Patent Application
20080095826
In the present invention, glutamic acid may be either in the form of a free acid or a salt thereof. The salt may be either inorganic or organic. Examples of inorganic salts include salts with alkali metals, such as sodium, potassium, and the like, and salts with alkaline earth metals, such as calcium, magnesium, and the like. Examples of organic salts include salts with organic amines, such as ammonia, monoethanolamine, diethanolamine, triethanolamine, and the like, salts with basic amino acids, such as arginine, lysin, and the like, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like, salts with organic acids such as formic acid, oxalic acid, acetic acid, lactic acid, tartaric acid, citric acid, fumaric acid, malonic acid, methanesulfonic acid, and the like. A particular kind of these salts may be used, or two or more kinds thereof may be used. Due to their ready availability and ease of handling, and the like, salts with alkali metals such as sodium, potassium, and the like, salts with organic amines, and salts with basic amino acids are preferable.
Glutamic acid or the salt thereof may be a hydrate.
In the method of increasing the lymphocytes in the peripheral blood and the method of stimulating the immune system, glutamic acid or a salt thereof may be administered, for example, in the form of an immunostimulator to be described in detail below.
In the present invention, the term “immunostimulator” encompasses pharmaceutical agents and/or compositions and food compositions. Food compositions include nutritionally beneficial foods and foods for specified health uses, and the like. The immunostimulator includes a package containing the pharmaceutical agent or food of the present invention, and written matter stating that the pharmaceutical agent or food is to be administered or taken to stimulate the immune system or to increase the lymphocyte count in peripheral blood, and also stating the method of administration or intake.
The immunostimulator of the present invention can be mixed with an appropriate excipient, an appropriate diluent, and the like, such as those generally used in pharmacological compositions. The immunostimulator, or the mixture thereof, can be prepared by a conventional method to be in the form of a solid or liquid oral dosage form, such as a powder, granule, tablet, capsule, suspension, emulsion, syrup, aerosol, and the like, and/or an external preparation, a suppository, or a sterile injection.
As the carrier, excipient, and/or diluent, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, maltitol, starch, glycerol, gum acacia, alginate, gelatin, calcium sulfate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil can be used.
In addition, the diluent and excipient may include a filler, extender, binder, wetting agent, disintegrant, surfactant, and the like, or any other agents which are generally used in such a preparation.
The solid dosage form for oral administration includes a tablet, pill, powder, granule, capsule, and the like. The solid dosage form can be prepared by adding at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, and the like, to the aforementioned glutamic acid or the salt thereof. Besides simple excipients, a lubricant such as magnesium stearate and talc can also be used. As a liquid preparation for oral administration, a suspension, internal liquid, emulsion, syrup, and the like can be used, which may contain various excipients, such as a wetting agent, sweetening agent, aromatic, preservative, and the like. Water and liquid paraffin are frequently used as simple diluents. The preparation for parenteral administration includes a sterile aqueous solution, non-water-soluble preparation, suspension, emulsion, freeze-dry preparation, and suppository. For the non-water-soluble preparation and suspension, plant oil such as propylene glycol, polyethylene glycol and olive oil, injectable ester such as ethyloleate, and the like, can be used. As the base of a suppository, hard fat (witepsol), macrogol, Tween 61, cacao butter, laurisilva fat, glycerogelatin, and the like can be used.
Glutamic acid or a salt thereof can be prepared as a food, such as foods for the sick, nutritionally-beneficial food, food for specified health uses, and the like. When prepared as a food, the amount of glutamic acid or a salt thereof in the food is 0.008-30 wt %, preferably 0.4-10 wt %, relative to the total weight of the food based on glutamic acid. When the food is a beverage, the amount of glutamic acid is about 0.008-10 g (0.008-10 wt %), preferably about 0.08-2 g, relative to 100 mL of the beverage. The food may be a powder, granule, tablet, capsule, cookie, jelly, beverage, or general food.
