CN1633280A - 含有至少一种维生素d或一种维生素d类似物和至少一种皮质类固醇的局部组合物 - Google Patents
含有至少一种维生素d或一种维生素d类似物和至少一种皮质类固醇的局部组合物 Download PDFInfo
- Publication number
- CN1633280A CN1633280A CNA018177964A CN01817796A CN1633280A CN 1633280 A CN1633280 A CN 1633280A CN A018177964 A CNA018177964 A CN A018177964A CN 01817796 A CN01817796 A CN 01817796A CN 1633280 A CN1633280 A CN 1633280A
- Authority
- CN
- China
- Prior art keywords
- compositions
- dihydroxy
- breaks
- triolefins
- vitamin
- 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.)
- Granted
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 90
- 150000003710 vitamin D derivatives Chemical group 0.000 title claims abstract description 37
- 229930003316 Vitamin D Natural products 0.000 title claims abstract description 35
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products 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-XFEUOLMDSA-N 0.000 title claims abstract description 35
- 239000011710 vitamin D Substances 0.000 title claims abstract description 35
- 235000019166 vitamin D Nutrition 0.000 title claims abstract description 35
- 229940046008 vitamin d Drugs 0.000 title claims abstract description 35
- 239000003246 corticosteroid Substances 0.000 title claims abstract description 23
- 230000000699 topical effect Effects 0.000 title claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 13
- 239000008252 pharmaceutical gel Substances 0.000 claims abstract description 3
- 150000002148 esters Chemical class 0.000 claims description 23
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 20
- -1 polyethylene Polymers 0.000 claims description 20
- 201000004681 Psoriasis Diseases 0.000 claims description 14
- 229960002882 calcipotriol Drugs 0.000 claims description 14
- LWQQLNNNIPYSNX-UROSTWAQSA-N calcipotriol Chemical compound C1([C@H](O)/C=C/[C@@H](C)[C@@H]2[C@]3(CCCC(/[C@@H]3CC2)=C\C=C\2C([C@@H](O)C[C@H](O)C/2)=C)C)CC1 LWQQLNNNIPYSNX-UROSTWAQSA-N 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 12
- 210000004761 scalp Anatomy 0.000 claims description 12
- 239000011248 coating agent Substances 0.000 claims description 11
- 238000000576 coating method Methods 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 9
- VCLJODPNBNEBKW-UHFFFAOYSA-N 2,2,4,4,6,8,8-heptamethylnonane Chemical compound CC(C)(C)CC(C)CC(C)(C)CC(C)(C)C VCLJODPNBNEBKW-UHFFFAOYSA-N 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 229960002537 betamethasone Drugs 0.000 claims description 6
- 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 claims description 6
- 239000004359 castor oil Substances 0.000 claims description 6
- 235000019438 castor oil Nutrition 0.000 claims description 6
- 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 6
- 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 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- 239000012453 solvate Substances 0.000 claims description 6
- 239000004094 surface-active agent Substances 0.000 claims description 6
- 230000001225 therapeutic effect Effects 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 5
- 230000001965 increasing effect Effects 0.000 claims description 5
- DTXXSJZBSTYZKE-ZDQKKZTESA-N Maxacalcitol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](OCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C DTXXSJZBSTYZKE-ZDQKKZTESA-N 0.000 claims description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 229960005084 calcitriol Drugs 0.000 claims description 4
- 239000011612 calcitriol Substances 0.000 claims description 4
- 235000020964 calcitriol Nutrition 0.000 claims description 4
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 claims description 4
- 239000007765 cera alba Substances 0.000 claims description 4
- 239000007766 cera flava Substances 0.000 claims description 4
- 239000003349 gelling agent Substances 0.000 claims description 4
- 229950006319 maxacalcitol Drugs 0.000 claims description 4
- 229960004907 tacalcitol Drugs 0.000 claims description 4
- BJYLYJCXYAMOFT-RSFVBTMBSA-N tacalcitol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CC[C@@H](O)C(C)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C BJYLYJCXYAMOFT-RSFVBTMBSA-N 0.000 claims description 4
- FFJCNSLCJOQHKM-CLFAGFIQSA-N (z)-1-[(z)-octadec-9-enoxy]octadec-9-ene Chemical compound CCCCCCCC\C=C/CCCCCCCCOCCCCCCCC\C=C/CCCCCCCC FFJCNSLCJOQHKM-CLFAGFIQSA-N 0.000 claims description 3
- 239000004698 Polyethylene Substances 0.000 claims description 3
- 229920002675 Polyoxyl Polymers 0.000 claims description 3
- 229960002842 clobetasol Drugs 0.000 claims description 3
- CBGUOGMQLZIXBE-XGQKBEPLSA-N clobetasol propionate 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)CCl)(OC(=O)CC)[C@@]1(C)C[C@@H]2O CBGUOGMQLZIXBE-XGQKBEPLSA-N 0.000 claims description 3
- 229960000890 hydrocortisone Drugs 0.000 claims description 3
- 239000004200 microcrystalline wax Substances 0.000 claims description 3
- 229920000573 polyethylene Polymers 0.000 claims description 3
- 238000004062 sedimentation Methods 0.000 claims description 3
- 229960005294 triamcinolone Drugs 0.000 claims description 3
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 claims description 3
- 238000009827 uniform distribution Methods 0.000 claims description 3
- 229940070710 valerate Drugs 0.000 claims description 3
- ODZFJAXAEXQSKL-WRJREGAQSA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-1-[(e,2r,5s)-5-hydroxy-5,6-dimethylhept-3-en-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@@](C)(O)C(C)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C ODZFJAXAEXQSKL-WRJREGAQSA-N 0.000 claims description 2
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 claims description 2
