JP4690672B2 - Emulsion skin external preparation - Google Patents
Emulsion skin external preparation Download PDFInfo
- Publication number
- JP4690672B2 JP4690672B2 JP2004211906A JP2004211906A JP4690672B2 JP 4690672 B2 JP4690672 B2 JP 4690672B2 JP 2004211906 A JP2004211906 A JP 2004211906A JP 2004211906 A JP2004211906 A JP 2004211906A JP 4690672 B2 JP4690672 B2 JP 4690672B2
- Authority
- JP
- Japan
- Prior art keywords
- mass
- external preparation
- skin external
- hydrogenated castor
- castor oil
- 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 - Lifetime
Links
- 238000002360 preparation method Methods 0.000 title claims description 35
- 239000000839 emulsion Substances 0.000 title claims description 28
- -1 diphenhydramines Chemical compound 0.000 claims description 42
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 36
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 22
- 239000004359 castor oil Substances 0.000 claims description 22
- 235000019438 castor oil Nutrition 0.000 claims description 22
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 22
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 claims description 17
- DNTGGZPQPQTDQF-XBXARRHUSA-N crotamiton Chemical compound C/C=C/C(=O)N(CC)C1=CC=CC=C1C DNTGGZPQPQTDQF-XBXARRHUSA-N 0.000 claims description 15
- 229960003338 crotamiton Drugs 0.000 claims description 15
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 claims description 12
- 229940041616 menthol Drugs 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- CIVCELMLGDGMKZ-UHFFFAOYSA-N 2,4-dichloro-6-methylpyridine-3-carboxylic acid Chemical compound CC1=CC(Cl)=C(C(O)=O)C(Cl)=N1 CIVCELMLGDGMKZ-UHFFFAOYSA-N 0.000 claims description 6
- 229960000525 diphenhydramine hydrochloride Drugs 0.000 claims description 6
- IJALWSVNUBBQRA-UHFFFAOYSA-N 4-Isopropyl-3-methylphenol Chemical compound CC(C)C1=CC=C(O)C=C1C IJALWSVNUBBQRA-UHFFFAOYSA-N 0.000 claims description 5
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 claims description 5
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 5
- NFIDBGJMFKNGGQ-UHFFFAOYSA-N isopropylmethylphenol Natural products CC(C)CC1=CC=CC=C1O NFIDBGJMFKNGGQ-UHFFFAOYSA-N 0.000 claims description 5
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- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 2
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 2
- LRJOMUJRLNCICJ-JZYPGELDSA-N Prednisolone acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O LRJOMUJRLNCICJ-JZYPGELDSA-N 0.000 claims 2
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- 239000003755 preservative agent Substances 0.000 claims 1
- 230000002335 preservative effect Effects 0.000 claims 1
- 239000002562 thickening agent Substances 0.000 claims 1
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- 239000000203 mixture Substances 0.000 description 16
- 230000000052 comparative effect Effects 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 9
- DGYSDXLCLKPUBR-SLPNHVECSA-N prednisolone valerate acetate Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(C)=O)(OC(=O)CCCC)[C@@]1(C)C[C@@H]2O DGYSDXLCLKPUBR-SLPNHVECSA-N 0.000 description 8
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- 150000003431 steroids Chemical class 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 4
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 4
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- 230000000694 effects Effects 0.000 description 4
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- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 4
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 4
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 229960002537 betamethasone Drugs 0.000 description 3
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
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- 201000004624 Dermatitis Diseases 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 2
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- ALEXXDVDDISNDU-JZYPGELDSA-N cortisol 21-acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O ALEXXDVDDISNDU-JZYPGELDSA-N 0.000 description 1
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- PGRHXDWITVMQBC-UHFFFAOYSA-N dehydroacetic acid Natural products CC(=O)C1C(=O)OC(C)=CC1=O PGRHXDWITVMQBC-UHFFFAOYSA-N 0.000 description 1
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- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
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- ACGUYXCXAPNIKK-UHFFFAOYSA-N hexachlorophene Chemical compound OC1=C(Cl)C=C(Cl)C(Cl)=C1CC1=C(O)C(Cl)=CC(Cl)=C1Cl ACGUYXCXAPNIKK-UHFFFAOYSA-N 0.000 description 1