The food composition of the present invention may contain general food materials as a base and, for example, various nutritional supplements, such as vitamins, mineral substances (electrolyte), minerals, synthetic flavors, natural flavors, colorants, fillers (cheese, chocolate, and the like), pectic acids or a salt thereof, alginic acids or a salt thereof, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerol, alcohols, and the like.
When the food is in the form of a beverage, it may contain fruit pulp and grain which results from the production of natural fruit juices. The beverage may also be a fruit juice beverage, grain and/or vegetable beverage, or a carbonated beverage containing carbonation agents. The components in the beverage other than glutamic acid and a salt thereof are not particularly limited and, various flavors, natural carbohydrates, and the like can be added as additional components. Natural carbohydrates may include, for example, general saccharides such as monosaccharides (glucose, fructose and the like), disaccharides (maltose, sucrose and the like) and polysaccharides (dextrin, cyclodextrin and the like), as well as sugar alcohols such as xylitol, sorbitol, erythritol and the like. Flavors other than those mentioned above may include natural flavors (thaumatin, extract of stevia (rebaudioside A), glycyrrhizin and the like) and synthetic flavors (saccharin, aspartame and the like).
These materials and components can be used independently or in combination. While the proportion of such additives is not limited, it is generally in the range of about 0.01-20 wt % per 100 wt % of the beverage composition. The proportion of the aforementioned natural carbohydrate is generally about 1-20 g (1-20 wt %), preferably about 5-12 g, per 100 mL of the composition.
When the food is in the form of a powder, granule, tablet, or capsule, it can be processed into a preparation using the additive, and using known methods for formulating pharmaceutical products.
The pharmaceutical composition and food composition of the present invention can be a part of a package also containing written matter stating that the pharmaceutical composition or food composition can be administered or taken for the purpose of stimulating the immune system or increasing lymphocytes in the peripheral blood, and also stating the method of administration or intake, and the like.
The glutamic acid or a salt thereof is administered in an effective amount for a human and/or other animals in need of enhanced immunity (e.g., cattle, horse, sheep, goat, pig, dog, cat, domestic fowl, and the like). When administering to animals, an effective amount of glutamic acid or a salt thereof may be added to the feed. To enhance immunity against infectious diseases, glutamic acid or a salt thereof may be added to the feed within the range of 0.008-95 wt %, preferably 0.08-80 wt %, relative to the total weight of the feed composition based on glutamic acid.
The pharmaceutical composition or food composition of the present invention may also contain, besides glutamic acid or a salt thereof, glutamine and the like, other peripheral blood lymphocyte-increasing agents, or a known immunoenhancing substance, which is known to potentiate immunity by enhancing lymphocyte activation, though it may not increase the lymphocyte count in peripheral blood. Furthermore, any of these additives may be used alone or in combination. Immunoenhancing substances known to potentiate immunity by enhancing lymphocyte activation include polysaccharides from a mushroom extract (krestin, lentinan and the like), plant extracts of Viscum album (mistletoe), polygamma-glutamic acid, Ginseng Radix (Ginseng Radix Rubre, Sun Ginseng and the like), garlic, bamboo salt, beans, fermentation products, green sap, various vegetables, organic germanium, various yeasts, elm bark, various marine plants, and the like.
Combining these conventional immunoenhancing substances enables greater enhancement of immunity because of the synergistic effect provided thereby. For example, cytokines are known to have problematic side effects, therefore, combining the administration of cytokines with glutamic acid or a salt thereof can increase the lymphocyte count in the peripheral blood, reduce the amount of cytokine needed, and reduce the side effects.
While the dose or amount of glutamic acid or a salt thereof will vary depending on the age, sex, body weight, pathology of the subject, and chosen administration pathway, it is generally 8-300 mg/kg, preferably 40-200 mg/kg, based on glutamic acid, for an adult subject per day, which can be administered at one time, or in several portions. The dose or amount is preferably about 0.4 g-3 g.
