PT1562531E - Composição tópica para cuidado da pele - Google Patents
Composição tópica para cuidado da pele Download PDFInfo
- Publication number
- PT1562531E PT1562531E PT37765369T PT03776536T PT1562531E PT 1562531 E PT1562531 E PT 1562531E PT 37765369 T PT37765369 T PT 37765369T PT 03776536 T PT03776536 T PT 03776536T PT 1562531 E PT1562531 E PT 1562531E
- Authority
- PT
- Portugal
- Prior art keywords
- cream
- hydroquinone
- quot
- mixture
- tretinoin
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims description 118
- 230000000699 topical effect Effects 0.000 title claims description 30
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 claims description 150
- 239000006071 cream Substances 0.000 claims description 94
- -1 aliphatic fatty alcohols Chemical class 0.000 claims description 92
- 238000000034 method Methods 0.000 claims description 78
- 239000003995 emulsifying agent Substances 0.000 claims description 69
- 229960004337 hydroquinone Drugs 0.000 claims description 69
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 52
- 239000008346 aqueous phase Substances 0.000 claims description 51
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 claims description 50
- 229960001727 tretinoin Drugs 0.000 claims description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 48
- ATTPXNCCXYEULE-JOBJWGHLSA-N triluma Chemical compound OC1=CC=C(O)C=C1.OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C.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 ATTPXNCCXYEULE-JOBJWGHLSA-N 0.000 claims description 47
- 229940051117 tri-luma Drugs 0.000 claims description 46
- 206010008570 Chloasma Diseases 0.000 claims description 43
- 208000003351 Melanosis Diseases 0.000 claims description 43
- 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 43
- 238000002156 mixing Methods 0.000 claims description 42
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 40
- 229960001347 fluocinolone acetonide Drugs 0.000 claims description 38
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 claims description 37
- 239000012071 phase Substances 0.000 claims description 36
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 claims description 35
- 210000003491 skin Anatomy 0.000 claims description 35
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 30
- KWIUHFFTVRNATP-UHFFFAOYSA-N Betaine Natural products C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 claims description 27
- 229960003237 betaine Drugs 0.000 claims description 27
- 238000001816 cooling Methods 0.000 claims description 26
- 239000000839 emulsion Substances 0.000 claims description 26
- 239000000194 fatty acid Substances 0.000 claims description 26
- 239000003921 oil Substances 0.000 claims description 26
- 229920001223 polyethylene glycol Polymers 0.000 claims description 26
- 235000019198 oils Nutrition 0.000 claims description 25
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 24
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical group CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 23
- 235000011187 glycerol Nutrition 0.000 claims description 23
- 229960005150 glycerol Drugs 0.000 claims description 23
- 230000002209 hydrophobic effect Effects 0.000 claims description 22
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 22
- 239000002202 Polyethylene glycol Substances 0.000 claims description 21
- 239000013543 active substance Substances 0.000 claims description 21
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 21
- 229930195729 fatty acid Natural products 0.000 claims description 21
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 21
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 21
- 239000004615 ingredient Substances 0.000 claims description 20
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 19
- 230000008569 process Effects 0.000 claims description 19
- 229960000541 cetyl alcohol Drugs 0.000 claims description 18
- 239000007788 liquid Substances 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 18
- 235000019441 ethanol Nutrition 0.000 claims description 16
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 claims description 16
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 15
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims description 15
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 15
- 229960002216 methylparaben Drugs 0.000 claims description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 235000021355 Stearic acid Nutrition 0.000 claims description 14
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 claims description 14
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 14
- 239000008117 stearic acid Substances 0.000 claims description 14
- 229960004106 citric acid Drugs 0.000 claims description 13
- 239000004094 surface-active agent Substances 0.000 claims description 13
- 239000004322 Butylated hydroxytoluene Substances 0.000 claims description 12
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 12
- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims description 12
- 229940095259 butylated hydroxytoluene Drugs 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims description 12
- 229940079593 drug Drugs 0.000 claims description 12
- 150000002191 fatty alcohols Chemical class 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 12
- 238000012360 testing method Methods 0.000 claims description 12
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 11
- 150000004665 fatty acids Chemical class 0.000 claims description 11
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 claims description 11
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 claims description 11
- 229960003415 propylparaben Drugs 0.000 claims description 11
- 239000011734 sodium Substances 0.000 claims description 11
- 229910052708 sodium Inorganic materials 0.000 claims description 11
- 239000004480 active ingredient Substances 0.000 claims description 10
- 230000002411 adverse Effects 0.000 claims description 10
- 239000012455 biphasic mixture Substances 0.000 claims description 10
- 239000007854 depigmenting agent Substances 0.000 claims description 10
- 150000002433 hydrophilic molecules Chemical class 0.000 claims description 10
- 230000006872 improvement Effects 0.000 claims description 10
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 9
- 229940075529 glyceryl stearate Drugs 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 9
- 239000004166 Lanolin Substances 0.000 claims description 8
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 8
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 8
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 claims description 8
- 239000000654 additive Substances 0.000 claims description 8
- 150000001298 alcohols Chemical class 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- SPCNPOWOBZQWJK-UHFFFAOYSA-N dimethoxy-(2-propan-2-ylsulfanylethylsulfanyl)-sulfanylidene-$l^{5}-phosphane Chemical compound COP(=S)(OC)SCCSC(C)C SPCNPOWOBZQWJK-UHFFFAOYSA-N 0.000 claims description 8
- 150000002170 ethers Chemical class 0.000 claims description 8
- 239000003925 fat Substances 0.000 claims description 8
- 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 8
- 235000019388 lanolin Nutrition 0.000 claims description 8
- 229940039717 lanolin Drugs 0.000 claims description 8
- 230000003902 lesion Effects 0.000 claims description 8
- 230000036470 plasma concentration Effects 0.000 claims description 8
- 235000010356 sorbitol Nutrition 0.000 claims description 8
- 238000002560 therapeutic procedure Methods 0.000 claims description 8
- 239000001993 wax Substances 0.000 claims description 8
- UITSPQLTFPTHJZ-UHFFFAOYSA-N 2-[[3,4,5-tris(2-hydroxyethoxy)-6-methoxyoxan-2-yl]methoxy]ethanol Chemical compound COC1OC(COCCO)C(OCCO)C(OCCO)C1OCCO UITSPQLTFPTHJZ-UHFFFAOYSA-N 0.000 claims description 7
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 7
- 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 claims description 7
- KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical compound C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 claims description 7
- 239000003599 detergent Substances 0.000 claims description 7
- 229940100485 methyl gluceth-10 Drugs 0.000 claims description 7
- 239000000600 sorbitol Substances 0.000 claims description 7
- 239000007762 w/o emulsion Substances 0.000 claims description 7
- 208000003251 Pruritus Diseases 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000003963 antioxidant agent Substances 0.000 claims description 6
- 235000006708 antioxidants Nutrition 0.000 claims description 6
- 230000008901 benefit Effects 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 239000003246 corticosteroid Substances 0.000 claims description 6
- 239000002537 cosmetic Substances 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 229940043075 fluocinolone Drugs 0.000 claims description 6
- 150000002334 glycols Chemical class 0.000 claims description 6
- 239000008204 material by function Substances 0.000 claims description 6
- 230000037311 normal skin Effects 0.000 claims description 6
- 239000003208 petroleum Substances 0.000 claims description 6
- 230000035935 pregnancy Effects 0.000 claims description 6
- 239000008213 purified water Substances 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 150000003431 steroids Chemical class 0.000 claims description 6
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 claims description 5
- 241001465754 Metazoa Species 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 239000003974 emollient agent Substances 0.000 claims description 5
- 230000003647 oxidation Effects 0.000 claims description 5
- 238000007254 oxidation reaction Methods 0.000 claims description 5
- 229940100460 peg-100 stearate Drugs 0.000 claims description 5
- 230000035515 penetration Effects 0.000 claims description 5
- 239000003531 protein hydrolysate Substances 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- 239000000516 sunscreening agent Substances 0.000 claims description 5
- XWAMHGPDZOVVND-UHFFFAOYSA-N 1,2-octadecanediol Chemical compound CCCCCCCCCCCCCCCCC(O)CO XWAMHGPDZOVVND-UHFFFAOYSA-N 0.000 claims description 4
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 claims description 4
- SVTBMSDMJJWYQN-UHFFFAOYSA-N 2-methylpentane-2,4-diol Chemical compound CC(O)CC(C)(C)O SVTBMSDMJJWYQN-UHFFFAOYSA-N 0.000 claims description 4
- 208000002874 Acne Vulgaris Diseases 0.000 claims description 4
- 239000005711 Benzoic acid Substances 0.000 claims description 4
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 4
- 235000013162 Cocos nucifera Nutrition 0.000 claims description 4
- 244000060011 Cocos nucifera Species 0.000 claims description 4
- 241000196324 Embryophyta Species 0.000 claims description 4
- 206010015150 Erythema Diseases 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical class CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 claims description 4
- NWGKJDSIEKMTRX-BFWOXRRGSA-N [(2r)-2-[(3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)C1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-BFWOXRRGSA-N 0.000 claims description 4
- 206010000496 acne Diseases 0.000 claims description 4
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- 239000002280 amphoteric surfactant Substances 0.000 claims description 4
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 4
- 239000003212 astringent agent Substances 0.000 claims description 4
- JBIROUFYLSSYDX-UHFFFAOYSA-M benzododecinium chloride Chemical compound [Cl-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 JBIROUFYLSSYDX-UHFFFAOYSA-M 0.000 claims description 4
- 235000010233 benzoic acid Nutrition 0.000 claims description 4
- 229960004365 benzoic acid Drugs 0.000 claims description 4
- 229960004217 benzyl alcohol Drugs 0.000 claims description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 4
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 4
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 4
- 125000002091 cationic group Chemical group 0.000 claims description 4
- 235000015165 citric acid Nutrition 0.000 claims description 4
- 229960001334 corticosteroids Drugs 0.000 claims description 4
- 239000008406 cosmetic ingredient Substances 0.000 claims description 4
- DKJLEUVQMKPSHB-UHFFFAOYSA-N dimethyl-[3-(octadecanoylamino)propyl]-(2-oxo-2-tetradecoxyethyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCCCC(=O)NCCC[N+](C)(C)CC(=O)OCCCCCCCCCCCCCC DKJLEUVQMKPSHB-UHFFFAOYSA-N 0.000 claims description 4
- NTLIJZACUWTZFB-UHFFFAOYSA-N dimethyl-[3-(octadecanoylamino)propyl]azanium;2-hydroxypropanoate Chemical compound CC(O)C(O)=O.CCCCCCCCCCCCCCCCCC(=O)NCCCN(C)C NTLIJZACUWTZFB-UHFFFAOYSA-N 0.000 claims description 4
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 230000001804 emulsifying effect Effects 0.000 claims description 4
- 231100000321 erythema Toxicity 0.000 claims description 4
- WBJQGBBEPJLNKP-UHFFFAOYSA-N ethyl-dimethyl-[3-(octadecanoylamino)propyl]azanium;ethyl sulfate Chemical compound CCOS([O-])(=O)=O.CCCCCCCCCCCCCCCCCC(=O)NCCC[N+](C)(C)CC WBJQGBBEPJLNKP-UHFFFAOYSA-N 0.000 claims description 4
- 229940093476 ethylene glycol Drugs 0.000 claims description 4
- 150000002194 fatty esters Chemical class 0.000 claims description 4
- 239000003205 fragrance Substances 0.000 claims description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 4
- 239000003906 humectant Substances 0.000 claims description 4
- 229960000890 hydrocortisone Drugs 0.000 claims description 4
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- 230000007794 irritation Effects 0.000 claims description 4
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- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
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- 230000002207 retinal effect Effects 0.000 claims description 4
- 108700004121 sarkosyl Proteins 0.000 claims description 4
- KSAVQLQVUXSOCR-UHFFFAOYSA-M sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 claims description 4
- 229940045885 sodium lauroyl sarcosinate Drugs 0.000 claims description 4
- 238000010561 standard procedure Methods 0.000 claims description 4
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 230000000475 sunscreen effect Effects 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 4
- 235000010215 titanium dioxide Nutrition 0.000 claims description 4
- 239000004408 titanium dioxide Substances 0.000 claims description 4
- 150000003626 triacylglycerols Chemical class 0.000 claims description 4
- 239000011787 zinc oxide Substances 0.000 claims description 4
- 235000014692 zinc oxide Nutrition 0.000 claims description 4
- 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 claims description 3
- HOVAGTYPODGVJG-UVSYOFPXSA-N (3s,5r)-2-(hydroxymethyl)-6-methoxyoxane-3,4,5-triol Chemical compound COC1OC(CO)[C@@H](O)C(O)[C@H]1O HOVAGTYPODGVJG-UVSYOFPXSA-N 0.000 claims description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 3
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical compound CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 claims description 3
- 239000004909 Moisturizer Substances 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 3
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Description
DESCRIQÄO
COMPOSIςΑΟ TÓPICA PARA CUIDADO DA PELE CAMPO DA INVENQAO
A invengáo refere-se geralmente a um método de fabricar lama composigáo medicada parca tratamento da pele. ANTECEDENTES DA INVENQAO 0 melasma ου. el oasma é urna condi gao pigmentária com.um que afeta principalmente mulheres nos seus anos reprodutivos. As manchas escuras, mosqueadas (hiperpigmentadas) aparecem no rosto e pescogo, especialmente ñas bochechas e testa. 0 melasma é normalmente desencadeado pela atividade hormonal que é o resultado da gravidez ou pílulas anticoncecionais. Assim, a condigáo é condecida como a "máscara da gravidez". A condigáo ocorre guando excesso de melanina é depositado ñas células da epiderme e derme. 0 melasma pode persistir durante longos periodos de tempo e normalmente recorre com gestagóes subsequentes. A condigáo é menos comum entre homens, que sao responsáveis por cerca de 10 % de todos os casos. A terapéutica padráo envolve a despigmentagáo ou branqueamento das áreas atetadas da pele, a utilizagáo de protetores solares e evitar a luz solar. A hidroquinona é o agente de despigmentagáo tópico mais popular. Concentragoes de 5 %—10 % de hidroquinona sao muito eficazes, mas podem ser irritantes. A estabilidade química das formulagóes de hidroquinona é importante porque a hidroquinona é fácilmente oxidada e perde potencia. O agente mais comumente utilizado normalmente envolve um curso de terapéutica de 16 semanas a 20 semanas, e algumas terapéuticas podem demorar mais tempo. A tretinoína (Retin-A) é outra terapéutica amplamente utilizada para o melasma.
