JP5865623B2 - External preparation for skin and method for producing the same - Google Patents
External preparation for skin and method for producing the same Download PDFInfo
- Publication number
- JP5865623B2 JP5865623B2 JP2011168580A JP2011168580A JP5865623B2 JP 5865623 B2 JP5865623 B2 JP 5865623B2 JP 2011168580 A JP2011168580 A JP 2011168580A JP 2011168580 A JP2011168580 A JP 2011168580A JP 5865623 B2 JP5865623 B2 JP 5865623B2
- Authority
- JP
- Japan
- Prior art keywords
- phosphate
- skin
- external preparation
- ascorbic acid
- higher fatty
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000002360 preparation method Methods 0.000 title claims description 101
- 238000004519 manufacturing process Methods 0.000 title claims description 22
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 85
- 239000000194 fatty acid Substances 0.000 claims description 85
- 229930195729 fatty acid Natural products 0.000 claims description 85
- -1 fatty acid salt Chemical class 0.000 claims description 82
- 239000002736 nonionic surfactant Substances 0.000 claims description 58
- 239000000203 mixture Substances 0.000 claims description 23
- MIJPAVRNWPDMOR-ZAFYKAAXSA-N L-ascorbic acid 2-phosphate Chemical class OC[C@H](O)[C@H]1OC(=O)C(OP(O)(O)=O)=C1O MIJPAVRNWPDMOR-ZAFYKAAXSA-N 0.000 claims description 19
- 239000002537 cosmetic Substances 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 125000003289 ascorbyl group Chemical group [H]O[C@@]([H])(C([H])([H])O*)[C@@]1([H])OC(=O)C(O*)=C1O* 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 61
- 229920001451 polypropylene glycol Polymers 0.000 description 50
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 26
- 238000001556 precipitation Methods 0.000 description 23
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 22
- 239000006210 lotion Substances 0.000 description 18
- 150000003839 salts Chemical class 0.000 description 18
- 150000004665 fatty acids Chemical class 0.000 description 17
- 238000000034 method Methods 0.000 description 16
- 238000011156 evaluation Methods 0.000 description 15
- 238000006116 polymerization reaction Methods 0.000 description 15
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- 229960005070 ascorbic acid Drugs 0.000 description 10
- 235000010323 ascorbic acid Nutrition 0.000 description 10
- 239000011668 ascorbic acid Substances 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- LTSWUFKUZPPYEG-UHFFFAOYSA-N 1-decoxydecane Chemical compound CCCCCCCCCCOCCCCCCCCCC LTSWUFKUZPPYEG-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 9
- 238000002156 mixing Methods 0.000 description 9
- 238000000354 decomposition reaction Methods 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 8
- UYZQWKKNVBJVOF-UHFFFAOYSA-N 1-decoxytetradecane Chemical compound CCCCCCCCCCCCCCOCCCCCCCCCC UYZQWKKNVBJVOF-UHFFFAOYSA-N 0.000 description 7
- FDCJDKXCCYFOCV-UHFFFAOYSA-N 1-hexadecoxyhexadecane Chemical compound CCCCCCCCCCCCCCCCOCCCCCCCCCCCCCCCC FDCJDKXCCYFOCV-UHFFFAOYSA-N 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 125000006353 oxyethylene group Chemical group 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 230000000087 stabilizing effect Effects 0.000 description 6
- 150000000996 L-ascorbic acids Chemical class 0.000 description 5
- 238000003860 storage Methods 0.000 description 5
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical class C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 238000004040 coloring Methods 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 230000036541 health Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- 150000005846 sugar alcohols Polymers 0.000 description 4
- 239000004094 surface-active agent Substances 0.000 description 4
- CMCBDXRRFKYBDG-UHFFFAOYSA-N 1-dodecoxydodecane Chemical compound CCCCCCCCCCCCOCCCCCCCCCCCC CMCBDXRRFKYBDG-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 230000001771 impaired effect Effects 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- XMWRBQBLMFGWIX-UHFFFAOYSA-N C60 fullerene Chemical compound C12=C3C(C4=C56)=C7C8=C5C5=C9C%10=C6C6=C4C1=C1C4=C6C6=C%10C%10=C9C9=C%11C5=C8C5=C8C7=C3C3=C7C2=C1C1=C2C4=C6C4=C%10C6=C9C9=C%11C5=C5C8=C3C3=C7C1=C1C2=C4C6=C2C9=C5C3=C12 XMWRBQBLMFGWIX-UHFFFAOYSA-N 0.000 description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000005215 alkyl ethers Chemical class 0.000 description 2
- 239000003945 anionic surfactant Substances 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003093 cationic surfactant Substances 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 238000004945 emulsification Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 229910003472 fullerene Inorganic materials 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- 229920003170 water-soluble synthetic polymer Polymers 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- AFINAILKDBCXMX-PBHICJAKSA-N (2s,3r)-2-amino-3-hydroxy-n-(4-octylphenyl)butanamide Chemical compound CCCCCCCCC1=CC=C(NC(=O)[C@@H](N)[C@@H](C)O)C=C1 AFINAILKDBCXMX-PBHICJAKSA-N 0.000 description 1
- FKKAGFLIPSSCHT-UHFFFAOYSA-N 1-dodecoxydodecane;sulfuric acid Chemical compound OS(O)(=O)=O.CCCCCCCCCCCCOCCCCCCCCCCCC FKKAGFLIPSSCHT-UHFFFAOYSA-N 0.000 description 1
- HBXWUCXDUUJDRB-UHFFFAOYSA-N 1-octadecoxyoctadecane Chemical compound CCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCC HBXWUCXDUUJDRB-UHFFFAOYSA-N 0.000 description 1
- HANWHVWXFQSQGJ-UHFFFAOYSA-N 1-tetradecoxytetradecane Chemical compound CCCCCCCCCCCCCCOCCCCCCCCCCCCCC HANWHVWXFQSQGJ-UHFFFAOYSA-N 0.000 description 1
- NLMKTBGFQGKQEV-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-hexadecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO NLMKTBGFQGKQEV-UHFFFAOYSA-N 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 239000004909 Moisturizer Substances 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 230000006750 UV protection Effects 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 239000006096 absorbing agent Substances 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000005233 alkylalcohol group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000002280 amphoteric surfactant Substances 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000007844 bleaching agent Substances 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- WOWHHFRSBJGXCM-UHFFFAOYSA-M cetyltrimethylammonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+](C)(C)C WOWHHFRSBJGXCM-UHFFFAOYSA-M 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008406 cosmetic ingredient Substances 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 230000001333 moisturizer Effects 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- 229920000223 polyglycerol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000011814 protection agent Substances 0.000 description 1
- 239000003352 sequestering agent Substances 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- YRWWOAFMPXPHEJ-OFBPEYICSA-K sodium L-ascorbic acid 2-phosphate Chemical compound [Na+].[Na+].[Na+].OC[C@H](O)[C@H]1OC(=O)C(OP([O-])([O-])=O)=C1[O-] YRWWOAFMPXPHEJ-OFBPEYICSA-K 0.000 description 1
- 229940045870 sodium palmitate Drugs 0.000 description 1
- GGXKEBACDBNFAF-UHFFFAOYSA-M sodium;hexadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCC([O-])=O GGXKEBACDBNFAF-UHFFFAOYSA-M 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000005314 unsaturated fatty acid group Chemical group 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
- 230000002618 waking effect Effects 0.000 description 1
- 230000002087 whitening effect Effects 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/55—Phosphorus compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
- A61K8/86—Polyethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/52—Stabilizers
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Birds (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Cosmetics (AREA)
Description
本発明は、皮膚外用剤およびその製造方法に関する。 The present invention relates to an external preparation for skin and a method for producing the same.
アスコルビン酸（ビタミンＣ）およびその種々の誘導体は、美白作用、抗酸化作用、コラーゲン合成促進作用等の効能効果を呈する化合物として知られており、医薬品、化粧料、飼料等に配合されている。
アスコルビン酸誘導体のうち、アスコルビン酸の２位の水酸基をリン酸エステル化したアスコルビン酸−２−リン酸誘導体は、空気中で酸化されにくいことから汎用されている。アスコルビン酸−２−リン酸誘導体としては、アスコルビン酸−２−リン酸やその６位の水酸基をパルミチン酸等の高級脂肪酸でエステル化したアスコルビン酸−２−リン酸−６−高級脂肪酸が知られており、これらは通常、塩の形態で用いられている。塩としては、アスコルビン酸−２−リン酸のナトリウム塩やマグネシウム塩、あるいはアスコルビン酸−２−リン酸−６−高級脂肪酸のナトリウム塩等が一般的である。
Ascorbic acid (vitamin C) and various derivatives thereof are known as compounds exhibiting effects such as whitening action, antioxidant action, and collagen synthesis promoting action, and are incorporated in pharmaceuticals, cosmetics, feeds and the like.
Among ascorbic acid derivatives, ascorbic acid-2-phosphate derivatives obtained by phosphorylating the 2-position hydroxyl group of ascorbic acid are widely used because they are not easily oxidized in air. Ascorbic acid-2-phosphoric acid derivatives, ascorbic acid-2-phosphoric acid and ascorbic acid-2-phosphoric acid-6-higher fatty acid obtained by esterifying its 6-position hydroxyl group with a higher fatty acid such as palmitic acid are known. These are usually used in the form of salts. As the salt, a sodium salt or magnesium salt of ascorbic acid-2-phosphate, a sodium salt of ascorbic acid-2-phosphate-6-higher fatty acid, or the like is generally used.
上記のうち、アスコルビン酸−２−リン酸−６−高級脂肪酸塩は、両親媒性であるため生体への親和性が高く、皮膚等の生体組織への移行が速やかであることから、化粧料等の皮膚外用剤への適用が期待されている。
しかし、アスコルビン酸−２−リン酸−６−高級脂肪酸塩を皮膚外用剤として製剤化すると、剤中で分解が起こり、外観に変化が生じるなどの問題があった。沈殿の発生は、外観の変化だけでなく、皮膚外用剤を皮膚に適用した際の感触の悪化の原因ともなる。
アスコルビン酸−２−リン酸−６−高級脂肪酸塩の分解は主として、アスコルビン酸の６位の水酸基にエステル結合した高級脂肪酸の加水分解により生じる。この分解により、パルミチン酸ナトリウム等の、水に不溶の高級脂肪酸塩が生じ、剤中に沈殿として表れる。クリームのような白濁した剤型では目視で確認できないが、透明ローション系や美容液系では、濁りや沈殿として外観に変化が生じるという問題が発生する。
また、アスコルビン酸−２−リン酸−６−高級脂肪酸塩は、低温で保存した場合に溶解度が下がるため、配合した製剤中でアスコルビン酸−２−リン酸−６−高級脂肪酸塩自体が沈殿を起こすという問題もある。この問題は、アスコルビン酸−２−リン酸−６−パルミチン酸ナトリウムを配合する場合に特に生じやすい。
Among the above, ascorbic acid-2-phosphate-6-higher fatty acid salt is amphiphilic and therefore has a high affinity for the living body, so that it can be rapidly transferred to living tissues such as skin. Application to topical skin preparations is expected.