- OCAPBUJLXMYKEJ-UHFFFAOYSA-N 1-[biphenyl-4-yl(phenyl)methyl]imidazole Chemical compound C1=NC=CN1C(C=1C=CC(=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 OCAPBUJLXMYKEJ-UHFFFAOYSA-N 0.000 claims description 2
- LEZWWPYKPKIXLL-UHFFFAOYSA-N 1-{2-(4-chlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound C1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 LEZWWPYKPKIXLL-UHFFFAOYSA-N 0.000 claims description 2
- MUQNGPZZQDCDFT-JNQJZLCISA-N Halcinonide Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CCl)[C@@]1(C)C[C@@H]2O MUQNGPZZQDCDFT-JNQJZLCISA-N 0.000 claims description 2
- 235000017858 Laurus nobilis Nutrition 0.000 claims description 2
- BYBLEWFAAKGYCD-UHFFFAOYSA-N Miconazole Chemical compound ClC1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 BYBLEWFAAKGYCD-UHFFFAOYSA-N 0.000 claims description 2
- 235000005212 Terminalia tomentosa Nutrition 0.000 claims description 2
- 244000125380 Terminalia tomentosa Species 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 230000000843 anti-fungal effect Effects 0.000 claims description 2
- 229940121375 antifungal agent Drugs 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 229960002206 bifonazole Drugs 0.000 claims description 2
- 229960001146 clobetasone Drugs 0.000 claims description 2
- XXIFVOHLGBURIG-OZCCCYNHSA-N clobetasone 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)CCl)(O)[C@@]1(C)CC2=O XXIFVOHLGBURIG-OZCCCYNHSA-N 0.000 claims description 2
- 229960004022 clotrimazole Drugs 0.000 claims description 2
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 claims description 2
- 229960002593 desoximetasone Drugs 0.000 claims description 2
- VWVSBHGCDBMOOT-IIEHVVJPSA-N desoximetasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@H](C(=O)CO)[C@@]1(C)C[C@@H]2O VWVSBHGCDBMOOT-IIEHVVJPSA-N 0.000 claims description 2
- 229960004154 diflorasone Drugs 0.000 claims description 2
- WXURHACBFYSXBI-XHIJKXOTSA-N diflorasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H](C)[C@@](C(=O)CO)(O)[C@@]2(C)C[C@@H]1O WXURHACBFYSXBI-XHIJKXOTSA-N 0.000 claims description 2
- 229960004091 diflucortolone Drugs 0.000 claims description 2
- OGPWIDANBSLJPC-RFPWEZLHSA-N diflucortolone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@H](C(=O)CO)[C@@]2(C)C[C@@H]1O OGPWIDANBSLJPC-RFPWEZLHSA-N 0.000 claims description 2
- 229960003913 econazole Drugs 0.000 claims description 2
- 229950007545 falecalcitriol Drugs 0.000 claims description 2
- XPYGGHVSFMUHLH-UUSULHAXSA-N falecalcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(O)(C(F)(F)F)C(F)(F)F)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C XPYGGHVSFMUHLH-UUSULHAXSA-N 0.000 claims description 2
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 claims description 2
- 229960001347 fluocinolone acetonide Drugs 0.000 claims description 2
- FEBLZLNTKCEFIT-VSXGLTOVSA-N fluocinolone acetonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O FEBLZLNTKCEFIT-VSXGLTOVSA-N 0.000 claims description 2
- 229960003238 fluprednidene Drugs 0.000 claims description 2
- YVHXHNGGPURVOS-SBTDHBFYSA-N fluprednidene Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@](C(=C)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 YVHXHNGGPURVOS-SBTDHBFYSA-N 0.000 claims description 2
- 229960002714 fluticasone Drugs 0.000 claims description 2
- MGNNYOODZCAHBA-GQKYHHCASA-N fluticasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(O)[C@@]2(C)C[C@@H]1O MGNNYOODZCAHBA-GQKYHHCASA-N 0.000 claims description 2
- 229960002383 halcinonide Drugs 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- 229960004125 ketoconazole Drugs 0.000 claims description 2
- 229960002509 miconazole Drugs 0.000 claims description 2
- 229960001664 mometasone Drugs 0.000 claims description 2
- QLIIKPVHVRXHRI-CXSFZGCWSA-N mometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CCl)(O)[C@@]1(C)C[C@@H]2O QLIIKPVHVRXHRI-CXSFZGCWSA-N 0.000 claims description 2
- 229960000988 nystatin Drugs 0.000 claims description 2
- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 claims description 2
- 229960000987 paricalcitol Drugs 0.000 claims description 2
- BPKAHTKRCLCHEA-UBFJEZKGSA-N paricalcitol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](\C=C\[C@H](C)C(C)(C)O)C)=C\C=C1C[C@@H](O)C[C@H](O)C1 BPKAHTKRCLCHEA-UBFJEZKGSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229950009921 seocalcitol Drugs 0.000 claims description 2
- LVLLALCJVJNGQQ-ZCPUWASBSA-N seocalcitol Chemical compound C1(/[C@H]2CC[C@@H]([C@@]2(CCC1)C)[C@H](C)/C=C/C=C/C(O)(CC)CC)=C/C=C1/C[C@H](O)C[C@@H](O)C1=C LVLLALCJVJNGQQ-ZCPUWASBSA-N 0.000 claims description 2
- 229960002722 terbinafine Drugs 0.000 claims description 2
- DOMXUEMWDBAQBQ-WEVVVXLNSA-N terbinafine Chemical compound C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 DOMXUEMWDBAQBQ-WEVVVXLNSA-N 0.000 claims description 2
- 239000001993 wax Substances 0.000 claims description 2
- WJOHZNCJWYWUJD-IUGZLZTKSA-N Fluocinonide Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)COC(=O)C)[C@@]2(C)C[C@@H]1O WJOHZNCJWYWUJD-IUGZLZTKSA-N 0.000 claims 1
- 230000003203 everyday effect Effects 0.000 claims 1
- 229960003469 flumetasone Drugs 0.000 claims 1
- WXURHACBFYSXBI-GQKYHHCASA-N flumethasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]2(C)C[C@@H]1O WXURHACBFYSXBI-GQKYHHCASA-N 0.000 claims 1
- 229960000785 fluocinonide Drugs 0.000 claims 1
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 7
- 239000000499 gel Substances 0.000 description 6
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical group O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000002674 ointment Substances 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 206010048768 Dermatosis Diseases 0.000 description 3
