JP2012144462A - Prostaglandin production inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a material having activities for inhibiting prostaglandin production, and useful for antiinflammatory or amelioration of dermal inflammatory symptom due to pimple or the like.SOLUTION: The prostaglandin Eproduction inhibitor includes Rhododendron dauricum L. or an extract thereof as an active ingredient. Preferably, the extract is the one extracted with an aqueous solution of ethanol in the prostaglandin E2 production inhibitor.

Description

  The present invention relates to a prostaglandin production inhibitor.

  Inflammation is inherently a defensive response of the body. For example, when a pathogen or toxin invades a living body, an inflammatory reaction occurs locally at the invasion site, vascular permeability is increased at that site, leukocyte leaching occurs, and as a result, the growth of the pathogen is suppressed, Prevent the spread of toxins. On the other hand, the inflammatory reaction may lead to unpleasant conditions such as vasodilation, increased vascular permeability, pain, fever, redness, swelling, etc., and excessive inflammatory reaction may cause damage to self-organized tissues or autoimmune diseases. cause.

  Redness, acne, atopic dermatitis and the like are known as inflammatory symptoms in the skin. These symptoms have been frequently seen among children and adolescents, but in recent years, the number of older generation patients has also increased. In addition, due to the recent increase in interest in beauty, there is a high demand for treatment of these symptoms as being cosmetically unfavorable.

  Prostaglandins (PGs) are known as one of the inflammatory mediators. It has also been reported that the action mechanism of non-steroidal anti-inflammatory drugs (NSAIDs) has a PGs production inhibitory action. PGs regulate the inflammatory response by cooperating with various other inflammatory mediators. When tissue is damaged due to trauma or pathogen infection, phospholipids in the cell membrane are changed to arachidonic acid, and cyclooxygenase (COX) acts there to produce PGs. PGs, together with other factors, causes vasodilation, increased vascular permeability, pain sensitization, leukocyte migration, and causes inflammatory symptoms such as pain, fever, redness, and swelling. By controlling the production of PGs, the inflammatory reaction can be controlled, and inflammatory symptoms in the skin such as redness, acne, and atopic dermatitis can be improved.

It is disclosed that Ezomura Azalea ( Rhododendron dauricum ) has a melanin production inhibitory effect and can be contained in a whitening cosmetic (Patent Document 1). On the other hand, it has not been known so far that this plant is involved in PGs production or exerts an anti-inflammatory effect.

Japanese Patent Laid-Open No. 2001-206819

  The present invention relates to the provision of a material having a prostaglandin production inhibitory effect and useful for the improvement of anti-inflammatory or skin inflammatory symptoms such as acne.

The present inventors examined materials that can be used to improve skin inflammation such as anti-inflammatory or acne. As a result, Ezomura azalea has an action of suppressing prostaglandin E ₂ production, and anti-inflammatory and acne. It was found useful for the improvement of skin inflammatory symptoms.

That is, the present invention provides the following.
(1) A prostaglandin E ₂ production inhibitor comprising an Ezomura azalea or an extract thereof as an active ingredient.
(2) The prostaglandin E ₂ production inhibitor according to (1), wherein the extract is an aqueous ethanol extract.
(3) An anti-inflammatory agent comprising Ezomura Sekiza or an extract thereof as an active ingredient.
(4) The anti-inflammatory agent according to (3), wherein the extract is an aqueous ethanol extract.
(5) An acne improving agent comprising an Ezomura azalea or an extract thereof as an active ingredient.
(6) The acne ameliorating agent according to (5), wherein the extract is an aqueous ethanol extract.

According to the present invention, a prostaglandin production inhibitor capable of suppressing the production of prostaglandin E ₂ is provided. The prostaglandin production inhibitor has an anti-inflammatory action and can improve skin inflammatory symptoms such as acne.

Suppression of PGE ₂ production by plant extracts.