However, when an ascorbic acid-2-phosphate-6-higher fatty acid salt is formulated as an external preparation for skin, there are problems such as decomposition in the agent and a change in appearance. Generation | occurrence | production of precipitation becomes a cause of the deterioration of the touch at the time of applying a skin external preparation to skin not only the change of an external appearance.
The decomposition of ascorbic acid-2-phosphate-6-higher fatty acid salt is mainly caused by hydrolysis of higher fatty acid ester-bonded to the 6-position hydroxyl group of ascorbic acid. By this decomposition, a higher fatty acid salt insoluble in water, such as sodium palmitate, is generated and appears as a precipitate in the agent. Although it cannot be visually confirmed in a cloudy dosage form such as a cream, a problem arises in the appearance of a change in appearance as turbidity or precipitation in a transparent lotion system or a cosmetic liquid system.
In addition, ascorbic acid-2-phosphate-6-higher fatty acid salt has a lower solubility when stored at low temperature, so that ascorbic acid-2-phosphate-6-higher fatty acid salt itself precipitates in the formulated preparation. There is also the problem of waking up. This problem is particularly likely to occur when sodium ascorbyl-2-phosphate-6-palmitate is blended.
これまで、アスコルビン酸−２−リン酸−６−高級脂肪酸塩に対して他の成分を配合することにより、皮膚外用剤を安定化する種々の方法が提案されている。
たとえば特許文献１では、アスコルビン酸−２−リン酸−６−高級脂肪酸塩を含有する皮膚外用剤を安定化する方法として、カルボシキビニルポリマー等の水溶性合成高分子化合物および水を配合する方法が開示されている。該方法によれば、皮膚外用剤中でのアスコルビン酸−２−リン酸−６−高級脂肪酸塩の分解および減少が抑制され、皮膚外用剤の経時的な着色や沈殿の発生を抑制できるとされている。
特許文献２では、アスコルビン酸−２−リン酸−６−高級脂肪酸塩を含有する皮膚外用剤を安定化する方法として、多価アルコールを配合する方法が開示されている。該方法によれば、皮膚外用剤の経時的な濁りや沈殿の発生を抑制できるとされている。
特許文献３では、アスコルビン酸−２−リン酸−６−高級脂肪酸塩を含有する皮膚外用剤を安定化する方法として、平均重合度が８〜１２のポリグリセリンと炭素数１４〜２２の不飽和脂肪酸残基とからなるポリグリセリン脂肪酸エステル、および平均重合度が２〜６のポリグリセリンと炭素数１４〜２２の不飽和脂肪酸残基とからなるポリグリセリンモノ脂肪酸エステルを乳化剤として用いて、平均のエマルション粒子径が１〜２００ｎｍのエマルションとする方法が開示されている。該方法によれば、皮膚外用剤中でのアスコルビン酸−２−リン酸−６−高級脂肪酸塩の分解が抑制され、保存安定性が向上するとともに、透明〜半透明の美しい外観が保持されるとされている。
なお、アスコルビン酸およびその誘導体は、その抗酸化作用から、皮膚外用剤等の有効成分としてだけでなく、他の有効成分を安定化するためにも用いられている。たとえば特許文献４では、単独では安定性の悪いフラーレン、その誘導体、包接化合物またはその塩類を含有する組成物の安定性を高めるために、Ａ成分：保存安定剤又はキレート効果を有する有機酸またはその塩類、Ｂ成分：非イオン界面活性剤、Ｃ成分：アスコルビン酸又はその誘導体又はその塩類、Ｄ成分：紫外線防御剤、のうち少なくとも１種を配合することが提案されている。
So far, various methods for stabilizing a skin external preparation by blending other components with ascorbic acid-2-phosphate-6-higher fatty acid salt have been proposed.
For example, in Patent Document 1, as a method for stabilizing a skin external preparation containing ascorbyl 2-phosphate-6-higher fatty acid salt, a method of blending water-soluble synthetic polymer compound such as carboxyvinyl polymer and water Is disclosed. According to this method, it is said that decomposition and decrease of ascorbyl-2-phosphate-6-higher fatty acid salt in the external preparation for skin can be suppressed, and coloration and precipitation of the external preparation for skin over time can be suppressed. ing.
Patent Document 2 discloses a method of blending a polyhydric alcohol as a method for stabilizing an external preparation for skin containing ascorbic acid-2-phosphate-6-higher fatty acid salt. According to this method, it is said that generation of turbidity and precipitation over time of the external preparation for skin can be suppressed.
In Patent Document 3, as a method for stabilizing an external preparation for skin containing ascorbic acid-2-phosphate-6-higher fatty acid salt, polyglycerol having an average polymerization degree of 8 to 12 and unsaturated having 14 to 22 carbon atoms are used. A polyglycerin fatty acid ester composed of a fatty acid residue and a polyglycerin monofatty acid ester composed of a polyglycerin having an average degree of polymerization of 2 to 6 and an unsaturated fatty acid residue having 14 to 22 carbon atoms are used as an emulsifier. A method for producing an emulsion having an emulsion particle size of 1 to 200 nm is disclosed. According to this method, decomposition of ascorbic acid-2-phosphate-6-higher fatty acid salt in the external preparation for skin is suppressed, storage stability is improved, and a beautiful transparent to translucent appearance is maintained. It is said that.
Note that ascorbic acid and its derivatives are used not only as active ingredients such as external preparations for skin but also for stabilizing other active ingredients because of their antioxidant action. For example, in Patent Document 4, in order to increase the stability of a composition containing fullerene, a derivative thereof, an inclusion compound or a salt thereof, which is not stable by itself, component A: an organic acid having a storage stabilizer or a chelating effect or It has been proposed to blend at least one of salts thereof, B component: nonionic surfactant, C component: ascorbic acid or a derivative thereof or salts thereof, and D component: UV protection agent.
しかし、特許文献１に開示されるような水溶性合成高分子化合物を配合する方法の場合、ある程度のアスコルビン酸−２−リン酸−６−高級脂肪酸塩の分解抑制効果は得られるものの、製剤が不安定で、たとえばｐＨの変化や、塩化ナトリウム、クエン酸ナトリウム等の解離性化合物の添加による粘度の低下、沈殿、着色等が生じやすい。特に、カルボシキビニルポリマーの配合は、系の粘度を増大させることから乳化の安定化には有効であるが、水酸化カリウムや水酸化ナトリウムといった強アルカリ剤を添加し中和操作を行なうため、アスコルビン酸−２−リン酸−６−高級脂肪酸塩の分解が進みやすく、経時的な沈殿や着色が著しい。
特許文献２に開示されるような多価アルコールを配合する方法の場合、乳化剤型では多価アルコールの多用により粘度が低下して製剤を不安定化する傾向がある。
特許文献３に開示されるようなポリグリセリンモノ脂肪酸エステルを配合する方法の場合、塩化ナトリウム、クエン酸ナトリウム等の解離性化合物の添加により乳化が不安定になり、配合する化合物の種類によっては、クリーミングを引き起こすため油を含まない透明ローション系には使用できないなど、適用できる剤型が限られる問題がある。
特許文献４に開示される方法は、フラーレン類の安定性向上させる方法であり、アスコルビン酸−２−リン酸−６−高級脂肪酸塩自体の安定性を向上させる方法ではなく、配合成分によっては、アスコルビン酸−２−リン酸−６−高級脂肪酸塩の安定性が損なわれることがある。
このような背景の元、アスコルビン酸−２−リン酸−６−高級脂肪酸塩を含有し、かつ製剤安定性に優れ、経時的な濁りや沈殿が抑制され、感触にも優れた皮膚外用剤の創生がなお強く求められている。
However, in the case of the method of blending a water-soluble synthetic polymer compound as disclosed in Patent Document 1, although some degree of ascorbic acid-2-phosphate-6-higher fatty acid salt decomposition inhibitory effect is obtained, the formulation is It is unstable and tends to cause a decrease in viscosity, precipitation, coloring, etc. due to a change in pH, for example, addition of a dissociative compound such as sodium chloride or sodium citrate. In particular, the incorporation of a carboxyvinyl polymer is effective in stabilizing the emulsification because it increases the viscosity of the system. However, since a strong alkaline agent such as potassium hydroxide or sodium hydroxide is added to perform neutralization operation, Ascorbic acid-2-phosphate-6-higher fatty acid salt is easily decomposed, and precipitation and coloring over time are remarkable.
In the method of blending polyhydric alcohol as disclosed in Patent Document 2, the emulsifier type tends to destabilize the preparation by reducing the viscosity due to heavy use of polyhydric alcohol.
In the case of a method of blending a polyglycerin monofatty acid ester as disclosed in Patent Document 3, emulsification becomes unstable due to the addition of dissociative compounds such as sodium chloride and sodium citrate, and depending on the type of compound to be blended, There is a problem that applicable dosage forms are limited, for example, it cannot be used in a transparent lotion system containing no oil because it causes creaming.
The method disclosed in Patent Document 4 is a method for improving the stability of fullerenes, not a method for improving the stability of ascorbic acid-2-phosphate-6-higher fatty acid salt itself. The stability of ascorbic acid-2-phosphate-6-higher fatty acid salt may be impaired.
Based on this background, an external skin preparation containing ascorbyl 2-phosphate-6-higher fatty acid salt, excellent in formulation stability, suppressed turbidity and precipitation over time, and excellent in touch. There is still a strong demand for creation.
本発明は、上記事情に鑑みてなされたものであり、アスコルビン酸−２−リン酸−６−高級脂肪酸塩を含有し、かつ製剤安定性に優れた皮膚外用剤およびその製造方法を提供することを目的とする。 The present invention has been made in view of the above circumstances, and provides an external skin preparation containing ascorbic acid-2-phosphate-6-higher fatty acid salt and excellent in preparation stability, and a method for producing the same. With the goal.
