JP5965187B2 - Oily ointment - Google Patents
Oily ointment Download PDFInfo
- Publication number
- JP5965187B2 JP5965187B2 JP2012082251A JP2012082251A JP5965187B2 JP 5965187 B2 JP5965187 B2 JP 5965187B2 JP 2012082251 A JP2012082251 A JP 2012082251A JP 2012082251 A JP2012082251 A JP 2012082251A JP 5965187 B2 JP5965187 B2 JP 5965187B2
- Authority
- JP
- Japan
- Prior art keywords
- ointment
- oil
- droplet
- acetate
- steroid
- 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.)
- Active
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- 239000002674 ointment Substances 0.000 title claims description 67
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 37
- 150000003431 steroids Chemical class 0.000 claims description 33
- 239000007787 solid Substances 0.000 claims description 29
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 24
- 239000003921 oil Substances 0.000 claims description 24
- 235000019198 oils Nutrition 0.000 claims description 24
- 239000003021 water soluble solvent Substances 0.000 claims description 24
- 239000003883 ointment base Substances 0.000 claims description 21
- -1 liquid paraffin Substances 0.000 claims description 17
- 239000006185 dispersion Substances 0.000 claims description 14
- NOPFSRXAKWQILS-UHFFFAOYSA-N docosan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCO NOPFSRXAKWQILS-UHFFFAOYSA-N 0.000 claims description 12
- 235000019271 petrolatum Nutrition 0.000 claims description 12
- 239000001993 wax Substances 0.000 claims description 11
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 claims description 10
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 claims description 8
- 239000004166 Lanolin Substances 0.000 claims description 8
- 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 description 8
- 229940039717 lanolin Drugs 0.000 claims description 8
- 235000019388 lanolin Nutrition 0.000 claims description 8
- 239000004200 microcrystalline wax Substances 0.000 claims description 8
- 235000019808 microcrystalline wax Nutrition 0.000 claims description 8
- 229960002800 prednisolone acetate Drugs 0.000 claims description 8
- 239000004094 surface-active agent Substances 0.000 claims description 8
- 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 claims description 7
- 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 claims description 7
- 229960001067 hydrocortisone acetate Drugs 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 7
- 239000003871 white petrolatum Substances 0.000 claims description 7
- 239000007765 cera alba Substances 0.000 claims description 6
- 229960000735 docosanol Drugs 0.000 claims description 6
- 229960003957 dexamethasone Drugs 0.000 claims description 5
- 229960000890 hydrocortisone Drugs 0.000 claims description 5
- 229940057995 liquid paraffin Drugs 0.000 claims description 5
- 229940058015 1,3-butylene glycol Drugs 0.000 claims description 4
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims description 4
- 239000004264 Petrolatum Substances 0.000 claims description 4
- FPVRUILUEYSIMD-RPRRAYFGSA-N [(8s,9r,10s,11s,13s,14s,16r,17r)-9-fluoro-11-hydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthren-17-yl] acetate 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)(OC(C)=O)[C@@]1(C)C[C@@H]2O FPVRUILUEYSIMD-RPRRAYFGSA-N 0.000 claims description 4
- 235000019437 butane-1,3-diol Nutrition 0.000 claims description 4
- BMCQMVFGOVHVNG-TUFAYURCSA-N cortisol 17-butyrate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CO)(OC(=O)CCC)[C@@]1(C)C[C@@H]2O BMCQMVFGOVHVNG-TUFAYURCSA-N 0.000 claims description 4
- 229960003657 dexamethasone acetate Drugs 0.000 claims description 4
- 229960001524 hydrocortisone butyrate Drugs 0.000 claims description 4
- 229940066842 petrolatum Drugs 0.000 claims description 4
- 229940070710 valerate Drugs 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 3
- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 3
- 239000008158 vegetable oil Substances 0.000 claims description 3
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000010703 silicon Substances 0.000 claims description 2
- 229910052710 silicon Inorganic materials 0.000 claims description 2
- 238000000926 separation method Methods 0.000 description 17
- 238000011156 evaluation Methods 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 10
- 239000000203 mixture Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 229960004063 propylene glycol Drugs 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- 150000002430 hydrocarbons Chemical class 0.000 description 4
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 4
- 229960005205 prednisolone Drugs 0.000 description 4
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 3
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 125000004432 carbon atom Chemical group C* 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
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 229960000520 diphenhydramine Drugs 0.000 description 3
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 239000003589 local anesthetic agent Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 3
- 208000017520 skin disease Diseases 0.000 description 3
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 2
- XHXUANMFYXWVNG-ADEWGFFLSA-N (-)-Menthyl acetate Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(C)=O XHXUANMFYXWVNG-ADEWGFFLSA-N 0.000 description 2
- DSEKYWAQQVUQTP-XEWMWGOFSA-N (2r,4r,4as,6as,6as,6br,8ar,12ar,14as,14bs)-2-hydroxy-4,4a,6a,6b,8a,11,11,14a-octamethyl-2,4,5,6,6a,7,8,9,10,12,12a,13,14,14b-tetradecahydro-1h-picen-3-one Chemical compound C([C@H]1[C@]2(C)CC[C@@]34C)C(C)(C)CC[C@]1(C)CC[C@]2(C)[C@H]4CC[C@@]1(C)[C@H]3C[C@@H](O)C(=O)[C@@H]1C DSEKYWAQQVUQTP-XEWMWGOFSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical compound CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 2
- SVTBMSDMJJWYQN-UHFFFAOYSA-N 2-methylpentane-2,4-diol Chemical compound CC(O)CC(C)(C)O SVTBMSDMJJWYQN-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- GLZPCOQZEFWAFX-UHFFFAOYSA-N Geraniol Chemical compound CC(C)=CCCC(C)=CCO GLZPCOQZEFWAFX-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].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(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000012164 animal wax Substances 0.000 description 2
