Blood Pressure

Agents for improving lipid metabolism and reducing high blood pressure

Blood Pressure Abstract
A milk-derived basic protein fraction and a basic peptide fraction are provided for use as an effective component for agents for improving lipid metabolism and reducing high blood pressure which can be administered orally, are effective with a relatively small dosage, have good taste and are stable during storage.

Blood Pressure Claims
1. A method of improving lipid metabolism and/or reducing high blood pressure comprising administering an effective amount of a milk-derived basic protein fraction to a candidate for the treatment or a patient in need thereof.

2. A method of improving lipid metabolism and/or reducing high blood pressure according to claim 1, comprising orally administering about 20 mg or more of the milk-derived basic protein fraction per day.

3. A method of improving lipid metabolism and/or reducing high blood pressure comprising administering an effective amount of a basic peptide fraction which is obtained by digesting a milk-derived basic protein fraction with a protease to a candidate for the treatment or a patient in need thereof.

4. A method of improving lipid metabolism and/or reducing high blood pressure according to claim 3, comprising orally administering about 20 mg or more of the basic peptide fraction per day.

Blood Pressure Description
BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to agents, drinks and food products for improving lipid metabolism and reducing high blood pressure and the combination thereof that are effective in treating and preventing diseases such as fatty liver, hyperlipidemia, arteriosclerosis, obesity and hypertension.

2. Description of the Related Art

Lipid metabolism refers to catabolic (decomposing) and anabolic (accumulating) in vivo processes of lipids, mainly comprising triglicerides derived from food. Lipid metabolism generally includes energy-releasing reaction of lipids, biosynthesis of fatty acids, biosynthesis of acylglycerols, phospholipid metabolism, cholesterol metabolism, and the like ("Biochemistry for Nutrition" by Akira Misaki, Asakura Shoten, 1993, pp. 123-134).

In recent years, the mortality rate from cardiovascular disease has been rapidly increasing and the correlation between the risk of getting cardiovascular disease and the blood cholesterol concentration has been pointed out. Meantime, several attempts have been made to reduce the blood cholesterol concentration by using food materials, which can be ingested in daily life. For example, soybean protein (Arteriosclerosis 1988 72:115), whey protein (Agric Biol Chem 1991 55:813; Japanese Patent Application Laid-open No. H5-176713), soybean protein hydrolyzates (J Nutr 1990 120:977), and egg yolk phospholipid (Agric Biol Chem 1989 53:2469) have been tried. Further, a method making use of lactoalbumin, collagen, soybean protein or wheat gluten and soybean lecithin in combination (Nutr Rep Int 1983 28:621) and a method making use of tissue-like soybean protein containing soybean lecithin (Ann Nutr Metab 1985 29:348), and the like have been proposed.

High blood pressure refers to essential hypertension, etiology of which is unknown, and secondary hypertension, which is associated with disease of the kidney, adrenal gland or nervous system. In recent years, 90% of cases are reported to be essential hypertension. Today, antihypertensive agents are frequently used for the prevention and treatment of essential hypertension. However, every conventional antihypertensive agent has a disadvantage to show a certain adverse effect. For example, individual drugs show characteristic adverse effects: antihypertensive diuretics cause hypokaliemia or acidemia, antihypertensive peripheral vasodilators cause hypoglobulia, ß-blockers cause bronchoasthma, and a-methyldopa increases glutamic-oxaloacetic transaminase (GOT) or glutamic-pyruvic transaminase (GPT) values in the blood and causes hemolytic anemia. Accordingly, a special consideration is required in administering these antihypertensive agents, and the dosage and period of administration for these agents are naturally restricted.

Under the abovementioned circumstances, development of antihypertensive agents without adverse effects has been strongly urged, and antihypertensive agents having a microorganism-derived substance as an effective component have drawn attention. Such substances comprise, for example, high molecular weight polysaccharides derived from lactic acid bacteria as an effective component (Japanese Patent Application Laid-open No. S59-190929), glycoproteins having a molecular weight of more than 10,000 isolated from chlorella algae (Japanese Patent Application Laid-open No. S60-45603), viable or dead cells of bacteria of genus Streptococcus (Japanese Patent Application Laid-open S61-221124), dried beer yeast as an effective component (Japanese Patent Application Laid-open No. S63-255234), or a hot water extract of lactic acid bacteria (Japanese Patent Application Laid-open S63-139129; Japanese Patent Application Laid-open No. H2-247127). However, many of these substances are water insoluble and have unpleasant taste, which prevent them from practical use.

Therefore, attempts have been made to develop antihypertensive agents comprising substances contained in food materials, which can be administered orally in daily life, as an effective component. For example, an enzyme-digested casein product (Food Develop 1997 32:37-39), and an enzyme-digested fish meat product (Health Nutr Food Res 1998 1:62-71; Food Develop 1996 31:50-52) have been reported.