本発明者らは、上記課題を解決すべく鋭意研究した結果、アスコルビン酸−２−リン酸−６−高級脂肪酸塩に特定のノニオン界面活性剤を組み合わせることによって上記の課題が達成されることを見出し、本発明を完成するに至った。
本発明は、以下の態様を有する。
［１］アスコルビン酸−２−リン酸−６−高級脂肪酸塩と、下記式（１）：
Ｒ１−Ｏ−（Ｒ２Ｏ）ｍ−（ＣＨ２ＣＨ２Ｏ）ｎ−Ｈ …（１）
［ただし、式（１）中のＲ１は直鎖状または分岐状のアルキル基であり；Ｒ２は−ＣＨ２ＣＨ（ＣＨ３）−または−ＣＨ（ＣＨ３）ＣＨ２−であり；ｍ、ｎはそれぞれ正の整数である。］
で表され、前記式（１）中のｍの平均値が２〜２５であり、ｎの平均値が３〜３４であるノニオン界面活性剤（１）と、を含有する皮膚外用剤。
［２］前記式（１）中のｍの平均値が６〜１２であり、かつｎの平均値が１２〜３０である、［１］に記載の皮膚外用剤。
［３］アスコルビン酸−２−リン酸誘導体として、前記アスコルビン酸−２−リン酸−６−高級脂肪酸塩のみが配合されている、［１］または［２］に記載の皮膚外用剤。
［４］前記アスコルビン酸−２−リン酸−６−高級脂肪酸塩が、アスコルビン酸−２−リン酸−６−パルミチン酸塩である、［１］〜［３］のいずれか一項に記載の皮膚外用剤。
［５］前記アスコルビン酸−２−リン酸−６−高級脂肪酸塩が、アルカリ金属塩である、［１］〜［４］のいずれか一項に記載の皮膚外用剤。
［６］前記ノニオン性界面活性剤（１）の含有量が、０．１〜１０質量％である、［１］〜［５］のいずれか一項に記載の皮膚外用剤。
［７］前記アスコルビン酸−２−リン酸−６−高級脂肪酸塩の含有量が、０．０１〜１０質量％である、［１］〜［６］のいずれか一項に記載の皮膚外用剤。
［８］ｐＨが６．５〜７．５である、［１］〜［７］のいずれか一項に記載の皮膚外用剤。
［９］さらに、下記式（２）：
ＨＯ−（ＣＨ２ＣＨ２Ｏ）ａ−（Ｒ３Ｏ）ｂ−（ＣＨ２ＣＨ２Ｏ）ｃ−Ｈ …（２）
［ただし、式（２）中のＲ３は−ＣＨ２ＣＨ（ＣＨ３）−または−ＣＨ（ＣＨ３）ＣＨ２−であり；ａ、ｂ、ｃはそれぞれ正の整数である。］
で表されるノニオン界面活性剤（２）を含有する、［１］〜［８］のいずれか一項に記載の皮膚外用剤。
［１０］前記式（２）中のａ＋ｃの平均値が４〜４００であり、ｂの平均値が５〜７０である、［９］に記載の皮膚外用剤。
［１１］前記ノニオン性界面活性剤（２）の含有量が、０．１〜１０質量％である、［９］または［１０］に記載の皮膚外用剤。
［１２］化粧料である、［１］〜［１１］のいずれか一項に記載の皮膚外用剤。
［１３］アスコルビン酸−２−リン酸−６−高級脂肪酸塩と、下記式（１）：
Ｒ１−Ｏ−（Ｒ２Ｏ）ｍ−（ＣＨ２ＣＨ２Ｏ）ｎ−Ｈ …（１）
［ただし、式（１）中のＲ１は直鎖状または分岐状のアルキル基であり；Ｒ２は−ＣＨ２ＣＨ（ＣＨ３）−または−ＣＨ（ＣＨ３）ＣＨ２−であり；ｍ、ｎはそれぞれ正の整数である。］
で表され、前記式（１）中のｍの平均値が２〜２５であり、ｎの平均値が３〜３４であるノニオン界面活性剤（１）と、を配合することを特徴とする皮膚外用剤の製造方法。
［１４］前記式（１）中のｍの平均値が６〜１２であり、かつｎの平均値が１２〜３０である、［１３］に記載の皮膚外用剤の製造方法。
［１５］アスコルビン酸−２−リン酸誘導体として、前記アスコルビン酸−２−リン酸−６−高級脂肪酸塩のみを配合する、［１３］または［１４］に記載の皮膚外用剤の製造方法。
［１６］前記ノニオン性界面活性剤（１）を、当該皮膚外用剤全量中の含有量が０．１〜１０質量％となるように配合する、［１３］〜［１５］のいずれか一項に記載の皮膚外用剤の製造方法。
［１７］前記アスコルビン酸−２−リン酸−６−高級脂肪酸塩を、当該皮膚外用剤全量中の含有量が０．０１〜１０質量％となるように配合する、［１３］〜［１６］のいずれか一項に記載の皮膚外用剤の製造方法。
［１８］さらに、下記式（２）：
ＨＯ−（ＣＨ２ＣＨ２Ｏ）ａ−（Ｒ３Ｏ）ｂ−（ＣＨ２ＣＨ２Ｏ）ｃ−Ｈ …（２）
［ただし、式（２）中のＲ３は−ＣＨ２ＣＨ（ＣＨ３）−または−ＣＨ（ＣＨ３）ＣＨ２−であり；ａ、ｂ、ｃはそれぞれ正の整数である。］
で表されるノニオン界面活性剤（２）を配合する、［１３］〜［１７］のいずれか一項に記載の皮膚外用剤の製造方法。
［１９］前記ノニオン性界面活性剤（２）を、当該皮膚外用剤全量中の含有量が０．１〜１０質量％となるように配合する、［１８］に記載の皮膚外用剤の製造方法。
As a result of intensive studies to solve the above problems, the present inventors have found that the above problems can be achieved by combining a specific nonionic surfactant with ascorbyl 2-phosphate-6-higher fatty acid salt. The headline and the present invention were completed.
The present invention has the following aspects.
[1] Ascorbic acid-2-phosphate-6-higher fatty acid salt and the following formula (1):
R 1 —O— (R 2 O) m — (CH 2 CH 2 O) n —H (1)
[Wherein R 1 in formula (1) is a linear or branched alkyl group; R 2 is —CH 2 CH (CH 3 ) — or —CH (CH 3 ) CH 2 —; m , N are each a positive integer. ]
And a nonionic surfactant (1) having an average value of m in the formula (1) of 2 to 25 and an average value of n of 3 to 34.
[2] The skin external preparation according to [1], wherein the average value of m in the formula (1) is 6 to 12, and the average value of n is 12 to 30.
[3] The external preparation for skin according to [1] or [2], wherein only the ascorbic acid-2-phosphate-6-higher fatty acid salt is blended as an ascorbic acid-2-phosphate derivative.
[4] The ascorbic acid-2-phosphate-6-higher fatty acid salt according to any one of [1] to [3], wherein the ascorbic acid-2-phosphate-6-palmitate is used. Skin external preparation.
[5] The external preparation for skin according to any one of [1] to [4], wherein the ascorbic acid-2-phosphate-6-higher fatty acid salt is an alkali metal salt.
[6] The external preparation for skin according to any one of [1] to [5], wherein the content of the nonionic surfactant (1) is 0.1 to 10% by mass.
[7] The external preparation for skin according to any one of [1] to [6], wherein the content of the ascorbic acid-2-phosphate-6-higher fatty acid salt is 0.01 to 10% by mass. .
[8] The external preparation for skin according to any one of [1] to [7], wherein the pH is 6.5 to 7.5.
[9] Further, the following formula (2):
HO— (CH 2 CH 2 O) a — (R 3 O) b — (CH 2 CH 2 O) c —H (2)
[Wherein R 3 in the formula (2) is —CH 2 CH (CH 3 ) — or —CH (CH 3 ) CH 2 —; a, b and c are each a positive integer. ]
The skin external preparation as described in any one of [1]-[8] containing the nonionic surfactant (2) represented by these.
[10] The skin external preparation according to [9], wherein the average value of a + c in the formula (2) is 4 to 400, and the average value of b is 5 to 70.
[11] The external preparation for skin according to [9] or [10], wherein the content of the nonionic surfactant (2) is 0.1 to 10% by mass.
[12] The external preparation for skin according to any one of [1] to [11], which is a cosmetic.
[13] Ascorbic acid-2-phosphate-6-higher fatty acid salt and the following formula (1):
R 1 —O— (R 2 O) m — (CH 2 CH 2 O) n —H (1)
[Wherein R 1 in formula (1) is a linear or branched alkyl group; R 2 is —CH 2 CH (CH 3 ) — or —CH (CH 3 ) CH 2 —; m , N are each a positive integer. ]
And a nonionic surfactant (1) having an average value of m in the formula (1) of 2 to 25 and an average value of n of 3 to 34. A method for producing an external preparation.
[14] The method for producing an external preparation for skin according to [13], wherein the average value of m in the formula (1) is 6 to 12, and the average value of n is 12 to 30.
[15] The method for producing an external preparation for skin according to [13] or [14], wherein only the ascorbic acid-2-phosphate-6-higher fatty acid salt is blended as an ascorbic acid-2-phosphate derivative.
[16] Any one of [13] to [15], wherein the nonionic surfactant (1) is blended so that the content in the total amount of the external preparation for skin is 0.1 to 10% by mass. The manufacturing method of skin external preparation as described in any one of.
[17] The above ascorbic acid-2-phosphate-6-higher fatty acid salt is blended so that the content in the total amount of the external preparation for skin is 0.01 to 10% by mass. [13] to [16] The manufacturing method of the skin external preparation as described in any one of these.
[18] Further, the following formula (2):
HO— (CH 2 CH 2 O) a — (R 3 O) b — (CH 2 CH 2 O) c —H (2)
[Wherein R 3 in the formula (2) is —CH 2 CH (CH 3 ) — or —CH (CH 3 ) CH 2 —; a, b and c are each a positive integer. ]
The manufacturing method of the external preparation for skin as described in any one of [13]-[17] which mix | blends nonionic surfactant (2) represented by these.
[19] The method for producing a skin external preparation according to [18], wherein the nonionic surfactant (2) is blended so that the content in the total amount of the skin external preparation is 0.1 to 10% by mass. .
本発明によれば、アスコルビン酸−２−リン酸−６−高級脂肪酸塩を含有し、かつ製剤安定性に優れた皮膚外用剤およびその製造方法を提供できる。 ADVANTAGE OF THE INVENTION According to this invention, the skin external preparation which contains ascorbic acid-2-phosphate-6-higher fatty acid salt, and was excellent in formulation stability, and its manufacturing method can be provided.
