WO2011040082A1 - ラミニン332産生促進組成物 - Google Patents
ラミニン332産生促進組成物 Download PDFInfo
- Publication number
- WO2011040082A1 WO2011040082A1 PCT/JP2010/058219 JP2010058219W WO2011040082A1 WO 2011040082 A1 WO2011040082 A1 WO 2011040082A1 JP 2010058219 W JP2010058219 W JP 2010058219W WO 2011040082 A1 WO2011040082 A1 WO 2011040082A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alanine
- hydroxyproline
- laminin
- composition
- production
- Prior art date
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-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Definitions
- the present invention relates to a composition for promoting laminin 332 production comprising one or more compounds selected from the group consisting of D-alanine and D-hydroxyproline, and derivatives and / or salts thereof,
- the present invention relates to a method for suppressing and / or ameliorating a skin disorder including an administering step.
- Laminin is a three-chain protein consisting of an ⁇ chain, a ⁇ chain, and a ⁇ chain, and it is known that at least 15 isomers exist in a combination of 5 types of ⁇ chain, 3 types of ⁇ chain, and 3 types of ⁇ chain. Yes. Among them, laminin 332 ( ⁇ 3 ⁇ 3 ⁇ 2, laminin 5 in the previous nomenclature) is abundant in the basement membrane that separates the epidermis from the dermis, and is considered to play an important role in the structure and function of the skin (non-patent literature). 1).
- Laminin 332 knockout mice have a phenotype similar to that of connective epidermolysis bullosa, a human hereditary disease in which epidermis and dermis separate and form blisters, and laminin 332 is essential for adhesion between epidermis and dermis (Non-Patent Document 2).
- Non-Patent Document 2 when a purified sample of laminin 332 is added to a skin equivalent model in which keratinocytes are cultured on a collagen gel in which human fibroblasts are embedded, basement membrane formation is enhanced.
- Activated proteolytic enzyme plasmin produced in epidermal cells cleaves the amino-terminal and carboxyl-terminal peptides of the ⁇ 3 subunit of laminin 332 and the amino-terminal peptide of the ⁇ 3 subunit.
- Each of the cleaved fragments includes a recognition site for a cell adhesion molecule and a binding site for type 7 collagen.
- laminin 332 digested with plasmin has a reduced ability to adhere to corneocytes.
- laminin 332 digested with plasmin has a reduced affinity with type 7 collagen. Therefore, it is considered that aging of the skin by ultraviolet irradiation or the like involves laminin 332 digestion by plasmin and a decrease in the function of the basement membrane due to this (Non-patent Document 4).
- HIF1 Non-patent Document 5
- Smad4 Non-patent Document 6
- HIF1 is a transcriptional regulator that responds to environmental stimuli such as oxygen deprivation and mechanical stimuli, and is also up-regulated by proinflammatory cytokines.
- Smad4 is a transcriptional regulatory factor involved in TGF ⁇ signaling.
- the present invention provides a composition for promoting production of laminin 332 comprising one or more compounds selected from the group consisting of D-alanine and D-hydroxyproline and derivatives and / or salts thereof.
- the laminin 332 production promoting composition of the present invention may be used to suppress and / or improve the skin condition.
- the skin condition includes, but is not limited to, photoaging, wrinkles, rough skin, fine wrinkles and dryness.
- the laminin 332 production promoting composition of the present invention may be used as a medicine.
- the laminin 332 production promoting composition of the present invention may be used as an external preparation for skin.
- the laminin 332 production promoting composition of the present invention may be used as food.
- the present invention comprises the step of administering a laminin 332 production promoting composition comprising one or more compounds selected from the group consisting of D-alanine and D-hydroxyproline, and derivatives and / or salts thereof.
- a laminin 332 production promoting composition comprising one or more compounds selected from the group consisting of D-alanine and D-hydroxyproline, and derivatives and / or salts thereof.
- Skin conditions that are suppressed and / or improved by the method of the present invention include, but are not limited to, photoaging, wrinkles, rough skin, fine wrinkles and dryness.
- the laminin 332 production promoting composition may be a pharmaceutical product.
- the laminin 332 production promoting composition may be a skin external preparation.
- the laminin 332 production promoting composition may be a food composition.
- salts of D-alanine and D-hydroxyproline include metal salts, amine salts and the like, provided that the promoting effect of laminin 332 production of D-alanine and D-hydroxyproline is not impaired.
- the metal salt may include an alkali metal salt, an alkaline earth metal salt, and the like.
- the amine salt may include a triethylamine salt, a benzylamine salt, or the like.
- D-alanine and D-hydroxyproline refer to D-alanine and D-hydroxyproline on the condition that the promoting effect of laminin 332 production by D-alanine and D-hydroxyproline is not impaired.
- the molecule is covalently bonded to any atomic group in the amino group, carboxyl group or side chain.
- Any of the atomic groups includes a protecting group such as an N-phenylacetyl group or a 4,4′-dimethoxytrityl (DMT) group, and a biopolymer such as a protein, peptide, sugar, lipid, nucleic acid, or the like.
- Synthetic polymers such as polystyrene, polyethylene, polyvinyl, and polyester, and functional groups such as ester groups, but are not limited thereto.
- the ester group may include, for example, methyl ester, ethyl ester, other aliphatic esters, or aromatic esters.
- Amino acids have L-isomers and D-isomers as optical isomers, but natural proteins are L-amino acids with peptide bonds, and only L-amino acids are used with the exception of bacterial cell walls. Therefore, it has been considered that mammals including humans have only L-amino acids and use only L-amino acids.
- D-amino acids are used as a starting material for antibiotics produced by bacteria, and when L-amino acids and D-amino acid mixtures obtained in equal amounts when amino acids are chemically synthesized are L-
- L-amino acids and D-amino acid mixtures obtained in equal amounts when amino acids are chemically synthesized are L-
- D-amino acid is used as it is as a DL-amino acid mixture in order to save the cost of fractionating only amino acids.
- only D-amino acids are used industrially as a substance having physiological activity.
- D-Serine and D-aspartic acid are relatively researched due to the high proportion of D-form.
- D-serine is localized in the cerebrum and hippocampus and has been clarified as a regulator of NMDA receptors in the brain.
- D-aspartic acid is found to be localized in the testis and pineal gland and has been shown to be involved in the regulation of hormone secretion (Japanese Patent Laid-Open No. 2005-3558). However, the physiological effects of D-alanine and D-hydroxyproline in the skin have not been clarified.
- the laminin 332 production promoting composition of the present invention containing D-alanine and / or D-hydroxyproline is a novel invention.
- the D-alanine of the present invention has the effect of promoting laminin 332 production at a concentration of 0.1 ⁇ M to 1 ⁇ M for cultured human epidermal keratinocytes, as shown in the following examples. Therefore, the amount of D-alanine contained in the skin symptom improving agent, external preparation for skin, and food composition of the present invention is such that D-alanine in this concentration range is delivered to fibroblasts in living skin tissue. As long as the above conditions are satisfied, any content may be used. When the composition of the present invention is an external preparation, the content of D-alanine may be in the range of 0.000015 wt% to 50 wt% or the maximum weight concentration that can be blended in the total amount of the composition of the present invention. .
- the content of D-alanine is preferably 0.00003 wt% to 30 wt%, and most preferably 0.0003 wt% to 3 wt%.
- the D-alanine content may be in the range of 0.00001 wt% to 100 wt%.
- the content of D-alanine is preferably 0.00002 wt% to 80 wt%, and most preferably 0.0002 wt% to 60 wt%.
- the lower limit of the daily intake of D-alanine contained in the composition of the present invention may be 0.01 ng per kg body weight, preferably 0.1 ng, more preferably 1 ng.
- the D-hydroxyproline of the present invention has an effect of promoting laminin 332 production at a concentration of 0.1 ⁇ M to 1 ⁇ M on cultured human epidermal keratinocytes as shown in the following examples. Therefore, the amount of D-hydroxyproline contained in the skin symptom improving agent, the external preparation for skin, and the food composition of the present invention is such that D-hydroxyproline in this concentration range is delivered to fibroblasts in living skin tissue. However, any content is acceptable. When the composition of the present invention is an external preparation, the content of D-hydroxyproline is in the range from 0.000015 wt% to 50 wt% or the maximum weight concentration that can be blended in the total amount of the composition of the present invention. Good.
- the content of D-hydroxyproline is preferably 0.00003 wt% to 30 wt%, and most preferably 0.0003 wt% to 3 wt%.
- the content of D-hydroxyproline may be in the range of 0.00001 wt% to 100 wt%.
