EP2291180A1 - Anhydrous depigmenting compositions comprising, within the fatty phase, a solubilized phenolic derivative and a retinoid - Google Patents
Anhydrous depigmenting compositions comprising, within the fatty phase, a solubilized phenolic derivative and a retinoidInfo
- Publication number
- EP2291180A1 EP2291180A1 EP09769520A EP09769520A EP2291180A1 EP 2291180 A1 EP2291180 A1 EP 2291180A1 EP 09769520 A EP09769520 A EP 09769520A EP 09769520 A EP09769520 A EP 09769520A EP 2291180 A1 EP2291180 A1 EP 2291180A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- composition according
- composition
- retinoid
- phase
- hydroquinone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 139
- 150000004492 retinoid derivatives Chemical class 0.000 title claims abstract description 25
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 title claims abstract description 21
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 claims description 103
- 239000002904 solvent Substances 0.000 claims description 38
- CSHZYWUPJWVTMQ-UHFFFAOYSA-N 4-n-Butylresorcinol Chemical compound CCCCC1=CC=C(O)C=C1O CSHZYWUPJWVTMQ-UHFFFAOYSA-N 0.000 claims description 29
- 229960002916 adapalene Drugs 0.000 claims description 23
- LZCDAPDGXCYOEH-UHFFFAOYSA-N adapalene Chemical compound C1=C(C(O)=O)C=CC2=CC(C3=CC=C(C(=C3)C34CC5CC(CC(C5)C3)C4)OC)=CC=C21 LZCDAPDGXCYOEH-UHFFFAOYSA-N 0.000 claims description 22
- 239000003921 oil Substances 0.000 claims description 17
- 239000004094 surface-active agent Substances 0.000 claims description 16
- -1 behenyl glyceryl Chemical group 0.000 claims description 14
- 150000002989 phenols Chemical class 0.000 claims description 13
- 239000002270 dispersing agent Substances 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 11
- 239000002562 thickening agent Substances 0.000 claims description 11
- 150000003626 triacylglycerols Chemical class 0.000 claims description 11
- 229920001971 elastomer Polymers 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 239000000806 elastomer Substances 0.000 claims description 9
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 9
- 239000000126 substance Substances 0.000 claims description 9
- 208000000069 hyperpigmentation Diseases 0.000 claims description 7
- 208000003351 Melanosis Diseases 0.000 claims description 6
- 239000003349 gelling agent Substances 0.000 claims description 6
- 230000003810 hyperpigmentation Effects 0.000 claims description 6
- 230000001476 alcoholic effect Effects 0.000 claims description 5
- 150000002148 esters Chemical group 0.000 claims description 5
- 206010008570 Chloasma Diseases 0.000 claims description 4
- 201000004624 Dermatitis Diseases 0.000 claims description 3
- 206010036229 Post inflammatory pigmentation change Diseases 0.000 claims description 3
- 150000002170 ethers Chemical class 0.000 claims description 3
- 230000002503 metabolic effect Effects 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- LKVFCSWBKOVHAH-UHFFFAOYSA-N 4-Ethoxyphenol Chemical compound CCOC1=CC=C(O)C=C1 LKVFCSWBKOVHAH-UHFFFAOYSA-N 0.000 claims description 2
- 206010014970 Ephelides Diseases 0.000 claims description 2
- 206010020751 Hypersensitivity Diseases 0.000 claims description 2
- 208000007256 Nevus Diseases 0.000 claims description 2
- 206010064127 Solar lentigo Diseases 0.000 claims description 2
- 206010047642 Vitiligo Diseases 0.000 claims description 2
- 238000005299 abrasion Methods 0.000 claims description 2
- 230000032683 aging Effects 0.000 claims description 2
- 208000026935 allergic disease Diseases 0.000 claims description 2
- 230000007815 allergy Effects 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 208000035475 disorder Diseases 0.000 claims description 2
- 230000002068 genetic effect Effects 0.000 claims description 2
- 206010024217 lentigo Diseases 0.000 claims description 2
- 230000003902 lesion Effects 0.000 claims description 2
- 201000001441 melanoma Diseases 0.000 claims description 2
- NWVVVBRKAWDGAB-UHFFFAOYSA-N p-methoxyphenol Chemical compound COC1=CC=C(O)C=C1 NWVVVBRKAWDGAB-UHFFFAOYSA-N 0.000 claims description 2
- 229920001296 polysiloxane Polymers 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 230000037390 scarring Effects 0.000 claims description 2