No entanto, permanece urna necessidade na técnica de urna abordagem terapéutica que poderia confer vários medicamentos para o tratamento de melasma na mesara composigáo. Além disso, poderla ser útil ter um portador terapéutico, tal como um creme, que facilitarla a penetragáo dos medicamentos na pele. 0 documento de patente U.S. N.° 5.538.737 divulga um método para fabricar urna emulsáo de água em óleo contendo um sal farmacéuticamente aceitável de um antagonista de H2. As etapas incluem dissolver o sal farmacéuticamente aceitável nurri meio aguoso para formar urna porgäo de água; combinar a porgao de água com urna porgäo de óleo, compreendendo um óleo comestível que compreende um éster ou éster de glicerol misturado e um agente emulsionante para formar urna matriz de porgäo de água e porgäo de óleo; posteriormente emulsificar a matriz para formar a emulsao de água em óleo. 0 documento de patente U.S, N.° 5.656.672 divulga um processo piara a preparagäo de urna emulsao de água em óleo com retinal como o ingrediente ativo. A emulsao contém urna fase oleosa incluindo pelo menos um solvente orgánico para retinal (tais como álcoois gordos alifáticos) e aditivos lipofílicos opcionais; urna fase aguosa contendo água e opcionalmente aditivos hidrofílíeos; e um agente para emulsificar a fase aguosa na tase oleosa. A fase oleosa e a fase aguosa sao preparadas independentemente, e a fase aguosa é incorporada na fase oleosa, com adigäo subseguente de urna fase contendo retinol e o seu solvente. 0 documento de patente U.S. N.° 5.660.837 divulga um processo para a preparagäo de urna formulagáo farmacéutica sob a forma de urna emulsáo de água em óleo. As etapas do processo incluem adicionar o fármaco ativo de superficie estabilizante de emulsáo e um tensioativo convencional ótimo a um sistema de duas fases, de óleo-água á temperatura ambiente; permitir que o fármaco ativo de superficie estabilizante de emulsáo se equilibre numa interface; adicionar um agente que proporciona isotonicidade á formulagáo final; e homogeneizar através de urna técnica de alta pressáo. O documento de patente U.S. N.° 5.976.555 divulga composigóes para o cuidado da pele. Urna base de emulsáo de óleo era água contérn retinoides; álcool cetearílico e glucósido de cetearilo ou urna mistura de éteres de polietilenoglicol de álcool estearilico; álcool cetílico, álcool estearílico e misturas dos mesmos; um óleo leve, seco e absorvível; e óleos ou ceras emolientes, substanciáis.
Clark et al., Dermatology Times 23(5), página 1 (2002) descreve um creme tópico gire combina 4 % de hidroquinona, 0, 05 % de tretinoina e 0, 01 % de acetonida de fluocinolona para utilizagao no tratamiento de melasma. O documento de patente U.S. N.° 6.080.393 divulga urna composigao de cuidado da píele que compreende urna emulsao de óleo em água com urna quantidade terapéuticamente eficaz de um retinoide; em que a fase oleosa compreende um ou mais óleos, e urna quantidade eficaz de pelo menos um antioxidante solúvel em óleo; e em que a composigao compreende um corticosteroide.
No en tanto, permanece urna necessida.de na técnica de um método de fabricar urna base de creme mais suave para a aplicagao de agentes terapéuticos para o tratamento de melasma, que facilitará a penetragäo dos medicamentos na pele.
SUMARIO DA INVENQAO A invengáo proporciona um método de fabricar urna composigao tópica medicada, como definida na reivindicagáo 1. O processo para fabricar ¿a base de creme envolve (a) misturar os compostos hidrofílicos com água para formar urna fase aguosa; (b) misturar os compostos hidrofóbicos para formar urna fase hidrofóbica (nao aguosa ou cera) ; depois (c) misturaras fases hidrofílica e hidrofóbica urna com a outra para formar urna mistura bifásica; e finalmente (d) adicionar um emulsionante á mistura bifásica para formar a emulsao, Ao misturar o emulsionante depois de que as fases aquosa e nao aguosa se tenham misturado, o resultado é um creme de textura mais suave que desaparece aguando da aplicagao na pele, em. comparagao com cremes fabricados por processes onde o emulsionante é adicionado äs fases aguosa ou nao aquosa mais cedo no processo. Dado que o emulsionante é adicionado como a etapa final, é necessária menos cera para fabricar o creme, resultando num creme hidrofílico "mais fino" que desaparece mais depressa quando aplicado á pele, em comparagäo com cremes fabricados por processes onde o emulsionante é adicionado äs fases aquosa ou nao aquosa mais cedo no processo. A base de creme fabricada pelo método de Interesse pode ser urn portador para qua 1 quer de urna variedade de agentes farmacéuticamente ativos para utilizagäo dermatológica. Por exernplo, agentes ativos anti-acne, anticancerígenos, antibióticos, anti-inflamatórios, hormonais, antifúngicos e analgésicos podern ser incorporados numa base de creme de Interesse.
Na presente invengäo, a base de creme compreende um esteroide, um agente queratolítico e um agente de despigmentagao, em que o esteroide é acetonida de fluocinolona, o agente queratolítico é tretinoina e o agente de despigmentagao é hidroquinona.
Numa forma de realizagao mais especifica, o creme também incluí os ingredientes inativos hidroxitolueno butilado, álcool cetílico, ácido cítrico, glicerina, estearato de glicerilo, silicato de magnésio e aluminio, metil gluceth-10, metilparabeno, estearato de PEG-100, propilparabeno, água purificada metabissulfito de sodio, ácido esteárico e álcool estearílico. 0 creme pode ser creme Tri-Luma®, que é o primeiro produto a combinar o agente de despigmentagao padreo, hidroquinona, com tretinoina e um esteroide de baixa potencia tópico que pode ser aplicado como urna preparagáo única. 0 curso de terapéutica recomendado para o creme Tri-Luma®é de 8 semanas, e resultados significativos foram observados depois das primeiras 4 semanas de tratamento. Outra vantagem do processo da invengäo consiste em que através do controlo da temperatura á qual os componentes, incluindo a hidroquinona, sao adicionados, o creme nao se torna tao castanho, resultando num produto com urna cor mais agradável.
DESCRigÄO DETÄLHADA DA INVENQAO
Os cremes säo emulsöes de componentes hidrofílíeos e lipofílicos (hidrofóbleos) . Geralmente, um emulsionante ou agente ativo de superficie é incluido para melhorar a mistura dos reagentes resultando numa emulsáo estável.
Os vários compostos que compreendem um portador inerte sao geralmente conhecidos na técnica. Por "inerte" entende-se nao tendo urna atividade farmacológica. Exemplos típicos de compostos inertes que compreendem urna base de creme incluem álcool cetílico, lanolina, glicerina, etanol, EDTA, metil parabeno, óxido de zinco, dióxido de titanio, ácido benzoico, carboximetilcelulose, dimetilsulfóxido, polietilenoglicol; petróleo, ácido cítrico e ácido esteárico. A presente invengao refere-se a um método para fabricar urna base de creme como um veiculo para um ou mais agentes farmacológicamente ativos para aplicagoes dermatológicas. 0 método de Interesse compreende urna ordern particular de adicionar e misturar os ingredientes de um creme. Os ingredientes hidrofílicos, incluindo a água, sao misturados. 0 aquecimento pode ser utilizado para facilitar a dissolugao e solubilidade para produzir urna solugao. Os ingredientes lipofílicos e hidrofóbicos sao misturados separadamente. 0 aquecimento pode ser utilizado para facilitar a mistura e homogene!zagao. A solugao hidrofílica e a solugao lipofílica sao depois misturadas e combinadas. Um ou mais agentes farmacéuticamente ativos sao depois adicionados á mistura combinada. Posteriormente, um ou mais emulsionantes sao adicionados e toda a mistura é combinada para produzir um creme dermatológico de Interesse.
As temperaturas para aquecimento das solugóes hidrofóbicas e hidrofílicas sao aquelas suficientes para facilitar a obtengao de urna solugao homogénea. Geralmente, urna temperatura elevada mais baixa com um tempo de mistura mais prolongado é preferida. A temperatura também. pode ser limitada pelas propriedades de qualquer um dos ingredientes individuáis presentes. Geralmente, a temperatura nao excede cerca de 100 °C. Preferentemente, a temperatura nao excede cerca de 90 °C ou cerca de 80 °C ou cerca de 70 °C ou cerca de 60 °C. Geralmente, a temperatura de aquecimento nao necessita de ser exata, pelo menos dentro da precisäo dos meios padráo para medígao da temperatura.
As solugoes hidrofóbicas e hidrofílicas nao tém de ser aquecidas até á rnesma temperatura. Ter a mesma temperatura facilita a mistura das duas solugoes. Se as solugöes se encontram a temperaturas diferentes, a solugao mais quente é arrefecida até á temperatura da solugao mais fría antes da mis tiara. A mistura combinada opcionalmente pode ser arrefecida antes ser misturado o um ou mais agente ou agentes farmacéuticamente ativos. As prop.riedad.es físicas dos agentes ativos pode ditar urna necessidade para o arrefecimento.
Após essa etapa e combinagäo, um ou mais emulsionantes sao adicionados. A mistura é combinada minuciosamente para produzir um creme de interesse. Se elevada, a temperatura pode ser reduzida durante a combinagäo.
No que diz respeito aos ingredientes lipofílicos, tal como conhecido na técnica, os óleos podem ser derivados a partir de animals, plantas, frutos secos, petróleo, etc. Aqueles derivados a partir de animáis, sementes de plantas e frutos secos sao semelhantes a gorduras e consequentemente, podem conter um número significativo de ácido polar e/ou grupos éster. Alternativamente, óleos derivados a partir de petróleo sao normalmente hidrocarbonetos alifáticos ou aromáticos que sao essencialmente livres de substituigao polar.
Os produtos baseados em óleo que podem ser utilizados incluem hidrocarbonetos ou gorduras minerals obtidas a partir da destilagáo de petróleo (vaselina); óleos vegetáis e triglicéridos líquidos; gorduras animáis ou triglicéridos sólidos, naturals; e ceras ou éteres sólidos de ácidos gordos, tais como ácido esteárico e ácido palmitico e álcoois orgánicos. Lanolina ou gorduras de la feitas de ácidos gordos e ásteres de colesterol; e álcoois cetílico e estearílico, que sao álcoois sólidos obtidos a partir de hidrogenagáo dos seus respetivos ácidos sao também utilizáveis. Os compostos anfotéricos tais como saboes ou sais de ácidos gordos que podem ser ácidos ou básicos dependendo de se o grupo lipofílico é aniónico ou catiónico, álcoois sulfatados que sao substancias semi-sintéticas e agentes ativos de superficie sintéticos sao condecidos na técnica e também podem ser utilizados. A glicerina é obtida a partir de gorduras e, devido ä hidrofobicidade das mesmas, tem a propriedade de extrair água a partir da superficie das mucosas ou pele desnudada. A glicerina nao danifica a pele intacta porque tem propriedades hidrofilicas, e é um humectante útil.
Outros materials que podem ser utilizados numa preparagáo tópica de Interesse incluem álcoois líquidos, glicóis líquidos, polialquilenoglicóis líquidos, ásteres líquidos, amidas liquidas, hidrolisados proteicos líquidos, hidrolisados proteicos alquilados líquidos, lanolina líquida e derivados de lanolina e outros materials semelhantes. Exemplos particulares incluem álcoois monohídricos e polihídricos, por exemplo, etanol, Isopropanol, glicerol, sorbitol, 2-metoxietanol, dietilenoglicol, etilenoglicol, hexilenoglicol, manitol, álcool cetílico e propilenoglicol; éteres tais como éter dietílico ou dipropílico; polietilenoglicóis e metoxipolioxietilenos; carboceras tendo massas moleculares que variam desde 200 a 20.000; gliceróis de polioxietileno; polioxietileno; sorbí tóis; e diacetina ele estearoilo.
Os portadores tópicos incluem normalmente ambos um álcool e água de modo a acomodar os componentes lipofi líeos e hidrofílicos. Outros ingredientes incluem tampoes, tais como hidróxido de sodio, citrato de sodio ou EDTA tetrassódico; excipientes; fragrancias tais como mentol; opacificantes tais como óxido de zinco, silicato de magnésio e aluminio e dióxido de titanio; conservantes tais como álcool diclorobenzílico, ácido benzoico, metilparabenoe fenil carbinol; antioxidantes; agentes de gelificagäo tais como petrolato e cera mineral; agentes espessantes tais como carboximetilcelulose; estabilizantes; tensioativos; emolientes; agentes corantes e semelhantes.
Adicionalmente, o portador tópico pode incluir um potenciador da penetragao como um material, que aumenta a permeabilidade da pele a um ou mais agentes ativos ele modo a permitir a distribuigao cutanea de um agente farmacológicamente ativo. Vários compostos para potenciar a permeabilidade da pele sao condecidos na técnica. Por exemplo, dimetilsulfóxido (DMSO), dimetilformamida (DMF) e N,N-dimetilacetamida (DMA), decilmetilsulfóxido, monolaurato de polietilenoglicol e as azacicloheptan-2-onas 1-substituídas.
Urna série de emulsionantes ou tensioativos diferentes podem ser utilizados para preparar urna preparagäo tópica de Interesse. Exemplos nao limitantes de tensioativos anfotéricos úteis ñas composicoes da presente invengäo sao divulgados em Mc-Cutcheon’s "Detergents and Emulsifiers", North American edition (1986) e McCutcheon’s, "Functional Materials", North American edition (1992). Os tensioativos que podem ser utilizados sao as betaínas, sultaínas e hidroxissultainas. Exemplos de betaínas incluem as betaínas ele alquilo de cadera longa, tal como coco dimetil carboximetil betaína, lauril dimetil carboximetil betaína, lauril dimetil alfacarboxiet.il betaína, cetil dimetil carboximetil betaína, cetil dimetil betaína, lauril bis-(2-hidroxietil) carboximetil betaína, estéril bis-(2-hidroxipropil) carboximetil betaína, oleil dimetil gama-carboxipropil betaína, lauril bis-(2-hidroxipropil)alfa carboxietil betaína, coco dimetil sulfopropil betaína, estearil dimetil sulfopropil betaína, estearil betaína, lauril. dimetil sul.foet.il betaína, lauril bis- (2-hidroxietil) sulfopropil betaina, amidobetainas, amidosulfobetainas, oleil betaina e comamidopropril betaina. Exemplos de sultainas e hidroxisultainas incluem cocamidopropil hidroxisultaina. Exemplos de outros tensioativos anfotéricos säo alquiliminoacetatos, i mi n o di a1can o a t o s e amin oa1canoatos.
