular diseases, such as, for example, a disease selected from the group consisting of from arteriosclerosis, atherosclerosis, arteriolosclerosis, coronary heart disease, angina pectoris, thrombosis, myocardial infarction and hypertension. Arteriosclerosis is a general term for a group of conditions related to the arterial system and leading to a thickening of the arterial wall and the corresponding loss of their elasticity. The three main groups of arteriosclerosis that are most often mentioned are atherosclerosis, Menkeberg media sclerosis, and arteriolosclerosis. Atherosclerosis is most often observed in the aorta and in the main arteries associated with it, in the coronary arteries and arteries of the brain. Menkeberg's media sclerosis leads to a narrowing of the middle wall of the arteries of the limbs, and arteriolosclerosis is associated with the narrowing of small arteries and arterioles, mainly due to hypertension.

The composition in accordance with the present invention is effective in reducing cholesterol in patients with normal blood cholesterol by at least 2%, for example at least 5%, such as at least 8%, for example at least 10 %, such as at least 12%, for example at least 14%, such as at least 16%, for example at least 18%, such as at least 20%, for example at least 25%, such as at least 30%. The composition of the present invention is effective in reducing triglycerides in patients with normal blood cholesterol by at least 10%, such as at least 12%, for example at least 14%, such as at least at least 16%, for example at least 18%, such as at least 20%, for example at least 25%, such as at least 30%.

The composition in accordance with the present invention is effective in reducing cholesterol in patients with moderately high blood cholesterol by at least 3%, for example at least 5%, such as at least 8%, for example at least 10%, such as at least 12%, for example at least 15%, such as at least 20%, for example at least 25%, such as at least 30%, for example, at least at least 35%, such as at least 40%, for example at least 45%. The composition of the present invention is effective in reducing triglycerides in patients with moderately high blood cholesterol by at least 15%, such as at least 20%, for example at least 25%, such as at least at least 30%, for example at least 35%, such as at least 40%, for example at least 45%.

The composition in accordance with the present invention is effective in reducing cholesterol in patients with very high cholesterol in the blood by at least 3%, for example at least 5%, such as at least 8%, for example at least 10%, such as at least 12%, for example at least 15%, such as at least 20%, for example at least 25%, such as at least 30%, for example, at least at least 35%, such as at least 40%, for example at least 45%, such as at least at least 50%, for example at least 55%, such as at least 60%. The composition in accordance with the present invention is effective in reducing triglycerides in patients with very high cholesterol in the blood by at least 20%, for example at least 25%, such as at least 30%, for example at least 35%, such as at least 40%, for example at least 45%, such as at least 50%, for example at least 55%, such as at least 60%.

The composition of the present invention for use as a medicament may be effective in reducing the deposition of cholesterol and / or triglycerides in the artery wall, and / or in reducing the content of oxidized LDL cholesterol present in the artery wall in the serum, and / or reducing the content cholesterol and / or LDL cholesterol and / or homocysteine and / or serum triglycerides and / or increasing the ratio of HDL cholesterol to LDL cholesterol and / or HDL cholesterol TKE.

In another embodiment, the present invention relates to the use of a composition in accordance with the present invention for the treatment of cardiovascular diseases, for example arteriosclerosis. The use of the composition of the present invention as a medicament and / or for the manufacture of a medicament for the treatment of patients with cardiovascular diseases is another embodiment of the present invention. The use of the composition of the present invention as a medicament and / or for the manufacture of a medicament for the treatment of patients with arteriosclerosis is yet another embodiment of the present invention. Such a medicament may, for example, be effective in the prophylaxis and / or treatment and / or prophylactic treatment and / or the alleviation of, for example, a cardiovascular disease selected from the group consisting of hypercholesterolemia, hypertriglyceridemia, other hyperlipidemia, arteriosclerosis, atherosclerosis, arteriolosclerosis, angina pectoris, thrombosis, myocardial infarction and hypertension in a subject, the drugs being effective in the prophylaxis and / or treatment and / or prophylactic treatment and / or weakening of the arterio kleroza and / or atherosclerosis in a subject are more preferred. The drug may also be effective in lowering serum total cholesterol and / or serum LDL cholesterol and / or serum total triglycerides and / or serum homocysteine and / or reducing cholesterol and / or triglyceride deposits in artery wall, and / or a decrease in the content of oxidized LDL cholesterol present in the artery wall. A drug may also be effective in increasing the ratio of HDL cholesterol to LDL cholesterol in a subject and / or in increasing HDL cholesterol in serum in a subject. The drug may also be effective in preventing, reducing or eliminating the formation of fatty bands, and / or preventing, reducing or eliminating the development of fibrous plaques, and / or preventing, reducing or eliminating the development of complicated damage. A drug may also be effective in reducing or eliminating the risk of developing angina pectoris and / or reducing or eliminating the risk of developing myocardial infarction in a subject.

