WO2015178492A1 - Anti-allergy agent, agent for alleviating diarrhea caused by allergies, and medical composition - Google Patents

Abstract

The present invention alleviates allergic disease, and enables an anti-allergy agent containing β-palmitic acid as the active ingredient to be used as an antiallergy agent having no side effects.

Description

Antiallergic agent, allergic diarrhea ameliorating agent and pharmaceutical composition

The present invention relates to an antiallergic agent, an allergic diarrhea improving agent, and a pharmaceutical composition containing them.

In the modern society, the number of patients suffering from allergic diseases is increasing, and allergic diseases are also called modern diseases. Factors of allergic diseases include environmental factors such as dust and mites, and food-derived factors. However, once an allergic disease occurs, it is forced to live away from allergic factors. As a method for alleviating allergic diseases, there is a drug therapy in which a drug is administered (Non-patent Document 1), but it is not always an effective means from the viewpoint of side effects.

Accumulation and activation of mast cells are prominent in many allergic diseases. Mast cells express a high-affinity receptor for IgE. When specific allergen-specific IgE is produced, mast cell accumulation occurs, and allergen / IgE-mediated cross-linking and degranulation of mast cells occurs. And inflammatory mediators are released [FIG. 1 (a) to FIG. 1 (c)].

An object of the present invention is to provide an antiallergic agent that improves allergic diseases and has no side effects.

Through extensive studies by the present inventors, it was found that palmitic acid that binds to the β-position of glycerides (hereinafter referred to as β-palmitic acid) has an antiallergic action, particularly an allergic diarrhea-ameliorating action, and the present invention was completed. I let you.

That is, the present invention is as follows.
(1) An antiallergic agent containing β-palmitic acid as an active ingredient.
(2) An agent for improving allergic diarrhea containing β-position palmitic acid as an active ingredient.
(3) A pharmaceutical composition comprising the antiallergic agent according to (1) or the allergic diarrhea improving agent according to (2).
(4) An additive for preventing or treating allergies containing β-palmitic acid as an active ingredient.
(5) An oral composition for preventing or treating allergy to which the additive according to (4) is added.

β-palmitic acid is contained in certain edible oils and fats such as lard derived from pigs, suppresses the production of allergen-specific IgE in allergic diseases, reduces the number of colon mast cells, and removes mast cells. Granules can be suppressed.

Therefore, by adding the anti-allergic agent or the allergic diarrhea improving agent of the present invention containing β-palmitic acid as an active ingredient, it is safe and has an anti-allergic effect or an allergic diarrhea improving action with few side effects. The composition can be applied to oral compositions for preventing or treating allergies.

Β-palmitic acid is known for its effects other than antiallergic effects, such as bone strengthening in infants and improvement of intestinal flora, but the present inventors have found the functionality of antiallergy itself. First.

FIG. 1 (a) to FIG. 1 (c) are diagrams for explaining the mechanism of mast cell accumulation and activation in the local area of allergic diseases. FIG. 2 shows the results of observing the incidence of allergic diarrhea after administration of soybean oil, vegetable oil or fat, or vegetable oil or fat (test fat or oil) with an increased β-palmitic acid ratio. 3 (a) to 3 (c) are obtained using soybean oil (Soy4), vegetable oil (Soy0.4 + Cont3.6), or vegetable oil (Soy0.4 + Beta3.6) with an increased β-palmitic acid ratio. The results of analyzing the influence on each parameter (allergen-specific IgE production amount, colon mast cell number, mast cell degranulation number) in allergic diarrhea are shown.

The β-palmitic acid, which is an active ingredient of the present invention, refers to all the same compounds in the chemical formula. Further, β-palmitic acid may be a pure product or a mixture with other substances. For example, a β-palmitic acid is measured by a known measuring method, and a raw material whose existence is confirmed may be used as it is.

As a raw material (mixture) rich in β-position-palmitic acid, a typical one is lard, and this can also be used. On the other hand, lard has a peculiar “food odor”, and in order to eliminate this, plant oils and fats rich in palmitic acid are chemically or enzymatically modified to enrich β-palmitic acid. It is also known to obtain raw materials (Japanese National Publication No. 8-509620, Japanese National Publication No. 8-509621, Japanese Unexamined Patent Publication No. 6-70786). Moreover, for example, there is Betapol (Rodels Crocran) as a commercial product, which may be purchased directly and blended with other raw materials as appropriate.

When β-palmitic acid is contained in the mixture with the other substance, the fatty acid composition preferably contains β-palmitic acid at 10% or more, more preferably 20 to 90%, and still more preferably 30 to 80%, particularly preferably 40 to 70%, most preferably 50 to 60%. By setting the β-palmitic acid content of the fatty acid composition to 10% or more, a sufficient antiallergic action can be obtained.

