JP2015193588A - External composition for skin - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an external composition for skin which is highly effective in alleviating/treating the symptoms of allergic dermatitis or atopic dermatitis without using steroid, can inhibit a nonspecific stimulus-response in addition to inhibition of an allergen specific stimulus-response, and which is also friendly to the environment.SOLUTION: An external composition for skin of this invention contains Citrus jabara dry peel powders as an active ingredient. As the Citrus jabara dry peel used for the external composition for skin of this invention, the one which is dried by heat-drying method, freeze-drying method, spray-drying method, and the like can be illustrated.

Description

  The present invention relates to a composition for external use containing dry dried fruit peel as an active ingredient.

Allergies are broadly classified from type I to type V (Coombs classification) depending on the mechanism of development.
Among them, hay fever and allergic rhinitis are known to be type I allergies, also called immediate hypersensitivity. Type I allergy is humoral immunity involving IgE that reacts specifically with allergens that cause allergies and some immunoglobulins such as IgG4 (see Non-Patent Document 1).

  In contrast, allergic dermatitis and atopic dermatitis, in addition to type I allergy, type IV allergy, which is a cellular immunity involving sensitized T cells that specifically react to allergens, It has been found that non-specific stimulatory responses that are not associated with allergens are involved.

  Furthermore, we will consider the differences between hay fever, food allergies and atopic dermatitis, which are classified as type I allergies. In the case of hay fever, symptoms disappear when the pollen allergen exposure is removed. That is, when the pollen scattering season ends, the symptoms disappear, and the onset of hay fever can be avoided by evacuating to an area where pollen does not scatter during the pollen scattering period. Food allergies can prevent the development of food allergies by not taking or exposing allergens that develop allergies. In other words, hay fever and food allergies are associated with allergen exposure / allergic reaction and symptoms.

  On the other hand, atopic dermatitis is a chronic disease and does not ameliorate just by leaving the patient unexposed to allergens. To treat atopic dermatitis, a part other than the allergic reaction that is the manifestation of symptoms must be dealt with. That is, atopic dermatitis is a chronic disease having a complicated pathological mechanism including allergic reaction. From the above, the treatment of atopic dermatitis is very different from the case of hay fever and food allergy, which are classified as the same type I allergy.

  By the way, according to the Japanese Dermatological Association guidelines, atopic dermatitis is described as “a variety of non-specific irritation reactions and idiosyncrasies, accompanied by skin abnormalities such as dryness of the epidermis, especially skin caused by abnormalities in the stratum corneum, and abnormal barrier function. It is defined as "a disease of the eczema / dermatitis group that is caused by chronic allergic inflammation and pruritus caused by a positive allergic reaction".

  In addition, according to the criteria for diagnosis of atopic dermatitis of the Japanese Dermatological Association, it is diagnosed as atopic dermatitis that applies to all three of itching, characteristic rash and its distribution, and chronic / repetitive course.

  Considering the definition of such atopic dermatitis and the actual state of the pathology, it is not sufficient to suppress allergen-specific stimulation responses to alleviate the symptoms. Rather, (1) skin dryness and It is more important to suppress the nonspecific stimulation reaction by returning the abnormal barrier function to normal, (2) suppressing nonspecific stimulation reaction and suppressing inflammation, and (3) suppressing itchiness.

  This non-specific stimulus response is a symptom of chronic inflammation and itching. The cause of the nonspecific stimulation reaction is that the skin of the patient is dried and the barrier function of the skin is impaired, thereby directly stimulating nerve fibers extending directly under the skin of the skin, and stimulation of nerve fibers. The neuropeptide (Substance P) generated by the keratinocytes binds to keratinocytes in the epidermis and releases various inflammatory cytokines.

  In addition, if the non-specific stimulation reaction is left as it is, the symptom is further worsened by the patient scratching the inflamed part. Therefore, antiallergic agents that suppress allergic reactions are rarely used alone in the treatment of allergic dermatitis and atopic dermatitis, and steroids such as clobetasol propionate are used to suppress nonspecific reactions. Are often used in combination, or steroids are often used alone.

