KR101981482B1 - Composition for alleviating allergy comprising ethyl ferulate as an effective ingredient - Google Patents

Abstract

Disclosed herein are compositions for alleviating allergies comprising ethyl ferulate as an active ingredient. The composition according to one aspect of the present invention can improve the allergic reaction effectively by improving skin barrier function and degranulation reaction of mast cells, which are important causes of allergic reaction. In addition, when combined with a cosmetic composition, a pharmaceutical composition, and a food composition that are in direct contact with a human body, allergic reactions caused by the compositions can be prevented or minimized.

Description

TECHNICAL FIELD [0001] The present invention relates to a composition for alleviating allergies comprising ethyl ferulate as an active ingredient,

Disclosed herein are compositions for alleviating allergies comprising ethyl ferulate as an active ingredient.

Allergy is a pathological reaction that occurs due to contact with an allergen, due to inherited or acquired immune function abnormalities. Typical allergic circles include pollen, drugs, vegetable fibers, bacteria, fungi, house dust mites, food, dust, dyes, and chemicals. In recent years, there have also been increasing cases of allergic diseases caused by various chemical substances and natural extracts contained in cosmetics.

Typical allergic diseases include atopic dermatitis, bronchial asthma, allergic rhinitis, allergic keratitis, and skin rash. As for the mechanism of the allergic reaction, when the allergen enters the living body, T-helper cells and B cells are sequentially activated and IgE is produced. The IgE thus produced binds to the high affinity IgE receptor in the mast cell membrane. When the allergen such as mites and pollen binds to the IgE receptor, the receptor aggregates. By crosslinking and aggregation of the receptor, mast cells are activated and the calcium ion concentration in the cytoplasm increases. The increase in calcium ion concentration acts on various kinds of intracellular regulators such as cholesterol and cytoskeleton of the cell membrane to move the granules to the cell membrane, and at the same time, the granules are released into the air, the granules are fused and the granules and cell membranes are fused, ≪ / RTI > When degranulation occurs, a chemically transferable substance such as histamine that is stored in advance in the mast cell is liberated, and a newly synthesized prostaglandin leukotriene and the like are secreted together. In addition to histamine, serotonin, and leukotrienes, which act as vasodilators, vasoconstrictors, and bronchial smooth muscle contractions or secretion enhancement, the chemical messengers liberated by degranulation include NCF, ECF, PAF, etc., allergic reaction occurs

Alkylamines and anti-IgE agents are currently used as antiallergic drugs, but the side effects are often severe and only temporarily relieve symptoms rather than fundamentally eliminating the cause of allergies.

Therefore, it is necessary to develop a new substance which is able to fundamentally improve allergic diseases, but has a low side effect and a continuous effect.

 Kim, Hyun-Hee, Role of basophils in the mechanism of allergy inflammation, Department of Pediatrics, College of Medicine, Catholic University, Korea, Vol 46, No 6, 2003

In one aspect, an object of the present invention is to improve the skin allergy phenomenon.

In one aspect, an object of the present invention is to effectively improve skin troubles due to an allergic phenomenon.

In one aspect, the present invention provides a composition for alleviating allergies comprising ethylparulate, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof as an active ingredient.

The composition comprising ethylperulate, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof as an active ingredient of the present invention is useful as a skin barrier function The degranulation reaction of mast cells can be improved, and the allergic reaction can be effectively improved. In addition, when combined with a cosmetic composition, a pharmaceutical composition, and a food composition that are in direct contact with a human body, allergic reactions caused by the compositions can be prevented or minimized.

FIG. 1 is a graph showing the amount of beta-hexosaminidase secreted when a composition of the present invention is treated after allergen-inducing substances are treated with mast cells.
FIG. 2 is a graph showing the inhibitory effect of histamine secretion upon treatment of a composition of the present invention after treating an allergen with a mast cell.
FIG. 3 is a graph showing changes in expression of serine-palmitoyl-converting enzyme 1 when human keratinocytes were treated with a composition of the present invention.
FIG. 4 is a graph showing changes in the expression of ceramide synthase 3 when human keratinocytes were treated with a composition of the present invention.

Hereinafter, the present invention will be described in detail.

In one aspect, the present invention is a composition for alleviating allergies comprising ethyl ferulate, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof as an active ingredient.

The ethyl ferulate is also referred to as ethyl 4-hydroxy-3-methoxycinnamate and has a molecular weight of C ₁₂ H ₁₄ O ₄ and a molecular weight of 224.24 g / mol. Is represented by the following general formula (1).