- LADGBHLMCUINGV-UHFFFAOYSA-N tricaprin Chemical compound CCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCC)COC(=O)CCCCCCCCC LADGBHLMCUINGV-UHFFFAOYSA-N 0.000 claims description 2
- 125000000687 hydroquinonyl group Chemical group C1(O)=C(C=C(O)C=C1)* 0.000 claims 1
- VYQNWZOUAUKGHI-UHFFFAOYSA-N monobenzone Chemical compound C1=CC(O)=CC=C1OCC1=CC=CC=C1 VYQNWZOUAUKGHI-UHFFFAOYSA-N 0.000 claims 1
- 229960000990 monobenzone Drugs 0.000 claims 1
- 239000013543 active substance Substances 0.000 abstract description 10
- 238000002360 preparation method Methods 0.000 abstract description 10
- 230000000699 topical effect Effects 0.000 abstract description 8
- 238000000034 method Methods 0.000 abstract description 7
- 239000012071 phase Substances 0.000 description 49
- 235000019198 oils Nutrition 0.000 description 16
- 150000001875 compounds Chemical class 0.000 description 14
- 239000004480 active ingredient Substances 0.000 description 13
- 239000002674 ointment Substances 0.000 description 13
- 235000013824 polyphenols Nutrition 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000003963 antioxidant agent Substances 0.000 description 9
- 235000006708 antioxidants Nutrition 0.000 description 9
- 238000009472 formulation Methods 0.000 description 9
- 239000000654 additive Substances 0.000 description 8
- 239000011230 binding agent Substances 0.000 description 8
- 239000004359 castor oil Substances 0.000 description 8
- 235000019438 castor oil Nutrition 0.000 description 8
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 239000007788 liquid Substances 0.000 description 7
- 238000005259 measurement Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 235000014113 dietary fatty acids Nutrition 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000000194 fatty acid Substances 0.000 description 6
- 229930195729 fatty acid Natural products 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 229920002685 Polyoxyl 35CastorOil Polymers 0.000 description 5
- 230000015556 catabolic process Effects 0.000 description 5
- 238000006731 degradation reaction Methods 0.000 description 5
- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 description 5
- 239000008389 polyethoxylated castor oil Substances 0.000 description 5
- 150000008442 polyphenolic compounds Chemical class 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 239000001993 wax Substances 0.000 description 5
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 239000002537 cosmetic Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 150000002334 glycols Chemical class 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- 150000002430 hydrocarbons Chemical class 0.000 description 4
- 238000010348 incorporation Methods 0.000 description 4
- 230000007794 irritation Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 description 3
- ZQCIPRGNRQXXSK-UHFFFAOYSA-N 1-octadecoxypropan-2-ol Chemical compound CCCCCCCCCCCCCCCCCCOCC(C)O ZQCIPRGNRQXXSK-UHFFFAOYSA-N 0.000 description 3
- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000000470 constituent Substances 0.000 description 3
- 239000007854 depigmenting agent Substances 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 229940049654 glyceryl behenate Drugs 0.000 description 3
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 description 3
- 229940075529 glyceryl stearate Drugs 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 3
- 229940119170 jojoba wax Drugs 0.000 description 3
- 238000003760 magnetic stirring Methods 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- 229940078491 ppg-15 stearyl ether Drugs 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 3
- 229930002330 retinoic acid Natural products 0.000 description 3
- 230000003381 solubilizing effect Effects 0.000 description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 235000015112 vegetable and seed oil Nutrition 0.000 description 3
- 239000008158 vegetable oil Substances 0.000 description 3
- LEACJMVNYZDSKR-UHFFFAOYSA-N 2-octyldodecan-1-ol Chemical compound CCCCCCCCCCC(CO)CCCCCCCC LEACJMVNYZDSKR-UHFFFAOYSA-N 0.000 description 2
- QCDWFXQBSFUVSP-UHFFFAOYSA-N 2-phenoxyethanol Chemical compound OCCOC1=CC=CC=C1 QCDWFXQBSFUVSP-UHFFFAOYSA-N 0.000 description 2