- 239000000043 antiallergic agent Substances 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- KVYGGMBOZFWZBQ-UHFFFAOYSA-N benzyl nicotinate Chemical compound C=1C=CN=CC=1C(=O)OCC1=CC=CC=C1 KVYGGMBOZFWZBQ-UHFFFAOYSA-N 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- ULDHMXUKGWMISQ-UHFFFAOYSA-N carvone Chemical compound CC(=C)C1CC=C(C)C(=O)C1 ULDHMXUKGWMISQ-UHFFFAOYSA-N 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000010642 eucalyptus oil Substances 0.000 description 2
- 229940044949 eucalyptus oil Drugs 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 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 description 2
- 208000014617 hemorrhoid Diseases 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- NFLGAXVYCFJBMK-UHFFFAOYSA-N isomenthone Natural products CC(C)C1CCC(C)CC1=O NFLGAXVYCFJBMK-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 2
- CDOSHBSSFJOMGT-UHFFFAOYSA-N linalool Chemical compound CC(C)=CCCC(C)(O)C=C CDOSHBSSFJOMGT-UHFFFAOYSA-N 0.000 description 2
- UWKAYLJWKGQEPM-LBPRGKRZSA-N linalyl acetate Chemical compound CC(C)=CCC[C@](C)(C=C)OC(C)=O UWKAYLJWKGQEPM-LBPRGKRZSA-N 0.000 description 2
- 230000007721 medicinal effect Effects 0.000 description 2
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 2
- 239000012184 mineral wax Substances 0.000 description 2
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 2
- NUJGJRNETVAIRJ-UHFFFAOYSA-N octanal Chemical compound CCCCCCCC=O NUJGJRNETVAIRJ-UHFFFAOYSA-N 0.000 description 2
- 235000019477 peppermint oil Nutrition 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N squalane Chemical compound CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 2
- 150000005846 sugar alcohols Polymers 0.000 description 2
- HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 description 2
- RUVINXPYWBROJD-ONEGZZNKSA-N trans-anethole Chemical compound COC1=CC=C(\C=C\C)C=C1 RUVINXPYWBROJD-ONEGZZNKSA-N 0.000 description 2
- DTGKSKDOIYIVQL-NQMVMOMDSA-N (+)-Borneol Natural products C1C[C@]2(C)[C@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-NQMVMOMDSA-N 0.000 description 1
- NFLGAXVYCFJBMK-RKDXNWHRSA-N (+)-isomenthone Natural products CC(C)[C@H]1CC[C@@H](C)CC1=O NFLGAXVYCFJBMK-RKDXNWHRSA-N 0.000 description 1
- REPVLJRCJUVQFA-UHFFFAOYSA-N (-)-isopinocampheol Natural products C1C(O)C(C)C2C(C)(C)C1C2 REPVLJRCJUVQFA-UHFFFAOYSA-N 0.000 description 1
- AJZJIYUOOJLBAU-CEAXSRTFSA-N (2r,3r)-2,3-dihydroxybutanedioic acid;n,n,2-trimethyl-3-phenothiazin-10-ylpropan-1-amine Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1=CC=C2N(CC(CN(C)C)C)C3=CC=CC=C3SC2=C1.C1=CC=C2N(CC(CN(C)C)C)C3=CC=CC=C3SC2=C1 AJZJIYUOOJLBAU-CEAXSRTFSA-N 0.000 description 1
- CUNWUEBNSZSNRX-RKGWDQTMSA-N (2r,3r,4r,5s)-hexane-1,2,3,4,5,6-hexol;(z)-octadec-9-enoic acid Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O CUNWUEBNSZSNRX-RKGWDQTMSA-N 0.000 description 1
- 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
- 239000001490 (3R)-3,7-dimethylocta-1,6-dien-3-ol Substances 0.000 description 1
- 239000001605 (5-methyl-2-propan-2-ylcyclohexyl) acetate Substances 0.000 description 1
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 1
- KJPRLNWUNMBNBZ-QPJJXVBHSA-N (E)-cinnamaldehyde Chemical compound O=C\C=C\C1=CC=CC=C1 KJPRLNWUNMBNBZ-QPJJXVBHSA-N 0.000 description 1
- CDOSHBSSFJOMGT-JTQLQIEISA-N (R)-linalool Natural products CC(C)=CCC[C@@](C)(O)C=C CDOSHBSSFJOMGT-JTQLQIEISA-N 0.000 description 1
- PMGQWSIVQFOFOQ-BDUVBVHRSA-N (e)-but-2-enedioic acid;(2r)-2-[2-[1-(4-chlorophenyl)-1-phenylethoxy]ethyl]-1-methylpyrrolidine Chemical compound OC(=O)\C=C\C(O)=O.CN1CCC[C@@H]1CCOC(C)(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 PMGQWSIVQFOFOQ-BDUVBVHRSA-N 0.000 description 1
- FWLKKPKZQYVAFR-LVEZLNDCSA-N (e)-but-2-enedioic acid;1-(2-ethoxyethyl)-2-(4-methyl-1,4-diazepan-1-yl)benzimidazole Chemical compound OC(=O)\C=C\C(O)=O.OC(=O)\C=C\C(O)=O.N=1C2=CC=CC=C2N(CCOCC)C=1N1CCCN(C)CC1 FWLKKPKZQYVAFR-LVEZLNDCSA-N 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- CMCBDXRRFKYBDG-UHFFFAOYSA-N 1-dodecoxydodecane Chemical compound CCCCCCCCCCCCOCCCCCCCCCCCC CMCBDXRRFKYBDG-UHFFFAOYSA-N 0.000 description 1
- FDCJDKXCCYFOCV-UHFFFAOYSA-N 1-hexadecoxyhexadecane Chemical compound CCCCCCCCCCCCCCCCOCCCCCCCCCCCCCCCC FDCJDKXCCYFOCV-UHFFFAOYSA-N 0.000 description 1
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 description 1
- 239000000263 2,3-dihydroxypropyl (Z)-octadec-9-enoate Substances 0.000 description 1
- 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 description 1
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 description 1
- XULHFMYCBKQGEE-UHFFFAOYSA-N 2-hexyl-1-Decanol Chemical compound CCCCCCCCC(CO)CCCCCC XULHFMYCBKQGEE-UHFFFAOYSA-N 0.000 description 1
- MUHFRORXWCGZGE-KTKRTIGZSA-N 2-hydroxyethyl (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCCO MUHFRORXWCGZGE-KTKRTIGZSA-N 0.000 description 1
- LEACJMVNYZDSKR-UHFFFAOYSA-N 2-octyldodecan-1-ol Chemical compound CCCCCCCCCCC(CO)CCCCCCCC LEACJMVNYZDSKR-UHFFFAOYSA-N 0.000 description 1
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Landscapes
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Description
本発明は、ステロイドを含有する、皮膚疾患の予防・治療に有用な軟膏剤に関する。 The present invention relates to an ointment containing a steroid and useful for the prevention and treatment of skin diseases.
従来より、肌荒れや湿疹、皮膚炎等の皮膚疾患や、出血や痛み、痒みなどを伴う痔疾患の予防・治療にステロイド等の抗炎症剤を含む油性軟膏剤が使用されている。 Conventionally, oily ointments containing anti-inflammatory agents such as steroids have been used for the prevention and treatment of skin diseases such as rough skin, eczema and dermatitis, and hemorrhoids associated with bleeding, pain and itching.
ステロイドのように油性軟膏基剤に難溶性の薬物を含む軟膏剤においては、薬物を固体のまま油性軟膏基剤中に分散させた、いわゆる固体分散型軟膏剤が知られている（特許文献１）。しかしながら、薬物を固体のまま油性軟膏基剤中に分散させるため、薬物の経皮吸収性が悪く、薬効を充分に発揮できないという問題があった。 As an ointment containing a drug that is sparingly soluble in an oily ointment base such as a steroid, a so-called solid dispersion-type ointment in which a drug is dispersed in an oily ointment base in a solid state is known (Patent Document 1). ). However, since the drug is dispersed in the oily ointment base as a solid, there is a problem in that the drug has poor percutaneous absorbability and cannot fully exhibit its medicinal effects.
