JP2017124984A - Ceramide regulator - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide novel ceramide degrading enzyme inhibitors which is excellent in ceramidase inhibitory effect and is also highly safe, and to provide compositions containing the same.SOLUTION: A ceramidase activity inhibitor is characterized by containing as an active ingredient at least one extract derived from plants selected from the group consisting of Malvaceae, Rubiaceae, Poaceae, Parmeliaceae, Styracaceae, Asteraceae, Lauraceae, Verbenaceae, Juglandaceae, Papaveraceae, Scrophulariaceae, Araceae, Combretaceae, Lamiaceae, Tiliaceae, Zingiberaceae, Caprifoliaceae, Ribes, Violaceae, Umbelliferae, Ericaceae, Ulmaceae, Bignoniaceae, Rosaceae, Polygalaceae, Santalaceae, Myrtaceae, Fabaceae, Hamamelidaceae, Rutaceae, Sapindaceae, Thamnolia vermicularis Ach., Boraginaceae, and Oleaceae.SELECTED DRAWING: None

Description

  The present invention relates to a plant-derived processed product, for example, a ceramidase activity inhibitor containing an extract and a composition containing the same.

  Ceramide is a major component of intercellular lipids in the stratum corneum, and by sandwiching water molecules, it forms a lamellar structure in which lipid and water are layered to prevent water from evaporating from the body. In addition, it supports corneocytes as intercellular lipids and prevents foreign substances from entering the skin by filling the gaps. Therefore, ceramide is an essential component for moisture retention and barrier function of the skin (see Non-Patent Document 1).

  Ceramide is synthesized from serine and palmitoyl CoA and then decomposed into sphingosine by ceramidase. This ceramidase is known to increase in activity with aging, and the amount of skin ceramide decreases with age. In addition, senile xeroderma is thought to be caused by a decrease in the amount of ceramide and destruction of the lamellar structure caused by increased activity of ceramidase, resulting in an increase in transepidermal water transpiration. Therefore, it can be said that inhibiting ceramidase prevents the skin from drying and leads to maintenance of the barrier function.

  Furthermore, it has been observed that the amount of ceramide in the patient's skin is lower than that in healthy people even in atopic dermatitis, and a decrease in the epidermal barrier function due to a decrease in the amount of skin ceramide is characteristic of various inflammations and atopic dermatitis. This is considered to be one of the factors that cause pruritus (see Non-Patent Document 2). Therefore, a drug that inhibits ceramidase and increases the amount of ceramide is very useful for various skin diseases such as atopic dermatitis.

  Currently, as a method of increasing the amount of skin ceramide, a method of orally ingesting or applying to the skin ceramide derived from animals, plants or yeast, or synthetic ceramide is used. Extracted from mammalian spinal cord, there is a risk of pathogen contamination. In addition, yeast-derived ceramide generally has low penetrating power and poor efficacy. Furthermore, plant-derived ceramides and synthetic ceramides have a structure different from that of ceramides that are biosynthesized by mammals, and thus are liable to cause allergic reactions, resulting in problems of itching and swelling. As described above, since there are a number of problems with the “method of replenishing ceramide from outside the body” that has been conventionally used, it is desirable to “increase the amount of ceramide biosynthesized in vivo” using a ceramidase inhibitor. .

  Ceramidase that metabolizes ceramide is also called acyl sphingosine deacylase, which hydrolyzes the acyl group to decompose ceramide, a double-stranded structure, into single-stranded sphingosine and fatty acids. Ceramidases are classified into three families, acid ceramidase, neutral ceramidase, and alkaline ceramidase, due to differences in optimum pH. For example, acid ceramidase inhibitors include desipramine and N-oleoylethanolamine (see Non-Patent Document 3), and neutral ceramidase and alkaline ceramidase inhibitors include De-MAPP (D-erythro-2-N- Myristoylamino-1-phenyl-1-propanol) is known (see Non-Patent Document 4). Patent Document 1 includes extracts of turmeric, saxifrage, dextran, and diatomaceous earth, and Patent Document 2 includes ginkgo, shirori, cucumber, tougan, bitter gourd, orange, grapefruit, lime, gagome, macombu, wakame, eucalyptus, and mugwort. It is disclosed that the extract has ceramidase activity inhibition.

JP 2002-308791 A JP 2012-36213 A

Fablo N, 5 others, Neurobiology of Aging, 35, 1801-1812 (2014) Imokawa G, 5 others, The Journal of Investigative Dermatology, 96, 523-526 (1991) Canals D, 3 others, British Journal of Pharmacology, 163, 694-712 (2011) Bielawska A, 6 others, The Journal of Biological Chemistry, Vol.271, 12646-12654 (1996)

  However, acid ceramidase inhibitor, desipramine has a low selectivity such as affecting other lysosomal enzymes, and N-oleoylethanolamine has a problem of low inhibitory activity. Neutral ceramidase and alkaline ceramidase De-MAPP, an inhibitor, is not satisfactory because of its weak inhibitory activity. Further, the extracts disclosed in Patent Document 1 and Patent Document 2 are not sufficient in ceramidase inhibitory effect, and a further highly active product has been desired.

  An object of the present invention is to provide a novel ceramide-degrading enzyme inhibitor having a ceramidase inhibitory effect and high safety, and a composition containing the same.