However, the methods described above have problems such that a relatively large amount of ingestion is required, that flavor is not desirable, and that precipitation occurs during storage when made into drinks interfering with stable storage.

More importantly, no substance which can improves lipid metabolism and reduce high blood pressure simultaneously is known. A problem in lipid metabolism can be a cause of raising blood pressure, and in that case, inadequate lipid metabolism is associated with high blood pressure. For example, in some cases, high blood cholesterol levels tend to cause arteriosclerosis which leads to high blood pressure. Thus, if a substance which can both improve lipid metabolism and reduce high blood pressure is developed, the problem in both lipid metabolism and blood pressure can effectively be resolved.

SUMMARY OF THE INVENTION

The present inventors found that a milk-derived basic protein fraction or a basic peptide fraction, which is obtained by digesting said basic protein fraction with a protease, e.g. pepsin and pancreatin, can improve lipid metabolism and reduce high blood pressure when administered orally. Further, the inventors found that these basic protein fraction and basic peptide fraction can be effectively used as an effective component for agents and drinks or food products for improving lipid metabolism and high blood pressure and the combination thereof.

In one embodiment an agent for improving lipid metabolism is provided comprising a milk-derived basic protein fraction as an effective component and a suitable carrier (e.g., for oral administration). Preferably, this milk-derived basic protein fraction contains 15% or more by weight basic amino acids in its amino acid composition. Preferably, the milk-derived basic protein fraction is obtained by bringing milk or a milk-derived material into contact with cation exchange resins to adsorb basic proteins and eluting a fraction adsorbed on the resins with an eluent having a salt concentration of about 0.1 M to about 1.0 M.

In another embodiment an agent for improving lipid metabolism is provided comprising a basic peptide fraction as an effective component which is obtained by digesting the milk-derived basic protein fraction by a protease. Preferably, the milk-derived basic protein fraction is digested by at least one of proteases selected from the group consisting of pepsin, trypsin, chymotrypsin, and pancreatin.

In another embodiment a drink or food product for improving lipid metabolism is provided to which the milk-derived basic protein fraction or basic peptide fraction of the present invention is admixed.

In another embodiment an agent for reducing high blood pressure is provided comprising a milk-derived basic protein fraction as an effective component and a suitable carrier (e.g., for oral administration). Preferably, this milk-derived basic protein fraction contains 15% or more by weight basic amino acids in its amino acid composition. Preferably, the milk-derived basic protein fraction is obtained by bringing milk or a milk-derived material into contact with cation exchange resins to adsorb basic proteins and eluting a fraction adsorbed on the resins with an eluent having a salt concentration of about 0.1 M to about 1.0 M.

In another embodiment an agent for reducing high blood pressure is provided comprising a basic peptide fraction as an effective component which is obtained by digesting the milk-derived basic protein fraction by a protease. Preferably the milk-derived basic protein fraction is digested by at least one of proteases selected from the group consisting of pepsin, trypsin, chymotrypsin, and pancreatin.

In another embodiment a drink or food product for reducing high blood pressure is provided to which the milk-derived basic protein fraction or basic peptide fraction of the present invention is admixed.

An agent for improving lipid metabolism and an agent for reducing high blood pressure can include basically the same component. By examining activities and effects on each lipid metabolism and blood pressure with respect to the content of the component and other supplemental ingredients, desired balance therebetween can readily be achieved. Agents for improving lipid metabolism and/or reducing high blood pressure of the present invention can be administered not only to a patient having the symptoms but also to a candidate for the treatment of preventing these symptoms.

For purposes of summarizing the invention and the advantages achieved over the prior art, certain objects and advantages of the invention have been described above. Of course, it is to be understood that not necessarily all such objects or advantages may be achieved in accordance with any particular embodiment of the invention. Thus, for example, those skilled in the art will recognize that the invention may be embodied or carried out in a manner that achieves or optimizes one advantage or group of advantages as taught herein without necessarily achieving other objects or advantages as may be taught or suggested herein. Further aspects, features and advantages of this invention will become apparent from the detailed description of the preferred embodiments which follow.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Agents for improving lipid metabolism and reducing high blood pressure and a combination thereof are characterized in that they contain a milk-derived basic protein fraction or a basic peptide fraction as an effective component. Said milk-derived basic protein fraction can be obtained from mammalian milk such as cow milk, human milk, goat milk, and ewe milk. The basic peptide fraction can be obtained by digesting the milk-derived basic milk fraction of the present invention with a protease.

In an embodiment, this milk-derived basic protein fraction has the following characteristics as described hereinafter in Test Examples 1 through 3. The present invention is not limited to this embodiment.

1) It comprises various proteins having a molecular weight ranging from about 2,000 to about 80,000, preferably from about 3,000 to about 24,000, according to sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). It has an isoelectric point ranging from about 7.5 to about 11, preferably from about 8 to about 10.