The present invention also provides a method for the prophylaxis and / or treatment and / or prophylactic treatment and / or therapeutic treatment of a cardiovascular disease in a human or animal organism, such as an arteriosclerotic condition in a human or animal organism, said method comprising administering to the specified human or animal body composition in accordance with the present invention in an amount effective to reduce serum cholesterol and / or LDL-C serum olesterol and / or serum triglycerides and / or serum homocysteine and / or increasing the ratio of HDL cholesterol to serum LDL cholesterol and / or increasing HDL cholesterol and / or lowering cholesterol deposits and / or triglycerides in the artery wall, and / or reducing the content of oxidized LDL cholesterol present in the artery wall, and / or preventing, reducing or eliminating the formation of fatty bands, and / or preventing, reducing or eliminating the formation of fibrosis x plaques, and / or prevention, reducing or eliminating the formation of complicated damage, and / or reducing or eliminating the risk of developing angina pectoris, and / or reducing or eliminating the risk of developing myocardial infarction and / or weakening the clinical condition of patients at risk of developing myocardial infarction. Cardiovascular disease is preferably a cardiovascular disease selected from the group consisting of hypercholesterolemia, hypertriglyceridemia, other hyperlipidemia, arteriosclerosis, atherosclerosis, arteriolosclerosis, angina pectoris, thrombosis, myocardial infarction and hypertension, and more preferably selected from arteriosclerosis.

The duration of treatment is preferably in the range from 1 to 12 months or more, such as from 2 weeks to 9 months, for example from 3 weeks to 6 months, such as from 4 weeks to 4 months, such as from 6 weeks to 3 months. However, the duration of treatment cannot be limited to these periods and can, for example, be longer than 12 months, such as, for example, treatment throughout the life span in order to prevent cardiovascular diseases.

In one embodiment, the present invention provides a pharmaceutical preparation comprising a composition in accordance with the present invention. The pharmaceutical preparation can be obtained by any means known to the experienced person.

In another embodiment, the present invention relates to the use of a composition in accordance with the present invention as a nutritional preparation and / or to obtain a nutritional preparation for reducing serum cholesterol and / or serum LDL cholesterol and / or serum triglycerides, and / or serum homocysteine content, and / or increasing the ratio of HDL cholesterol to LDL cholesterol and / or serum HDL cholesterol in a subject. The nutritional preparation may take any form suitable for human and animal consumption. In one preferred embodiment, the composition is a powder mixture that is capable of suspending, dispersing or emulsifying in a liquid for human and animal consumption. The liquid is preferably an aqueous liquid, such as, for example, water, coffee, tea or juice. To this end, the composition may be packaged in a package designed to cover part or all of the nutritional needs for a certain period of time, such as, for example, three days or a week. The present invention also relates to a nutritional preparation in the form of a nutritional supplement.

The nutritional preparation in one embodiment of the present invention is preferably a functional food or drink, i.e. readily available food and drinkable substance to which the composition of the present invention is added to provide a medical or pharmaceutical effect. Thus, the present invention provides a composition in accordance with the present invention for use as a functional ingredient in food. Functional foods and drinks are preferably selected from the group consisting of dairy products, such as yogurt and yogurt ice cream, juice, such as orange juice or tomato juice, ready-to-drink liquids, a spreadable product, such as margarine or vegetable or oil extracted from plants, a cereal product such as a traditional breakfast cereal, nutrition bars, biscuit, bread, soups such as tomato soup, a meat product such as a hamburger, meat substitute of the product and the vegetable product. In a further embodiment, the nutritional preparation of the present invention may be in the form of a ready-to-drink liquid, or in the form of a powder, or in the form of a troche, a solid composition such as a nutrition bar, fruit bar, cookie, cake, bread or roll.

In another embodiment, the composition of the present invention is a liquid nutritional preparation in an aqueous liquid in which the solid ingredients are suspended, dispersed or emulsified in an amount of 10 to 25 weight percent. If a liquid nutritional preparation is intended to be drunk, it usually includes a flavoring agent as described above. However, a liquid nutrient preparation may also be used to administer the probe.