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 3
- 239000006210 lotion Substances 0.000 description 3
- 208000017520 skin disease Diseases 0.000 description 3
- LEACJMVNYZDSKR-UHFFFAOYSA-N 2-octyldodecan-1-ol Chemical compound CCCCCCCCCCC(CO)CCCCCCCC LEACJMVNYZDSKR-UHFFFAOYSA-N 0.000 description 2
- IYFATESGLOUGBX-YVNJGZBMSA-N Sorbitan monopalmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O IYFATESGLOUGBX-YVNJGZBMSA-N 0.000 description 2
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229940057995 liquid paraffin Drugs 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000001185 psoriatic effect Effects 0.000 description 2
- 210000002374 sebum Anatomy 0.000 description 2
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 2
- NWFOBODUYTUMNC-VPSCEVSQSA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-1-[(2r,5r)-5-ethyl-6-methylheptan-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CC[C@@H](CC)C(C)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C NWFOBODUYTUMNC-VPSCEVSQSA-N 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N (R)-alpha-Tocopherol Natural products OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
- HBXWUCXDUUJDRB-UHFFFAOYSA-N 1-octadecoxyoctadecane Chemical compound CCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCC HBXWUCXDUUJDRB-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
- SGRCVQDBWHCTIS-UHFFFAOYSA-N 2-nonanoyloxypropyl nonanoate Chemical compound CCCCCCCCC(=O)OCC(C)OC(=O)CCCCCCCC SGRCVQDBWHCTIS-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- QSXXLDDWVCEBFP-UHFFFAOYSA-N 7-(ethoxymethyl)-1-(5-hydroxy-5-methylhexyl)-3-methylpurine-2,6-dione Chemical compound CN1C(=O)N(CCCCC(C)(C)O)C(=O)C2=C1N=CN2COCC QSXXLDDWVCEBFP-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- BYPFEZZEUUWMEJ-UHFFFAOYSA-N Pentoxifylline Chemical compound O=C1N(CCCCC(=O)C)C(=O)N(C)C2=C1N(C)C=N2 BYPFEZZEUUWMEJ-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- RBQOQRRFDPXAGN-UHFFFAOYSA-N Propentofylline Chemical compound CN1C(=O)N(CCCCC(C)=O)C(=O)C2=C1N=CN2CCC RBQOQRRFDPXAGN-UHFFFAOYSA-N 0.000 description 1
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 1
- LWZFANDGMFTDAV-BURFUSLBSA-N [(2r)-2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O LWZFANDGMFTDAV-BURFUSLBSA-N 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229960000552 alclometasone Drugs 0.000 description 1
- DJHCCTTVDRAMEH-DUUJBDRPSA-N alclometasone dipropionate Chemical compound C([C@H]1Cl)C2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O DJHCCTTVDRAMEH-DUUJBDRPSA-N 0.000 description 1
- OFHCOWSQAMBJIW-AVJTYSNKSA-N alfacalcidol 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)C[C@H](O)C1=C OFHCOWSQAMBJIW-AVJTYSNKSA-N 0.000 description 1
- 229960002535 alfacalcidol Drugs 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- CIWBQSYVNNPZIQ-XYWKZLDCSA-N betamethasone dipropionate 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)COC(=O)CC)(OC(=O)CC)[C@@]1(C)C[C@@H]2O CIWBQSYVNNPZIQ-XYWKZLDCSA-N 0.000 description 1
- 229960001102 betamethasone dipropionate Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- BIABMEZBCHDPBV-UHFFFAOYSA-N dipalmitoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCC BIABMEZBCHDPBV-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- HKXBNHCUPKIYDM-CGMHZMFXSA-N doxercalciferol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C HKXBNHCUPKIYDM-CGMHZMFXSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 150000002194 fatty esters Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- XUGNVMKQXJXZCD-UHFFFAOYSA-N isopropyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229960001476 pentoxifylline Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- XEIOPEQGDSYOIH-MURFETPASA-N propan-2-yl (9z,12z)-octadeca-9,12-dienoate Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(=O)OC(C)C XEIOPEQGDSYOIH-MURFETPASA-N 0.000 description 1
- NEOZOXKVMDBOSG-UHFFFAOYSA-N propan-2-yl 16-methylheptadecanoate Chemical compound CC(C)CCCCCCCCCCCCCCC(=O)OC(C)C NEOZOXKVMDBOSG-UHFFFAOYSA-N 0.000 description 1
- 229960002934 propentofylline Drugs 0.000 description 1
- 239000001570 sorbitan monopalmitate Substances 0.000 description 1
- 235000011071 sorbitan monopalmitate Nutrition 0.000 description 1
- 229940031953 sorbitan monopalmitate Drugs 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000013008 thixotropic agent Substances 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 229950011536 torbafylline Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000007762 w/o emulsion Substances 0.000 description 1
- 229940075420 xanthine Drugs 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明涉及涂敷在皮肤上的药物凝胶组合物,所述组合物包含至少一种维生素D或维生素D类似物和至少一种皮质类固醇以及粘度增加性赋形剂。
Description
发明领域
本发明涉及涂敷在皮肤上的局部组合物,它含有至少一种维生素D或维生素D类似物和至少一种皮质类固醇。
发明背景
在利用皮肤涂敷治疗大量病症时,例如在治疗牛皮癣时,经常采用联合治疗,其中结合有两种或者甚至更多不同的药理活性化合物。因而,例如在牛皮癣的治疗中,已知使用联合治疗,其中牵涉一种类固醇化合物,例如皮质类固醇化合物,和一种维生素D类似物,例如卡泊三醇,其中每种活性化合物被配制在单独的制剂中,因为皮质类固醇在碱性pH值下的不稳定性和维生素D类似物在酸性pH值下的不稳定性。
所以,医师不得不让患者置于这种类型的双组分制度之下,进行两种霜剂/软膏剂的先后用药,各自含有在其最大稳定性pH下配制的化合物之一。这可能引起制剂的不相容性,以致患者例如必须在早晨涂敷一种霜剂/软膏剂,在晚上涂敷另一种。毋庸赘述,患者顺应性以及正确的给药剂量是在这类情形下所面临的问题。Richards,H.L.等在J AmAcad Dermatol 1999 Oct;41(4):581-3中报道了牛皮癣患者和他们对药物治疗的顺应性。他们报道了在慢性病症、例如牛皮癣中对治疗建议的顺应性差代表保健业的重大挑战:39%的参与者报告说他们没有遵从所推荐的治疗制度。不顺应组具有更高程度的自我评价的牛皮癣严重性,更年轻,发作年龄也比顺应者更年轻。不顺应组报告说牛皮癣对日常生活的影响更大。
WO 00/64450描述了皮肤用药物组合物,包含维生素D类似物与皮质类固醇的组合,该组合物减轻用于治疗牛皮癣和有关皮肤疾病的双组分或多组分制度的不便。不过,这种组合物趋于是更油性的,涂敷后在皮肤上留下不被吸收的赋形剂的油腻性膜。
发明概述
因此,本发明的目的是提供组合物,包含活性组分的制剂形式,它表现提高了的皮肤吸收(和较少的油性外观)和容易涂敷,这两种品质都提高了患者顺应性。
因此,本发明涉及涂敷在皮肤上的药物凝胶组合物,所述组合物包含至少一种维生素D或维生素D类似物和至少一种皮质类固醇,所述组合物进一步包含粘度增加性赋形剂,其含量使粘度在一方面足以基本上防止皮质类固醇在组合物的涂敷和贮存期间沉降,在另一方面足以促进组合物在患病皮肤部位上的均匀分布。
已经发现本发明的凝胶组合物特别有利于涂敷在头皮上,因为它容易涂敷,具有较少的油性外观,这使组合物更可为头皮牛皮癣患者所接受。