- the content of D-hydroxyproline is preferably 0.00002 wt% to 80 wt%, and most preferably 0.0002 wt% to 60 wt%.
- the lower limit of the daily intake of D-hydroxyproline contained in the composition of the present invention may be 0.01 ng per kg body weight, preferably 0.1 ng, more preferably 1 ng.
- D-alanine and D-hydroxyproline In addition to D-alanine and D-hydroxyproline, salts of D-alanine and D-hydroxyproline, and / or derivatives capable of releasing D-alanine by drug metabolizing enzymes and the like in vivo, It may further contain one or more pharmaceutically acceptable additives provided that it does not impair the promoting effect of D-alanine and D-hydroxyproline on laminin 332 production.
- the additives include diluents and swelling agents, binders and adhesives, lubricants, glidants, plasticizers, disintegrants, carrier solvents, buffering agents, colorants, fragrances, Includes, but is not limited to, sweeteners, preservatives and stabilizers, adsorbents, and other pharmaceutical additives known to those skilled in the art.
- the composition of the present invention contains D-alanine and D-hydroxyproline, D-alanine and D-hydroxyproline salts as active ingredients, and / or D-alanine and D-hydroxy by drug metabolizing enzymes and the like in vivo.
- the components can be appropriately blended as necessary.
- the other components include oils, surfactants, powders, coloring materials, water, alcohols, thickeners, chelating agents, silicones, antioxidants, ultraviolet absorbers, and humectants. , Fragrances, various medicinal ingredients, preservatives, pH adjusters, neutralizers and the like.
- the dosage form of the composition for promoting production of laminin 332 (hereinafter referred to as “skin condition improving agent”) used for suppressing and / or improving the skin condition of the present invention is, for example, an ointment, cream, emulsion, lotion, pack,
- a conventional quasi-drug composition comprising an external preparation such as a gel or a patch, an oral preparation such as powder, granule, soft capsule or tablet, a nasal preparation such as nasal spray, and an injection.
- any material may be used as long as it is used for a pharmaceutical composition.
- the dosage form of the external preparation for skin of the present invention may be any form as long as it is used for conventional external preparations for skin including ointments, creams, emulsions, lotions, packs, gels, patches and the like.
- the food composition of the present invention releases D-alanine and D-hydroxyproline by D-alanine and D-hydroxyproline, D-alanine and D-hydroxyproline salts, and / or drug metabolizing enzymes and the like in vivo.
- it may contain seasonings, colorants, preservatives and other food-acceptable ingredients, provided that the promoting effect of D-alanine and D-hydroxyproline on laminin 332 production is not impaired. .
- the food composition of the present invention is used in conventional food compositions such as candy, cookies, miso, French dressing, mayonnaise, French bread, soy sauce, yogurt, sprinkle, seasoning / natto sauce, natto, moromi black vinegar, etc. Any material can be used, and the present invention is not limited to the above examples.
- the graph which shows the influence of D-alanine with respect to KC cell Graph showing the effect of D-alanine on laminin 332 production in KC cells.
- the graph which shows the influence of D-alanine with respect to a HaCaT cell The graph which shows the influence of D-hydroxyproline with respect to HaCaT cell.
- Graph showing the effect of D-alanine on laminin 332 production in HaCaT cells Graph showing the effect of D-hydroxyproline on laminin 332 production in HaCaT cells.
- Cells Cells include HaCaT cells derived from human epidermal cells (H. Hans et al., Experimental Cell Research 239: 399 (1998)) and KC cells derived from human keratinocytes (Sanko Junyaku Co., Ltd.) , Manufacturer: LONZA Walkersville Inc.). The cells are seeded at a density of 4 ⁇ 10 4 per well in a 24-well plate, and a medium in which BSA is added to cell culture medium (D-MEM (1 g / L glucose), Wako Pure Chemical Industries, Ltd.) at 0.1%. (Hereinafter, referred to as “normal medium”) was cultured at 37 ° C., 5% CO 2 and saturated water vapor atmosphere for 24 hours.
- D-MEM cell culture medium
- the cells are either 1 ⁇ M of L- or D-alanine, 0.5 ⁇ M of both L- and D-alanine, 1 ⁇ M of L- or D-hydroxyproline, Both L- and D-hydroxyproline at 0.5 ⁇ M were added to the above-mentioned normal medium and cultured for 24 hours.
- the normal medium without the addition of alanine and hydroxyproline was used as a negative control.
- the D-hydroxyproline used in this example was 4-cis-D-hydroxyproline.
- the ELISA method is a sandwich ELISA method using BM165 which is a monoclonal antibody against the ⁇ 3 chain of laminin 5 and a biotinylated conjugate of 6F12 which is a monoclonal antibody against the ⁇ 3 chain of laminin 5, which is a horseradish peroxidase-labeled avidin D ( Detected by Vector Labs, catalog number A-2004). PBS was used as a control.
- FIG. 1 shows the experimental results of examining the influence of alanine addition on the proliferation of KC cells.
- the error bar for each experimental condition indicates the standard deviation of the measured value of the experimental result repeated three times under the same condition.
- the relative value (hereinafter the same) of the fluorescence intensity of the negative control alamarBlue (trademark) was 50.
- the fluorescence intensities of KC cells cultured in 1 ⁇ M L-alanine supplemented medium, 1 ⁇ M D-alanine supplemented medium, and 0.5 ⁇ M each of L- and D-alanine supplemented medium were 40, 45, and 50, respectively.
- Met the fluorescence intensity of alamarBlue TM in cells cultured in an alanine-added medium was not significantly different in the Tukey-Kramer test compared to the negative control. Thus, it was shown that L- and D-alanine are not cytotoxic to KC cells.
- FIG. 2 shows the results of experiments examining the effect of alanine addition on laminin 332 production by KC cells.
- the vertical axis of the graph of FIG. 2 is a quotient obtained by dividing the absorbance of ELISA measurement proportional to the concentration of laminin 332 in the culture supernatant of each well by the fluorescence intensity of alamarBlue (trademark) proportional to the number of cells in each well (hereinafter referred to as the quotient). , “Relative value of laminin 332 concentration per number of cells”).
- the error bar for each experimental condition indicates the standard deviation of the calculated value of the experimental result repeated three times under the same condition.
- An asterisk (**) indicates that p is less than 1% in the Tukey-Kramer test.
- the relative value of laminin 332 concentration per cell number was 0.35 in the negative control.
- the relative value of laminin 332 concentration per cell number of KC cells cultured in 1 ⁇ M L-alanine supplemented medium, 1 ⁇ M D-alanine supplemented medium, and 0.5 ⁇ M each of L- and D-alanine supplemented medium is , 0.40, 0.50 and 0.45, respectively.
- the promotion of laminin 332 production in KC cells by adding D-alanine was proved.
- FIG. 3 and FIG. 4 show the experimental results of examining the effects of addition of alanine and hydroxyproline on the growth of HaCaT cells.
- D-hydroxyproline (D-Hyp) refers to 4-cis-D-hydroxyproline.
- the error bar for each experimental condition indicates the standard deviation of the measured value of the experimental result repeated three times under the same condition.
- the fluorescence intensity of negative control alamarBlue (trademark) was 300.
- the fluorescence intensity of HaCaT cells cultured in 1 ⁇ M L-alanine-added medium, 1 ⁇ M D-alanine-added medium, and 0.5 ⁇ M each of L- and D-alanine-added medium was 250 (FIG. 5).
- the fluorescence intensity of HaCaT cells cultured in 1 ⁇ M L-hydroxyproline supplemented medium, 1 ⁇ M D-hydroxyproline supplemented medium, and 0.5 ⁇ M each of L- and D-hydroxyproline supplemented medium was 280. (FIG. 4).
- FIG. 5 shows the experimental results of examining the effect of alanine addition on laminin 332 production in HaCaT cells.
- the vertical axis of the graph of FIG. 5 shows the relative value of laminin 332 concentration per number of cells in the culture supernatant of each well.
- the error bar for each experimental condition indicates the standard deviation of the calculated value of the experimental result repeated three times under the same condition.
- An asterisk (**) indicates that p is less than 1% in the Scheffe's F-test, and an asterisk (*) indicates that p is less than 5%.
- the relative value of laminin 332 concentration per cell number was 0.04 in the negative control.
- the relative value of laminin 332 concentration per number of HaCaT cells cultured in 1 ⁇ M L-alanine supplemented medium, 1 ⁇ M D-alanine supplemented medium, and 0.5 ⁇ M each of L- and D-alanine supplemented medium is , 0.07, 0.11 and 0.10, respectively.