  In view of the above situation, the present inventors have comprehensively investigated the inhibitory activity against ceramidase for various plant extracts, and as a result, the specific extract has a specific inhibitory activity against ceramidase. It was confirmed that the amount of ceramide in the cells was increased by using the headings and further using these extracts, and the present invention was completed based on these.

That is, the present invention relates to the following [1] to [3].
[1] Aoi family, Rubiaceae family, Gramineae family, Pleurotus department, Echinaceae family, Asteraceae family, Camphoraceae family, Oenaceae family, Walnut family, Poppy family, Pomaceae family, Araceae family, Cykushi family, Perilla family, Linden family, Ginger family , Honeysuckle family, Currant family, Violet family, Apiaceae, Azalea family, Elmaceae, Nozenkazura family, Rose family, Himehagi family, Sandalwood family, Myrtaceae family, Leguminosae family, Mantis family, Citrus family, Mucous family, Mussoke family, Murasaki A ceramidase activity inhibitor characterized by containing, as an active ingredient, at least one plant-derived extract selected from the group consisting of the family Glycidae and Cryptaceae.
[2] A ceramide amount adjusting agent comprising the ceramidase activity inhibitor according to [1].
[3] A composition comprising the ceramidase activity inhibitor according to [1] or the ceramide amount adjusting agent according to [2].

  The ceramide-degrading enzyme inhibitor of the present invention has an excellent effect of being excellent in ceramidase inhibitory effect and having high safety.

FIG. 1 is a diagram showing a correlation between an enzyme reaction and a human skin test.

  The ceramidase activity inhibitor of the present invention inhibits the enzyme activity of ceramidase, but does not necessarily have to act directly on ceramidase to inhibit the activity. Examples of the ceramidase activity inhibitor of the present invention include ceramidase inhibitors.

  The ceramidase activity inhibitor of the present invention comprises an extract derived from a predetermined plant as an active ingredient and exhibits excellent inhibitory activity against ceramidase. The “extract” in the present specification is not particularly limited as long as it is obtained by artificially treating a plant. For example, in addition to an extract (extract), an essential oil (for example, water vapor) Distillates, juices, presses, solvent extracts, supercritical fluid extracts). These can be used alone or in combination of two or more. Hereinafter, the extract may be referred to as the extract of the present invention.

  Plants used in the present invention include mallow, rhododendron, gramineae, umeaceae, asteraceae, asteraceae, camphoraceae, oleaceae, walnut, poppy, scorpionaceae, taro, cicaceae, and perilla , Lindenaceae, ginger, honeysuckle, currant, violet, serpentine, rhododendron, elmaceae, genus roseaceae, rose, scorpionaceae, sandalwood, cornaceae, legume, witch hazel, citrus And at least one plant selected from the group consisting of Family, Mussaceae, Murasakie, and Oleaceae. About these families, the plant illustrated below is used suitably, respectively. In addition to the case where the name shown below is a plant name itself, even a herbal medicine name is included in the present invention.

  Examples of the plant of the family Malvaceae used in the present invention include Hibiscus Hybrids belonging to the genus Fuyo, Marshmallow belonging to the genus Orcaia (Altbaea officinalis), Malva sylvestris belonging to the genus Mallow Can be mentioned. Among these, plants belonging to the genus Orcaia and Genoa are preferred, and marshmallows and malva flowers can be exemplified as preferred examples.

  Examples of the Rubiaceae plant used in the present invention include, for example, Aubi (Rubia akane), Woodruff (Galium odoratum), Madder (Rubia tinctorum); Uncaria gambir belonging to others. Can be mentioned. Of these, plants belonging to the genus Rubiaceae are preferred, and woodruff and muder can be exemplified as preferred examples.

  Examples of the Poaceae plant used in the present invention include, for example, Kobayei (Oryza sativa) belonging to the subfamily Gramineae, Sasa veitchii belonging to the subfamily Daemon, Lemongrass (Cymbopogon citratus) belonging to the subfamily Etc., and these can be preferably used.

  Examples of the Parmeliaceae plant used in the present invention include oak moss (Evernia prunastri) and the like, which can be preferably used.

  Examples of the Styracaceae plant used in the present invention include benzoin (Styrax benzoin) and the like, which can be preferably used.

  As Asteraceae plants used in the present invention, for example, artichoke (Cynara scolymus), cornflower (Centaurea cyanus), sage (Atractylodes japonica), milk thistle (Silybum) belonging to the family of thistle marianum); Arnica montana, Echinacea purpurea, Chamomile (Matricaria recutita), Sunflower (Helianthus annuus), Tansy (Tanacetum vulgare), Feverfue (Tanacetum parthenium), Marigold (Tagetes) ), Yakon (Smallanthus sonchifolius), Yarrow (Achillea millefolium); Dandelion (Taraxacum Cass) belonging to the dandelion subfamily, chicory (Cichorium intybus) and the like. Among them, plants belonging to the genus Subfamily, Asteraceae, and Subfamily of Dandelion are preferable, and artichoke, cornflower, milk thistle, sunflower, tansy, feverfu, yarrow, and chicory can be exemplified as preferable examples.

  Examples of Lauraceae plants used in the present invention include, for example, Lindera umbellata, Sassafras albidum, Cinnamomum verum, and bay moss belonging to the genus Nikkei. Laurel (Laurus nobilis) etc. which belong to the genus are mentioned. Among these, plants belonging to the genus Kuromoji and the genus Landai Dwarf are preferable, and examples of the plants include Kuromoji and Sasafras.