Exemplos de tensioativos aniónicos também säo divulgados em McCutcheon’s, "Detergents and Emulsifiers", North American edition (1986) e McCutcheon’s, "Functional Materials", North American edition (1992). Exemplos incluem os isotionatos de alcoilo, os sulfatos de alquilo e alquiléter, tais como, cocoil isotionato de amonio, cocoil isotionato de sodio, lauroil isotionato de sodio, estearoil isotionato de sodios e misturas dos mesrnos, os sarcosínatos, tais como lauroil sarcosinato de sodio, cocoil sarcosinato de sodio e lauroil sarcosinato de amonio, lauril sulfato de sodio, lauril sulfato de amonio, cetil sulfato de amonio, cetil sulfato de sodio, estearil sulfato de sodio, cocoil isetionato de amonio, lauroil isetionato de sodio, lauroil sarcosinato de sodio e misturas dos mesrnos.
Outros emulsificantes incluem tricetareth-4-fosfato, laureth-4-fosfato de sodio ou. oieth-3.
Exemplos de emulsionantes nao iónicos incluem monoestearato de sorbitano, monoestearato de glicerilo, polissorbatos, derivados de polietiieno ou álcoois gordos, éteres de polioxietileno ou álcoois gordos, tais como éter cetilico de polioxietileno, éter oleilico de polioxietileno, éter nonilfenilico de polioxietileno e semelhant.es, estearato de sorbitano, estearato de glicerilo, álcoois gordo Ci2-Ci8, ésteres e éteres dos mesrnos, álcoois gordos alifáticos tais como álcool cetilico ou álcool estearilico ou urna mistura dos dois, álcoois gordos ou oí-dióis oxietilenados ou poliglicerolados tais como álcool oleilico polioxietileñado com 10 moles de dióxido de etileno, 1,2-octadecanediol poliglicerolado com. 2 ou 7 moles de glicidol, álcoois gordos cíclicos, ésteres de glicol ou ácidos gordos tais como estearato de etilenoglicol, os monoestearatos ou diestearatos de glicerol, ésteres de glicol ou ácidos gordos tais como estearatos de etilenoglicol, os ésteres gordos de sorbitano oxietilenados ou nao e vendidos sob o nome comercial de Tweens ou Spans, os ésteres gordos de sacarose, os ésteres gordos de derivados de glucose tais como sesquiestearato de metilglucósido e sesquiestearato de metilglucósido polioxietileñado com. 20 moles de óxido de etileno, Arlacel 165 e Myrj 52, álcoois gordos tendo 10 a 20 átomos de carbono, álcoois gordos tendo 10 a 20 átomos de carbono condensados com 2 a 20 moles de óxido de etileno ou óxido de propileno, fenóis de ¿alquilo com 6 a 12 átomos de carbono na cadera de alquilo condensados com 2 a 20 moles de óxido de etileno, ésteres de ácido mono-gordo e di-gordo de óxidos de etileno, ésteres de ácido mono-gordo e di-gordo de etilenoglicol em que a fraqáo de ácido gordo contém desde 10 a 20 átomos de carbono, dietilenoglicol, polietilenoglicóis de massa molecular 200 a 6000, propilenoglicóis de massa molecular 200 a 3000, glicerol, sorbitol, sorbitano, polioxietileno sorbitol, polioxietileno sorbitano e ésteres de cera hidrofílicos, éteres de álcoois gordos de polioxietileno, éster de ácido gordo de polioxietileno, ésteres de ácido gordo de polioxietileno sorbitano, ésteres de ácido gordo de sorbitano, ésteres de ácido gordo de polioxietileno e ésteres de ácido gordo de poliol.
Exemplos de emulsionantes catiónicos incluem sais de brometo e cloreto de amonio quaternizado, cloreto de cetiltrimetilamónio, cloreto de benzalcónio e cloreto de cetil piridínio, aminas alifáticas tendo cadeias gordas, por exemplo, oleilaminae dihidroabietilamina; compostos de amonio quaternário, por exemplo, cloreto de lauril dimetilbenz.il amonio, amidas derivadas a partir de amino álcoois, por exemplo, oleiamida de N-aminoetilo, cloreto de n- (estearoil-colamino-formilmetil) piridínio, etossulfato de N-soja-N-etil morfolínio, cloreto de alquil dimetil benzil amonio, cloreto de di-isobutilfenoxietoxietil dimetil benzil amonio, cloreto de cetil piridinio, cloreto de N- (estearoil-colamino-formilmetil) piridinio, etossulfato de N-soja-N-etil morfolínio, cloreto de alquil dimetil benzil amonio, cloreto de (di-isobutil-fenoxi-etoxi) etil dimetil benzil amonio, fosfato de cloreto de PG-dimónio, etossulfato de estearamidopropil etildimónio, cloreto de estearamidopropil dimetil (acetato de miristilo) amonio, tosilato ele estearamidopropil dimetil cetearil amonio, cloreto de estearamidopropil dimetil amonio, lactato de estearamidopropil dimetil amonio, haletos de amonio, mais especialmente cloretos e brometos, tais como cloreto de alquil trimetilamónio, cloretos de dialquil dimetilamónio e cloretos de trialquil metilamónio, por exemplo, cloreto de estearil trimetilamónio, cloreto de diestearilo dimetilamónio, cloreto de lauril dimetilamónio, cloreto de lauril dimetil benzilamónio e cloreto de tricetil metilamónio, hidrolisados proteicos quaternizados ou hidrolisados proteicos derivados com grupos amino que sao comercializados, por exemplo, sob os nomes Lamequat® e Mackpro®, fosfato de cloreto de estearamidopropil PG-dimónio, etossulfato de estearamidopropil etildimónio, cloreto de estearamidopropil dimetil (acetato de miristilo) amonio, tosilato de estearamidopropil dimetil cetearil amonio, cloreto de estearamidopropil dimetil amonio, e lactato de estearamidopropil dimetil amonio.
As composigóes da presente invengäo podem compreender urna ampia gama de componentes adicionáis. 0 "CTFA Cosmetic Ingredient Handbook", Segunda edigäo, 1992, descreve urna ampia variedade de ingredientes cosméticos e farmacéuticos comumente utilizados na indústria do cuidado da pele, que sao adequados para utilizagao ñas composigóes da presente invengäo. Exemplos de classes funcionáis de ingredientes sao absorvent.es, abrasivos, agentes anti-acne, agentes antiaglomerantes, agentes anti-espuma, agentes antimicrobianos, antioxidantes, aglutinantes, aditivos biológicos, agentes de tamponamento, agentes espessant.es, agentes quelant.es, aditivos químicos, corantes, adstringentes cosméticos, biocidas cosméticos, desnaturantes, adstringentes de fármacos, analgésicos externos, formadores de película, componentes de fragrancia, humectantes, agentes opacificantes, ¿ajustadores do pH, plastificantes, conservantes, propulsores, agentes redutores, agentes de branqueamento da pele, agentes de condicionamento da pele (emolientes e humectantes), protetores da pele, solventes, potenciadores de espuma, hidrotropos, agentes solubilizant.es, agentes de suspensáo (nao tensioativos) , agentes de protegao solar, ¿absorbedores de luz ultravioletas e agentes de aumento de viscosidade (aquosos e nao aquosos).
Os vários materials de partida para fazer urna preparagao tópica sao conhecidos na técnica e pode ser feita referencia a tratados conhecidos, bem como os documentos de patente N.°s 6.013.271; 6.267.985; 4.992.478; 5.645.854; 5.811.111; e 5.851.54 3 .
Os agentes farmacéuticamente ativos ñas preparagóes dermatológicas de interesse sao acetonida de fluocinolona, h i d r o qui nona e t re t i n o i na.
As quantidades dos ingredientes inertes e agente (s) ativo(s) na preparagao dermatológica de interesse geralmente sao conhecidos na técnica. Está dentro do ámbito do perito derivar quantidades particulares dos ingredientes para obter um creme de interesse. A quantidade particular de qualquer um dos ingredientes utilizados náo é substancialmente crítica e as quantidades utilizadas encontram-se na precisáo dos meios de medigáo ou distribuigáo conhecidos na técnica.
Numa forma de realizagáo da invengáo, aproximadamente 344,8 kg de água, 15,0 kg de silicato de magnésio e aluminio, e 0,2 kg de hidroxitolueno butilado sao em primeiro lugar combinados e misturados a 75-80 °C para formar a fase aguosa. A mistura pode ser agitagao por raspagem lateral a urna velocidade fixa. A fase aguosa resultante é urna suspensäo.
Em segundo lugar, aproximadamente 20,0 kg de álcool cetilico, 15,0 kg de ácido esteárico, 20,0 kg de álcool estearilico, 25,0 kg de metil gluceth-10, 0,9 kg de metilparabeno, 0,1 kg de propilparabeno e 20,0 kg de glicerina sao misturados em conjunto a urna velocidade média a cerca de 75-80 °C para formar a fase nao aguosa. A mistura pode ser a velocidade média num misturador Lightnin®. A fase nao aguosa resultante é urna suspensäo, A segunda etapa pode ser realizada antes, depois ou simultáneamente com a primeira etapa.
Depois, a fase nao aguosa é adicionada á fase aguosa e a mistura bifásica combinada é arrefecida até urna temperatura no intervalo de 68 °C. a 72 °C, ou cerca de 7 0 °C, depois do gue cerca de 17,5 kg de Arlacel® 165, 0,25 kg de tretinoina e 0,050 kg de acetonida de fluocinolona sao adicionados e agitados com arrefecimento. Quando a mistura atinge 60 °C, 0,25 kg de ácido cítrico sao adicionados com mistura e arrefecimento. Quando a temperatura atinge 55 °C, 2 0,0 kg de hidroguinona sao adicionados com mistura e arrefecimento. Quando a temperatura atinge cerca de 50 °C, a mistura é homogeneizada com um homogene i z ador, com arrefecimento continuado. Quando a mistura atinge 45 °C, 1,0 kg de metabissulfito de sodio é adicionado com agitagäo e arrefecimento. Típicamente, o metabissulfito de sodio é adicionado cerca de 30 minutos depois da adigao da hidroguinona. A mistura pode ser a urna velocidade fixa num agitador de raspagem lateral. A composigäo resultante de matéria é urna emulsao, isto é, um creme. A presenga de metabissulf ito ele sodio no creme impede a oxidaeäo da hidroguinona. A adigäo de metabissulfito de sodio ä medida gue o creme está a arrefecer resulta, vantajosamente, numa composigäo de matéria bem misturada, com o metabissulf ito de sodio misturado de forma homogénea em todo o creme e impedindo a oxidagao da hidroguinona em todo o creme. Outra vantagem do processo da invengäo consiste em que através do controlo da temperatura ä qual os componentes, incluindo a hidroquinona, sao adicionados, o creme nao se torna táo castanho, resultando nurn produto com urna cor rriais agradável. A adigáo de emulsionante depois da mistura das fases aquosa e nao aquosa é vantajosa para o fabrico da composigáo farmacéutica da invencáo. Quando foi utilizada urna técnica padräo para adicionar o emulsionante ¿1 fase nao aquosa e depois misturar com a fase aquosa, nao se formou qualquer emulsáo. Contudo, quando o emulsionante foi adicionado á mistura das fases aquosa e nao aquosa com arrefecimento, de acordo com o método da invencáo, formou-se urna emulsao útil. Esta emulsao formou-se mesmo embora a proporgálo relativa das fases aquosa e nao aquosa, de acordo com o método bem-sucedido da invengao, fosse a mesma de quando nao se formou urna emulsao utilizando a técnica padräo de adicionar urna fase nao aquosa contendo um emulsionante a urna fase aquosa. 0 creme TRI-LUMA® resultante contení acetonida de fluocinolona, hidroquinona e tretinoína numa base de creme hidrofílica para a aplicagao tópica. Cada grama de creme TRI-LUMA® contém como ingredientes ativos, acetonida de fluocinolona a. 0,01 % (0,1 mg) , hidroquinona a 4 % (40 mg) , e tretinoína 0,05 % (0,5 mg) , e como ingredientes inativos, hidroxitolueno butilado, álcool cetílico, ácido cítrico, glicerina, estearato de glicerilo, silicato de magnésio e aluminio, metil gluceth-10, metilparabeno, estearato de PEG-100, propilparabeno, água purificada metabissulfito ele sodio, ácido esteárico e álcool estearílico, veia-se o QUADRO 1. QUADRO 1
Lote de 500 Lote de 800
Ingrediente kg de kg de Fórmula quantidade quantidade silicato de magnésio e aluminio NF 15 kg 24 kg 3,00% hidroxitolueno butilado NF 200 g 320 g 0,04% álcool cetílico NF 20 kg 32 kg 4,00% ácido esteárico NF 15 kg 24 kg 3,00% álcool estearílico NF 20 kg 32 kg 4,00% metilparabeno NF 900 g 1,440 g 0,18% propilparabeno NF 100 g 160 g 0,02%
Arlacel® 165 [estearato de glicerol e monoestearato de glicerol de estearato 17,5 kg 28 kg 3,50% de PEG-100] metil gluceth-10 25 kg 40 kg 5,00% glicerina USP 20 kg 32 kg 4,00% tretinoina USP 250 g 400 g 0,05% acetonida de fluocinolona USP 50 g 80 g 0,01% ácido cítrico USP 250 g 400 g 0,05% hidroquinona USP 20 kg 32 kg 4,00% metabissulfito de sodio NF 1 kg 1,6 kg 0,20% água purificada USP 344,8 kg 551,6 kg 68, 95% TOTAL 100,00% A acetonida de fluocinolona é um corticosteroide fluorinado sintético para utilizagao dermatológica tópica e é classificado terapéuticamente como um anti-inflamatório. É um pió cristalino branco que é inodoro e estável na luz. O nome químico da acetonida de fluocinolona é (6, 11,16}- 6,9-difluoro-11,21-dihidroxi-l6, 17-[(1-metíletili deno)bis(oxi)]-pregna-1,-4-dieno-3,20-diona. A fórmula molecular é C24H30F2O6 e a massa molecular é 452,50. A hidroquinona é classificada terapéuticamente como um agente de despigmentagao. É preparada a partir da redugáo de p-benzoquinona com bissulfito de sodio. Ocorre como agulhas brancas finas que escurecem aquando da exposigáo ao ar. O nome químico da hidroquinona é 1,4-benzenediol. A fórmula molecular é C6Hg02 e a massa molecular é 110,11. A tretinoina é um ácido holo-transretinoico formado a partir da oxidagao do grupo aldeído do retineno a urn grupo carboxilo. É altamente reativa á luz e humidade. A tretinoina é classificada terapéuticamente como um queratolitico. O nome químico da tretinoina é: ácido (holo-E)-3,7-dimeti1-9-(2,6,6-trimetil-l- ciclohexen-l-il)-2,4,6,8-nonatetraenoico. A fórmula molecular é C2 0H 28O2 e a massa molecular é 300,44. O creme TRI-LUMA™ é típicamente fornecido em tubos de aluminio de 30 g, NDC 0299-5950-30, e é armazenado á temperatura ambiente controlada de 68 a 77 °F (20-25 °C).