- p was less than 1% between the addition of 1 ⁇ M D-alanine and the negative control, and between the addition of 0.5 ⁇ M D-alanine and L-alanine and the negative control, Scheffe's.
- FIG. 6 shows the experimental results of examining the effect of hydroxyproline addition on the production of laminin 332 in HaCaT cells.
- the vertical axis of the graph of FIG. 6 shows the relative value of laminin 332 concentration per number of cells in the culture supernatant of each well.
- the error bar for each experimental condition indicates the standard deviation of the calculated value of the experimental result repeated three times under the same condition.
- laminin 332 concentration per cell number was 0.04 in the negative control.
- the relative values were 0.05, 0.065 and 0.06, respectively.
- FIG. 7 shows the experimental results of examining the effects of adding various concentrations of alanine on the production of laminin 332 in HaCaT cells.
- the vertical axis of the graph in FIG. 7 indicates the laminin 332 concentration (ng / mL) in the culture supernatant of each well.
- the error bar of each experimental condition indicates the standard deviation of the calculated value of the experimental result repeated four times under the same condition.
- the laminin 332 concentration was 1.7 ng / mL in the negative control.
- the laminin 332 concentrations of HaCaT cells cultured in 10 nM, 100 nM and 1000 nM L-alanine and D-alanine supplemented media were 1.7 ng / mL and 1.7 ng / mL, 2.3 ng / mL and 3.4 ng / mL, 2.8 ng / mL and 4.8 ng / mL. From the above results, it was shown that D-alanine promotes laminin 332 production at a concentration of 100 ng / mL or more.
- FIG. 8 shows the experimental results of examining the effects of various concentrations of hydroxyproline on the production of laminin 332 in HaCaT cells.
- the vertical axis of the graph in FIG. 8 indicates the laminin 332 concentration (ng / mL) in the culture supernatant of each well.
- the error bar of each experimental condition indicates the standard deviation of the calculated value of the experimental result repeated four times under the same condition.
- the laminin 332 concentration was 1.5 ng / mL in the negative control.
- the laminin 332 concentrations of HaCaT cells cultured in 10 nM, 100 nM and 1000 nM L-hydroxyproline and D-hydroxyproline supplemented media were 1.5 ng / mL and 1.5 ng / mL and 2.3 ng / mL, respectively.
- FIG. 9 shows the experimental results of examining the effects of various concentrations of aspartic acid on the production of laminin 332 in HaCaT cells.
- the vertical axis of the graph in FIG. 9 indicates the laminin 332 concentration (ng / mL) in the culture supernatant of each well.
- the error bar of each experimental condition indicates the standard deviation of the calculated value of the experimental result repeated four times under the same condition.
- the laminin 332 concentration was 1.7 ng / mL in the negative control.
- the laminin 332 concentrations of HaCaT cells cultured in 10 nM, 100 nM and 1000 nM L-aspartic acid-added medium and D-aspartic acid-added medium were 1.8 ng / mL and 1.9 ng / mL and 1.8 ng / mL, respectively.
- FIG. 10 shows the experimental results of examining the effects of adding various concentrations of asparagine on the production of laminin 332 in HaCaT cells.
- the vertical axis of the graph in FIG. 10 indicates the laminin 332 concentration (ng / mL) in the culture supernatant of each well.
- the error bar of each experimental condition indicates the standard deviation of the calculated value of the experimental result repeated four times under the same condition.
- the laminin 332 concentration was 1.5 ng / mL in the negative control.
- the laminin 332 concentrations of HaCaT cells cultured in 10 nM, 100 nM and 1000 nM L-asparagine and D-asparagine supplemented media were 1.6 ng / mL and 1.5 ng / mL, 1.5 ng / mL and 1.5 ng / mL, 1.6 ng / mL and 1.5 ng / mL. From the above results, it was shown that L- and D-asparagine do not promote laminin 332 production.
- FIG. 11 shows the experimental results of examining the effect of addition of various concentrations of proline on the production of laminin 332 in HaCaT cells.
- the vertical axis of the graph in FIG. 11 indicates the laminin 332 concentration (ng / mL) in the culture supernatant of each well.
- the error bar of each experimental condition indicates the standard deviation of the calculated value of the experimental result repeated four times under the same condition.
- the laminin 332 concentration was 1.8 ng / mL in the negative control.
- the laminin 332 concentrations of HaCaT cells cultured in 10 nM, 100 nM and 1000 nM L-proline and D-proline supplemented media were 1.8 ng / mL and 2.0 ng / mL, 1.9 ng / mL and 1.9 ng / mL, 1.9 ng / mL and 1.9 ng / mL. From the above results, it was shown that L- and D-proline do not promote laminin 332 production.
- FIG. 12 shows the experimental results of examining the effect of adding various concentrations of serine on the production of laminin 332 in HaCaT cells.
- the vertical axis of the graph in FIG. 12 indicates the laminin 332 concentration (ng / mL) in the culture supernatant of each well.
- the error bar of each experimental condition indicates the standard deviation of the calculated value of the experimental result repeated four times under the same condition.
- the laminin 332 concentration was 1.7 ng / mL in the negative control.
- the laminin 332 concentrations of HaCaT cells cultured in 10 nM, 100 nM and 1000 nM L-serine supplemented media and D-serine supplemented media were 1.8 ng / mL and 1.8 ng / mL, 1.9 ng / mL and 1.8 ng / mL, 1.9 ng / mL and 1.8 ng / mL. From the above results, it was shown that L- and D-serine do not promote laminin 332 production.
- emulsion preparation preparation, patch, tablet, soft capsule, granule, drink, candy, cookie, miso, French dressing, mayonnaise, French bread, soy sauce, yogurt, containing D-alanine and / or D-hydroxyproline
- Formulation examples of sprinkles, seasoning / natto sauce, natto, moromi black vinegar, cream, body cream, gel agent, peel-off mask, impregnation mask, emulsion, lotion and aerosol are shown below. These formulation examples are listed for the purpose of illustration and are not intended to limit the technical scope of the present invention.
- Formulation Example 1 (Emulsion formulation) (Composition) Compounding amount (% by weight) D-alanine or D-hydroxyproline 0.42 Behenyl alcohol 0.2 Cetanol 0.5 Glycerin mono fatty acid ester 1.8 Hardened castor oil POE (60) 1.0 White petrolatum 2.0 Liquid paraffin 10.0 Isopropyl myristate 3.0 Methyl polysiloxane (6cs) 1.5 Concentrated glycerin 13.0 Dipropylene glycol 2.0 Carboxyvinyl polymer 0.25 Sodium hyaluronate 0.005 Potassium hydroxide Appropriate amount of lactic acid Appropriate amount of sodium edetate Appropriate amount of ethyl paraben Appropriate amount of purified water Residue 100.000
- Formulation Example 2 (Patch) (Composition) Compounding amount (% by weight) D-alanine or D-hydroxyproline 0.3 Polyacrylic acid 3.0 Sodium polyacrylate 2.5 Gelatin 0.5 Sodium carboxymethylcellulose 4.0 Polyvinyl alcohol 0.3 Concentrated glycerin 14.0 1,3-butylene glycol 12.0 Aluminum hydroxide 0.1 Sodium edetate 0.03 Methylparaben 0.1 Purified water residue 100.00
- Formulation Example 3 (tablet) (Composition) Formulation amount (mg / tablet) D-alanine or D-hydroxyproline 360.5 Lactose 102.4 Carboxymethylcellulose calcium 29.9 Hydroxypropylcellulose 6.8 Magnesium stearate 5.2 Crystalline cellulose 10.2 515.0
- Formulation Example 4 (tablet) (Composition) Formulation amount (mg / tablet) Sucrose ester 70 Crystalline cellulose 74 Methylcellulose 36 Glycerin 25 D-alanine or D-hydroxyproline 475 N-acetylglucosamine 200 Hyaluronic acid 150 Vitamin E 30 Vitamin B6 20 Vitamin B2 10 ⁇ -Lipoic acid 20 Coenzyme Q10 40 Ceramide (konjac extract) 50 L-proline 300 1500
- Formulation Example 5 (soft capsule) (Composition) Blending amount (mg / 1 capsule) Edible soybean oil 530 Eucommia extract 50 Carrot extract 50 D-alanine or D-hydroxyproline 100 Royal Jelly 50 Maca 30 GABA 30 Beeslow 60 Gelatin 375 Glycerin 120 Glycerin fatty acid ester 105 1500
- Formulation Example 6 (soft capsule) (Composition) Blending amount (mg / 1 capsule) Brown rice germ oil 659 D-alanine or D-hydroxyproline 500 Resveratrol 1 Lotus germ extract 100 Elastin 180 DNA 30 Folic acid 30 1500
- Formulation Example 7 (granule) (Composition) Blending amount (mg / pack) D-alanine or D-hydroxyproline 400 Vitamin C 100 Soy isoflavone 250 Reduced lactose 300 Soybean oligosaccharide 36 Erythritol 36 Dextrin 30 Fragrance 24 Citric acid 24 1200
- Formulation Example 8 (Drink) (Composition) Compounding amount (in g / 60 mL) Eucommia extract 1.6 Carrot extract 1.6 D-alanine or D-hydroxyproline 1.6 Reduced maltose starch syrup 28 Erythritol 8 Citric acid 2 Fragrance 1.3 N-acetylglucosamine 1 Hyaluronic acid Na 0.5 Vitamin E 0.3 Vitamin B6 0.2 Vitamin B2 0.1 ⁇ -Lipoic acid 0.2 Coenzyme Q10 1.2 Ceramide (konjac extract) 0.4 L-proline 2 Purified water residue 60
- Formulation Example 10 (Cookie) (Composition) Compounding amount (% by weight) Soft flour 45.0 Butter 17.5 Granulated sugar 20.0 D-alanine or D-hydroxyproline 4.0 Egg 12.5 Fragrance 1.0 100.0
- Formulation Example 11 (Miso) (Composition) Blending amount (g) Soybean 1000 Rice bran 1000 Salt 420 D-alanine or D-hydroxyproline 158 Water residue 4000
- rice bran that produces a large amount of D-alanine or D-hydroxyproline may be used.
