JPH0324442B2 - - Google Patents
Info
- Publication number
- JPH0324442B2 JPH0324442B2 JP4060183A JP4060183A JPH0324442B2 JP H0324442 B2 JPH0324442 B2 JP H0324442B2 JP 4060183 A JP4060183 A JP 4060183A JP 4060183 A JP4060183 A JP 4060183A JP H0324442 B2 JPH0324442 B2 JP H0324442B2
- Authority
- JP
- Japan
- Prior art keywords
- skin
- dicarboxylic acid
- glyceryl
- diglyceryl
- monoglyceryl
- 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.)
- Expired
Links
- 239000000203 mixture Substances 0.000 claims description 23
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 13
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 claims description 11
- 206010014970 Ephelides Diseases 0.000 claims description 10
- 208000003351 Melanosis Diseases 0.000 claims description 10
- 208000002874 Acne Vulgaris Diseases 0.000 claims description 9
- 206010000496 acne Diseases 0.000 claims description 9
- 239000004480 active ingredient Substances 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 2
- -1 diglyceryl acelate Chemical compound 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 150000001991 dicarboxylic acids Chemical class 0.000 description 10
- 230000000144 pharmacologic effect Effects 0.000 description 9
- BDJRBEYXGGNYIS-UHFFFAOYSA-N nonanedioic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 150000001990 dicarboxylic acid derivatives Chemical class 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- BQRISQXLSXCXSC-UHFFFAOYSA-N 9-(2,3-dihydroxypropoxy)-9-oxononanoic acid Chemical compound OCC(O)COC(=O)CCCCCCCC(O)=O BQRISQXLSXCXSC-UHFFFAOYSA-N 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- XKPPNYCAIAQVKU-UHFFFAOYSA-N bis(2,3-dihydroxypropyl) decanedioate Chemical compound OCC(O)COC(=O)CCCCCCCCC(=O)OCC(O)CO XKPPNYCAIAQVKU-UHFFFAOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 206010040880 Skin irritation Diseases 0.000 description 3
- MLZFWBOTPATWKQ-UHFFFAOYSA-N bis(2,3-dihydroxypropyl) nonanedioate Chemical compound OCC(O)COC(=O)CCCCCCCC(=O)OCC(O)CO MLZFWBOTPATWKQ-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000006210 lotion Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000002884 skin cream Substances 0.000 description 3
- 230000036556 skin irritation Effects 0.000 description 3
- 231100000475 skin irritation Toxicity 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 208000006981 Skin Abnormalities Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000002537 cosmetic Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000014593 oils and fats Nutrition 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- YBADLXQNJCMBKR-UHFFFAOYSA-M (4-nitrophenyl)acetate Chemical compound [O-]C(=O)CC1=CC=C([N+]([O-])=O)C=C1 YBADLXQNJCMBKR-UHFFFAOYSA-M 0.000 description 1
- ORZQTUZEWSLMLB-UHFFFAOYSA-N 10-(2,3-dihydroxypropoxy)-10-oxodecanoic acid Chemical compound OCC(O)COC(=O)CCCCCCCCC(O)=O ORZQTUZEWSLMLB-UHFFFAOYSA-N 0.000 description 1