Os detalhes de uma ou mais formas de realizacäo da invengäo säo estabelecidos na descrigäo anexa acima.
Embora quaisquer métodos e materials semelhantes ou equivalentes aqueles descritos no presente documento possam ser utilizados na prática ou testagem da presente invengäo, os métodos e materials preferidos sao agora descritos. Outras características, objetos e ventagens da invengäo seräo aparentes a partir da descrigäo e das reivindicagöes. Na memoria descritiva e ñas reivindicagöes anexas, as formas singulares incluem os respetivos plurais a nao ser que o contexto claramente dite o contrário. A nao ser que definido o contrário, todos os termos técnicos e científicos utilizados no presente documento possuem o mesmo significado como habitualmente entendido por um perito na especialidade ao qual esta invengäo pertence.
Os seguintes EXEMPLOS sao incluidos para ilustrar de forma mais completa as formas de realizagao da invengäo. Estes EXEMPLOS näo devem, de qualquer forma, ser considerados como limitantes do ámbito da invengäo, conforme definido pelas reivindicagöes anexas.
EXEMPLO I
FARMACOCINÉTICAS HUMANAS A absorgäo percutánea da tretinoína, hidroquinona e acetonida de fluocinolona näo modificadas para a circulagäo sistémica de dois grupos de voluntários saudáveis (total n=59) foi verificado como sendo mínima depois de 8 semanas de aplicagäo diária de 1 g (Grupo I, n=45) ou 6 g (Grupo II, n=14) de creme TRI-LUMA®.
Para a tretinoína, concentragöes plasmáticas quantificáveis foram obtidas em 57,78 % (26 de 45) dos
individuos do Grupo I e 57,14 % (8 de 14) do Grupo II. A exposigäo ¿i tretinoína como refletida pelos valores de Cmáx variou desde 2,01 até 5,34 ng/ml (Grupo I) e 2,0 a 4,99 ng/ml (Grupo II) . Assim, a aplicagäo diária do creme TRI-LUMA® resultou num aumento mínimo dos níveis endógenos de tretinoína. Os níveis de tretinoína circulante representan! apenas urna porgao dos retinoides associados com. tretinoína totals, que poderiam incluir metabolites da tretinoína e que estejam sequestrados nos tecidos periféricos.
Para a hidroquinona, concentragöes plasmáticas quantificáveis foram obtidas em 18% {8 de 44) dos individuos do Grupo I. A exposigáo a hidroquinona como refletida pelos valores de Cmáx variou desde 25,55 até 86, 52 ng/ml. Todos os individuos do Grupo II (dose de 6 g) apresentaram concentragöes plasmáticas pós-dose indetetavelmente baixas.
Para a acetonida de fluocinolona, os individuos do Grupo I e II apresentaram concentragöes plasmáticas pós-dose indetetavelmente baixas.
Os seguintes testes podem ser úteis na avaliagáo dos pacientes: (a) testes de estimulagáo de ACTH ou cosintropina; (b) o teste de cortisol plasmático A.M. e (c) o teste de cortisol livre urinário.
EXEMPLO II
ESTUDOS CLÍNICOS HUMANOS
Dois estudos de eficácia e seguranga foram realizados em 641 pacientes de melasma entre as idades de 21 a 75 anos, tendo fototipos de pele I-IV e melasma modero a grave no rosto. 0 creme TRI-LUMA® foi comparado com tres combinagöes possíveis de dois dos tres ingredientes ativos [(1) hidroquinona a 4 % (HQ) + tretinoína a 0,05 % (RA); (2) acetonida de fluocinolona a 0,01 % (FA) + tretinoína a 0,05 % (RA) ; (3) acetonida de fluocinolona a 0,01 % (FA) + hidroquinona a 4 % (HQ)], contidos no mesmo veículo que o creme TRI-LUMA®.
Os pacientes foram instruidos para aplicar a sua mediagäo do estudo cada noite, depois de lavar o seu rosto com urn agente de 1impeza sem sabäo suave, durante 8 semanas. Os pacientes também foram instruidos a aplicar urna fina camada da medicagáo do estudo sobre a lesáo hiperpigmentada, assegurando-se de cobrir a totalidade da lesáo incluindo as margens exteriores que se estendem até á pele pigmentada normal. Foi fornecido aos pacientes um hidratante suave para utilizagao conforme necessário e um protetor solar com SPF 30 para utilizagao diária. Além disso, os pacientes foram instruidos a evitar a exposigao a luz solar no rosto, utilizar roupa protetora. Roupa protetora e evitar a exposigao solar no rosto foi recomendada.
Os pacientes foram avallados quanto á gravi da de do melasma na linha de base e ñas semanas 1, 2, 4 e 8 de tratamento. A eficácia primária foi baseada na proporgäo de pacientes que tiveram urna avaliagäo dos investigadores quanto ao sucesso do tratamento, definido como o desaparecimento de melasma no final do periodo de tratamento de oito semanas. A maioria dos pacientes inscritos nos dois estados era caucasiano (aproximadamente 66 %) e do sexo feminino (aproximadamente 9 8 %) . Foi demonstrado que o creme TRI-LUMA®' é significativamente mais eficaz do que quaisquer outras combinagoes dos ingredientes ativos.
Os pacientes experimentaran! urna melhoria no seu melasma com a utilizagäo do creme TRI-LUMA® täo cedo como as 4 semanas . Contado, entre 7 pacientes que apresentaram eliminagao no final das 4 semanas de tratamento com o creme TRI-LUMA®, 4 deles näo manteve a remissao depois de 4 semanas de tratamento adicionáis.
Depois de 8 semanas de tratamento com o fármaco do estudo, os pacientes entraram num periodo de extensáo aberto no qual o creme TRI-LUMA® foi dado rruma base conforme necessário para o tratamento de melasma. Nos estudos, depois de 8 semanas de tratamento com o creme TRI-LUMA®, a maioria dos pacientes apresentou pelo menos alguma melhoria, Alguns apresentaram urna eliminagao completa das suas manchas escuras (38 % num estudo e 13 % noutro). Na maioria dos paciente tratados com creme TRI-LUMA®, o seu melasma voltou. depois do tratamento. Os periodos de remissao pareceram reduzir-se entre cursos de tratamento progressives. Adicionalmente, poucos pacientes mantiveram urna eliminagao completa do melasma (aproximadamente 1 a 2 %) . QUADRO 2
Avaliagäo dos investigadores do sucesso de tratamento* no final de 8 semanas de tratamento
Creme TRI-LUMA® HQ+RA FA+RA FA+HQ
Estudo N,° 1 Numero de pacientes 85 83 85 85 Número de sucessos 32 12 0 3
Proporgäo de suc.essos 38% 15% 0% 4% valor de P <0,001 <0,001 0,001
Estudo N.° 2 Número de pacientes 76 75 7 6 78 Número de sucessos 10 331
Proporgäo de sucessos 13% 4% 4% 1% valor de P# 0,045 0,042 0,005 *0 sucesso do tratamento foi definido como pontuagäo de gravidade de melasma de zero (lesoes de melasma asentas de pigmentagao). #0 valor de P é das estatisticas de qui-quadrado de
Cochran-Mantel-Haenszel controladas pelo investigador combinado e comparando o creme TRI-LUMA® com outros grupos de tratamento.
Com base na gravidade do melasma no inicio do ensaio, 161 pacientes foram avallados para melhoria no dia 56 de tratamento. 61 % (99 pacientes) experimentaram uma melhoria dos síntomas de "moderados" a "leve" ou "eliminados" e 68 % (25) mostraram melhoria de "grave" para "leve" ou "eliminado" ao longo do período de tratamento de 8 semanas como mostrado no QUADRO 3. QUADRO 3
Avaliagäo dos investigadores quanto ä alteragäo na gravidade do melasma desde a linha de base até ao dia 56 de tratamento (resultados combinados _dos estudos 1 e 2)_ Número (%) de pacientes no dia 56a
Linha de base -Eliminado13 Leveb Moderado13 Grave13 Ausente
Classificagao N n(%) N(%) N(%) N(%) N(%) de gravidade
Moderado 124 36 (29) 63 (51) 18 (16) 0(0) 7 (6 %)
Creme Tri-Luma® N=1 61
Grave 37 6(16) 19(51) 9 (24) 2(5) 1 (3 %) a Avaliagäo baseada nos pacientes com pontuagöes de gravidade ao dia 56. As percentagens säo baseadas no número total na populagäo do grupo de tratamento. ° Näo incluí pacientes que apresentaram eliminagäo antes do dia 56 ou estavam ausentes da avaliagao do dia 56. Escala de avaliagao: Eliminado (lesöes de melasma aproximadamente equivalentes ä pele circundante normal ou com hiperpigmentagäo residual mínima); Leve (ligeiramente mais escuro que a pele normal circundante); Moderado (moderadamente mais escuro que a pele normal circundante); Grave (marcadamente mais escuro que a pele normal circundante).
EXEMPLO III
REAQÖES ADVERSAS EM SERES HUMANOS
Num estudo de teste de manchas para determinar o potencial de sensibilizagao em 221 voluntários saudáveis, tres voluntários desenvolveram reaqoes de sensibilidade ao creme TRI-LUMA® ou os seus componentes.
Nos ensaios clínicos controlados, eventos adversos foram monitorizados nos 161 pacientes que utilizaram o creme TRI-LUMA® urna vez ao dia durante um período de tratamento de 8 semanas. Existiram 102 (63 %) pacientes que experimentaran! pelo menos um evento adverso relacionado com o tratamento durante estes estudos. Os eventos mais frequentemente relatados foram eritema, descamacao, ardor, secura e prurido no sitio de aplicagáo. A maioria destes eventos foram leves a moderados na gravidade. Eventos adversos relatados por pelo menos 1 % dos pacientes e julgados pelos investigadores como sendo razoavelmente relacionados com o tratamento com o creme TRI-LUMA® a partir dos estudos clínicos controlados estäo resumidos (em ordern decrescente de frequéncia) como se segue: QUADRO 4
Incidencia e frequéncia dos eventos adversos relacionados com o tratamento com o creme TRI-LUMA® em pelo menos 1 % ou mais dos pacientes (N=161)
Evento adverso Número (%) de pacientes
Eritema 66 (41%)
Descamagäo 61 (38%)
Ardor 29 (18%)
Secura 23 (14%)
Prurido 18 (11%)
Acne 8 (5%) Parestesia 5 (3%) Telangiectasia 5 (3%) Hiperestesia 3 (2%) Alteragöes da pigmentagäo 3 (2%) Irritagäo 3 (2%) Pápulas 2 (1%) Erupgäo semelhante a acne 1 (1%) Rosacea 1 (1%)
Boca seca 1 (1%) Erupgäo 1 (1%) Vesículas 1 (1%)
Num estudo de seguranga a longo prazo aberto, os pacientes que tiveram tratamento cumulativo de melasma com o creme TRI-LUMA* durante 6 meses mostraram um padräo semelhante de eventos adversos como nos estucos de 8 semanas. As seguintes reagdes adversas locáis foram relatadas de forma näo frequente com corticosteroides tópicos. Elas podem ocorrer mais frequentemente com a utilizagäo de curativos oclusivos, especialmente com corticosteroides de potencia mais elevada. Estas reagdes estäo listadas numa ordern de ocorréncia decrescente aproximada: ardor, prurido, irritagáo, secura, foliculite, erupgöes acneiformes, hipopigmentagao, dermatite perioral, dermatite de contacto alérgica, infegäo secundária, atrofia cutánea, estrías e miliária. A descrigáo anterior foi apresentada apenas para os propósitos de ilustragáo e nao se destina a limitar a invengáo a forma precisa divulgada, mas sim pelas reivindicagöes a mesma.
DOCUMENTOS REFERIDOS NA DESCRIQÄO
Esta lista de documentos referidos pelo autor do presente pedido de patente foi elaborada apenas para informagao do leitor. Nao é parte integrante do documento de patente europeia. Nao obstante o cuidado na sua elaboragäo, o IEP nao assume qualquer responsabilidade por eventuais erros ou. omissoes.
Documentos de patente referidos na descrigao • US 5538737 A [0005] • US 5656672 A [0006] • US 5660837 A [0007] • US 5976555 A [0008] • US 6080393 A [0010] • US 6013271 A [0037] • US 6267985 B [0037] • US 4992478 A [0037] » US 5645854 A [0037] • US 5811111 A [0037] » US 5851543 A [0037]
Documentos de nao patente citados na descrigao ® CLARK et al. Dermatology Times, 2002, vol. 23 (5), 1 [0009] • MCCUTCHEON' S. Detergents and. Emulsifiers. 198 6 [0031] [0032] • MCCUTCHEON'S. Functional Materials. 1992 [0031] [0032] • CTFA Cosmetic Ingredient Handbook. 1992 [0036]
Claims (23)
- REIVINDICALES 1. Um método para fabricar urna composigao medicada tópica para aplicagao tópica, a composigao sendo urna emulsao que compreende água e, como ingredientes ativos, acetonida de fluocinolona, hidroquinona e tretinoína, o método compreendendo: (a) misturar água e pelo menos um composto hidrofílico para formar urna fase aguosa; (b) misturar pelo menos dois compostos hidrofóbicos para formar urna fase nao aquosa; (c) combinar a fase aquosa e fase nao aquosa para formar urna mistura bifásica na ausencia de urn emulsionante; (d) misturar acetonida de fluocinolona e tretinoína na mistura da etapa (c); (e) misturar pelo menos um emulsionante na mistura da etapa (d), ou durante a etapa (d); e (f} homogeneizar a mistura da etapa (e) para formar a emulsao; em que hidroquinona é adicionada na etapa (d) ou depois de adicionar o pelo menos um emulsionante, 2. 0 método de acordo com a reivindicagao 1, em que a dita etapa (a) , etapa (b) ou ambas sao realizadas a urna temperatura maior que a temperatura ambiente para dar urna fase aquecida. 3. 0 método ele acordo com a reivindicagao 2, em que a dita fase aquecida é arrefecida antes da dita etapa (c) de combinagäo. 4. 0 método de acordo com a reivindicagao 2, em que a dita mistura bifásica aquecida é arrefecida antes da etapa (d) . 5. 0 método de acordo com ¿a reivindicagao 1, em que a dita hidroquinona é adicionada depois da adigao do dito pelo menos um emulsionante na etapa (e).