  However, steroids may cause side effects such as high blood pressure, diabetes, osteoporosis, glaucoma, cataracts, and easy infections in the case of internal medicine, and skin with ointment applied in the case of external medicine. Its use is avoided because it may cause side effects such as faintness (skin atrophy), worsening of infections such as acne and herpes.

  Therefore, instead of steroidal drugs, herbal medicines, particularly herbal medicines based on citrus fruits, have been studied. For example, a contact dermatitis inhibitor containing an extract of chimpi (see Patent Document 1), a RANTES production inhibitor containing an extract of Yuzu or Citrus unshiu (see Patent Document 2), and a salamander extract. A topical preparation for atopic dermatitis (see Patent Document 3), a histamine H1 receptor blocker containing Chen as an active ingredient (see Patent Document 4), and a cosmetic containing a bellows extract (see Patent Document 5) .).

  Moreover, the external preparation for skin containing the extract of the flower part of Citrus unshiu (refer patent document 6), the hyaluronic acid synthesis promoter containing cryptoxanthin derived from citrus fruits and / or its derivative (refer patent document 7), Topical skin care composition containing bellows extract (see Patent Document 8), anti-inflammatory agent containing Cryptoxanthin and / or its derivatives derived from Wenzhou oranges (see Patent Document 9), Yawata, Kanatsu, Summer oranges And an expression inhibitor of MCP-1 (see Patent Document 10) containing aurapten contained in citrus fruits such as grapefruit as an active ingredient.

  However, although these external preparations for skin and the like provide a certain degree of therapeutic effect, the effect is limited, and in particular, the effect of suppressing non-specific stimulation reaction is insufficient. Therefore, allergic dermatitis and atopic dermatitis cannot be treated with these external preparations for skin alone, and steroids must be used at present.

JP 2001-81037 A JP 2003-63980 A JP 2003-306438 A JP 2004-59545 A JP 2007-238464 A JP 2009-173682 A JP 2011-42627 A JP 2011-510980 A JP 2014-189522 A International Publication No. WO2007 / 132893

"Allergy", [online], Wikipedia, [Search August 8, 2014], Internet <URL: http://en.wikipedia.org/wiki/Allergy>

  Therefore, the present invention is highly effective in alleviating and treating symptoms of allergic dermatitis and atopic dermatitis without using a steroid, and in addition to suppressing allergen-specific stimulation reactions, non-specific stimulation An object of the present invention is to provide a composition for external use on the skin which can suppress the reaction and is friendly to the environment.

  As a result of intensive studies, the inventor has been able to sufficiently reduce and treat symptoms of allergic dermatitis and atopic dermatitis without using steroids by using dried dry skin powder in the composition for external use. In particular, in addition to the suppression of allergen-specific stimulation responses, it was found that non-specific stimulation responses can also be suppressed, and that these effects are produced by nariltin, and the present invention has been completed.

  That is, the external composition for skin according to claim 1 of this application contains dried dried fruit peel as an active ingredient. The external composition for skin according to claim 2 is the external composition for skin according to claim 1, wherein the peel is dried by any one of a heat drying method, a freeze drying method and a spray drying method. is there. The external composition for skin according to claim 3 is the external composition for skin according to claim 2, wherein the peel is dried by a freeze drying method and then dried by a heat drying method. Furthermore, the external composition for skin of Claim 4 is the external composition for skin of Claim 3, Comprising: It heat-drys at 80 degreeC.

  The external composition for skin of this invention is excellent in the effect of reducing the symptoms of atopic dermatitis and allergic dermatitis. In addition, it is environmentally friendly because it can use the peels that had been discarded by incineration.

FIG. 1 is a graph showing the effect of the dose of nariltin on the transcription amount of the chemokine (CXCL1) gene. FIG. 2 is a graph showing the influence of the dose of nariltin on the transcription amount of the chemokine (CCL4) gene. FIG. 3 is a graph showing the effect of the dose of narilutin on the transcription level of the interleukin (IL-16) gene. FIG. 4 is a graph showing the influence of the dose of narilutin on the transcription amount of the L-histidine decarboxylase (HDC) gene.