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- NFLGAXVYCFJBMK-UHFFFAOYSA-N isomenthone Natural products CC(C)C1CCC(C)CC1=O NFLGAXVYCFJBMK-UHFFFAOYSA-N 0.000 description 1
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- 229940074928 isopropyl myristate Drugs 0.000 description 1
- XUGNVMKQXJXZCD-UHFFFAOYSA-N isopropyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 description 1
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- 235000019388 lanolin Nutrition 0.000 description 1
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- 230000007774 longterm Effects 0.000 description 1
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- PLBHSZGDDKCEHR-LFYFAGGJSA-N methylprednisolone acetate Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(C)=O)CC[C@H]21 PLBHSZGDDKCEHR-LFYFAGGJSA-N 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
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- 239000002674 ointment Substances 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
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- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
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- 235000008160 pyridoxine Nutrition 0.000 description 1
- 239000011677 pyridoxine Substances 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
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- 239000004299 sodium benzoate Substances 0.000 description 1
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- 235000019250 sodium sorbate Nutrition 0.000 description 1
- DSOWAKKSGYUMTF-GZOLSCHFSA-M sodium;(1e)-1-(6-methyl-2,4-dioxopyran-3-ylidene)ethanolate Chemical compound [Na+].C\C([O-])=C1/C(=O)OC(C)=CC1=O DSOWAKKSGYUMTF-GZOLSCHFSA-M 0.000 description 1
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- 239000008347 soybean phospholipid Substances 0.000 description 1
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- 239000003381 stabilizer Substances 0.000 description 1
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- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Cosmetics (AREA)
Description
本発明は、エステル系ステロイド、ジフェンヒドラミン類およびメントールを含有する皮膚疾患の予防・治療に有用な乳剤性皮膚外用剤に関する。さらに詳しくは、エステル系ステロイドの分解をクロタミトン、ポリオキシエチレン硬化ヒマシ油およびプロピレングリコールにより防止した保存安定性に極めて優れた乳剤性皮膚外用剤に関する。 The present invention relates to an emulsion skin external preparation useful for the prevention and treatment of skin diseases containing ester steroids, diphenhydramines and menthol. More specifically, the present invention relates to an emulsion skin external preparation having excellent storage stability in which degradation of ester steroids is prevented by crotamiton, polyoxyethylene hydrogenated castor oil and propylene glycol.
従来より、肌荒れ、湿疹、皮膚炎等の皮膚疾患の予防・治療にエステル系ステロイド等の抗炎症剤と塩酸ジフェンヒドラミン等の抗ヒスタミン薬を組み合わせたものが用いられている。更に、これに消炎鎮痛剤、香料、清涼化剤としてのメントール、鎮痒剤としてのクロタミトンを配合した薬剤が知られている（例えば特許文献１参照）。しかしながら、エステル系ステロイドは、貯蔵中に加水分解するため、安定な製剤が求められている。
本発明は、エステル系ステロイド、ジフェンヒドラミン類およびメントールを含有する保存安定性に優れた乳剤性皮膚外用剤を提供することである。 An object of the present invention is to provide an emulsion skin external preparation excellent in storage stability, which contains an ester steroid, diphenhydramines and menthol.
本発明者は、エステル系ステロイドとジフェンヒドラミン類の組み合わせにメントールを加えた場合にはエステル系ステロイドの加水分解が促進されること、クロタミトンはエステル系ステロイドに対する安定化効果を発揮すること、しかしながら、安定化剤としてクロタミトン、ポリオキシエチレン硬化ヒマシ油およびプロピレングリコールを組み合わせて添加した場合、驚くべきことにエステル系ステロイドの安定化効果の外に製剤の分離安定性が長期間に亘って改善されることを見出した。
したがって、保存安定性に優れたエステル系ステロイド、ジフェンヒドラミン類およびメントールを含む乳剤性皮膚外用剤は、クロタミトン、ポリオキシエチレン硬化ヒマシ油およびプロピレングリコールを組み合わせることによってエステル系ステロイドの安定化と製剤の分離安定性の両者を改善したものとすることができる。
The present inventor shows that when menthol is added to a combination of ester steroids and diphenhydramines, hydrolysis of the ester steroid is promoted, and crotamiton exhibits a stabilizing effect on the ester steroid. When crotamiton, polyoxyethylene hydrogenated castor oil, and propylene glycol are added in combination as an agent, surprisingly, the separation stability of the preparation is improved over a long period of time in addition to the stabilizing effect of the ester steroid. I found.
Therefore, the emulsion-type skin external preparation containing ester steroids with excellent storage stability, diphenhydramines and menthol, stabilizes ester steroids and separates the preparation by combining crotamiton, polyoxyethylene hydrogenated castor oil and propylene glycol. Both stability can be improved.
この組み合わされた安定化剤の使用により、長期間に亘りエステル系ステロイドの加水分解が抑制され、分解物である有機酸による悪臭が防止され、さらに乳剤性皮膚外用剤の分離安定性が改善され、保存安定性に優れた乳剤性皮膚外用剤が提供される。 By using this combined stabilizer, hydrolysis of the ester steroid is suppressed over a long period of time, malodor due to the decomposed organic acid is prevented, and the separation stability of the emulsion skin external preparation is improved. Thus, an emulsion skin external preparation excellent in storage stability is provided.