- GHCZTIFQWKKGSB-UHFFFAOYSA-N 2-hydroxypropane-1,2,3-tricarboxylic acid;phosphoric acid Chemical compound OP(O)(O)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O GHCZTIFQWKKGSB-UHFFFAOYSA-N 0.000 description 1
- LZTCLRFNOWIKKM-UHFFFAOYSA-N 8-(2,3-dihydroxypropoxy)-8-oxooctanoic acid Chemical compound OCC(O)COC(=O)CCCCCCC(O)=O LZTCLRFNOWIKKM-UHFFFAOYSA-N 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 230000037374 absorbed through the skin Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- CRXRYWJJCILREM-UHFFFAOYSA-N bis(2,3-dihydroxypropyl) octanedioate Chemical compound OCC(O)COC(=O)CCCCCCC(=O)OCC(O)CO CRXRYWJJCILREM-UHFFFAOYSA-N 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001142 dicarboxylic acid group Chemical group 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- QFYNUCAKHMSPCY-UHFFFAOYSA-L disodium;nonanedioate Chemical compound [Na+].[Na+].[O-]C(=O)CCCCCCCC([O-])=O QFYNUCAKHMSPCY-UHFFFAOYSA-L 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 229940040145 liniment Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011076 safety test Methods 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000011782 vitamin Substances 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
- 150000003722 vitamin derivatives Chemical class 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
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/39—Derivatives containing from 2 to 10 oxyalkylene groups
-
- 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
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
Description
本発明は、ジカルボン酸由来の新規薬理的知見
にもとずくしみ、そばかす、色黒、にきび等の治
療などに用いて効果のある皮膚塗布用組成物に関
するものである。
ジカルボン酸とその還元性誘導体およびこれら
の塩がしみ、そばかすなどの色素過多皮膚病やに
きび等の治療に対し有効的な薬理作用があること
は、既に出願人により明らかにされた。これらジ
カルボン酸等は、その薬理効果を目的とした皮膚
塗布用の組成物としてみるとき、ジカルボン酸
は、それ自体、油脂等に対する溶解性が極めて悪
く、その薬理作用と相俟つて、実用上、その剤型
化に非常な困難を伴ない、しかも、経時により結
晶化分離等を起こしやすい不安定な傾向がある。
従つて、当初から期待すべきジカルボン酸の有す
る本来的な薬理作用は発揮されにくゝ、製剤とし
て充分に満足されたものは得られない。さらにそ
の塩は、水分散性が向上するので剤型化は比較的
容易になるものの、石鹸としての性質を有するた
め、中和率の程度によつては、不用意に皮膚へ適
用すると皮膚刺激が生じ、安定性において障害を
おこしやすく、それに加えて使用感においても難
点がある。また、場合により、上記効果を阻害し
かねないものである。ジカルボン酸の環元性誘導
体についても、これらとほゞ同等の問題があり、
未だ解決に到つていない。
本発明は、皮膚塗布用組成物に用いても上記欠
点が克服されるとともに、ジカルボン酸由来のし
み、そばかす、色黒、にきび等の治療や予防など
に効果的な薬理作用に基づく、しみ、そばかす、
色黒、にきび等に用いる皮膚塗布用組成物を提供
せんとするものであつて、その要旨とするところ
は、活性成分として炭素原子７〜13を有するジカ
ルボン酸の一般式
で表わされる化合物を有効成分として0.1〜40重
量％、好ましくは３〜20重量％含有することを特
徴とする。
なお、一般式中において
ｎ＝５〜11
R1＝グリセリル
R2＝グリセリルまたはＨ基
であり、式中の組合せは、ジグリセリルと、Ｈと
グリセリルの各組合せである。
本発明に適用されるジカルボン酸エステルを具
体的に挙げると、例えば、ピメリン酸モノグリセ
リル、ピメリン酸ジグリセリル、スベリン酸モノ
グリセリル、スベリン酸ジグリセリル、アゼライ
ン酸モノグリセリル、アセライン酸ジグリセリ
ル、セバシン酸モノグリセリル、セバシン酸ジグ
リセリル、１，９−ノナメチレンジカルボン酸モ
ノグリセリル、１，９−ノナメチレンジカルボン
酸ジグリセリル、１，10−デカメチレンジカルボ
ン酸モノグリセリル、１，10−デカメチレンジカ
ルボン酸ジグリセリル、１，11−ウンデカメチレ
ンカルボン酸モノグリセリル、１，11−ウンデカ
メチレンカルボン酸ジグリセリル等で、これらを
一種又は二種以上用いるものであり、その中でも
好ましくは、アゼライン酸モノグリセリル、アゼ
ライン酸ジグリセリル、セバシン酸モノグリセリ
ル、セバシン酸ジグリセリル等である。特にジカ
ルボン酸類のモノグリセリルエステルは、他のエ
ステル類例えば上記一般式のR1，R2がエチル、
イソプロピルであるエステル類に比べ皮膚上およ