- 6. O método de acordo com a reivindicagäo 1, que compreende adicionalmente a adigäo de metabissulfito de sodio á dita mistura da etapa (e) depois da adigäo do dito pelo menos um emulsionante. 7. 0 método de acordo com a reivindicagäo 1, em que a dita água e o dito pelo menos um composto hidrofílico sao misturados a urna temperatura elevada. 8. 0 método de acordo com a reivindicagäo 1, em que os ditos píelo menos dois compostos hidrofóbicos sao misturados a urna temperatura elevada. 9. 0 método de acordo com a reivindicagäo 7 ou 8, em que a dita temperatura elevada näo é superior a 80 °C.
- 10. O método de acordo com a reivindicagäo 1, em que a dita água e o dito pelo menos um composto hidrofílico säo misturados a urna temperatura näo superior a 80 °C, e os ditos pelo menos dois compostos hidrofóbicos sao misturados a urna temperatura näo superior a 80 °C.
- 11. O método de acordo com a reivindicagäo 10, em que a dita mistura da etapa (c) é arrefecida antes da adigäo da dita acetonida de fluocinolona e da dita tretinoina na etapa (d).
- 12. O método de acordo com a reivindicagäo 10, em que a dita mistura da etapa (d) é arrefecida enquanto o dito pelo menos um emulsionante é misturado na dita mistura.
- 13. O método de acordo com a reivindicagäo 10, em que a dita hidroquinona é adicionada na etapa (d) depois do arrefecimento da dita mistura.
- 14. O método de acordo com a reivindicagäo 10, em que a dita hidroquinona é adicionada na etapa (e) depois de o dito pelo menos um emulsionante ser misturado na dita mistura. 15. 0 método de acordo com a reivindicagáo 14, em que a dita mistura é arrefecida e metabissulfito de sodio é adicionado enquanto a dita mistura está a arrefecer. 16. 0 método de acordo com a reivindicagáo 1, em que a fase aquosa compreende água, silicato de magnésio e aluminio e hidroxitolueno butilado. 17. 0 método de acordo com a reivindicagáo 1, em que o emulsionante é estearato de glicerilo, estearato de polietilenoglicol (PEG) ou urna combinagáo dos mesmos.
- 18. Urna composigäo medicada tópica, que compreende 0,01 % em peso de acetonida de f luocinolona: 4 % em peso de hidroquinona; 0,05 % em peso de tretinoína; 0,04 % em peso de hidroxitolueno butilado; 4 % em peso de álcool cetílico; 0,05 % em peso de ácido cítrico; 4 % era peso de glicerina; 3 % em peso ele silicato de magnésio e aluminio; 5 % em peso de metil gluceth; 0,18 % em peso de metilparabeno; 3,5 % em peso de estearato de glicerilo, estearato de polietilenoglicol (PEG) ou urna combinagáo dos mesmos, 0,02 % em peso de propilparabeno, 0,2 % em peso de metabissulf ito de sodio, 3 % em peso de ácido esteárico e 4 % em peso de álcool estearílico.
- 19. Um método de acordo com a reivindicagáo 1 em que: (a) a dita composigäo aquosa que compreende água e pelo menos um composto hidrofílico é preparada enquanto se aquece a urna temperatura nao superior a 80 °C; (b) a dita composigäo náo aquosa que compreende pelo menos dois compostos hidrofóbicos é preparada enquanto se aquece a urna temperatura náo superior a 80 °C; (c) as etapas (a) e (b) e a mistura das composigóes aquosa e nao aquosa sao realizadas na ausencia de um emulsionante.
- 20. O método de acordo com. a reivindicagao 19, em. que a etapa (c) compreende adicionalmente o arrefecimento da mistura.
- 21. O método de acordo com a reivindicagao 19, que compreende adicionalmente o arref ecimento da mistura após a adigäo de pelo menos um emulsionante.
- 22. O método de acordo com a reivindicagao 19, que compreende adicionalmente o arrefecimento da mistura antes da adigäo da hidroquinona. (19)(12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 9106 <2006 01> A01N 25100 <2006 01> 13.01.2016 Bulletin 2016/02 A61K 31I05<200601> A61K 8163 <2006 01> A61K 8I67<2006 01> A61K 8169 <2006 01> (21) Application number: 03776536.9 A61K 31I58<2°°°<"> A61Q 19Ι02<2°°°<"> (22) Date of filing- 24.10.2003 (86) International application number: PCT/US2003/033876 (87) International publication number: WO 2004/037201 (06.05.2004 Gazette 2004/19) (54) TOPICAL SKIN CARE COMPOSITION TOPISCHE HAUTPFLEGEZUSAMMENSETZUNG COMPOSITION DE SOIN POUR LA PEAU A APPLICATION TOPIQUE (84) Designated Contracting States: · ROTH, Jerry, AT BE BG CH CY CZ DE DK EE ES Fl FR GB GR c/o HILL DERMACEUTICALS, INC. HU IE IT LI LU MC NL PT RO SE Sl SK TR Sanford, FL 32773 (US) (30) Priority: 25.10.2002 US 280483 (74) Representative: Brasnett, Adrian Hugh et al Mewburn Ellis LLP (43) Date of publication of application: City Tower 17.08.2005 Bulletin 2005/33 40 Basinghall Street London EC2V 5DE (GB) (60) Divisional application: 15189356.7 (56) References cited: WO-A1-97/03648 US-A- 3 856 934 (73) Proprietor: Galderma S.A. US-A- 4 489 071 US-A- 5 538 737 6330 Cham (CH) US-A- 5 656 672 US-A- 5 660 837 US-A- 5 976 555 US-A- 6 080 393 (72) Inventors: • PUGLIA, Nancy, · CLARK J: "CREAM COMBO CALLED MELASMA c/o HILL DERMACEUTICALS, INC. ’DRUG OF CHOICE’", DERMATOLOGY TIMES, Sanford, FL 32773 (US) ADVANSTAR COMMUNICATIONS, CLEVELAND, • RAMIREZ, Rosario, OH, US, vol. 23, no. 5, 1 May 2002 (2002-05-01), c/o HILL DERMACEUTICALS, INC. page 1/02, XP008062911, ISSN: 0196-6197 Sanford, FL 32773 (US) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). Printed by Jouve, 75001 PARIS (FR) Description FIELD OF THE INVENTION [0001] The invention relates generally to a method of making a medicated skin treating composition. BACKGROUND OF THE INVENTION [0002] Melasma or chloasma is a common pigmentary condition that affects primarily women in their reproductive years. Dark, mottled (hyperpigmented) patches appear on the face and neck, especially on the cheeks and forehead. Melasma is usually triggered by hormonal activity that is the result of pregnancy or birth control pills. Thus, the condition is known as the "mask of pregnancy."The condition occurs when excess melanin is deposited in the cells of the epidermis and dermis. Melasma can persist for long periods of time and often recurs with subsequent pregnancies. The condition is less common among men, who account for about 10% of all cases. [0003] Standard therapy involves depigmenting, or bleaching, the affected areas of the skin, the use of sunscreens, and avoidance of sunlight. Hydroquinone is the most popular topical depigmenting agent. Concentrations of 5%-10% hydroquinone are very effective, but can be irritating. The chemical stability of hydroquinone formulations is important because hydroquinone is easily oxidized and loses potency. The most commonly used agent usually involves a 16-week to 20-week course of therapy, and some therapies can take longer. Tretinoin (Retin-A) is another widely used therapy for melasma. [0004] Nevertheless, there remains a need in the art for a therapeutic approach that would contain several medicines for the treatment of melasma in a single composition. Moreover, it would be useful to have a therapeutic carrier, such as a cream, that would facilitate the penetration of the medicaments into the skin. [0005] U.S. Pat. No. 5,538,737 discloses a method of making a water-in-oil emulsion containing a pharmaceutically acceptable salt of an H2-antagonist. The steps include dissolving the pharmaceutically acceptable salt in an aqueous medium to form a water portion; combining the water portion with an oil portion, comprising an edible oil comprising an ester or mixed ester of glycerol and an emulsifying agent to form a water portion and oil portion matrix; then emulsifying the matrix to form the water-in-oil emulsion. [0006] U.S. Pat. No. 5,656,672 discloses a process for preparing a water-in-oil emulsion with retinal as the active ingredient. The emulsion contains an oil phase including at least one organic solvent for retinal (such as aliphatic fatty alcohols) and optional lipophilic additives; an aqueous phase containing water and optional hydrophilic additives; and an agent for emulsifying the aqueous phase in the oil phase. The oil phase and the aqueous phase are independently prepared, and the aqueous phase is incorporated into the oil phase, with subsequent addition of a phase-containing retinol and its solvent. [0007] U.S. Pat. No. 5,660,837 discloses a process for the preparation of a pharmaceutical formulation in the form of an oil-in-water emulsion. The steps of the process include of adding the emulsion-stabilizing surface active drug and an optimal conventional surfactant to a two-phase, oil-water system at room temperature; allowing the emulsion-stabilizing surface active drug to equilibrate at an interface; adding an agent giving isotonicity to the final formulation; and homogenizing by high pressure technique. [0008] U.S. Pat. No. 5,976,555 discloses skin care compositions. An oil-in-water emulsion base contains retinoids; cetearyl alcohol and cetearyl glucoside or a mixture of a polyethylene glycol ethers of stearyl alcohol; cetyl alcohol, stearyl alcohol and mixtures thereof; a light, dry absorbable oil; and substantive, emollient oils or waxes. [0009] Clark et al., Dermatology Times 23(5), page 1 (2002) describes a topical cream combining 4% hydroquinone, 0.05% tretinoin and 0.01% fluocinolone acetonide for use in treating melasma. [0010] U.S. Pat. No. 6,080,393 discloses a skin care composition comprising an oil-in-water emulsion with a therapeutically effective amount of a retinoid; wherein the oil phase comprising one or more oils, and an effective amount of at least one oil-soluble antioxidant; and wherein the composition comprises a corticosteroid. [0011] Nevertheless, there remains a need in the art for a method of making a smoother cream base for the application of therapeutic agents for the treatment of melasma, which will facilitate the penetration of the medicaments into the skin. SUMMARY OF THE INVENTION [0012] The invention provides a method of making a topical medicated composition, as defined in claim 1. [0013] The process for making the cream base entails (a) mixing the hydrophilic compounds with water to form an aqueous phase; (b) mixing the hydrophobic compounds to form a hydrophobic (non-aqueous or wax) phase; then (c) mixing the hydrophilic and hydrophobic phases with one another to form a biphasic mixture; and finally (d) adding an emulsifier to the biphasic mixture to form the emulsion. By mixing the emulsifier after the aqueous and non-aqueous phases have been mixed, the result is a smoother-textured cream that disappears on application to skin, as compared to creams made by processes where the emulsifier is added to the aqueous or non-aqueous phases earlier in the process. Because the emulsifier is added as the final step, less wax is needed in making the cream, resulting in a "thinner" hydrophilic cream that disappears faster when applied to the skin, as compared to creams made by processes where the emulsifier is added to the aqueous or non-aqueous phases earlier in the process. [0014] The cream base made by the method of interest can be a carrier for any of a variety of pharmaceutically active agents for dermatologic use. For example, anti-acne, anti-cancer, antibiotic, anti-inflammatory, hormone, anti-fungal and analgesic active agents can be incorporated into a cream base of interest. [0015] In this invention, the cream base comprises a steroid, a keratolytic agent and a depigmenting agent, wherein the steroid is fluocinolone acetonide, the keratolytic agent is tretinoin and the depigmenting agent is hydroquinone. [0016] In a more specific embodiment, the cream also includes the inactive ingredients butylated hydroxytoluene, cetyl alcohol, citric acid, glycerin, glyceryl stearate, magnesium aluminum silicate, methyl gluceth-10, methylparaben, PEG-100 stearate, propylparaben, purified water, sodium metabisulfite, stearic acid and stearyl alcohol. [0017] The cream can be Tri-Luma® Cream, which is the first approved product to combine the standard depigmenting agent, hydroquinone, with tretinoin and a topical low-potency steroid that can be applied as a single preparation. The recommended course of therapy for Tri-Luma® Cream is 8 weeks, and significant results have been seen after the first 4 weeks of treatment. Another advantage of the process of the invention is that by controlling the temperature at which the components, including hydroquinone, are added, the cream does not turn as brown, resulting in a more pleasing-colored product. DETAILED DESCRIPTION OF THE INVENTION [0018] Creams are emulsions of hydrophilic and lipophilic (hydrophobic) components. Generally, an emulsifier or surface active agent is included to enhance the mixing of the reagents resulting in a stable emulsion. [0019] The various compounds that comprise an inert carrier are generally known in the art. By "inert" is meant not having a pharmacologic activity. Typical examples of inert compounds comprising a cream base include cetyl alcohol, lanolin, glycerin, ethanol, EDTA, methyl paraben, zinc oxide, titanium dioxide, benzoic acid, carboxymethylcellulose, dimethylsulfoxide, polyethyleneglycol, petroleum, citric acid and stearic acid. [0020] The instant invention relates to a method of making a cream base asa vehicle for one or more pharmacologically active agents for dermatologic applications. The method of interest comprises a particular order of adding and mixing of the ingredients of a cream. The hydrophilic ingredients, including water, are mixed. Heating may be used to facilitate dissolving and solubility to produce a solution. The lipophilic or hydrophobic ingredients are mixed separately. Heating may be used to facilitate mixing and homogenization. [0021] The hydrophilic solution and the lipophilic solution then are mixed and blended. One or more pharmaceutically active agents then are added to the blended mixture. Then, one or more emulsifiers are added and the entire mixture blended to produce a dermatologic cream of interest. [0022] The temperatures for heating the hydrophobic and hydrophilic solutions is that sufficient to facilitate the obtention of a homogeneous solution. Generally, a lower elevated temperature with longer mixing time is preferred. The temperature also may be limited by the properties of any one of the individual ingredients therein. Generally, the temperature does not exceed about 100°C. Preferably, the temperature does not exceed about 90°C or about 80°C or about 70°C or about 60°C. Generally, the temperature of heating need not be exact, at least within the accuracy of standard temperature measurement means. [0023] The hydrophobic and hydrophilic solutions need not be heated to the same temperature. Having the same temperature facilitates the mixing of the two solutions. If