抗炎症性ステロイド類としては、例えばプレドニゾロン、ヒドロコルチゾン、デキサメサゾン、ベタメタゾン等が用いられ、これらは、通常エステルの形（エステル系ステロイド）で用いられる。本発明に用いられるエステル系ステロイドは、有機酸とのエステルをなし、消炎活性を有するものが好ましい。ステロイドとしては、ヒドロコルチゾン、プレドニゾロン、デキサメタゾン、ベタメタゾン等が挙げられる。
有機酸としては、酢酸、酪酸、吉草酸、プロピオン酸等が挙げられる。本発明で用いられるエステル系ステロイドの具体例としては、吉草酸酢酸プレドニゾロン、酢酸メチルプレドニゾロン、酢酸ヒドロコルチゾン、酪酸ヒドロコルチゾン、プロピオン酸アルクロメタゾン、酪酸クロベタゾン、プロピオン酸デプロドン、プロピオン酸ベクロメタゾン、吉草酸デキサメタゾン、吉草酸べタメタゾン、酪酸プロピオン酸ヒドロコルチゾン、吉草酸
ジフルコルトロン、ジプロピオン酸デキサメタゾン、ジプロピオン酸ベタメタゾン、酢酸ジフロラゾン、プロピオン酸クロベタゾールが示されるが、好ましくは、吉草酸酢酸プレドニゾロンである。
エステル系ステロイドの配合量は、用いるステロイドによってその作用の強弱が異なることから、一概にはいえないが、皮膚外用剤中、０.０１〜１０w／w％程度配合でき、好ましくは、０.１〜０.２w／w％である。
As anti-inflammatory steroids, for example, prednisolone, hydrocortisone, dexamethasone, betamethasone and the like are used, and these are usually used in the form of an ester (ester steroid). The ester-based steroid used in the present invention is preferably an ester with an organic acid and having anti-inflammatory activity. Examples of the steroid include hydrocortisone, prednisolone, dexamethasone, betamethasone and the like.
Examples of the organic acid include acetic acid, butyric acid, valeric acid, and propionic acid. Specific examples of ester steroids used in the present invention include prednisolone valerate acetate, methylprednisolone acetate, hydrocortisone acetate, hydrocortisone butyrate, alcromethasone propionate, clobetasone butyrate, deprodon propionate, beclomethasone propionate, dexamethasone valerate, valeric acid Betamethasone, hydrocortisone butyrate propionate, diflucortron divalerate, dexamethasone dipropionate, betamethasone dipropionate, diflorazone acetate and clobetasol propionate are preferred, and prednisolone valerate is preferred.
The amount of the ester-based steroid varies depending on the steroid used, so that it cannot be generally specified. However, about 0.01 to 10 w / w% can be added in the external preparation for skin, preferably 0.1. ~ 0.2 w / w%.
本発明のジフェンヒドラミン類は、ジフェンヒドラミンまたはその塩である。配合量は、０.１〜５w／w％含有でき、好ましくは、１〜２w／w％である。 The diphenhydramine of the present invention is diphenhydramine or a salt thereof. A compounding quantity can contain 0.1-5 w / w%, Preferably, it is 1-2 w / w%.
本発明では、エステル系ステロイドにジフェンヒドラミン類を配合した系にメントールが添加されるが、メントールとは、ｌ−メントール、ｄｌ−メントールであり、好ましくは、ｌ−メントールである。添加量は、０.１〜４w／w％含有でき、好ましくは、０.３〜２w／w％である。 In the present invention, menthol is added to a system in which diphenhydramines are blended with an ester-based steroid, and the menthol is l-menthol or dl-menthol, and preferably l-menthol. The addition amount can be 0.1-4 w / w%, preferably 0.3-2 w / w%.
本発明のクロタミトン添加量は、３〜７w／w％添加でき、好ましくは、４〜６w／w％である。 The amount of crotamiton added according to the present invention can be 3 to 7 w / w%, preferably 4 to 6 w / w%.