＜アスコルビン酸−２−リン酸−６−高級脂肪酸塩＞
アスコルビン酸−２−リン酸−６−高級脂肪酸塩は、アスコルビン酸の２位の炭素原子に結合した水酸基にリン酸がエステル結合し、６位の炭素原子に結合した水酸基に高級脂肪酸がエステル結合し、前記リン酸基中のリン原子に結合した水酸基２つとアスコルビン酸の３位の炭素原子に結合した水酸基とのいずれか少なくとも１つから水素原子が解離して形成されるアニオンと、対イオンとが塩を形成した化合物であり、例えば、下記構造式で表されるアニオンと対イオンとの塩が挙げられる。なお、高級脂肪酸とは、通常、炭素数１１以上の脂肪酸を指す。
アスコルビン酸−２−リン酸−６−高級脂肪酸塩としての取り扱いやすさから、前記高級脂肪酸の炭素数としては１２〜２８が好ましい。
前記対イオンとしては、アルカリ金属イオンが好ましい。すなわちアスコルビン酸−２−リン酸−６−高級脂肪酸塩としてはアルカリ金属塩が好ましい。アルカリ金属として具体的にはナトリウム、カリウム等が挙げられる。
<Ascorbic acid-2-phosphate-6-higher fatty acid salt>
Ascorbic acid-2-phosphate-6-higher fatty acid salt has phosphoric acid ester-bonded to the hydroxyl group bonded to the 2-position carbon atom of ascorbic acid, and higher fatty acid ester-bonded to the hydroxyl group bonded to the 6-position carbon atom An anion formed by dissociation of a hydrogen atom from at least one of two hydroxyl groups bonded to the phosphorus atom in the phosphate group and a hydroxyl group bonded to the 3-position carbon atom of ascorbic acid; Is a compound that forms a salt, and examples thereof include a salt of an anion and a counter ion represented by the following structural formula. The higher fatty acid usually refers to a fatty acid having 11 or more carbon atoms.
In view of ease of handling as ascorbic acid-2-phosphate-6-higher fatty acid salt, the higher fatty acid preferably has 12 to 28 carbon atoms.
The counter ion is preferably an alkali metal ion. That is, as the ascorbic acid-2-phosphate-6-higher fatty acid salt, an alkali metal salt is preferable. Specific examples of the alkali metal include sodium and potassium.
本発明の皮膚外用剤においては、後述するように、アスコルビン酸−２−リン酸−６−高級脂肪酸塩以外のアスコルビン酸−２−リン酸誘導体を配合してもよいが、アスコルビン酸−２−リン酸誘導体としてアスコルビン酸−２−リン酸−６−高級脂肪酸塩のみを配合すると、アスコルビン酸−２−リン酸−６−高級脂肪酸塩の分解がより抑えられ、製剤の安定性が良好になり、着色や沈殿等が増加しにくくなる。
このような効果を得やすい点で、アスコルビン酸−２−リン酸−６−高級脂肪酸塩としては、アスコルビン酸−２−リン酸−６−パルミチン酸塩が好ましく、アスコルビン酸−２−リン酸−６−高級脂肪酸アルカリ金属塩がより好ましく、アスコルビン酸−２−リン酸−６−高級脂肪酸ナトリウム塩が更に好ましく、アスコルビン酸−２−リン酸−６−パルミチン酸ナトリウムが特に好ましい。
In the skin external preparation of the present invention, ascorbic acid-2-phosphate derivative other than ascorbic acid-2-phosphate-6-higher fatty acid salt may be blended as will be described later. When only ascorbic acid-2-phosphate-6-higher fatty acid salt is added as a phosphoric acid derivative, the decomposition of ascorbic acid-2-phosphate-6-higher fatty acid salt is further suppressed, and the stability of the preparation is improved. Coloring, precipitation and the like are less likely to increase.
As the ascorbic acid-2-phosphate-6-higher fatty acid salt is preferable ascorbic acid-2-phosphate-6-palmitate, ascorbic acid-2-phosphate- 6-higher fatty acid alkali metal salts are more preferable, ascorbic acid-2-phosphate-6-higher fatty acid sodium salt is more preferable, and sodium ascorbyl-2-phosphate-6-palmitate is particularly preferable.
アスコルビン酸−２−リン酸−６−高級脂肪酸塩としては、１種を単独で用いても２種以上を併用してもよい。
アスコルビン酸−２−リン酸−６−高級脂肪酸塩の配合量は、皮膚外用剤全量中、０．０１〜１０質量％が好ましく、０．５〜５質量％がより好ましい。０．０１質量％以上であると、本発明の皮膚外用剤を皮膚に適用した際に、アスコルビン酸−２−リン酸−６−高級脂肪酸塩の皮膚への移行が速やかであり、皮膚外用剤に求められる効能効果が充分に発揮される。１０質量％を超えて配合しても、さらに高い効果が得られるとは限らないので、経済的ではない。
As ascorbic acid-2-phosphate-6-higher fatty acid salt, one kind may be used alone, or two or more kinds may be used in combination.
The amount of ascorbic acid-2-phosphate-6-higher fatty acid salt is preferably 0.01 to 10% by mass and more preferably 0.5 to 5% by mass in the total amount of the external preparation for skin. When the skin external preparation of the present invention is applied to the skin when it is 0.01% by mass or more, the ascorbic acid-2-phosphate-6-higher fatty acid salt is rapidly transferred to the skin, and the skin external preparation The effects and effects required for this are fully demonstrated. Even if it exceeds 10% by mass, a higher effect is not always obtained, so it is not economical.
＜ノニオン界面活性剤（１）＞
本発明の皮膚外用剤は、アスコルビン酸−２−リン酸−６−高級脂肪酸塩とともに、下記式（１）：
Ｒ１−Ｏ−（Ｒ２Ｏ）ｍ−（ＣＨ２ＣＨ２Ｏ）ｎ−Ｈ …（１）
［ただし、式（１）中のＲ１は直鎖状または分岐状のアルキル基であり；Ｒ２は−ＣＨ２ＣＨ（ＣＨ３）−または−ＣＨ（ＣＨ３）ＣＨ２−であり；ｍ、ｎはそれぞれ正の整数である。］
で表され、前記式（１）中のｍの平均値が２〜２５であり、ｎの平均値が３〜３４であるノニオン界面活性剤（１）を含有する。
ノニオン界面活性剤（１）は、直鎖状または分岐状のアルキルアルコールとポリオキシエチレン（ＰＯＥ）鎖（（ＣＨ２ＣＨ２Ｏ）ｎ）がエーテル結合し、さらに直鎖状または分岐状のアルキル鎖とＰＯＥ鎖にポリオキシプロピレン（ＰＯＰ）鎖（（Ｒ２Ｏ）ｍ）がエーテル結合した構造をとるＰＯＥ・ＰＯＰアルキルエーテルである。
<Nonionic surfactant (1)>
The skin external preparation of the present invention has the following formula (1) together with ascorbic acid-2-phosphate-6-higher fatty acid salt:
R 1 —O— (R 2 O) m — (CH 2 CH 2 O) n —H (1)
[Wherein R 1 in formula (1) is a linear or branched alkyl group; R 2 is —CH 2 CH (CH 3 ) — or —CH (CH 3 ) CH 2 —; m , N are each a positive integer. ]
The nonionic surfactant (1) in which the average value of m in the formula (1) is 2 to 25 and the average value of n is 3 to 34 is contained.
Nonionic surfactant (1) is a linear or branched alkyl alcohol and a polyoxyethylene (POE) chain ((CH 2 CH 2 O) n ) ether-bonded, and further a linear or branched alkyl This is a POE / POP alkyl ether having a structure in which a polyoxypropylene (POP) chain ((R 2 O) m ) is ether-bonded to a chain and a POE chain.
前記式（１）中、Ｒ１は直鎖状または分岐状のアルキル基である。Ｒ１のアルキル基は、直鎖状、分岐状のいずれであってもよく、分岐が少ない方が好ましく、分岐が１箇所の分岐状のアルキル基または直鎖状のアルキル基が好ましい。Ｒ１の炭素数は、特に限定されないが、８〜３０が好ましく、１０〜２６がより好ましく、１６〜２４がさらに好ましい。
Ｒ１の直鎖状または分岐状のアルキル基としては、特に限定するものではないが、例えば、デシル基、ラウリル基、セチル基、ステアリル基、デシルテトラデシル基などが挙げられる。
前記式（１）中、ｍはＰＯＰ鎖を構成するオキシプロピレン基（ＣＨ２ＣＨ（ＣＨ３）ＯまたはＣＨ（ＣＨ３）ＣＨ２Ｏ）の数（重合度）を示す。また、ｎはＰＯＥ鎖を構成するオキシエチレン基（ＣＨ２ＣＨ２Ｏ）の数（重合度）を示す。
ノニオン界面活性剤（１）において、ｍの平均値、すなわちノニオン界面活性剤（１）１分子あたりのオキシプロピレン基の数（平均重合度）は、２〜２５であり、３〜２５が好ましく、５〜３４がより好ましい。また、ｎの平均値、すなわちノニオン界面活性剤（１）１分子あたりのオキシエチレン基の数（平均重合度）は、３〜３４であり、６〜１２が好ましく、３〜３４がより好ましい。ｍおよびｎの値がそれぞれ上記範囲内であれば、皮膚外用剤の製剤安定性が充分に得られる。
ｍ＋ｎの平均値、すなわちノニオン界面活性剤（１）１分子あたりのオキシプロピレン基およびオキシエチレン基の合計数は、ｍ、ｎの値がそれぞれ上記範囲内であれば特に限定されないが、５〜５９が好ましく、２５〜３８がより好ましい。
ｍ／ｎ比は、ｍ、ｎの値がそれぞれ上記範囲内であれば特に限定されないが、０．０５〜２０が好ましく、０．２〜１がより好ましい。
In the formula (1), R 1 is a linear or branched alkyl group. The alkyl group for R 1 may be either linear or branched, and is preferably less branched, and is preferably a branched alkyl group having one branch or a linear alkyl group. The number of carbon atoms of R 1 is not particularly limited, but is preferably 8 to 30, more preferably from 10 to 26, more preferably 16 to 24.
Examples of the linear or branched alkyl group of R 1, is not particularly limited, for example, decyl group, lauryl group, cetyl group, stearyl group, and decyltetradecyl group.
In the formula (1), m represents the number (degree of polymerization) of oxypropylene groups (CH 2 CH (CH 3 ) O or CH (CH 3 ) CH 2 O) constituting the POP chain. N represents the number (degree of polymerization) of oxyethylene groups (CH 2 CH 2 O) constituting the POE chain.
In the nonionic surfactant (1), the average value of m, that is, the number of oxypropylene groups (average polymerization degree) per molecule of the nonionic surfactant (1) is 2 to 25, preferably 3 to 25, 5-34 is more preferable. Moreover, the average value of n, ie, the number of nonoxysurfactant (1) oxyethylene groups per molecule (average polymerization degree), is 3 to 34, preferably 6 to 12, and more preferably 3 to 34. When the values of m and n are within the above ranges, the preparation stability of the external preparation for skin can be sufficiently obtained.
The average value of m + n, that is, the total number of oxypropylene groups and oxyethylene groups per molecule of the nonionic surfactant (1) is not particularly limited as long as the values of m and n are within the above ranges, respectively. Is preferable, and 25-38 are more preferable.
Although m / n ratio will not be specifically limited if the value of m and n is in the said range, respectively, 0.05-20 are preferable and 0.2-1 are more preferable.