一方、経皮吸収性を改善し、薬効を充分に発揮させるために、薬物を水溶性溶媒に溶解させたものを、油性軟膏基剤中に均一に分散させた液滴分散型軟膏剤が知られている（非特許文献１）。しかしながら、一般に、油性軟膏基剤に難溶性の薬物を溶解させることのできる溶剤と油性軟膏基剤との相溶性が悪いため、高温下で両者が容易に分離して製剤化が難しく、また、常温での保存安定性にも劣るという問題があった。 On the other hand, in order to improve the transdermal absorbability and to fully exert its medicinal effects, there is known a droplet dispersion type ointment in which a drug dissolved in a water-soluble solvent is uniformly dispersed in an oily ointment base. (Non-Patent Document 1). However, in general, since the compatibility of a solvent capable of dissolving a poorly soluble drug in an oily ointment base and an oily ointment base is poor, both are easily separated at high temperatures, making formulation difficult, There was a problem that storage stability at room temperature was inferior.
本発明は、ステロイドを予め水溶性溶媒に溶解させ、油性軟膏基剤中に均一に分散させた液滴分散型軟膏剤において、軟膏剤の分離を防ぎ、製剤の保存安定性を改善することを目的とする。 The present invention aims to prevent ointment separation and improve the storage stability of a preparation in a droplet dispersion type ointment in which a steroid is previously dissolved in a water-soluble solvent and uniformly dispersed in an oily ointment base. Objective.
本発明者は、ステロイドを含む、液滴分散型軟膏剤の分離の問題を解決すべく種々検討を重ねた結果、常温固体基剤を配合すると、高温でも分離することなく製剤化が容易であり、常温での保存安定性にも優れた安定な液滴分散型軟膏剤を製造できることを見出した。 The present inventor has conducted various studies to solve the problem of separation of droplet dispersion type ointment containing a steroid, and as a result, when a room temperature solid base is blended, it can be easily formulated without separation even at high temperatures. The present inventors have found that a stable droplet dispersion type ointment having excellent storage stability at room temperature can be produced.
すなわち、本発明は、ステロイド、水溶性溶媒、常温固体基剤、及び油性軟膏基剤を含有する軟膏剤に関する。 That is, the present invention relates to an ointment containing a steroid, a water-soluble solvent, a room temperature solid base, and an oily ointment base.
常温固体基剤が、ワックス又は高級アルコールから選択される１種又は２種以上であることが好ましい。 The room temperature solid base is preferably one or more selected from waxes or higher alcohols.
ワックスが、マイクロクリスタリンワックス又はサラシミツロウから選択される１種又は２種以上であることが好ましい。 The wax is preferably one or more selected from microcrystalline wax or white beeswax.
高級アルコールが、ベヘニルアルコール又はラノリンアルコールから選択される１種又は２種以上であることが好ましい。 The higher alcohol is preferably one or more selected from behenyl alcohol or lanolin alcohol.
ステロイドが、ヒドロコルチゾン、酢酸ヒドロコルチゾン、酪酸ヒドロコルチゾン、プレドニゾロン、酢酸プレドニゾロン、吉草酸酢酸プレドニゾロン、デキサメタゾン、及び酢酸デキサメタゾンからなる群から選択される１種又は２種以上であることが好ましい。 The steroid is preferably one or more selected from the group consisting of hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, prednisolone, prednisolone acetate, prednisolone acetate valerate, dexamethasone, and dexamethasone acetate.
水溶性溶媒が、プロピレングリコール、１，３−ブチレングリコール、及びエタノールからなる群から選択される１種又は２種以上であることが好ましい。 The water-soluble solvent is preferably one or more selected from the group consisting of propylene glycol, 1,3-butylene glycol, and ethanol.
油性軟膏基剤が、白色ワセリン、黄色ワセリン、流動パラフィン、シリコン油、植物油、及び豚脂からなる群から選択される１種又は２種以上であることが好ましい。 The oily ointment base is preferably one or more selected from the group consisting of white petrolatum, yellow petrolatum, liquid paraffin, silicon oil, vegetable oil, and lard.
軟膏剤は、さらに、極性油を含有することが好ましい。 The ointment preferably further contains a polar oil.
軟膏剤は、さらに、界面活性剤を含有することが好ましい。 It is preferable that the ointment further contains a surfactant.
軟膏剤は、液滴分散型軟膏剤であることが好ましい。 The ointment is preferably a droplet dispersion type ointment.
軟膏剤は、ステロイドとして酢酸ヒドロコルチゾンを含有し、水溶性溶媒としてプロピレングリコールを含有し、常温固体基剤としてマイクロクリスタリンワックスを含有し、油性軟膏基剤として白色ワセリンを含有し、液滴分散型軟膏剤であることが好ましい。 The ointment contains hydrocortisone acetate as a steroid, propylene glycol as a water-soluble solvent, microcrystalline wax as a room temperature solid base, white petrolatum as an oily ointment base, and a droplet dispersion type ointment It is preferable that it is an agent.
本発明の軟膏剤は、常温固体基剤を含有するため、高温でも分離することなく製剤化が容易であり、常温での保存安定性にも優れた安定な軟膏剤を製造することができる。 Since the ointment of the present invention contains a room temperature solid base, it can be easily formulated without separation even at high temperatures, and a stable ointment excellent in storage stability at room temperature can be produced.
本発明の軟膏剤は、ステロイド、水溶性溶媒、常温固体基剤、及び油性軟膏基剤を含有する。ここで、軟膏剤とは、皮膚に塗布するための、有効成分を基剤に溶解又は分散させた半固形の製剤であり、皮膚に適用する上で適切な粘性を有するものである。本発明の軟膏剤は、ステロイドが溶解した水溶性溶媒が液滴の状態で油性軟膏基剤中に分散した液滴分散型軟膏剤である。 The ointment of the present invention contains a steroid, a water-soluble solvent, a room temperature solid base, and an oily ointment base. Here, an ointment is a semi-solid preparation in which an active ingredient is dissolved or dispersed in a base for application to the skin, and has an appropriate viscosity when applied to the skin. The ointment of the present invention is a droplet dispersion type ointment in which a water-soluble solvent in which a steroid is dissolved is dispersed in an oily ointment base in the form of droplets.
常温固体基剤における常温とは、１５〜２５℃の温度であり、この温度で固体であるものであれば特に限定されることなく常温固体基剤として使用することができる。ここで、固体とは、常温で粘性のない、結晶、粉末又は塊状のものである。常温固体基剤を軟膏剤に配合することにより、ステロイドが溶解した水溶性溶媒の分離を防止することができる。 The room temperature in the room temperature solid base is a temperature of 15 to 25 ° C., and any solid material can be used as a room temperature solid base as long as it is solid at this temperature. Here, the solid is a crystal, powder or lump that is not viscous at room temperature. By blending the room temperature solid base with the ointment, separation of the water-soluble solvent in which the steroid is dissolved can be prevented.
常温固体基剤としては、ワックス、高級アルコールなどが挙げられる。ワックス、高級アルコールなどを１種のみで使用することも可能であるが、２種以上使用することも可能であり、例えば、ワックス２種と高級アルコール２種を同時に使用することも可能である。 Examples of the room temperature solid base include wax and higher alcohol. It is possible to use only one kind of wax, higher alcohol, or the like, but it is also possible to use two or more kinds. For example, two kinds of wax and two kinds of higher alcohol can be used simultaneously.