本発明のポリオキシエチレン硬化ヒマシ油とは、ポリオキシエチレン硬化ヒマシ油、ポリオキシエチレン硬化ヒマシ油６０、ポリオキシエチレン硬化ヒマシ油５、ポリオキシエチレン硬化ヒマシ油１０、ポリオキシエチレン硬化ヒマシ油２０、ポリオキシエチレン硬化ヒマシ油４０、ポリオキシエチレン硬化ヒマシ油５０、ポリオキシエチレン硬化ヒマシ油１００等である。好ましくは、ポリオキシエチレン硬化ヒマシ油６０である。ポリオキシエチレン硬化ヒマシ油を含有させることで乳化安定性を向上させ、分離に関する安定性に優れた乳剤性皮膚外用剤が得られる。ポリオキシエチレン硬化ヒマシ油の添加量は、１〜７.５w／w％添加でき、好ましくは、２〜６w／w％である。 The polyoxyethylene hydrogenated castor oil of the present invention refers to polyoxyethylene hydrogenated castor oil, polyoxyethylene hydrogenated castor oil 60, polyoxyethylene hydrogenated castor oil 5, polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 20 Polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 100, and the like. Polyoxyethylene hydrogenated castor oil 60 is preferable. By incorporating polyoxyethylene hydrogenated castor oil, the emulsion stability is improved, and an emulsion skin external preparation excellent in stability regarding separation can be obtained. The polyoxyethylene hydrogenated castor oil can be added in an amount of 1 to 7.5 w / w%, preferably 2 to 6 w / w%.
本発明のプロピレングリコールの添加量は、０.１〜１０w／w％添加でき、好ましくは、３〜７w／w％である。 The addition amount of propylene glycol of the present invention can be 0.1 to 10 w / w%, preferably 3 to 7 w / w%.
本発明の油分は、中鎖脂肪酸トリグリセライド、白色ワセリン、セトステアリルアルコール、セタノール、ステアリルアルコール、ステアリン酸、ミリスチン酸イソプロピル、オクチルドデカノール、パルミチン酸イソプロピル、乳酸セチル、酪酸ラノリン等が添加でき、好ましくは、中鎖脂肪酸トリグリセライド、白色ワセリン、セトステアリルアルコール、セタノールである。 In the oil of the present invention, medium chain fatty acid triglyceride, white petrolatum, cetostearyl alcohol, cetanol, stearyl alcohol, stearic acid, isopropyl myristate, octyldodecanol, isopropyl palmitate, cetyl lactate, lanolin butyrate can be added, preferably , Medium chain fatty acid triglyceride, white petrolatum, cetostearyl alcohol, cetanol.
本発明の乳剤性皮膚外用剤には、上記成分の他に、通常、医薬品や化粧品の皮膚外用剤に用いられる成分を本発明の目的、効果を損なわない質的、量的範囲内で添加することができる。 In addition to the above components, the emulsion-based external preparation for skin of the present invention usually contains components used for external preparations for pharmaceuticals and cosmetics within the qualitative and quantitative ranges that do not impair the purpose and effect of the present invention. be able to.
ポリオキシエチレン硬化ヒマシ油以外の界面活性剤として、モノステアリン酸グリセリン、モノステアリン酸ソルビタン、モノラウリン酸ソルビタン、モノパルミチン酸ソルビタン、セスキオレイン酸ソルビタン、ポリオキシエチレンステアリルエーテル等が添加でき、好ましくは、モノステアリン酸グリセリンである。 As surfactants other than polyoxyethylene hydrogenated castor oil, glyceryl monostearate, sorbitan monostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan sesquioleate, polyoxyethylene stearyl ether, etc., preferably, It is glyceryl monostearate.
油溶性成分として酢酸トコフェロール、大豆レシチン、ジブチルヒドロキシトルエン、ベンゾトリアゾールの酸化防止剤、イソプロピルメチルフェノール、安息香酸、サリチル酸、ソルビン酸、デヒドロ酢酸、パラオキシ安息香酸アルキルエステル（メチルパラベン、エチルパラベン、プロピルパラベン、ブチルパラベン等）、ヘキサクロロフェン等の抗菌・防腐剤、リドカイン、ジブカイン等の局所麻酔剤、コレカルシフェロール、レチノール等及びそのエステルのビタミン剤を添加できる。好ましい成分は、酢酸トコフェロール、イソプロピルメチルフェノール、メチルパラベン、エチルパラベン、ブチルパラベン、プロピルパラベンである。 Oil-soluble ingredients such as tocopherol acetate, soy lecithin, dibutylhydroxytoluene, benzotriazole antioxidant, isopropylmethylphenol, benzoic acid, salicylic acid, sorbic acid, dehydroacetic acid, paraoxybenzoic acid alkyl ester (methylparaben, ethylparaben, propylparaben, Butylparaben, etc.), antibacterial and antiseptic agents such as hexachlorophene, local anesthetics such as lidocaine and dibucaine, cholecalciferol, retinol and the like and vitamins of esters thereof can be added. Preferred components are tocopherol acetate, isopropylmethylphenol, methyl paraben, ethyl paraben, butyl paraben, propyl paraben.