Prostaglandin E ₂ (PGE ₂ ) is the most prostaglandin in the body that exists from the center of the body to the periphery. PGE ₂ has various physiological activities. It has been known for some time that the pain-inducing action and vascular permeability enhancing action of bradykinin and inflammatory exudation by bradykinin and histamine are enhanced through the production of PGE ₂ and PGI ₂ . PGE ₂ is also known as the final mediator of fever (Nichi Pharmacology, 117: 248-254, 2001; Nichi Pharmacology, 117: 255-261, 2001; Nichi Pharmacology, 120: 373-378, 2002) ).
Therefore, by suppressing the production of prostaglandin E ₂ , it is possible to suppress fever and suppress the inflammatory response by suppressing the action of other inflammatory mediators (such as bradykinin and histamine) and inflammatory cytokines. Thus, an anti-inflammatory effect is achieved.

  Acne, also known as acne, acne, is caused by various factors such as hormone secretion, abnormal keratinization of the capillaries, increased sebum secretion, mechanical and chemical stimulation, and bacteria. It is an inflammatory skin disease that occurs in hair follicles. Acne worsens with the progression of inflammation and damages skin tissue (Cosmetics Dictionary, Japan Cosmetic Engineers Association (ed.), Maruzen Co., Ltd., issued December 15, 2003, pages 629-631). Application of non-steroidal anti-inflammatory drugs (NSAIDs) is recommended as one of the means of acne treatment (Japanese acne treatment guidelines [Japanese Dermatological Association Guidelines], JSSI 118 (10): 1893- 1923, 2008).

In the present specification, “Ezomura Sekiza Azalea” refers to Rhododendron dauricum belonging to the genus Azalea.
Unless specifically limited, the plant extract listed above is any part of the plant, such as whole grass, leaves, stems, buds, flowers, buds, wood parts, bark, lichens, roots, rhizomes, corpuscles, It may be an extract from corms, tubers, seeds, fruits, mycorrhiza or resin, or combinations thereof, but leaves are preferred. The parts listed above may be subjected to the extraction step as they are, or may be subjected to the extraction step after being pulverized, cut or dried.

  As the above extract, commercially available ones may be used, or various solvent extracts obtained by a conventional method, or diluted solutions thereof, concentrated solutions thereof, dried powders thereof, pastes or activated carbon treatments thereof. There may be. As an example, the extract in the present invention is extracted by extracting the plant at room temperature (for example, 1 to 30 ° C.) or under heating (room temperature to solvent boiling point), or using an extraction device such as a Soxhlet extractor. Can be obtained.

  As the solvent for extraction, either a polar solvent or a nonpolar solvent can be used. Specific examples of the solvent include water; alcohols such as methanol, ethanol, propanol and butanol; polyhydric alcohols such as propylene glycol and butylene glycol; ketones such as acetone and methyl ethyl ketone; methyl acetate and ethyl acetate Esters; linear and cyclic ethers such as tetrahydrofuran and diethyl ether; polyethers such as polyethylene glycol; hydrocarbons such as squalane, hexane, cyclohexane and petroleum ether; aromatic hydrocarbons such as toluene; dichloromethane and chloroform And halogenated hydrocarbons such as dichloroethane; and supercritical carbon dioxide; pyridines; organic solvents such as oils and fats, other oils such as wax; and mixtures thereof. Preferable examples include water, alcohols and aqueous solutions thereof, and ethanol is preferable as the alcohols. More preferred solvents are water and an aqueous ethanol solution.