- HBTAOSGHCXUEKI-UHFFFAOYSA-N 4-chloro-n,n-dimethyl-3-nitrobenzenesulfonamide Chemical compound CN(C)S(=O)(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 HBTAOSGHCXUEKI-UHFFFAOYSA-N 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 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 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- 241001440269 Cutina Species 0.000 description 2
- 235000001815 DL-alpha-tocopherol Nutrition 0.000 description 2
- 239000011627 DL-alpha-tocopherol Substances 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ZDQWESQEGGJUCH-UHFFFAOYSA-N Diisopropyl adipate Chemical compound CC(C)OC(=O)CCCCC(=O)OC(C)C ZDQWESQEGGJUCH-UHFFFAOYSA-N 0.000 description 2
- MPDGHEJMBKOTSU-UHFFFAOYSA-N Glycyrrhetinsaeure Natural products C12C(=O)C=C3C4CC(C)(C(O)=O)CCC4(C)CCC3(C)C1(C)CCC1C2(C)CCC(O)C1(C)C MPDGHEJMBKOTSU-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- SHGAZHPCJJPHSC-NUEINMDLSA-N Isotretinoin Chemical compound OC(=O)C=C(C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NUEINMDLSA-N 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 2
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 2
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- 239000004166 Lanolin Substances 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
- REYJJPSVUYRZGE-UHFFFAOYSA-N Octadecylamine Chemical compound CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-UHFFFAOYSA-N 0.000 description 2
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
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- 239000012072 active phase Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 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 description 2
- 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 description 2
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
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- PMMXXYHTOMKOAZ-UHFFFAOYSA-N hexadecyl 7-methyloctanoate Chemical compound CCCCCCCCCCCCCCCCOC(=O)CCCCCC(C)C PMMXXYHTOMKOAZ-UHFFFAOYSA-N 0.000 description 2
- 239000012073 inactive phase Substances 0.000 description 2
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- 150000002634 lipophilic molecules Chemical class 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
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- HLSHNXLMUMGCSV-UHFFFAOYSA-N 2-hydroxy-4-[3-hydroxy-3-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)prop-1-ynyl]benzoic acid Chemical compound C=1C=C2C(C)(C)CCC(C)(C)C2=CC=1C(O)C#CC1=CC=C(C(O)=O)C(O)=C1 HLSHNXLMUMGCSV-UHFFFAOYSA-N 0.000 description 1
- BGRXBNZMPMGLQI-UHFFFAOYSA-N 2-octyldodecyl tetradecanoate Chemical compound CCCCCCCCCCCCCC(=O)OCC(CCCCCCCC)CCCCCCCCCC BGRXBNZMPMGLQI-UHFFFAOYSA-N 0.000 description 1
- PUTQZOMYROSUPH-UHFFFAOYSA-N 4-[3-[4-(2-ethoxyethoxy)-5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl]-3-hydroxyprop-1-ynyl]benzoic acid Chemical compound C=1C(C(CCC2(C)C)(C)C)=C2C(OCCOCC)=CC=1C(O)C#CC1=CC=C(C(O)=O)C=C1 PUTQZOMYROSUPH-UHFFFAOYSA-N 0.000 description 1
- OVMCYQMEOOZBKP-UHFFFAOYSA-N 4-[4-[4-(propan-2-ylamino)butoxy]-3-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)phenyl]benzoic acid Chemical compound C1=C(C=2C=C3C(C(CCC3(C)C)(C)C)=CC=2)C(OCCCCNC(C)C)=CC=C1C1=CC=C(C(O)=O)C=C1 OVMCYQMEOOZBKP-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/203—Retinoic acids ; Salts thereof
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A61K8/92—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof
- A61K8/922—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof of vegetable origin
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- A61K2800/20—Chemical, physico-chemical or functional or structural properties of the composition as a whole
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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Definitions
- the present invention relates to a new cosmetic or pharmaceutical depigmenting composition characterized in that it comprises, as pharmaceutical active ingredients, a retinoid and a phenolic derivative solubilized in the fatty phase, for a topical application, and to its process preparation and its use in dermatology.
- hydroquinone is the most used pharmaceutical active ingredients.
- Hydroquinone has been the subject of various patent applications, and in particular US Pat. No. 3,856,934, in which hydroquinone is in combination with retinoic acid and a corticosteroid as depigmenting composition.
