JP2005350412A - Nerve growth factor production inhibitor, and skin care preparation for external use, cosmetic, quasi-medicine, itching-preventing and treating agent, and atopic dermatitis medicine which contain the nerve growth factor production inhibitor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a nerve growth factor production inhibitor having an action on inhibiting the production of a nerve growth factor deeply related to the elongation of C fibers to skin and simultaneously having high safety, and to provide a skin care preparation for external use, a cosmetic, a quasi-medicine, an itching-preventing and treating agent, and an atopic dermatitis medicine each of which contain the nerve growth factor production inhibitor. <P>SOLUTION: The nerve growth factor production inhibitor is characterized by containing at least one extract selected from a rose fruit extract, a wild rose extract, a rosemary extract, a Plectranthus rugosus extract, a clove extract, a Rehmannia glutinosa extract, a Paeonia lactiflora extract, a Gentiana lutea extract, a Scutellaria root extract, a coltsfoot extract, a clematis extract and a Houttuynia cordata extract. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a nerve growth factor production inhibitor, and a skin external preparation, a cosmetic, a quasi-drug, an itching prevention and treatment agent, and an atopic dermatitis treatment agent containing the nerve growth factor production inhibitor.

  Itching is a unique sensation that occurs only in the skin, mucous membranes, and cornea and is described as an “unpleasant sensation with a desire to scratch”. In inflammatory and allergic skin diseases such as atopic skin diseases, hay fever, food allergies and urticaria that have become social problems in recent years, this sensation of itchiness is one of the very important and serious symptoms. . Itching is also a problem in senile dermatosis with dry skin, jaundice and itch associated with dialysis, and complications of diabetes and malignant tumors.

Itching is induced centrally and centrally by a wide variety of stimuli, including physical irritation such as skin dryness and temperature changes, sweat, pressure, and contact, and chemical stimuli with palliative substances. It is the most important endogenous endogenous substance, and its antagonist is clinically used only for histamine, and it is considered that the H ₁ receptor is involved. An external preparation containing a competitive antagonist for histamine, such as chlorpheniramine maleate, diphenhydramine and related substances, has been used externally for the treatment of pruritus. However, these external preparations having an antihistamine action have been problematic in that they have side effects.

Therefore, an application such as the following Patent Document 1 relating to a skin external preparation formulated with natural ingredients is focused on safety. This Patent Document 1 discloses an invention relating to an external preparation for skin containing a bamboo extract component. However, in the column of the prior art, the use of the stability of mast cell membrane of borneol is disclosed (Japanese Patent Application Laid-Open No. Hei 6-2111713). ), Those utilizing the anti-inflammatory effect of actinomycete culture solution (Japanese Patent Laid-Open No. 5-25053), those utilizing the anti-allergic properties of fats and oils containing docosahexaenoic acid (DHA) and linolenic acid (Japanese Patent Laid-Open No. 2-29081) These naturally-occurring anti-allergic agents have few side effects, but are described as having insufficient effects.
JP 2003-212786 A

  However, the invention according to Patent Document 1 also only shows the effect of suppressing itchiness in the histamine release inhibition test and leukotriene secretion inhibition test.

  On the other hand, in recent studies, it has been found that the itch transmission fiber ending (C fiber ending), which is found only in the boundary of the epidermis in healthy human skin, is the epidermal layer of the skin in atopic dermatitis skin and dry skin. It has been pointed out that the elongation of the C fiber end to the epidermis may be one of the causes of senile pruritus, atopic dermatitis, and severe itching in dry skin.

Such problems are described in, for example, the prior art section of Patent Document 2 below (specifications [0005] to [0007]). The invention according to Patent Document 2 is characterized in that an extract of petals of echidna grass is contained in an antiallergic composition. However, after clarifying the mechanism of itching as described above, the solution is solved. Since it is not intended, the effects of the invention are only anti-allergic and anti-anaphylactic.
Japanese Patent Laid-Open No. 2001-27879

  In any case, no itching agent has been developed yet, which is based on the suppression of C fiber elongation to the skin epidermis.

  The present invention has been made to solve such problems, and has a function of suppressing the production of nerve growth factor that is deeply involved in the elongation of C fibers to the epidermis and at the same time has high safety. It is an object of the present invention to provide a production inhibitor, and an external preparation for skin, a cosmetic, a quasi-drug, an itching preventive and therapeutic agent, and a therapeutic agent for atopic dermatitis, in which the nerve growth factor production inhibitor is blended.

  As a result of diligent research to solve such problems, the present inventors have clarified the following: Age extract, Novara extract, Rosemary extract, Enmiso extract, Clove extract, Diou extract, Peonies extract, Gentian extract , Ogon extract, dandelion extract, clematis extract, and dokudami extract have excellent nerve growth factor production inhibitory action, especially the inflammation and itching that occurs in the skin, and at the same time safe for the living body As a result, the present invention has been completed.

  That is, the present invention is made as a nerve growth factor production inhibitor, and a skin external preparation, a cosmetic, a quasi-drug, an itching prevention and treatment agent, and an atopic dermatitis treatment agent containing the nerve growth factor production inhibitor. The invention according to claim 1 relating to the nerve growth factor production inhibitor comprises the following: Age extract, Novara extract, Rosemary extract, Enmiso extract, Clove extract, Diou extract, Peonies extract, Gentian The nerve growth factor production inhibitor contains at least one selected from an extract, an extract of urgon, an extract of dandelion, a clematis extract, and a dokudami extract.