  Examples of Verbenaceae plants used in the present invention include Verbena officinalis and Lemon verbena (Aloysia citrodora) belonging to the genus Euphorbia, which can be preferably used.

  Examples of the walnut family (Juglandaceae) plant used in the present invention include black walnut (Juglans) belonging to the genus Walnut and can be preferably used.

  Examples of the Papaveraceae plant used in the present invention include poppy (Papaver somniferum) belonging to the genus Poppy and can be preferably used.

  Examples of the genus Scrophulariaceae used in the present invention include, for example, eyebright (Euphrasia officinalis) belonging to the genus Kormegusa, rehmannia glutinosa belonging to the genus Dermatopha, and malein (Verbascum thapsus) belonging to the genus Mud squid. It is done. Of these, plants belonging to the genus Koromogusa and Mud genus are preferred, and eyebright and male can be exemplified as preferred examples.

  Examples of the Araceae plant used in the present invention include, for example, corasus (Acorus calamus) belonging to the genus Shobu, Hange (Pinellia ternate) belonging to the genus Hange. Especially, the plant which belongs to the genus Camellia is preferable, and can be illustrated as a suitable example.

  Examples of the Combretaceae plant used in the present invention include oak (Terminalia chebula) belonging to the genus Momotamana, Quisqualis indica belonging to the genus Sikunushi, and these can be preferably used.

  As the Lamiaceae plant used in the present invention, for example, water calamint (Mentha aquatica), oregano (Origanum vulgare), catnip (Nepeta cataria), snail (Schizonepeta tenuifolia), sage ( Salvia officinalis), savory (Satureja), thyme (Thymus), basil (Ocimum basilicum), hyssop (Hyssopus officinalis), peppermint (Mentha x piperita), penny royal (Mentha pulegium), marjoram (Origanum majorana), lavender (Lavandula) , Lemon thyme (Thymus x citriodorus), lemon balm (Melissa officinalis), rosemary (Rosmarinus officinalis); patchouli (Pogostemon cablin); Examples include skull caps (Scutellaria lateriflora). Among these, plants belonging to the subfamily of Catnipaceae and Papaveraceae are preferable, and water calamint, catnip, sage, savory, peppermint, penny royal, marjoram, lemon thyme, lemon balm and hoahound can be exemplified as preferred examples.

  Examples of the Tiliaceae plant used in the present invention include linden (Tilia europaea) belonging to the genus Linden and can be preferably used.

  Examples of the ginger family (Zingiberaceae) plant used in the present invention include cardamom (Elettaria cardamomum) belonging to the genus Ginger, Alpinia zerumbet, ginger (Zingiber officinale), and the like. Plants belonging to the genus Hanamyouga are preferred, and ghetto is a suitable example.

  Examples of the honeysuckle family (Caprifoliaceae) plant used in the present invention include, for example, elderflowers belonging to the genus Elderberry (Sambucus nigra), honeysuckles belonging to the genus Honeysuckle (Lonicera periclymenum), among others, plants belonging to the genus Honeysuckle A honeysuckle can be exemplified as a suitable example.

  Examples of the Currant family (Grossulariaceae) plant used in the present invention include, for example, black currant (Ribes nigrum) belonging to the genus Currant, which can be preferably used.

  Violaceae plants used in the present invention include, for example, violet (Viola odorata) belonging to the genus Violet and can be preferably used.

  As Aceraceae (Apiaceae) plants used in the present invention, for example, Ashitaba (Angelica keiskei), Angelica archangelica, Caraway (Carum carvi), Cumin (cyminum), Kauhon (Ligusticum) sinense), coriander (Coriandrum sativum), psycho (Bupleurum falcatum), celery (Apium graveolens), nematode (Cnidium officinale), chervil (Anthriscus cerefolium), dill (Anethum graveolens), toki (Angelica acutiloba), fennel (Foenic veulum) , Bowfu (Saposhnikovia divaricata), Labage (Levisticum officinale); Others belonging to Ajowan (Trachyspernum ammi), Gotucola (Hydrocotyle asiatica) and the like. Of these, plants belonging to the subfamily Apaceae are preferred, and angelica, chervil, and fennel can be exemplified as preferred examples. In addition, Ajowan and Gotu Cola belonging to others can be exemplified as preferable examples.

  Examples of the plants belonging to the family Aceraceae (Ericaceae) include winter green (Gaultheria procumbens) belonging to the genus Shiratama, heather flower (Calluna vulgaris) belonging to the genus Erica, blueberry (Vaccinium corymbosum) and the like. Of these, plants belonging to the genus Shiratama and Erika are preferred, and winter green and heather flowers can be exemplified as preferred examples.

  Examples of the elmaceae (Ulmaceae) plant used in the present invention include slippery elm (Ulmus rubra) belonging to the genus Elm and can be preferably used.

  Examples of the Bignoniaceae plant used in the present invention include Pau de Arco (Tabebuia impetiginosa) and the like, which can be preferably used.