- Rucinol or lucinol, or 4-butyl-resorcinol is a phenol derivative pharmaceutical active agent, polyphenol type marketed as agent for lightening brown spots related to pigmentation disorders (product Iklen ®).
- hydroquinone, rucinol or their salts or their derivatives are solubilized in the aqueous phase of the preparation.
- phenol derivatives such as hydroquinone or rucinol
- phenol derivatives are often exposed to heat during the embodiment phase of the composition, especially in conventional emulsions, a phenomenon that initiates and accelerates the phenomenon. browning.
- reducing agents are used to combat this degradation, in particular sulfites, which are almost unavoidable.
- these antioxidants have a number of disadvantages such as skin irritation problems, odor in the formulations or destabilization of the formula related to a loss of viscosity.
- Hydroquinone because of its high concentration of irritating effect can cause post-inflammatory hypermelanosis and ochronosis phenomena.
- hydroquinone Treatment with hydroquinone may be accompanied by irritation that may lead to post-inflammatory hyperpigmentation.
- the incidence of irritation depends on the concentration of hydroquinone. The latter is quite important for the 10% concentrations and strongly decreases for the 5% virtually zero at 2% concentration ["Depigmenting Chemicals" JP. Ortonne Ann. Dermatol. Venerol. 1986, 13: 733-736].
- the galenic chosen can therefore play a leading role in minimizing these effects.
- hydroquinone is generally solubilized in alcoholic or glycol solvents before being incorporated in the rest of the anhydrous preparation.
- This is particularly the case in US patent application 2006/0120979 describes a composition comprising hydroquinone and an anhydrous base consisting of an anhydrous solvent and a high molecular weight silicone vehicle.
- the hydroquinone is in this case solubilized in a solvent preferably selected from the group of monohydric alcohols (such as isopropanol), dihydric alcohols (such as glycols), trihydric alcohols (such as glycerol).
- These compositions do not contain sulphites but require lipophilic antioxidants in a fairly large amount. Indeed, the hydroquinone in such a medium undergoes any degradation, less marked than in water but sufficiently important to require the presence of lipophilic antioxidants in proportions of up to 1% of the composition.
- One of the aims of the present invention is here to solubilize the phenolic derivative in an oily solvent in which the active agent is both soluble and stable and in which it is then possible to envisage the incorporation of the active ingredient into manufacturing processes that require heating steps without having an impact on the stability of the asset.
- Another object of the present invention is to provide an anhydrous pharmaceutical composition intended for topical application having a prolonged stability, allowing optimized release active while being very well tolerated.
- the present invention thus relates to a novel anhydrous stable composition, especially for topical application, comprising a solubilized polyphenol phenol derivative and a retinoid in the fatty phase.
- composition according to the invention by virtue of its anhydrous composition, guarantees both excellent stability and harmlessness of the composition.
- the object of the present invention is an anhydrous pharmaceutical composition
- a phenolic derivative-type pharmacological active agent and in particular of the polyphenol type, and characterized in that the said phenolic derivative is solubilized in the fatty phase.
- phenolic derivative-type pharmaceutical active agent By phenolic derivative-type pharmaceutical active agent according to the invention, mention may be made, without limitation, of polyphenols and more particularly hydroquinone, rucinol or lucinol and their salts, 4-hydroxyanisol, hydroquinone monoethyl ether and monobenzyl ether. hydroquinone. Preferably, hydroquinone, or rucinol and its salts are used.
- the term "rucinol salt” is intended especially to mean salts formed with a pharmaceutically acceptable base, in particular a mineral base such as sodium hydroxide, potassium hydroxide and ammonia, or an organic base such as lysine, arginine or N-methyl. -glucamine, but also the salts formed with fatty amines such as dioctylamine, aminomethyl propanil and stearylamine.
- the amount of phenol derivative is from 0.01 to 10% by weight relative to the total weight of the composition, preferably from 0.1 to 6% by weight and more particularly from 0.1 to 5% by weight.
- composition according to the invention comprises, as a second pharmaceutical active ingredient, a retinoid.
- retinoid any compound binding to receptors (retinoic acid receptors (RARs) and / or retinoic receptors X (RXRs)) as well as their precursors and derivatives.
