JP5024807B2 - Suppression composition for increasing blood pressure - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to inhibiting composition pressor chitin oligosaccharides brings an effect to improve the prevention of primary hypertension.
[0002]
[Prior art]
Various research and development have been conducted on the pathogenesis of hypertension as a lifestyle-related disease, especially primary hypertension (hypertension without other underlying diseases), and it has been elucidated that complex blood pressure regulation mechanisms develop. It's getting on. In particular, renal pressor factor, adrenocortical factor, neurological and neurohumoral factor, blood circulation factor, genetic factor, factor related to sodium metabolism, and various drugs that lower blood pressure with different mechanism of action for the treatment of primary hypertension It is used. There are many types of drugs, drugs that directly act on vascular smooth muscle to cause vasodilation, drugs that suppress the activity of the exchange nervous system in any of the pathways from the central to the receptors of peripheral blood vessels (central exchange nerves) Inhibitors, drugs that suppress both centrally and peripherally, ganglion blockers, adrenergic neuron blockers, α receptor blockers, etc.), diuretics, angiotensin antagonists, and the like are known. However, the above drugs are prescribed as a therapeutic drug based on an appropriate diagnosis by a doctor.
[0003]
On the other hand, many researches and developments have confirmed that primary hypertension can be improved by diet therapy such as controlling salt intake without using therapeutic agents. In addition, plant-derived dietary fibers such as cellulose and alginic acid contained in vegetables and seaweeds have attracted attention as an improvement or prevention of primary hypertension through various factors, and many researches and developments have been conducted. In other words, excessive intake of salt greatly affects the blood pressure regulation mechanism related to primary hypertension, and as a result, it has been confirmed that hypertension develops, and in particular, it is known that hypertension is caused by an increase in the blood concentration of sodium ions. It has been attracting attention as an improvement or prevention of hypertension by adsorbing to dietary fibers such as alginic acid and promoting the excretion of sodium ions. Shita keto fructooligosaccharides [Kabir, Y et al J. Nutr. Sci. Vitaminol., 33, 341 (1987)] and bovine thymus powder [Fujino et al. It is known to have an antihypertensive effect due to various factors such as fiber factors and immune function improvement.
[0004]
Naturally, there are many polysaccharides that are effective as dietary fiber, and many are derived from plants, but mainly N-acetyl-D contained in crustacean shells such as crabs and shrimps, insect epidermis, mushrooms and yeasts, etc. -Polysaccharide chitin, which has a structure in which glucosamine is linked by β- (1,4) bonds, is a natural polysaccharide that is presumed to have a resource amount next to cellulose and is expected to be used effectively. This is a basidiomycetous fungus such as mushrooms, yeast contained in fermented foods, rice crackers with shrimp shells, etc., which have been used as food materials on a daily basis, and also medically as a result of oral administration and tissue implantation tests, It is known that it is non-toxic and highly safe, and also exhibits effective effects on the human body such as immunostimulatory action.
Such chitin is hydrolyzed with acid or enzyme to reduce its molecular weight, and water-soluble low molecular weight chitin, commonly called chitin oligosaccharide, is N-acetyl-D-glucosamine β- (1,4) It is a mixture of oligosaccharides having a structure in which about 7 to 8 structures connected in a bond are connected in the molecule. These chitin oligosaccharides improved the intestinal bacterial flora by oral administration of chitin and promoted the growth of intestinal bifidobacteria by reducing the molecular weight of chitin oligosaccharides by chitinase secreted by intestinal bacteria. It is known to promote the production of β-galactosidase required for digestion.
[0005]
A substance obtained by deacetylating chitin is generally called chitosan, and chitosan is a highly safe food material that is approved as a food additive. Chitosan is a polysaccharide mainly composed of D-glucosamine linked by β- (1,4) bonds. Since D-glucosamine has an amino group, it is positively charged and negatively charged in aqueous solution. It is known to adsorb the substances and anions. As a physiological effect using this action, an effect similar to that of cholestyramine, which is a therapeutic agent for hypercholesterolemia, and an antihypertensive effect with respect to hypertension are known (Japanese Patent Laid-Open No. 6-56774), and functional foods expected in the future It is a material.
Such chitosan is hydrolyzed with acid or enzyme to reduce its molecular weight, and water-soluble low-molecular chitosan generally called chitosan oligosaccharide has a β- (1,4) bond with salt-containing D-glucosamine. It is a mixture of oligosaccharides having a structure in which about 10 consecutive structures are connected in a molecule. These chitosan oligosaccharides, like chitin oligosaccharides, have been shown to significantly promote the growth of intestinal bifidobacteria, particularly L. bulgaricus, and their usefulness has been recognized.