ワックスとは、高級脂肪酸と一価又は二価の高級アルコールとのエステル、及びこれらに類似する中性脂肪や高級脂肪酸、炭化水素である。ワックスとして、植物性ワックス、動物性ワックス、鉱物性ワックスが挙げられる。植物性ワックスとして、カルナウバロウ、キャンデリラロウ等が挙げられるが、これらに限定されない。動物性ワックスとして、鯨ロウ、ミツロウ、サラシミツロウ、セラック、ラノリン等が挙げられるが、これらに限定されない。鉱物性ワックスとして、マイクロクリスタリンワックス、パラフィンワックス、モンタンワックス、オゾケライト、セレシン等が挙げられるが、これらに限定されない。中でも、使用感の点で、マイクロクリスタリンワックス、サラシミツロウが好ましい。 The wax is an ester of a higher fatty acid and a monohydric or dihydric higher alcohol, and a similar neutral fat, higher fatty acid, or hydrocarbon. Examples of the wax include vegetable wax, animal wax, and mineral wax. Examples of plant wax include, but are not limited to, carnauba wax and candelilla wax. Animal waxes include, but are not limited to, whale wax, beeswax, white beeswax, shellac, lanolin and the like. Examples of the mineral wax include, but are not limited to, microcrystalline wax, paraffin wax, montan wax, ozokerite, and ceresin. Of these, microcrystalline wax and white beeswax are preferred from the viewpoint of usability.
高級アルコールとは、一般的に炭素数６以上のアルコールであるが、炭素数１４〜２２が好ましく、炭素数が１８〜２２がより好ましい。具体例として、たとえばミリスチルアルコール、イソステアリルアルコール、セチルアルコール、ステアリルアルコール、オレイルアルコール、アラキルアルコール、２−オクチルドデカノール、コレステロール、フィトステロール、２−ヘキシルデカノール、ベヘニルアルコール、ラノリンアルコール、ラウリルアルコール等が挙げられるが、これらに限定されない。中でも、使用感の点でベヘニルアルコール、ラノリンアルコール、ステアリルアルコールなどが好ましい。 The higher alcohol is generally an alcohol having 6 or more carbon atoms, preferably 14 to 22 carbon atoms, and more preferably 18 to 22 carbon atoms. Specific examples include myristyl alcohol, isostearyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, aralkyl alcohol, 2-octyldodecanol, cholesterol, phytosterol, 2-hexyldecanol, behenyl alcohol, lanolin alcohol, lauryl alcohol and the like. However, it is not limited to these. Of these, behenyl alcohol, lanolin alcohol, stearyl alcohol and the like are preferable in terms of the feeling of use.
常温固体基剤の軟膏剤における配合量は、軟膏剤中１〜２０重量％であることが好ましく、２〜１５重量％であることがより好ましい。２０重量％を超えると、軟膏剤が硬くなり使用感が悪化する傾向がある。一方、１重量％未満では、高温時の安定性が悪くなってしまう傾向がある。 The blending amount of the room temperature solid base in the ointment is preferably 1 to 20% by weight in the ointment, and more preferably 2 to 15% by weight. When it exceeds 20% by weight, the ointment becomes hard and the feeling of use tends to deteriorate. On the other hand, if it is less than 1% by weight, the stability at high temperatures tends to deteriorate.
ステロイドは、医薬品に使用されるステロイドであれば特に限定されない。具体例としては、デキサメタゾン、トリアムシノロンアセトニド、プロピオン酸ベクロメタゾン、プロピオン酸フルチカゾン、フランカルボン酸モメタゾン、コハク酸ヒドロコルチゾン、コハク酸メチルプレドニゾロン、酢酸デキサメタゾン、酢酸ヒドロコルチゾン、酢酸プレドニゾロン、デキサメタゾンメタスルホ酸安息香酸、トリアムノシノロンジアセテート、ブチル酢酸プレドニゾロン、リン酸デキサメタゾン、リン酸ヒドロコルチゾン、リン酸プレドニゾロン、リン酸ベタメタゾン、コハク酸プレドニゾロン、酢酸コルチゾン、酢酸パラメタゾン、酢酸メチルプレドニゾロン、トリアムシノロン、ヒドロコルチゾン、プレドニゾロン、ベタメタゾン、吉草酸酢酸プレドニゾロン、吉草酸ジフルコルトロン、吉草酸デキサメタゾン、吉草酸ベタメタゾン、酢酸ジフルプレドナート、酢酸ジフロラゾン、ジフルプレドナート、ジプロピオン酸ベタメタゾン、ピバル酸フルメタゾン、フルオノシノニド、フルオノシノロンアセトニド、プロピオン酸アルクロメタゾン、酪酸クロベタゾン、酪酸ヒドロコルチゾン、酪酸プロピオン酸ヒドロコルチゾン、酢酸フルドロコルチゾン、パルミチン酸デキサメタゾン、メチルプレドニゾロン等が挙げられる。中でも、ヒドロコルチゾン、酢酸ヒドロコルチゾン、酪酸ヒドロコルチゾン、プレドニゾロン、酢酸プレドニゾロン、デキサメタゾン、酢酸デキサメタゾン、吉草酸酢酸プレドニゾロンが好ましい。 The steroid is not particularly limited as long as it is a steroid used for pharmaceutical products. Specific examples include dexamethasone, triamcinolone acetonide, beclomethasone propionate, fluticasone propionate, mometasone furanate, hydrocortisone succinate, methylprednisolone succinate, dexamethasone acetate, hydrocortisone acetate, prednisolone acetate, dexamethasone metasulfonate benzoate, tria Munocinolone diacetate, prednisolone butyl acetate, dexamethasone phosphate, hydrocortisone phosphate, prednisolone phosphate, betamethasone phosphate, prednisolone succinate, cortisone acetate, parameterzone acetate, methylprednisolone acetate, triamcinolone, hydrocortisone, prednisolone, betamethasone acetate, valeric acid acetate Prednisolone, diflucortron valerate, dexamethasone valerate, Yoshi Betamethasone acid, diflupredone acetate, diflorazone acetate, diflupredone, betamethasone dipropionate, flumethasone pivalate, fluonosinide, fluonosinol acetonide, alcrometasone propionate, clobetasone butyrate, hydrocortisone butyrate, hydrocortisone propionate, hydrocortisone acetate propionate Cortisone, dexamethasone palmitate, methylprednisolone and the like can be mentioned. Of these, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, prednisolone, prednisolone acetate, dexamethasone, dexamethasone acetate, and prednisolone acetate valerate are preferred.
ステロイドの軟膏剤における配合量は、軟膏剤中０．０１〜２．０重量％であることが好ましく、０．０２〜１．０重量％であることがより好ましい。配合量が多すぎると安全性の問題が生じ、少なすぎると軟膏剤としての効果が低下してしまう可能性が生じる。 The blending amount of the steroid in the ointment is preferably 0.01 to 2.0% by weight and more preferably 0.02 to 1.0% by weight in the ointment. If the amount is too large, a safety problem will occur, and if it is too small, the effect as an ointment may be reduced.