the solutions are at different temperatures, the warmer solution is cooled to the temperature of the cooler solution prior to mixing. [0024] The blended mixture optionally may be cooled prior to mixing in the one or more pharmacologically active agent or agents. The physical properties of the active agents may dictate a need for cooling. [0025] Following that step and blending, one or more emulsifiers are added. The mixture is blended thoroughly to produce a cream of interest. If elevated, the temperature can be reduced during the blending. [0026] As to the lipophilic ingredients, as known in the art, oils may be derived from animals, plants, nuts, petroleum etc. Those derived from animals, plant seeds and nuts are similar to fats and consequently, may contain a significant number of polar acid and/or ester groups. Alternatively, oils derived from petroleum are usually aliphatic or aromatic hydrocarbons that are essentially free of polar substitution. [0027] Oil-based products which can be used include hydrocarbons or mineral fats obtained by the distillation of petroleum (petroleum jelly); vegetable oils and liquid triglycerides; animal fats or solid, natural triglycerides; and waxes or solid ethers of fatty acids, such as stearic acid and palmitic acid, and organic alcohols. Lanolin or wool fats made of fatty acids and cholesterol esters; and cetyl and stearyl alcohols, which are solid alcohols obtained by hydrogenation of their respective acids are also useable. Amphoteric compounds such as soaps or salts of fatty acids that may be acidic or basic depending on whether the lipophilic group is anionic or cationic, sulfated alcohols which are semi-synthetic substances and synthetic surface active agents are known in the art and also can be used. Glycerin is obtained from fats and, due to the hydrophobicity thereof, has the property of extracting water from the surface of mucosa or denuded skin. Glycerin does not damage intact skin because of having hydrophilic properties, and is a useful humectant. [0028] Other materials that may be used in a topical preparation of interest include liquid alcohols, liquid glycols, liquid polyalkylene glycols, liquid esters, liquid amides, liquid protein hydrosylates, liquid alkylated protein hydrosylates, liquid lanolin and lanolin derivatives and other like materials. Particular examples include monohydric and polyhydric alcohols, e.g ., ethanol, isopropanol, glycerol, sorbitol, 2-methoxyethanol, diethylene glycol, ethylene glycol, hexylene glycol, mannitol, cetyl alcohol and propylene glycol; ethers such as diethyl or dipropyl ether; polyethylene glycols and methox-ypolyoxyethylenes; carbowaxes having molecular weights ranging from 200 to 20,000; polyoxyethylene glycerols; polyoxyethylene; sorbitols; and stearoyl diacetin. [0029] The topical carriers often include both an alcohol and water so as to accommodate lipophilic and hydrophilic components. Other ingredients include buffers, such as sodium hydroxide, sodium citrate or tetrasodium EDTA; excipients; fragrances such as menthol; opacifiers such as zinc oxide, magnesium aluminum silicate and titanium dioxide; preservatives such as dichlorobenzyl alcohol, benzoic acid, methylparaben and phenyl carbinol; antioxidants; gelling agents such as petrolatum and mineral wax; thickening agents such as carboxymethylcellulose; stabilizers; surfactants; emollients; coloring agents and the like. [0030] In addition, the topical carrier may include a penetration enhancer defined as a material that increases the permeability of the skin to one or more active agents so as to allow for cutaneous delivery of a pharmacologically active agent. Various compounds for enhancing the permeability of skin are known in the art. For example, dimethylsulfoxide (DMSO), dimethylformamide(DMF)and Ν,Ν-dimethylacetamide(DMA),decylmethylsulfoxide, polyethyleneglycol mon-olaurate and the 1-substituted azacycloheptan-2-ones. [0031] A number of different emulsifiers or surfactants can be used to prepare a topical preparation of interest. Nonlimiting examples of amphoteric surfactants useful in the compositions of the present invention are disclosed in Mc-Cutcheon’s, "Detergents and Emulsifiers", North American edition (1986) and McCutcheon’s, "Functional Materials", North American edition (1992). Surfactants that can used are the betaines, sultaines and hydroxysultaines. Examples of betaines include the higher alkyl betaines, such as coco dimethyl carboxymethyl betaine, lauryl dimethyl carboxymethyl betaine, lauryl dimethyl alphacarboxyethyl betaine, cetyl dimethyl carboxymethyl betaine, cetyl dimethyl betaine, lauryl bis-(2-hydroxyethyl) carboxymethyl betaine, steryl bis-(2-hydroxypropyl) carboxymethyl betaine, oleyl dimethyl gamma-carboxypropyl betaine, lauryl bis-(2-hydroxypropyl)alpha carboxyethyl betaine, coco dimethyl sulfopropyl betaine, stearyl dimethyl sulfopropyl betaine, stearyl betaine, lauryl dimethyl sulfoethyl betaine, lauryl bis-(2-hydroxyethyl) sulfopropyl betaine, amidobetaines, amidosulfobetaines, oleyl betaine and cocamidopropyl betaine. Examples of sultaines and hydroxysultaines include cocamidopropyl hydroxysultaine. Examples of other amphoteric surfactants are alkyliminoac-etates, iminodialkanoates and aminoalkanoates. [0032] Exam pies of anionic surfactants also are disclosed in McCutcheon’s, "Detergents and Emulsifiers", North American edition (1986) and McCutcheon’s, "Functional Materials", North American edition (1992). Examples include the alkoyl isothionates, the alkyl and alkyl ether sulfates, such as, ammonium cocoyl isothionate, sodium cocoyl isothionate, sodium lauroyl isothionate, sodium stearoyl isothionate and mixtures thereof, the sarcosinates, such as sodium lauroyl sarcosinate, sodium cocoyl sarcosinate and ammonium lauroyl sarcosinate, sodium lauryl sulfate, ammonium lauryl sulfate, ammonium cetyl sulfate, sodium cetyl sulfate, sodium stearyl sulfate, ammonium cocoyl isethionate, sodium lauroyl isethionate, sodium lauroyl sarcosinate and mixtures thereof. [0033] Other emulsifiers includes tricetareth-4-phosphate, sodium laureth-4-phosphate oroleth-3. [0034] Examples of non-ionic emulsifiers include sorbitan monostearate, glyceryl monostearate, polysorbates, polyethylene derivatives of fatty alcohols, polyoxyethylene ethers of fatty alcohols, such as polyoxyethylene cetyl ether, polyoxyethylene oleyl ether, polyoxyethylene nonylphenyl ether and the like, sorbitan stearate, glyceryl stearate, C12-C18 fatty alcohols, esters and ethers thereof, aliphatic fatty alcohols such as cetyl alcohol or stearyl alcohol or a mixture of the two, fatty alcohols or a-diols oxyethylenated or polyglycerolated such as oleyl alcohol polyoxyethylenated with 10 moles of ethylene oxide, 1,2-octadecanediol polyglycerolated with 2 or 7 moles of glycidol, cyclic fatty alcohols, glycol esters of fatty acids such as ethylene glycol stearate, the monostearates or distearates of glycerol, the polyethylene glycol esters of fatty acids such as polyethylene glycol stearates, the fatty esters of sorbitan oxyethylenated or not and sold under the trade name of Tweens or Spans, the fatty esters of sucrose, the fatty esters of glucose derivatives such as methylglucoside sesqu¡stearate and methylglucoside sesqu¡stearate polyoxyethylenated with 20 moles of ethylene oxide, Arlacel 165 and Myrj 52, fatty alcohols having 10 to 20 carbon atoms, fatty alcohols having 10 to 20 carbon atoms condensed with 2 to 20 moles of ethylene oxide or propylene oxide, alkyl phenols with 6 to 12 carbon atoms in the alkyl chain condensed with 2 to 20 moles of ethylene oxide, mono-fatty acid and di-fatty acid esters of ethylene oxides, monofatty acid and di-fatty acid esters of ethylene glycol wherein the fatty acid moiety contains from 10 to 20 carbon atoms, diethylene glycol, polyethylene glycols of molecular weight 200 to 6000, propylene glycols of molecular weight 200 to 3000, glycerol, sorbitol, sorbitan, polyoxyethylene sorbitol, polyoxyethylene sorbitan and hydrophilic wax esters, polyoxyethylene fatty alcohol ethers, polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid esters, sorbitan fatty acid esters, polyoxyethylene glycol fatty acid esters and polyol fatty acid esters. [0035] Examples of cationic emulsifiers include quaternized ammonium bromide and chloride salts, cetyltrimethylam-monium chloride, benzalkonium chloride and cetyl pyridinium chloride, aliphatic amines having fatty chains, e.g., oleylamine anddihydroabietylamine; quaternary ammonium compounds, e.g., lauryldimethylbenzyl ammonium chloride, amides derived from amino alcohols, e.g., N-aminoethyl oleylamide, n-(stearoyl-colamino-formylmethyl) pyridinium chloride, N-soya-N-ethyl morpholinium ethosulphate, alkyl dimethyl benzyl ammonium chloride, di-isobutylphenoxyethox-yethyl dimethyl benzyl ammonium chloride, cetyl pyridinium chloride, N-(stearoyl-colamino- formylmethyl) pyridinium chloride, N-soya-N-ethyl morpholinium ethosulfate, alkyl dimethyl benzyl ammonium chloride, (diisobutyl-phenoxy-ethoxy) ethyl dimethyl benzyl ammonium chloride, PG-dimonium chloride phosphate, stearamidopropyl ethyldimonium ethosulfate, stearamidopropyl dimethyl (myristyl acetate) ammonium chloride, stearamidopropyl dimethyl cetearyl ammonium tosylate, stearamidopropyl dimethyl ammonium chloride, stearamidopropyl dimethyl ammonium lactate, ammonium halides, more especially chlorides and bromides, such as alkyl trimethylammonium chlorides, dialkyl dimethy-lammonium chlorides and trialkyl methylammonium chlorides, for example, stearyl trimethylammonium chloride, distearyl dimethylammonium chloride, lauryl dimethylammonium chloride, lauryl dimethyl benzylammonium chloride and tricetyl methylammonium chloride, quaternized protein hydrolyzatesor protein hydrolyzatesderivatized with amino groups which are marketed, for example, under the names Lamequat® and Mackpro®, stearamidopropyl PG-dimonium chloride phosphate, stearamidopropyl ethyldimonium ethosulfate, stearamidopropyl dimethyl (myristyl acetate) ammonium chloride, stearamidopropyl dimethyl cetearyl ammonium tosylate, stearamidopropyl dimethyl ammonium chloride, and stearamidopropyl dimethyl ammonium lactate. [0036] The compositions of the instant invention can comprise a wide range of additional components. The "CTFA Cosmetic Ingredient Handbook", Second edition, 1992, describes a wide variety of cosmetic and pharmaceutical ingredients commonly used in the skin care industry, which are suitable for use in the compositions of the instant invention. Examples offunctional classes of ingredients are absorbents, abrasives, anti-acne agents, anticaking agents, antifoaming agents, antimicrobial agents, antioxidants, binders, biological additives, buffering agents, bulking agents, chelating agents, chemical additives, colorants, cosmetic astringents, cosmetic biocides, denaturants, drug astringents, external analgesics, film formers, fragrance components, humectants, opacifying agents, pH adjusters, platicizers, preservatives, propellants, reducing agents, skin bleaching agents, skin conditioning agents (emollients and humectants), skin protectants, solvents, foam boosters, hydrotropes, solubilizing agents, suspending agents (nonsurfactant), sunscreen agents, ultraviolet light absorbers and viscosity increasing agents (aqueous and nonaqueous). [0037] The various starting materials for making a topical preparation are known in the art and reference can be made to known treatises, as well as U.S. Patent Nos. 6,013,271; 6,267,985; 4,992,478; 5,645,854; 5,811,111; and 5,851,543. [0038] The pharmaceutically active agents in the dermatological preparations of interest are fluocinolone acetonide, hydroquinone, and tretinoin. [0039] The amounts of the inert ingredients and active agent(s) in the dermatologic preparation of interest generally are known in the art. It is within the ambit of the artisan to derive particular amounts of the ingredients to obtain a cream of interest. [0040] The particular amount of any one ingredient used is not substantially critical and the amounts used are at the accuracy of the measuring or dispensing means known in the art. [0041] In one embodiment of the invention, approximately 344.8 kg of water, 15.0 kg magnesium aluminum silicate, and 0.2 kg butylated hydroxytoluene are first combined and mixed at 75-80°C to form the aqueous phase. The mixing can be by side scrape agitation at a fixed speed. The resulting aqueous phase is a suspension. [0042] Second, approximately 20.0 kg of cetyl alcohol, 15.0 kg of stearic acid, 20.0 kg of stearyl alcohol, 25.0 kg of methyl gluceth-10, 0.9 kg of methylparaben, 0.1 kg of propylparaben, and 20.0 kg of glycerin are mixed together at medium speed at about 75-80°C to form the non-aqueous phase. The mixing can be at medium speed in a Lightnin® mixer. The resulting non-aqueous phase is a suspension. The second step can be performed before, after or concurrently with the first step. [0043] Then, the non-aqueous phase is added to the aqueous phase and the combined biphasic mixture is cooled to a temperature in the range of 68°C to 72°C, or about 70°C, after which about 17.5 kg of Arlacel® 165, 0.25 kg tretinoin and 0.050 kg fluocinolone acetonide are added and stirred with cooling. When the mixture reaches 60°C, 0.25 kg citric acid is added with mixing and cooling. When the temperature reaches 55°C, 20.0 kg hydroquinone is added with mixing and cooling. When the temperature reaches about 50°C, the mixture is homogenized with a homogenizer, with continued cooling. When the mixture reaches 45°C, 1.0 kg of sodium metabisulfite is added with stirring and cooling. Typically, the sodium metabisulfite is added about 30 minutes after the addition of the hydroquinone. The mixing can be at fixed speed in a side scrape agitator. The resulting composition of matter is an emulsion, i.e., a cream. [0044] The presence of sodium metabisulfite in the cream prevents the oxidation of hydroquinone. The addition of sodium metabisulfite as the cream is cooling advantageously results in a well-mixed composition of matter, with the sodium metabisulfite evenly mixed throughout the cream and preventing the oxidation of the hydroquinone throughout the cream. Another advantage of the process of the invention is that by controlling the temperature at which the com ponents, including hydroquinone, are added, the cream does not turn as brown, resulting in a more pleasing-colored product. [0045] The addition of the emulsifier following the mixing of the non-aqueous and aqueous phases is advantageous for the