另一方面,本发明涉及如上所定义的凝胶组合物在药物制造中的用途,该药物用于治疗人牛皮癣和相关病症,例如头皮的皮脂性牛皮癣。
发明的详细说明
本文中,关于粘度所用的术语“足够的”被理解为表示这样一种粘度,在一方面是足够高的,以确保皮质类固醇(以分散离子的形式存在于组合物中)不从组合物中沉降出来,这种沉降当然会导致皮质类固醇在患病部位上的不均匀涂敷。另一方面,涂敷的粘度应当是足够低的,以使患者能够容易从可利用的容器(例如管子等)中取出所需剂量的组合物,并且均匀涂敷在患病部位上,以确保活性组分的均匀给药。
关于本发明组合物涂敷在头皮上,特别重要的是确保粘度是足够高的,以基本上防止组合物从涂敷部位“渗漏”至其他部位,确切为面部。同样重要的是组合物容易涂敷在被头发覆盖的皮肤部位上,以确保活性组分的正确给药。
在实践中,这意味着粘度应当优选地在约5mPa.s至约500mPa.s范围内,确切为约10mPa.s至约250mPa.s,例如约20mPa.s至约100mPa.s。粘度可以通过杯/转子法加以适当确定,该方法涉及NV1装置、Haake VT 550粘度计、700s-1和20℃。
在目前可取的实施方式中,适合的组合物粘度可以这样获得,包括一种触变胶凝剂作为粘度增加性赋形剂,以便组合物在静置时是凝胶的形式。触变剂的优点是容易涂敷,在静置时、例如在涂敷后粘度增加,以便组合物通常将不会从所涂敷的患病皮肤部位渗漏至未患病部位。适合的触变胶凝剂的实例是氢化蓖麻油。
在可供替代的实施方式中,粘度增加性赋形剂可以选自蜡,例如白蜂蜡(白蜡)或黄蜂蜡(黄蜡),聚乙烯或微晶蜡,例如Esma-P。
当组合物是乳剂时,它可以是油包水或水包油型乳剂,其中包含适合的乳化剂,例如可以选自聚氧乙烯鲸蜡醚、聚氧乙烯硬脂醚或聚氧乙烯油醚、或聚乙二醇二多羟基硬脂酸酯。
为了解决某些维生素D类似物在酸性环境中的不稳定性(它们在约8以上的pH值下具有最大稳定性)问题和皮质类固醇在碱性环境中的不稳定性(它们在约4-6的pH值下具有最大稳定性)问题,进而优选的是组合物是基本上不含水的。术语“基本上不含水”打算表示组合物的含水量低于约5%,优选低于约2%,例如低于约1.5%。
所以,组合物优选地包含至少一种基本上不含水的溶剂,它的选择是根据其溶解或增溶维生素D类似物的能力。溶剂可以适当地选自下组:
(i)通式R3(OCH2C(R1)H)xOR2(I)化合物,其中x在2-60的范围内,R1在每个x单元中独立地是H或CH3,R2是直链或支链C1-20烷基或苯甲酰基,R3是H或苯基碳酰氧基;
(ii)C4-C8二羧酸的二-(直链或支链)-C4-10烷基酯;
(iii)直链或支链C12-18烷基苯甲酸酯;
(iv)直链或支链C10-18链烷酸或链烯酸的直链或支链C2-4烷基酯;
(v)C8-14链烷酸的丙二醇二酯;和
(vi)支链C18-24伯醇。
已经发现在这类含有选自上组之一的溶剂的组合物中,以及在基本上不含水的环境中,活性组分能够共存,不会降解,即使它们的pH/稳定性不同也是如此。活性化合物因pH而彼此影响的趋势被最小化或消除了。
在上述通式(I)中,优选的是系数x(它指定括号内单元的数量)在4-50的范围内,更优选4-40,确切为4-30,尤其是5-25,更尤其是10-20,例如约15。进一步优选的是R1是CH3。
优选的是溶剂选自通式H(OCH2C(R1)H)xOR2(II)化合物及其混合物,其中R1、x和R2是如上所定义的。
作为上述(i)-(vi)型溶剂的非限制性具体实例,可以提到下列溶剂,包括商品名:
Arlamol E(聚氧乙烯(15)硬脂醚);
Arlamol DoA(己二酸的二异辛基酯);
Arlasolve 200(聚氧乙烯-20-异十六烷基醚);
Eutanol G(2-辛基十二烷醇);
Finsolv(异硬脂酰基苯甲酸酯);
Finsolv P(聚氧丙烯-15-硬脂醚苯甲酸酯);
直链或支链C10-C18链烷酸或链烯酸的异丙基酯,例如肉豆蔻酸异丙酯、
棕榈酸异丙酯、异硬脂酸异丙酯、亚油酸异丙酯和单油酸异丙酯;
Miglyol 840(辛酸与癸酸的丙二醇二酯);
DPPG(丙二醇二壬酸酯);
Procetyl AWS(CH3(CH2)14CH2(OCH(CH3)CH2)5-(OCH2)20OH)。
本文中,术语“维生素D类似物”打算表示这样的合成化合物,它包含维生素D骨架,具有侧链修饰和/或维生素D骨架本身的修饰。该术语不打算包括天然存在的维生素D衍生物,例如代谢产物。
包括在本发明组合物中的维生素D类似物优选地是选自下组的化合物:seocalcitol、卡泊三醇、骨化三醇、他卡西醇、maxacalcitol、paricalcitol、falecalcitriol、1α,24S-二羟基-维生素D2、和1(S),3(R)-二羟基-20(R)-[((3-(2-羟基-2-丙基)-苯基)-甲氧基)-甲基]-9,10-断-孕甾-5(Z),7(E),10(19)-三烯,以及它们的混合物。
更优选的是选自下组的维生素D类似物:卡泊三醇、骨化三醇、他卡西醇、maxacalcitol和1(S),3(R)-二羟基-20(R)-[((3-(2-羟基-2-丙基)-苯基)-甲氧基)-甲基]-9,10-断-孕甾-5(Z),7(E),10(19)-三烯,以及它们的混合物。合成的维生素D类似物在根据本发明的组合物中更优选于天然存在的维生素D类或维生素D衍生物,因为后者的治疗效果可能对皮肤疾病、例如牛皮癣的治疗的选择性更差。
维生素D类似物的进一步非限制性实例是:alphacalcidol;
1α-羟基-维生素D2;
1α-羟基-维生素D5;
1(S),3(R)-二羟基-20(R)-(5-乙基-5-羟基-1-庚基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(6-羟基-6-甲基-1-庚基)-9,10-断-孕甾-5(2),7(E)10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(6-羟基-6-甲基庚-1(E)-烯-1-基-9,10)-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(6-乙基-6-羟基-1-辛基)-9,10)-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(7-羟基-7-甲基-1-辛基)-9,10)-断-孕甾-5(2),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(7-羟基-7-甲基辛-1(E)-烯-1-基-9,10)-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(6’-甲基-1’-庚基)-9,10-断-孕甾-5(Z),7(E),10(19)三烯;
1(S),3(R)-二羟基-20(S)-(5’-羟基-5’-甲基-1’-己氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(4’-羟基-4’-乙基-1’-己氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(6’-羟基-1’-己氧基)-9,10-断-孕甾-5(Z),7(E),10(19)三烯;
1(S),3(R)-二羟基-20(R)-(5’-羟基-5’-乙基-1’-庚氧基)-9,10-断-孕甾-5(Z),7(E),10,19-三烯;
1(S),3(R)-二羟基-20(R)-(5’-羟基-5’-甲基-1’-己氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(5’-甲基-1’-己氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(4’-羟基-4’-(1″-丙基)-1’-庚氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(4’-羟基-4’-甲基-1’-戊氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(3’-羟基-3’-甲基-1’-丁氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(S)-(4-羟基-4-甲基-1-戊基)-9,10-断-孕甾-(5Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(S)-(5-乙基-5-羟基-1-庚基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(S)-(5-乙基-5-羟基-庚-1(E)-烯-1-基),9,10-断-孕甾-5(2),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20-(5’-羟基-5’-甲基-己-1’(E),3’(E)-二烯-1’-基)-9,10-断-孕甾-5(2),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20-(5’-乙基-5’羟基-庚-1’(E),3’(E)-二烯-1’-基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20-(6’-羟基-己-1’(E),3’(E)-二烯-1’-基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20-(5’-环丙基-5’-羟基-戊-1’(E),3’(E)-二烯-1’-基)-9,10-断-孕甾-5(Z)-7(E),10,19-三烯(5’(R)与5’(S)异构体);
1(S),3(R)-二羟基-20-(6’-羟基-6’-甲基-庚-1’(E),3″(E)-二烯-1’-基)-9,10-断孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(3-(2-羟基-2-戊基)-苯甲氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(3-(3-羟基-3-丙基)-苯甲氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(4-羟基-4-甲基-1-戊氧基甲基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(4-羟基-4-甲基-1-戊-2-炔氧基甲基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(4-羟基-4-三氟甲基-5,5,5-三氟-1-戊-2-炔氧基甲基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-[3-(2-羟基-2-丙基)-苯氧基甲基]-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-[((3-(2-羟基-2-丙基)-苯基)-甲氧基)-甲基]-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-[((3-(2-羟基-2-丙基)-5-甲基苯基)-甲氧基]-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-[((3-(2-羟基-2-丙基)-5-甲氧基苯基)-甲氧基)甲基]-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(3-羟基-3-乙基-1-戊硫基甲基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(3-羟基-3-乙基-1-戊磺酰基甲基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(3-((1-羟基-1-甲基)乙基)苯硫基甲基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(3,3-二氟-4-羟基-4-甲基-1-戊氧基甲基)-9,10-断-孕甾-5(Z)-7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(6’-乙基-6’-羟基-辛-1’-炔-1’-基)-9,10-断-孕甾-5(Z),7(E)-10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(7’-乙基-7’-羟基-壬-1’-炔-1’-基)-9,10-断-孕甾-5(Z),7(E)-10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(1,5-二羟基-5-乙基-2-庚炔-1-基)-9,10-断-孕甾-5(Z),7(E)-10(19)-三烯;异构体A;
1(S),3(R)-二羟基-20(R)-(5-乙基-5-羟基-1-甲氧基-2-庚炔-1-基)-9,10-断-孕甾-5(Z),7(E)-10(19)-三烯;异构体A;