When the dosage amount is less than 8 mg/kg, the total lymphocyte count in peripheral blood will not increase sufficiently, and when it is more than 300 mg/kg, the effect cannot be enhanced sufficiently to outweigh the difficulty in dosing and increase in cost.
In the present invention, the amount of glutamic acid or a salt thereof for an adult per day is preferably 75-10,000 mg, more preferably 2,000-10,000 mg, based on glutamic acid.
The aforementioned doses are not limited, but can be determined appropriately by those skilled in the art. Since glutamic acid or a salt thereof per se is not toxic or exhibits side effects, it can be administered over a long period of time for the purpose of preventing a decrease in the lymphocyte count in the peripheral blood, preventing infectious diseases, and the like.
The subject to be administered with glutamic acid or a salt thereof is generally healthy, but may be at risk to develop infectious diseases due to a low total lymphocyte count in the peripheral blood, or the subject is elderly or sick, or has already developed an infectious disease and is in need of treatment. The etiology of decreased lymphocyte count in the peripheral blood, followed by the onset of an infectious disease, and the like includes, but is not limited to, nutritional deficiency, radiation therapy, extreme stress, immunosuppressive therapy, inherited lymphocytopenia (agammaglobulinemia, DiGeorge malformation, Wiskott-Aldrich syndrome, severe composite immunodeficiency syndrome, ataxia telangiectasia and the like), viral infection (HIV, granulomatous infection, Hodgkin's lymphoma and the like), acute bacterial or fungal infection, protein-losing gastroenteropathy, and the like.
The normal level of total lymphocytes in the peripheral blood is 1000-4800/μL for an adult, and the total lymphocytes in blood include both T-lymphocytes and B-lymphocytes. About 65% of T-lymphocytes are CD4+ (helper) T-lymphocytes, and it is known that most patients with lymphocytopenia have a decreased absolute count of T-lymphocytes, particularly a decrease in their CD4+ T-lymphocyte count. In the present invention, therefore, healthy subjects and patients with a total lymphocyte count in the peripheral blood below this level are candidates for glutamic acid administration. It is also possible to prophylactically administer glutamic acid or a salt thereof as described herein to healthy subjects and/or patients having a total lymphocyte count within the normal range, but with an upcoming event which may decrease their total lymphocyte count, such as patients scheduled for a medical procedure that may reduce the lymphocyte count, and/or healthy subjects and patients possibly exposed to a a high level of stress.
The present invention is explained in more detail in the following by referring to Examples and Production Example, which are not to be construed as limiting.
Monosodium glutamate monohydrate was added to rice gruel to 0.5 wt %.
Hospitalized elderly test subjects (n=11 (2 males, 9 females), average age of 85.8±8.2, average body weight of 39.7±5.7 kg), were fed the above-mentioned rice gruel with glutamic acid 3 times a day for 2 months, establishing a continuous administration of 0.8 g on average of monosodium glutamate monohydrate per meal.
From 1 month before the start of administration to 2 months after the start of administration, the eating ratio (ratio of weight of food actually eaten to weight of provided food) was measured. Blood samples were collected early in the morning immediately before the start of administration, 1 month after the start of adminstration, 2 months after the start of administration, and 1 month after the completion of administration, and the blood indices were measured. In addition, the body weight was measured.
There was no significant difference in the eating ratio after the start of administration as compared to that before the start of administration for both the principal food of rice gruel containing monosodium glutamate monohydrate and the side dish. The energy intake amount and the nutrient intake amount also showed no changes. The blood index and albumin value were also free of significant change, but the peripheral lymphocyte count increased significantly (Friedman test, p<0.05) (
Furthermore, at 1 month after the completion of administration, the peripheral lymphocyte count significantly decreased as compared to during administration (Friedman test, p<0.05) (
From these results, it can be seen that, even when the energy intake amount and the nutrient intake amount are of the same level, once monosodium glutamate is taken, the peripheral lymphocyte count significantly increases.