  Examples of the Rosaceae plant used in the present invention include, for example, apple (Malus pumila), icrinin (Prunus japonica), kyounin (Prunus armeniaca), cherry (Prunus avium), torunin (Prunus persica) belonging to the subfamily Shimotake. ), Mocha (Chaenomeles sinensis), Recompi (Prunus salicina); Roses belonging to the subfamily Rosa (Rosa multiflora), Golden ox (Rosa laevigata), Diyu (Sanguisorba officinalis), Strawberry (Fragaria x ananassa), Agrimonia pilosa, Examples include tencha (Rubus suavissimus), fukubonshi (Rubus chingii), blackberry (Rubus fruticosus), peach (Amygdalus persica), raspberry (Rubus idaeus), ladies mantle (Alchemilla vulgaris), rose (Rosa) and the like. Of these, plants belonging to the subfamily of Shimotsuki subfamily and subfamily Rosaceae are preferable, and icrinin, cherry, mocca, recompi, peach, ladies' mantle can be exemplified as preferred examples.

  Examples of the plant belonging to the family Polygalaceae used in the present invention include, for example, Polygala tenuifolia, which belongs to the genus Himehagi.

  Examples of sandalwood (Santalaceae) plants used in the present invention include sandalwood (Santalum spicatum) belonging to the genus Sandalwood, which can be preferably used.

  Examples of Myrtaceae plants used in the present invention include Syzygium aromaticum, Myrtus communis, Eucalyptus globulus belonging to the genus Eucalyptus, etc. . Especially, the plant which belongs to Myrtle genus is preferable, and myrtle can be illustrated as a suitable example.

  Examples of the legaceae (Fabaceae) plant used in the present invention include, for example, a carob (Ceratonia siliqua), a cassame obtusifolia belonging to the subfamily, and alfalfa (Medicago sativa) belonging to the subfamily, Glycyrrhiza uralensis. , Kudin (Sophora flavescens), goat roux (Galega officinalis), honey bush (Cyclopia intermedia), fenugreek (Trigonella foenum-graecum), red clover (Trifolium pratense) and the like. Of these, plants belonging to the subfamily of Jack Tsubara and subfamily of legumes are preferable, and carob, alfalfa, goat roux, honey bush, and red clover can be exemplified as preferable examples.

  Examples of the plant belonging to the family Hammeridaceae used in the present invention include witch hazel belonging to the genus Hawthorn (Hamamelis virginiana), and can be preferably used.

  As the Rutaceae plant used in the present invention, for example, sweet summer mandarin (Citrus natsudaidai), pheasant (Citrus aurantium), kumquat (Fortunella), sudachi (Citrus sudachi), Shiranuhi (decopon, Citrus unshiu x C. sinensis x C. reticulata), spruce (Citrus aurantium), mandarin (Citrus unshiu), citron (Citrus junos), lemon (Citrus limon); other belonging to Tetradium ruticarpum, salamander (Zanthoxylum piperitum) ), Ruta graveolens and the like. Among them, plants belonging to the mandarin orange subfamily are preferable, and Shiranuhi and spruce can be exemplified as preferable examples.

  Examples of Sapindaceae plants used in the present invention include, for example, Acer rubrum, Acer mono, Acer crataegifolium, Acer rufinerve, and Acer amoenum belonging to the genus Maple. ), Acer sieboldianum, Acer carpinifolium, Acer buergerianum, Acer negundo, Acer pycnanthum, Acer cissifoski, Acer cissifode, Acer cissifode, Acer cissifode, Acer cissifode Examples include guarana (Paullinia cupana) and the like. Among them, plants belonging to the genus Maple and Gharana are preferable, and American red maple, Itaya maple, Urica maple, Urihada maple, Japanese maple, Kochachiwa maple, plover tree, Japanese maple, Minnea maple, Megurinoki, Guarana can be exemplified as preferred examples.

  Examples of the moss family used in the present invention include Yukicha (Thamnolia vermicularis) and the like, which can be preferably used.

  Examples of the Boraginaceae plant used in the present invention include alkanats (Anchusa officinalis) and polydi (Borago officinalis) belonging to the genus Bonositagusa, which can be preferably used.

  Examples of the Oleaceae plant used in the present invention include olives belonging to the genus Olive (Olea europaea); jasmine belonging to the genus Sokei; forsythia suspensa belonging to the genus Forsythia. Of these, plants belonging to the genus Olive are preferable, and olive can be exemplified as a preferred example.

  These plants can be used alone or in combination of two or more. When combining, plants of the same or different families may be combined. As for the plant part to be used, for example, rhizomes, leaves, fruits, seeds, mekabu, or the whole plant can be used, and as processed products such as shredded products, crushed products, and dried products. It can also be used.

  The extract used in the present invention can be obtained by extracting with a solvent using the above-mentioned plant according to a known method and distilling off the solvent.

  Examples of the extraction solvent include lower alcohols (methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutyl alcohol, etc.), polyhydric alcohols (ethylene glycol, propylene glycol, 1,3-butylene glycol, etc.), acetone, acetic acid. Various organic solvents such as ethyl, ether, chloroform, dichloroethane, toluene, n-hexane, petroleum ether, or water can be used alone or in combination. Among these, from the viewpoint of the extraction efficiency of the active ingredient, it is preferable to use only water or a combination of water and an organic solvent.