[0006]
Although some of these substances that suppress blood pressure increase such as shiitake fructooligosaccharide and bovine thymus powder are known, there have been no reports on chitosan oligosaccharides containing chitin oligosaccharides or salts focusing on suppression of blood pressure increase. Chitosan oligosaccharides containing chitin oligosaccharides or salts are not known except for the physiological functions as described above, and there have been no reports on the antihypertensive effect.
[0007]
[Problems to be solved by the invention]
The present invention is effective utilization of high safety derived from natural dietary fiber, which is expected natural polysaccharides, contain substances that can improve the primary hypertension, ingestible elevated blood pressure inhibiting composition in any form It is intended to provide.
[0008]
[Means for solving the problems]
As a result of intensive studies to achieve the above object, the present inventors mixed chitin or chitosan with feed and administered it to rats that develop primary hypertension, thereby suppressing an increase in blood pressure or exerting an antihypertensive effect. In addition, chitinsan oligosaccharides containing chitin or chitosan having a low molecular weight and mixed with diet are mixed with feed and administered to rats that develop primary hypertension. Alternatively, the inventors have found that the antihypertensive action is more effectively exhibited and have completed the present invention.
[0009]
The present invention relates to a mammal containing a chitin oligosaccharide as an active ingredient , including a human who develops hypertension with aging, by aging for oral intake on a regular basis in order to suppress an increase in blood pressure due to aging. The gist is a composition for suppressing an increase in blood pressure.
[0012]
The composition is a pharmaceutical, and in this case, the present invention is intended to suppress an increase in blood pressure due to aging for mammals including humans who develop hypertension with aging, which contains chitin oligosaccharides as an active ingredient. The gist is a drug for suppressing an increase in blood pressure due to aging to be taken orally on a regular basis.
[0013]
DETAILED DESCRIPTION OF THE INVENTION
The chitin oligosaccharide that can be used in the composition for suppressing blood pressure elevation of the present invention hydrolyzes chitin purified by chemical treatment and biochemical treatment from crustacean shells such as crabs and shrimps, mushrooms, yeast, etc. Can be obtained. The chitin oligosaccharide obtained by this method is a mixture of oligosaccharides having a degree of polymerization of about 1 to 10 sugars including monosaccharides. This chitin oligosaccharide mixture can be used as it is.
[0014]
The chitosan oligosaccharide that can be used in the antihypertensive composition of the present invention can be obtained by hydrolyzing chitosan purified by chemical treatment and biochemical treatment of the chitin. The chitosan oligosaccharide containing a salt obtained by this method is a mixture of oligosaccharides having a degree of polymerization containing about 1 to 10 sugars including monosaccharides.
[0015]
Chitosan oligosaccharide can be used in the form of hydrochloride, sulfate or the like.
[0016]
The composition of the present invention is an antihypertensive composition containing chitin oligosaccharides and / or chitosan oligosaccharides or salts of chitosan oligosaccharides as a substance that suppresses an increase in blood pressure or a substance that has an antihypertensive action. Alternatively, it is a food, feed, beverage or medicine to which chitosan oligosaccharide or a salt thereof is added in the form of powder or dissolved. The blending amount in food, beverage or feed is not particularly limited, but is preferably about 0.01 to 10% by weight.
[0017]
In the case of pharmaceuticals, they can be administered orally as capsules, powders, tablets, etc., and chitosan oligosaccharides containing chitin oligosaccharides or salts are soluble in water, so in addition to oral administration, administration methods such as intravenous injection and intramuscular injection can be used. It is possible to adopt. The dose varies depending on the degree of symptoms of hypertension, body weight, age, sex, etc., but it is desirable to determine an appropriate amount according to the symptoms. The compounding amount in medicine is not particularly limited, but is preferably about 0.1 to 2000 mg for oral, 0.01 to 1000 mg for intravenous injection, and about 0.01 to 1000 mg for intramuscular injection per 1 kg body weight.
[0018]
[Action]
As shown in the test examples to be described later, according to the feed containing a chitin oligosaccharide or a salt of chitosan oligosaccharide, it exerts a remarkable effect of suppressing an increase in blood pressure in rats that develop primary hypertension or It was recognized that the antihypertensive effect was exerted remarkably. Therefore, chitin oligosaccharides and / or chitosan oligosaccharides or chitosan oligosaccharide salts can be expected to bring about an increase in blood pressure and a hypotensive effect on animals including humans.