making of the pharmaceutical composition of the invention. When a standard technique of adding the emulsifier to the non-aqueous phase and then mixing with the aqueous phase was used, no emulsion formed. However, when the emulsifier was added to the mixture of the non-aqueous and aqueous phases with cooling, according to the method of the invention, a useful emulsion did form. This emulsion formed even though the relative proportion of the non-aqueous and aqueous phases according to the successful method of the invention was the same as when an emulsion did not form using the standard technique of adding a non-aqueous phase containing an emulsifier to an aqueous phase. [0046] The resulting TRI-LUMA® Cream contains fluocinolone acetonide, hydroquinone and tretinoin in a hydrophilic cream base for topical application. Each gram of TRI-LUMA® Cream contains as active ingredients, fluocinolone acetonide 0.01% (0.1 mg), hydroquinone 4% (40 mg), and tretinoin 0.05% (0.5 mg), and as inactive ingredients, butylated hydroxytoluene, cetyl alcohol, citric acid, glycerin, glyceryl stearate, magnesium aluminum silicate, methyl gluceth-10, methylparaben, PEG-100 stearate, propylparaben, purified water, sodium metabisulfite, stearic acid, and stearyl alcohol, see TABLE 1. TABLE 1 500 kg Batch 800 kg Batch Ingredient Quantity Quantity Formula magnesium aluminum silicate NF 15 kg 24 kg 3.00% butylated hydroxytoluene NF 200 g 320 g 0.04% cetyl alcohol NF 20 kg 32 kg 4.00% stearic acid NF 15 kg 24 kg 3.00% stearyl alcohol NF 20 kg 32 kg 4.00% methylparaben NF 900 g 1,440g 0.18% propylparaben NF 100g 160g 0.02% Arlacel® 165 [glycerol stearate and PEG-100 stearate 17.5 kg 28 kg 3.50% glycerol monostearate] methyl gluceth-10 25 kg 40 kg 5.00% glycerin USP 20 kg 32 kg 4.00% tretinoin USP 250 g 400 g 0.05% fluocinolone acetonide USP 50 g 80 g 0.01% citric acid USP 250 g 400 g 0.05% hydroquinone USP 20 kg 32 kg 4.00% sodium metabisulfite NF 1kg 1.6 kg 0.20% purified water USP 344.8 kg 551.6 kg 68.95% TOTAL 100.00% [0047] Fluocinolone acetonide is a synthetic fluorinated corticosteroid for topical dermatological use and is classified therapeutically as an anti-inflammatory. It is a white crystalline powder that is odorless and stable in light. The chemical name for fluocinolone acetonide is (6,11,16)-6,9-difluoro-11,21-dihydroxy-16,17-[(1-methylethylidene)bis(oxy)]-pregna-1 ,-4-diene-3,20-dione. The molecular formula is C24H30F2O6 and molecular weight is 452.50. [0048] Hydroquinone is classified therapeutically as a depigmenting agent. It is prepared from the reduction of p-ben-zoquinone with sodium bisulfite. It occurs as fine white needles that darken on exposure to air. The chemical name for hydroquinone is 1,4-benzenediol. The molecular formula is C6H602 and molecular weight is 110.11. [0049] Tretinoin is all-frans-retinoic acid formed from the oxidation of the aldehyde group of retinene to a carboxyl group. It is highly reactive to light and moisture. Tretinoin is classified therapeutically as a keratolytic. The chemical name for tretinoin is: (a//-£)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoic acid. The molecular formula is C2oH2802 and molecular weight is 300.44. [0050] TRI-LUMA™ Cream is typically supplied in 30 g aluminum tubes, NDC 0299-5950-30, and is stored at controlled room temperature 68 to 77°F (20-25 °C). [0051] The details of one or more embodiments of the invention are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing ofthe present invention, the preferred methods and materials are nowdescribed. Otherfeatures, objects, and advantages of the invention will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. [0052] The following EXAMPLES are presented to more fully illustrate the preferred embodiments ofthe invention. These EXAMPLES should in no way be construed as limiting the scope ofthe invention, as defined by the appended claims. EXAMPLE I HUMAN PHARMACOKINETICS [0053] Percutaneous absorption of unchanged tretinoin, hydroquinone and fluocinolone acetonide into the systemic circulation of two groups of healthy volunteers (Total n=59) was found to be minimal following 8 weeks of daily application of 1 g (Group I, n=45) or 6 g (Group II, n=14) of TRI-LUMA® Cream. [0054] For tretinoin quantifiable plasma concentrations were obtained in 57.78% (26 out of 45) of Group I and 57.14% (8 out of 14) of Group II subjects. The exposure to tretinoin as reflected by the Cmax values ranged from 2.01 to 5.34 ng/mL (Group I) and 2.0 to 4.99 ng/mL (Group II). Thus, daily application of TRI-LUMA® Cream resulted in a minimal increase of normal endogenous levels of tretinoin. The circulating tretinoin levels represent only a portion of total tretinoin-associated retinoids, which would include metabolites of tretinoin and that sequestered into peripheral tissues. [0055] For hydroquinone quantifiable plasma concentrations were obtained in 18% (8 out of 44) Group I subjects. The exposure to hydroquinone as reflected by the Cmax values ranged from 25.55 to 86.52 ng/mL. All Group II subjects (6g dose) had undetectably low post-dose plasma concentrations. [0056] For fluocinolone acetonide, Groups I and II subjects had undetectably low post-dose plasma concentrations. [0057] The following tests may be helpful in evaluating patients: (a) ACTH or cosyntropin stimulation tests; (b) the A.M. plasma cortisol test; and (c) the urinary free cortisol test. EXAMPLE II HUMAN CLINICAL STUDIES [0058] Two efficacy and safety studies were conducted in 641 melasma patients between the ages of 21 to 75 years, having skin phototypes l-IV and moderate to severe melasma ofthe face. TRI-LUMA® Cream was compared with three possible combinations of two ofthe three active ingredients [(1) hydroquinone 4% (HQ) + tretinoin 0.05% (RA); (2) fluocinolone acetonide 0.01% (FA) + tretinoin 0.05% (RA); (3) fluocinolone acetonide 0.01% (FA) + hydroquinone 4% (HQ)], contained in the same vehicle as TRI-LUMA® Cream. [0059] The patients were instructed to apply their study medication each night, after washing their face with a mild soapless cleanser, for 8 weeks. The patients were also instructed to apply a thin layer of study medication to the hyperpigmented lesion, making sure to cover the entire lesion including the outside borders extending to the normal pigmented skin. The patients were provided a mild moisturizer for use as needed and a sunscreen with SPF 30 for daily use. Moreover, the patients were instructed to avoid sunlight exposure to the face, wear protective clothing Protective clothing and avoidance of sunlight exposure to the face was recommended. [0060] The patients were evaluated for melasma severity at baseline and at weeks 1,2,4, and 8 of treatment. Primary efficacy was based on the proportion of patients who had an investigators’ assessment of treatment success, defined as the clearing of melasma at the end of the eight-week treatment period. The majority of patients enrolled in the two studies were white (approximately 66%) and female (approximately 98%). TRI-LUMA® Cream was demonstrated to be significantly more effective than any ofthe other combinations ofthe active ingredients. [0061] Patients experienced improvement of their melasma with the use of TRI-LUMA® Cream as early as 4 weeks. However, among 7 patients who had clearing at the end of 4 weeks of treatment with TRI-LUMA® Cream, 4 of them did not maintain the remission after an additional 4 weeks of treatment. [0062] After 8 weeks of treatment with the study drug, patients entered into an open-label extension period in which TRI-LUMA® Cream was given on an as-needed basis for the treatment of melasma. In studies, after 8 weeks of treatment with TRI-LUMA® Cream, most patients had at least some improvement. Some had their dark spots clear up completely (38% in one study and 13% in another). In most patients treated with TRI-LUMA® Cream, their melasma came back after treatment. The remission periods appeared to shorten between progressive courses of treatment. Additionally, few patients maintained complete clearing of melasma (approximately 1 to 2%). TABLE 2 Investigators’ Assessment of Treatment Success* At the End of 8 Weeks of Treatment TRI-LUMA® Cream HQ+RA FA+RA FA+HQ Study No. 1 Number of Patients 85 83 85 85 Number of Successes 32 12 0 3 Proportion of Successes 38% 15% 0% 4% P-value <0.001 <0.001 0.001 Study No. 2 Number of Patients 76 75 76 78 Number of Successes 10 3 3 1 Proportion of Successes 13% 4% 4% 1% P-value# 0.045 0.042 0.005 ‘Treatment success was defined as melasma severity score of zero (melasma lesions cleared of hyperpigmentation). #P-value is from Cochran-Mantel-Haenszel chi-square statistics controlling for pooled investigator and comparing TRI-LUMA® Cream to the other treatment groups. [0063] Based on melasma severity at the beginning of the trial, 161 patients were assessed for improvement at day 56 of treatment. 61% (99 patients) experienced symptom improvement from "moderate" to "mild" or "cleared," and 68% (25) showed improvement from "severe" to "mild" or "cleared" over the 8-week treatment period as shown in TABLE 3. TABLE 3 Investigators’ Assessment of Change in Melasma Severity from Baseline to Day 56 of Treatment (combined results from studies 1 and 2) Number(%) of Patients at Day 56a Baseline Clearedb Mildb Moderate13 Severe13 Missin Severity Ñ N(%) N(%) N(%) N(%) N(%) Rating Tri-Luma® Moderate 124 36 (29) 63 (51) 18 (16) 0(0) 7 (6%) Cream Severe 37 6(16) 19(51) 9 (24) 2(5) 1 (3%) N=161 a Assessment based on patients with severity scores at day 56. Percentages are based on the total number in the treatment group population. b Does not include patients who cleared before day 56 or were missing from the day 56 assessment. Assessment scale: Cleared (melasma lesions approximately equivalent to surrounding normal skin or with minimal residual hyperpigmentation); Mild (slightly darker than the surrounding normal skin); Moderate (moderately darker than the surrounding normal skin); Severe (markedly darker than the surrounding normal skin). EXAMPLE III ADVERSE REACTIONS IN HUMANS [0064] In a patch test study to determine sensitization potential in 221 healthy volunteers, three volunteers developed sensitivity reactions to TRI-LUMA® Cream or its components. [0065] In the controlled clinical trials, adverse events were monitored in the 161 patients who used TRI-LUMA® Cream once daily during an 8-week treatment period. There were 102 (63%) patients who experienced at least one treatment-related adverse event during these studies. The most frequently reported events were erythema, desquamation, burning, dryness, and pruritus at the site of application. The majority of these events were mild to moderate in severity. Adverse events reported by at least 1% of patients and judged by the investigators to be reasonably related to treatment with TRI-LUMA® Cream from the controlled clinical studies are summarized (in decreasing order of frequency) as follows: TABLE 4 Incidence and Frequency of Treatment-Related Adverse Events with TRI-LUMA® Cream In At Least 1% or More of Patients (N=161) Adverse Event Number (%) of Patients Erythema 66 (41 %) Desquamation 61 (38%) Burning 29 (18%) Dryness 23 (14%) Pruritus 18 (11%) Acne 8 (5%) Paresthesia 5 (3%) Telangiectasia 5 (3%) Hyperesthesia 3 (2%) Pigmentary changes 3 (2%) Irritation 3 (2%) Papules 2 (1%) Acne-like rash 1 (1%) Rosacea 1 (1%) Dry mouth 1 (1%) Rash 1 (1%) Vesicles 1 (1%) [0066] In an open-label long-term safety study, patients who have had cumulative treatment of melasma with TRILUMA® Cream for 6 months showed a similar pattern of adverse events as in the 8-week studies. The following local adverse reactions have been reported infrequently with topical corticosteroids. They may occur more frequently with the use of occlusive dressings, especially with higher potency corticosteroids. These reactions are listed in an approximate decreasing order of occurrence: burning, itching, irritation, dryness, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, allergic contact dermatitis, secondary infection, skin atrophy, striae, and miliaria. [0067] The foregoing description has been presented only for the purposes of illustration and is not intended to limit the invention to the precise form disclosed, but by the claims appended hereto. Claims 1. A method of making a topical medicated composition for topical application, the composition being an emulsion comprising water and, as active ingredients, fluocinolone acetonide, hydroquinone, and tretinoin, the method comprising: (a) mixing water and at least one hydrophilic compound to form an aqueous phase; (b) mixing at least two hydrophobic compounds to form a non-aqueous phase; (c) combining the aqueous phase and non-aqueous phase to form a biphasic mixture in the absence of an emulsifier; (d) mixing fluocinolone acetonide and tretinoin into the mixture of step (c); (e) mixing at least one emulsifier into the mixture of step (d), or during step (d); and (f) homogenizing the mixture of step (e) to form the emulsion; wherein hydroquinone is added in step (d) or after adding the at least one emulsifier. 2. The method of claim 1, wherein said step (a), step (b) or both are conducted at a temperature greater than room temperature to yield a heated phase. 3. The method of claim 2, wherein said heated phase is cooled prior to said combining step (c). 4. The method of claim 2, wherein said heated biphasic mixture is cooled prior to step (d). 5. The method of claim 1, wherein said hydroquinone is added after adding said at least one emulsifier in step (e). 6. The method of claim 1, further comprising adding sodium metabisulfite to said mixture of step (e) after adding said at least one emulsifier. 7. The method of claim 1, wherein said water and said at least one hydrophilic compound are mixed at an elevated temperature. 8. The method of claim 1, wherein said at least two hydrophobic compounds are mixed at an elevated temperature. 9. The method of claim 7 or 8, wherein said elevated temperature is not greater than 80°C. 10. The method of claim 1, wherein said water and said at least one hydrophilic compound are mixed at a temperature of not greater than 80°C, and said at least two hydrophobic compounds are mixed at a temperature of not greater than 80°C. 11. The method of claim 10, wherein said mixture of step (c) is cooled before adding said fluocinolone acetonide and said tretinoin in step (d).
- 12. The method of claim 10, wherein said mixture of step (d) is cooled while said at least one emulsifier is mixed into said mixture.