  The extraction temperature cannot be generally set depending on the solvent or plant used, but from the viewpoint of extraction efficiency, the lower limit may be 4 ° C. and the upper limit may be 120 ° C. In this invention, if it is in an above-described temperature range, an upper limit and a lower limit can be suitably set according to the solvent and plant to be used, for example, 20 degreeC, 40 degreeC, 60 degreeC, 80 degreeC, 100 degreeC. Etc. can be set as the upper limit value or the lower limit value. Therefore, as a suitable temperature range, for example, 4 to 20 ° C., 20 to 40 ° C., 40 to 60 ° C., 60 to 80 ° C., 80 to 100 ° C., 100 to 120 ° C., 20 to 120 ° C., 40 to 120 ° C. 60-120 degreeC, 80-120 degreeC, 20-100 degreeC, 40-100 degreeC, 60-100 degreeC, 20-80 degreeC, 40-80 degreeC, 20-60 degreeC etc. can be illustrated. The extraction time can be appropriately set according to the amount of raw material used for extraction and the apparatus.

  In addition, for the extract obtained by extraction, one or more treatments selected from the group consisting of filtration, centrifugation, concentration, ultrafiltration, lyophilization, pulverization, and fractionation, It may be carried out according to a known method, and the treated product is included as one embodiment of the ceramidase activity inhibitor of the present invention.

  The extract of the present invention exhibits an excellent ceramidase activity inhibitory action as described in the Examples described later. In the present specification, the ceramidase activity inhibitory action refers to an action of reducing the activity of ceramidase compared to the original activity of ceramidase, and can be confirmed by, for example, the method described in the examples described later. . The extract of the present invention is not particularly limited as long as it reduces the original activity of ceramidase. For example, it is 5% or more, preferably 10% or more, more preferably 20% or more, and further preferably 30%. As described above, it is desirable to have an inhibitory action for reducing by 40% or more, more preferably by 60% or more.

  The content of the extract in the ceramidase activity inhibitor of the present invention is not particularly limited, and is usually about 0.1 to 100% by mass as a dry weight.

  In addition, since the ceramidase activity inhibitor of the present invention has a specific inhibitory activity against ceramidase and can thereby increase the amount of ceramide in cells, the ceramidase activity inhibitor of the present invention is a ceramide amount regulator. Is preferably used. Therefore, as one embodiment of the present invention, there is provided a ceramide amount adjusting agent comprising the ceramidase activity inhibitor of the present invention.

  The ceramidase activity inhibitor of the present invention or the ceramide amount adjusting agent of the present invention increases the amount of ceramide or suppresses the decrease in the amount of ceramide, thereby improving the moisturizing effect, improving wrinkles, improving the symptoms of atopic dermatitis, Cells such as prevention / improvement of sebum deficiency (dry skin disease), prevention of stains, improvement of skin tarmi, anti-pruritic action, melanin production suppression effect, improvement of barrier function, fibroblast activation effect, skin cell regeneration effect, etc. It can be suitably used as a preventive, ameliorating, and / or therapeutic agent for symptoms and diseases based on a decrease in the amount of ceramide in the skin or skin. It is also suitable for diseases caused by these diseases such as alopecia areata, contact dermatitis, infectious impetigo, Kaposi's chickenpox-like rash, cataract, retinal detachment, prurigo, lysosomal disease Can be used.

  The form of the ceramidase activity inhibitor of the present invention or the ceramide amount adjusting agent of the present invention is not particularly limited as long as it is a form in which the extract of the present invention can be applied to the surface of a target substance or taken into the body. Or may be prepared in a form that can be used for raw materials such as pharmaceuticals, quasi drugs, and cosmetics.

  The present invention also provides a composition containing the ceramidase activity inhibitor of the present invention. The form of the composition is not particularly limited as long as the extract of the present invention can be taken into cells. For example, the form as an external preparation composition can be easily ingested from the viewpoint of effect. The form as an internal use composition is illustrated from a viewpoint.

  As an external preparation composition, it can provide as a pharmaceutical composition, a quasi-drug composition, and a cosmetic composition.

  Examples of the form of the external preparation composition include a solid, semi-solid or liquid preparation for transdermal administration or transmucosal (intraoral or intranasal) administration. Suppositories are also included. For example, emulsions such as emulsions and lotions, tinctures for external use, liquid preparations such as liquids for transmucosal administration, ointments such as oily ointments and hydrophilic ointments, transdermal administration such as films, tapes, and poultices Or for transmucosal administration, aerosols, sprays such as sprays, bathing agents and the like. In the case of a cosmetic composition, for example, basic cosmetics such as lotions, emulsions, creams, oils, packs, gels, makeup cosmetics such as foundations, blushers, lipsticks, waxes, hair artnics, It can be used in any form such as soaps, shampoos, facial cleansing foams, cleansing agents such as body cleansing agents, skin perfumes such as eau de cologne, deodorant and perfume, bathing agents.

  As an internal use composition, it can provide as a pharmaceutical composition, a quasi-drug composition, and a cosmetic composition (beauty composition).

  As a form of an internal use composition, the form (for example, powder form, granule form) which can be mix | blended easily, a tablet form, a liquid form, etc. are illustrated from a viewpoint which can be ingested easily. Specifically, liquids, extracts, elixirs, capsules (hard capsules, soft capsules, etc.), granules, pills, suspensions, emulsions, suppositories, powders, spirits, tablets, syrups , Dip, decoction, tincture, troche, fragrance, limonade, fluid extract, etc., quasi-drug composition, cosmetic composition.

  As long as the composition of the present invention having the above-described form contains at least one extract of the present invention, a carrier, base, and / or that is usually used in the pharmaceutical field, cosmetic field, etc. according to a conventional method. Additives and the like can be appropriately blended and prepared within a range that achieves the object of the present invention.