  In the present invention, “Ages extract, Novara extract, Rosemary extract, Enmezo extract, Clove extract, Ginger extract, Peonies extract, Gentian extract, Ogon extract, Fukidan popo extract, Clematis extract and The phrase “containing at least one kind selected from Dokudami extract in the nerve growth factor production inhibitor” means that only one of these, or two or more kinds, and those other than the above-mentioned extracts are included. It means that it may contain.

  The invention according to claim 2 is an invention relating to an external preparation for skin containing the nerve growth factor production inhibitor according to claim 1, and the invention according to claim 3 is the nerve growth factor production according to claim 1. A cosmetic comprising an inhibitor, and the invention according to claim 4 is an invention related to a quasi-drug containing the nerve growth factor production inhibitor according to claim 1.

  Furthermore, the invention according to claim 5 is an invention relating to a itch prevention and treatment agent containing the nerve growth factor production inhibitor according to claim 1, and the invention according to claim 6 is a nerve growth factor according to claim 1. It is an invention related to a therapeutic agent for atopic dermatitis containing a production inhibitor.

  As mentioned above, C fiber endings are found only up to the epidermal dermis boundary in healthy human skin, but in skin such as atopic dermatitis and dry skin, it extends to the epidermal layer of the skin. The elongation of the C fiber terminal to the epidermis is considered to be a cause of the occurrence of itchiness. And it is presumed that the C fiber endings extend to the epidermis in this way because NGF, which is a nerve growth factor, acts on the C fiber endings, and therefore, by using the nerve growth factor production inhibitor of the present invention. NGF production can be suppressed, thereby preventing the C fiber ending from extending to the epidermis.

  As described above, according to the present invention, by inhibiting the production of NGF, which is a nerve growth factor that is deeply involved in the elongation of C fibers to the epidermis, the itch factor can be directly removed, and It is possible to provide a nerve growth factor production inhibitor with high safety, and an external preparation for skin, a cosmetic and the like containing the nerve growth factor production inhibitor.

  The extract used in the present invention, after drying or pulverizing without drying one or more of the whole plants of each plant or their leaves, stems, roots, fruits, seeds and flowers, Means various solvent extracts obtained by extraction with a solvent at low temperature or at room temperature or under heating, or extraction using an extractor such as a Soxhlet extractor, diluted solutions thereof, concentrated solutions thereof, or dried powder thereof. To do. The parts of each plant to be extracted are not particularly limited, but wild rose, ages are fruits, rosemary and clematis are leaves, enmeado is leaves and stems, clove is buds, jiou, peonies, red gon are roots, gentian It is preferable to use the roots and stems, the flowers of dandelions and the aerial parts of Dokudami as extraction materials.

  Examples of the extraction solvent include one or more of water, lower monohydric alcohols such as methanol and ethanol, liquid polyhydric alcohols such as glycerin, propylene glycol, and 1,3-butylene glycol, and hydrous alcohols. They can be used in combination. As an example of a preferable extraction method, there may be mentioned a method in which ethanol or 1,3-butylene glycol having a water content of 20 to 80% by volume is extracted at room temperature for 1 to 5 days and then filtered.

  Age extract, Novara extract, Rosemary extract, Enmiso extract, Clove extract, Diou extract, Peonies extract, Gentian extract, Ogon extract, Fukidan popo extract The compounding amount of each nerve growth factor production inhibitor such as a product, clematis extract and dokudami extract is not particularly limited, but in dry solid weight (the total amount when multiple extracts are included), 0.0001 to 20.0% by weight based on the total amount is preferred. This is because if the blending amount is less than 0.0001% by weight, the effect of the present invention cannot be sufficiently obtained, and if the blending amount exceeds 20.0% by weight, no improvement in the effect commensurate with the increase is observed. . From this viewpoint, the content is more preferably 0.0005 to 5.0% by weight.

  The nerve growth factor production inhibitor of the present invention can be in the form of, for example, lotions, emulsions, creams, ointments, packs, foundations and the like as external preparations for skin. The nerve growth factor production inhibitor of the present invention can be appropriately mixed with a dye, an antiseptic, a surfactant, a fragrance, a pigment, and the like depending on the form.

Examples of the present invention will be described below.
(Example 1)
This Example is an example of a nerve growth factor production inhibitor containing Agetsu extract. The age extract is prepared as follows. That is, first, 100 ml of ethanol having a water content of 50% by volume is added to 10 g of dried and finely crushed fruit of Ages. Next, after extracting for 5 days at room temperature (temperature of about 20-30 degreeC), the Ages extract was obtained by filtering. At this time, the dry solid content was 1.61% by weight.

(Example 2)
This example is an example of a nerve growth factor production inhibitor containing Novara extract. 100 g of ethanol with a water concentration of 50 vol% was added to 10 g of dried and finely crushed fruit of Novara, extracted at room temperature for 5 days, and then filtered to obtain a Novara extract. The amount of dry solid was 1.57% by weight.