ノニオン界面活性剤（１）として具体的には、ＰＯＥ（４）ＰＯＰ（２）デシルエーテル、ＰＯＥ（７）ＰＯＰ（２）デシルエーテル、ＰＯＥ（８）ＰＯＰ（２）デシルエーテル、ＰＯＥ（１０）ＰＯＰ（２）デシルエーテル、ＰＯＥ（１５）ＰＯＰ（２）デシルエーテル、ＰＯＥ（２０）ＰＯＰ（２）デシルエーテル、ＰＯＥ（３０）ＰＯＰ（２）デシルエーテル、ＰＯＥ（４０）ＰＯＰ（２）デシルエーテル、ＰＯＥ（８）ＰＯＰ（２）ラウリルエーテル、ＰＯＥ（１５）ＰＯＰ（４）ラウリルエーテル、ＰＯＥ（１０）ＰＯＰ（４）セチルエーテル、ＰＯＥ（２０）ＰＯＰ（４）セチルエーテル、ＰＯＥ（２０）ＰＯＰ（８）セチルエーテル、ＰＯＥ（２０）ＰＯＰ（６）デシルテトラデシルエーテル、ＰＯＥ（３０）ＰＯＰ（６）デシルテトラデシルエーテルなどが挙げられるが、これらに限定されるものではない。これらの中では、ＰＯＥ（２０）ＰＯＰ（８）セチルエーテル、ＰＯＥ（１２）ＰＯＰ（６）デシルテトラデシルエーテル、ＰＯＥ（２０）ＰＯＰ（６）デシルテトラデシルエーテル、ＰＯＥ（３０）ＰＯＰ（６）デシルテトラデシルエーテルが好ましい。なお、ＰＯＥの後の括弧内の数値は、ＰＯＥ鎖の平均重合度（すなわち前記式（１）中のｎの平均値）を示す。ＰＯＰの後の括弧内の数値は、ＰＯＰ鎖の平均重合度（すなわち前記式（１）中のｍの平均値）を示す。
ノニオン界面活性剤（１）は、公知の製造方法により製造してもよく、市販品を用いてもよい。市販品としては、例えば、日本エマルジョン（株）製の商品名「ＥＭＡＬＥＸ」シリーズ、第一工業製薬（株）製の商品名「ノイゲン」シリーズ、日光ケミカルズ（株）製の商品名「ＮＩＫＫＯＬ ＰＢＣ」シリーズ、「ＮＩＫＫＯＬ ＰＥＮ」シリーズ、などが挙げられる。
Specific examples of the nonionic surfactant (1) include POE (4) POP (2) decyl ether, POE (7) POP (2) decyl ether, POE (8) POP (2) decyl ether, POE (10). POP (2) decyl ether, POE (15) POP (2) decyl ether, POE (20) POP (2) decyl ether, POE (30) POP (2) decyl ether, POE (40) POP (2) decyl ether , POE (8) POP (2) lauryl ether, POE (15) POP (4) lauryl ether, POE (10) POP (4) cetyl ether, POE (20) POP (4) cetyl ether, POE (20) POP (8) Cetyl ether, POE (20) POP (6) decyl tetradecyl ether, POE (30) POP (6) de Le tetradecyl ether and the like, but not limited thereto. Among these, POE (20) POP (8) cetyl ether, POE (12) POP (6) decyl tetradecyl ether, POE (20) POP (6) decyl tetradecyl ether, POE (30) POP (6) Decyl tetradecyl ether is preferred. The numerical value in parentheses after POE indicates the average degree of polymerization of the POE chain (that is, the average value of n in the formula (1)). The numerical value in parentheses after POP indicates the average degree of polymerization of the POP chain (that is, the average value of m in the formula (1)).
The nonionic surfactant (1) may be produced by a known production method, or a commercially available product may be used. Examples of commercially available products include “EMALEX” series manufactured by Nippon Emulsion Co., Ltd., “Neugen” series manufactured by Daiichi Kogyo Seiyaku Co., Ltd., and “NIKKOL PBC” manufactured by Nikko Chemicals Co., Ltd. Series, “NIKKOL PEN” series, and the like.
ノニオン界面活性剤（１）は、１種を単独で用いても２種以上を併用してもよい。
ノニオン界面活性剤（１）の含有量は、皮膚外用剤全量中、０．１〜１０質量％が好ましく、０．５〜２質量％がより好ましい。０．１質量％以上であると、製剤の安定性に優れ、保存時の沈殿や濁りが生じにくい。１０質量％を超えて配合しても、さらに高い効果が得られるとは限らないので、経済的ではない。
Nonionic surfactant (1) may be used individually by 1 type, or may use 2 or more types together.
The content of the nonionic surfactant (1) is preferably 0.1 to 10% by mass and more preferably 0.5 to 2% by mass in the total amount of the external preparation for skin. When the content is 0.1% by mass or more, the stability of the preparation is excellent, and precipitation and turbidity during storage are less likely to occur. Even if it exceeds 10% by mass, a higher effect is not always obtained, so it is not economical.
＜ノニオン界面活性剤（２）＞
本発明の皮膚外用剤は、さらに、下記式（２）：
ＨＯ−（ＣＨ２ＣＨ２Ｏ）ａ−（Ｒ３Ｏ）ｂ−（ＣＨ２ＣＨ２Ｏ）ｃ−Ｈ …（２）
［ただし、式（２）中のＲ３は−ＣＨ２ＣＨ（ＣＨ３）−または−ＣＨ（ＣＨ３）ＣＨ２−であり；ａ、ｂ、ｃはそれぞれ正の整数である。］
で表されるノニオン界面活性剤（２）を含有することが好ましい。
ノニオン界面活性剤（２）は、ＰＯＥ鎖の間にＰＯＰ鎖がエーテル結合したＰＯＥ−ＰＯＰ−ＰＯＥブロック共重合体の構造（以下、ＰＯＥ−ＰＯＰ−ＰＯＥ型ということがある。）をとるＰＯＥ・ＰＯＰグリコールである。
このようなノニオン界面活性剤（２）をさらに配合することにより、低温から高温の広い温度範囲で、皮膚外用剤の製剤安定性がより良好になる。
<Nonionic surfactant (2)>
The skin external preparation of the present invention further includes the following formula (2):
HO— (CH 2 CH 2 O) a — (R 3 O) b — (CH 2 CH 2 O) c —H (2)
[Wherein R 3 in the formula (2) is —CH 2 CH (CH 3 ) — or —CH (CH 3 ) CH 2 —; a, b and c are each a positive integer. ]
It is preferable to contain the nonionic surfactant (2) represented by these.
The nonionic surfactant (2) has a POE-POP-POE block copolymer structure in which POP chains are ether-bonded between POE chains (hereinafter sometimes referred to as POE-POP-POE type). POP glycol.
By further blending such a nonionic surfactant (2), the formulation stability of the external preparation for skin becomes better in a wide temperature range from low temperature to high temperature.
前記式（２）中、ａは、ＰＯＥ鎖（ＣＨ２ＣＨ２Ｏ）ａを構成するオキシエチレン基の数（重合度）を示す。ｂはＰＯＰ鎖（Ｒ３Ｏ）ｂを構成するオキシプロピレン基の数（重合度）を示す。ｃはＰＯＥ鎖（ＣＨ２ＣＨ２Ｏ）ｃを構成するオキシエチレン基の数（重合度）を示す。
ノニオン界面活性剤（２）において、ａ＋ｃの平均値、すなわちノニオン界面活性剤（２）１分子あたりのオキシエチレン基の数（平均重合度）は、４〜４００が好ましく、２０〜１６０がより好ましい。また、ｂの平均値、すなわちノニオン界面活性剤（２）１分子あたりのオキシプロピレン基の数（平均重合度）は、５〜７０が好ましく、２０〜５０がより好ましい。ａ＋ｃおよびｂの値がそれぞれ上記範囲内であれば、皮膚外用剤の製剤安定性向上効果に優れる。
ａ＋ｂ＋ｃの平均値、すなわちノニオン界面活性剤（２）１分子あたりのオキシプロピレン基およびオキシエチレン基の合計数は、７〜４７０が好ましく、２０〜１００がより好ましい。
（ａ＋ｃ）／ｂ比は、０．０５〜８０が好ましく、０．３〜３がより好ましい。
In the formula (2), a represents the number of oxyethylene groups (degree of polymerization) constituting the POE chain (CH 2 CH 2 O) a . b represents the number (degree of polymerization) of oxypropylene groups constituting the POP chain (R 3 O) b . c is a number (polymerization degree) of oxyethylene groups constituting the POE chain (CH 2 CH 2 O) c .
In the nonionic surfactant (2), the average value of a + c, that is, the number of oxyethylene groups (average degree of polymerization) per molecule of the nonionic surfactant (2) is preferably 4 to 400, more preferably 20 to 160. . Moreover, 5-70 are preferable and, as for the average value of b, ie, the number of nonoxysurfactant (2) oxypropylene groups per molecule (average polymerization degree), 20-50 are more preferable. If the value of a + c and b is in the said range, respectively, it is excellent in the formulation stability improvement effect of a skin external preparation.
The average value of a + b + c, that is, the total number of oxypropylene groups and oxyethylene groups per molecule of the nonionic surfactant (2) is preferably 7 to 470, more preferably 20 to 100.
The (a + c) / b ratio is preferably 0.05 to 80, and more preferably 0.3 to 3.
ノニオン界面活性剤（２）として具体的には、ＰＯＥ（５）ＰＯＰ（５）グリコール、ＰＯＥ（５）ＰＯＰ（３０）グリコール、ＰＯＥ（１０）ＰＯＰ（８）グリコール、ＰＯＥ（１６）ＰＯＰ（１７）グリコール、ＰＯＥ（２０）ＰＯＰ（２０）グリコール、ＰＯＥ（２５）ＰＯＰ（３０）グリコール、ＰＯＥ（３５）ＰＯＰ（４０）グリコール、ＰＯＥ（１００）ＰＯＰ（４０）グリコール、ＰＯＥ（３００）ＰＯＰ（５５）グリコール、ＰＯＥ（４００）ＰＯＰ（７０）グリコールなどが挙げられるが、これらに限定されるものではない。これらの中では、ＰＯＥ（２５）ＰＯＰ（３０）グリコール、ＰＯＥ（３５）ＰＯＰ（４０）グリコールが、前記皮膚外用剤の製剤安定性の観点からより好ましい。
なお、これらはいずれもＰＯＥ−ＰＯＰ−ＰＯＥ型のＰＯＥ・ＰＯＰグリコールである。ＰＯＥの後の括弧内の数値は、ＰＯＥ鎖の平均重合度（すなわち前記式（２）中のａ＋ｃの平均値）を示す。ＰＯＰの後の括弧内の数値は、ＰＯＰ鎖の平均重合度（すなわち前記式（２）中のｂの平均値）を示す。
ノニオン界面活性剤（２）は、公知の製造方法により製造してもよく、市販品を用いても良い。市販品としては、例えば、（株）アデカ製の商品名「アデカプルロニックＬ」シリーズ、「アデカプルロニックＰ」シリーズ、「アデカプルロニックＦ」シリーズ、三洋化成工業（株）製の商品名「ニューポールＰＥ」シリーズなどが挙げられる。
Specific examples of the nonionic surfactant (2) include POE (5) POP (5) glycol, POE (5) POP (30) glycol, POE (10) POP (8) glycol, POE (16) POP (17). ) Glycol, POE (20) POP (20) glycol, POE (25) POP (30) glycol, POE (35) POP (40) glycol, POE (100) POP (40) glycol, POE (300) POP (55) ) Glycol, POE (400) POP (70) glycol and the like, but are not limited thereto. Among these, POE (25) POP (30) glycol and POE (35) POP (40) glycol are more preferable from the viewpoint of the formulation stability of the external preparation for skin.