水溶性成分としてエデト酸Ｎａ、安息香酸Ｎａ、サリチル酸Ｎａ、ソルビン酸Ｎａ、デヒドロ酢酸Ｎａ等の抗菌・防腐剤塩類等、メチルセルロース、エチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、結晶セルロース・カルメロースＮａ、ポビドン等の分散剤、リドカイン及びジブカインの塩等の局所麻酔剤、ピリドキサール、ピリドキシン、リボフラビン、アスコルビン酸等及びその塩又はエステルのビタミン剤を添加できる。皮膚に塗布する場合、伸展性を良くする成分としてプロピレングリコール、１,３−ブチレングリコール、ポリエチレングリコール、グリセリン等の多価アルコールを添加できるが、好ましい伸展剤は、プロピレングリコールである。 Water-soluble ingredients such as sodium edetate, sodium benzoate, sodium salicylate, sodium sorbate, sodium dehydroacetate, etc., methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose / carmellose Na, povidone And the like, local anesthetics such as lidocaine and dibucaine salts, pyridoxal, pyridoxine, riboflavin, ascorbic acid and the like, and salts or esters of vitamins thereof can be added. When applied to the skin, polyhydric alcohols such as propylene glycol, 1,3-butylene glycol, polyethylene glycol, and glycerin can be added as a component that improves the extensibility, but a preferred extender is propylene glycol.
ｐＨ調整剤として水酸化ナトリウム、塩酸、リン酸、リン酸塩、炭酸塩、クエン酸、クエン酸塩、ジエタノールアミン、トリエタノールアミン、イソプロパノールアミンを適量添加できるが、好ましくは、水酸化ナトリウム、リン酸である。ｐＨ調整剤を添加した本発明の乳剤性皮膚外溶剤のｐＨ範囲は、３.０〜５.０であるが、好ましくは、４.０〜５.０である。 Sodium hydroxide, hydrochloric acid, phosphoric acid, phosphate, carbonate, citric acid, citrate, diethanolamine, triethanolamine, isopropanolamine can be added in an appropriate amount as a pH adjuster, but preferably sodium hydroxide, phosphoric acid It is. The pH range of the emulsion external skin solvent of the present invention to which a pH adjusting agent has been added is 3.0 to 5.0, preferably 4.0 to 5.0.
本発明の乳剤性皮膚外用剤は、医薬品、医薬部外品、化粧品等、外皮に適用されるもので、剤型は、乳剤性軟膏剤〜乳剤性ローション剤の形態をとり、乳化型は、Ｏ／Ｗ型である。本発明の乳剤性皮膚外用剤は、２０〜８０w／w％の水分を含むことができ、好ましい水の含有量は５５〜６５w／w％である。 The emulsion skin external preparation of the present invention is applied to the outer skin of pharmaceuticals, quasi drugs, cosmetics, etc., the dosage form takes the form of an emulsion ointment to an emulsion lotion, and the emulsion type is O / W type. The emulsion skin external preparation of this invention can contain 20-80 w / w% of water | moisture content, and content of preferable water is 55-65 w / w%.
本発明の乳剤性皮膚外用剤は、当業者に良く知られている方法によって製造することができる。まず、油分、非イオン界面活性剤（乳化剤）を加温溶融した組成物にエステル系ステロイド、メントール、クロタミトン、その他の油溶性成分を溶解させた油性組成物を調製する。ジフェンヒドラミンを添加する場合は、油溶性成分として添加する。加温した水に水溶性成分を添加し、溶解、又は分散して水性組成物を調製する。油性組成物と水性組成物を加温状態で撹拌・混合し乳化させ、撹拌しながら５５〜６５℃に徐冷し、ジフェンヒドラミンの塩を添加する場合は、溶解可能な水量に溶解後、添加する。その後、ｐＨ調整する。更に撹拌しながら徐冷して室温とし、本発明乳剤性皮膚外用剤を調製する。 The emulsion skin external preparation of the present invention can be produced by methods well known to those skilled in the art. First, an oily composition is prepared by dissolving an ester-based steroid, menthol, crotamiton, and other oil-soluble components in a composition obtained by heating and melting an oil and a nonionic surfactant (emulsifier). When diphenhydramine is added, it is added as an oil-soluble component. An aqueous composition is prepared by adding a water-soluble component to warm water and dissolving or dispersing it. Stir, mix and emulsify the oily composition and aqueous composition with heating, slowly cool to 55-65 ° C. with stirring, and add diphenhydramine salt after dissolving in a soluble amount of water. . Thereafter, the pH is adjusted. Further, the mixture is slowly cooled with stirring to room temperature to prepare the emulsion skin external preparation of the present invention.