In another embodiment, the present invention relates to the use of a composition in accordance with the present invention as a partial or complete diet for overweight subjects or for overweight subjects suffering from arteriosclerotic condition. Overweight subjects often have high serum cholesterol and high serum triglycerides and therefore have a greater predisposition to the development of cardiovascular diseases. However, the present invention is not limited to treating obese diabetes patients with an increased risk of developing arteriosclerosis, i.e. subjects typically having high serum cholesterol and / or triglycerides. The composition in accordance with the present invention also has the effect of significantly lowering cholesterol, LDL cholesterol and serum triglycerides in subjects with a more normal lipid profile. The use of the composition in accordance with the present invention as a medicine is not limited to overweight and obese subjects, but can be used in subjects with normal weight, having high cholesterol and / or LDL cholesterol and / or serum triglycerides, or in subjects with a cardiovascular condition, such as, for example, arteriosclerosis or a related condition, with normal cholesterol and / or LDL cholesterol and / or serum triglycerides. This high content of cholesterol and / or LDL cholesterol and / or triglycerides in serum can be caused by the consumption of fat-rich foods or can be genetically determined.

For the purposes of the present invention, it is believed that individuals with an initial serum cholesterol of 5.7 mmol / L or lower have normal or reduced blood cholesterol, while a serum cholesterol of more than 5.7 mmol / L is considered to be elevated. Thus, exposure to subjects with normal blood cholesterol levels can prevent the development of cardiovascular diseases that develop when serum cholesterol levels are below 5.7 mmol / L in patients with diabetes mellitus, especially predisposed to develop, for example, arteriosclerosis, or prevention of the development of cardiovascular diseases in patients with diabetes mellitus with acute cardiovascular disorders in history.

Exposure to subjects with high blood cholesterol levels may prevent the development of cardiovascular diseases that develop when serum cholesterol levels are higher than 5.7 mmol / L in subjects who are particularly prone to developing, for example, arteriosclerosis under these conditions.

More specifically, it is believed that individuals with a serum total cholesterol content of 5.7 to 7.9 mmol / L have a moderately elevated blood cholesterol level. Accordingly, exposure to these subjects with a moderately elevated blood cholesterol level can prevent the development of cardiovascular diseases that develop with an increase in serum cholesterol in the concentration range from 5.7 to 7.9 mmol / L. It is believed that individuals with a serum total cholesterol content of more than 7.9 mmol / L have a very high blood cholesterol content. Accordingly, exposure to these subjects with very high cholesterol levels in the blood can prevent the development of cardiovascular diseases that develop when the serum cholesterol content is in a concentration of more than 7.9 mmol / L.

It was also shown that the composition in accordance with the present invention has a potentiating effect on the effect of drugs, such as, for example, statins. The combination of a composition in accordance with the present invention, for example with statins, such as a hydroxymethylglutaryl CoA reductase inhibitor, bile acid resins, fibrates, nicotinic acid derivatives, oat-based products, such as oat flour, rye-based products, such as for example, rye flour, and various fish oil concentrates with a high content of ω-3 fatty acids, it is possible to achieve a further decrease in serum cholesterol and / or LDL cholesterol and / or triglycerides in serum by 5-15 percent. The present invention also relates to a composition in accordance with the present invention in combination with a statin, such as a hydroxymethylglutaryl CoA reductase inhibitor, bile acid resins, fibrates, oat products, rye products, nicotinic acid derivatives and various fish oil concentrates with high in ω-3 fatty acids.

EXAMPLE 1

The aim of this study was to determine whether a product containing isolated soy protein, soy fiber, and a consistently high isoflavone content was significantly more effective in lowering serum LDL cholesterol and total cholesterol compared to placebo. The study was conducted according to a random double-blind scheme with placebo as a control. Fifty-two patients with an average control value of cholesterol of 7.6 mmol / L underwent a six-week course of treatment. Twenty-four of them received the composition according to the invention (Abacor ^® , Nutri Pharma ASA, Oslo) containing isolated soy protein with a consistently high content of isoflavones and soybean cotyledon fiber (52 g of soy protein, 230 mg of soy isoflavones and 15.5 g of fiber soybean cotyledons per day). Twenty-eight patients received a product with the same protein and fiber content, which was based on casein and cellulose (placebo). The preparations were given in the form of two liquid supplements per day in addition to the regular diet of patients. Both groups were observed for one month after discontinuation of the drug.