水溶性溶媒は、ステロイドを溶解できるものであれば特に限定されず、１価アルコール、２価アルコール、３価アルコール、４価アルコール、５価アルコール、６価アルコール、多価アルコール重合体などが挙げられる。１価アルコールとしては、エタノール、イソプロパノールなどが挙げられる。２価アルコールとしては、エチレングリコール、プロピレングリコール、１，３−ブチレングリコール、ヘキシレングリコールなどが挙げられる。３価アルコールとしては、グリセリンなどが挙げられる。４価アルコールとしては、ペンタエリスリトールなどが挙げられる。５価アルコールとしては、キシリトールなどが挙げられる。６価アルコールとしては、ソルビトール、マンニトールなどが挙げられる。多価アルコールとしては、ジエチレングリコール、ジプロピレングリコール、ジグリセリン、ポリエチレングリコールなどが挙げられる。中でも、ステロイドの溶解性が高い、プロピレングリコール、１，３−ブチレングリコール、エタノールが好ましい。 The water-soluble solvent is not particularly limited as long as it can dissolve steroids, and examples thereof include monohydric alcohol, dihydric alcohol, trihydric alcohol, tetrahydric alcohol, pentahydric alcohol, hexahydric alcohol, and polyhydric alcohol polymer. It is done. Examples of monohydric alcohols include ethanol and isopropanol. Examples of the dihydric alcohol include ethylene glycol, propylene glycol, 1,3-butylene glycol, hexylene glycol and the like. Examples of the trihydric alcohol include glycerin. Examples of the tetrahydric alcohol include pentaerythritol. Examples of the pentahydric alcohol include xylitol. Examples of the hexavalent alcohol include sorbitol and mannitol. Examples of the polyhydric alcohol include diethylene glycol, dipropylene glycol, diglycerin, and polyethylene glycol. Of these, propylene glycol, 1,3-butylene glycol, and ethanol, which have high steroid solubility, are preferred.
水溶性溶媒の軟膏剤における配合量は、ステロイドを溶解できれば特に限定されないが、０．１〜３０重量％であることが好ましく、０．５〜２５重量％であることがより好ましい。３０重量％を超えると、高温安定性が悪く分離しやすくなり、また軟膏剤の粘性が低下する傾向がある。 Although the compounding quantity in the ointment of a water-soluble solvent will not be specifically limited if steroid can be melt | dissolved, it is preferable that it is 0.1-30 weight%, and it is more preferable that it is 0.5-25 weight%. If it exceeds 30% by weight, the high temperature stability is poor and the separation tends to occur, and the viscosity of the ointment tends to decrease.
水溶性溶媒のステロイドに対する重量比率は、ステロイド１重量部に対して水溶性溶媒１０〜３０００重量部であることが好ましく、２５〜１２５０重量部であることがより好ましい。１０重量部未満では、ステロイドを完全に溶解できず、析出してしまう傾向がある。 The weight ratio of the water-soluble solvent to the steroid is preferably 10 to 3000 parts by weight, more preferably 25 to 1250 parts by weight with respect to 1 part by weight of the steroid. If it is less than 10 parts by weight, the steroid cannot be completely dissolved and tends to precipitate.
油性軟膏基剤は、皮膚に付着し、有効成分を長く皮膚にとどめ、塗りやすく、皮膚に対する刺激性がなく、有効成分の安定性に影響しないものを使用できる。常温（１５〜２５℃）で粘性のある半固形もしくは液状油分の油性軟膏基剤であることが好ましい。このような油性軟膏基剤としては、白色ワセリン、黄色ワセリン、ラノリン、ゲル化炭化水素（商品名：プラスチベース）、流動パラフィン、軽質流動パラフィン、スクワランなどの炭化水素、シリコン油、中鎖脂肪酸トリグリセライドを含む植物油や豚脂などが挙げられる。中でも、刺激性が低く、病変部の性質を選ばず使用できるという理由で、白色ワセリン、ゲル化炭化水素（商品名：プラスチベース）、黄色ワセリンが好ましく、白色ワセリンがより好ましい。 Oily ointment bases can be used that adhere to the skin, keep the active ingredient on the skin for a long time, are easy to apply, do not irritate the skin, and do not affect the stability of the active ingredient. It is preferably an oily ointment base that is viscous at room temperature (15 to 25 ° C.) and is semi-solid or liquid. Such oil-based ointment bases include white petrolatum, yellow petrolatum, lanolin, gelled hydrocarbons (trade name: Plastibase), liquid paraffin, light liquid paraffin, hydrocarbons such as squalane, silicone oil, and medium chain fatty acid triglycerides. Examples include vegetable oil and pork fat. Among them, white petrolatum, gelled hydrocarbon (trade name: Plastibase), and yellow petrolatum are preferable, and white petrolatum is more preferable because it is low in irritation and can be used regardless of the nature of the lesion.
本発明の軟膏剤は、極性油を含有することが好ましい。極性油としては、カルボン酸エステルが挙げられ、そのうち、脂肪酸モノエステル、脂肪酸ジエステルなどが挙げられる。具体的には、ミリスチン酸イソプロピル、アジピン酸ジイソプロピル、セバシン酸ジエチル、セバシン酸ジイソプロピル、アジピン酸ジオクチル、ミリスチン酸オクチルドデシル、ミリスチン酸ミリスチル、イソステアリン酸ヘキサデシル、イソオクタン酸セチル等が挙げられるが、これらに限定されない。 The ointment of the present invention preferably contains a polar oil. Examples of polar oils include carboxylic acid esters, of which fatty acid monoesters and fatty acid diesters. Specific examples include, but are not limited to, isopropyl myristate, diisopropyl adipate, diethyl sebacate, diisopropyl sebacate, dioctyl adipate, octyldodecyl myristate, myristyl myristate, hexadecyl isostearate, cetyl isooctanoate, and the like. Not.
極性油の軟膏剤における配合量は、軟膏剤中１〜１５重量％であることが好ましく、２〜１０％であることがより好ましい。１重量％未満では、べたつきなど、油性軟膏剤特有の不具合が生じる傾向がある。１５重量％を超えると、高温状態での油の染み出しが生じる傾向がある。 The blending amount of the polar oil in the ointment is preferably 1 to 15% by weight in the ointment, and more preferably 2 to 10%. If it is less than 1% by weight, there is a tendency to cause problems peculiar to oily ointments such as stickiness. If it exceeds 15% by weight, the oil tends to ooze out at a high temperature.