(Example 3)
This example is an example of a nerve growth factor production inhibitor containing a rosemary extract. To 10 g of dried and finely crushed leaves of rosemary, 100 ml of ethanol having a water content of 50% by volume was added, heated to 70 ° C., extracted for 5 days, and then filtered to obtain a rosemary extract. . The amount of dry solid was 1.75% by weight.

Example 4
This example is an example of a nerve growth factor production inhibitor containing an enamel extract. 100 g of ethanol with a water content of 50% by volume was added to 10 g of dried and finely crushed leaves and stalks of enamel and extracted at room temperature for 5 days, followed by filtration to obtain an enamel extract. The dry solid content was 1.27% by weight.

(Example 5)
This example is an example of a nerve growth factor production inhibitor containing a clove extract. 100 g of ethanol with a water content of 50% by volume was added to 10 g of dried and finely crushed buds of clove and extracted at room temperature for 5 days, followed by filtration to obtain a clove extract. The amount of dry solid was 1.13% by weight.

(Example 6)
This example is an example of a nerve growth factor production inhibitor containing an extract of Jiu. Preparation of ziou extract is carried out as follows. First, 100 ml of ethanol having a water content of 50% by volume was added to 10 g of dried and finely crushed radish roots, followed by extraction at room temperature for 5 days, followed by filtration to obtain a ziwo extract. The amount of dry solid was 1.28% by weight.

(Example 7)
This example is an example of a nerve growth factor production inhibitor containing a peony extract. 100 g of ethanol with a water content of 50% by volume was added to 10 g of dried and finely ground peonies roots, extracted at room temperature for 5 days, and then filtered to obtain a peonies extract. The amount of dry solids was 1.53% by weight.

(Example 8)
This example is an example of a nerve growth factor production inhibitor containing a gentian extract. A gentian extract was obtained by adding 100 ml of ethanol with a water content of 50% by volume to 10 g of dried and finely ground roots and stems of gentian, followed by extraction at room temperature for 5 days, followed by filtration. The amount of dry solid was 1.41% by weight.

Example 9
This example is an example of a nerve growth factor production inhibitor containing an orgon extract. To 10 g of dried and finely ground roots, 100 ml of ethanol with a water content of 50% by volume was added, followed by extraction at room temperature for 5 days, followed by filtration to obtain a hornon extract. The amount of dry solid was 1.35% by weight.

(Example 10)
This example is an example of a nerve growth factor production inhibitor containing a dandelion extract. To 10 g of dried and finely pulverized flowers, 100 ml of ethanol having a water content of 50% by volume was added, followed by extraction at room temperature for 5 days, followed by filtration to obtain an extract of dandelion. The amount of dry solid was 1.39% by weight.

(Example 11)
This example is an example of a nerve growth factor production inhibitor containing a clematis extract. To 10 g of dried and finely crushed leaves of clematis was added 100 ml of ethanol with a water content of 50% by volume, followed by extraction at room temperature for 5 days, followed by filtration to obtain a clematis extract. The amount of dry solid was 1.46% by weight.

(Example 12)
The present Example is an example of a nerve growth factor production inhibitor containing a Dokudami extract. To 10 g of dried and finely ground dokudami was added 100 ml of ethanol with a water content of 50% by volume, followed by extraction at room temperature for 5 days, followed by filtration to obtain a dokudami extract. The amount of dry solid was 1.28% by weight.

(Test Example 1)
This test example is a nerve growth factor suppression test using normal human dermal fibroblasts (NHDF). In this test example, the nerve growth factor production inhibitor consisting of Ages extract is targeted.

Normal human skin fibroblasts (NHDF) were cultured in Dulbecco's MEM medium (manufactured by Sigma) containing 10% fetal calf serum (manufactured at 56 ° C. for 30 minutes) at 37 ° C. and 5% CO ₂ . NHDF is suspended in Dulbecco's MEM medium containing 10% fetal bovine serum (56 ° C, treated for 30 minutes) at 10 ⁵ cells / ml, and 1 ml per well of the suspension is added to a 24-well microplate (IWAKI Dispensed).

  After culturing for 24 hours, the supernatant is removed by aspiration, and 10% fetal calf containing 0.2%, 0.1%, 0.05%, or 0.025% by volume of Ages extract prepared in advance. 450 μl of Dulbecco's MEM medium (manufactured by Sigma) containing serum (treated at 56 ° C. for 30 minutes, manufactured by ICN) was dispensed. After incubation for 30 minutes, 50 μl of Dulbecco's MEM medium (Sigma) solution containing 100 ng / ml human interleukin 1α / 10% fetal calf serum (56 ° C., 30 minutes treatment) was added, and further incubated for 24 hours. The culture supernatant was collected, and the nerve growth factor concentration in the culture supernatant was measured with NGF Emax Immunoassay kit (manufactured by Promega). The measurement was performed at N = 4 and expressed as an average value and a standard deviation. The result is shown in FIG.