As a compounding ratio (volume ratio) of alcohol and water, 0.001-100: 99.999-0 are preferable, 5-95: 95-5 are more preferable, 20-80: 80-20 are more preferable. 30-70: 70-30 is still more preferable, and 40-60: 60-40 is still more preferable. In the case of an ethanol aqueous solution, the ethanol concentration is preferably 40 to 60% by volume.
As a usage-amount of a solvent, 1-100 mL is preferable with respect to 1 g of plants (dry mass conversion). The extraction conditions are not particularly limited as long as sufficient extraction can be performed, but the extraction time is preferably 1 minute to 2 months, more preferably 10 minutes to 5 weeks, and the extraction temperature is 0 ° C. to the boiling point of the solvent. Is preferable, and 5-70 degreeC is more preferable. Usually, extraction is performed for a long time at a low temperature and for a short time at a high temperature.
Specific examples of the extraction means for obtaining the extract include solid-liquid extraction, liquid-liquid extraction, immersion, decoction, leaching, reflux extraction, ultrasonic extraction, microwave extraction, and stirring.
Examples of extraction conditions include 15 to 40 ° C. for 1 hour to 5 weeks, about 70 ° C. for 5 hours, and the like.
Moreover, when shortening extraction time, solid-liquid extraction with stirring is desirable. An example of suitable conditions for this solid-liquid extraction is stirring at 100 to 5000 rpm for 30 to 300 minutes at 10 to 100 ° C. (preferably 20 to 70 ° C.).
In order to prevent the oxidation of the extract, a means for extracting under a so-called non-oxidizing atmosphere while removing dissolved oxygen by bubbling degassing or inert gas such as nitrogen gas may be used in combination.

  In the present specification, “non-therapeutic” is a concept that does not include a medical act, that is, a treatment act on the human body by therapy.

  In the present specification, “improvement” refers to improvement of a disease, symptom or condition, prevention or delay of deterioration of the disease, symptom or condition, or reversal, prevention or delay of progression of the disease, symptom or condition.

As shown in the Examples below, Ezomura Azalea or an extract thereof has an action of suppressing PGE ₂ production of cells. Therefore, the plant or an extract thereof are useful as PGE ₂ production inhibitor. In addition, the plant or an extract thereof can exert an anti-inflammatory action through the PGE ₂ production inhibitory action, and inflammatory symptoms in the skin, such as acne, hot flashes, itching, redness, red face, atopic properties It is useful for improving allergic dermatitis such as dermatitis.

That is, the plant or an extract thereof may be used for the PGE ₂ production inhibitory. Alternatively, the plant or an extract thereof can be used for anti-inflammation, and based on the anti-inflammatory effect, inflammatory symptoms in the skin, such as acne, hot flashes, itching, redness, red-faced, atopic It can be used for improving allergic dermatitis such as dermatitis, preferably for improving acne.
Any one of these plants or extracts thereof may be used alone, or two or more of them may be used in combination. The use can be in humans or non-human animals, or tissues, organs, cells derived therefrom, and can be therapeutic or non-therapeutic.

Therefore, as one aspect, the present invention provides a PGE ₂ production inhibitor containing Ezomura red azalea or an extract thereof as an active ingredient.
As another aspect, the present invention provides an anti-inflammatory agent containing Ezomura szalea or an extract thereof as an active ingredient.
As another aspect, the present invention relates to inflammatory symptoms in the skin containing Ezomura red azalea or an extract thereof as an active ingredient, for example, allergic dermatitis such as acne, hot flashes, itching, redness, red face, atopic dermatitis Provide an improving agent. Preferably, the agent for improving inflammatory symptoms in the skin is an acne improving agent.
In one aspect, the agent consists essentially of at least one of the plants or extracts thereof.

The above plant or extract thereof is for inhibiting PGE ₂ production, for anti-inflammation, or for inflammatory symptoms in the skin, such as acne, hot flashes, itching, redness, red face, allergic dermatitis such as atopic dermatitis, etc. It can be used for the production of a composition, a pharmaceutical, a quasi-drug, a cosmetic, etc. Such compositions, pharmaceuticals, quasi drugs, cosmetics and the like are also within the scope of the present invention.

The above composition, medicine, quasi-drug, cosmetic and the like can be produced or used for human or non-human animals. The plant or an extract thereof is blended in the composition, medicine, quasi-drug, cosmetics, etc., for suppressing PGE ₂ production, for anti-inflammatory, or for inflammatory symptoms in the skin, such as acne, hot flashes It may be an active ingredient for improving allergic dermatitis such as itching, redness, redness, and atopic dermatitis.