本発明の軟膏剤は、界面活性剤を含有することが好ましい。界面活性剤としては、系の安定性を高めることのできる界面活性剤であれば特に限定されないが、非イオン系の界面活性剤であることが好ましい。界面活性剤の具体例として、セスキオレイン酸ソルビタン、モノステアリン酸グリセリル、モノオレイン酸グリセリル、モノステアリン酸ソルビタン、モノオレイン酸ソルビタン、モノステアリン酸ポリオキシエチレン（２０）ソルビタン、モノオレイン酸ポリオキシエチレン（２０）ソルビタン、テトラステアリン酸ポリオキシエチレン（２０）ソルビット、テトラオレイン酸ポリオキシエチレン（２０）ソルビット、ポリオキシエチレン（６０）ヒマシ油、ポリオキシエチレン（６０）硬化ヒマシ油、モノステアリン酸ポリエチレングリコール（４Ｅ０）、モノオレイン酸ポリエチレングリコール（１０Ｅ０）、ポリオキシエチレン（９）ラウリルエーテル、ポリオキシエチレン（１０）セチルエーテル、ポリオキシエチレン（２０）オレイルエーテル、ポリオキシエチレン（２０）ソルビタンオレイン酸エステル等が挙げられる。 The ointment of the present invention preferably contains a surfactant. The surfactant is not particularly limited as long as it can improve the stability of the system, but is preferably a nonionic surfactant. Specific examples of surfactants include sorbitan sesquioleate, glyceryl monostearate, glyceryl monooleate, sorbitan monostearate, sorbitan monooleate, polyoxyethylene (20) sorbitan monostearate, polyoxyethylene monooleate (20) Sorbitan, polyoxyethylene tetrastearate (20) sorbit, polyoxyethylene tetraoleate (20) sorbit, polyoxyethylene (60) castor oil, polyoxyethylene (60) hydrogenated castor oil, polyethylene monostearate Glycol (4E0), polyethylene glycol monooleate (10E0), polyoxyethylene (9) lauryl ether, polyoxyethylene (10) cetyl ether, polyoxyethylene (20) Yl ether, polyoxyethylene (20) sorbitan oleate, and the like.
界面活性剤の軟膏剤における配合量は、軟膏剤中０．１〜１０重量％であることが好ましい。１０重量％を超えると、刺激性が高まる傾向があり、０．１重量％未満では、軟膏剤の安定性が低下する傾向がある。 The blending amount of the surfactant in the ointment is preferably 0.1 to 10% by weight in the ointment. If it exceeds 10% by weight, the irritation tends to increase, and if it is less than 0.1% by weight, the stability of the ointment tends to decrease.
本発明の軟膏剤には、上記の他に、局所麻酔剤、抗ヒスタミン又は抗アレルギー薬、清涼化剤、殺菌剤、血行促進剤、抗酸化剤等を配合することができる。 In addition to the above, a local anesthetic, an antihistamine or an antiallergic agent, a refreshing agent, a bactericidal agent, a blood circulation promoter, an antioxidant and the like can be added to the ointment of the present invention.
局所麻酔剤としては、リドカイン、プロカイン、アミノ安息香酸エチル、ジブカイン、メピバカイン、これらの塩又は誘導体等が挙げられるが、これらに限定されない。これらの局所麻酔剤は、一種単独で又は二種以上を混合して用いることができる。 Examples of the local anesthetic include, but are not limited to, lidocaine, procaine, ethyl aminobenzoate, dibucaine, mepivacaine, salts or derivatives thereof, and the like. These local anesthetics can be used alone or in combination of two or more.
抗ヒスタミン又は抗アレルギー薬としては、塩酸イソチペンジル、塩酸プロメタジン、メチレンジサリチル酸プロメタジン、カルビノキサミン、アステミゾール、フマル酸クレマスチン、メキタジン、マレイン酸クロルフェニラミン、塩酸ジフェンヒドラミン、サリチル酸ジフェンヒドラミン、タンニン酸ジフェンヒドラミン、ジフェンヒドラミン、イブジラスト、アンレキサノクス、シプロヘプタジン、フマル酸ケトチフェン、酒石酸アリメマジン、トラニラスト、ペミロラストカリウム、塩酸アゼラスチン、オキサトミド、フマル酸エメダスチン、塩酸エピナスチン等又はそれらの塩類が挙げられる。 Antihistamines or antiallergic agents include isothipentil hydrochloride, promethazine hydrochloride, promethazine methylene disalicylate, carbinoxamine, astemizole, clemastine fumarate, mequitazine, chlorpheniramine maleate, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tanninate, diphenhydramine, Examples include amlexanox, cyproheptadine, ketotifen fumarate, alimemazine tartrate, tranilast, pemirolast potassium, azelastine hydrochloride, oxatomide, emedastine fumarate, epinastine hydrochloride, and salts thereof.
清涼化剤としては、メントール（ｌ−メントール、ｄｌ−メントール）、カンフル（ｄｌ−カンフル、ｄ−カンフル）、ボルネオール（ｄ−ボルネオール、リュウノウ）、ゲラニオール、シネオール、リナロール、リモネン、メントン、カルボン、アネトール、サリチル酸メチル、シンナミックアルデヒド、オクチルアルデヒド、リナリールアセテート、メンチルアセテート、ピネン、乳酸メンチル、ユーカリ油、ベルガモット油、ウイキョウ油、ローズ油、ハッカ油、ペパーミント油、スペアミント油、フタバガキ科植物の精油、ロズマリン油、ラベンダー油、マスティック油、パセリ油、アニス油、ユーカリ油、ウィンターグリーン油、カシア油、レモン油、オレンジ油、カルダモン油、コリアンダー油、マンダリン油、ライム油、ローレル油、カモミル油、キャラウェイ油、ベイ油、レモングラス油、パインニードル油、ネロリ油、及びジャスミン油等が挙げられるが、これらに限定されない。これらの清涼剤は、一種単独で又は二種以上を混合して用いることができる。 As a refreshing agent, menthol (l-menthol, dl-menthol), camphor (dl-camphor, d-camphor), borneol (d-borneol, agate), geraniol, cineol, linalool, limonene, menthone, carvone, anethole , Methyl salicylate, cinnamic aldehyde, octyl aldehyde, linalyl acetate, menthyl acetate, pinene, menthyl lactate, eucalyptus oil, bergamot oil, fennel oil, rose oil, peppermint oil, peppermint oil, spearmint oil, dipterocarpaceae essential oil, Rosmarin oil, lavender oil, mastic oil, parsley oil, anise oil, eucalyptus oil, winter green oil, cassia oil, lemon oil, orange oil, cardamom oil, coriander oil, mandarin oil, lime oil, rho Le oil, chamomile oil, caraway oil, bay oil, lemon grass oil, pine needle oil, neroli oil, and jasmine oil, and the like, without limitation. These refreshing agents can be used alone or in combination of two or more.
殺菌剤としては、塩化ベンザルコニウム、塩化デカリニウム、塩化ベンゼトニウム、イソプロピルメチルフェノール、塩酸クロルヘキシジン、グルコン酸クロルヘキシジン、アンモニア水、スルファジアジン、乳酸、フェノール等が挙げられるが、これらに限定されない。 Examples of the disinfectant include, but are not limited to, benzalkonium chloride, decalinium chloride, benzethonium chloride, isopropylmethylphenol, chlorhexidine hydrochloride, chlorhexidine gluconate, aqueous ammonia, sulfadiazine, lactic acid, and phenol.
血行促進剤としては、酢酸トコフェロール、ニコチン酸ベンジル等が挙げられるが、これらに限定されない。 Examples of the blood circulation promoter include, but are not limited to, tocopherol acetate and benzyl nicotinate.