[0019]
In addition, the substance that suppresses the increase in blood pressure or the substance that has an antihypertensive action in the blood pressure increase inhibitory composition of the present invention is obtained from chitosan that is naturally present as crustacean shells or approved as a food additive. Since chitin oligosaccharides, chitosan oligosaccharides or chitosan oligosaccharide salts are used as active ingredients, they are highly safe and can be produced in a relatively simple process, so that the utility value is also high in terms of cost. In addition, the acute oral toxicity test of chitin oligosaccharide, chitosan oligosaccharide, or a salt of chitosan oligosaccharide is 5,000 mg / kg body weight or more and is highly safe.
[0020]
In addition, chitosan oligosaccharides, which are chiefly derived from chitin, which is a natural product and exists in large quantities in nature, or chitosan oligosaccharides containing chitosan derived from chitin as raw materials are used as active ingredients, so they are safe and inexpensive to handle. Therefore, it can be easily used as a food additive, a feed additive, a beverage additive or a pharmaceutical additive.
Therefore, it is expected that foods, beverages, feeds, and pharmaceuticals contain chitin oligosaccharides and / or chitosan oligosaccharides or chitosan oligosaccharide salts in animals, including humans, to suppress blood pressure elevation and to lower blood pressure.
[0021]
【Example】
The present invention will be described in more detail with reference to examples or test examples, but the present invention is not limited to these examples or test examples. In addition, the example regarding chitosan oligosaccharide is a reference example.
[0022]
Example 1
(Production of chitin oligosaccharides)
10 kg of Benizwai crust was reacted with 100 liters of a 5% hydrochloric acid solution at 30 ° C. or less for 16 hours with appropriate stirring. After washing with water until neutrality was obtained, decalcified crab shells were obtained. This decalcified crab shell was added with 100 liters of 5% sodium hydroxide solution, reacted at 100 ° C. for 3 hours, washed with water until neutral, and dried to obtain 3.8 kg of chitin. When this chitin was analyzed, the residue on ignition was 1.08%.
Adjust 2 liters of concentrated hydrochloric acid to a liquid temperature of 20 ° C., add 1 kg of the chitin obtained above while stirring, and gradually mix the chitin into the liquid, followed by hydrolysis at a liquid temperature of 35 ° C. for 5 hours. It was. Thereafter, 3 liters of water was added to stop the reaction, and 20 g of purified diatomaceous earth (“Radiolite FNF-A” manufactured by Showa Chemical Co., Ltd.) and 40 g of activated carbon (“SW-50” manufactured by Nimura Chemical Co., Ltd.) were added to this diluted solution. After stirring for 15 minutes and mixing, suction filtration was performed, 300 ml of water was poured into the filtration residue, washed and filtered, and combined with the filtrate to obtain 5.3 liters of chitin oligosaccharide hydrochloric acid solution.
Next, desalting treatment was performed on the chitin oligosaccharide hydrochloric acid solution using an ion exchange membrane electrodialyzer (Japanese Patent Laid-Open No. 2000-17475). 5 liters of chitin oligosaccharide hydrochloric acid solution was placed in a diluting liquid tank, 1500 ml of 0.2% sodium hydroxide aqueous solution was placed in the concentrate (anolyte) tank, and 1500 ml of 15% sodium hydroxide aqueous solution was placed in the caustic soda tank. . A pump provided in a pipe connected to the dilution liquid tank and the concentrated liquid (anolyte) tank is operated, and the diluted liquid and concentrated liquid (anode liquid) are fed into the ion exchange membrane dialysis tank, and the space between each tank is 400 ml / Circulated at a flow rate of minutes. Next, using a direct current power supply device, a 24 volt, 20 ampere direct current was passed through the anode and cathode to start the operation. After 17 hours from the start of operation, it was confirmed that the pH of the diluent had increased to 6.5, and the operation was stopped to obtain 4.3 liters of diluent. The residual chlorine concentration in the diluted solution was 0.1 g / 100 ml. 20 g of activated carbon was added to this diluted solution and stirred for 15 minutes, followed by suction filtration. The filtrate was spray-dried (“Spray dryer L-8 type” manufactured by Okawara Kako Co., Ltd.) to yield 582 g of chitin oligosaccharide (yield from raw chitin). 58%). When this chitin oligosaccharide was analyzed, the pH was 6.1 with a 1% aqueous solution and the ignition residue was 0.83%.