1(S),3(R)-二羟基-20(R)-(1-乙氧基-5-乙基-5-羟基-2-庚炔-1-基)-9,10-断-孕甾-5(Z),7(E)-10(19)-三烯;异构体A;
1(S),3(R)-二羟基-20(R)-(1-甲氧基-4-羟基-4-乙基-2-己炔-1-基)-9,10-断-孕甾-5(Z),7(E)-10(19)-三烯;异构体A;
1(S),3(R)-二羟基-20(R)-(1-乙氧基-4-羟基-4-乙基-2-己炔-1-基)-9,10-断-孕甾-5(Z),7(E)-10(19)-三烯;异构体A;
1(S),3(R)-二羟基-20-(4-乙基-4-羟基-1-己炔-1-基)-9,10-断-孕甾-5(Z),7(E),10(19),17(20)(Z)-四烯;
1(S),3(R)-二羟基-20-(5-乙基-5-羟基-1-庚炔-1-基)-9,10-断-孕甾-5(Z),7(E),10(19),17(20)(Z)-四烯;
1(S),3(R)-二羟基-20-(6-乙基-6-羟基-1-辛炔-1-基)-9,10-断-孕甾-5(Z),7(E),10(19),17(20)(Z)-四烯;
1(S),3(R)-二羟基-20(R)-(5-乙基-4,4-二氟-5-羟基-庚氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(4,4-二氯-5-羟基-5-甲基-己氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(4,4-二氟-5-羟基-5-甲基-己氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(4-氟-4-甲基-戊氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(4-乙基-4-氟-己氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(5-氟-5-甲基-己氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R),20(S)-三羟基-20-(4-乙基-4-羟基-1-己基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(S)-甲氧基-20-(4-乙基-4-羟基-1-己基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(S)-乙氧基-20-(4-乙基-4-羟基-1-己基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(S)-[3-(2-羟基-2-甲基-1-丙氧基)-丙-1E-烯-1-基]-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(4-乙基-4-羟基-1-己硫基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-[5-甲基-5-羟基-1-己硫基]-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-[3-(1-甲基-1-羟基乙基)苄硫基]-9,10-断-孕甾-5(Z),7E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(3-甲基-3-羟基-1-丁硫基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(5-乙基-5-羟基-庚-1(E)-烯-3-炔-1-基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
24-氧代-1(S),3(R),25-三羟基-20(S)-9,10-断-胆甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(3-氧代-4-羟基-4-乙基-1-己氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20-甲基-18-(5-甲基-5-羟基-己氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20-甲基-18-(4-乙基-4-羟基-己氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20-甲基-18-(4-乙基-4-羟基-己-2-炔氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20-甲基-18-(4-羟基-4-甲基戊氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20-甲基-18-(4-羟基-4-甲基戊-2-炔-1-基氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20-甲基-18-(3,1-羟基-1-甲基乙基)苯基甲氧基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R)-二羟基-20(R)-(1-甲氧基-4-羟基-4-甲基-1-戊基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;异构体A;
1(S),3(R)-二羟基-20(R)-(1-乙氧基-4-羟基-4-甲基-1-戊基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;异构体A;
1(S),3(R),25-三羟基-(20(S)-9,10-断-胆甾-5(Z),7(E),10(19),23(E)-四烯;
1(S),3(R)-二羟基-(20(S)-(6’-羟基-6’-甲基-4’(E)-庚烯-1’基)-9,10-断-孕甾-5(Z),7(E),10(19)-三烯;
1(S),3(R),22(S),25-四羟基-20(R),9,10-断-胆甾-5(Z),7(E),10(19),23(E)-四烯;
22(S)-乙氧基-1(S)-3(R),25-三羟基-10(R)-9,10-断-胆甾-5(Z),7(E),10(19),23(E)-四烯;
1(S),3(R)-二羟基-20(S)-(3-(1-羟基-1-甲基乙基)苯氧基甲基)-9,10-断-孕甾-5(Z),7(E),10(19),16-四烯或对应的20(R)异构体;
1(S),3(R)-二羟基-20(S)-(3-(1-羟基-1-甲基乙基)苯硫基甲基)-9,10-断-孕甾-5(Z),7(E),10(19),16-四烯或对应的20(R)异构体;
1(S),3(R)-二羟基-20(S)-(4-羟基-4-甲基戊-1-基)-9,10-断-孕甾-5(Z),7(E),10(19),16-四烯;
1(S),3(R)-二羟基-20(R)-(5-乙基-5-羟基庚-1-基)-9,10-断-孕甾-5(Z),7(E),10(19),16-四烯或对应的20(S)异构体;
1(S),3(R)-二羟基-20(R)-(5-乙基-5-羟基庚-1(E),3(E)-二烯-1-基)-9,10-断-孕甾-5(Z),7(E),10(19),16-四烯或对应的20(S)异构体;
1(S),3(R)-二羟基-20(R)-(3-环丙基-3-羟基丙-1(E)-烯-1-基)-9,10-断-孕甾-5(Z),7(E),10(19),16-四烯(24(S)异构体)或对应的24(R)异构体;和
1(S),3(R)-二羟基-20(1,5-二羟基-5-乙基-2-庚炔-1-基)-9,10-断-孕甾-5(Z),7(E),10(19),17(20)Z-四烯,都是22-异构体。
皮质类固醇可以是第I、II、III或IV组局部类固醇。皮质类固醇优选地选自下组:倍他米松(9-氟-11,17,21-三羟基-16-甲基孕甾-1,4-二烯-3,20-二酮)及其酯,例如21-乙酸酯、17-金刚烷酸酯、17-苯甲酸酯、17-戊酸酯和17,21-二丙酸酯;阿氯米松及其酯,例如二丙酸酯;氯倍他索及其酯,例如丙酸酯;氯倍他松及其酯,例如17-丁酸酯;去羟米松;二氟可龙及其酯,二氟拉松及其酯,例如二乙酸酯;氟轻松及其醚和酯,例如丙酮化物;氟替卡松及其酯,例如丙酸酯;氟泼尼定及其酯,例如乙酸酯;哈西奈德;氢化可的松及其酯,例如17-丁酸酯;莫米松及其酯,例如糠酸酯;和曲安西龙及其醚和酯,例如丙酮化物;以及它们的混合物。更优选的皮质类固醇实例是倍他米松或其酯,例如17-戊酸酯或17,21-二丙酸酯;氯倍他索或其酯,例如丙酸酯;曲安西龙或其醚和/或酯,例如丙酮化物或丙酮化物-21-N-苯甲酰基-2-甲基-β-丙氨酸酯或丙酮化物-21-(3,3-二甲基丁酸酯);或氢化可的松或其酯,例如17-丁酸酯。
本发明的组合物可以按照药物制剂领域技术人员熟知的方法加以制备。因而,不含水的组合物可以这样制备,将各组分掺入到熟知的软膏剂或洗剂基质赋形剂中,例如液体石蜡或PlastibaseTM(由聚乙烯(平均MW约21,000)和石蜡液制成的基质)或ESMA-PTM(微晶蜡)。
不过,一般优选的是选择这样的软膏剂或洗剂基质赋形剂,与液体石蜡相比,例如七甲基壬烷,它们在涂敷时赋予皮肤、头发和头皮较少的油性外观。
作为实例,根据本发明的组合物的制备通常是这样进行的,熔化基质赋形剂(例如七甲基壬烷和/或氢化蓖麻油),加入维生素D类似物在所需量溶剂、例如ArlamolE中的溶液(浓度通常在0.0005-2.5%w/w的范围内),再加入皮质类固醇在基质赋形剂中的分散系,粒径通常从0.1至20μm,然后冷却该混合物。各种组分在最终的根据本发明的组合物中的典型含量范围是从约0.005至约0.3%w/w、优选0.01-0.2%w/w的皮质类固醇,从约0.0001至约0.035%w/w的维生素D类似物,从约0.1至约25%w/w、优选约0.5-10%w/w的粘度增加剂,可选的从约0.5至约10%w/w的表面活性剂和从约1至约30%w/w的溶剂,其余部分通常主要是基质赋形剂,例如上述七甲基壬烷。组合物还可以含有其他常用的添加剂,例如抗氧化剂(例如α-生育酚)。
在打算敷用在头皮上的特定实施方式中,本发明组合物可以另外包含表面活性剂。这在一些情况下可能是有利的,其中打算将组合物涂敷在头皮上并留置足够长的时间,以确保活性组分被吸收进入头皮皮肤,此后组合物的其余部分可以被洗去,带给头发“清洁的”(非油性)外观。表面活性剂可以选自公认适合涂敷在头皮上的脂肪酯,例如脱水山梨醇单月桂酸酯、脱水山梨醇单棕榈酸酯、脱水山梨醇单硬脂酸酯、脱水山梨醇单油酸酯、聚氧乙烯脱水山梨醇单月桂酸酯、聚氧乙烯脱水山梨醇单棕榈酸酯、聚氧乙烯脱水山梨醇单硬脂酸酯或聚氧乙烯脱水山梨醇单油酸酯。不过,有些维生素D类似物趋于在即使少量的酯杂质游离脂肪酸的存在下降解。优选包括在包含这类维生素D类似物的组合物中的表面活性剂因此是醚,例如选自下组的醚:式C8H17C6H4(OCH2CH2)nOH的辛苯昔醇-n,其中n是从1至70的整数;式C9H19C6H4(OCH2CH2)pOH的壬苯醇醚-n,其中p是从4至40的整数;和聚氧乙烯C12-22烷基醚,例如聚氧乙烯月桂醚、聚氧乙烯鲸蜡醚、聚氧乙烯硬脂醚或聚氧乙烯油醚。
所得组合物适宜被装填在适当的容器内,例如金属或塑料的管子、瓶子或分散器,带有适合测量组合物准确剂量的装置。
本发明的组合物可以进一步包含抗真菌剂,例如选自下组:咪康唑、克霉唑、特比萘芬、环吡司、联苯苄唑、制霉菌素、酮康唑、益康唑和氟康唑。
优选地,根据本发明的组合物不含选自黄嘌呤衍生物的治疗性化合物,即己酮可可碱、丙戊茶碱和托巴茶碱或任意其他黄嘌呤或黄嘌呤衍生物。
本发明还涉及牛皮癣和相关皮肤疾病、例如头皮的皮脂性牛皮癣的治疗方法,包含将有效量的根据本发明的组合物对需要这类治疗的患者局部给药。所述方法优选地包含治疗上足够剂量的所述组合物的局部给药,每天一次或两次。根据本发明的组合物优选地含有约0.001-0.5mg/g或ml、优选约0.001-0.25mg/g或ml的维生素D或维生素D类似物,和约0.05-2mg/g或ml、优选约0.1-1.5mg/g或ml的皮质类固醇。
下列实施例进一步阐述本发明,它们决不打算限制所要求保护的发明范围。
实施例1
含有卡泊三醇和倍他米松的凝胶制剂
为了制备1kg凝胶制剂,将30g氢化蓖麻油与749g七甲基壬烷一起在85-90℃下熔化,在均化作用下冷却至约60℃。然后在搅拌下将混合物冷却至2 5-30℃。将643mg倍他米松二丙酸酯悬浮在50g七甲基壬烷中,加入到均化的凝胶基质中。将52.2mg卡泊三醇水合物或50mg卡泊三醇溶于170g聚氧丙烯-15-硬脂醚,加入到其他成分的混合物中,使制剂均化,以确保活性组分的均匀分布。所得凝胶制剂在40℃下贮存3个月保持稳定,说明保存期在室温下至少2年。稳定性数据如下表1和2所示。
表1
表2
开始5℃/1个月 | 40℃/1个月 | 40℃/3个月 | |||
BDP%FOS | 卡泊三醇%Epi | BDP%FOS | 卡泊三醇%Epi | BDP%FOS | 卡泊三醇%Epi |
0.23 | 0.62 | 0.91 | 0.66 | 1.02 | 0.8 |
1g洗剂含有:
倍他米松(二丙酸酯:0.643mg) 0.5mg
卡泊三醇(水合物:52.2μg) 50μg
聚氧丙烯-15-硬脂醚(ArlamolE) 170mg
氢化蓖麻油 30mg
七甲基壬烷(ArlamolHD),加至 1g
Claims (27)
1、涂敷在皮肤上的药物凝胶组合物,所述组合物包含至少一种维生素D或维生素D类似物和至少一种皮质类固醇,所述组合物进一步包含粘度增加性赋形剂,其含量使粘度在一方面足以基本上防止皮质类固醇在组合物的涂敷和贮存期间沉降,在另一方面足以促进组合物的均匀分布。
2、根据权利要求1的组合物,它的粘度范围从约5mPa.s至约500mPa.s,确切为约10mPa.s至约250mPa.s,例如约20mPa.s至约100mPa.s。
3、根据权利要求1或2的组合物,包含一种触变胶凝剂作为粘度增加性赋形剂。
4、根据权利要求3的组合物,其中该触变胶凝剂是氢化蓖麻油。
5、根据权利要求1或2的组合物,包含粘度增加性赋形剂,它是一种蜡,例如白蜂蜡(白蜡)或黄蜂蜡(黄蜡),聚乙烯或微晶蜡,例如Esma-P。
6、根据权利要求1-5任意一项的组合物,它是基本上不含水的组合物。
7、根据权利要求1-6任意一项的组合物,另外包含至少一种选自下组的溶剂:
(i)通式R3(OCH2C(R1)H)xOR2(I)化合物,其中x在2-60的范围内,R1在每个x单元中独立地是H或CH3,R2是直链或支链C1-20烷基或苯甲酰基,R3是H或苯基碳酰氧基;
(ii)C4-C8二羧酸的二-(直链或支链)-C4-10烷基酯;
(iii)直链或支链C12-18烷基苯甲酸酯;
(iv)直链或支链C10-18链烷酸或链烯酸的直链或支链C2-4烷基酯;
(v)C8-14链烷酸的丙二醇二酯;和
(vi)支链C18-24伯醇。
8、根据权利要求7的组合物,其中所述溶剂选自通式H(OCH2C(R1)H)xOR2(II)化合物及其混合物,其中R1、x和R2是如权利要求8所定义的。
9、根据权利要求7的组合物,其中R1是CH3。
10、根据权利要求8的组合物,其中所述溶剂是聚氧丙烯-15-硬脂醚。
11、根据权利要求1-10任意一项的组合物,其中所述维生素D类似物选自下组:seocalcitol、卡泊三醇、骨化三醇、他卡西醇、maxacalcitol、paricalcitol、falecalcitriol、1α,24S-二羟基-维生素D2、和1(S),3(R)-二羟基-20(R)-[((3-(2-羟基-2-丙基)-苯基)-甲氧基)-甲基]-9,10-断-孕甾-5(Z),7(E),10(19)-三烯,以及它们的混合物。
12、根据权利要求1-11任意一项的组合物,其中所述维生素D类似物选自下组:卡泊三醇、骨化三醇、他卡西醇、maxacalcitol和1(S),3(R)-二羟基-20(R)-[((3-(2-羟基-2-丙基)-苯基)-甲氧基)-甲基]-9,10-断-孕甾-5(Z),7(E),10(19)-三烯,以及它们的混合物。
13、根据权利要求1-12任意一项的组合物,其中该维生素D类似物有效对抗人牛皮癣和相关病症。
14、根据权利要求15的组合物,其中所述维生素D类似物是卡泊三醇或其水合物。
15、根据权利要求1-14任意一项的组合物,其中所述皮质类固醇选自下组:倍他米松、氯倍他索、氯倍他松、去羟米松、二氟可龙、二氟拉松、氟轻松醋酸酯、氟米松、氟轻松、氟替卡松、氟泼尼定、哈西奈德、氢化可的松、莫米松、曲安西龙、和它们的药学上可接受的酯和丙酮化物以及混合物。
16、根据权利要求15的组合物,其中所述酯或丙酮化物选自下组:17-戊酸酯、17-丙酸酯、17,21-二丙酸酯、丙酮化物、丙酮化物-21-N-苯甲酰基-2-甲基-β-丙氨酸酯、丙酮化物-21-(3,3-二甲基丁酸酯)和17-丁酸酯。
17、根据权利要求1-16任意一项的组合物,含有0.001-0.25mg/g或ml的所述维生素D类似物和0.05-2mg/g或ml的所述皮质类固醇,确切为0.1-1.5mg/g或ml的所述皮质类固醇。
18、根据权利要求1-17任意一项的组合物,本质上包含下列成分(每g组合物):
倍他米松(二丙酸酯:0.643mg) 0.5mg
卡泊三醇(水合物:52.2μg) 50μg
聚氧丙烯-15-硬脂醚(ArlamolE) 170mg
氢化蓖麻油 30mg
七甲基壬烷(ArlamolHD),加至 1g
19、根据权利要求1-18任意一项的组合物,它进一步包含抗真菌剂,优选地选自下组:咪康唑、克霉唑、特比萘芬、环吡司、联苯苄唑、制霉菌素、酮康唑、益康唑和氟康唑。
20、涂敷在头皮上的根据权利要求1-19任意一项的组合物。
21、根据权利要求20的组合物,另外包含一种表面活性剂。
22、根据权利要求2 1的组合物,其中该表面活性剂选自下组:式C8H17C6H4(OCH2CH2)nOH的辛苯昔醇-n,其中n是从1至70的整数;式C9H19C6H4(OCH2CH2)pOH的壬苯醇醚-n,其中p是从4至40的整数;和聚氧乙烯C12-22烷基醚,例如聚氧乙烯月桂醚、聚氧乙烯鲸蜡醚、聚氧乙烯硬脂醚或聚氧乙烯油醚。
23、根据权利要求1-22任意一项的组合物在药物制造中的用途,该药物用于人牛皮癣和相关病症的局部治疗。
24、权利要求23的在药物制造中的用途,该药物用于头皮牛皮癣的局部治疗。
25、治疗牛皮癣和相关病症的方法,该方法包含对需要治疗的患者的患病皮肤部位给以有效量的根据权利要求1-22任意一项的组合物。
26、权利要求25的方法,其中所述组合物是每天给药一次或两次的。
27、权利要求25的方法,其中所述组合物是对头皮给药的。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US24347100P | 2000-10-27 | 2000-10-27 | |
US60/243,471 | 2000-10-27 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1633280A true CN1633280A (zh) | 2005-06-29 |
CN100382803C CN100382803C (zh) | 2008-04-23 |
Family
ID=22918889
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB018177964A Expired - Lifetime CN100382803C (zh) | 2000-10-27 | 2001-09-26 | 含有至少一种维生素d或一种维生素d类似物和至少一种皮质类固醇的局部组合物 |
Country Status (22)
Country | Link |
---|---|
US (1) | US6787529B2 (zh) |
EP (1) | EP1331927B1 (zh) |
JP (3) | JP4451061B2 (zh) |
KR (1) | KR100844285B1 (zh) |
CN (1) | CN100382803C (zh) |
AT (1) | ATE380542T1 (zh) |
AU (2) | AU2001291637B2 (zh) |
BR (1) | BRPI0114927B8 (zh) |
CA (1) | CA2423930C (zh) |
CY (1) | CY1107294T1 (zh) |
CZ (1) | CZ305984B6 (zh) |
DE (1) | DE60131881T2 (zh) |
DK (1) | DK1331927T3 (zh) |
ES (1) | ES2298264T3 (zh) |
HK (1) | HK1077208A1 (zh) |
HU (1) | HU230005B1 (zh) |
IL (2) | IL154888A0 (zh) |
MX (1) | MXPA03003511A (zh) |
PL (1) | PL212660B1 (zh) |
PT (1) | PT1331927E (zh) |
RU (1) | RU2271810C2 (zh) |
WO (1) | WO2002034235A1 (zh) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104138352A (zh) * | 2013-04-19 | 2014-11-12 | 江苏知原药业有限公司 | 卡泊三醇非水凝胶 |
CN108282998A (zh) * | 2015-06-18 | 2018-07-13 | 凡利亚药品北美公司 | 用于治疗银屑病的包含皮质类固醇和类视黄醇的局部组合物 |
CN115569199A (zh) * | 2022-02-14 | 2023-01-06 | 南京海融医药科技股份有限公司 | 一种药物组合物及其制备方法和应用 |
Families Citing this family (46)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8263580B2 (en) * | 1998-09-11 | 2012-09-11 | Stiefel Research Australia Pty Ltd | Vitamin formulation |
US20090098065A1 (en) * | 2000-01-11 | 2009-04-16 | Avikam Harel | Composition and methods for the treatment of skin disorders |
MXPA03003511A (es) * | 2000-10-27 | 2004-05-04 | Leo Pharma As | Composicion topica que contiene al menos una vitamina d o un analogo de vitamina de y al menos un corticosteroide. |
US20090143328A1 (en) * | 2001-08-13 | 2009-06-04 | Mcdonald George | Method of Treating Cancer by Administration of Topical Active Corticosteroids |
RU2361594C2 (ru) * | 2002-12-17 | 2009-07-20 | Галдерма Са | Фармацевтические композиции, включающие комбинацию кальцитриола и клобетазола пропионат |
US8404667B2 (en) * | 2006-12-29 | 2013-03-26 | Wisconsin Alumni Research Foundation | Compounds, compositions, kits and methods of use to orally and topically treat acne and other skin conditions by 19-Nor vitamin D analog |
FR2871693B1 (fr) * | 2004-06-17 | 2006-08-25 | Galderma Sa | Utilisation d'une composition pharmaceutique comprenant du calcitriol et du propionate de clobetasol pour le traitement du psoriasis |
FR2871698B1 (fr) * | 2004-06-17 | 2008-07-04 | Galderma Sa | Composition sous forme de spray comprenant une association d'actifs pharmaceutiques et une phase huileuse |
FR2871694B1 (fr) * | 2004-06-17 | 2008-07-04 | Galderma Sa | Composition pharmaceutique comprenant un onguent oleagineux et deux principes actifs solubilises |
FR2871697B1 (fr) * | 2004-06-17 | 2007-06-29 | Galderma Sa | Composition sous forme de spray comprenant une association d'actifs pharmaceutiques, une phase alcoolique, au moins un silicone volatile et une phase huileuse non volatile |
FR2871696B1 (fr) * | 2004-06-17 | 2006-11-10 | Galderma Sa | Composition topique pour le traitement du psoriasis |