These are all POE-POP-POE type POE / POP glycols. The numerical value in parentheses after POE indicates the average degree of polymerization of the POE chain (that is, the average value of a + c in the formula (2)). The numerical value in parentheses after POP indicates the average degree of polymerization of the POP chain (that is, the average value of b in the formula (2)).
The nonionic surfactant (2) may be produced by a known production method, or a commercially available product may be used. Commercially available products include, for example, trade names “Adeka Pluronic L” series, “Adeka Pluronic P” series, “Adeka Pluronic F” series manufactured by Adeka Co., Ltd., “New Pole PE” manufactured by Sanyo Chemical Industries, Ltd. ”Series.
ノニオン界面活性剤（２）は、１種を単独で用いても２種以上を併用してもよい。
ノニオン界面活性剤（２）を配合する場合、皮膚外用剤中のノニオン界面活性剤（２）の含有量は、皮膚外用剤全量中、０．１〜１０質量％が好ましく、０．５〜２質量％がより好ましい。０．１質量％以上であると、ノニオン界面活性剤（２）を配合する効果が充分に得られる。１０質量％を超えて配合しても、さらに高い効果が得られるとは限らないので、経済的ではない。
Nonionic surfactant (2) may be used individually by 1 type, or may use 2 or more types together.
When mix | blending nonionic surfactant (2), 0.1-10 mass% is preferable in content of nonionic surfactant (2) in skin external preparation in the skin external preparation whole quantity, 0.5-2 The mass% is more preferable. The effect which mix | blends nonionic surfactant (2) is fully acquired as it is 0.1 mass% or more. Even if it exceeds 10% by mass, a higher effect is not always obtained, so it is not economical.
＜その他の任意成分＞
本発明の皮膚外用剤は、本発明の効果を損なわない範囲で、アスコルビン酸およびその塩、ならびにアスコルビン酸−２−リン酸−６−高級脂肪酸塩以外のアスコルビン酸誘導体から選ばれる少なくとも１種を配合してもよい。
アスコルビン酸の塩としては、ナトリウム塩、カリウム塩等が挙げられる。
アスコルビン酸−２−リン酸−６−高級脂肪酸塩以外のアスコルビン酸誘導体としては、アスコルビン酸−２−リン酸およびその塩、アスコルビン酸−３−リン酸−６−高級脂肪酸およびその塩、アスコルビン酸−６−高級脂肪酸およびその塩、アスコルビン酸−２，６−ジ高級脂肪酸およびその塩、アスコルビン酸−２，３，５，６−テトラ高級脂肪酸およびその塩、アスコルビン酸−２−硫酸およびその塩、アスコルビル−２−グルコシド等が挙げられる。塩としては、ナトリウム塩、カリウム塩等が挙げられる。高級脂肪酸としては、炭素数８〜２２の脂肪酸が挙げられる。
ただし、本発明の皮膚外用剤は、アスコルビン酸−２−リン酸誘導体として、前記アスコルビン酸−２−リン酸−６−高級脂肪酸塩のみが配合されていることが好ましい。すなわち、本発明の皮膚外用剤には、アスコルビン酸−２−リン酸−６−高級脂肪酸塩以外のアスコルビン酸−２−リン酸誘導体を配合しないことが好ましい。本発明者の検討によれば、アスコルビン酸−２−リン酸誘導体として、アスコルビン酸−２−リン酸−６−高級脂肪酸塩と、それ以外のアスコルビン酸−２−リン酸誘導体を共に配合するよりも、アスコルビン酸−２−リン酸−６−高級脂肪酸塩のみを配合した方が、アスコルビン酸−２−リン酸−６−高級脂肪酸塩の分解が抑制され、製剤安定性が向上しやすい。すなわちアスコルビン酸−２−リン酸−６−高級脂肪酸塩以外のアスコルビン酸−２−リン酸誘導体を配合しないことで製剤安定性がより優れたものとなる。
アスコルビン酸−２−リン酸誘導体は、アスコルビン酸誘導体のうち、少なくとも、アスコルビン酸の２位の炭素原子に結合した水酸基にリン酸がエステル結合した化合物を意味する。上記のアスコルビン酸誘導体のうち、アスコルビン酸−２−リン酸−６−高級脂肪酸塩以外のアスコルビン酸−２−リン酸誘導体としては、アスコルビン酸−２−リン酸およびその塩が挙げられる。
なお、皮膚外用剤中で、アスコルビン酸−２−リン酸−６−高級脂肪酸塩が分解して高級脂肪酸とアスコルビン酸−２−リン酸が生じることがある。そのため、本発明の皮膚外用剤には、製造時に配合していなくても、微量のアスコルビン酸−２−リン酸やその塩が含まれることがある。
また、皮膚外用剤中で、アスコルビン酸−２−リン酸−６−高級脂肪酸塩の２位のリン酸基が経時的に３位へ転位することがある。そのため、本発明の皮膚外用剤には、製造時に配合していなくても、微量のアスコルビン酸−３−リン酸−６−高級脂肪酸塩が含まれることがある。
<Other optional components>
The external preparation for skin of the present invention contains at least one selected from ascorbic acid and its salts, and ascorbic acid derivatives other than ascorbic acid-2-phosphate-6-higher fatty acid salts, as long as the effects of the present invention are not impaired. You may mix | blend.
Examples of ascorbic acid salts include sodium salts and potassium salts.
Ascorbic acid-2-phosphoric acid and its salt, ascorbic acid-3-phosphate-6-higher fatty acid and its salt, ascorbic acid, other than ascorbic acid-2-phosphate-6-higher fatty acid salt -6 higher fatty acids and salts thereof, ascorbic acid-2,6-di higher fatty acids and salts thereof, ascorbic acid-2,3,5,6-tetra higher fatty acids and salts thereof, ascorbic acid-2-sulfuric acid and salts thereof And ascorbyl-2-glucoside. Examples of the salt include sodium salt and potassium salt. Examples of higher fatty acids include fatty acids having 8 to 22 carbon atoms.
However, it is preferable that the skin external preparation of the present invention contains only the ascorbic acid-2-phosphate-6-higher fatty acid salt as the ascorbic acid-2-phosphate derivative. That is, it is preferable not to mix | blend the ascorbic acid-2-phosphate derivative other than ascorbyl 2-phosphate-6-higher fatty acid salt with the skin external preparation of this invention. According to the inventor's study, ascorbic acid-2-phosphate derivative, ascorbyl-2-phosphate-6-higher fatty acid salt and other ascorbic acid-2-phosphate derivatives are mixed together. However, when only ascorbic acid-2-phosphate-6-higher fatty acid salt is added, decomposition of ascorbic acid-2-phosphate-6-higher fatty acid salt is suppressed, and the stability of the preparation is easily improved. That is, the preparation stability is further improved by not incorporating an ascorbyl 2-phosphate derivative other than ascorbyl 2-phosphate-6-higher fatty acid salt.
The ascorbic acid-2-phosphate derivative means a compound in which phosphoric acid is ester-bonded to at least a hydroxyl group bonded to the carbon atom at the 2-position of ascorbic acid among the ascorbic acid derivatives. Among the above ascorbic acid derivatives, ascorbic acid-2-phosphate derivatives other than ascorbic acid-2-phosphate-6-higher fatty acid salts include ascorbic acid-2-phosphate and salts thereof.
In addition, in a skin external preparation, ascorbic acid-2-phosphate-6-higher fatty acid salt may be decomposed to produce higher fatty acid and ascorbic acid-2-phosphate. Therefore, the skin external preparation of the present invention may contain a trace amount of ascorbic acid-2-phosphate or a salt thereof even if it is not blended at the time of manufacture.
Further, in the external preparation for skin, the phosphate group at the 2-position of the ascorbic acid-2-phosphate-6-higher fatty acid salt may rearrange to the 3-position over time. Therefore, the skin external preparation of the present invention may contain a trace amount of ascorbic acid-3-phosphate-6-higher fatty acid salt even if it is not blended at the time of manufacture.
本発明の皮膚外用剤は、上記のほか、必要に応じて、本発明の効果を損なわない範囲で、皮膚外用剤に通常用いられる成分、たとえば皮膚外用剤として薬学的に許容され得る担体、添加剤等を含有してもよい。このような成分としては、たとえば、炭化水素類、天然油脂類、脂肪酸類、高級アルコール類、アルキルグリセリルエーテル類、エステル類、シリコーン油類、多価アルコール類、一価の低級アルコール類、糖類、高分子類、アニオン界面活性剤、カチオン界面活性剤、両性界面活性剤、前記ノニオン界面活性剤（１）および（２）に該当しないノニオン界面活性剤、天然系界面活性剤、紫外線吸収剤、粉体類、色材類、アミノ酸類、ペプチド類、ビタミン類、ビタミン様作用因子類、防腐剤、酸化防止剤、金属イオン封鎖剤、保湿剤、抗炎症剤、ｐＨ調整剤、塩類、有機酸類、美白剤、精油類、テルペン類、香料、水等が挙げられる。 In addition to the above, the external preparation for skin of the present invention contains components usually used for external preparation for skin, for example, a pharmaceutically acceptable carrier as an external preparation for skin, as long as the effects of the present invention are not impaired. An agent or the like may be contained. Examples of such components include hydrocarbons, natural fats and oils, fatty acids, higher alcohols, alkyl glyceryl ethers, esters, silicone oils, polyhydric alcohols, monovalent lower alcohols, saccharides, Polymers, anionic surfactants, cationic surfactants, amphoteric surfactants, nonionic surfactants not corresponding to the nonionic surfactants (1) and (2), natural surfactants, UV absorbers, powders Body, coloring materials, amino acids, peptides, vitamins, vitamin-like agents, preservatives, antioxidants, sequestering agents, moisturizers, anti-inflammatory agents, pH adjusters, salts, organic acids, Whitening agents, essential oils, terpenes, fragrances, water and the like.