The said pharmaceutical or quasi-drug contains the said plant or its extract as an active ingredient. The pharmaceutical or quasi drug can be administered in any dosage form. Administration may be oral or parenteral. Dosage forms for oral administration include, for example, solid dosage forms such as tablets, coated tablets, granules, powders, capsules, and liquid dosage forms such as elixirol, syrups and suspensions, Examples of the dosage form for parenteral administration include injection, infusion, topical, external preparation, transdermal, transmucosal, nasal, enteral, inhalation, suppository, bolus, patch and the like.
The medicament or quasi-drug may preferably be in a parenteral form, more preferably in the form of a skin external preparation.

The said pharmaceutical or quasi-drug may contain the said plant or its extract individually or in plurality, or may contain it in combination with a pharmaceutically acceptable carrier. Examples of such carriers include excipients, coating agents, binders, extenders, disintegrating agents, lubricants, diluents, osmotic pressure adjusting agents, pH adjusting agents, dispersing agents, emulsifiers, preservatives, and stabilizers. , Antioxidants, colorants, ultraviolet absorbers, humectants, thickeners, lubricants, activity enhancers, anti-inflammatory agents, bactericides, fragrances, flavoring agents, flavoring agents and the like. Moreover, the pharmaceutical and quasi drugs, as long as the PGE ₂ production inhibitory action of the plant or an extract thereof is not lost, may contain other active ingredients or pharmaceutical agent.

  The said pharmaceutical or quasi-drug can be manufactured by the conventional method from the said plant or its extract, or combining the said carrier and / or another active ingredient and pharmacological component as needed. The content of the plant or extract thereof in the medicine or quasi-drug is preferably 0.01 to 100% by mass in terms of the dry mass of the plant or extract when, for example, an external preparation for skin is used. 0.05 to 70% by mass, more preferably 0.1 to 20% by mass, and still more preferably 0.5 to 10% by mass.

The said cosmetics contain the said plant or its extract as an active ingredient. The said cosmetics may contain the said plant or its extract individually or in multiples, or may contain it in combination with the carrier accept | permitted as cosmetics. Examples of such carriers include excipients, coating agents, binders, extenders, disintegrating agents, lubricants, diluents, osmotic pressure adjusting agents, pH adjusting agents, dispersing agents, emulsifiers, preservatives, and stabilizers. , Antioxidants, colorants, ultraviolet absorbers, humectants, thickeners, lubricants, activity enhancers, anti-inflammatory agents, bactericides, fragrances, flavoring agents, flavoring agents and the like. Moreover, the cosmetic, unless PGE ₂ production inhibitory action of the plant or an extract thereof is not lost, other active ingredients or cosmetic ingredients such as moisturizing agents, whitening agents, UV protection agents, cell activators, washed Agents, keratolytic agents, makeup ingredients (for example, makeup bases, foundations, funny, powder, teak, lipstick, eye makeup, eyebrow, mascara, etc.) may be contained. Examples of the form of the cosmetic include creams, emulsions, lotions, suspensions, gels, powders, packs, sheets, patches, sticks, cakes, and the like, which can be used for cosmetics. Preferably, the cosmetic may be an acne cosmetic or an anti-inflammatory cosmetic that suppresses hot flashes, redness, itching or allergies. More preferably, the cosmetic is an acne cosmetic.

  The cosmetic can be produced by a conventional method from the plant or an extract thereof, or in combination with the carrier and / or other active ingredients and cosmetic ingredients as necessary. The content of the plant or extract thereof in the cosmetic is preferably 0.01 to 100% by mass, and 0.05 to 70% by mass in terms of dry mass of the plant or extract thereof. Is more preferable, 0.1 to 20% by mass is further preferable, and 0.5 to 10% by mass is even more preferable.

The present invention also provides a method for suppressing cellular PGE ₂ production. The method includes a step of adding Ezomura Azalea or an extract thereof to a cell having PGE ₂ production ability and desired to suppress PGE ₂ production.
"Cells" suppressing PGE ₂ production in the present invention is not particularly limited as long as the cell has a natural or genetically modified PGE ₂ production ability or PGE ₂ expression ability. Preferably, the cells include skin constituent cells, more preferably epidermal cells or dermal fibroblasts.
Alternatively, the “cell” may be a cell fragment or cell fraction of the cells listed above, or a tissue containing the cells listed above or a culture derived from the cells listed above. Also good. When the cell is a cell culture, the cell is preferably cultured in the presence of the plant or an extract thereof.
When the cell is a cell culture, the concentration of the plant or the extract to be added is 0.00001 to 5% (w in terms of the dry mass of the plant or the extract as the final concentration in the culture. / V) is preferable, 0.0001 to 2% (w / v) is more preferable, and 0.001 to 1% (w / v) is still more preferable.