FR2871700B1 (fr) * | 2004-06-17 | 2006-11-17 | Galderma Sa | Composition sous forme de spray comprenant une association d'actifs pharmaceutiques, une phase alcoolique, et une phase huileuse |
WO2006011849A1 (en) * | 2004-07-28 | 2006-02-02 | Lipopeptide Ab | New use |
US20060078580A1 (en) | 2004-10-08 | 2006-04-13 | Mediquest Therapeutics, Inc. | Organo-gel formulations for therapeutic applications |
ZA200710371B (en) | 2005-05-10 | 2009-07-29 | Dermipsor Ltd | Compositions and methods for treating hyperproliferative epidermal diseases |
EP2526930B1 (en) * | 2005-06-01 | 2013-12-25 | GlaxoSmithKline Intellectual Property Development Limited | Vitamin formulation |
KR20080016612A (ko) * | 2005-06-10 | 2008-02-21 | 갈데르마 소시에떼아노님 | 약물, 필름형성 실리콘 및 하나 이상의 휘발성 용매를포함하는 국소조성물을 기초로 하는 피부를 통한 약물의조절된 방출 |
MXPA05009381A (es) * | 2005-09-02 | 2007-03-01 | Fernando Ahumada Ayala | Preparaciones para el cuidado de la piel que contienen mupirocina y dipropionato de betametasona. |
US8497258B2 (en) | 2005-11-12 | 2013-07-30 | The Regents Of The University Of California | Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract |
US8324192B2 (en) | 2005-11-12 | 2012-12-04 | The Regents Of The University Of California | Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract |
US8679545B2 (en) | 2005-11-12 | 2014-03-25 | The Regents Of The University Of California | Topical corticosteroids for the treatment of inflammatory diseases of the gastrointestinal tract |
RU2412165C2 (ru) | 2006-03-17 | 2011-02-20 | Лео Фарма А/С | Изомеризация фармацевтических интермедиатов |
BRPI0715636A2 (pt) * | 2006-08-29 | 2013-07-02 | Teva Pharma | composiÇÕes farmacologicamente ativas estÁveis incluindo compostos contendo vitamina d e corticosteràide com compatibilidade para ph baixo |
FR2909284B1 (fr) * | 2006-11-30 | 2012-09-21 | Galderma Sa | Nouvelles compositions sous forme d'onguent sans vaseline comprenant un derive de vitamine d et eventuellement un anti-inflammatoire steroidien |
ES2272198B1 (es) * | 2006-12-28 | 2008-06-01 | Laboratorios Viñas S.A. | Procedimiento para la obtencion de hidrato de calcipotriol. |
US10265265B2 (en) | 2007-03-15 | 2019-04-23 | Drug Delivery Solutions Limited | Topical composition |
EP1970049A1 (en) * | 2007-03-15 | 2008-09-17 | Drug Delivery Solutions Limited | Polyaphron topical composition with vitamin D and corticosteroid |
EP1970048A1 (en) * | 2007-03-15 | 2008-09-17 | Drug Delivery Solutions Limited | Polyaphron topical composition with vitamin D |
EP2008651A1 (en) | 2007-06-26 | 2008-12-31 | Drug Delivery Solutions Limited | A bioerodible patch |
US20090123551A1 (en) * | 2007-11-13 | 2009-05-14 | Meritage Pharma, Inc. | Gastrointestinal delivery systems |
HUE038452T2 (hu) | 2007-11-13 | 2018-10-29 | Meritage Pharma Inc | Gyomor és bélrendszeri gyulladások kezelésére szolgáló kompozíciók |
US8865692B2 (en) | 2007-11-13 | 2014-10-21 | Meritage Pharma, Inc | Compositions for the treatment of gastrointestinal inflammation |
US20100216754A1 (en) * | 2007-11-13 | 2010-08-26 | Meritage Pharma, Inc. | Compositions for the treatment of inflammation of the gastrointestinal tract |
US20090264392A1 (en) * | 2008-04-21 | 2009-10-22 | Meritage Pharma, Inc. | Treating eosinophilic esophagitis |
US9254296B2 (en) * | 2009-12-22 | 2016-02-09 | Leo Pharma A/S | Pharmaceutical composition comprising vitamin D analogue and cosolvent-surfactant mixture |
CN102770125B (zh) * | 2009-12-22 | 2015-02-11 | 利奥制药有限公司 | 钙泊三醇一水化合物纳米晶体 |
AU2010335654B2 (en) * | 2009-12-22 | 2015-04-09 | Leo Pharma A/S | Cutaneous composition comprising vitamin D analogue and a mixture of solvent and surfactants |
KR101619077B1 (ko) | 2010-06-11 | 2016-05-10 | 레오 파마 에이/에스 | 비타민 d 유사체 및 코르티코스테로이드를 포함하는 약제학적 분무 조성물 |
US8968755B2 (en) | 2010-10-23 | 2015-03-03 | Joel Schlessinger | Topical base and active agent-containing compositions, and methods for improving and treating skin |
US8685381B2 (en) | 2010-10-23 | 2014-04-01 | Joel Schlessinger | Topical base and active agent-containing compositions, and methods for improving and treating skin |
JP6105494B2 (ja) | 2011-03-14 | 2017-03-29 | ドラッグ デリバリー ソリューションズ リミテッド | 眼科用組成物 |
JP5897299B2 (ja) * | 2011-10-14 | 2016-03-30 | 岩城製薬株式会社 | ローション剤 |
TW201636025A (zh) * | 2015-04-15 | 2016-10-16 | Maruho Kk | 皮膚用之醫藥組成物 |
EP3542788A1 (en) | 2018-03-19 | 2019-09-25 | MC2 Therapeutics Limited | Topical composition comprising calcipotriol and betamethasone dipropionate |
KR102354028B1 (ko) | 2020-05-13 | 2022-01-24 | 동국대학교 경주캠퍼스 산학협력단 | 건선 예방, 개선 또는 치료용 피부 외용제 조성물 |
CN114159567B (zh) * | 2020-09-10 | 2023-03-31 | 南京海融医药科技股份有限公司 | 一种治疗皮肤病的混悬凝胶剂 |
Family Cites Families (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4569935A (en) * | 1983-03-17 | 1986-02-11 | University Of Tennessee Research Corp. | Topical treatment of psoriasis with imidazole antibiotics |
US4610978A (en) * | 1983-03-22 | 1986-09-09 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Compositions containing 1α-hydroxycholecalciferol for topical treatment of skin disorders and methods employing same |
SE457055B (sv) * | 1986-08-18 | 1988-11-28 | Ferring Ab | Topisk straalskyddsgel foer mukosa innehaallande kaerlsammandragande substanser |
IL86170A (en) * | 1987-05-01 | 1992-12-01 | Elan Transdermal Ltd | Preparations and compositions comprising nicotine for percutaneous administration |
US4847071A (en) | 1987-10-22 | 1989-07-11 | The Procter & Gamble Company | Photoprotection compositions comprising tocopherol sorbate and an anti-inflammatory agent |
US5002938A (en) | 1988-03-21 | 1991-03-26 | Bristol-Myers Squibb Company | Antifungal gel formulations |
EP0437225B1 (de) * | 1990-01-10 | 1994-04-20 | F. Hoffmann-La Roche Ag | Topische Präparate |