  Carriers, bases, and / or additives used in the pharmaceutical field include excipients (glucose, lactose, sucrose, sodium chloride, starch, calcium carbonate, kaolin, crystalline cellulose, cocoa butter, hydrogenated vegetable oil, talc, etc. ), Binder (distilled water, physiological saline, ethanol water, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.), disintegrator (sodium alginate, agar, sodium bicarbonate, Calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, gum arabic powder, gelatin, ethanol, etc.), disintegration inhibitors (sucrose, stearin, cocoa butter, hydrogenated oil, etc.), absorption accelerators (quaternary ammonium base) , Sodium lauryl sulfate, etc.), adsorbent (glycerin, starch) Lactose, kaolin, bentonite, silicic acid, etc.), lubricants (purified talc, stearate, polyethylene glycol, and the like) can be exemplified. These contents are not particularly limited, and can be used according to a known technique.

  Carriers, bases, and / or additives used in the cosmetics field include oils (butyl myristate, isobutyl myristate, butyl palmitate, isobutyl palmitate, butyl stearate, isobutyl stearate, butyl isostearate, myristine Cetyl acid, isostearyl laurate, isostearyl myristate, propylene glycol dicaprate, isostearyl adipate, squalane, liquid paraffin, isoparaffin, beef tallow, lard, mink oil, fish oil, corn oil, cocoa butter, almond oil, beeswax Lanolin, reduced lanolin, liquid lanolin, etc.), higher alcohols (lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, behenyl alcohol, hexa Silic alcohol, etc.), fatty acids (caprylic acid, capric acid, undecylenic acid, lauric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, behenic acid, etc.), UV absorber (paraamino) Benzoic acid, ethyl dihydroxypropyl paraaminobenzoate, amyl paraaminobenzoate, urocanic acid, sodium hydroxymethoxybenzophenone disulfonate, octyl salicylate, phenyl salicylate, triethanolamine salicylate, etc., powder and pigment (red 104, red 201) , Yellow 4, Blue 1, Black 401, Nylon powder, Silk powder, Chromium oxide, Carbon black, Aluminum silicate, Magnesium myristate, Bentonite, Zinc palmitate, Sericite, Calcium acid, barium sulfate, etc.), surfactant (fatty acid soap, alkyl sulfonate, alkyl allyl sulfonate, alkyl amide sulfate, alkyl phosphate, alkyl trimethyl ammonium chloride, stearyl trimethyl ammonium chloride, stearyl trimethyl bromide Ammonium, benzalkonium chloride, carboxybetaine type amphoteric surfactant, phosphobetaine type amphoteric surfactant, lecithin, saponin, glycerin fatty acid ester, sorbitan fatty acid ester, etc.), polyhydric alcohol and saccharides (ethylene glycol, diethylene glycol, propylene glycol) , Mannitol, erythritol, glucose, sucrose, fructose, trehalose, maltitol, sulfated trehalose, etc.), polymer compounds (acrylic ester / methacrylic acid) Ester copolymers, vinyl acetate / crotonic acid copolymers, etc.), antioxidants (sodium sulfite, erythorbic acid, sodium erythorbate, butylhydroxyanisole, lignan, tannins, flavonoids, carotenoids, ascorbyl stearate, parahydroxyanisole, etc. ), Solvents (ethanol, purified water, lower alcohol, ethers, N-methylpyrrolidone, fluoroalcohol, etc.). These contents are not particularly limited, and can be used according to a known technique.

  These compositions can be prepared according to a known production method when at least one extract of the present invention is used as a raw material when preparing a known pharmaceutical, quasi-drug, or cosmetic.

  Specifically, for example, at least one of the extracts of the present invention is used as it is, or a combination of two or more is mixed with a highly water-soluble solvent or compound such as purified water, ethanol, glycerin and dissolved. The product can be prepared as a cosmetic liquid and / or cosmetic cream by slowly mixing the product with a pre-mixed fat-soluble substance such as squalane, jojoba oil, glycerin monostearate. In addition, at least one of the extracts of the present invention may be used as it is, or a combination of two or more types may be dried, various solutions, pastes, etc., and various additives, carriers, base materials, etc. may be blended therein. According to conventional methods in the art, it can be formulated into solid preparations such as tablets, granules, powders, powders and capsules, and liquid preparations such as normal solutions, suspensions and emulsions.

  In addition, the composition of the present invention contains other components that can be used in the same applications as the extract of the present invention, such as known ceramidase activity inhibitory activity and known moisturizing activity (for example, aloe vera, betaine, pullulan, petroleum jelly). , Glycerin, sodium lactate, urea, propylene glycol, ribonucleic acid sodium, 1,3-butylene glycol, chitosan, trehalol, royal jelly, niacinamide, ceramide, sodium tocopheryl phosphate, lactoferrin, oligomarine, extensin), etc. can do.

  In addition to the above, the composition of the present invention can contain an antioxidant. Examples of the antioxidant include, but are not limited to, for example, tocopherol, tocopherol acetate, propyl gallate, butylhydroxyanisole, dibutylhydroxytoluene, coenzyme Q10, α-lipoic acid, fullerene, astaxanthin, organic germanium, dimethylaminoethanol, hydroxy Examples include tyrosol and platinum nanocolloid.