The average decrease in LDL cholesterol in the Abacor ^® group after six weeks was 13.1%, while in the placebo group it was 7.8% (p = 0.014). The decrease in total cholesterol was also higher in the group receiving the active compound compared with the placebo group (8.4% versus 5.1%, p = 0.049), without correction for multiple testing. It was shown that high density lipoprotein cholesterol (HDL) increases both in the active group and in the placebo group (6.2% versus 5.8%). In the following month, the cholesterol content in both groups returned to its original value.

The results show that consumption of a product including isolated soy protein with a consistently high content of isoflavones and soybean cotyledon fiber significantly reduces serum LDL cholesterol and serum total cholesterol and improves the ratio of HDL cholesterol to LDL cholesterol. Positive results were obtained in this group of patients after six weeks of exposure.

EXAMPLE 2

The aim of this study was to find out whether a product containing isolated soy protein, soy fiber, and a consistently high isoflavone content is significantly more effective in lowering serum LDL cholesterol, serum HDL cholesterol, and total cholesterol compared to placebo . The study was conducted according to a random double-blind scheme with placebo as a control. One hundred and sixty patients with plasma LDL cholesterol ≥ 4.0 mmol, total cholesterol 5.8-7.9 mmol and triglycerides <4.5 mmol underwent a six-week course of treatment. 80 patients, divided into two groups of the same size, received a product based on soybeans (Abacor ^® , Nutri Pharma ASA, Oslo) containing isolated soy protein with a consistently high content of soy isoflavones and fiber. Group I (40 patients) received Abacor ^® I: 18.5 g soy protein (SUPRO ^® FXP-HO159), 4.63 g soy fiber (FIBRIM ^® 1020), 3.44 g cocoa with lecithinized fat removed and 1.31 g soya lecithin in the daily diet); group II (40 patients) received Abacor ^® II: 31 g of soy protein (SUPRO ^® FXP-HO159), 7.75 g of soy fiber (FIBRIM ^® 1020), 5.77 g of cocoa with lecithinized fat removed and 2.2 g of soy lecithin in the daily diet). Eighty patients, divided into two groups, received a product with the same protein and fiber content, which was based on casein, whole milk powder and cellulose (placebo). Drugs were given once a day in addition to the regular diet of patients.

The study began with a dietary standardization program for an average of four months for all study participants (visits 1–4, on average over a four-month course) with a broad study of dietary changes and dietary guidelines. Subsequently, study participants received Abacor ^® or a placebo as described above (visits 4-8, between each one month). Serum total cholesterol (table I and figure 1), serum LDL cholesterol (table II and Fig. 2), serum HDL cholesterol (serum III and Fig. 3), serum triglycerides (table IV and Fig. 4) were measured during all visits throughout the period. The average ratio of HDL cholesterol to HDL cholesterol was also calculated (FIG. 5).

The following notation is used in the tables.

A: patients of group I.

B: patients receiving placebo with the same protein and fiber content as patients of group I.

C: patients of group II.

D: patients receiving placebo with the same protein and fiber content as patients of group II.

These results demonstrate that taking the composition according to the invention reduced the total serum cholesterol by more than 11% for Abacor ^® I and Abacor ^® II (Table I and Figure 1). More significantly, administration of the composition of the invention reduces serum LDL cholesterol by more than 18.2% for Abacor ^® II after an initial decrease of about 5% as a result of a dietary change that resulted in an overall decrease in serum LDL cholesterol 23% when taking the composition in accordance with the invention and changing the diet (table II and figure 2). This is one of the largest decreases in serum LDL cholesterol observed for food. Surprisingly, taking Abacor ^® I (with a protein content of only 60% of that of Abacor ^® II) led to a decrease in serum LDL cholesterol by 16.0% after the initial decrease, which is very similar to the result observed for Abacor ^® II . Further, the results show that the HDL cholesterol content in serum increased by approximately 10% for Abacor ^® II (table III and figure 3), and the serum triglycerides decreased by more than 10% for both Abacor ^® I and Abacor ^® II (table IV and Fig. 4), and that the ratio of HDL cholesterol to HDL cholesterol increased by more than 33% for Abacor ^® I and 25% for Abacor ^® II (Fig. 5).