2) It contains more than about 95% by weight protein and small amounts of fat and ash.

3) Proteins contained are mainly lactoferrin and lactoperoxidase.

4) As for the amino acid composition of proteins, it contains more than about 15% by weight basic amino acids such as lysine, histidine and arginine.

Such a basic protein fraction can be obtained, for example, by bringing a milk material, such as skimmed milk and whey, into contact with cation exchange resins to adsorb basic proteins, eluting a basic protein fraction adsorbed on these resins with an eluent having a salt concentration of about 0.1 M to about 1.0 M, recovering this eluate fraction, desalting and concentrating this fraction with a reverse osmotic (RO) membrane or by the electrodialysis (ED) method, and drying the resulting fraction, if necessary.

Further, a milk-derived basic protein fraction can be obtained, for example, by a method in which milk or milk-derived material is brought into contact with cation exchanger to adsorb basic proteins, and then a basic protein fraction adsorbed on this cation exchanger is eluted with an eluent having a pH higher than 5 and an ionic strength greater than 0.5 (Japanese Patent Application Laid-open No. H5-202098), a method in which alginic acid gel is used (Japanese Patent Application Laid-open No. S61-246198), a method in which the fraction is obtained from whey using inorganic porous particles (Japanese Patent Application Laid-open No. H1-86839), and a method in which the fraction is obtained from milk using a sulfate ester compound (Japanese Patent Application Laid-open No. S63-255300). In the present invention, a basic protein fraction obtained by any of such a method can be used. The disclosure of the above references is herein incorporated by reference.

Further, a milk-derived basic peptide fraction has the same amino acid composition as the basic protein fraction. For example, the milk-derived basic protein fraction obtained by any of the abovementioned methods is treated with protease such as pepsin, trypsin, and chymotrypsin, and if necessary further with protease such as pancreatin, to obtain a peptide composition having an average molecular weight of less than about 4,000, preferably from about 1,000 to about 3,000.

In administering agents of the present invention for improving lipid metabolism and reducing high blood pressure and the combination thereof, a milk-derived basic protein fraction or the basic peptide fraction as an effective component can be used without further processing. Also, the milk-derived basic protein and basic peptide fractions of the present invention can be formulated into powders, granules, tablets, capsules, drinks, or the like according to conventional methods. Further, these basic protein fraction and basic peptide fraction, without further processing or after formulation, can be admixed with nutrients, drinks or food products to improve lipid metabolism and reduce high blood pressure. An increased activity for improving lipid metabolism and reducing high blood pressure and the combination thereof can be expected by admixing the basic protein fraction or the basic peptide fraction of the present invention along with other components which are considered to have an activity to improve lipid metabolism (e.g., 50 to 50,000% by weight with respect to the basic protein fraction or the basic peptide fraction), such as soybean protein, whey protein, soybean lecithin, diacylglycerol, and soybean isoflavone, as well as the other components which are considered to have an antihypertensive activity (e.g., 100 to 50,000% by weight with respect to the basic protein fraction or the basic peptide fraction), such as calcium, magnesium, potassium, and dietary fiber. For example, 10 g of soybean protein and 40 mg of soybean isoflavone can be used with 20 to 100 mg of the milk-derived basic protein fraction. In other examples, 10 g of dietary fiber and 100 mg of magnesium can be used with 20 to 100 mg of the milk-derived basic protein fraction. By adjusting the amounts of the above supplemental components, an activity of improving lipid metabolism and an activity of lowering blood pressure can effectively be balanced. Further, materials containing the milk-derived basic protein fraction or basic peptide fraction of the present invention can be sterilized by heating under ordinary conditions known to a skilled artisan (for example, at 90° C. for 10 min., at 121° C. for 2 sec.) since the milk-derived basic protein fraction and basic peptide fraction of the present invention are relatively heat-stable.

For the purpose of this invention the "effective component" means causing a result, such as the improvement of lipid metabolism, reduction of high blood pressure, or both.

The dosage of agents for improving lipid metabolism and reducing high blood pressure and the combination thereof according to the present invention varies depending on age, therapeutic effect and pathologic conditions. However, results of animal experiments using rats revealed that an administration of 20 mg or more of a basic protein fraction or basic peptide fraction per kg body weight of rat was necessary to improve lipid metabolism and high blood pressure. Therefore, according to an extrapolation method (A Sequel to Medicinal Development, 1993 8:7-18), an effective daily dose for a human adult is estimated to be about 20 mg or more, preferably from about 20 to about 1000 mg, more preferably from about 40 to about 100 mg. Accordingly, the fractions can be admixed with drinks or food products or administered as a medicine so as to securely attain this dosage (for example, 2 m % to 2% in a drink or food product, 0.2% to 20% in a medicine).