  The content of the extract of the present invention in the composition of the present invention is particularly limited as long as the desired effect of the present invention can be obtained in consideration of its use form, method of use and the like. It is not something. For example, in the case of an external preparation composition, the content of the extract of the present invention is preferably 0.001% by mass or more, more preferably 0.05% by mass or more, and still more preferably 0.001% by dry weight. The upper limit is not particularly set, but is preferably 10% by mass or less, more preferably 7% by mass or less, and still more preferably 5% by mass or less. Moreover, when it is set as an internal use composition, from the viewpoint of exhibiting the effect, the content of the extract of the present invention is preferably 0.01% by mass or more, more preferably 0.1% by mass, as a dry weight. % Or more, more preferably 1.0% by mass or more. Moreover, although an upper limit is not set in particular, For example, 50 mass% or less is preferable.

  The composition of the present invention is used in an appropriate usage according to the form. Specifically, for example, it can be used by internal use, external use, and injection.

  The amount of use of the composition of the present invention is appropriately set according to the form, method of use, purpose of use, and age, weight, and symptom of the patient who is the subject of the composition, and is not constant. For example, in the case of a composition for external use, usually about 0.1 kg to 5 g / day is exemplified as a dry weight per adult body weight of about 50 kg, and within a desired usage range, within one day It may be used once or divided into several times. The period of use is also arbitrary. In the present specification, “use” includes not only “use” but also “administration” and “intake”.

  The subject of the composition of the present invention is preferably a human who inhibits ceramidase in the skin and needs to increase the amount of ceramide, but may be a pet animal or the like.

  EXAMPLES Hereinafter, although an Example is shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example.

Test example 1
To 10 g of each plant (parts are appropriately selected), 100 mL of distilled water was added, stirred, and extracted for 30 minutes while boiling (extraction temperature 100 ° C.). This was filtered, concentrated with a rotary evaporator, air-dried to obtain a hot water extraction sample, and in vitro ceramidase inhibitory activity was measured.

  Specifically, a rat brain-derived ceramidase enzyme solution was prepared by the method of Yavin, Gatt et al. Rat brain-derived enzyme solution 5 μL and hot water extraction sample 15 μL (prepared aqueous solution or aqueous dispersion so that the concentration is 5 mg / mL), C6-NBD-ceramide (made by Matreya) 10 μL as a substrate, mixed at 37 ° C. For 15 hours. The reaction was stopped by adding 100 μL of methanol, and solidified using nitrogen gas. This was dissolved in 20 μL of methanol and spotted on TLC. This was developed with chloroform / methanol / ammonia (90/20 / 0.5 (v / v / v)) and analyzed using an image analyzer (ImageQuant LAS-4000, manufactured by FUJIFILM / GE Healthcare). The inhibition rate was calculated from the ratio of the sample activity when the activity of the control (without sample addition) was 100%. Measurement was performed at n = 3, and an average value was adopted. The results are shown in Tables 1-6.

  From the above results, the ceramidase inhibitory action by these plant extracts is confirmed, and it is considered that the effect of maintaining the skin barrier function and moisturizing is high.

Example 2
100 g of each dried plant (part appropriately selected) was boiled and extracted in 1 L of distilled water for 30 minutes (extraction temperature 100 ° C.). Thereafter, the plant was removed by filtration, water was distilled off under reduced pressure, and the resulting residue was used as a plant extract.

  Next, the emulsions prepared according to the formulation shown in Table 7 below were used as plant extract-containing emulsions a, b, c and plant extract blank emulsion d, and the increase in the amount of ceramide in vivo was measured.

  Specifically, four sites (each 3.6 cm × 3.6 cm) of the left forearm of one healthy person (male: 52 years old) were defined as application sites A, B, C and non-application site D, respectively. Next, each of the A to D sites is described in the literature [G. Imokawa, S. Akasaki, H. Hattori and N. Yoshizuka, J. Invest. Dermatol. 87, 758 (1986), G. Grubauer, KRFingolg, RMHarris. and PMElias, J. Lipid. Res., 30, 89 (1989)], the skin was made rough by removing intercellular lipids. Thereafter, the aforementioned plant extract-containing emulsions a, b, and c were applied to the A, B, and C portions, respectively, and the plant extract blank emulsion d was applied to the D portion twice each morning and evening for 7 days. On the 8th day, the keratin was collected by tape stripping from the A to D sites, and the following operations were performed to calculate the amount of skin ceramide. The results are shown in Table 8. In addition, the result of Example 1 was described for the ceramidase inhibition rate of each compound.

<Extraction of ceramide>
After gently pressing the 3.0 cm x 3.0 cm square Sekisui Supreme Tape E (base polypropylene, acrylic adhesive), remove the tape 5 times and collect 5 tapes at each site.
5 tapes obtained were immersed in a mixed solution of 90 mL of methanol and 10 mL of chloroform, extracted for about 20 minutes using ultrasonic waves, passed through a membrane filter (5 μm), and the solvent was removed at 25 ° C. or lower. Distill off. After the obtained residue was dried using a vacuum pump, 100 mL of a chloroform / methanol = 99.5 / 0.5 (v / v) solution was added and dissolved therein, and then Sep-Pak (registered trademark) Vac manufactured by waters was used. Pass through RC (500mg). After passing 60 mL of chloroform / methanol = 99.5 / 0.5 (v / v) solution through the obtained Sep-Pak (registered trademark) cartridge, 60 mL of chloroform / methanol = 95/5 (v / v) solution is passed. . Fraction through which 60 mL of chloroform / methanol = 95/5 (v / v) solution was passed was concentrated under reduced pressure at 25 ° C. or lower, and 0.5 mL of chloroform / methanol = 9/1 (v / v) was added to the residue to make it uniform. Sample dissolved in