び経皮的吸収過程で短時間にて薬理効果のあるジ
カルボン酸に復原する。
本発明におけるジカルボン酸エステルの場合、
ジカルボン酸に基づく治療効果の発現の点から、
特定のものに限定される。例えば、上記一般式中
のｎが４以下もしくは12以上の場合、いずれにし
ても目的とする有効な皮膚塗布用組成物は得られ
ない。また、処方中での含有量は0.1重量％未満
の場合、充分な効果は期待できず、25重量％を超
える場合、効果の増強はみとめられ難い。
上記本発明に係るジカルボン酸エステルを得る
方法としては種々あるが、例えばアゼライン酸、
セバシン酸等の炭素数７〜13のジカルボン酸一種
又は２種以上とジカルボン酸に対してその少なく
とも１当量以上のグリセリル等のアルコールを混
合し、これに硫酸等の触媒を加え、室温もしくは
加温反応させ、反応終了後、蒸溜又はカラム等を
用いて分離精製する方法により、ジカルボン酸エ
ステルが得られるものである。尚、上記脂肪酸と
グリシドールとの付加反応によつても同様のもの
が得られる。
次に本発明に用いるジカルボン酸エステルの合
成例を示す。
合成例１ アゼライン酸モノグリセリルエステル
アゼライン酸158g、グリセリル250g、アセト
ン500ml、濃硫酸２mlを混合し、室温化８〜10時
間撹拌反応させた。終了後ベンゼン500mlを加え
て抽出し、未反応のグリセリルを分離した。この
操作を数回くり返した。次いでベンゼン層に、５
％炭酸水素ナトリウム水溶液を炭酸ガスの発生し
なくなるまで加え水層を分離する。この水層を５
％HCl水溶液で弱酸性にした後酢酸エチルで３回
抽出する。溶媒留去後シリカゲルカラムにかけ、
エチルエテル、次いで、クロロホルムメタノール
（８：２）で分離しアゼライン酸モノグリセリル
エステル80gを得た。
合成例２ アゼライン酸ジグリセリルエステル
アゼライン酸158g、グリセリル500gをアセト
ン700mlと混合し、濃硫酸２mlを加えて室温下で
４時間撹拌反応させた。更に反応を完結させる為
アセトンを留去後アスピレーターで50〜60℃にて
数時間吸引し生成する水を除去した。終了後ｎ−
ブタノール500mlを加えて抽出し、溶媒を留去後
シリカゲルカラム（クロロホルム：メタノール＝
９：１）で分離精製する事によつてアゼライン酸
ジグリセリルエステル約250gを得た。
合成例３ セバシン酸ジグリセリルエステル
セバシン酸172g、グリセリル500gをアセトン
700mlと混合し、濃硫酸２mlを加えて室温下で４
時間撹拌反応させた。更に反応を完結させる為ア
セトンを留去後アスピレーターで50〜60℃にて数
時間吸引し生成する水を除去した。後了後ｎ−ブ
タノール500mlを加えて抽出し、溶媒を留去後シ
リカゲルカラム（クロロホルム：メタノール＝
９：１）で分離精製する事によつてセバシン酸ジ
グリセリルエステル約270gを得た。
本発明において重要なことは、従来より、ジカ
ルボン酸エステルの一部について、室温で液状を
有すると云う特徴の故に、化粧用などの油性基剤
として用いることは知られているが、本発明の如
く、しみ、そばかす、色黒、にきび等の薬理上の
効果を目的とする有効成分として実用に供された
例は皆無と云える点である。これまで、このよう
な目的で効果が客観的に実証され、外用に用いる
有効成分として認められているものは極めて少な
く、例外的に各種ビタミンＣ類や胎盤成分などが
あるが、剤型化の問題も含めて、本来的意味での
治療効果は充分に発現されなかつたのが事実であ
る。本発明の場合、ジカルボン酸エステルが製剤
中では安定に存在し、皮膚に適用されたときに
は、皮膚内の酵素活性により、ジカルボン酸に復
原し、各種の肌質異常を呈する症状に対し、顕著
な治癒効果が発揮され、所期の目的が達成される
利点がある。
次に本発明に適用される各種ジカルボン酸エス
テルが経皮吸収された際、エステル結合が切れ、
フリーの活性成分であるジカルボン酸へ復元する
ことを実験的に確認した結果を表−(A)欄に示
す。実験方法としては、ｐ−ニトロフエニルアセ
テートを基質として用いて、除毛したモルモツト
背部皮膚をクエン酸−リン酸バツフア−溶液で処
理した皮膚ホモジネートと各種ジカルボン酸エス
テルとをインキユベーシヨンすることにより行な
い、モルモツト皮膚中のエステラーゼ活性により
ジカルボン酸に変換する所要時間と変換率を求め
た。また、各種油脂類との相溶性をジカルボン酸
原体の例と共に副次的に表−(B)欄に示す。
TECHNICAL FIELD The present invention relates to a composition for application to the skin that is effective for treating age spots, freckles, dark skin, acne, etc., based on new pharmacological findings derived from dicarboxylic acids. It has already been revealed by the applicant that dicarboxylic acids, their reducing derivatives, and salts thereof have effective pharmacological effects in the treatment of hyperpigmented skin diseases such as age spots and freckles, as well as acne. When these dicarboxylic acids and the like are considered as compositions to be applied to the skin for the purpose of their pharmacological effects, dicarboxylic acids themselves have extremely poor solubility in oils and fats, etc., and together with their pharmacological effects, they are difficult to use in practice. It is very difficult to formulate it into a dosage form, and moreover, it tends to be unstable and prone to crystallization and separation over time.