- it can be selected by quantifying D-alanine or D-hydroxyproline by the method described in JP-A-2008-185558. Further, D-alanine or D-hydroxyproline or a salt thereof may be added to commercially available miso.
- Formulation Example 12 (French dressing) (Composition) Blending amount (g) Salad oil 27.0 Vinegar 30.0 Sodium chloride 0.9 D-alanine or D-hydroxyproline 1.1 Pepper 1.0 60.0
- Formulation Example 13 (mayonnaise) (Composition) Blending amount (g) Salad oil 134.0 Vinegar 5 Sodium chloride 0.9 D-alanine or D-hydroxyproline 1 Yolk 18 Sugar 0.2 Pepper 0.9 160.0
- Formulation Example 14 (French bread) (Composition) Blending amount (g) Powerful powder 140 Soft flour 60 Sodium chloride 3 Sugar 6 D-alanine or D-hydroxyproline 2 Dry yeast 4 Lukewarm water 128 343
- Formulation Example 15 (soy sauce) (Composition) Blending amount (g) Commercial soy sauce 900 D-alanine or D-hydroxyproline 100 1000
- soy sauce D-alanine, D-hydroxyproline, or a salt thereof is added to commercially available soy sauce and stirred well. Further, instead of adding D-alanine or D-hydroxyproline or a salt thereof, soy sauce may be brewed using a koji producing a large amount of D-alanine or D-hydroxyproline. In order to obtain the sputum, it can be selected by quantifying D-alanine or D-hydroxyproline by the method described in JP-A-2008-185558.
- Formulation Example 16 (yogurt) (Composition) Blending amount (g) Milk 880 L. Bulgaricus 50 S. Thermophilus 50 D-alanine or D-hydroxyproline 20 1000
- Formulation Example 17 (sprinkle) (Composition) Blending amount (g) D-alanine or D-hydroxyproline 50 Paste 15 L-glutamic acid Na 10 Sodium chloride 2 Roasted sesame 10 Crusher Clause 10 Sugar 1 Soy sauce 2 100
- Formulation Example 18 (Seasoning and natto sauce) (Composition) Blending amount (g) Commercial natto sauce 9 D-alanine or D-hydroxyproline 1 10
- natto D-alanine, D-hydroxyproline, or a salt thereof is added to commercially available natto and stirred well. Further, instead of adding D-alanine or D-hydroxyproline or a salt thereof, natto may be made using a bacterium that produces a large amount of D-alanine or D-hydroxyproline. In order to obtain the bacterium, it can be selected by quantifying D-alanine or D-hydroxyproline by the method described in JP-A-2008-185558.
- Formulation Example 20 (Moromi black vinegar) (Composition) Blending amount (g) Commercially available moromi black vinegar 900 D-alanine or D-hydroxyproline 100 1000
- D-alanine, D-hydroxyproline, or a salt thereof is added to commercially available moromi black vinegar and stirred well.
- vinegar, black vinegar, and moromi may be made using bacteria that produce a large amount of D-alanine or D-hydroxyproline. In order to obtain the bacterium, it can be selected by quantifying D-alanine or D-hydroxyproline by the method described in JP-A-2008-185558.
- Formulation Example 21 (cream) (Composition) Compounding amount (% by weight) Liquid paraffin 3 Vaseline 1 Dimethylpolysiloxane 1 Stearyl alcohol 1.8 Behenyl alcohol 1.6 Glycerin 8 Dipropylene glycol 5 Macadamia nut oil 2 Hardened oil 3 Squalane 6 Stearic acid 2 Cholesteryl hydroxystearate 0.5 Cetyl 2-ethylhexanoate 4 Polyoxyethylene hydrogenated castor oil 0.5 Self-emulsifying glyceryl monostearate 3 Potassium hydroxide 0.15 Sodium hexametaphosphate 0.05 Trimethylglycine 2 ⁇ -tocopherol 2-L-ascorbic acid potassium phosphate diester 1 Tocopherol acetate 0.1 D-alanine or D-hydroxyproline 4 Paraben appropriate amount edetate trisodium 0.05 4-t-butyl-4′-methoxydibenzoylmethane 0.05 Diparamethoxycinna
- Formulation Example 22 (Body Cream) (Composition) Compounding amount (% by weight) Dimethylpolysiloxane 3 Decamethylcyclopentasiloxane 13 Dodecamethylcyclohexasiloxane 12 Polyoxyethylene methylpolysiloxane copolymer 1 Ethanol 2 Isopropanol 1 Glycerin 3 Dipropylene glycol 5 Polyethylene glycol 6000 5 Sodium hexametaphosphate 0.05 Tocopherol acetate 0.1 D-alanine or D-hydroxyproline 5 Fennel extract 0.1 Hamelis extract 0.1 Carrot extract 0.1 L-menthol appropriate amount paraoxybenzoate appropriate amount edetate trisodium 0.05 Dimorpholinopyridazinone 0.01 Methyl bis (trimethylsiloxy) trimethoxycinnamate Silyl isopentyl 0.1 Yellow iron oxide Appropriate amount Cobalt titanate Appropriate amount Dimethyl distearyl ammonium hector