[Chemical Formula 1]

As used herein, the term " isomers " refers in particular to optical isomers (for example, essentially pure enantiomers, essentially pure diastereomers or mixtures thereof) as well as morphological isomers (i. e., isomers differing only in the angle of one or more chemical bonds), position isomers (especially tautomers) or geometric isomers (e.g., cis-trans isomers) do.

As used herein, " essentially pure ", when used in reference to an enantiomer or partial isomer, refers to an enantiomer or partial isomer of a specific compound, such as about 90% or more, specifically about 95% More specifically about 97% or more, or about 98% or more, more specifically about 99% or more, still more specifically about 99.5% or more (w / w).

As used herein, the term " pharmaceutically acceptable " refers to the approval of a government or equivalent regulatory agency that can be used on animals, and more specifically on humans, by avoiding significant toxic effects when used in conventional medicinal dosage Received, approved, or listed in pharmacopoeia or other general pharmacopoeia.

As used herein, " pharmaceutically acceptable salt " means a salt according to one aspect of the present invention which is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. The salt may be (1) formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; (4-hydroxybenzoyl) benzoic acid, acetic acid, propionic acid, hexanoic acid, cyclopentenepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, Benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4- chlorobenzenesulfonic acid, 2- 4-methylbicyclo [2,2,2] -oct-2-en-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert Acid addition salts formed with organic acids such as butylacetic acid, lauric sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid; Or (2) salts formed when the acidic proton present in the parent compound is substituted.

As used herein, the term " prodrug " refers to a drug that chemically changes a drug to control its physical and chemical properties. Although it does not exhibit physiological activity itself, The drug can be turned into a drug.

As used herein, " hydrate " means a compound to which water is bound, and is a broad concept that includes an inclusion compound having no chemical bonding force between water and the compound.

As used herein, " solvate " means a higher order compound formed between a molecule or ion of a solute and a molecule or ion of a solvent.

The composition can improve skin troubles due to allergy. In the present specification, " skin trouble " means a case where the skin is not in a normal state due to allergy.

As used herein, the term " skin " refers to a tissue covering an animal's body surface, and is a broad concept including not only a tissue covering a body surface such as a face or a body but also a scalp.

In the present specification, " allergy " is a concept of the best known as the change of the body which is caused by an antigen-antibody reaction when an organism comes into contact with an allergen, In the present specification, there is no limitation on the kind of the adventitious substance, and specific examples thereof include pollen, drug, vegetable fiber, bacteria, food,

And the like, but are not limited thereto. In this specification, the specific parts of the body which are changed due to the adventitious substance are not limited.

Also, in this specification, allergy is meant to include changes in the body which are caused by changes in the in vivo response to endogenous factors such as hormonal changes, stress, emotional disturbance, fatigue, insufficient sleep, and the like.

The allergic diseases include edema, anaphylaxis, allergic rhinitis, allergic asthma, hay fever, Quincke's edema, allergic conjunctivitis, allergic conjunctivitis, Allergic keratitis, allergic dermatitis, atopic dermatitis, contact dermatitis, hives, pruritus, insect allergies, food allergies and allergic dermatitis. Drug allergies, but it is not limited to these, and it includes all the changes in the living body caused by adventitious factors or endogenous factors.

On the other hand, skin is an exemplary organ exhibiting an immune response while retaining moisture in the body and performing an essential barrier function to protect the intrusion of external invading factors (antigen, infectious agent, etc.). Such barrier function has an overall effect on skin health. Thus, by strengthening the skin barrier function, skin troubles including allergies can be alleviated or improved.

The composition can inhibit the degranulation reaction of mast cells or enhance the skin barrier function. Specifically, when mast cell degranulation is induced, histamine can be secreted, resulting in skin troubles such as inflammation, itching or skin redness. The composition suppresses skin troubles due to histamine secretion, can do.

Specifically, the composition may include one or more of the following features: 1) inhibition of secretion of beta-hexosaminidase from mast cells; 2) inhibiting the secretion of histamine from mast cells; 3) increased expression of serine-palmitoyltransferase (SPTLC); And 4) increased expression of ceramide synthase (CerS).

Specifically, when the above composition containing ethylpearlate at 20 ppm is administered, the amount of histamine secreted can be suppressed to 35% or more as compared with the case where only allergen-inducing chemicals PMA 50 nM and A23187 1 μM are administered . In addition, when the above composition containing ethyl persulate at 50 ppm is administered, the expression of SPTLC can be promoted by 50% or more and the expression of CerS can be promoted by 30% or more as compared with the group not administered.