Therefore, the original pharmacological action of the dicarboxylic acid that should be expected from the beginning is difficult to exhibit, and a fully satisfactory preparation cannot be obtained. Furthermore, the salt has improved water dispersibility, making it relatively easy to formulate into a dosage form; however, because it has soap-like properties, it may cause skin irritation if applied carelessly to the skin, depending on the degree of neutralization. This tends to cause problems in stability, and in addition, there are also disadvantages in terms of usability. Moreover, in some cases, the above effects may be inhibited. There are almost the same problems with cyclic derivatives of dicarboxylic acids.
No solution has been reached yet. The present invention overcomes the above-mentioned drawbacks even when used in a composition for application to the skin, and also provides stains and pigments based on the pharmacological action effective for the treatment and prevention of dicarboxylic acid-derived stains, freckles, dark skin, acne, etc. freckles,
The purpose of the present invention is to provide a composition for skin application for use in treating dark skin, acne, etc., the gist of which is that the general formula of a dicarboxylic acid having 7 to 13 carbon atoms is used as an active ingredient. It is characterized by containing the compound represented by 0.1 to 40% by weight, preferably 3 to 20% by weight as an active ingredient. In addition, in the general formula, n=5-11 R1 =glyceryl R2 =glyceryl or H group, and the combinations in the formula are each combination of diglyceryl and H and glyceryl. Specific examples of dicarboxylic acid esters applicable to the present invention include monoglyceryl pimelate, diglyceryl pimelate, monoglyceryl suberate, diglyceryl suberate, monoglyceryl azelaate, diglyceryl acelate, and sebacic acid. Monoglyceryl, diglyceryl sebacate, monoglyceryl 1,9-nonamethylenedicarboxylate, diglyceryl 1,9-nonamethylenedicarboxylate, monoglyceryl 1,10-decamethylenedicarboxylate, monoglyceryl 1,10-decamethylenedicarboxylate Glyceryl, monoglyceryl 1,11-undecamethylenecarboxylate, diglyceryl 1,11-undecamethylenecarboxylate, etc., and one or more of these are used, and among these, monoglyceryl azelaate, monoglyceryl azelaate, These include diglyceryl azelaate, monoglyceryl sebacate, diglyceryl sebacate, and the like. In particular, monoglyceryl esters of dicarboxylic acids are suitable for other esters, such as those in which R 1 and R 2 in the above general formula are ethyl,
Compared to esters such as isopropyl, it is restored to dicarboxylic acid with pharmacological effects in a short time during skin and transdermal absorption. In the case of the dicarboxylic acid ester in the present invention,
In terms of the expression of therapeutic effects based on dicarboxylic acids,
limited to certain things. For example, if n in the above general formula is 4 or less or 12 or more, the desired effective composition for application to the skin cannot be obtained. Further, if the content in the formulation is less than 0.1% by weight, no sufficient effect can be expected, and if the content exceeds 25% by weight, it is difficult to notice any enhancement of the effect. There are various methods for obtaining the dicarboxylic acid ester according to the present invention, such as azelaic acid,
Mix one or more dicarboxylic acids having 7 to 13 carbon atoms, such as sebacic acid, and an alcohol such as glyceryl in an amount of at least 1 equivalent to the dicarboxylic acid, add a catalyst such as sulfuric acid, and heat at room temperature or by heating. A dicarboxylic acid ester can be obtained by a method of reacting and, after the reaction is completed, separating and purifying using distillation or a column. Incidentally, a similar product can also be obtained by an addition reaction between the above fatty acid and glycidol. Next, a synthesis example of the dicarboxylic acid ester used in the present invention will be shown. Synthesis Example 1 Azelaic acid monoglyceryl ester 158 g of azelaic acid, 250 g of glyceryl, 500 ml of acetone, and 2 ml of concentrated sulfuric acid were mixed and reacted with stirring at room temperature for 8 to 10 hours. After completion of extraction, 500 ml of benzene was added to extract, and unreacted glyceryl was separated. This operation was repeated several times. Then, in the benzene layer, 5