本発明の皮膚外用剤としては、化粧料、医薬品等が挙げられる。
本発明の皮膚外用剤が化粧料である場合、さらに、既存の化粧品原料を一般的な濃度で添加することもできる。たとえば、化粧品原料基準第二版注解、日本公定書教会編、１９８４（薬事日報社）、化粧品原料基準外成分規格、厚生省薬務局審査課監修、１９９３（薬事日報社）、化粧品原料基準外成分規格追補、厚生省薬務局審査課監修、１９９３（薬事日報社）、化粧品種別許可基準、厚生省薬務局審査課監修、１９９３（薬事日報社）、化粧品種別配合成分規格、厚生省薬務局審査課監修、１９９７（薬事日報社）、および化粧品原料辞典、平成３年（日光ケミカルズ）等に記載されている全ての化粧品原料を使用することができる。
Examples of the external preparation for skin of the present invention include cosmetics and pharmaceuticals.
When the skin external preparation of the present invention is a cosmetic, an existing cosmetic raw material can be added at a general concentration. For example, Cosmetic Material Standards Second Edition Commentary, Japan Official Church Church, 1984 (Pharmaceutical Daily Report), Cosmetic Raw Material Standards Independent Component Standard, Ministry of Health and Welfare Pharmaceutical Affairs Bureau Supervision Division, 1993 (Pharmaceutical Daily Report) Standard supplement, supervised by Ministry of Health and Welfare Pharmacy Examination Division, 1993 (Pharmaceutical Daily), permission standards by cosmetics type, supervised by Ministry of Health and Welfare Pharmacy Examination Division, 1993 (Pharmaceutical Daily), Standards for Cosmetic Ingredients, Examination Division by Ministry of Health and Welfare All cosmetic raw materials described in the supervision, 1997 (Pharmaceutical Daily), cosmetic raw material dictionary, 1991 (Nikko Chemicals), etc. can be used.
本発明の皮膚外用剤の剤型としては、使用時に皮膚に接触させて用いられるものであれば特に制限はなく、用途に応じて適宜設定される。たとえばローション、乳液、クリーム、パック等に適用することが出来る。本発明の皮膚外用剤は、特に、沈殿の目立つローション製剤で効果を発揮する。
本発明の皮膚外用剤のｐＨは、６．５〜７．５であることが好ましい。ｐＨがこの範囲内であると、アスコルビン酸−２−リン酸−６−高級脂肪酸塩の安定性が良好で、製剤安定性もより良好となる。なお該ｐＨは、約２５℃における値である。
The dosage form of the external preparation for skin of the present invention is not particularly limited as long as it is used in contact with the skin at the time of use, and is appropriately set according to the use. For example, it can be applied to lotions, emulsions, creams, packs and the like. The external preparation for skin of the present invention is particularly effective in a lotion preparation with a noticeable precipitate.
The pH of the external preparation for skin of the present invention is preferably 6.5 to 7.5. When the pH is within this range, the stability of the ascorbyl 2-phosphate-6-higher fatty acid salt is good, and the formulation stability is also better. The pH is a value at about 25 ° C.
本発明の皮膚外用剤は、アスコルビン酸−２−リン酸−６−高級脂肪酸塩、ノニオン界面活性剤（１）およびその他の任意成分を配合して製剤化することにより製造される。このとき、アスコルビン酸−２−リン酸−６−高級脂肪酸塩以外のアスコルビン酸−２−リン酸誘導体は配合しないことが好ましい。
製剤化は、剤型に応じて、常法に従って実施できる。
The external preparation for skin of the present invention is produced by blending and formulating ascorbic acid-2-phosphate-6-higher fatty acid salt, nonionic surfactant (1) and other optional components. At this time, it is preferable that no ascorbic acid-2-phosphate derivative other than ascorbic acid-2-phosphate-6-higher fatty acid salt is blended.
Formulation can be performed according to a conventional method according to the dosage form.
本発明では、アスコルビン酸−２−リン酸−６−高級脂肪酸塩とノニオン界面活性剤（１）とを配合することで、理由は定かではないが、皮膚外用剤の経時的な沈殿や濁りの発生が抑制されている。
そのため本発明の皮膚外用剤は、化粧料や医薬品を含む皮膚外用剤全般に有用に用いることができ、中でも特に化粧料に有用である。
In the present invention, ascorbic acid-2-phosphate-6-higher fatty acid salt and nonionic surfactant (1) are blended, although the reason is not clear, the precipitation of skin external agents over time and turbidity Occurrence is suppressed.
Therefore, the skin external preparation of the present invention can be usefully used for all skin external preparations including cosmetics and pharmaceuticals, and is particularly useful for cosmetics.
以下、実施例に基づいて本発明をより具体的に説明するが、本発明はこれらの実施例に限定されるものではない。 EXAMPLES Hereinafter, although this invention is demonstrated more concretely based on an Example, this invention is not limited to these Examples.
〔参考例１〜６、比較例１〜４〕
表１に示す組成（単位：質量％）となるように各成分を均一に分散溶解し、攪拌することによってローションを得た。表１に、調製直後のローションのｐＨ（２５℃）を併記した。
得られたローションについて、調製直後および１ヶ月保存後の、濁りおよび沈殿の発生状況を以下の手順で評価した。保存は、４℃、２５℃または４０℃の条件下で静置することにより行った。結果を表１に併記した。
[ Reference Examples 1-6, Comparative Examples 1-4]
Each component was uniformly dispersed and dissolved so as to have the composition (unit: mass%) shown in Table 1, and a lotion was obtained by stirring. Table 1 also shows the pH (25 ° C.) of the lotion immediately after preparation.
The resulting lotion was evaluated for turbidity and precipitation immediately after preparation and after storage for 1 month according to the following procedure. The storage was performed by allowing to stand at 4 ° C, 25 ° C or 40 ° C. The results are also shown in Table 1.
［１．濁り評価方法］
目視により、下記評価基準に従い評価した。
−：濁りが全く見られない。
±：ローション製剤として許容範囲内であるが、濁りがわずかに見られる。
＋：濁りが明らかに認められる。
[1. Turbidity evaluation method]
Visual evaluation was performed according to the following evaluation criteria.
-: Turbidity is not seen at all.
±: Although it is within an acceptable range as a lotion preparation, turbidity is slightly observed.
+: Turbidity is clearly observed.
［２．沈殿評価方法］
目視により、下記評価基準に従い評価した。
−：沈殿が全く見られない。
±：ローション製剤として許容範囲内であるが、沈殿がわずかに見られる。
＋：沈殿が明らかに認められる。
[2. Precipitation evaluation method]
Visual evaluation was performed according to the following evaluation criteria.
-: No precipitation is observed.
±: It is acceptable as a lotion preparation, but slight precipitation is observed.
+: Precipitation is clearly observed.
表１の評価結果に示すとおり、ノニオン界面活性剤（１）を配合した参考例１〜６では、界面活性剤を配合しなかった比較例１、ノニオン界面活性剤（１）以外のノニオン界面活性剤（ＰＯＰ鎖を含まないＰＯＥアルキルエーテル）を配合した比較例２〜４に比べて、幅広い温度範囲で、経時的な濁りおよび沈殿の発生が抑制され、ローションの安定性が向上していた。 As shown in the evaluation results of Table 1, in Reference Examples 1 to 6 in which the nonionic surfactant (1) was blended, the nonionic surfactants other than the comparative example 1 and the nonionic surfactant (1) in which the surfactant was not blended. Compared with Comparative Examples 2 to 4 in which an agent (a POE alkyl ether containing no POP chain) was blended, turbidity and precipitation over time were suppressed over a wide temperature range, and the stability of the lotion was improved.
〔参考例７〜８、比較例５〜１０、参考例Ａ〕
表２に示す組成（単位：質量％）となるように各成分を均一に分散溶解し、攪拌することによってローションを得た。表２に、調製直後のローションのｐＨ（２５℃）を併記した。
得られたローションについて、参考例１と同様の評価（濁り評価、沈殿評価）を行った。結果を表２に併記した。
[ Reference Examples 7 to 8, Comparative Examples 5 to 10, Reference Example A]
Each component was uniformly dispersed and dissolved so as to have the composition (unit: mass%) shown in Table 2, and a lotion was obtained by stirring. Table 2 also shows the pH (25 ° C.) of the lotion immediately after preparation.
About the obtained lotion, evaluation (turbidity evaluation, precipitation evaluation) similar to Reference Example 1 was performed. The results are shown in Table 2.
表２の評価結果に示すとおり、ノニオン界面活性剤（１）を配合した参考例７〜８では、エステル型のノニオン界面活性剤を配合した比較例５〜８と比べて、幅広い温度範囲で、経時的な濁り及び沈殿の発生が抑制され、ローションの安定性が向上していた。
アニオン界面活性剤、カチオン界面活性剤を配合した比較例９、１０では、調製直後から濁りや沈殿が著しかった。
参考例Ａの結果に示すように、アスコルビン酸−２−リン酸誘導体であっても、アスコルビン酸−２−リン酸ナトリウムの場合は、アスコルビン酸−２−リン酸−６−高級脂肪酸塩とは異なり、経時的に沈殿が生じにくい。本発明においては、参考例７〜８に示すように、アスコルビン酸−２−リン酸−６−高級脂肪酸塩であるアスコルビン酸−２−リン酸−６−パルミチン酸ナトリウムを用いても、ノニオン界面活性剤（１）と組み合わせることで、経時的に沈殿が生じにくい参考例Ａと同等の結果が得られた。
As shown in the evaluation results of Table 2, in Reference Examples 7 to 8 containing the nonionic surfactant (1), compared with Comparative Examples 5 to 8 containing the ester type nonionic surfactant, in a wide temperature range, The occurrence of turbidity and precipitation over time was suppressed, and the stability of the lotion was improved.
In Comparative Examples 9 and 10 containing an anionic surfactant and a cationic surfactant, turbidity and precipitation were remarkable immediately after preparation.
As shown in the results of Reference Example A, even ascorbic acid-2-phosphate derivative, in the case of sodium ascorbate-2-phosphate, ascorbic acid-2-phosphate-6-higher fatty acid salt is Unlikely, precipitation hardly occurs over time. In the present invention, as shown in Reference Examples 7-8, ascorbic acid-2-phosphate-6-higher fatty acid salt, ascorbic acid-2-phosphate-6-palmitic acid sodium salt, is used. By combining with the activator (1), a result equivalent to that of Reference Example A in which precipitation hardly occurs over time was obtained.
〔実施例９〜１０、参考例１１〕
表３に示す組成（単位：質量％）となるように各成分を均一に分散溶解し、攪拌することによってローションを得た。表３に、調製直後のローションのｐＨ（２５℃）を併記した。
得られたローションについて、参考例１と同様の評価（濁り評価、沈殿評価）を行った。結果を表３に併記した。
[Examples 9 to 10, Reference Example 11]
Each component was uniformly dispersed and dissolved so that the composition (unit: mass%) shown in Table 3 was obtained, and a lotion was obtained by stirring. Table 3 also shows the pH (25 ° C.) of the lotion immediately after preparation.
About the obtained lotion, evaluation (turbidity evaluation, precipitation evaluation) similar to Reference Example 1 was performed. The results are also shown in Table 3.