  Whereas the release amount of nerve growth factor (NGF) (NGF concentration in the culture supernatant) into the culture supernatant of fibroblasts when no Agez extract was added was 10.28 pg / ml, The NGF concentration in the culture supernatant when the Ages extract was added was 8.96 pg / ml when 0.025% by volume was added, 7.57 pg / ml when 0.05% by volume was added, and 0.1% by volume. 5.47 pg / ml, 2.78 pg / ml when 0.2% by volume was added, both decreased the amount of NGF released into the culture supernatant (NGF concentration) compared to when no Agetsu extract was added . Therefore, it was found that NGF production was suppressed by adding Agetsu extract. It was also found that the NGF concentration decreased as the amount of added Age extract (volume%) increased, and the NGF production inhibitory effect increased.

(Test Example 2)
Nerve growth factor production inhibition test using NHDF was conducted in the same manner as in Example 1 above, targeting the nerve growth factor production inhibitor comprising the Novara extract of Example 2. The result is shown in FIG. The NGF concentration in the culture supernatant when the Novara extract was not added was 9.69 pg / ml, whereas the NGF concentration in the culture supernatant when the Novara extract was added was 0.025 vol. % Addition 8.23 pg / ml, 0.05 volume% addition 6.95 pg / ml, 0.1 volume% addition 3.68 pg / ml, 0.2 volume% addition 1.25 pg / ml, In either case, the amount of NGF released into the culture supernatant (NGF concentration) decreased compared to the case where no rose extract was added. Therefore, it was found that the production of NGF was suppressed by adding Novara extract. It was also found that the NGF concentration decreased as the added amount of Novara extract (volume%) increased, and the NGF production inhibitory effect increased.

(Test Example 3)
A nerve growth factor production inhibition test using NHDF was performed in the same manner as in Example 1 above, targeting the nerve growth factor production inhibitor comprising the rosemary extract of Example 3. The result is shown in FIG. The NGF concentration in the culture supernatant when the rosemary extract was not added was 11.33 pg / ml, whereas the NGF concentration in the culture supernatant when the rosemary extract was added was 0. 7.28 pg / ml with 025 vol% addition, 5.62 pg / ml with 0.05 vol% addition, 3.78 pg / ml with 0.1 vol% addition, 2.06 pg / ml with 0.2 vol% addition In both cases, the amount of NGF released into the culture supernatant (NGF concentration) decreased compared to the case where no rosemary extract was added. Therefore, it was found that NGF production was suppressed by adding the rosemary extract. It was also found that the NGF concentration decreased as the amount of rosemary extract added (volume%) increased, and the NGF production inhibitory effect increased.

(Test Example 4)
The NHDF nerve growth factor production inhibition test was conducted in the same manner as in Example 1 above, targeting the nerve growth factor production inhibitor comprising the enamel extract of Example 4. The result is shown in FIG. The NGF concentration in the culture supernatant in the absence of the addition of the enamel extract was 10.81 pg / ml, whereas the NGF concentration in the culture supernatant when the enamel extract was added was 0.025 volume. % Addition 9.38 pg / ml, 0.05 volume% addition 8.7 pg / ml, 0.1 volume% addition 7.05 pg / ml, 0.2 volume% addition 4.73 pg / ml, In either case, the amount of NGF released into the culture supernatant (NGF concentration) decreased as compared with the case where no enamel extract was added. Therefore, it was found that the production of NGF is suppressed by adding an enamel extract. It was also found that the NGF concentration decreased as the added amount (volume%) of the enamel extract increased, and the NGF production inhibitory effect increased.

(Test Example 5)
An NHDF nerve growth factor production inhibition test was conducted in the same manner as in Example 1 above, targeting nerve growth factor production inhibition comprising the clove extract of Example 5. The result is shown in FIG. The nerve growth factor production suppression test was conducted in the same manner as in Example 1 with the concentration of the clove extract added to the culture supernatant being 0.1% by volume, 0.05% by volume, or 0.025% by volume. The NGF concentration in the culture supernatant when the clove extract was not added was 15.51 pg / ml, whereas the NGF concentration in the culture supernatant when the clove extract was added was 0.025 vol. 6.0 pg / ml with 0.05% addition, 3.91 pg / ml with 0.05% addition by volume, and 1.04 pg / ml with addition of 0.1% by volume. The amount of NGF released into the supernatant (NGF concentration) decreased. Therefore, it was found that the production of NGF is suppressed by adding the clove extract. It was also found that the NGF concentration decreased as the amount of clove extract added (volume%) increased, and the NGF production inhibitory effect increased.

(Test Example 6)
The NHDF nerve growth factor production inhibition test was conducted in the same manner as in Example 1 above, targeting the nerve growth factor production inhibitor composed of the extract of Example 6. The result is shown in FIG. The NGF concentration in the culture supernatant in the case where no Diou extract was added was 27.25 pg / ml, whereas the NGF concentration in the culture supernatant when the Diou extract was added was 0.025 vol. % Addition 24.75 pg / ml, 0.05 volume% addition 23.08 pg / ml, 0.1 volume% addition 21.62 pg / ml, 0.2 volume% addition 16.91 pg / ml, In either case, the amount of NGF released into the culture supernatant (NGF concentration) decreased as compared with the case where no Geou extract was added. Therefore, it was found that the production of NGF is suppressed by the addition of the Geow extract. It was also found that the NGF concentration decreased as the added amount (volume%) of the geojoic extract increased, and the NGF production inhibitory effect increased.