% sodium bicarbonate aqueous solution until no carbon dioxide gas is generated, and the aqueous layer is separated. This water layer is 5
% HCl aqueous solution and then extracted three times with ethyl acetate. After evaporating the solvent, apply it to a silica gel column,
The mixture was separated with ethyl ether and then with chloroform-methanol (8:2) to obtain 80 g of azelaic acid monoglyceryl ester. Synthesis Example 2 Azelaic acid diglyceryl ester 158 g of azelaic acid and 500 g of glyceryl were mixed with 700 ml of acetone, 2 ml of concentrated sulfuric acid was added, and the mixture was stirred and reacted at room temperature for 4 hours. Furthermore, in order to complete the reaction, acetone was distilled off, and the resulting water was removed by suction at 50 to 60°C for several hours using an aspirator. After finishing n-
Add 500ml of butanol for extraction, distill off the solvent, and then use a silica gel column (chloroform: methanol =
Approximately 250 g of azelaic acid diglyceryl ester was obtained by separation and purification at a ratio of 9:1). Synthesis Example 3 Sebacic acid diglyceryl ester Sebacic acid 172g and glyceryl 500g were mixed with acetone.
700ml, add 2ml of concentrated sulfuric acid, and cool at room temperature for 4 hours.
The reaction was stirred for hours. Furthermore, in order to complete the reaction, acetone was distilled off, and the resulting water was removed by suction at 50 to 60°C for several hours using an aspirator. After that, 500 ml of n-butanol was added for extraction, and after distilling off the solvent, the silica gel column (chloroform: methanol =
Approximately 270 g of sebacic acid diglyceryl ester was obtained by separation and purification at a ratio of 9:1). What is important in the present invention is that some dicarboxylic acid esters have been known to be used as oil-based bases for cosmetics etc. due to their characteristic of being liquid at room temperature. However, it can be said that there are no examples of it being put to practical use as an active ingredient for the purpose of pharmacological effects on age spots, freckles, dark skin, acne, etc. Until now, there have been very few substances whose effectiveness has been objectively demonstrated for this purpose and which have been recognized as active ingredients for external use.Exceptions include various vitamin Cs and placenta ingredients, but there are still few substances that can be formulated into dosage forms. The fact is that, despite the problems, the therapeutic effects in the original sense were not fully realized. In the case of the present invention, the dicarboxylic acid ester exists stably in the formulation, and when applied to the skin, it is restored to dicarboxylic acid by the enzyme activity within the skin, and is significantly effective against various skin abnormalities. It has the advantage that a curative effect is exerted and the intended purpose is achieved. Next, when the various dicarboxylic acid esters applied to the present invention are absorbed through the skin, the ester bonds are broken,
Column (A) of the table shows the results of experimentally confirming that the dicarboxylic acid is restored to the free active ingredient dicarboxylic acid. The experimental method involved using p-nitrophenyl acetate as a substrate and incubating the skin homogenate obtained by treating the depilated dorsal skin of a guinea pig with a citric acid-phosphate buffer solution with various dicarboxylic acid esters. The time required for conversion to dicarboxylic acid and the conversion rate were determined by the esterase activity in the guinea pig skin. In addition, compatibility with various oils and fats is shown in column (B) of the table along with examples of dicarboxylic acid raw materials.