- Formulation Example 23 (gel agent) (Composition) Compounding amount (% by weight) Dimethylpolysiloxane 5 Glycerin 2 1,3-butylene glycol 5 Polyethylene glycol 1500 3 Polyethylene glycol 20000 3 Cetyl octanoate 3 Citric acid 0.01 Sodium citrate 0.1 Sodium hexametaphosphate 0.1 Dipotassium glycyrrhizinate 0.1 D-alanine or D-hydroxyproline 2 Tocopherol acetate 0.1 Ogon Extract 0.1 Yukinoshita extract 0.1 Edetate trisodium 0.1 Xanthan gum 0.3 Acrylic acid / methacrylic acid alkyl copolymer (Pemulene TR-2) 0.05 Agar powder 1.5 Phenoxyethanol Appropriate amount Dibutylhydroxytoluene Appropriate amount of purified water Residue 100.00
- Formulation Example 24 (Peel-off mask) (Composition) Compounding amount (% by weight) Ethanol 10 1,3-butylene glycol 6 Polyethylene glycol 4000 2 Olive oil 1 Macadamia nut oil 1 Phytosteryl hydroxystearate 0.05 Lactic acid 0.05 Sodium lactate 0.1 L-ascorbic acid sulfate disodium salt 0.1 ⁇ -tocopherol 2-L-ascorbic acid potassium phosphate diester 0.1 D-alanine or D-hydroxyproline 10 Fish collagen 0.1 Chondroitin thorium sulfate 0.1 Sodium carboxymethylcellulose 0.2 Polyvinyl alcohol 12 Paraoxybenzoic acid ester Appropriate amount of fragrance Appropriate amount of purified water Residue 100.00
- Formulation Example 25 Composition
- Compounding amount (% by weight) Glycerin 1 1,3-butylene glycol 8
- Xylit 2 Polyethylene glycol 1500 2 Rosemary oil 0.01 Sage oil 0.1
- Citric acid 0.02 Sodium citrate 0.08
- Sodium hexametaphosphate 0.01 Hydroxypropyl- ⁇ -cyclodextrin 0.1 D-alanine or D-hydroxyproline 0.5
- Lavender oil 0.01 Xanthan gum 0.05
- Carboxyvinyl polymer 0.15 P-Hydroxybenzoate appropriate amount purified water remaining 100.00
- Formulation Example 26 (Emulsion) (Composition) Compounding amount (% by weight) Liquid paraffin 7 Vaseline 3 Decamethylcyclopentasiloxane 2 Behenyl alcohol 1.5 Glycerin 5 Dipropylene glycol 7 Polyethylene glycol 1500 2 Jojoba oil 1 Isostearic acid 0.5 Stearic acid 0.5 Behenic acid 0.5 Tetra-2-ethylhexanoic acid pentaerythrit 3 Cetyl 2-ethylhexanoate 3 Glycerol monostearate 1 Polyoxyethylene glyceryl monostearate 1 Potassium hydroxide 0.1 Sodium hexametaphosphate 0.05 Stearyl glycyrrhetinate 0.05 D-alanine or D-hydroxyproline 1 Royal Jelly Extract 0.1 Yeast extract 0.1 Tocopherol acetate 0.1 Acetylated sodium hyaluronate 0.1 Edetate trisodium 0.05 4-t-butyl-4′-
- Formulation Example 27 (milky lotion) (Composition) Compounding amount (% by weight) Dimethylpolysiloxane 2 Behenyl alcohol 1 Batyl alcohol 0.5 Glycerin 5 1,3-butylene glycol 7 Erythritol 2 Hardened oil 3 Squalane 6 Tetra-2-ethylhexanoic acid pentaerythrit slit 2 Polyoxyethylene glyceryl isostearate 1 Polyoxyethylene glyceryl monostearate 1 D-alanine or D-hydroxyproline 0.3 Potassium hydroxide appropriate amount Sodium hexametaphosphate 0.05 Phenoxyethanol appropriate amount carboxyvinyl polymer 0.1 Purified water residue 100.00
- Formulation Example 28 Composition
- Compounding amount (% by weight) Ethyl alcohol 5
- Sodium hexametaphosphate 0.03 Trimethylglycine 1
- Sodium polyaspartate 0.1 ⁇ -tocopherol 2-L-ascorbic acid potassium phosphate diester 0.1
- Thiotaurine 0.1 D-alanine or D-hydroxyproline
- EDTA3 sodium 0.1
- Potassium hydroxide 0.02 Phenoxyethanol appropriate amount perfume appropriate amount purified water remaining 100.00
- Formulation Example 30 (Aerosol urea external preparation stock solution) (Composition) Compounding amount (% by weight) Ethanol 15.0 Polyoxyethylene hydrogenated castor oil 50 1.5 Diphenhydramine 1.0 Jibcaine 2.0 Tocopherol acetate 0.5 D-alanine or D-hydroxyproline 0.1 Isostearic acid 0.1 1,3-butylene glycol 3.0 Polyethylene glycol 400 3.0 Camphor 0.05 Urea 20.0 Purified water residue 100.00
- Formulation Example 31 (Aerosol urea propellant) (Composition) Compounding amount (% by weight) Aerosol urea external preparation stock solution 65.0 Dimethyl ether 35.0 100.00
- Formulation Example 31 (Aerosol Urea Propellant) Filling Method
- An aerosol urea preparation is prepared by filling an inner surface Teflon (registered trademark) coated pressure-resistant aerosol aluminum can with an aerosol urea external preparation stock solution and dimethyl ether.
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Abstract
Description
1-1.材料と方法
(1)細胞
細胞は、ヒト表皮細胞由来のHaCaT細胞(H. Hansら、Experimental Cell Research 239:399(1998))と、ヒト角化細胞由来のKC細胞(三光純薬(株)、製造元:LONZA Walkersville Inc.)とが用いられた。前記細胞は、24ウェルプレートに1ウェルあたり4x104個となるように播種され、細胞培養用培地(D-MEM(1g/Lグルコース)、和光純薬)にBSAを0.1%添加した培地(以下、「通常培地」という。)を用いて、37°C、5%CO2及び飽和水蒸気雰囲気下で24時間培養された。