抗酸化剤としては、アスコルビン酸、トコフェロール、クエン酸、ジブチルヒドロキシトルエン（ＢＨＴ）、ブチルヒドロキシアニソール（ＢＨＡ）等が挙げられるが、これらに限定されない。 Antioxidants include, but are not limited to, ascorbic acid, tocopherol, citric acid, dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA) and the like.
本発明の軟膏剤の用途としては、ステロイドが処方される用途であれば特に限定されることなく適用することができる。たとえば、痔疾患、皮膚疾患、口腔疾患などが挙げられる。 The use of the ointment of the present invention is not particularly limited as long as it is a use for which a steroid is prescribed. Examples include hemorrhoid diseases, skin diseases, oral diseases and the like.
本発明の軟膏剤の製造方法は、特に限定されないが、たとえば、加温（たとえば５０〜６０℃）した水溶性溶媒に、ステロイドを均一に溶解させ、ステロイドの水溶性溶媒溶液を調製する。別途、加温溶融（たとえば７０〜８０℃）した油性軟膏基剤及び常温固体基剤に、界面活性剤やその他の油溶性成分を加えて溶解させ、油性組成物を調製する。該油性組成物を攪拌しながら徐冷（たとえば６０℃程度）し、ステロイドの水溶性溶媒溶液を添加し、ホモミキサーを用いて高速攪拌（３０００ｒｐｍ、３分間）し、軟膏剤を製造する。ステロイドの水溶性溶媒溶液を油性組成物に分散させることで、液滴分散型軟膏剤を製造することができる。 Although the manufacturing method of the ointment of this invention is not specifically limited, For example, steroid is uniformly dissolved in the water-soluble solvent heated (for example, 50-60 degreeC), and the water-soluble solvent solution of steroid is prepared. Separately, a surfactant and other oil-soluble components are added to and dissolved in an oil-based ointment base and a room-temperature solid base that are heated and melted (for example, 70 to 80 ° C.) to prepare an oil-based composition. The oily composition is gradually cooled with stirring (for example, about 60 ° C.), a water-soluble solvent solution of steroid is added, and high-speed stirring (3000 rpm, 3 minutes) is performed using a homomixer to produce an ointment. A droplet dispersion type ointment can be produced by dispersing a water-soluble solvent solution of a steroid in an oily composition.
実施例において、本発明を具体的に説明するが、本発明はこれらのみに限定されるものではない。 The present invention will be specifically described with reference to examples, but the present invention is not limited to these examples.
（実施例１〜１２及び比較例１〜４、１３）
表１に記載の処方に従って、以下の工程により配合成分を混合して軟膏剤を得た。まず、約６０℃に加温した水溶性溶媒に、ステロイド及び水溶性成分を投入し均一に溶解させ、ステロイドの水溶性溶媒溶液を調製した。別途、約８０℃に加温溶融した油性軟膏基剤及び常温固体基剤に、界面活性剤やその他の油溶性成分を加えて溶解させ、油性組成物を調製した。該油性組成物を攪拌しながら約６０℃に徐冷し、ステロイドの水溶性溶媒溶液を添加し、ホモミキサー（微小量真空乳化装置（Ｔ．Ｋ．アヂホモキクサー ２Ｍ−０３型、プライミクス株式会社製）、及び超高速マルチ攪拌システム（Ｔ．Ｋ．ＲＯＢＯＭＩＸ ＲＭ型、プライミクス株式会社製））を用いて高速攪拌し均一な溶融物を調製した後、攪拌・混合しながら室温まで徐冷した。
(Examples 1 12 and Comparative Examples 1 to 4, 13)
According to the formulation described in Table 1, the ingredients were mixed by the following steps to obtain an ointment. First, a steroid and a water-soluble component were added to a water-soluble solvent heated to about 60 ° C. and uniformly dissolved to prepare a water-soluble solvent solution of the steroid. Separately, a surfactant and other oil-soluble components were added to an oil-based ointment base and a room-temperature solid base that had been heated and melted at about 80 ° C., and dissolved to prepare an oil-based composition. The oil-based composition is slowly cooled to about 60 ° C. while stirring, and a water-soluble solvent solution of steroid is added, and a homomixer (a micro-volume vacuum emulsifier (TK AZ Homomixer 2M-03, manufactured by Primix Co., Ltd.)) And a high-speed multi-stirring system (TK ROBOMIX RM type, manufactured by Primix Co., Ltd.) to prepare a uniform melt, and then gradually cooled to room temperature while stirring and mixing.
なお、常温固体基剤を配合しない比較例１〜３では、常温固体基剤の代わりに、油性軟膏基剤の流動パラフィンを配合した。 In Comparative Examples 1 to 3 in which the room temperature solid base was not blended, an oily ointment base liquid paraffin was blended in place of the room temperature solid base.
軟膏剤の分離性、液滴分散性、及び使用感を、後述の方法で評価した。評価結果を表１に示す。 The separability, droplet dispersibility, and feeling of use of the ointment were evaluated by the methods described below. The evaluation results are shown in Table 1.
（分離度評価方法）
各実施例及び比較例の軟膏剤をそれぞれスクリュー管（２４×５０）に約５ｇ投入する。スクリュー管を５０℃／７日間静置する。静置後サンプルの全体の高さ（ｈ１）及び静置後サンプルの分離部分の高さ（ｈ２）を測定する。ｈ１及びｈ２を下記の式に代入し、分離比率を計算する。
（分離比率）＝ｈ２／ｈ１×１００
(Separation degree evaluation method)
About 5 g of each ointment of each example and comparative example is put into a screw tube (24 × 50). The screw tube is allowed to stand at 50 ° C./7 days. The overall height (h1) of the sample after standing and the height (h2) of the separated portion of the sample after standing are measured. Substitute h1 and h2 into the following equation to calculate the separation ratio.
(Separation ratio) = h2 / h1 × 100
上記の方法で算出した分離比率を４段階で判定する。
◎：分離比率０％以上、５％未満
○：分離比率５％以上、１０％未満
△：分離比率１０％以上、１５％未満
×：分離比率１５％以上
The separation ratio calculated by the above method is determined in four stages.
◎: Separation ratio 0% or more, less than 5% ○: Separation ratio 5% or more, less than 10% △: Separation ratio 10% or more, less than 15% ×: Separation ratio 15% or more
（液滴分散性評価方法）
各実施例及び比較例の軟膏剤をそれぞれスライドガラス上に少量採取する。デジタルマイクロスコープ（ＶＨＸ−１０００、ＶＨ−Ｓ５（耐振・高倍率観察システム）、株式会社キーエンス製）を使用し、倍率１０００倍で粒子径を観察する。結晶化成分の析出の有無により判定し、結晶が析出しないものを○とし、結晶が析出したものを×とする。
(Droplet dispersibility evaluation method)
A small amount of each ointment of each example and comparative example is collected on a glass slide. Using a digital microscope (VHX-1000, VH-S5 (vibration resistance / high magnification observation system), manufactured by Keyence Corporation), the particle diameter is observed at a magnification of 1000 times. Judgment is made based on the presence or absence of precipitation of the crystallization component.