<Measurement of ceramide amount>
20 μL for each sample (A, B, C, D) and 10 μL of N-Tetracosanoyl-D-erythro-sphingosine (5 mg / 10 mL chloroform solution) manufactured by Matereya as standard ceramide, After developing using a layer chromatograph plate (TLC Silica gel 60F254 glass plate), chloroform / methanol / acetic acid = 190/10/1 (v / v / v) as the mobile phase, 8% copper sulfate aqueous solution, 10% phosphorus After sequentially spraying the acid aqueous solution, it is heated at 160 ° C. for 15 minutes. The obtained spot was analyzed using ImageJ, and the relative values of the plant extract-containing emulsion application sites A, B, and C when the color of the plant extract blank emulsion application site D was set to 1 were calculated, and the extract of the present invention Analyzes the degree of increase in skin ceramide content.

  From the above results, it was confirmed that the ceramidase inhibitory action in vivo was exhibited and the increase in the amount of skin ceramide by the plant extract of the present invention was observed. The figure also suggests a weak but correlated relationship between in vitro and in vivo.

  Hereinafter, specific formulations of cosmetics and medical preparations containing the ceramide-degrading enzyme inhibitor of the present invention will be exemplified. The numerical value at the right end of each formulation example means mass% of each component.

  The ceramidase activity inhibitor of the present invention increases the amount of ceramide in cells or skin. For example, moisturizing effect, improvement of wrinkles, improvement of symptoms of atopic dermatitis, prevention / improvement of xerosis, prevention of spots, skin It is preferably used for the improvement of tarmi, antipruritic action, melanin production inhibitory effect, barrier function improvement, fibroblast activation effect, and skin cell regeneration effect.

Claims (9)

  Mushroom, rhododendron, gramineae, umeaceae, rhododendron, chrysanthemum, camphoraceae, anemone walnut, walnut, poppy, scorpionaceae, taro, cicaceae, perilla, linden, ginger, honeysuckle , Currantaceae, Violetaceae, Apiaceae, Elmaceae, Elmaceae, Nozenkazura, Rosaceae, Himegiidae, Sandalwoodaceae, Myrtaceae, Legumes, Mansacaceae, Citrus, Mucoliaceae, Mussomaceae, Murasidae, and A ceramidase activity inhibitor characterized by containing, as an active ingredient, at least one plant-derived extract selected from the group consisting of the family Moleaceae.   The mallow is at least one selected from the group consisting of marsh mallows and malva flowers, the Rubiaceae is at least one selected from the group consisting of woodruff and mudder, and the grasses are Koubay, Kumazasa, At least one selected from the group consisting of lemongrass, oak moss, oak moss, benzoin, chrysanthemum, artichoke, cornflower, milk thistle, sunflower, tansy, fever At least one selected from the group consisting of Yarrow, Chicory, at least one selected from the group consisting of Crocodiles and Sasafras, and from the group consisting of Verbain and Lemon Verbena At least selected The walnut plant is black walnut, the poppy plant is poppy, the scorpion plant is at least one selected from the group consisting of eyebright and malein, and the taro plant is calamas Yes, the succulent plant is at least one selected from the group consisting of oak and scorpion, and the Lamiaceae plant is water calamint, catnip, sage, savory, peppermint, penny royal, marjoram, lemon thyme, lemon balm, and hoahound At least one selected from the group consisting of: lindenaceae is linden, ginger is ghetto, honeysuckle is honeysuckle, currant is blackcurrant, violet is Violet, celery family The object is at least one selected from the group consisting of angelica, chervil, fennel, ajowan, and gotucola, and the azalea plant is at least one selected from the group consisting of winter green and heather flowers, Is a slippery elm, a physaceae plant is Pau de Arco, a rosaceae plant is at least one selected from the group consisting of icrinin, cherry, mocca, recompi, peach, and ladies' mantle, and The sandalwood plant is sandalwood, the myrtaceae plant is myrtle, and the legume plant is at least one selected from the group consisting of carob, alfalfa, goat roux, honey bush, and red clover, Family plant A witch hazel, wherein the citrus plant is at least one selected from the group consisting of Shiranuhi and spruce; And at least one selected from the group consisting of guarana, the moss family is Yukicha, the purple plant is at least one selected from the group consisting of alkanes and polydi, and oleaceae is olive. The ceramidase activity inhibitor according to claim 1.   A ceramide amount adjusting agent comprising the ceramidase activity inhibitor according to claim 1 or 2.   A composition comprising the ceramidase activity inhibitor according to claim 1 or 2 or the ceramide amount adjusting agent according to claim 3.   The composition according to claim 4, which is an internal use composition.   The composition of Claim 4 which is an external preparation composition.   The composition according to any one of claims 4 to 6, which is used for improving or treating a symptom of a disease caused by a decrease in the amount of ceramide.   The composition according to any one of claims 4 to 7, which is used for improving or treating atopic dermatitis or a symptom of a disease caused by atopic dermatitis.   The composition according to any one of claims 4 to 7, which is used for improving or treating a symptom of sebum deficiency or a disease caused by sebum deficiency.

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