[0023]
Example 2
(Manufacture of chitosan oligosaccharide)
2 kg of the chitin obtained in Example 1 was deacetylated for 3 hours while stirring at 10 liters of 45% sodium hydroxide solution at 100 ° C. or more, washed with water until neutral and dried, and then again with 45% water. A 10-liter sodium oxide solution was deacetylated for 3 hours with stirring at 100 ° C. or higher, and 1.6 kg of chitosan washed with water and dried until neutrality was obtained. When this chitosan was analyzed, the ignition residue was 0.10% and the degree of deacetylation was 95%.
2 liters of concentrated hydrochloric acid was adjusted to a liquid temperature of 40 ° C., 1 kg of the chitosan obtained as described above was added little by little while stirring, and the chitosan was homogeneously mixed in the liquid, followed by hydrolysis at 80 ° C. for 3 hours. Thereafter, 3 liters of water was added to stop the reaction, and 20 g of purified diatomaceous earth (“Radiolite FNF-A” manufactured by Showa Chemical Co., Ltd.) and 40 g of activated carbon (“SW-50” manufactured by Nimura Chemical Co., Ltd.) were added to this diluted solution. After stirring for 15 minutes and mixing, suction filtration was performed, and 300 ml of water was poured into the filtration residue, washed and filtered, and combined with the filtrate to obtain 5.3 liters of a chitosan oligosaccharide hydrochloric acid solution.
Subsequently, the chitosan oligosaccharide hydrochloric acid solution was spray-dried (“Spray dryer L-8 type” manufactured by Okawara Kako Co., Ltd.) to obtain 604 g of chitosan oligosaccharide hydrochloride (yield 60% from the raw material chitosan). When this chitosan oligosaccharide hydrochloride was analyzed, the pH was 5.6 with a 1% aqueous solution, and the ignition residue was 0.18%.
[0024]
Test example 1
(Effect of chitin and chitin oligosaccharide administration to primary hypertensive rats)
Spontaneously spontaneously hypertensive rat (Spontaneously) as a model animal of primary hypertension
Hypertensive Rat: hereinafter referred to as SHR). SHR is known to be the best model animal for human primary hypertension, such as developing hypertension with age without artificial treatment.
This SHR (n = 5) is feed for breeding containing 2% of the chitin obtained in Example 1 or the chitin oligosaccharide obtained in Example 1 from the age of 6 weeks after birth ("MF: Powder" manufactured by Oriental Yeast Co., Ltd.) )), And the control group was fed a breeding feed not containing chitin and chitin oligosaccharides. Blood pressure was measured on the 5th day for the first time and every 10 days thereafter, and the body weight and feed intake were measured every 3 days. The blood pressure was measured with a non-invasive blood pressure measuring device (“BP-98A” manufactured by Softron).
As a result of the above, the change in body weight (Fig. 1) and the change in food intake (Fig. 2) did not change significantly in the control group and 2% chitin group, and in the control group and 2% chitin oligosaccharide group. A noticeable decrease was observed in the transition (Fig. 3). In particular, inhibition of elevation was remarkably confirmed in the chitin oligosaccharide group compared with the control group than the chitin group compared with the control group. This shows that chitin oligosaccharides have no significant effect on body weight or food intake and significantly reduce blood pressure increase with aging.
[0025]
Test example 2
(Effects of chitosan and chitosan oligosaccharide administration to primary hypertensive rats)
Similar to Test Example 1, SHR was used as a model animal for primary hypertension. This SHR (n = 5) is feed for breeding containing 2% of chitosan obtained in Example 2 and chitosan oligosaccharide obtained in Example 2 from 6 weeks of age ("MF: Powder" manufactured by Oriental Yeast Co., Ltd.) )), And the control group was fed a breeding feed not containing chitosan and chitosan oligosaccharide hydrochloride. Blood pressure was measured on the 5th day for the first time and every 10 days thereafter, and the body weight and feed intake were measured every 3 days. The blood pressure was measured with a non-invasive blood pressure measuring device (“BP-98A” manufactured by Softron).