  The composition for external use of the skin of the present invention contains dry dried fruit skin powder as an active ingredient. Then, the dry rose peel powder which is a component of this invention, another component, a preparation method, etc. are explained in full detail below.

1. Jabal dried fruit powder (1) Jabal fruit Jabal fruit used in the present invention can be used without any particular limitation. Especially, since there is much content of the narirutin per unit weight, the fruit of the immature stage before yellowing of the fruit and fruit peel which were picked is preferable. Here, specifically, the immature stage fruit is preferably a fruit that has been harvested three to four months after fruit set. In addition, since potatoes generally fruit around June, fruits harvested around September to October are preferable.

(2) Jara pericarp Jara pericarp can be peeled off by hand from the perilla fruit, peeled off by a known automatic peeler, or residue left after squeezing the fruit juice from the fruit juice press. The residue of a fruit juice press is preferred.

(3) Drying method Jabara dried skin powder is a general method, that is, after the skin has been cut or shredded, shaded, dried naturally, dried by a dryer, freeze dried, spray dried, spray Examples thereof include those produced by a dry method or a combination of these methods.

  Among these, those produced by drying by freeze drying and then drying by heat drying are preferred, and those produced by heat drying at 80 ° C. are more preferred. Limonene, which is an allergen when it is oxidized, is completely removed from the dried dry peel of the rose thus produced while maintaining a high concentration of naliltin. Therefore, the possibility of developing allergies or the like due to the external composition for skin of the present invention can be almost completely eliminated.

(4) Peeling of fruit peel The dried dry peel is processed into a powdered powder by a known grinding method using a ball mill or the like. In addition, as for the magnitude | size of the powder at the time of processing into a pericarp powder, the thing of 200-1000 mesh is preferable. This is because if the powder is so large that it does not pass through a 200-mesh sieve, the amount of nariltin eluted from the dried pericarp is limited, and if the powder is so small that it passes through a 1000-mesh sieve, it will take time to grind.

(5) Content The content of the dried dry skin powder in the composition for external use of skin is 0.01 to 10% (% by weight, the same shall apply hereinafter unless otherwise specified), and preferably 1 to 5%. This is because if it is 1% or more, a sufficient effect is obtained, and if it is 5% or less, the coating comfort, stability, and color are good.

(6) Other components The composition for external use of the skin of the present invention is a known optional component that is generally used for compositions for external use of skin such as cosmetics, quasi-drugs, and pharmaceuticals as long as the effects of the present invention are not impaired. You may add as needed.

  Specifically, for example, anions (higher fatty acid alkali metal salts, higher fatty acid amine salts, amino acid surfactants), nonionic surfactants, surfactants such as phospholipid sterol esters, hydrocarbons (liquid paraffin, Wetting agents (polyhydric alcohols such as glycerin, saccharides, biopolymers, amino acids) such as squalane and petrolatum), fats and oils (animal and vegetable oils, triglycerides, wax esters, higher alcohols, higher fatty acids, silicones, ester oils, waxes, etc.) , Peptides, etc.), alcohol (ethyl alcohol), film forming agents (polyvinyl alcohol, pectin), water-soluble, oil-soluble polymers, humectants such as cetyl ethylhexanoate, UV absorbers, preservatives (methylparaben, phenoxyethanol) ), Antioxidants, thickeners (polyacrylamide, laureth-7) Hydrogenated polyisobutene), sequestering agents, coloring agents (natural pigments, synthetic pigments), various fragrances, various plant extracts and animal extracts, vitamins (oil-soluble vitamins, water-soluble vitamins), arbutin, kojic acid, ellagic acid , Urea, allantoin, anti-inflammatory agents (glutyl retinoic acid, glycyrrhizic acid, azulene), astringents (zinc paraphenol sulfonate), organic acids and salts thereof including citric acid, and powders (organic powders, inorganic powders) Body).