その後、前記細胞は、L-又はD-アラニンの1μMか、L-及びD-アラニンをともに0.5μMずつか、L-又はD-ヒドロキシプロリンの1μMか、L-及びD-ヒドロキシプロリンをともに0.5μMずつかを前記通常培地に添加した培地に切り替えて24時間培養された。アラニン及びヒドロキシプロリンを添加しない前記通常培地が陰性対照として用いられた。本実施例で用いられたD-ヒドロキシプロリンは、4-シス-D-ヒドロキシプロリンであった。
培養終了後に培地を回収し、3000rpmで5分間遠心分離し、上清中のラミニン332濃度がELISA法(Amano, S.ら、J.Immunol.Methods、224:161(1999))を用いて測定された。前記ELISA法は、ラミニン5のα3鎖に対するモノクローナル抗体であるBM165と、ラミニン5のβ3鎖に対するモノクローナル抗体である6F12のビオチン化コンジュゲートとを用いるサンドイッチELISA法で、ホースラディッシュペロキシダーゼ標識アビジンD(Vector Labs社、カタログ番号A-2004)により検出される。PBSが対照として用いられた。
培地回収後、細胞はPBSで洗浄され、alamarBlue(商標、Biosource、バイオソース・インターナショナル)が最終濃度10%となるように添加された。2時間後、Ahmed S.A.ら、(J. Immunol. Method. 170,211-224(1994))及び製造者の指示書に従って励起波長544nm、蛍光波長590nmでalamarBlue液の蛍光強度が測定された。
(1)KC生細胞数の定量
図1は、KC細胞の増殖へのアラニン添加の影響を調べた実験結果を示す。各実験条件の誤差棒は同一条件で3回繰り返した実験結果の測定値の標準偏差を示す。
図2にKC細胞でのラミニン332産生に対するアラニン添加の効果を調べた実験結果を示す。図2のグラフの縦軸は、各ウェルの培養上清中のラミニン332濃度に比例するELISA測定の吸光度を、各ウェルの細胞数に比例するalamarBlue(商標)の蛍光強度で除算した商(以下、「細胞数あたりのラミニン332濃度の相対値」という。)を示す。各実験条件の誤差棒は同一条件で3回繰り返した実験結果の計算値の標準偏差を示す。また、アステリスク(**)はTukey-Kramer検定でpが1%未満であることを示す。
図3及び図4は、HaCaT細胞の増殖へのアラニン及びヒドロキシプロリンの添加の影響を調べた実験結果を示す。以下、D-ヒドロキシプロリン(D-Hyp)とは、4-シス-D-ヒドロキシプロリンを指す。各実験条件の誤差棒は同一条件で3回繰り返した実験結果の測定値の標準偏差を示す。
図5にHaCaT細胞でのラミニン332産生に対するアラニン添加の効果を調べた実験結果を示す。図5のグラフの縦軸は、各ウェルの培養上清中の細胞数あたりのラミニン332濃度の相対値を示す。各実験条件の誤差棒は同一条件で3回繰り返した実験結果の計算値の標準偏差を示す。また、アステリスク(**)はScheffe’s F-検定でpが1%未満であり、アステリスク(*)はpが5%未満であることを示す。
図6にHaCaT細胞でのラミニン332産生に対するヒドロキシプロリン添加の効果を調べた実験結果を示す。図6のグラフの縦軸は、各ウェルの培養上清中の細胞数あたりのラミニン332濃度の相対値を示す。各実験条件の誤差棒は同一条件で3回繰り返した実験結果の計算値の標準偏差を示す。
2-1.材料と方法
細胞はHaCaT細胞が用いられ、実施例1と同様に培養された。その後、前記細胞は、10nM、100nM及び1000nMのL-又はD-アラニンか、L-又はD-ヒドロキシプロリンか、L-又はD-アスパラギン酸か、L-又はD-アスパラギンか、L-又はD-プロリンか、L-又はD-セリンかのアミノ酸を通常培地に添加した培地に切り替えて24時間培養された。前記アミノ酸を添加しない前記通常培地が陰性対照として用いられた。本実施例で用いられたD-ヒドロキシプロリンは、4-シス-D-ヒドロキシプロリンであった。ラミニン332産生量は実施例1と同様に測定された。なお、以下の実験では、アミノ酸添加による細胞毒性はどの濃度でも認められなかったため、それぞれの実験条件で細胞のラミニン332産生量が比較された。
(1)アラニン添加
図7にHaCaT細胞でのラミニン332産生に対するさまざまな濃度のアラニンの添加効果を調べた実験結果を示す。図7のグラフの縦軸は、各ウェルの培養上清中のラミニン332濃度(ng/mL)を示す。各実験条件の誤差棒は同一条件で4回繰り返した実験結果の計算値の標準偏差を示す。
図8にHaCaT細胞でのラミニン332産生に対するさまざまな濃度のヒドロキシプロリンの添加効果を調べた実験結果を示す。図8のグラフの縦軸は、各ウェルの培養上清中のラミニン332濃度(ng/mL)を示す。各実験条件の誤差棒は同一条件で4回繰り返した実験結果の計算値の標準偏差を示す。
図9にHaCaT細胞でのラミニン332産生に対するさまざまな濃度のアスパラギン酸の添加効果を調べた実験結果を示す。図9のグラフの縦軸は、各ウェルの培養上清中のラミニン332濃度(ng/mL)を示す。各実験条件の誤差棒は同一条件で4回繰り返した実験結果の計算値の標準偏差を示す。
図10にHaCaT細胞でのラミニン332産生に対するさまざまな濃度のアスパラギンの添加効果を調べた実験結果を示す。図10のグラフの縦軸は、各ウェルの培養上清中のラミニン332濃度(ng/mL)を示す。各実験条件の誤差棒は同一条件で4回繰り返した実験結果の計算値の標準偏差を示す。
図11にHaCaT細胞でのラミニン332産生に対するさまざまな濃度のプロリンの添加効果を調べた実験結果を示す。図11のグラフの縦軸は、各ウェルの培養上清中のラミニン332濃度(ng/mL)を示す。各実験条件の誤差棒は同一条件で4回繰り返した実験結果の計算値の標準偏差を示す。
図12にHaCaT細胞でのラミニン332産生に対するさまざまな濃度のセリンの添加効果を調べた実験結果を示す。図12のグラフの縦軸は、各ウェルの培養上清中のラミニン332濃度(ng/mL)を示す。各実験条件の誤差棒は同一条件で4回繰り返した実験結果の計算値の標準偏差を示す。
実施例1及び2の実験結果から、ラミニン332産生促進効果は、D-アラニン及びD-ヒドロキシプロリンで認められたが、アスパラギン酸、アスパラギン、プロリン及びセリンでは認められなかった。そこで、D-アラニン及びD-ヒドロキシプロリンは、基底膜の構造及び機能に重要な役割を果たすラミニン332の産生を促進することによって、皮膚状態を抑制及び/又は改善できると示唆された。
(組成物) 配合量(重量%)
D-アラニン
又はD-ヒドロキシプロリン 0.42
ベヘニルアルコール 0.2
セタノール 0.5
グリセリンモノ脂肪酸エステル 1.8
硬化ヒマシ油POE(60) 1.0
白色ワセリン 2.0
流動パラフィン 10.0
ミリスチン酸イソプロピル 3.0
メチルポリシロキサン(6cs) 1.5
濃グリセリン 13.0
ジプロピレングリコール 2.0
カルボキシビニルポリマー 0.25
ヒアルロン酸ナトリウム 0.005
水酸化カリウム 適量
乳酸 適量
エデト酸ナトリウム 適量
エチルパラベン 適量
精製水 残余
100.000
(組成物) 配合量(重量%)
D-アラニン
又はD-ヒドロキシプロリン 0.3
ポリアクリル酸 3.0
ポリアクリル酸ナトリウム 2.5
ゼラチン 0.5
カルボキシメチルセルロースナトリウム 4.0
ポリビニルアルコール 0.3
濃グリセリン 14.0
1,3-ブチレングリコール 12.0
水酸化アルミニウム 0.1
エデト酸ナトリウム 0.03
メチルパラベン 0.1
精製水 残余
100.00
(組成物) 配合量(mg/1錠中)
D-アラニン
又はD-ヒドロキシプロリン 360.5
乳糖 102.4
カルボキシメチルセルロースカルシウム 29.9
ヒドロキシプロピルセルロース 6.8
ステアリン酸マグネシウム 5.2
結晶セルロース 10.2
515.0
(組成物) 配合量(mg/1錠中)
ショ糖エステル 70
結晶セルロース 74
メチルセルロース 36
グリセリン 25
D-アラニン
又はD-ヒドロキシプロリン 475
N-アセチルグルコサミン 200
ヒアルロン酸 150
ビタミンE 30
ビタミンB6 20
ビタミンB2 10
α-リポ酸 20
コエンザイムQ10 40
セラミド(コンニャク抽出物) 50
L-プロリン 300
1500
(組成物) 配合量(mg/1カプセル中)
食用大豆油 530
トチュウエキス 50
ニンジンエキス 50
D-アラニン
又はD-ヒドロキシプロリン 100
ローヤルゼリー 50
マカ 30
GABA 30
ミツロウ 60
ゼラチン 375
グリセリン 120
グリセリン脂肪酸エステル 105
1500
(組成物) 配合量(mg/1カプセル中)
玄米胚芽油 659
D-アラニン
又はD-ヒドロキシプロリン 500
レスベラトロール 1
ハス胚芽エキス 100
エラスチン 180
DNA 30
葉酸 30
1500
(組成物) 配合量(mg/1包中)
D-アラニン
又はD-ヒドロキシプロリン 400
ビタミンC 100
大豆イソフラボン 250
還元乳糖 300
大豆オリゴ糖 36
エリスリトール 36
デキストリン 30
香料 24
クエン酸 24
1200
(組成物) 配合量(g/60mL中)
トチュウエキス 1.6
ニンジンエキス 1.6
D-アラニン
又はD-ヒドロキシプロリン 1.6
還元麦芽糖水飴 28
エリスリトール 8
クエン酸 2
香料 1.3
N-アセチルグルコサミン 1
ヒアルロン酸Na 0.5
ビタミンE 0.3
ビタミンB6 0.2
ビタミンB2 0.1
α-リポ酸 0.2
コエンザイムQ10 1.2
セラミド(コンニャク抽出物) 0.4
L-プロリン 2