As a result of the above, the change in body weight (Fig. 4) and the change in food intake (Fig. 5) did not change significantly in the control group and 2% chitosan group, and in the control group and 2% chitosan oligosaccharide group, but the systolic blood pressure A noticeable decrease was observed in the transition (Fig. 6). In particular, the suppression of elevation was remarkably confirmed in the chitosan oligosaccharide group compared with the control group than in the chitosan group compared with the control group. From these results, it was found that chitosan oligosaccharide had no significant effect on body weight or food intake and significantly reduced blood pressure increase with aging.
[0026]
Test example 3
(Effect of chitin and chitin oligosaccharide administration to primary hypertensive rats)
Similar to Test Example 1, SHR was used as a model animal for primary hypertension.
This SHR (n = 5) is feed for breeding containing 2% of chitin obtained in Example 1 or chitin oligosaccharide obtained in Example 1 from 23 weeks of age ("MF: Powder" manufactured by Oriental Yeast Co., Ltd.) )), And the control group was fed a breeding feed not containing chitin and chitin oligosaccharides. Blood pressure was measured on the 5th day for the first time and every 10 days thereafter, and the body weight and feed intake were measured every 3 days. The blood pressure was measured with a non-invasive blood pressure measuring device (“BP-98A” manufactured by Softron).
As a result of the above, no significant changes were observed in the control group and 2% chitin group, and in the control group and 2% chitin oligosaccharide group in the change in body weight (FIG. 7) and the change in food intake (FIG. 8). A significant decrease was observed in the transition (Fig. 9). In particular, the antihypertensive effect was significantly confirmed in the chitin oligosaccharide group compared with the control group than the chitin group compared with the control group. This indicates that chitin oligosaccharides have no significant effect on body weight or food intake and significantly reduce systolic blood pressure, that is, have an antihypertensive effect.
[0027]
Test example 4
(Effects of chitosan and chitosan oligosaccharide administration to primary hypertensive rats)
Similar to Test Example 1, SHR was used as a model animal for primary hypertension. This SHR (n = 5) is feed for breeding containing 2% of chitosan obtained in Example 2 and chitosan oligosaccharide obtained in Example 2 from 23 weeks of age ("MF: Powder" manufactured by Oriental Yeast Co., Ltd.) )), And the control group was fed a breeding feed not containing chitosan and chitosan oligosaccharide hydrochloride. Blood pressure was measured on the 5th day for the first time and every 10 days thereafter, and the body weight and feed intake were measured every 3 days. The blood pressure was measured with a non-invasive blood pressure measuring device (“BP-98A” manufactured by Softron).
As a result of the above, no significant changes were observed in the control group and 2% chitosan group, and the control group and 2% chitosan oligosaccharide group in the change in body weight (FIG. 10) and the change in food intake (FIG. 11). A noticeable decrease was observed in the transition (Fig. 12). In particular, the antihypertensive action was remarkably confirmed in the chitosan oligosaccharide group compared with the control group than the chitosan group compared with the control group. This indicates that chitosan oligosaccharide has no significant effect on body weight or food intake and significantly reduces systolic blood pressure, that is, has an antihypertensive effect.
[0028]
【Effect of the invention】
An antihypertensive composition containing a substance capable of improving primary hypertension, which is a natural polysaccharide derived from natural dietary fiber, which is expected to be effectively used, is provided. Since it is highly safe, inexpensive and easy to handle, it can be provided in the form of food, beverage, feed or pharmaceutical.
[Brief description of the drawings]
FIG. 1 is a graph showing changes in body weight in Test Example 1. FIG.
FIG. 2 is a graph showing changes in feed intake in Test Example 1.
FIG. 3 is a graph showing changes in systolic blood pressure in Test Example 1.
4 is a graph showing the change in body weight in Test Example 2. FIG.
FIG. 5 is a graph showing changes in feed intake in Test Example 2.
6 is a graph showing changes in systolic blood pressure in Test Example 2. FIG.
7 is a graph showing a change in body weight in Test Example 3. FIG.
FIG. 8 is a graph showing changes in feed intake in Test Example 3.
9 is a graph showing changes in systolic blood pressure in Test Example 3. FIG.
10 is a graph showing the change in body weight in Test Example 4. FIG.
FIG. 11 is a graph showing changes in feed intake in Test Example 4.
12 is a graph showing changes in systolic blood pressure in Test Example 4. FIG.

Claims (2)

Suppression of blood pressure increase due to aging for oral intake of mammals, including humans who develop hypertension with age, containing chitin oligosaccharides as active ingredients Composition. Composition inhibiting composition of the blood pressure increase due to aging of claim 1 is a pharmaceutical.

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