(7) Preparation Method The external composition for skin of the present invention can be prepared by a known method for preparing cosmetics, quasi drugs, pharmaceuticals and the like. Specifically, it can be prepared by mixing the components of the composition for external use with a high-speed homomixer, a planetary mixer, a fluid mixer, or the like. In addition, you may mix, heating or cooling according to the component to add.

(8) Dosage form The external composition for skin of the present invention is not particularly limited as long as it is used on the skin. Specifically, solution system, solubilization system, emulsification system, powder dispersion system, water-oil two-layer system, water-oil-powder system, water-oil-silicone three-layer system, hydrophilic ointment and water absorption Any dosage form such as an ointment, a gel system, and an aerosol system may be used.

(9) Applications The external composition for skin of the present invention can be used in a wide range of cosmetics, quasi-drugs, pharmaceuticals and the like used for the outer skin. Specifically, skin care cosmetics such as facial cleansers, milky lotions, creams, lotions, packs, beauty essences, base makeup such as foundations, point makeup such as lipsticks, eye shadows, eyeliners, shampoos, rinses, conditioners, etc. It can also be used in hair care products including scalp care agents, bath preparations, aromatic cosmetics, etc., and can also be used in sun care products, body care products, whitening products and anti-aging products.

  Hereinafter, the present invention will be described more specifically based on examples. However, these examples do not limit the invention described in the claims in any way.

1. Effects on outer skin composition allergic dermatitis, etc. (1) Preparation of dried dried fruit skin Jabara fruits were collected from the grown fruit trees of Matsue-kita in Wakayama City, Wakayama Prefecture at the end of October and peeled off by hand. . The peeled peel was dried by a freeze-drying method at -70 ° C and then heat-dried at 80 ° C for 8 hours to obtain a dried peel. The dried pericarp was pulverized with a ball mill, passed through a 200 mesh sieve, and a dried dried pericarp powder that passed through the 200 mesh sieve was obtained.

(2) Preparation of external composition for skin The external composition for skin according to the present invention was prepared. Specifically, the components listed in Table 1 were put in a beaker and prepared by stirring with a homomixer or a stirrer.

(3) Performance test of composition for external use on skin The composition for external use in skin prepared in (2) was applied to the face and skin of 10 adult men and women (20s to 50s). ”,“ Irritation test ”, and“ Skin quality improvement test ”. The results are shown in Tables 2 to 4.

  The “use feeling test” is a test for evaluating skin familiarity immediately after application and moisturizing feeling immediately after application and the next day by a questionnaire to the subject. Further, the “stimulus test” is a test for evaluating a stimulus felt in the application part immediately after application by a questionnaire to the subject. Furthermore, the “skin quality improvement test” is a test in which after applying twice a day for 30 days, a change in symptoms of the applied part is visually evaluated.

  Table 2 shows the results of the “use feeling test”. From this table, the composition for external use of the present invention returns the skin dryness and abnormal barrier function to normal, and the feeling of use such as skin familiarity and moisturizing feeling. It turned out that it was excellent in the point. Table 3 shows the results of the “stimulation test”. From this table, it was found that the external composition for skin of the present invention does not give harmful irritation to the skin even when applied. Furthermore, Table 4 shows the results of the “skin quality improvement test”. From this table, the composition for external use of the skin of the present invention has the ability to improve skin quality by returning skin dryness and abnormal barrier function to normal. It was found that the symptoms were not worsened even when applied.

(4) Confirmation of effect on atopic dermatitis The topical skin composition produced in (2) was applied twice in the morning and evening to the affected area of 10 patients with atopic dermatitis, and changes in symptoms were examined visually. Table 5 shows changes in age, sex, and symptoms of patients.

  From Table 5, by applying the composition for external use of the skin of the present invention to the affected area, the symptoms of red swelling and itching (type I allergy) were improved 1 to 5 days after application, and the affected area was moistened by wetting of eosinophils. (Type IV allergy, atopic dermatitis) also improved 5-14 days after application. As described above, red swelling of the skin, itching, and wetness of the affected area are related to non-specific reactions. Therefore, it is considered that the external composition for skin of the present invention also contributes to suppression of non-specific reactions.