[Beta] -palmitic acid is not particularly limited as long as it is finally absorbed into the body, such as oral, tube or enteral, but is preferably taken orally.

The recommended intake of β-palmitic acid is preferably 0.1 g to 100 g per day, more preferably 0.2 g to 80 g, still more preferably 0.4 g to 60 g, still more preferably 0.6 g to 50 g, more preferably 0.8 g to 40 g, more preferably 1.2 g to 30 g, particularly preferably 1.6 g to 20 g, and most preferably 2 g to 10 g.

Further, as demonstrated in the examples, the recommended intake frequency of β-palmitic acid is continuous intake, and further anti-allergic effects can be expected, preferably 2 times or more, more preferably 3 times or more More preferably, it is 4 times or more, more preferably 5 times or more, particularly preferably 6 times or more, and most preferably 7 times or more. It is also possible to make this per packaging form.

β-palmitic acid and raw materials containing this are widely used as anti-allergic agents and allergic diarrhea improving agents, or pharmaceutical compositions containing these or oral compositions for preventing or treating allergies can do.

In the antiallergic agent or allergic diarrhea-improving agent of the present invention, β-palmitic acid or a combination thereof with a pharmaceutically acceptable carrier is orally or tube-administered to mammals including humans. can do.

In the antiallergic agent or allergic diarrhea improving agent of the present invention, the unit form of administration of the pharmaceutical preparation is not particularly limited, and those commonly used for ordinary drugs can be appropriately selected according to the purpose of treatment. Specifically, tablets, pills, powders, solutions, suspensions, emulsions, granules, fine granules, capsules, syrups, elixirs, suppositories, injections, ointments, patches In addition, eye drops and nasal drops can be selected and used. These can then be used to administer formulations according to conventional methods.

In the antiallergic agent or allergic diarrhea ameliorating agent of the present invention, the pharmaceutical carrier is not particularly limited in the production (formulation) of the pharmaceutical preparation, and those commonly used for ordinary drugs are appropriately selected according to the purpose of the preparation. it can. In this case, specifically, excipients, binders, disintegrants, lubricants, stabilizers, fluidity promoters, flavoring agents, flavoring agents, coloring agents, fragrances, diluents, surfactants and injections. Additives such as solvents can be selected and used. And a formulation can be manufactured according to a conventional method using these.

Examples of the binder include starch, dextrin, gum arabic powder, gelatin, hydroxypropyl starch, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone and macrogol.

Examples of the disintegrant include starch, hydroxypropyl starch, carboxymethylcellulose sodium, carboxymethylcellulose calcium, carboxymethylcellulose, and low-substituted hydroxypropylcellulose.

Examples of the surfactant include sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 80 and the like.

Examples of the lubricant include talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate and polyethylene glycol.

Examples of the fluidity promoter include light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, and magnesium silicate.

The content of β-position palmitic acid contained in the preparation of the present invention is not particularly limited, and can be appropriately selected according to the effect and efficacy of the present invention. At this time, for example, the recommended content of β-palmitic acid in a usual preparation is preferably 0.1 g to 100 g, more preferably 0.2 g to 80 g, still more preferably 0.4 g to 1 g per day. 60 g, more preferably 0.6 g to 50 g, further preferably 0.8 g to 40 g, more preferably 1.2 g to 30 g, particularly preferably 1.6 g to 20 g, and most preferably 2 g to 10 g.

Examples of the pharmaceutical composition include drugs and quasi drugs, and are not particularly limited as long as the effects and effects of the present invention can be expected.

Examples of oral compositions for preventing or treating allergies include, for example, supplements, infant formula, peptide milk, follow-up milk, glowing-up milk, formula for low birth weight infant formula, non-lactose powdered milk, low sodium special milk powder and breast milk An oral composition for preventing or treating allergies for infants and the like such as a powder for additive may be mentioned, and it is not particularly limited as long as the effect and efficacy of the present invention can be expected.

In particular, when β-palmitic acid is applied to an oral composition for preventing or treating allergies for infants such as infant formula, it is possible to suppress allergic diarrhea in infants and to expect effective growth of infants. it can.

In addition, when β-palmitic acid is applied to an oral composition for preventing or treating allergies for infants such as infant formula, addition of components other than β-palmitic acid is not particularly limited.

For example, docosahexaenoic acid (DHA), eicotapentaenoic acid (EPA), arachidonic acid (ARA), cholesterol, etc., which promote the growth and growth of infants, are blended in appropriate amounts, and the β-position is close to the composition of breast milk. When the infant formula containing palmitic acid is manufactured and provided, allergic diarrhea in infants can be suppressed, and further effective growth and growth of infants can be expected.