(Test Example 7)
The NHDF nerve growth factor production inhibition test was conducted in the same manner as in Example 1 above, targeting the nerve growth factor production inhibitor comprising the peony extract of Example 7. The result is shown in FIG. The NGF concentration in the culture supernatant when the peony extract was not added was 17.46 pg / ml, whereas the NGF concentration in the culture supernatant when the peony extract was added was 0.025 volume. % Addition, 13.5 pg / ml, 0.05 volume% addition, 12.82 pg / ml, 0.1 volume% addition, 11.57 pg / ml, 0.2 volume% addition, 7.83 pg / ml, In either case, the amount of NGF released into the culture supernatant (NGF concentration) decreased compared to the case where no peony extract was added. Therefore, it was found that NGF production was suppressed by adding the peony extract. It was also found that the NGF concentration decreased and the NGF production inhibitory effect increased as the amount of peony extract added (volume%) increased.

(Test Example 8)
The NHDF nerve growth factor production inhibition test was conducted in the same manner as in Example 1 above, targeting the nerve growth factor production inhibitor comprising the gentian extract of Example 8. The result is shown in FIG. The NGF concentration in the culture supernatant when the gentian extract was not added was 14.53 pg / ml, whereas the NGF concentration in the culture supernatant when the gentian extract was added was 0.025 volume. % Addition, 13.61 pg / ml, 0.05 volume% addition, 12.04 pg / ml, 0.1 volume% addition, 10.63 pg / ml, 0.2 volume% addition, 8.3 pg / ml, In either case, the amount of NGF released into the culture supernatant (NGF concentration) decreased compared to the case where no gentian extract was added. Therefore, it was found that the production of NGF was suppressed by adding the gentian extract. It was also found that the NGF concentration decreased as the amount of gentian extract added (volume%) increased and the NGF production inhibitory effect increased.

(Test Example 9)
The NHDF nerve growth factor production inhibition test was conducted in the same manner as in Example 1 above, targeting the nerve growth factor production inhibitor comprising the urgonum extract of Example 9. The result is shown in FIG. The NGF concentration in the culture supernatant when the ougon extract was not added was 14.74 pg / ml, whereas the NGF concentration in the culture supernatant when the ougon extract was added was 0.025 volume. % Addition was 11.91 pg / ml, 0.05 volume% addition was 10.38 pg / ml, 0.1 volume% addition was 9.28 pg / ml, and 0.2 volume% addition was 6.17. The amount of NGF released into the culture supernatant (NGF concentration) was reduced compared to the case where no Augon extract was added. Therefore, it was found that the production of NGF is suppressed by adding the Augon extract. It was also found that the NGF concentration decreased as the added amount (volume%) of ougon extract increased, and the NGF production inhibitory effect increased.

(Test Example 10)
NHDF nerve growth factor production inhibition test was conducted in the same manner as in Example 1 above, targeting the nerve growth factor production inhibitor composed of the extract of dandelion in Example 10. The result is shown in FIG. The NGF concentration in the culture supernatant in the case where no Fuquidan popo extract was added was 14.55 pg / ml, whereas the NGF concentration in the culture supernatant when the Fuquidan popo extract was added was 0.025 volume. % Addition, 12.33 pg / ml, 0.05 volume% addition, 10.55 pg / ml, 0.1 volume% addition, 9.18 pg / ml, 0.2 volume% addition, 7.14 pg / ml, In either case, the amount of NGF released into the culture supernatant (NGF concentration) decreased as compared with the case where no extract of dandelion was added. Therefore, it was found that the production of NGF is suppressed by adding the dandelion extract. It was also found that the NGF concentration decreased and the NGF production inhibitory effect increased as the amount added (capacity%) of the Fukitan popo extract increased.

(Test Example 11)
The NHDF nerve growth factor production inhibition test was conducted in the same manner as in Example 1 above, targeting the nerve growth factor production inhibitor comprising the clematis extract of Example 11. The result is shown in FIG. The NGF concentration in the culture supernatant when the clematis extract was not added was 14.39 pg / ml, whereas the NGF concentration in the culture supernatant when the clematis extract was added was 0.025 volume. % Addition 12.52 pg / ml, 0.05 volume% addition 12.16 pg / ml, 0.1 volume% addition 9.88 pg / ml, 0.2 volume% addition 0.82 pg / ml, In either case, the amount of NGF released into the culture supernatant (NGF concentration) decreased as compared with the case where no clematis extract was added. Therefore, it was found that NGF production is suppressed by adding the clematis extract. It was also found that the NGF concentration decreased as the amount of clematis extract added (volume%) increased, and the NGF production inhibitory effect increased.

(Test Example 12)
The NHDF nerve growth factor production inhibition test was conducted in the same manner as in Example 1 above, targeting the nerve growth factor production inhibitor composed of the dokudami extract of Example 12. The result is shown in FIG. The NGF concentration in the culture supernatant in the case where the dokudami extract was not added was 25.28 pg / ml, whereas the NGF concentration in the culture supernatant when the dokudami extract was added was 0.025 volume. % Addition, 20.62 pg / ml, 0.05 volume% addition, 21.84 pg / ml, 0.1 volume% addition, 20.62 pg / ml, 0.2 volume% addition, 17.16 pg / ml, In either case, the amount of NGF released into the culture supernatant (NGF concentration) decreased as compared with the case where no Dokudami extract was added. Therefore, it was found that the production of NGF is suppressed by adding the mandarin extract. It was also found that the NGF concentration decreased as the added amount (volume%) of the mandarin extract increased, and the NGF production inhibitory effect increased.