以下、実施例、比較例を上げて本発明をさらに詳細に説明するが、本発明の技術的範囲はこれによってなんら限定されるものでない。尚、配合量は重量％である。
〔参考例および実施例２〜２５〕
乳剤性皮膚外用剤の調製法
油分、界面活性剤を加温（８０℃）溶融した組成物に吉草酸酢酸プレドニゾロン、メントール、クロタミトン、その他の油溶性成分を溶解させた油性組成物を調製した。加温（８３℃）した精製水に塩酸ジフェンヒドラミン以外の水溶性成分を添加し、溶解、又は分散して水性組成物を調製した。油性組成物と水性組成物を加温（８０℃）状態で撹拌・混合し、乳化させ、撹拌しながら６０℃まで徐冷して精製水の一部（溶剤）に塩酸ジフェンヒドラミンを溶解し、添加後、撹拌し、ｐＨを４.５に調整し、更に撹拌しながら徐冷して室温とし、本発明の乳剤性皮膚外用剤を調製した。
上記の調製法を用いて調製された、参考例および実施例２〜２５の乳剤性皮膚外用剤の組成を表１〜５に示した。
EXAMPLES Hereinafter, although an Example and a comparative example are raised and this invention is demonstrated further in detail, the technical scope of this invention is not limited at all by this. In addition, a compounding quantity is weight%.
[ Reference Examples and Examples 2 to 25]
Preparation Method of Emulsion Skin External Preparation An oily composition was prepared by dissolving prednisolone valerate acetate, menthol, crotamiton, and other oil-soluble components in a composition in which oil and surfactant were heated (80 ° C.). Water-soluble components other than diphenhydramine hydrochloride were added to purified water heated (83 ° C.), and dissolved or dispersed to prepare an aqueous composition. Stir and mix the oily composition and aqueous composition in a heated (80 ° C) state, emulsify, slowly cool to 60 ° C while stirring, dissolve diphenhydramine hydrochloride in a portion (solvent) of purified water, and add Thereafter, the mixture was stirred, the pH was adjusted to 4.5, and further slowly cooled with stirring to room temperature to prepare the emulsion skin external preparation of the present invention.
Tables 1 to 5 show the compositions of the emulsion skin external preparations of Reference Example and Examples 2 to 25 prepared using the above preparation method.
１．製剤中の吉草酸酢酸プレドニゾロン安定性試験
吉草酸酢酸プレドニゾロンの加水分解の原因を解明し、その防止策を検討するために、表１の比較例１〜３の組成を有する乳剤性皮膚外用剤を、上記の方法と同様に調製した。比較例１〜３と参考例および実施例２〜６の乳剤性皮膚外用剤ポリエチレン製容器に入れ、４０℃、７５％ＲＨにおいて３ヶ月保存して、残存する吉草酸酢酸プレドニゾロン量（ＰＶＡ残存率％）を、日本薬局方の一般試験法の液体クロトグラフ法に従って測定した。その結果を表１に示す。
1. In order to elucidate the cause of hydrolysis of prednisolone valerate acetate in the preparation and to investigate the preventive measures thereof, an emulsion skin external preparation having the composition of Comparative Examples 1 to 3 in Table 1 was used. Were prepared in the same manner as described above. Emulsified skin external preparation of Comparative Examples 1 to 3 and Reference Examples and Examples 2 to 6, put into containers made of polyethylene, stored at 40 ° C. and 75% RH for 3 months, remaining amount of prednisolone valerate acetate (PVA remaining rate) %) Was measured according to the liquid chronograph method of the general test method of the Japanese Pharmacopoeia. The results are shown in Table 1.
比較例１と比較例２を対比すれば、ｌ−メントールを配合することによって、吉草酸酢酸プレドニゾロンの分解が促進されることが判明した。４０℃、７５％ＲＨにおいる３ヶ月保存は、通常の保存状態における１.５年後の結果に対応する。一方、通常の保存期間は３年であるため、比較例２のものは、その結果からみて、３年後には最低規格含量のＰＶＡ残存率９０％近く迄低下する可能性がある。 Comparing Comparative Example 1 and Comparative Example 2, it was found that the decomposition of prednisolone valerate acetate was promoted by adding 1-menthol. Storage for 3 months at 40 ° C. and 75% RH corresponds to the result after 1.5 years in normal storage conditions. On the other hand, since the normal storage period is 3 years, the result of Comparative Example 2 may decrease to a PVA residual rate of the minimum standard content of nearly 90% after 3 years.