精製水 残余
60
(組成物) 配合量(重量%)
砂糖 50
水飴 48
D-アラニン
又はD-ヒドロキシプロリン 1
香料 1
100
(組成物) 配合量(重量%)
薄力粉 45.0
バター 17.5
グラニュー糖 20.0
D-アラニン
又はD-ヒドロキシプロリン 4.0
卵 12.5
香料 1.0
100.0
バターを撹拌しながらグラニュー糖を徐々に添加し、卵及び香料と、D-アラニン又はD-ヒドロキシプロリンとを添加して撹拌した。十分に混合した後、均一に振るった薄力粉を加えて低速で撹拌し、塊状で冷蔵庫で寝かせた。その後、成型し170°C15分間焼成しクッキーとした。
(組成物) 配合量(g)
大豆 1000
米麹 1000
塩 420
D-アラニン
又はD-ヒドロキシプロリン 158
水 残余
4000
米こうじと塩とをよく混ぜ合わせる。洗浄した大豆を3倍量の水に一晩つけた後に水を切り、新しい水を加えながら煮込み、ざるにあける。煮汁(種水)を集め、D-アラニン又はD-ヒドロキシプロリンを10%w/vとなるように溶解する。煮あがった豆を直ちにすりつぶし、塩を混ぜた米麹を加えて、上記のD-アラニン又はD-ヒドロキシプロリンを溶解した種水を足しながら粘土程の固さになるまでむらなく混ぜ合わせる。団子状に丸めたものを桶に隙間のない様に隅々まで、しっかりと詰め込み、表面を平らにしてラップで覆い密封する。3箇月後に容器を移し変え、表面を平らにしてラップで覆う。なお、D-アラニン又はD-ヒドロキシプロリンを種水に加える代わりに、D-アラニン又はD-ヒドロキシプロリンを多く産生する米麹を用いてもよい。前記米麹を得るには、特開2008-185558に記載の方法で、D-アラニン又はD-ヒドロキシプロリンを定量することにより選抜することができる。また、市販の味噌にD-アラニン又はD-ヒドロキシプロリンか、それらの塩かを加えてもよい。
(組成物) 配合量(g)
サラダ油 27.0
酢 30.0
塩化ナトリウム 0.9
D-アラニン
又はD-ヒドロキシプロリン 1.1
胡椒 1.0
60.0
酢に塩化ナトリウムと、D-アラニン又はD-ヒドロキシプロリンとを加えた後に、よく攪拌して溶解する。サラダ油を加えて、よく攪拌し胡椒を加える。
(組成物) 配合量(g)
サラダ油 134.0
酢 5
塩化ナトリウム 0.9
D-アラニン
又はD-ヒドロキシプロリン 1
卵黄 18
砂糖 0.2
胡椒 0.9
160.0
卵黄(室温)に酢、塩化ナトリウム及び胡椒と、D-アラニン又はD-ヒドロキシプロリンとを加えて、泡立て器で十分に攪拌する。サラダ油を少しずつ加えながら攪拌を継続してエマルジョンにする。最後に砂糖を加えて攪拌する。
(組成物) 配合量(g)
強力粉 140
薄力粉 60
塩化ナトリウム 3
砂糖 6
D-アラニン
又はD-ヒドロキシプロリン 2
ドライイースト 4
ぬるま湯 128
343
ぬるま湯に砂糖1g及びドライイーストを入れて予備発酵させる。強力粉、薄力粉、塩化ナトリウム、砂糖5gと、D-アラニン又はD-ヒドロキシプロリンとをボウルに入れ、その中に予備発酵させたイーストを入れる。十分捏ねた後に球状にして30°Cで一次発酵させる。生地を再度捏ねてから休ませた後に適当な形に整形して電子発酵機を用いて最終発酵させる。クープを入れて220°Cのオーブンで30分間焼く。
(組成物) 配合量(g)
市販の醤油 900
D-アラニン
又はD-ヒドロキシプロリン 100
1000
市販の醤油にD-アラニン又はD-ヒドロキシプロリンか、それらの塩かを加えてよく攪拌する。また、D-アラニン又はD-ヒドロキシプロリンか、それらの塩かを加える代わりに、D-アラニン又はD-ヒドロキシプロリンを多く産生する麹を用いて醤油を醸造してもよい。前記麹を得るには、特開2008-185558に記載の方法で、D-アラニン又はD-ヒドロキシプロリンを定量することにより選抜することができる。
(組成物) 配合量(g)
牛乳 880
L.ブルガリカス菌 50
S.サーモフィルス菌 50
D-アラニン
又はD-ヒドロキシプロリン 20
1000
40°C~45°Cで発酵させる。他の市販の種菌を用いてもよく、市販のヨーグルトにD-アラニン又はD-ヒドロキシプロリンか、それらの塩かを加えてもよい。また、D-アラニン又はD-ヒドロキシプロリンか、それらの塩かを加える代わりに、D-アラニン又はD-ヒドロキシプロリンを多く産生する菌を用いてもよい。前記菌を得るには、特開2008-185558に記載の方法で、D-アラニン又はD-ヒドロキシプロリンを定量することにより選抜することができる。
(組成物) 配合量(g)
D-アラニン
又はD-ヒドロキシプロリン 50
のり 15
L-グルタミン酸Na 10
塩化ナトリウム 2
煎りごま 10
さば削り節 10
砂糖 1
醤油 2
100
(組成物) 配合量(g)
市販の納豆のたれ 9
D-アラニン
又はD-ヒドロキシプロリン 1
10
(組成物) 配合量(g)
市販の納豆 19.9
D-アラニン
又はD-ヒドロキシプロリン 0.1
20
市販の納豆に、D-アラニン又はD-ヒドロキシプロリンか、それらの塩かを加えてよく攪拌する。また、D-アラニン又はD-ヒドロキシプロリンか、それらの塩かを加える代わりに、D-アラニン又はD-ヒドロキシプロリンを多く産生する菌を用いて納豆を作ってもよい。前記菌を得るには、特開2008-185558に記載の方法で、D-アラニン又はD-ヒドロキシプロリンを定量することにより選抜することができる。
(組成物) 配合量(g)
市販のもろみ黒酢 900
D-アラニン
又はD-ヒドロキシプロリン 100
1000
市販のもろみ黒酢に、D-アラニン又はD-ヒドロキシプロリンか、それらの塩かを加えてよく攪拌する。D-アラニン又はD-ヒドロキシプロリンか、それらの塩かを加える代わりにD-アラニン又はD-ヒドロキシプロリンを多く産生する菌を用いて酢、黒酢、もろみを作ってもよい。前記菌を得るには、特開2008-185558に記載の方法でD-アラニン又はD-ヒドロキシプロリンを定量することにより選抜することができる。
(組成物) 配合量(重量%)
流動パラフィン 3
ワセリン 1
ジメチルポリシロキサン 1
ステアリルアルコール 1.8
ベヘニルアルコール 1.6
グリセリン 8
ジプロピレングリコール 5
マカデミアナッツ油 2
硬化油 3
スクワラン 6
ステアリン酸 2
ヒドロキシステアリン酸コレステリル 0.5
2-エチルヘキサン酸セチル 4
ポリオキシエチレン硬化ヒマシ油 0.5
自己乳化型モノステアリン酸グリセリン 3
水酸化カリウム 0.15
ヘキサメタリン酸ナトリウム 0.05
トリメチルグリシン 2
α-トコフェロール 2-L-アスコルビン酸
リン酸ジエステルカリウム 1
酢酸トコフェロール 0.1
D-アラニン
又はD-ヒドロキシプロリン 4
パラベン 適量
エデト酸3ナトリウム 0.05
4-t-ブチル-4’-メトキシジベンゾイルメタン 0.05
ジパラメトキシ桂皮酸モノ-2-エチルヘキサン酸グリセリル 0.05
色剤 適量
カルボキシビニルポリマー 0.05
精製水 残余
100.00
(組成物) 配合量(重量%)
ジメチルポリシロキサン 3
デカメチルシクロペンタシロキサン 13
ドデカメチルシクロヘキサシロキサン 12
ポリオキシエチレン・メチルポリシロキサン共重合体 1
エタノール 2
イソプロパノール 1
グリセリン 3
ジプロピレングリコール 5
ポリエチレングリコール6000 5
ヘキサメタリン酸ナトリウム 0.05
酢酸トコフェロール 0.1
D-アラニン
又はD-ヒドロキシプロリン 5
ウイキョウエキス 0.1
ハマメリスエキス 0.1
ニンジンエキス 0.1
L-メントール 適量
パラオキシ安息香酸エステル 適量
エデト酸三ナトリウム 0.05
ジモルホリノピリダジノン 0.01
トリメトキシ桂皮酸メチルビス(トリメチルシロキシ)
シリルイソペンチル 0.1
黄酸化鉄 適量
チタン酸コバルト 適量
ジメチルジステアリルアンモニウムヘクトライト 1.5
ポリビニルアルコール 0.1
ヒドロキシエチルセルロース 0.1
トリメチルシロキシケイ酸 2
香料 適量
精製水 残余
100.00
(組成物) 配合量(重量%)
ジメチルポリシロキサン 5
グリセリン 2
1,3-ブチレングリコール 5
ポリエチレングリコール1500 3
ポリエチレングリコール20000 3
オクタン酸セチル 3
クエン酸 0.01
クエン酸ナトリウム 0.1
ヘキサメタリン酸ナトリウム 0.1
グリチルリチン酸ジカリウム 0.1
D-アラニン
又はD-ヒドロキシプロリン 2
酢酸トコフェロール 0.1
オウゴンエキス 0.1
ユキノシタエキス 0.1
エデト酸三ナトリウム 0.1
キサンタンガム 0.3
アクリル酸・メタクリル酸
アルキル共重合体(ペミュレンTR-2) 0.05
寒天末 1.5
フェノキシエタノール 適量
ジブチルヒドロキシトルエン 適量
精製水 残余
100.00
(組成物) 配合量(重量%)
エタノール 10
1,3-ブチレングリコール 6
ポリエチレングリコール4000 2
オリーブ油 1
マカデミアナッツ油 1
ヒドロキシステアリン酸フィトステリル 0.05
乳酸 0.05
乳酸ナトリウム 0.1
L-アスコルビン酸硫酸エステル2ナトリウム 0.1
α-トコフェロール 2-L-アスコルビン酸
リン酸ジエステルカリウム 0.1
D-アラニン
又はD-ヒドロキシプロリン 10
魚コラーゲン 0.1
コンドロイチン硫酸トリウム 0.1
カルボキシメチルセルロースナトリウム 0.2
ポリビニルアルコール 12
パラオキシ安息香酸エステル 適量
香料 適量
精製水 残余
100.00
(組成物) 配合量(重量%)
グリセリン 1
1,3-ブチレングリコール 8
キシリット 2
ポリエチレングリコール1500 2
ローズマリー油 0.01
セージ油 0.1
クエン酸 0.02
クエン酸ナトリウム 0.08
ヘキサメタリン酸ナトリウム 0.01
ヒドロキシプロピル-β-シクロデキストリン 0.1