(Test Example 13)
This test example is a test of the inhibitory effect on mouse contact dermatitis. Seven-week-old BALB / c male mice were purchased from SLC Co., Ltd. and raised under conditions of room temperature 23 ± 3 ° C., humidity 55 ± 15%, light / dark cycle 12 hours (light period 7:00 to 19:00) did. Novara extract was administered 30 minutes after sensitization (N = 5). A 0.1% ml of 5% picryl chloride-ethanol solution was applied to the abdominal skin of a mouse that had been shaved on that day, and sensitized. Five days later, 20 μl of a 1% picryl chloride-acetone: olive oil (4: 1) solution was applied to both sides of the left auricle skin to induce an allergic reaction.

  Thirty minutes after the induction of allergic reaction, 50 μl of 5% by volume Novara extract solution prepared with 50% by volume ethanol solution was administered to the mouse auricle. The control group was similarly administered with 50 μl of a 50 vol% ethanol solution. The thickness of the left pinna was measured with a micrometer (MITUTOYO) before and 24 hours after the allergic reaction was induced, and the pinna edema suppression rate was determined from the pinna edema rate. The t-test was performed as a significant difference test between each group. The test results are shown in FIG.

  As apparent from FIG. 13, the ear edema rate in the subject group was 61.6 ± 13.9%, whereas the ear edema rate in the Novara extract administration group was 42.9 ± 6.7. % (P = 0.022). By administration of Novara extract, auricular edema was significantly suppressed. The above test is used as a screening for atopic dermatitis and hay fever.

(Test Example 14)
This test example is an itching suppression test using NC / Nga mice. NC / Nga mice are conventional grade animals and are atopic dermatitis model mice that spontaneously develop atopic dermatitis, and induce itching with the onset of atopy. Ten 4-week old NC / Nga male mice were purchased from Charles River Japan, room temperature 23 ± 3 ° C, humidity 55 ± 15%, light / dark cycle 12 hours (light period 7:00 to 19:00) Were bred under the following conditions. The mice were 5 cages per cage, and after preliminary breeding, animals that developed atopic dermatitis were subjected to the following experiment as 5 animals per group. Novara extract was set as a group for 5 consecutive days (N = 5).

  The back of the mouse was shaved with a clipper and an electric shaver, and 150 μl of a 5% by volume Novara extract solution prepared with a 50% by volume ethanol solution was applied and administered twice a day, 5 times a week. The control group was similarly administered with 150 μl of a 50 vol% ethanol solution. At the end of the test, the number of scratches of each mouse for 20 minutes was measured. The measured value was expressed as an average value and a standard deviation. A significant difference test between each group was performed by t-test, and a risk rate of 5% or less was considered significant.

  The test results are shown in FIG. In the measurement of the number of scratches for 20 minutes at the end of the test, the control group was 272 ± 92 times and the Novara extract-administered group was 121 ± 79 times, and a significant decrease in the number of scratches was observed.

(Prescription Example 1)
This prescription example is a prescription example of a cream as an example of cosmetics, and its composition is as follows.

Composition ratio (wt%)
Cetanol 2.5%
Squalene 10.0%
White beeswax 1.0%
Glyceryl trioctanoate 5.0%
Octyldodecyl myristate 15.0%
Tocopherol acetate 0.1%
1,3-butylene glycol 7.0%
Glycerol monostearate 3.0%
POE (20) sorbitan monostearate 1.0%
Sorbitan monostearate 2.0%
Novara extract 0.1%
Concentrated glycerin 5.0%
Butyl paraoxybenzoate 0.1%
Ethyl paraoxybenzoate 0.2%
Purified water remaining

  Among the above ingredients, cetanol, squalene, white beeswax, octyldodecyl myristate are dissolved by heating, and then glyceryl trioctanoate, tocopherol acetate, glyceryl monostearate, POE (20) sorbitan monostearate (surfactant), sorbitan mono Stearate was added, adjusted to 70 ° C., and uniformly dispersed and dissolved to obtain an oily gel. Next, after dissolving Novara extract, 1,3-butylene glycol, concentrated glycerin, butyl paraoxybenzoate (preservative), ethyl paraoxybenzoate (preservative) in purified water of a predetermined concentration and adjusting to 70 ° C., Slowly added into the oily gel with thorough stirring. After uniformly mixing with a homomixer, the mixture was deaerated and filtered, and then cooled to 30 ° C. to obtain a cream.

(Prescription example 2)
This prescription example is also a cream prescription example, but the composition is the same as that of prescription example 1 except that the compounding amount of Novara extract as a nerve growth factor production inhibitor is larger than that of prescription example 1. Its composition is as follows. The cream was prepared in the same manner as in Formulation Example 1 above.