Also prepared for infants containing β-palmitic acid with reduced or reduced allergenic β-lactoglobulin, prepared for infants containing β-palmitic acid containing appropriate amounts of nucleosides and nucleotides with immunomodulating function Produced infant formula containing β-palmitic acid containing no soy lecithin as milk powder and emulsifier can suppress allergic diarrhea in infants and effectively avoid different allergies derived from infants I can expect.

In addition, infant formula containing β-palmitic acid with lactadherin strengthened to prevent infection, formulated fructo-oligosaccharide to strengthen immunity, at least one of nucleosides, nucleotides, taurine, and zinc in appropriate amounts When infant formula containing infant formula containing β-position palmitic acid is produced and provided, allergic diarrhea for infants can be suppressed and effective enhancement of infant immunity can be expected.

In addition, infant formula containing β-palmitic acid that selectively decomposes β-lactoglobulin, which is difficult to digest and absorb, and infant formula containing beta-palmitic acid with enhanced digestible α-lactalbumin are manufactured. When it is provided, allergic diarrhea in infants can be suppressed, and an effective improvement in digestibility and absorption in the digestive tract of infants can be expected.

In addition, infant formula containing β-palmitic acid containing appropriate amounts of fructooligosaccharides or nucleosides or nucleotides that promote the formation of suitable intestinal flora, and lactose that promotes the formation of suitable intestinal flora When infant formula containing infant formula containing β-position-palmitic acid is produced and provided, allergic diarrhea in infants can be suppressed, and an effective improvement in the convenience of infants can be expected.

As used herein, infants include infants and infants, more specifically infants, infants and newborns, and more particularly infants, infants, newborns, premature infants, preterm infants and low birth weight infants. Including. In the present invention, infant species include humans unless otherwise specified.

“Infant” refers to a child in infancy, and “infant” means the period when milk such as breast milk is the main nutritional source. Infants generally refer to children in pre-school age. A newborn refers to a child in the neonatal period, and the neonatal period means a period just after birth. In the case of a human, the neonatal period usually falls within 4 weeks after birth.

The supplement containing β-position palmitic acid is not particularly limited as long as it can take β-position palmitic acid, and its form or specification is not particularly limited. For example, powder, liquid, pasty, tablet and solid forms are available. Can be mentioned.

Substances other than β-palmitic acid can be arbitrarily added (added) according to the individual design, but by adding supplement materials with known functionality, in addition to the effects and efficacy of the present invention, Multiple effects can be expected. As supplementary materials, known materials such as minerals, vitamins, proteins, carbohydrates (for example, dietary fibers), lipids, microorganisms or metabolites thereof can be used alone or in combination. However, they can be used in combination.

For example, supplements containing β-palmitin containing appropriate amounts of functional ingredients that have an intestinal function (eg, oligosaccharides, dietary fiber, lactic acid bacteria, bifidobacteria, and propionic acid bacteria fermentation composition) suppress allergy Alternatively, it can be treated, and effective relief or suppression of constipation and diarrhea can be expected. In addition, for example, a supplement containing β-palmitic acid containing calcium or vitamin D in an appropriate amount can suppress or treat allergies and can be expected to effectively prevent or treat osteoporosis.

In addition, supplements here are not only supplements in a narrow sense sold at pharmacies or drug stores, but also if supplemented into the body for the purpose of nutritional support, nutritional adjustment or maintenance of homeostasis, etc. Not limited.

In addition, β-palmitic acid, which is an active ingredient of the present invention, can be used as an additive for preventing or treating allergies. For example, β-palmitic acid may be used as an additive for pharmaceutical compositions, foods and drinks that have eating habits and are expected to have few side effects, or compositions for preventing or treating allergies. Or by tube.

Β-palmitic acid, which is an active ingredient of the present invention, is not limited to humans and exhibits the above-described excellent effects and efficacy for mammals (mammals). Accordingly, the present invention is also a feed and a feed additive containing β-palmitic acid as an active ingredient, and in particular, a milk powder and a milk powder additive for breeding mammals.

Hereinafter, test results according to examples and comparative examples according to the present invention will be shown, and the present invention will be described in more detail. The present invention is not limited to these examples.

Soybean oil, a lipid having a composition in which 90% by mass of the soybean oil is replaced with “vegetable fats and oils” shown in Table 1, or 90% by mass of the soybean oil shown in Table 1 “β-position- Feed 1, feed 2, and feed 3 were prepared by adding 4 wt% of each of the lipids having the composition substituted with the vegetable oil and fat (test fat and oil with increased palmitic acid ratio) to the purified feed described below, and 6 weeks old The mice were continuously ingested for 2 months (the mice ingested feed 1 were the soybean oil group, the mice ingested feed 2 were the vegetable oil group, and the mice ingested feed 3 were the test oil group).