In the present invention, the Ezomura Azalea or its extract is used for suppressing PGE ₂ production, for anti-inflammation, or for inflammatory symptoms in the skin, such as acne, hot flashes, itching, redness, red face, atopic dermatitis, etc. In order to ameliorate allergic dermatitis and the like, it can be administered in an effective amount to a subject in need thereof.
In one embodiment, the administration is performed non-therapeutically for health promotion or cosmetic purposes.
Preferably, the administration is topical administration to the skin.
The subject of administration needs to be improved for animals that require a reduction in inflammatory response and inflammatory symptoms in the skin, such as acne, hot flashes, itching, redness, red face, atopic dermatitis such as atopic dermatitis, etc. And animals. Preferably, the subject of administration includes animals suffering from acne. The animal is preferably a human or non-human mammal, more preferably a human.

  The preferred dosage may vary according to the subject's species, weight, sex, age, condition or other factors. The dose, route, interval, and amount and interval of intake can be determined appropriately by those skilled in the art. For example, when externally administered to human skin, the dose is preferably 0.001 to 1000 mg / day per adult (60 kg) in terms of dry mass of the plant or extract, 0.01 to 100 mg / day is more preferred.

  EXAMPLES Hereinafter, an Example is shown and this invention is demonstrated more concretely.

Production Example 1 Preparation of Ezomura Azalea Azalea Extract 40 mL of 50% ethanol aqueous solution was added to 40 g of Ezomura Azalea azalea leaves (Shinwa product) and immersed for 43 days at room temperature. This was filtered to obtain an Ezomura red azalea extract. The concentrated solid content of the extract was 6.68 g. The solid content concentration was 2.36% (w / v). It was diluted with 50% ethanol and used in the test with a solid content concentration of 1.0% (w / v).

Example 1 Plant Prostaglandin E ₂ Production Inhibitory Action Human dermal fibroblasts (Fibrocell, purchased from Kurashiki Boseki Co., Ltd.) were cultured at 37 ° C. in the presence of 5% CO ₂ . As the culture solution, DMEM medium (Invitrogen Corporation) was used. Cells are seeded in a 24-well plate at 1 × 10 ⁵ cells / well (N = 2), cultured in DMEM medium (Invitrogen Corp.) for 24 hours, and then prepared in Production Example 1 as a test substance in the medium. The extract (final concentration 0.1% v / v; 0.001% w / v% as extract) or 50% ethanol (0.1% v / v) as a negative control was added to the medium. After 30 minutes, cytokines (IL-1α and TNFα, final concentrations of 2.5 ng / ml each) were added to the medium, and further cultured for 24 hours. For reference, a cytokine-free group was prepared. After recovering the medium and removing the suspended cells by centrifugation, PGE _{2 in} the remaining medium was quantified. PGE ₂ was quantified by ELISA using Prostaglandin E2 Parameter Assay Kit (R & D SYSTEMS).
The results of quantification are shown in Table 1. It was expressed as a percentage of the production amount of the cytokine addition negative control group. The Ezomura azalea extract suppressed PGE ₂ production in cells after cytokine addition.

Claims (6)

A prostaglandin E ₂ production inhibitor comprising Ezomura Sekizae or an extract thereof as an active ingredient. The prostaglandin E ₂ production inhibitor according to claim 1, wherein the extract is an aqueous ethanol extract.   An anti-inflammatory agent comprising Ezomura Sekizae or its extract as an active ingredient.   The anti-inflammatory agent according to claim 3, wherein the extract is an aqueous ethanol extract.   An acne-improving agent comprising Ezomura Sekizae or its extract as an active ingredient.   The acne improving agent according to claim 5, wherein the extract is an aqueous ethanol extract.

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