Surprisingly, the decrease in cholesterol due to the use of Abacor ^® did not stop after about one month, as might be expected due to a turnover of cholesterol in the body equal to 2-3 weeks, and the cholesterol content was constantly reduced for four months (Figs. 1 and 2 )

Claims (58)

1. A composition for the prevention and / or treatment and / or weakening of cardiovascular diseases, comprising (a) a soy protein source selected from soy protein, a soy protein concentrate or soy flour, said soy protein source representing an amount of soy protein, which comprises at least 45 wt.% of the total protein content in the composition, said total protein content representing at least 15% of the total energy content in the composition, (b) at least one phytoestrogen compound in if more than 0.16 wt.% of the soy protein content of the composition, and (c) dietary fiber in an amount of more than 6 wt.% of the total weight of the nutrient composition in the dry residue. 2. The composition according to claim 1, where the cardiovascular disease is selected from the group consisting of hypercholesterolemia, hypertriglyceridemia, other hyperlipidemia, arteriosclerosis, atherosclerosis, arteriolosclerosis, coronary heart disease, angina pectoris, thrombosis, myocardial infarction and hypertension. 3. The composition according to claim 1, where the source of soy protein is an isolated soy protein and the amount of isolated soy protein is at least 50 wt.% Of the total protein content. 4. The composition according to claim 3, where the amount of isolated soy protein is at least 75 wt.% Of the total protein content. 5. The composition according to claim 4, where the amount of isolated soy protein is at least 90 wt.% Of the total protein content. 6. The composition according to claim 5, where, essentially, the entire protein is an isolated soy protein. 7. The composition according to claim 1, where the source of soy protein is a soy protein concentrate or soy flour and the amount of soy protein is at least 50 wt.% Of the total protein content. 8. The composition according to claim 7, where the amount of soy protein is at least 75 wt.% Of the total protein content. 9. The composition of claim 8, where the amount of soy protein is at least 90 wt.% Of the total protein content. 10. The composition according to claim 9, where almost all of the protein is soy protein. 11. The composition according to any one of claims 1 to 10, where the dietary fiber is fiber of soybeans. 12. The composition according to claim 11, where the fiber of soybeans is a fiber of soybean cotyledon. 13. The composition according to any one of claims 1 to 12, where the phytoestrogen compound is present in an amount of at least about 0.20 wt.% Of the soy protein content in the composition. 14. The composition of claim 13, wherein the phytoestrogen compound is present in an amount of at least about 0.30 wt.% Of the soy protein content in the composition. 15. The composition of claim 14, wherein the phytoestrogen compound is present in an amount of at least about 0.33 wt.% Of the soy protein content in the composition. 16. The composition of claim 15, wherein the phytoestrogen compound is present in an amount of at least about 0.45% by weight of the soy protein content of the composition. 17. The composition of claim 16, wherein the phytoestrogen compound is present in an amount of at least about 0.75% by weight of the soy protein content of the composition. 18. The composition of claim 17, wherein the phytoestrogen compound is present in an amount of at least about 1.0 wt.% Of the soy protein content in the composition. 19. The composition according to any one of claims 1 to 18, where the phytoestrogen compound is selected from isoflavones. 20. The composition according to claim 19, where the isoflavones are selected from the group consisting of genistein, daidzein, glycitein and equola. 21. The composition according to claim 20, where the isoflavones are genistein and / or daidzein. 22. The composition according to item 21, where the isoflavone is genistein. 23. The composition according to any one of paragraphs.19-22, where some or all of the isoflavones are presented in aglycon form. 24. The composition according to any one of claims 1 to 23, where the dietary fiber is present in an amount of at least 7 wt.% In the composition. 25. The composition according to any one of claims 1 to 24, where the mass ratio of soy protein to dietary fiber is at least about 1.0. 26. The composition according A.25, where the mass ratio of soy protein to dietary fiber is at least about 1.5. 27. The composition according to p, where the mass ratio of soy protein to dietary fiber is at least about 2.0. 28. The composition according to item 27, where the mass ratio of soy protein to dietary fiber is at least about 2.5. 29. The composition according to p, where the mass ratio of soy protein to dietary fiber is at least about 3.0. 30. The composition according to clause 29, where the mass ratio of soy protein to dietary fiber is at least about 4.0. 31. The composition according to p. 30, where the mass ratio of soy protein to dietary fiber is at least about 5.0. 32. The composition according to any one of claims 1 to 31 in combination with statins, bile resins, fibrates, nicotinic acid derivatives, oat products, rye products or fish oil concentrates with a high content of ω-3 fatty acids or their combination. 