  Well, in general, steroids have immediate effects, but there are adverse effects and side effects of long-term use. On the other hand, herbal medicines can not be expected to be effective immediately, but they act on the body in a gentle manner such as improving the constitution. So there are few side effects.

  Nevertheless, the composition for external use of the present invention has a very high immediate effect and a high symptom improving effect as a crude drug. That is, it was found that the composition for external use of the skin of the present invention has the safety of herbal medicine and the high immediate effect and medicinal effect of the steroid.

2. Effect of Nariltin on Transcription of Genes Related to Allergic Dermatitis, etc. Investigated using. Details are shown below.

(1) Experimental animals and materials Nariltine used was purified by Prof. Taniguchi, Osaka University of Pharmacy. Nallutin is an S-form compound having a molecular formula of C ₂₇ H ₃₂ O ₁₄ , and is expressed as 2S-nariltin when distinguishing three-dimensionally. Further, depending on the purification method, 2R-nariltin isomerized to R form in the isolation process of naryltin (2S-nariltin) is contained in an amount of about 20% by weight.

  Therefore, in this example, “nariltin purified product (2S-nariltin 100% by weight, hereinafter abbreviated as“ nariltin A ”)” and “crude product from which 2R-nariltin has not been removed (2S-nariltin 80% by weight and A mixture of 20% by weight of 2R-nariltin, hereinafter abbreviated as “nariltin B”) ”was used.

  The experimental animals were female NC / Nga mice, 7 weeks old, and were bred at 5 animals per cage in an animal breeding facility. Feeding during breeding was performed by free intake of solid feed CRF-1 in a feeder, and water during breeding was performed by free intake of tap water in a water bottle.

(2) Preparation of allergy model mouse The allergy model mouse was prepared according to the method of Yamamoto (see the following Reference 1). ). Specifically, first, the back and auricle of NC / Nga mice were shaved with a clipper and an electric shaver, and then an appropriate amount of a depilatory epirat was applied to remove the hair. After wiping off the hair remover, 100 mg of Biosta AD (manufactured by Biosta Co., Ltd.) was uniformly applied to the back and auricle on the back of the tip of the micropipette (initial induction).

  Re-induction was performed 3 days, 7 days, 10 days, 14 days, and 17 days after the initial induction. Specifically, after removing hair with a shaver, 150 μl of 4% SDS aqueous solution was dripped onto the back and auricle with a micropipette and uniformly applied on the back of the tip of the micropipette, and then naturally dried for about 2-3 hours. . After drying, Biosta AD 100 mg was evenly applied to the back and auricle at the back of the tip of a micropipette to prepare a mite allergen atopic dermatitis model. After the model was prepared, the symptoms of atopic dermatitis were scored, and whole blood was collected by heparin blood collection under anesthesia.

  Reference 1: A novel atopic dermatitis model induced by topical application with dermatophagoides farinae extract in NC / Nga mice. Yamamoto M, Haruna T, Yasui K, Takahashi H, Iduhara M, Takaki S, Deguchi M, Arimura A. Allergol Int. 2007. 56: 139-148.

(3) Measurement of mRNA transcription amount by ex vivo simulation method The mRNA transcription amount of cellular immunity-related genes in leukocytes of allergic model mice was measured by ex vivo simulation method. Specifically, it measured as follows.

  As a cellular immunity-related gene, it promotes neutrophil chemotaxis, nonspecific stimulation reaction of skin and chemokine CXCL1 gene and chemokine CCL4 gene related to inflammation, specific stimulation reaction of atopic dermatitis The amount of transcription of the related marker IL-16 gene and L-histidine decarboxylase HDC gene involved in the synthesis of histamine causing itchiness was measured.

(3a) Preparation of allergen mixed solution and narilutin solution Prepared allergen mixed solution by dissolving and suspending mite allergens Der f1 and Der f2 (Asahi Food and Healthcare Co., Ltd.) to a concentration of 100 μg / ml. did. In addition, Nariltin A and Nariltin B were dissolved in DMSO so that the concentration at the time of reaction with blood was 100 μM, 10 μM, and 1 μM to prepare a Nariltin solution. A solution containing no nariltin was prepared for use as an experimental control.