表３の評価結果に示すとおり、ノニオン界面活性剤として、ノニオン界面活性剤（１）だけでなくノニオン界面活性剤（２）も配合した実施例９および１０では、ノニオン界面活性剤（１）のみ配合した参考例１１に比べて、低温（４℃）〜高温（４０℃）の広い温度範囲で濁りや沈殿が生じず、ローションの安定性が向上していた。 As shown in the evaluation results of Table 3, in Examples 9 and 10 in which not only the nonionic surfactant (1) but also the nonionic surfactant (2) was blended as the nonionic surfactant, only the nonionic surfactant (1) was used. Compared with the blended Reference Example 11, turbidity and precipitation did not occur in a wide temperature range from low temperature (4 ° C.) to high temperature (40 ° C.), and the stability of the lotion was improved.
表１〜３に示す各成分のうち、ノニオン界面活性剤（１）、ノニオン界面活性剤（２）、その他の界面活性剤としては、それぞれ以下のものを使用した。ａ＋ｃの値、ｂの値はそれぞれ平均値である。
ヒドロキシエチルセルロースとしては、ダイセル化学工業（株）製「ＨＥＣ ＳＥ９００」を使用し、キサンタンガムとしては、大日本住友製薬（株）製「エコーガムＴ」を使用した。
Among the components shown in Tables 1 to 3, the following were used as the nonionic surfactant (1), the nonionic surfactant (2), and other surfactants. The values of a + c and b are average values.
“HEC SE900” manufactured by Daicel Chemical Industries, Ltd. was used as hydroxyethyl cellulose, and “Echo Gum T” manufactured by Dainippon Sumitomo Pharma Co., Ltd. was used as xanthan gum.
［ノニオン界面活性剤（１）］
ＰＯＥ（７）ＰＯＰ（２）デシルエーテル：日本エマルジョン社製「ＥＭＡＬＥＸ ＤＡＰＥ−０２０７」。
ＰＯＥ（８）ＰＯＰ（４）ラウリルエーテル：第一工業製薬社製「ノイゲン ＬＰ−１００」。
ＰＯＥ（１０）ＰＯＰ（４）セチルエーテル：日光ケミカルズ社製「ＮＩＫＫＯＬ ＰＢＣ−３３」。
ＰＯＥ（２０）ＰＯＰ（８）セチルエーテル：日光ケミカルズ社製「ＮＩＫＫＯＬ ＰＢＣ−４４」。
ＰＯＥ（２０）ＰＯＰ（６）デシルテトラデシルエーテル：日光ケミカルズ社製「ＮＩＫＫＯＬ ＰＥＮ−４６２０」。
ＰＯＥ（３０）ＰＯＰ（６）デシルテトラデシルエーテル：日光ケミカルズ社製「ＮＩＫＫＯＬ ＰＥＮ−４６３０」。
[Nonionic surfactant (1)]
POE (7) POP (2) decyl ether: “EMALEX DAPE-0207” manufactured by Nippon Emulsion Co., Ltd.
POE (8) POP (4) lauryl ether: “Neugen LP-100” manufactured by Daiichi Kogyo Seiyaku Co., Ltd.
POE (10) POP (4) cetyl ether: “NIKKOL PBC-33” manufactured by Nikko Chemicals.
POE (20) POP (8) cetyl ether: “NIKKOL PBC-44” manufactured by Nikko Chemicals.
POE (20) POP (6) decyl tetradecyl ether: “NIKKOL PEN-4620” manufactured by Nikko Chemicals.
POE (30) POP (6) decyl tetradecyl ether: "NIKKOL PEN-4630" manufactured by Nikko Chemicals.
［ノニオン界面活性剤（２）］
ＨＯ（Ｃ２Ｈ４Ｏ）ａ−（Ｃ３Ｈ６Ｏ）ｂ−（Ｃ２Ｈ４Ｏ）ｃ−Ｈ、ａ＋ｃ＝２０、ｂ＝２０：アデカ社製「アデカプルロニックＬ−４４」。
[Nonionic surfactant (2)]
HO (C 2 H 4 O) a - (C 3 H 6 O) b - (C 2 H 4 O) c -H, a + c = 20, b = 20: manufactured by Adeka Corporation "ADEKA PLURONIC L-44".
［その他の界面活性剤］
ＰＯＥ（２０）セチルエーテル：日光ケミカルズ社製「ＮＩＫＫＯＬ ＢＣ−２０ＴＸ」。
ＰＯＥ（２０）ステアリルエーテル：日光ケミカルズ社製「ＮＩＫＫＯＬ ＢＳ−２０」。
ＰＯＥ（２０）デシルテトラデシルエーテル：日本エマルジョン社製「ＥＭＡＬＥＸ ２４２０」。
モノステアリン酸デカグリセリル：日光ケミカルズ社製「ＮＩＫＫＯＬ Ｄｅｃａｇｌｙｎ１−ＳＶ」。
モノステアリン酸ＰＯＥ（１５）グリセリル：日光ケミカルズ社製「ＮＩＫＫＯＬ ＴＭＧＳ−１５」。
モノオレイン酸ＰＯＥ（２０）ソルビタン：日光ケミカルズ社製「ＮＩＫＫＯＬ ＴＯ−１０Ｖ」。
テトラオレイン酸ＰＯＥ（３０）ソルビット：日光ケミカルズ社製「ＮＩＫＫＯＬ ＧＯ−４３０ＮＶ」。
ＰＯＥ（３）ラウリルエーテル硫酸Ｎａ ２５％水溶液：花王社製「エマール２０Ｃ」。
塩化セチルトリメチルアンモニウム ３０％水溶液：花王社製「コータミン６０Ｗ」。
[Other surfactants]
POE (20) cetyl ether: “NIKKOL BC-20TX” manufactured by Nikko Chemicals.
POE (20) stearyl ether: “NIKKOL BS-20” manufactured by Nikko Chemicals.
POE (20) decyl tetradecyl ether: “EMALEX 2420” manufactured by Nippon Emulsion Co., Ltd.
Decaglyceryl monostearate: “NIKKOL Decaglyn1-SV” manufactured by Nikko Chemicals.
POE (15) glyceryl monostearate: “NIKKOL TMGS-15” manufactured by Nikko Chemicals.
Monooleic acid POE (20) sorbitan: "NIKKOL TO-10V" manufactured by Nikko Chemicals.
Tetraoleic acid POE (30) Sorbit: “NIKKOL GO-430NV” manufactured by Nikko Chemicals.
POE (3) Lauryl ether sulfate Na 25% aqueous solution: “Emar 20C” manufactured by Kao Corporation.
Cetyltrimethylammonium chloride 30% aqueous solution: “Coatamine 60W” manufactured by Kao Corporation.
Claims (17)
Ｒ１−Ｏ−（Ｒ２Ｏ）ｍ−（ＣＨ２ＣＨ２Ｏ）ｎ−Ｈ …（１）
［ただし、式（１）中のＲ１は炭素数８〜３０の直鎖状または分岐状のアルキル基であり；Ｒ２は−ＣＨ２ＣＨ（ＣＨ３）−または−ＣＨ（ＣＨ３）ＣＨ２−であり；ｍ、ｎはそれぞれ正の整数である。］
で表され、前記式（１）中のｍの平均値が２〜２５であり、ｎの平均値が３〜３４であるノニオン界面活性剤（１）と、下記式（２）：
ＨＯ−（ＣＨ ２ ＣＨ ２ Ｏ） ａ −（Ｒ ３ Ｏ） ｂ −（ＣＨ ２ ＣＨ ２ Ｏ） ｃ −Ｈ …（２）
［ただし、式（２）中のＲ ３ は−ＣＨ ２ ＣＨ（ＣＨ ３ ）−または−ＣＨ（ＣＨ ３ ）ＣＨ ２ −であり；ａ、ｂ、ｃはそれぞれ正の整数である。］
で表されるノニオン界面活性剤（２）と、を含有する皮膚外用剤。 Ascorbic acid-2-phosphate-6-higher fatty acid salt and the following formula (1):
R 1 —O— (R 2 O) m — (CH 2 CH 2 O) n —H (1)
[Wherein R 1 in the formula (1) is a linear or branched alkyl group having 8 to 30 carbon atoms ; R 2 is —CH 2 CH (CH 3 ) — or —CH (CH 3 ) CH 2 ; m and n are each a positive integer. ]
The nonionic surfactant (1) in which the average value of m in the formula (1) is 2 to 25 and the average value of n is 3 to 34, and the following formula (2):
HO— (CH 2 CH 2 O) a — (R 3 O) b — (CH 2 CH 2 O) c —H (2)
[Wherein R 3 in the formula (2) is —CH 2 CH (CH 3 ) — or —CH (CH 3 ) CH 2 —; a, b and c are each a positive integer. ]
And a nonionic surfactant (2) represented by the formula:
Ｒ１−Ｏ−（Ｒ２Ｏ）ｍ−（ＣＨ２ＣＨ２Ｏ）ｎ−Ｈ …（１）
［ただし、式（１）中のＲ１は直鎖状または分岐状のアルキル基であり；Ｒ２は−ＣＨ２ＣＨ（ＣＨ３）−または−ＣＨ（ＣＨ３）ＣＨ２−であり；ｍ、ｎはそれぞれ正の整数である。］
で表され、前記式（１）中のｍの平均値が２〜２５であり、ｎの平均値が３〜３４であるノニオン界面活性剤（１）と、下記式（２）：
ＨＯ−（ＣＨ ２ ＣＨ ２ Ｏ） ａ −（Ｒ ３ Ｏ） ｂ −（ＣＨ ２ ＣＨ ２ Ｏ） ｃ −Ｈ …（２）
［ただし、式（２）中のＲ ３ は−ＣＨ ２ ＣＨ（ＣＨ ３ ）−または−ＣＨ（ＣＨ ３ ）ＣＨ ２ −であり；ａ、ｂ、ｃはそれぞれ正の整数である。］
で表されるノニオン界面活性剤（２）と、を配合することを特徴とする皮膚外用剤の製造方法。 Ascorbic acid-2-phosphate-6-higher fatty acid salt and the following formula (1):
R 1 —O— (R 2 O) m — (CH 2 CH 2 O) n —H (1)
[Wherein R 1 in formula (1) is a linear or branched alkyl group; R 2 is —CH 2 CH (CH 3 ) — or —CH (CH 3 ) CH 2 —; m , N are each a positive integer. ]
The nonionic surfactant (1) in which the average value of m in the formula (1) is 2 to 25 and the average value of n is 3 to 34, and the following formula (2):
HO— (CH 2 CH 2 O) a — (R 3 O) b — (CH 2 CH 2 O) c —H (2)
[Wherein R 3 in the formula (2) is —CH 2 CH (CH 3 ) — or —CH (CH 3 ) CH 2 —; a, b and c are each a positive integer. ]
And a nonionic surfactant (2) represented by the formula:
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