This refined feed conformed to AIN-93M (for maintenance), which is a standard feed for nutritional research using mice or rats published in 1993 by the National Institute of Nutrition (AIN). Specifically, corn starch is 46.592% by mass, milk casein is 14.0% by mass, pregelatinized corn starch is 15.5% by mass, granulated sugar is 10% by mass, refined soybean oil is 4.0% by mass, cellulose 5.0% by weight powder, 3.5% by weight mineral mix (AIN-93-MX), 1.0% by weight vitamin mix (AIN-93VX), 0.18% by weight L-cystine, tartaric acid It contains 0.25% by mass of choline and 0.0008% by mass of tert-butylhydroquinone.

Of the compositions shown in Table 1, the main fatty acid composition of triglycerides was calculated by area% according to the standard oil and fat analysis method 17-2007 (capillary gas chromatograph method). In addition, the β-position-palmitic acid composition was determined using Candida antarctica Lipase B immobilized enzyme Novozyme 435 (manufactured by Novozyme) to fractionate the 2-position monoglyceride and the second-position by gas-liquid chromatography (GLC). Palmitic acid monoglyceride was analyzed. Furthermore, the β-position binding ratio in the entire palmitic acid was calculated by [[fatty acid content of palmitic acid monoglyceride at position 2 / (palmitic acid triglyceride content × 3)] × 100 [%].

Two months after the start of intake of each feed, mice bred with each feed 1 to 3 were subjected to whole body sensitization with 1 mg ovalbumin (OVA) using Freund's complete adjuvant. From 1 week after systemic sensitization, 50 mg of OVA was orally administered at a frequency of 3 times a week. As a result, allergic diarrhea was induced, and the symptoms were observed using the onset of diarrhea observed 30 to 60 minutes after the oral administration as an index. The result is shown in FIG.

As shown in FIG. 2, after the fourth oral administration, the test fat group showed a lower incidence of allergic diarrhea than the other two groups. From these results, it was found that β-palmitic acid has an antiallergic action and is effective in improving allergic diarrhea.

Next, in order to investigate the relationship between β-palmitic acid and each parameter in the development of allergic diseases, soybean oil, vegetable oils, or vegetable oils with a high β-palmitic acid ratio were used. The production amount of IgE, the number of colon mast cells, and the number of mast cell degranulations were analyzed by the following procedure.

Two months after the start of intake of each feed, mice bred with each feed 1 to 3 were subjected to whole body sensitization with 1 mg ovalbumin (OVA) using Freund's complete adjuvant. From 1 week after systemic sensitization, 50 mg of OVA was orally administered at a frequency of 3 times a week. Serum was collected the day after the oral administration of these OVA seven times, and the amount of IgE specific to OVA [FIG. 3 (a)] and the number of mast cell degranulation (mMCP-1) [FIG. 3 (c)] DS Mouse IgE ELISA (OVA) (DS Pharma Biomedical) and MouseMCPT-1 (mMCP-1) ELISA Ready-SET-Go! (Affymetrix). At the same time, mononuclear cells were collected from the lamina propria of the large intestine, and the number of mast cells was measured [FIG. 3 (b)].

As shown in FIG. 3 (a) to FIG. 3 (c), there was a correlation with the incidence of allergic diarrhea in FIG. 2, and in the test fat group, there was a decrease in each parameter compared to the other two groups. . From this result, it was found that β-palmitic acid suppresses the production of allergen-specific IgE in allergic diseases, reduces the number of colon mast cells, and suppresses degranulation of mast cells.

By using the antiallergic agent or allergic diarrhea improving agent of the present invention, prevention or treatment of allergic diseases can be expected without side effects. In particular, by applying the antiallergic agent of the present invention to an oral allergy preventive or therapeutic oral composition for infants, it is possible to prevent allergic diarrhea in infants and from the viewpoint of effectively growing and growing infants. It is valid.

Although the present invention has been described in detail using specific embodiments, it will be apparent to those skilled in the art that various modifications and variations can be made without departing from the spirit and scope of the invention. This application is based on a Japanese patent application filed on May 22, 2014 (Japanese Patent Application No. 2014-106059), which is incorporated by reference in its entirety.

Claims (5)

1. An antiallergic agent containing β-position palmitic acid as an active ingredient.
2. An agent for improving allergic diarrhea containing β-position palmitic acid as an active ingredient.
3. A pharmaceutical composition comprising the antiallergic agent according to claim 1 or the allergic diarrhea improving agent according to claim 2.
4. An additive for preventing or treating allergies containing β-position palmitic acid as an active ingredient.
5. An oral composition for preventing or treating allergy to which the additive according to claim 4 is added.

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