（使用感評価方法）
軟膏剤の使用感は、伸び及びべたつきの２項目の評価により検査する。被験者は各実施例の軟膏剤をそれぞれ適量を腕にとり、塗り広げ、各軟膏剤の１）伸び、２）べたつきの各項目について５段階で評価する。各評価項目とその程度は、以下の通りである。
１）伸びの評価項目
１＝不満 ２＝やや不満 ３＝どちらでもない ４＝やや満足 ５＝満足
２）べたつきの評価項目
１＝不満 ２＝やや不満 ３＝どちらでもない ４＝やや満足 ５＝満足
これらの各項目の平均値の合計を、評価点とする。
(Usage feeling evaluation method)
The feeling of use of the ointment is inspected by evaluation of two items of elongation and stickiness. The test subject takes an appropriate amount of the ointment of each example on the arm, spreads it, and evaluates each item of 1) elongation and 2) stickiness of each ointment in five stages. Each evaluation item and its degree are as follows.
1) Evaluation item for elongation 1 = Dissatisfied 2 = Slightly dissatisfied 3 = Neither 4 = Slightly satisfied 5 = Satisfied 2) Sticky evaluation item 1 = Dissatisfied 2 = Slightly dissatisfied 3 = None 4 = Slightly satisfied The sum of the average values of these items is used as the evaluation score.
上記の方法で算出した評価点を４段階で判定する（ｎ＝６）。
◎：評価点８点以上
○：評価点６点以上、８点未満
△：評価点４点以上、６点未満
×：評価点４点未満
The evaluation score calculated by the above method is determined in four stages (n = 6).
◎: Evaluation point 8 points or more ○: Evaluation point 6 points or more, less than 8 points Δ: Evaluation point 4 points or more, less than 6 points ×: Evaluation point 4 points or less
常温固体基剤を配合していない比較例１〜３では、いずれも静置後に分離が生じた。これに対して、常温固体基剤を配合した実施例１〜１２および比較例１３では、いずれも静置後に分離が生じなかったか、若しくは問題のない程度であった。常温固体基剤としてマイクロクリスタリンワックス、サラシミツロウ、ベヘニルアルコール、又はラノリンアルコールのみを含む実施例５、１０〜１２でも、分離は生じておらず、常温固体基剤は単独で配合されていても効果を奏することが示された。常温固体基剤として、マイクロクリスタリンワックス、サラシミツロウなどのワックスと、ベヘニルアルコール、ラノリンアルコールなどの高級アルコールを組み合わせて使用できることが示された。 In Comparative Examples 1 to 3 in which no room temperature solid base was blended, separation occurred after standing. On the other hand, in Examples 1 to 12 and Comparative Example 13 in which the room temperature solid base was blended, separation did not occur after standing, or there was no problem. Even in Examples 5 and 10-12 containing only microcrystalline wax, white beeswax, behenyl alcohol, or lanolin alcohol as the room temperature solid base, no separation occurred, and the room temperature solid base was effective even when blended alone. It was shown to play. It was shown that waxes such as microcrystalline wax and white beeswax can be used in combination with higher alcohols such as behenyl alcohol and lanolin alcohol as a room temperature solid base.
水溶性溶媒としてプロピレングリコールを配合しない比較例４では固体分散型軟膏剤となり、図２に示すように結晶がそのまま基剤中に分散していた。これに対して、水溶性溶媒としてプロピレングリコールにステロイドを溶解させたものを配合した実施例１〜１２および比較例１３では、図１に示すように、結晶が析出せず、液滴分散性が優れていた。 In Comparative Example 4 in which propylene glycol was not blended as a water-soluble solvent, a solid dispersion type ointment was formed, and the crystals were dispersed in the base as they were as shown in FIG. On the other hand, in Examples 1 to 12 and Comparative Example 13 in which steroids were dissolved in propylene glycol as a water-soluble solvent, as shown in FIG. It was excellent.
極性油であるミリスチン酸イソプロピルを配合しない比較例１３では、べたつきなど油性軟膏剤特有の不具合が生じ、使用感が劣った。ミリスチン酸イソプロピルを５％、又は１０％配合した実施例２又は７では、使用感が良好であった。 In Comparative Example 13 in which isopropyl myristate, which is a polar oil, was not blended, problems specific to the oily ointment such as stickiness occurred, and the usability was poor. In Example 2 or 7 containing 5% or 10% isopropyl myristate, the feeling of use was good.
Claims (10)
極性油の配合量が５〜１５重量％である、液滴分散型軟膏剤。 Steroids, water-soluble solvents, one or more cold solid base selected from wax or higher alcohol, oil-soluble ointment bases, and contains a polar oil,
A droplet dispersion type ointment , wherein the blending amount of polar oil is 5 to 15% by weight .
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| TWI726027B (en) * | 2015-12-28 | 2021-05-01 | 日商大塚製藥股份有限公司 | Ointment |
| WO2018182039A1 (en) * | 2017-03-31 | 2018-10-04 | テクノガード株式会社 | Non-aqueous composition having drug carried therein, and method for producing same |
| TW202237137A (en) * | 2021-01-26 | 2022-10-01 | 日商塩野義醫藥保健股份有限公司 | Ointment composition containing betamethasone valerate |
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| US4070462A (en) * | 1976-10-26 | 1978-01-24 | Schering Corporation | Steroid ointment |
| JPS54117022A (en) * | 1978-02-27 | 1979-09-11 | Taisho Pharmaceut Co Ltd | Steroid ointment |
| JPS58225009A (en) * | 1982-06-23 | 1983-12-27 | Shionogi & Co Ltd | Pharmaceutical preparation of corticosteroid for external use |
| JPH0676328B2 (en) * | 1987-04-14 | 1994-09-28 | 株式会社大塚製薬工場 | Steroid cream formulation |
| JP2655190B2 (en) * | 1989-06-21 | 1997-09-17 | エスエス製薬 株式会社 | Ointment containing corticosteroid |
| SE9100342D0 (en) * | 1991-02-04 | 1991-02-04 | Astra Ab | NOVEL STEROID ESTERS |
| JP3174590B2 (en) * | 1991-04-04 | 2001-06-11 | テルモ株式会社 | Steroid ointment |
| JP3851371B2 (en) * | 1995-02-25 | 2006-11-29 | 久光製薬株式会社 | Non-aqueous oil-based ointment base and skin external ointment |
| JPH111442A (en) * | 1997-06-09 | 1999-01-06 | Pola Chem Ind Inc | Composition for external use for skin |
| JPH11189546A (en) * | 1997-12-25 | 1999-07-13 | Saitama Daiichi Seiyaku Kk | Percutaneous absorption promoter |
| JP5300038B2 (en) * | 2000-03-07 | 2013-09-25 | 株式会社 資生堂 | Topical skin preparation |
| JP2002356430A (en) * | 2001-05-30 | 2002-12-13 | Ikeda Mohandou:Kk | Skin care preparation containing prednisolone valerate acetate and antihistamic agent |
| JP4863641B2 (en) * | 2005-03-31 | 2012-01-25 | 小林製薬株式会社 | Ointment for dispersal hemorrhoids with excellent usability and high temperature stability |
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