クロタミトンを添加していない比較例２、３を、クロタミトンを添加した参考例および実施例２〜６と対比すると、ｌ−メントールの存在下であっても、クロタミトンの添加によって吉草酸酢酸プレドニゾロンが安定化されることが判明した。さらに、実施例３から、酢酸トコフェロールが無くても吉草酸酢酸プレドニゾロンの安定化効果に影響がないことが、また、実施例４から、イソプロピルメチルフェノールが無くても吉草酸酢酸プレドニゾロンの安定化効果に影響がないことがわかる。 When Comparative Examples 2 and 3 to which crotamiton was not added were compared with Reference Examples and Examples 2 to 6 to which crotamiton was added, prednisolone valerate acetate was stabilized by the addition of crotamiton even in the presence of 1-menthol. Turned out to be. Furthermore, from Example 3, the absence of tocopherol acetate does not affect the stabilization effect of prednisolone valerate acetate. From Example 4, the stabilization effect of prednisolone valerate acetate without isopropylmethylphenol. It can be seen that there is no effect on.
２．製剤の分離安定性試験
上記の乳剤性皮膚外用剤の調製法に従い、実施例７のポリオキシエチレン硬化ヒマシ油６０（５.０w／w％）を添加せず、代わりにポリオキシエチレンステアリルエーテル（３.０w／w％）を添加した比較例４および実施例７のプロピレングリコール（５.０w／w％）を添加せず、代わりに１,３−ブチレングリコール（５.０w／w％）を添加した比較例５を作成し、これをポリエチレン製容器に入れ、４０℃、７５％ＲＨにおいて６ヶ月保存した。製剤の外観を観察した結果、比較例４および５は、水性成分が分離した状態にあった。
2. Separation stability test of the preparation According to the above-mentioned preparation method of the emulsion skin external preparation, the polyoxyethylene hydrogenated castor oil 60 (5.0 w / w%) of Example 7 was not added, but instead polyoxyethylene stearyl ether ( The propylene glycol (5.0 w / w%) of Comparative Example 4 and Example 7 to which 3.0 w / w% was added was not added, but 1,3-butylene glycol (5.0 w / w%) was used instead. The added Comparative Example 5 was prepared, placed in a polyethylene container, and stored at 40 ° C. and 75% RH for 6 months. As a result of observing the appearance of the preparation, Comparative Examples 4 and 5 were in a state where the aqueous component was separated.
このことから、乳剤性皮膚外用剤の長期安定化のためには、ポリオキシエチレン硬化ヒマシ油およびプロピレングリコールを組み合わせて配合することが必須であることが判明した。 From this, it has been found that it is essential to combine polyoxyethylene hydrogenated castor oil and propylene glycol in order to stabilize the emulsion external preparation for long term.
Claims (3)
５．０質量％、吉草酸酢酸プレドニゾロン ０．１５質量％、酢酸トコフェロール ０．５質量％、イソプロピルメチルフェノール ０．１質量％、１−メントール ０．７質量％、プロピレングリコール ９．０質量％、精製水 ５９．２７質量％、ポリオキシエチレン（６０）硬化ヒマシ油 ２．０質量％、塩酸ジフェンヒドラミン ２．０質量％、セルロース系増粘剤 ０．６質量％、ＥＤＴＡ−２Ｎａ・２Ｈ2Ｏ ０．０３質量％、防腐剤 ０．１５質量％の処方のＯ／Ｗ型乳剤性皮膚外用剤、および流動パラフィン １０．０質量％、ジメチルポリシロキサン（６ｃＳｔ） ２．０質量％、クロタミトン ５．０質量％、吉草酸酢酸プレドニゾロン ０．１５質量％、酢酸トコフェロール ０．５質量％、イソプロピルメチルフェノール ０．１質量％、１−メントール ０．７質量％、プロピレングリコール ４．５質量％、精製水 ６４．８２質量％、ポリオキシエチレン（６０）硬化ヒマシ油 １．２質量％、塩酸ジフェンヒドラミン ２．０質量％、ＥＤＴＡ−２Ｎａ・２Ｈ2Ｏ ０．０３質量％、エタノール ９．０質量％の処方のＯ／Ｗ型乳剤性皮膚外用剤を除く）。 O / W emulsion skin external preparation characterized by containing prednisolone valerate , diphenhydramines, menthol, crotamiton, polyoxyethylene hydrogenated castor oil, propylene glycol, water, and oil (however, liquid paraffin 15. 0% by mass, petrolatum 2.0% by mass, dimethylpolysiloxane (6cSt) 3.5% by mass, crotamiton 5.0% by mass, prednisolone acetate valerate 0.15% by mass, tocopherol acetate 0.5% by mass, isopropylmethyl Phenol 0.1% by mass, 1-menthol 0.7% by mass, propylene glycol 9.0% by mass, purified water 59.27% by mass, polyoxyethylene (60) hydrogenated castor oil 2.0% by mass, diphenhydramine hydrochloride 2 0.0% by mass, cellulosic thickener 0.6% by mass, EDTA-2 Na · 2H 2 O 0.03% by mass, preservative 0.15% by mass O / W emulsion skin external preparation, and liquid paraffin 10.0% by mass, dimethylpolysiloxane (6cSt) 2.0% by mass %, Crotamiton 5.0 mass%, prednisolone acetate valerate 0.15 mass%, tocopherol acetate 0.5 mass%, isopropylmethylphenol 0.1 mass%, 1-menthol 0.7 mass%, propylene glycol 4.5 Mass%, purified water 64.82 mass%, polyoxyethylene (60) hydrogenated castor oil 1.2 mass%, diphenhydramine hydrochloride 2.0 mass%, EDTA-2Na · 2H 2 O 0.03 mass%, ethanol 9. (Excluding 0% by mass of O / W type emulsion skin external preparation).