- 13. The method of claim 10, wherein said hydroquinone is added in step (d) following cooling of said mixture.
- 14. The method of claim 10, wherein said hydroquinone is added in step (e) after said at least one emulsifier is mixed into said mixture.
- 15. The method of claim 14, wherein said mixture is cooled and sodium metabisulfite is added while said mixture is cooling.
- 16. The method of claim 1, wherein the aqueous phase comprises water, magnesium aluminum silicate and butylated hydroxytoluene.
- 17. The method of claim 1 .wherein the emulsifier is glyceryl stearate, polyethylene glycol (PEG) stearate or a combination thereof.
- 18. A topical medicated composition, comprising 0.01 weight % fluocinolone acetonide; 4 weight % hydroquinone; 0.05 weight % tretinoin; 0.04 weight % butylated hydroxy toluene; 4 weight % cetyl alcohol; 0.05 weight % citric acid; 4 weight % glycerin; 3 weight % magnesium aluminum silicate; 5 weight % methyl gluceth; 0.18 weight % methylpa-raben; 3.5 weight % glyceryl stearate, polyethylene glycol (PEG) stearate or a combination thereof, 0.02 weight % propylparaben, 0.2 weight % sodium meta bisulfite, 3 weight % stearic acid and 4 weight % stearyl alcohol.
- 19. A method according to claim 1 wherein: (a) said aqueous composition comprising water and at least one hydrophilic compound is prepared while heating at a temperature not greater than 80°C; (b) said non-aqueous composition comprising at least two hydrophobic compounds is prepared while heating at a temperature not greater than 80°C; (c) steps (a) and (b) and the mixing of the aqueous and non-aqueous compositions are conducted in the absence of an emulsifier.
- 20. The method of claim 19, wherein step (c) further comprises cooling the mixture.
- 21. The method of claim 19, further comprising cooling the mixture after adding at least one emulsifier.
- 22. The method of claim 19, further comprising cooling the mixture before adding the hydroquinone. Patentansprüche 1. Verfahren zum Herstellen einer topischen, mit einem Arzneistoff versetzten Zusammensetzung zur topischen Anwendung, wobei die Zusammensetzung eine Emulsion ist, die Wasser und als Wirkstoffe Fluocinolonacetonid, Hydrochinon und Tretinoin umfasst, wobei das Verfahren Folgendes umfasst: (a) das Vermischen von Wasser und zumindest einer hydrophilen Verbindung, um eine wässrige Phase zu bilden; (b) das Vermischen von zumindest zwei hydrophoben Verbindungen, um eine nichtwässrige Phase zu bilden; (c) das Kombinieren der wässrigen Phase und der nichtwässrigen Phase, um in Abwesenheit eines Emulgators ein biphasisches Gemisch zu bilden; (d) das Vermischen von Fluocinolonacetonid und Tretinoin mit dem Gemisch aus Schritt (c); (e) das Vermischen von zumindest einem Emulgator mit dem Gemisch aus Schritt (d) oder während Schritt (d); und (f) das Homogenisieren des Gemischs aus Schritt (e), um die Emulsion zu bilden; worin Hydrochinon in Schritt (d) oder nach dem Hinzufügen des zumindest einen Emulgators hinzugefügt wird. 2. Verfahren nach Anspruch 1, worin Schritt (a), Schritt (b) oder beide bei einer Temperatur durchgeführt werden, die höher ist als die Raumtemperatur, um eine erhitzte Phase zu erhalten. 3. Verfahren nach Anspruch 2, worin die erhitzte Phase vor dem Schritt des Kombinierens (c) gekühlt wird. 4. Verfahren nach Anspruch 2, worin das erhitzte biphasische Gemisch vor Schritt (d) gekühlt wird. 5. Verfahren nach Anspruch 1, worin das Hydrochinon nach dem Hinzufügen des zumindest einen Emulgators in Schritt (e) hinzugefügt wird. 6. Verfahren nach Anspruch 1, ferner umfassend das Hinzufügen von Natriummetabisulfit zu dem Gemisch aus Schritt (e) nach dem Hinzufügen des zumindest einen Emulgators. 7. Verfahren nach Anspruch 1, worin das Wasser und die zumindest eine hydrophile Verbindung bei einer erhöhten Temperatur vermischt werden. 8. Verfahren nach Anspruch 1, worin die zumindest zwei hydrophoben Verbindungen bei einer erhöhten Temperatur vermischt werden. 9. Verfahren nach Anspruch 7 oder 8, worin die erhöhte Temperatur nicht höher als 80 °C ist. 10. Verfahren nach Anspruch 1, worin das Wasser und die zumindest eine hydrophile Verbindung bei einer Temperatur von nicht mehr als 80 °C vermischt werden und die zumindest zwei hydrophoben Verbindungen bei einer Temperatur von nicht mehr als 80 °C vermischt werden. 11. Verfahren nach Anspruch 10, worin das Gemisch aus Schritt (c) gekühlt wird, bevor das Fluocinolonacetonid und das Tretinoin in Schritt (d) hinzugefügt werden. 12. Verfahren nach Anspruch 10, worin das Gemisch aus Schritt (d) gekühlt wird, während derzumindest eine Emulgator mit dem Gemisch vermischt wird. 13. Verfahren nach Anspruch 10, worin das Hydrochinon in Schritt (d) nach dem Kühlen des Gemischs hinzugefügt wird. 14. Verfahren nach Anspruch 10, worin das Hydrochinon in Schritt (e) hinzugefügt wird, nachdem der zumindest eine Emulgator mit dem Gemisch vermischt wurde. 15. Verfahren nach Anspruch 14, worin das Gemisch gekühlt wird und Natriummetabisulfit hinzugefügt wird, während das Gemisch abkühlt. 16. Verfahren nach Anspruch 1, worin die wässrige Phase Wasser, Magnesiumaluminiumsilikat und butyliertes Hydro- xytoluol umfasst. 17. Verfahren nach Anspruch 1, worin der Emulgator Gylcerylstearat, Polyethylenglykol- (PEG-) Stearat oder eine Kombination davon ist. 18. Topische, mit einem Arzneistoff versetzte Zusammensetzung, umfassend 0,01 Gew.-% Fluocinolonacetonid; 4 Gew.-% Hydrochinon, 0,05 Gew.-% Tretinoin; 0,04 Gew.-% butyliertes Hydroxytoluol; 4 Gew.-% Cetylalkohol; 0,05 Gew.-% Citronensäure; 4 Gew.-% Glycerin; 3 Gew.-% Magnesiumaluminiumsilikat; 5 Gew.-% Methylgluceth; 0,18 Gew.-% Methylparaben; 3,5 Gew.-% Glycerylstearat, Polyethylenglykol-(PEG-) Stearat oder eine Kombination davon, 0,02 Gew.-% Propylparaben, 0,2 Gew.-% Natriummetabisulfit, 3 Gew.-% Stearinsäure und 4 Gew.-% Stearyl-alkohol. 19. Verfahren nach Anspruch 1, worin: (a) die wässrige Zusammensetzung, die Wasser und zumindest eine hydrophile Verbindung umfasst, hergestellt wird, während sie bei einer Temperatur von nicht mehr als 80 °C erhitzt wird; (b) die nichtwässrige Zusammensetzung, die zumindest zwei hydrophobe Verbindungen umfasst, hergestellt wird, während sie bei einer Temperatur von nicht mehr als 80 °C erhitzt wird; (c) die Schritte (a) und (b) und das Vermischen der wässrigen und der nichtwässrigen Zusammensetzung in Abwesenheit eines Emulgators durchgeführt werden. 20. Verfahren nach Anspruch 19, worin Schritt (c) ferner das Kühlen des Gemischs umfasst. 21. Verfahren nach Anspruch 19, ferner umfassend das Kühlen des Gemischs nachdem zumindest ein Emulgator hinzugefügt wurde. 22. Verfahren nach Anspruch 19, ferner umfassend das Kühlen des Gemischs bevor das Hydrochinon hinzugefügt wird. Revendications 1. Procédé de preparation d’une composition médicamenteuse topique pour application topique, la composition étant une émulsion comprenant de l’eau et, en tant que principes actifs, de l’acétonide de fluocinolone, de l’hydroquinone, et de la trétino'ine, le procédé comprenant les étapes consistant á : (a) mélangerde l’eau et au moins un composé hydrophile pour former une phase aqueuse ; (b) mélanger au moins deux composés hydrophobes pour former une phase non aqueuse ; (c) combiner la phase aqueuse et la phase non aqueuse pour former un mélange biphasique en I’absence d’émulsifiant; (d) mélanger de l’acétonide de fluocinolone et de la trétino'ine dans le mélange de l’étape (c) ; (e) mélanger au moins un émulsifiant dans le mélange de l’étape (d), ou pendant l’étape (d) ; et (f) homogénéiser le mélange de l’étape (e) pour former l’émulsion ; dans lequel l’hydroquinone est ajoutée dans l’étape (d) ou aprés l’ajout dudit au moins un émulsifiant. 2. Procédé selon la revendication 1, dans lequel ladite étape (a), étape (b) ou lesdeuxsont conduites á unetempérature supérieure á la température amblante pour donner une phase chauffée. 3. Procédé selon la revendication 2, dans lequel ladite phase chauffée est refroidie avant ladite étape de combinaison (c). 4. Procédé selon la revendication 2, dans lequel ledit mélange biphasique chauffé est refroidi avant l’étape (d). 5. Procédé selon la revendication 1, dans lequel ladite hydroquinone est ajoutée aprés l’ajout dudit au moins un émulsifiant dans l’étape (e). 6. Procédé selon la revendication 1, comprenant en outre l’ajout de métabisulfite de sodium audit mélange de l’étape (e) aprés l’ajout dudit au moins un émulsifiant. 7. Procédé selon la revendication 1, dans lequel ladite eau et ledit au moins un composé hydrophile sont mélangés á une température élevée. 8. Procédé selon la revendication 1, dans lequel lesdits au moins deux composés hydrophobes sont mélangés á une température élevée. 9. Procédé selon la revendication 7 ou 8, dans lequel ladite température élevée n’est pas supérieure á 80 °C. 10. Procédé selon la revendication 1, dans laquelle ladite eau et ledit au moins un composé hydrophile sont mélangés á une température non supérieure á 80 °C, et lesdits au moins deux composés hydrophobes sont mélangés á une température non supérieure á 80 °C. 11. Procédé selon la revendication 10, dans lequel ledit mélange de l’étape (c) est refroidi avant l’ajout dudit acétonide de fluocinolone et de ladite trétinoíne dans l’étape (d). 12. Procédé selon la revendication 10, dans lequel ledit mélange de l’étape (d) est refroidi pendant que ledit au moins un émulsifiant est mélangé dans ledit mélange. 13. Procédé selon la revendication 10, dans lequel ladite hydroquinone est ajoutée dans l’étape (d) ä la suite du refroi-dissement dudit mélange. 14. Procédé selon la revendication 10, dans lequel ladite hydroquinone est ajoutée dans l’étape (e) aprés que ledit au moins un émulsifiant est mélangé dans ledit mélange. 15. Procédé selon la revendication 14, dans lequel ledit mélange est refroidi et du métabisulfite de sodium est ajouté pendant que ledit mélange refroidit. 16. Procédé selon la revendication 1, dans lequel la phase aqueuse comprend de l’eau, de l’aluminosilicate de magné-sium et de l’hydroxytoluéne butylé. 17. Procédé selon la revendication 1, dans lequel l’émulsifiant est le stéarate de glycéryle, le stéarate de polyéthyléne-glycol (PEG) ou une combinaison de ceux-ci. 18. Composition médicamenteuse topique, comprenant 0,01 % en poids d’acétonide de fluocinolone ; 4 % en poids d’hydroquinone ; 0,05 % en poids de trétinoíne ; 0,04 % en poids d’hydroxytoluéne butylé ; 4 % en poids d’alcool cétylique ; 0,05 % en poids d’acide citrique ; 4 % en poids de glycérine ; 3 % en poids d’aluminosilicate de magnésium ; 5 % en poids de méthyl gluceth ; 0,18 % en poids de méthylparabéne ; 3,5 % en poids de stéarate de glycéryle, de stéarate de polyéthyléneglycol (PEG) ou d’une combinaison de ceux-ci, 0,02 % en poids de pro-pylparabéne, 0,2 % en poids de métabisulfite de sodium, 3 % en poids d’acide stéarique et 4 % en poids d’alcool stéarylique. 19. Procédé selon la revendication 1, dans lequel : (a) on prépare ladite composition aqueuse comprenant de l’eau et au moins un composé hydrophile tout en chauffant á une température non supérieure á 80 °C ; (b) on prépare ladite composition non aqueuse comprenant au moins deux composés hydrophobes tout en chauffant á une température non supérieure á 80 °C ; (c) les étapes (a) et (b) et le mélange des compositions aqueuse et non aqueuse sont conduits en l’absence d’émulsifiant. 20. Procédé selon la revendication 19, dans lequel l’étape (c) comprend en outre le refroidissement du mélange. 21. Procédé selon la revendication 19, comprenant en outre le refroidissement du mélange aprés l’ajout d’au moins un émulsifiant. 22. Procédé selon la revendication 19, comprenant en outre le refroidissement du mélange avant l’ajout de l’hydroqui-none. REFERENCES CITED IN THE DESCRIPTION This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard. Patent documents cited in the description • US 5538737 A [0005] · US 6267985 B [0037] • US 5656672 A [0006] · US 4992478 A [0037] • US 5660837 A [0007] · US 5645854 A [0037] • US 5976555 A [0008] · US 5811111 A [0037] • US 6080393 A [0010] · US 5851543 A [0037] • US 6013271 A [0037] Non-patent literature cited in the description • CLARK et al. Dermatology Times, 2002, vol. 23 (5), · MCCUTCHEON’S. Functional Materials. 1992 1 [0009] [0031] [0032] • MCCUTCHEON’S. Detergents and Emulsifiers. · CTFA Cosmetic Ingredient Handbook. 1992 [0036] 1986 [0031] [0032]
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SI (1) | SI1562531T1 (pt) |
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2002
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- 2010-09-30 JP JP2010221381A patent/JP5528973B2/ja not_active Expired - Fee Related
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2016
- 2016-03-11 US US15/067,919 patent/US20160193121A1/en not_active Abandoned
- 2016-03-18 CY CY20161100232T patent/CY1117292T1/el unknown
- 2016-09-29 HK HK16111416.5A patent/HK1223040A1/zh unknown
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