Composition ratio (wt%)
Cetanol 2.5%
Squalene 10.0%
White beeswax 1.0%
Glyceryl trioctanoate 5.0%
Octyldodecyl myristate 15.0%
Tocopherol acetate 0.1%
1,3-butylene glycol 7.0%
Glycerol monostearate 3.0%
POE (20) sorbitan monostearate 1.0%
Sorbitan monostearate 2.0%
Novara extract 0.5%
Concentrated glycerin 5.0%
Butyl paraoxybenzoate 0.1%
Ethyl paraoxybenzoate 0.2%
Purified water remaining

(Prescription Example 3)
This prescription example is also a cream prescription example, but the composition is the same as prescription examples 1 and 2 except that the amount of Novara extract as a nerve growth factor production inhibitor is larger than that of prescription examples 1 and 2 above. is there. Its composition is as follows. The cream was prepared in the same manner as in Formulation Example 1 above.

Composition ratio (wt%)
Cetanol 2.5%
Squalene 10.0%
White beeswax 1.0%
Glyceryl trioctanoate 5.0%
Octyldodecyl myristate 15.0%
Tocopherol acetate 0.1%
1,3-butylene glycol 7.0%
Glycerol monostearate 3.0%
POE (20) sorbitan monostearate 1.0%
Sorbitan monostearate 2.0%
Novara extract 1.0%
Concentrated glycerin 5.0%
Butyl paraoxybenzoate 0.1%
Ethyl paraoxybenzoate 0.2%
Purified water remaining

(Prescription Example 4)
This prescription example is also a cream prescription example, but is different from prescription example 1 using Novara extract in that Ages extract is used as a nerve growth factor production inhibitor. Its composition is as follows. The cream was prepared in the same manner as in Formulation Example 1 above.

Composition ratio (wt%)
Cetanol 2.5%
Squalene 10.0%
White beeswax 1.0%
Glyceryl trioctanoate 5.0%
Octyldodecyl myristate 15.0%
Tocopherol acetate 0.1%
1,3-butylene glycol 7.0%
Glycerol monostearate 3.0%
POE (20) sorbitan monostearate 1.0%
Sorbitan monostearate 2.0%
Ages extract 0.5%
Concentrated glycerin 5.0%
Butyl paraoxybenzoate 0.1%
Ethyl paraoxybenzoate 0.2%
Purified water remaining

(Prescription Example 5)
Although this prescription example is also a prescription example of cream, the point which used the rosemary extract as a nerve growth factor production inhibitor is different from each said prescription example. Its composition is as follows. The cream was prepared in the same manner as in Formulation Example 1 above.

Composition ratio (wt%)
Cetanol 2.5%
Squalene 10.0%
White beeswax 1.0%
Glyceryl trioctanoate 5.0%
Octyldodecyl myristate 15.0%
Tocopherol acetate 0.1%
1,3-butylene glycol 7.0%
Glycerol monostearate 3.0%
POE (20) sorbitan monostearate 1.0%
Sorbitan monostearate 2.0%
Rosemary extract 0.5%
Concentrated glycerin 5.0%
Butyl paraoxybenzoate 0.1%
Ethyl paraoxybenzoate 0.2%
Purified water remaining

(Prescription Example 6)
This formulation example is also a cream formulation example, but is different from each of the above formulation examples in that an enamel extract is used as a nerve growth factor production inhibitor. Its composition is as follows. The cream was prepared in the same manner as in Formulation Example 1 above.

Composition ratio (wt%)
Cetanol 2.5%
Squalene 10.0%
White beeswax 1.0%
Glyceryl trioctanoate 5.0%
Octyldodecyl myristate 15.0%
Tocopherol acetate 0.1%
1,3-butylene glycol 7.0%
Glycerol monostearate 3.0%
POE (20) sorbitan monostearate 1.0%
Sorbitan monostearate 2.0%
Nymphaea extract 0.5%
Concentrated glycerin 5.0%
Butyl paraoxybenzoate 0.1%
Ethyl paraoxybenzoate 0.2%
Purified water remaining

(Test Example 16)
In this test example, the itching suppression test was performed on the creams of the above-mentioned prescription examples 1 to 3.
The test method is as follows. The creams of Formulation Examples 1 to 3 were applied twice a day for 3 months to 25 female subjects (25 to 45 years old) who complain of skin itchiness associated with dryness. Evaluation was shown by the number of people who answered that they no longer feel itchy skin. On the other hand, the same test as Comparative Example 1 was performed with the cream having the following composition having the same cream base composition as in the above Formulation Examples 1 to 3 and not containing a plant extract.

(Comparative Example 1)
Composition ratio (wt%)
Cetanol 2.5%
Squalene 10.0%
White beeswax 1.0%
Glyceryl trioctanoate 5.0%
Octyldodecyl myristate 15.0%
Tocopherol acetate 0.1%
1,3-butylene glycol 7.0%
Glycerol monostearate 3.0%
POE (20) sorbitan monostearate 1.0%
Sorbitan monostearate 2.0%
Concentrated glycerin 5.0%
Butyl paraoxybenzoate 0.1%
Ethyl paraoxybenzoate 0.2%
Purified water remaining

  The test results are shown in Table 1.