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| ES2421613T3 (en) * | 2006-03-08 | 2013-09-04 | Nihon Nohyaku Co Ltd | External pharmaceutical composition |
| NZ571818A (en) | 2006-03-08 | 2011-10-28 | Nihon Nohyaku Co Ltd | External pharmaceutical composition comprising luliconazole and an alpha-hydroxycarboxylic acid such as lactic acid, glycolic acid or malic acid. |
| JP4965884B2 (en) * | 2006-04-10 | 2012-07-04 | 興和株式会社 | O / W type emulsion formulation containing prednisolone valerate acetate |
| JP2009029791A (en) * | 2007-06-26 | 2009-02-12 | Kowa Co | O/w type emulsified preparation containing steroid |
| EP2191828B1 (en) | 2007-09-05 | 2016-08-10 | Pola Pharma Inc. | Antifungal pharmaceutical composition |
| WO2009031643A1 (en) | 2007-09-05 | 2009-03-12 | Pola Pharma Inc. | Antifungal composition |
| KR20100075475A (en) | 2007-09-05 | 2010-07-02 | 가부시키가이샤 폴라 파마 | Pharmaceutical composition |
| KR101409792B1 (en) | 2009-04-09 | 2014-06-19 | 니혼노야쿠가부시키가이샤 | Antimycotic pharmaceutical composition |
| JP5688405B2 (en) | 2009-04-09 | 2015-03-25 | 株式会社ポーラファルマ | Antifungal pharmaceutical composition |
| US8952044B2 (en) | 2009-08-25 | 2015-02-10 | Pola Pharma Inc. | Antimycotic pharmaceutical composition |
| JP5507600B2 (en) * | 2012-03-08 | 2014-05-28 | 興和株式会社 | O / W type emulsion formulation containing prednisolone valerate acetate |
| KR102080034B1 (en) * | 2012-04-13 | 2020-02-24 | (주)아모레퍼시픽 | Nanoemulsion composition and manufacturing method thereof |
| JP6031024B2 (en) * | 2013-12-19 | 2016-11-24 | 池尻製薬株式会社 | Solid ointment containing prednisolone valerate acetate |
| JP6128018B2 (en) * | 2014-03-05 | 2017-05-17 | ライオン株式会社 | Cream pharmaceutical formulation |
| JP6289202B2 (en) * | 2014-03-26 | 2018-03-07 | 小林製薬株式会社 | Emulsified pharmaceutical composition |
| JP6765834B2 (en) * | 2016-03-31 | 2020-10-07 | 小林製薬株式会社 | Emulsified composition |
| WO2021187593A1 (en) * | 2020-03-19 | 2021-09-23 | シオノギヘルスケア株式会社 | Composition containing betamethasone valerate |
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| JPH0797326A (en) * | 1993-09-28 | 1995-04-11 | Hisamitsu Pharmaceut Co Inc | Creamy agent for skin external use |
| JP2002356430A (en) * | 2001-05-30 | 2002-12-13 | Ikeda Mohandou:Kk | Skin care preparation containing prednisolone valerate acetate and antihistamic agent |
| JP2005060233A (en) * | 2003-08-08 | 2005-03-10 | Rohto Pharmaceut Co Ltd | External preparation for skin |
| JP2005320257A (en) * | 2004-05-06 | 2005-11-17 | Shiseido Co Ltd | Emulsified skin care preparation for external use and method for producing the same |
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| JP2006028123A (en) | 2006-02-02 |
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