33. The composition of claim 32, wherein the statins are selected from hydroxymethylglutaryl CoA reductase inhibitors. 34. The composition according to claims 1-33, further comprising an additional source of protein, and / or an additional source of carbohydrates, and / or an additional source of fat. 35. The composition according to clause 34, where the specified additional source of fat selected from soya lecithins. 36. The composition according to clause 34, where the specified additional source of fat selected from polyunsaturated or monounsaturated fatty acids. 37. The composition according to any one of claims 1 to 36 in the form of a nutritional supplement. 38. The composition of claim 37, further comprising a DNA topoisomerase inhibitor, a ribosomal kinase inhibitor, and / or a growth suppression factor. 39. The composition of claim 38, wherein the growth inhibitory factor is a growth inhibitory factor controlled by tyrosine kinase activity. 40. The composition according to any one of paragraphs.37-39, further comprising oromeloxifene and / or levormeloxifene. 41. The composition according to any one of claims 1 to 40 in combination with a functional food ingredient containing sterol. 42. The composition according to paragraph 41, where the sterol-containing functional food ingredient is selected from the group consisting of stanol ester, tocotrienol, mevinolin and a phytosterol compound, or a combination thereof. 43. The composition according to any one of claims 1 to 42 for use as a functional ingredient in food. 44. The composition according to item 43, where the functional food is selected from the group consisting of dairy products, juice, ready-to-drink liquids for drinking, spreading product, cereal product, nutrition bars, biscuits, bread, soups, meat products, meat-substitute products and vegetable products. 45. The composition according to any one of claims 1 to 44 for special dietary use. 46. The composition according to item 45 for lowering glucose and / or total cholesterol and / or LDL cholesterol and / or serum triglycerides in a subject. 47. The composition according to item 45 for reducing serum glucose and / or to reduce total cholesterol and / or LDL cholesterol and / or serum triglycerides in patients with high blood lipids or in patients with normal the content of lipids in the blood, suffering from cardiovascular disease. 48. The composition according to any one of claims 1 to 47 for use as a medicine. 49. The composition according to item 46 for use in reducing the content of homocysteine and / or total cholesterol and / or LDL cholesterol and / or triglycerides in serum and / or reducing the deposition of cholesterol and / or triglycerides in the artery wall, and / or increasing the ratio of HDL cholesterol to serum LDL cholesterol and / or serum LDL cholesterol in a subject. 50. The composition according to any one of claims 1 to 49, suitable for the preparation of a nutritional preparation for reducing serum total cholesterol and / or serum LDL cholesterol and / or serum triglycerides and / or serum homocysteine and / or increasing the ratio of HDL cholesterol to LDL cholesterol and / or HDL cholesterol in a subject. 51. The composition of claim 50, wherein the nutritional preparation is in the form of a nutritional supplement. 52. The composition according to any one of claims 1 to 51, applicable as a partial or complete diet for obese persons suffering from arteriosclerotic condition. 53. A pharmaceutical preparation for the prophylaxis and / or treatment of cardiovascular diseases containing the composition in accordance with any one of claims 1 to 52. 54. A method for the prevention and / or treatment and / or weakening of a cardiovascular disease in a human or animal organism, said method comprising administering to said human or animal organism a composition according to any one of claims 1 to 52 in an amount effective in reducing serum cholesterol and / or serum LDL cholesterol and / or serum triglycerides and / or serum homocysteine and / or increasing the ratio of HDL cholesterol to LDL cholesterol and / or the content of HDL cholesterol in serum, and / or reducing the deposition of cholesterol and / or triglycerides in the artery wall, and / or preventing, reducing or eliminating the formation of fatty bands, and / or preventing, reducing or eliminating the formation of fibrous plaques, and / or preventing, reducing or eliminating the formation of complicated damage, and / or preventing, reducing or eliminating the risk of developing angina pectoris, and / or preventing, reducing or eliminating the risk of developing myocardial infarction. 55. The method according to item 54, where the cardiovascular disease is an arteriosclerotic condition of a human or animal body. 56. The method according to item 54, where the cardiovascular disease is selected from the group consisting of hypercholesterolemia, hypertriglyceridemia, other hyperlipidemia, arteriosclerosis, atherosclerosis, arteriolosclerosis, coronary heart disease, angina pectoris, thrombosis, myocardial infarction and hypertension. 57. The method of claim 56, wherein the cardiovascular disease is arteriosclerosis. 58. The method of claim 56, wherein the cardiovascular disease is atherosclerosis.

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