In one embodiment, the composition may increase the expression of serine-palmitoyl transferase or ceramide-producing enzyme in keratinocytes.

The serine-palmitoyl transferase may be serine-palmitoyl transferase 1, and the ceramide-producing enzyme may be ceramide-producing enzyme 3.

That is, the composition according to the present invention can inhibit the production of allergen-inducing substance itself, and contains an antagonistic antibody against the receptor of already generated and secreted allergen-inducing substance as its component, so that the cause of allergy can not be fundamentally solved. It is possible to solve the limitations of the composition for improving, alleviating or treating existing allergic diseases. Accordingly, the composition for anti-allergy according to the present invention can be usefully used as a composition having an excellent effect for preventing, improving or treating allergic diseases such as asthma, atopic dermatitis, rhinitis and the like.

In one embodiment, the composition may comprise from 0.0001 to 5% by weight of an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof. The content of ethylperulate, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof, contained in the composition, is 0.0001 If the amount is less than 10% by weight, the effective antiallergic effect can not be obtained. If the amount is more than 5% by weight, the formulation stability is deteriorated due to crystallization of the active ingredient in the formulation. The ethyl ferulate, the isomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof or the solvate thereof is preferably 0.0001 to 3% by weight, more preferably 0.001 to 2% by weight, , And 0.01 to 1% by weight.

In one embodiment, the composition may be a pharmaceutical composition, a food composition or a cosmetic composition.

In the present specification, the formulation of the cosmetic composition is not particularly limited, and can be appropriately selected according to the purpose.

For example, it may be formulated into a solution, an emulsion obtained by dispersing an oil phase in an aqueous phase, an emulsion obtained by dispersing an oil phase in water, a suspension, a solid, a gel, a powder, a paste, a foam or an aerosol composition But is not limited to.

In addition, the cosmetic composition may further contain, in addition to the above-mentioned substances, other ingredients which can give a synergistic effect to the main effect, without impairing the main effect. The cosmetic composition may further include a moisturizing agent, an emollient agent, an ultraviolet absorber, an antiseptic, a bactericide, an antioxidant, a pH adjuster, an organic and inorganic pigment, a fragrance, a cold agent or a limiting agent. The compounding amount of the above components can be easily selected and used by those skilled in the art within a range not to impair the objects and effects of the present invention.

In addition, the food composition may further contain other ingredients and the like that can give a synergistic effect to the main effect within a range in which the active ingredient does not impair the intended main effect. For example, additives such as perfume, coloring agent, bactericide, antioxidant, preservative, moisturizing agent, thickening agent, inorganic salt, emulsifier and synthetic polymer substance may be further added for improvement of physical properties. In addition, it may further contain auxiliary components such as water-soluble vitamins, oiliness vitamins, high molecular weight peptides, polymeric polysaccharides and seaweed extract. The ingredients may be selected and mixed by the person skilled in the art without difficulty depending on the purpose of formulation or use, and the amount thereof may be selected within a range that does not impair the objects and effects of the present specification.

In this specification, the pharmaceutical composition may be one comprising an external preparation for skin. Formulations of the pharmaceutical compositions may be, but are not limited to, solutions, suspensions, emulsions, gels, suspensions, suppositories, creams, ointments, patches, pads or spraying agents. The formulations can be readily prepared according to conventional methods in the art and can be prepared by conventional means such as excipients, wetting agents, emulsifying accelerators, suspending agents, salts or buffers for controlling osmotic pressure, coloring agents, spices, stabilizers, preservatives, Adjuvants may be used as appropriate.

Its daily dose may be, for example, from 0.1 mg / g / day to 100 mg / g / day, more specifically from 5 mg / g / day to 50 mg / g / day, but is not limited thereto .

The composition may preferably be an underwater type, and in one embodiment may be a cream formulation of the submersible type.

The cream formulations according to one embodiment are shown in Table 1 below.

ingredient Content (wt%) Disodium edetate 0.02 glycerin 5.00 Butylene glycol 5.00 Carbomer 0.30 Glyceryl monostearate 1.50 FAGE-40 stearate 1.00 Cetearyl alcohol 1.50 Sorbitan stearate 0.50 Hydrogenated polydecene 4.00 Cetyl hexanoate 5.00 Dimethicone 1.00 Phenoxyethanol 0.50 Ethyl ferulate 0.20 Water To 100

Hereinafter, the constitution and effects of the present invention will be described in more detail with reference to examples and test examples. However, these examples and test examples are provided for illustrative purposes only in order to facilitate understanding of the present invention, and the scope and scope of the present invention are not limited by the following examples.