【表】
油脂相溶性の評価基準
◎：易溶、○：溶解、×：難溶(又は不溶)
上記表−より明らかな如く、ジカルボン酸エ
ステルは皮膚内でジカルボン酸に復元が実証され
た。これにより、経皮吸収された場合、ジカルボ
ン酸由来のしみ、そばかす、色黒、にきび等への
治療効果が発揮される。また、人皮膚に対しても
復元の確認を行なつたが、ほゞ同様の実質的結果
を得た。
次に、本発明に係るジカルボン酸エステルを含
有した皮膚塗布用組成物が従来のものに比らべ優
れているかを実証した結果を従来品との比較にお
いて表−に示す。適用方法としては、症状の異
なる皮膚異常を呈する18〜40才の女性60名を４群
に分け、後記実施例１〜４の皮膚塗布用組成物を
各自の顔面患者に１日１回ずつ６ケ月間継続して
塗布し、適用患部の治療状態を観察して報告させ
た。実施例１は“しみ”、実施例２は“そばか
す”、実施例３，４は“にきび”の各症状を呈す
る者を対象とした。表−に示される改善程度
は、
１：変化なし
２：やゝ改善されたような気がする。
３：やゝ改善
４：明らかに改善
５：ほぼ完全に治癒
の各段階に区別し、その平均値を表わしたもので
ある。従来品との比較は半顔比較法を用いて行な
い、結果はその総合評価である。[Table] Evaluation criteria for fat and oil compatibility ◎: Easily soluble, ○: Soluble, ×: Slightly soluble (or insoluble)
As is clear from the table above, it was demonstrated that the dicarboxylic acid ester was restored to dicarboxylic acid within the skin. As a result, when absorbed transdermally, the therapeutic effect on dicarboxylic acid-derived age spots, freckles, dark skin, acne, etc. is exhibited. Restoration was also confirmed on human skin, and substantially the same results were obtained. Next, the results of demonstrating whether the composition for skin application containing the dicarboxylic acid ester according to the present invention is superior to conventional compositions are shown in Table 1 in comparison with conventional compositions. As for the method of application, 60 women aged 18 to 40 with different skin abnormalities were divided into four groups, and the compositions for skin application of Examples 1 to 4 described later were applied to each patient's face 6 times a day. The treatment was applied continuously for several months, and the treatment status of the affected area was observed and reported. Examples 1 and 4 targeted subjects exhibiting symptoms of "spots", "freckles" in embodiment 2, and "acne" in embodiments 3 and 4, respectively. The degree of improvement shown in the table is as follows: 1: No change 2: I feel like there has been some improvement. 3: Moderately improved 4: Clearly improved 5: Almost completely differentiated into each stage of healing, and the average value is shown. Comparisons with conventional products were made using the half-face comparison method, and the results are comprehensive evaluations.
【表】
表−において、本発明が従来品にくらべ優れ
ていることは明白である。尚、実施例１，２につ
いて“色黒”の症状を呈する女性を対象に同様の
治療も行つたが、ほゞ“しみ”、“そばかす”と同
じ改善結果が得られた。
さらに、本発明の皮膚塗布用組成物が製剤とし
ても安定であり、かつ、安全性においても優れて
いることを実証するため、後記実施例２の皮膚用
クリームと、この処方中よりジカルボン酸エステ
ル（セバシン酸ジグリセリル）を除去してジカル
ボン酸（アゼライン酸）とジカルボン酸塩（アゼ
ライン酸ナトリウム中和物、中和率100％）でそ
れぞれ置き換えた比較例Ａ，Ｂを用いて行なつた
試験結果を表−を以つて示す。安定性試験は上
記試料を20℃、40℃にて20日間恒温放置した結果
であり、安全性試験は動物（ウサギ）皮膚刺激テ
ストの結果である。[Table] It is clear from the table that the present invention is superior to conventional products. In Examples 1 and 2, the same treatment was performed on women exhibiting the symptoms of "dark skin," and almost the same improvement results as for "spots" and "freckles" were obtained. Furthermore, in order to demonstrate that the composition for skin application of the present invention is stable as a formulation and is also excellent in safety, the skin cream of Example 2 described later and a dicarboxylic acid ester from this formulation were prepared. Test conducted using Comparative Examples A and B in which (diglyceryl sebacate) was removed and replaced with dicarboxylic acid (azelaic acid) and dicarboxylic acid salt (neutralized sodium azelate, neutralization rate 100%). The results are shown in a table. The stability test is the result of keeping the above sample at a constant temperature of 20°C and 40°C for 20 days, and the safety test is the result of an animal (rabbit) skin irritation test.