US5185150A (en) * | 1990-08-24 | 1993-02-09 | Wisconsin Alumni Research Fdn. | Cosmetic compositions containing 19-nor-vitamin D compounds |
US5763428A (en) * | 1990-09-21 | 1998-06-09 | Bone Care International, Inc. | Methods of treating skin disorders with novel 1a-hydroxy vitamin D4 compounds and derivatives thereof |
JP2571493B2 (ja) * | 1992-06-04 | 1997-01-16 | 株式会社資生堂 | 皮膚外用剤 |
AU4841193A (en) * | 1992-08-28 | 1994-03-29 | Lunar Corporation | 1alpha,24(S)-dihydroxy vitamin D2, its formation and use |
GB9226860D0 (en) * | 1992-12-23 | 1993-02-17 | Leo Pharm Prod Ltd | Novel treatment |
DE4328217C2 (de) * | 1993-08-21 | 1996-01-11 | Lohmann Therapie Syst Lts | Therapeutisches System zur Behandlung der Psoriasis |
US5708017A (en) * | 1995-04-04 | 1998-01-13 | Merck & Co., Inc. | Stable, ready-to-use pharmaceutical paste composition containing proton pump inhibitors |
FR2740042B1 (fr) * | 1995-10-23 | 1997-11-14 | Oreal | Support, et composition contenant ce support et un actif cosmetique ou dermatologique stabilise |
JPH10158147A (ja) * | 1996-11-29 | 1998-06-16 | Kenji Nakamura | 皮膚保護用の被膜組成物とそれを用いた製品 |
DE59712694D1 (de) * | 1997-04-18 | 2006-08-24 | Fritz Stanislaus | Stabilisiertes arzneimittel enthaltend cysteinylderivate |
JPH11188054A (ja) * | 1997-12-25 | 1999-07-13 | Lion Corp | 皮膚外用部材 |
US5990100A (en) * | 1998-03-24 | 1999-11-23 | Panda Pharmaceuticals, L.L.C. | Composition and method for treatment of psoriasis |
FR2785284B1 (fr) * | 1998-11-02 | 2000-12-01 | Galderma Res & Dev | Analogues de la vitamine d |
HU230045B1 (hu) | 1999-04-23 | 2015-06-29 | Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Produktionsaktieselskab) | Bőrgyógyászati alkalmazásra szolgáló nem vizes gyógyszerkészítmény |
MXPA03003511A (es) * | 2000-10-27 | 2004-05-04 | Leo Pharma As | Composicion topica que contiene al menos una vitamina d o un analogo de vitamina de y al menos un corticosteroide. |
-
2001
- 2001-09-26 MX MXPA03003511A patent/MXPA03003511A/es active IP Right Grant
- 2001-09-26 BR BRPI0114927A patent/BRPI0114927B8/pt not_active IP Right Cessation
- 2001-09-26 PT PT01971719T patent/PT1331927E/pt unknown
- 2001-09-26 DE DE60131881T patent/DE60131881T2/de not_active Expired - Lifetime
- 2001-09-26 PL PL360941A patent/PL212660B1/pl unknown
- 2001-09-26 CA CA002423930A patent/CA2423930C/en not_active Expired - Lifetime
- 2001-09-26 EP EP01971719A patent/EP1331927B1/en not_active Expired - Lifetime
- 2001-09-26 CZ CZ2003-1162A patent/CZ305984B6/cs not_active IP Right Cessation
- 2001-09-26 KR KR1020037005809A patent/KR100844285B1/ko active IP Right Grant
- 2001-09-26 DK DK01971719T patent/DK1331927T3/da active
- 2001-09-26 HU HU0302881A patent/HU230005B1/hu unknown
- 2001-09-26 AU AU2001291637A patent/AU2001291637B2/en not_active Expired
- 2001-09-26 IL IL15488801A patent/IL154888A0/xx unknown
- 2001-09-26 AU AU9163701A patent/AU9163701A/xx active Pending
- 2001-09-26 RU RU2003115616/15A patent/RU2271810C2/ru active
- 2001-09-26 WO PCT/DK2001/000613 patent/WO2002034235A1/en active IP Right Grant
- 2001-09-26 JP JP2002537289A patent/JP4451061B2/ja not_active Expired - Lifetime
- 2001-09-26 AT AT01971719T patent/ATE380542T1/de active
- 2001-09-26 CN CNB018177964A patent/CN100382803C/zh not_active Expired - Lifetime
- 2001-09-26 ES ES01971719T patent/ES2298264T3/es not_active Expired - Lifetime
- 2001-10-26 US US09/984,072 patent/US6787529B2/en not_active Expired - Lifetime
-
2003
- 2003-03-12 IL IL154888A patent/IL154888A/en not_active IP Right Cessation
-
2005
- 2005-10-20 HK HK05109306A patent/HK1077208A1/xx not_active IP Right Cessation
-
2008
- 2008-03-03 CY CY20081100243T patent/CY1107294T1/el unknown
- 2008-07-24 JP JP2008191184A patent/JP5721927B2/ja not_active Expired - Lifetime
-
2013
- 2013-01-29 JP JP2013014295A patent/JP5699169B2/ja not_active Expired - Lifetime
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104138352A (zh) * | 2013-04-19 | 2014-11-12 | 江苏知原药业有限公司 | 卡泊三醇非水凝胶 |
CN104138352B (zh) * | 2013-04-19 | 2018-02-27 | 江苏知原药业有限公司 | 卡泊三醇非水凝胶 |
CN108282998A (zh) * | 2015-06-18 | 2018-07-13 | 凡利亚药品北美公司 | 用于治疗银屑病的包含皮质类固醇和类视黄醇的局部组合物 |
CN108282998B (zh) * | 2015-06-18 | 2021-07-06 | 凡利亚药品北美公司 | 用于治疗银屑病的包含皮质类固醇和类视黄醇的局部组合物 |
CN115569199A (zh) * | 2022-02-14 | 2023-01-06 | 南京海融医药科技股份有限公司 | 一种药物组合物及其制备方法和应用 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1633280A (zh) | 含有至少一种维生素d或一种维生素d类似物和至少一种皮质类固醇的局部组合物 | |
CN1173703C (zh) | 药物组合物 | |
AU2001291637A1 (en) | Topical composition containing at least one vitamin D or one vitamin D analogue and at least one corticosteroid | |
KR102203003B1 (ko) | 안정화되고 변형된 비타민 d 방출 제형 및 이의 투여 방법 | |
RU2452488C2 (ru) | Фармацевтические композиции, содержащие витамин группы d и кортикостероид | |
CN1266370A (zh) | 活性维生素d3乳状液类型的洗剂 | |
CN1917859A (zh) | 载药纳米微粒及其制备方法以及含有该纳米微粒的非肠道给药用制剂 | |
RU2003115616A (ru) | Композиции местного применения, содержащие, по меньшей мере, один витамин d или один аналог витамина d и, по меньшей мере, один кортикостероид | |
CN1082818C (zh) | 1α,24-(OH)2-V.D3乳膏组合物 | |
EA035087B1 (ru) | Лекарственные формы для трансдермального введения | |
CN1429105A (zh) | 含有作为活性成分的辅酶q的皮肤组合物 | |
ZA200407403B (en) | Androgen pharmaceutical composition and method for treating depression | |
KR101755407B1 (ko) | 건선의 예방 또는 치료용 약제학적 조성물 | |
US20210196631A1 (en) | Container system and pharmaceutical foam composition comprising betamethasone |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1077208 Country of ref document: HK |
|
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1077208 Country of ref document: HK |
|
CX01 | Expiry of patent term |
Granted publication date: 20080423 |
|
CX01 | Expiry of patent term |