[Example 1] Test for the anti-allergic effect of ethyl ferulolate - Suppression of secretion of allergens present in the granules of mast cells

[Example 1-1] Inhibition of activity of beta-hexosaminidase

(50 ppm, 25 ppm, 50 ppm, and 50 ppm, respectively) were mixed with 50 nM and 1 μM of PMA (Phorbol 12-myristate 13-acetate) and Calcium Ionophore A23187 100 ppm), and the activity of beta-hexosaminidase, the marker of degranulation, was determined. The activity of beta-hexasaminidase was determined by measuring the activity of p-nitrophenyl-acetyl- beta -D- glucosaminide The amount of p-nitrophenol liberated from p-nitrophenyl-acetyl-β-Dglucosamine was determined. Allergen-inducing substances were not treated with a negative control (without PMA), and only allergen-induced substances were treated with a positive control ((-) Con).

As a result, as shown in Fig. 1, ethyl ferulate inhibited the secretion of beta-hexasaminidase, a marker of mast cell degranulation. Thus, it was confirmed that ethyl ferulate is excellent in suppressing the secretion of allergen-inducing substances present in granules of mast cells.

[Example 1-2] Confirmation of inhibitory effect on histamine secretion

RBL-2H3 cells (purchased from Korean Cell Line Bank) were inoculated into 96-well plates at a concentration of 2.5 × 10 ⁵ cells / well and cultured. After the cells were attached, the cells were treated with ethyl ferulolate at various concentrations in Tyrodes's buffer (10 mM Hepes, 130 mM NaCl, 5 mM KCl, 1.4 mM CaCl 2, 1 mM MgCl 2, 5.6 mM glucose, and 0.1% BSA, pH 7.4) Lt; / RTI > After addition of 50 nM PMA and 1 μM of A23187, the reaction was carried out in an incubator for 1 hour, and the supernatant was recovered to determine whether it inhibited histamine release. Histamine release was measured by histamine kit (cisbio assays).

As a result, it was confirmed that the ethyl ferulate suppresses the secretion amount of histamine by at least 37% and is effective for the improvement of allergy (Fig. 2).

[Example 2] Confirmation of skin barrier function improving effect

Human keratinocyte (HaCaT) was cultured in a medium containing 10% FBS and 1% penicillin / streptomycin. The cells were seeded in a 6-well plate to a concentration of 1 × 10 ⁵ cells / well After inoculation, the cells were cultured for 48 hours, and ethylpyrrolate was added to each concentration, followed by incubation for 24 hours. After completion of the reaction, the supernatant was collected and the cells were washed with phosphate buffered saline (PBS), and the cells were recovered by the PureLink® RNA Mini Kit (ambion by life technologies) method MRNA was extracted. After that, cDNA was synthesized according to High Capacity RNA-to-cDNA Kit (Applid Biosystems) method, and then the test cells and control cells were subjected to real time PCR to analyze the expression levels of CerS3 and SPTLC1 genes. The primer information used in the PCR is as shown in Table 2 below.

Type of primer order CerS3 (Forward) TGG TTC TGG TCG GAG AGA TAC TGG C CerS3 (Reverse) GAA GCT CAT CAG ACT AAT AGC AGC C SPTLC1 (Forward) TGG AAG AGA GCA CTG GGT CT SPTLC1 (Reverse) GCT ACC TCC TTG ATG GTG GA

As a result, the expression of serine-palmitoyl transferase and ceramide synthase 3, which directly affect the synthesis of ceramide, was promoted by 50% or more and 25% or more, respectively, when treated with ethyl ferulate, (Fig. 3 and Fig. 4).

Claims (8)

As the composition for alleviating allergy,
The composition comprises ethyl ferulate, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof as an active ingredient,
Wherein said composition inhibits degranulation of mast cells or enhances skin barrier function. delete The method according to claim 1,
Said composition comprising one or more of the following features:
1) inhibition of secretion of beta-hexosaminidase from mast cells;
2) inhibiting the secretion of histamine from mast cells;
3) increased expression of serine-palmitoyltransferase; And
4) Increased expression of ceramide synthase. The method according to claim 1,
Wherein the composition comprises 0.0001 to 5% by weight of the ethyl ferulate, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof. The method according to claim 1,
The composition may comprise,
A composition for alleviating allergy, which is a pharmaceutical composition. The method according to claim 1,
Wherein the composition is a food composition. The method according to claim 1,
Wherein the composition is a cosmetic composition. 8. The method according to any one of claims 1 to 7,
Wherein the composition is an aqueous type.

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