D-アラニン
又はD-ヒドロキシプロリン 0.5
バーチエキス 0.1
ラベンダー油 0.01
キサンタンガム 0.05
カルボキシビニルポリマー 0.15
パラオキシ安息香酸エステル 適量
精製水 残余
100.00
(組成物) 配合量(重量%)
流動パラフィン 7
ワセリン 3
デカメチルシクロペンタシロキサン 2
ベヘニルアルコール 1.5
グリセリン 5
ジプロピレングリコール 7
ポリエチレングリコール1500 2
ホホバ油 1
イソステアリン酸 0.5
ステアリン酸 0.5
ベヘニン酸 0.5
テトラ2-エチルヘキサン酸ペンタエリスリット 3
2-エチルヘキサン酸セチル 3
モノステアリン酸グリセリン 1
モノステアリン酸ポリオキシエチレングリセリン 1
水酸化カリウム 0.1
ヘキサメタリン酸ナトリウム 0.05
グリチルレチン酸ステアリル 0.05
D-アラニン
又はD-ヒドロキシプロリン 1
ローヤルゼリーエキス 0.1
酵母エキス 0.1
酢酸トコフェロール 0.1
アセチル化ヒアルロン酸ナトリウム 0.1
エデト酸三ナトリウム 0.05
4-t-ブチル-4’-メトキシジベンゾイルメタン 0.1
パラメトキシ桂皮酸2-エチルヘキシル 0.1
カルボキシビニルポリマー 0.15
パラベン 適量
香料 適量
精製水 残余
100.00
(組成物) 配合量(重量%)
ジメチルポリシロキサン 2
ベヘニルアルコール 1
バチルアルコール 0.5
グリセリン 5
1,3-ブチレングリコール 7
エリスリトール 2
硬化油 3
スクワラン 6
テトラ2-エチルヘキサン酸ペンタエリスリット 2
イソステアリン酸ポリオキシエチレングリセリル 1
モノステアリン酸ポリオキシエチレングリセリン 1
D-アラニン
又はD-ヒドロキシプロリン 0.3
水酸化カリウム 適量
ヘキサメタリン酸ナトリウム 0.05
フェノキシエタノール 適量
カルボキシビニルポリマー 0.1
精製水 残余
100.00
(組成物) 配合量(重量%)
エチルアルコール 5
グリセリン 1
1,3-ブチレングリコール 5
ポリオキシエチレンポリオキシプロピレン
デシルテトラデシルエーテル 0.2
ヘキサメタリン酸ナトリウム 0.03
トリメチルグリシン 1
ポリアスパラギン酸ナトリウム 0.1
α-トコフェロール 2-L-アスコルビン酸
リン酸ジエステルカリウム 0.1
チオタウリン 0.1
D-アラニン
又はD-ヒドロキシプロリン 8
EDTA3ナトリウム 0.1
カルボキシビニルポリマー 0.05
水酸化カリウム 0.02
フェノキシエタノール 適量
香料 適量
精製水 残余
100.00
(組成物) 配合量(重量%)
エタノール 10
ジプロピレングリコール 1
ポリエチレングリコール1000 1
ポリオキシエチレンメチルグルコシド 1
ホホバ油 0.01
トリ2-エチルヘキサン酸グリセリル 0.1
ポリオキシエチレン硬化ヒマシ油 0.2
ジイソステアリン酸ポリグリセリル 0.15
N-ステアロイル-L-グルタミン酸ナトリウム 0.1
クエン酸 0.05
クエン酸ナトリウム 0.2
水酸化カリウム 0.4
グリチルリチン酸ジカリウム 0.1
塩酸アルギニン 0.1
L-アスコルビン酸 2-グルコシド 2
D-アラニン
又はD-ヒドロキシプロリン 0.5
エデト酸三ナトリウム 0.05
パラメトキシ桂皮酸2-エチルヘキシル 0.01
ジブチルヒドロキシトルエン 適量
パラベン 適量
海洋深層水 3
香料 適量
精製水 残余
100.00
(組成物) 配合量(重量%)
エタノール 15.0
ポリオキシエチレン硬化ヒマシ油50 1.5
ジフェンヒドラミン 1.0
ジブカイン 2.0
酢酸トコフェロール 0.5
D-アラニン
又はD-ヒドロキシプロリン 0.1
イソステアリン酸 0.1
1,3-ブチレングリコール 3.0
ポリエチレングリコール400 3.0
カンフル 0.05
尿素 20.0
精製水 残余
100.00
(組成物) 配合量(重量%)
エアゾール尿素外用剤原液 65.0
ジメチルエーテル 35.0
100.00
エアゾール尿素外用剤原液及びジメチルエーテルを内面テフロン(登録商標)コート処理耐圧エアゾールアルミ缶に充填してエアゾール剤を調製する。
Claims (6)
- D-アラニン及びD-ヒドロキシプロリンと、その誘導体及び/又は塩とからなる群から選択される1種類又は2種類以上の化合物を含むことを特徴とする、ラミニン332産生促進組成物。
- 皮膚状態を抑制及び/又は改善するために用いられることを特徴とする、請求項1に記載の組成物。
- 前記皮膚状態は、光老化、シワ、肌荒れ、小ジワ及び乾燥からなるグループから選択されることを特徴とする、請求項2に記載の組成物。
- 医薬品として用いられることを特徴とする、請求項1ないし3のいずれか1つに記載の組成物。
- 皮膚外用剤として用いられることを特徴とする、請求項1ないし3のいずれか1つに記載の組成物。
- 食品として用いられることを特徴とする、請求項1ないし3のいずれか1つに記載の組成物。
Priority Applications (9)
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RU2012114586/15A RU2581916C2 (ru) | 2009-09-30 | 2010-05-14 | Композиция для стимулирования продуцирования ламинина-332 |
JP2011534108A JP6023428B2 (ja) | 2009-09-30 | 2010-05-14 | ラミニン332産生促進組成物 |
BR112012007611A BR112012007611A2 (pt) | 2009-09-30 | 2010-05-14 | composição estimuladora da produção de laminina-232 |
AU2010302036A AU2010302036A1 (en) | 2009-09-30 | 2010-05-14 | Laminin-332 production stimulating composition |
US13/261,241 US8586622B2 (en) | 2009-09-30 | 2010-05-14 | Laminin-332 product on stimulating composition |
EP10820202.9A EP2484355B1 (en) | 2009-09-30 | 2010-05-14 | Laminin-332 production stimulating composition |
CN2010800436896A CN102939083A (zh) | 2009-09-30 | 2010-05-14 | 层粘连蛋白332生成促进组合物 |
ES10820202.9T ES2544268T3 (es) | 2009-09-30 | 2010-05-14 | Composición que estimula la producción de laminina 332 |
TW099116541A TWI451879B (zh) | 2009-09-30 | 2010-05-24 | Selected from the group consisting of D- alanine and D- hydroxy-proline, the above groups and D- alanine and proline salts of D- hydroxy consisting of one kind or two kinds of the compound for the production of laminin 332 the use of production accelerating composition |
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KR (1) | KR20120080178A (ja) |
CN (1) | CN102939083A (ja) |
AU (1) | AU2010302036A1 (ja) |
BR (1) | BR112012007611A2 (ja) |
ES (1) | ES2544268T3 (ja) |
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Also Published As
Publication number | Publication date |
---|---|
ES2544268T3 (es) | 2015-08-28 |
RU2581916C2 (ru) | 2016-04-20 |
TW201110997A (en) | 2011-04-01 |
EP2484355B1 (en) | 2015-07-08 |
JP6023428B2 (ja) | 2016-11-09 |
KR20120080178A (ko) | 2012-07-16 |
AU2010302036A1 (en) | 2012-04-19 |
US8586622B2 (en) | 2013-11-19 |
EP2484355A4 (en) | 2013-04-03 |
TWI451879B (zh) | 2014-09-11 |
US20120184593A1 (en) | 2012-07-19 |
CN102939083A (zh) | 2013-02-20 |
BR112012007611A2 (pt) | 2016-08-23 |
JPWO2011040082A1 (ja) | 2013-02-21 |
EP2484355A1 (en) | 2012-08-08 |
RU2012114586A (ru) | 2013-11-10 |
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