  As is apparent from Table 1, in the prescription example 1, the number of people who answered that they no longer feel itchy skin was slightly higher than in the comparative example 1, but in the prescription example 2, the number of persons compared to the comparative example 1 About 2 times, and in Formulation Example 3, it was about 3 times.

(Test Example 17)
This test example is an inflammation suppression test using ultraviolet rays. Using the creams of the above Formulation Examples 1 to 3, the effect of improving inflammation was tested. On the other hand, Inteban cream (Sumitomo Pharmaceutical Co., Ltd.), which is a pharmaceutical compounded with indomethacin, which is one of anti-inflammatory agents, as a positive target was used as Comparative Example 2.

〔Test method〕
A 4-week-old Hartley guinea pig was purchased from SLC, and was raised under conditions of room temperature 23 ± 3 ° C., humidity 55 ± 15%, and light / dark cycle 12 hours (light period 7:00 to 19:00). The back of the guinea pig was shaved with a clipper and an electric shaver, and the samples of Formulation Examples 1 to 3 and Comparative Examples 1 and 2 were used continuously for 3 days on a shaved part 2 cm × 2 cm) and irradiated with ultraviolet rays. The skin color at the ultraviolet irradiation site was measured using a color difference meter. The skin erythema was shown as an a * value that was calculated by comparing the case of Comparative Example 1 with 100.

  The test results are shown in Table 2.

  As is apparent from Table 2, the a * value was slightly reduced in Comparative Example 1 as compared to Comparative Example 1, but the a * value was reduced by approximately 30% in Comparative Example 2 compared to Comparative Example 1. In Formulation Example 3, it was reduced to about half. However, it did not reach the reduction rate of Comparative Example 2. However, it is generally known that the indomethacin of Comparative Example 2 has side effects, and it is recognized that those of Formulation Examples 1 to 3 are superior to Comparative Example 2 in terms of safety.

  The nerve growth factor production inhibitor of the present invention can be widely applied to skin external preparations, cosmetics, quasi-drugs, etc., and from the viewpoint of use, it is a therapeutic agent for atopic dermatitis, itching prevention In addition, it can be widely applied to therapeutic agents, compositions having an effect of improving rough skin due to allergies, and the like.

It is a nerve growth factor suppression test using normal human skin fibroblasts (NHDF), Comprising: The graph which shows the correlation with the density | concentration of Ages extract, and the release amount of NGF. It is a nerve growth factor suppression test using normal human skin fibroblasts (NHDF), Comprising: The graph which shows the correlation with the density | concentration of a Novara extract, and the release amount of NGF. It is a nerve growth factor suppression test using normal human skin fibroblasts (NHDF), and is a graph showing the correlation between the concentration of rosemary extract and the amount of NGF released. It is a nerve growth factor suppression test using normal human dermal fibroblasts (NHDF), and is a graph showing the correlation between the concentration of enamel extract and the amount of NGF released. It is a nerve growth factor suppression test using normal human skin fibroblasts (NHDF), Comprising: The graph which shows the correlation with the density | concentration of a clove extract, and the release amount of NGF. It is a nerve growth factor suppression test using normal human skin fibroblasts (NHDF), Comprising: The graph which shows the correlation with the density | concentration of a Giant extract and the release amount of NGF. The graph which shows the nerve growth factor suppression test using normal human skin fibroblasts (NHDF), Comprising: The correlation of the density | concentration of a peony extract and the release amount of NGF. It is a nerve growth factor suppression test using normal human skin fibroblasts (NHDF), Comprising: The graph which shows the correlation with the density | concentration of a gentian extract, and the release amount of NGF. It is a nerve growth factor suppression test using normal human skin fibroblasts (NHDF), and is a graph showing the correlation between the concentration of ougon extract and the amount of NGF released. It is a nerve growth factor suppression test using normal human skin fibroblasts (NHDF), and is a graph showing the correlation between the concentration of the extract of Fukidan popo and the amount of NGF released. It is a nerve growth factor suppression test using normal human skin fibroblasts (NHDF), Comprising: The graph which shows the correlation with the density | concentration of a clematis extract, and the release amount of NGF. The nerve growth factor suppression test using normal human skin fibroblasts (NHDF), Comprising: The graph which shows the correlation with the density | concentration of Dokudami extract, and the release amount of NGF. The graph which shows the inhibitory effect with respect to mouse contact dermatitis. The graph which shows the itch suppression effect using NC / Nga mouse.

Claims (6)

  Choose from Ages extract, Novara extract, Rosemary extract, Enmezo extract, Clove extract, Ginger extract, Peonies extract, Gentian extract, Ogon extract, Fukidan popo extract, Clematis extract and Dokdami extract A nerve growth factor production inhibitor characterized by comprising at least one selected from the group consisting of:   An external preparation for skin, comprising the nerve growth factor production inhibitor according to claim 1.   A cosmetic comprising the nerve growth factor production inhibitor according to claim 1.   A quasi-drug containing the nerve growth factor production inhibitor according to claim 1.   An agent for preventing and treating itchiness comprising the nerve growth factor production inhibitor according to claim 1.   The therapeutic agent for atopic dermatitis which mix | blended the nerve growth factor production inhibitor of Claim 1.

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