Table 1 shows the composition of 4,000 g of enteral nutrient (PEG agent) containing glutamic acid.
Water (1,420 g) was measured in a 5 L stainless bucket and heated to 70-80° C. Then, dextrin, granulated sugar, sodium ferrous citrate, sodium phosphate, potassium phosphate, potassium citrate and sodium gluconate were added to the water and dissolved by stirring in T. K. ROBOMICS (Tokushu Kika Kogyo Co., Ltd.) at 3,000 rpm. Edible fat and oil previously heated to 70-80° C. and an emulsifier were added thereto. Then, a source material for milk protein (Fonterra: casein content 66.8 wt %), monosodium glutamate monohydrate, mineral yeast Mix, and flavor were added in order and mixed to give a uniform solution/dispersion. Then, dissolved water-soluble food fiber, magnesium chloride, and calcium lactate were gradually added. Furthermore, vitamin Mix, sodium ascorbate and sodium erythorbate were added, dispersed, and dissolved. After adding water to a total weight of 4,000 g, the mixture was dissolved and dispersed until it reached a uniform state, and put in an aluminum pouch with a vent plug at 150 g per pouch. The pouch was subjected to a retort sterilization treatment by 2-step heating at 110° C. and 126° C.
Since a hospitalized test subject (64 years old, male) developed aspiration pneumonia, the feeding method was changed from percutaneous endoscopic gastrostomy (PEG) without glutamic acid to intravenous hyperalimentation. However, the C-reactive protein value was high, and the test subject became repeatedly feverish. When the fever disappeared, the PEG agent with glutamic acid was administered in combination. The PEG agent with glutamic acid was intragastrically administered 3 times a day. The dose profile is shown in
The profile of peripheral lymphocytes and the like after administration of the PEG agent with glutamic acid is as shown in
In the test of Example 1, the test subject was assessed by a nurse or a care assistant for the improvement of the general condition between immediately before the start of the administration of the rice gruel containing a salt of glutamic acid e and 2 months thereafter. The results are shown in Table 2. The test subjects took the Hasegawa Dementia Scale-Revised for the following 9 items immediately before the administration and 2 months thereafter. The results are shown in
1. age?
2. what year, what month, what date, what day of the week?
3. where are you now?
4. memory of 3 words
5. continue to subtract 7 from 100
6. say numbers in reverse order
7. read out from memory of item 4
8. memory of 5 goods
9. say name of vegetables.
As is clear from Table 2, almost all test subjects showed a tendency toward improvement of mind and body conditions such as speech recovery, expression of emotion, and the like. In the Hasegawa Dementia Scale-Revised, the grade points increased particularly for the items relating to speech.
Chronically compromised immunity in the elderly not only weakens the ability to defend against infectious diseases, but also causes general deterioration of the mind and body. The amount of lymphocytes in peripheral blood of the test subjects who took glutamic acid or a salt thereof increased as shown in Example 1, and immunity was enhanced. As a result, the condition of the mind and body can also be improved, namely, the overall quality of life can be improved.
To a powder (380 g) of monosodium glutamate monohydrate, which was passed through a 60 mesh sieve, are added lactose (883 g), which was passed through a 80 mesh sieve, and corn starch, which was passed through a 120 mesh sieve, and the mixture is thoroughly blended in a V-type mixer (powder A). Separately, to hydroxypropylcellulose (16 g), which was passed through a 60 mesh sieve, is added an appropriate amount of sterile purified water, and the mixture is dispersed at 90° C. and cooled to 20° C. (solution B). Solution B and powder A are kneaded in a biaxial kneading machine, and granulated in an extrusion-granulator (cylindrical shape, 0.5-1.0 mm). This is dried at 60° C. for 50 min in a through-flow dryer to give dry granules, which are sized in a tornado mill to give granules (1500 g).
| Number | Date | Country | Kind |
|---|---|---|---|
| 289259/2006 | Oct 2006 | JP | national |