(3b) Measurement of mRNA transcription amount by ex vivo simulation method To 60 μl of mouse whole blood collected from heparin, 1.2 μl of an allergen mixed solution and 1.2 μl of a nariltin solution were added and reacted at 37 ° C. for 4 hours. The amount of transcription of mRNA of each gene in the whole blood of this naliltin-added mouse was measured according to the method of Mitsuhashi (see Reference Document 2 below). Specifically, it was performed as follows.

  First, the whole blood of mice with naliltin was passed through a 96-well filter plate that captures only white blood cells from the whole blood. Cell lysate was added to each well of the filter plate to lyse leukocytes captured on the filter plate. The cell lysate contains one of the mRNA antisense primers for the gene to be measured.

  Next, the cell lysate on the filter plate is transferred to a 96-well oligo (dT) plate by centrifugation, and the mRNA in the cell lysate and the oligo dT in the well are hybridized. dT) Each well of the plate was washed with a suction nozzle to purify mRNA.

  Reverse transcriptase and dNTP were added directly to each well, and cDNA was synthesized simultaneously from two sites starting from oligo (dT) and antisense primer that had already hybridized to mRNA. DNA polymerase was added to each well, and changes in the amount of mRNA transcription were measured by real-time PCR, and the effects of differences in the concentration of nariltin on the amount of mRNA transcription were compared. The results are shown in FIGS. The vertical axis in FIGS. 1 to 4 is a relative value when the transcription amount of mRNA when the dose of narilutin is 0 μM is 1.0.

  Reference 2: Mitsuhashi M. Ex vivo simulation of leukocyte function: stimulation of specific subset of leukocytes in whole blood followed by the measurement of function-associated mRNAs. J Immunol Methods. 2010, 363: 95-100.

(4) Experimental Results FIG. 1 is a graph showing the influence of the dose of narilutin on the transcription amount of the chemokine CXCL1 gene. FIG. 2 is a graph showing the influence of the dose of nariltin on the transcription amount of the chemokine CCL4 gene. Further, FIG. 3 is a graph showing the effect of the dose of nariltin on the transcription amount of the interleukin IL-16 gene. In addition, FIG. 4 is a graph showing the effect of the dose of narilutin on the transcription amount of the L-histidine decarboxylase HDC gene.

  As shown in FIGS. 1 to 3, the transcription of the gene related to cellular immunity is sufficiently reduced even when the blood concentration of nariltin is as low as 1 μM. In particular, the chemokine CXCL1 gene (FIG. 1) is hardly even at 1 μM. It was found that the transfer amount was reduced to such an extent that it was not.

  In addition, as shown in FIG. 4, the amount of transcription of the L-histidine decarboxylase HDC gene associated with the synthesis of histamine that causes itchiness was also reduced. From this, it is considered that the itching symptom in atopic dermatitis is suppressed by administration of nariltin, and the QOL of the patient can be improved. From the above results, it can be presumed that the external composition for skin of the present invention has a high effect on allergic dermatitis and atopic dermatitis.

  As described above, the composition for external use of skin of the present invention (1) restores normal skin dryness and abnormal barrier function (see Tables 2 and 4), and (2) non-specific skin irritation reaction And by suppressing inflammation (see Table 5, FIG. 1 and FIG. 2) and (3) by suppressing itching (see Table 5 and FIG. 4), specific and non-specific stimulation of atopic dermatitis It became clear that any of these can be suppressed. That is, it was found that the composition for external use of the skin of the present invention has the safety of herbal medicine and the high immediate effect and medicinal effect of the steroid.

Claims (4)

  An external composition for skin comprising dry rose peel powder as an active ingredient.   The external composition for skin according to claim 1, wherein the peel is dried by any one of a heat drying method, a freeze drying method and a spray drying method.   The composition for external use of the skin according to claim 2, wherein the peel is dried by a freeze drying method and then dried by a heat drying method.   The external composition for skin according to claim 3, which is heat-dried at 80 ° C.

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