【表】
表−において、本発明の場合、ジカルボン酸
配合の比較例Ａが有する製剤としての不安定性は
なく、また、ジカルボン酸塩類の配合に基づく比
較例Ｂの皮膚刺激の問題は解決された。特に、比
較例Ｂの本発明皮膚塗布剤は、所望に応じて賦形
剤、希釈剤、補助剤等と共に、クリーム、ローシ
ヨン、乳液、粉末剤、軟膏、ゲル等の形で用いら
れ、常法により製剤化することができる。
以上、詳述した如く、本発明はしみ、そばか
す、にきびに用いる皮膚塗布用組成物に関するも
のであり、ジカルボン酸に由来する外用における
薬理効果を製剤的な解決をはかることにより従来
になく発揮せしめると共に、製剤としても安定か
つ安全なものが提供できる。本発明の皮膚塗布剤
は、その有する利点において、外用医薬のほか、
化粧料などに応用することも可能である。
次に、本発明皮膚塗布用組成物の実施例を述べ
る。含有割合は重量％である。[Table] In the case of the present invention, there was no instability as a preparation that Comparative Example A, which contained dicarboxylic acids, had, and the skin irritation problem of Comparative Example B, which was based on the combination of dicarboxylic acid salts, was resolved. . In particular, the skin liniment of the present invention of Comparative Example B can be used in the form of a cream, lotion, milky lotion, powder, ointment, gel, etc., together with excipients, diluents, adjuvants, etc. as desired, and can be used in the conventional manner. It can be formulated by As detailed above, the present invention relates to a composition for application to the skin for use in treating age spots, freckles, and acne, and is capable of exerting unprecedented pharmacological effects derived from dicarboxylic acids for external use by providing formulation solutions. At the same time, stable and safe formulations can be provided. The skin application agent of the present invention has the advantage that it can be used as a topical medicine as well as
It can also be applied to cosmetics, etc. Next, examples of the composition for application to the skin of the present invention will be described. The content is expressed in weight%.
【表】【table】
【表】
Ａ，Ｂ各々を75℃に加熱し、Ａの中にＢを撹拌
しながら添加し、次いで、添加終了後、冷却を行
い30℃にて冷却を止めて目的とする皮膚用クリー
ムを得る。[Table] Heat each of A and B to 75°C, add B into A with stirring, then, after the addition is complete, cool it and stop cooling at 30°C to prepare the desired skin cream. obtain.
【表】
上記実施例１と同様にして皮膚用クリームを得
る。[Table] A skin cream was obtained in the same manner as in Example 1 above.
【表】
Ａ，Ｂを各々70℃に加熱し、Ａを撹拌しながら
Ｂを添加し、次いで添加終了後、冷却を行い、35
℃において冷却を止めて目的とする皮膚用軟膏を
得る。[Table] Heat A and B to 70°C, add B while stirring A, and then cool after the addition is complete.
Cooling is stopped at 0.degree. C. to obtain the desired skin ointment.
【表】
Ａを70℃にて溶解し、それにＢを添加した後、
Ｃを加えて希釈し、次いで冷却を行ない、30℃に
て冷却を止めて目的とする皮膚用ローシヨンを得
る。[Table] After dissolving A at 70℃ and adding B to it,
The mixture is diluted by adding C, then cooled, and the cooling is stopped at 30°C to obtain the desired skin lotion.
Claims (1)
ルボン酸の一般式 ただし ・ ｎ＝５〜11 ・ R1＝グリセリル ・ R2＝グリセリルまたはＨ基 ・ 式中の組合せは、ジグリセリルと、 Ｈとグリセリルの各組合せである。 で表わされる化合物を有効成分として0.1〜40重
量％含有することを特徴とするしみ、そばかす、
色黒、にきびに用いる皮膚塗布用組成物。[Claims] 1. General formula of dicarboxylic acid having 7 to 13 carbon atoms as active ingredient However, · n = 5 to 11 · R 1 = glyceryl · R 2 = glyceryl or H group · The combinations in the formula are each combination of diglyceryl and H and glyceryl. Spots, freckles, etc. characterized by containing 0.1 to 40% by weight of the compound represented by as an active ingredient.
A composition for skin application for treating dark skin and acne.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4060183A JPS58170713A (en) | 1983-03-14 | 1983-03-14 | Composition for skin application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4060183A JPS58170713A (en) | 1983-03-14 | 1983-03-14 | Composition for skin application |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP20008581A Division JPS58103319A (en) | 1981-12-14 | 1981-12-14 | Composition for skin application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS58170713A JPS58170713A (en) | 1983-10-07 |
| JPH0324442B2 true JPH0324442B2 (en) | 1991-04-03 |
Family
ID=12585029
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4060183A Granted JPS58170713A (en) | 1983-03-14 | 1983-03-14 | Composition for skin application |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS58170713A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2505434Y2 (en) * | 1989-10-30 | 1996-07-31 | 鹿島建設株式会社 | Air conditioning control detector mounting structure |
-
1983
- 1983-03-14 JP JP4060183A patent/JPS58170713A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS58170713A (en) | 1983-10-07 |
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