- RARs retinoic acid receptors
- RXRs retinoic receptors X
- the retinoids that can be used in the context of the invention include in particular all-trans retinoic acid or tretinoin, 13-cis-retinoic acid or isotretinoin, acitretin, arotinoic acid, retinol, tazarotene, retinaldehyde, etretinate and the compounds protected in patent applications EP 0 199 636, US 4,666,941, US 4,581,380, EP 0 210 929, EP 0 232 199, EP 0 260 162, EP 0 292 348, EP 0 325 540, EP 0 359 621, EP 0 409 728, EP 0 409 740, EP 0 552 282, EP 0 584 191, EP 0 514 264, EP 0 514 269, EP 0 661 260, EP 0 661 258, EP 0 658,553, EP 0 679 628, EP 0 679 631, EP 0 679
- adapalene and its salts are preferred, and 3 "-tert-butyl-4 '- (2-hydroxyethoxy) -4" -pyrrolidin-1-yl- [1, 1'; 3 ', 1 "] terphenyl-4-carboxylic acid.
- Suitable salts of adapalene are in particular salts formed with a pharmaceutically acceptable base, in particular mineral bases such as sodium hydroxide, potassium hydroxide and aqueous ammonia or organic bases such as lysine, arginine, N- methylglucamine, and salts formed with fatty amines such as dioctylamine and stearylamine.
- retinoid precursors are meant their immediate biological precursors or substrates, as well as their chemical precursors.
- Derivatives of retinoids include both their metabolic derivatives and their chemical derivatives.
- the composition comprises an amount of retinoid agent of between 0.0001 and 1% by weight relative to the total weight of the composition, preferably between 0.001 and 0.3%, even more preferably between 0.01. and 0.1% by weight.
- the present invention thus relates to a new anhydrous stable composition, especially for topical application, comprising within a fatty phase, a retinoid and a solubilized phenol derivative.
- composition according to the invention by its anhydrous nature guarantees both excellent stability and harmlessness of the composition.
- anhydrous composition is meant a composition comprising a quantity of water less than or equal to 5% by weight relative to the total weight of the composition.
- the composition does not contain water.
- stable composition is meant a chemically and physically stable composition.
- chemical stability is meant in particular that no degradation of the active is observed over time and at temperatures between 4 and 40 ° C.
- physical stability it is meant in particular that the compositions do not exhibit a macroscopic appearance modification in particular of color or of microscopic appearance without evolution of viscosity with time and at temperatures between 4 and 40 ° C.
- a Flow threshold measurement can be carried out to characterize the finished product.
- a HAAKE rheometer of type VT550 with a measurement mobile SVDIN was used.
- the rheograms are produced at 25 ° C and imposed speed from 0 to 100 s "1.
- the viscosity values are given to the shear values of 4 s" 1, 20s “1 100s” 1 ( ⁇ ).
- flow threshold ⁇ 0 expressed in Pascal
- ⁇ 0 expressed in Pascal is meant the force required (minimum shear stress) to overcome Van der Waals cohesive forces and cause flow.
- ambient temperature means a temperature between 20 and 30 ° C.
- the anhydrous nature of the composition according to the invention makes it possible to avoid the instability of the phenol derivative, in particular its oxidation in an aqueous medium.
- the use of sulphites essential for the stabilization of hydroquinone in an aqueous medium is no longer necessary. Therefore, in a preferred embodiment according to the invention, the composition does not contain sulfites and contains an amount of antioxidants strictly less than 0.3% and preferably less than 0.2% by weight relative to the total weight of the composition.
- antioxidants that can be used according to the invention are preferably antioxidants such as vitamin E and its derivatives, such as DL alpha Tocopherol or Roche tocopherol acetate; vitamin C and its derivatives, such as Roche's Ascorbyl Palmitate, butylhydroxytoluene sold under the name Nipanox BHT by Clariant.
- vitamin E and its derivatives such as DL alpha Tocopherol or Roche tocopherol acetate
- vitamin C and its derivatives such as Roche's Ascorbyl Palmitate, butylhydroxytoluene sold under the name Nipanox BHT by Clariant.
- composition according to the invention comprises at least one subsequent fatty phase, or the following oily phase, of the compound of the family of phenolic derivatives, and preferably hydroquinone or rucinol.
- composition according to the invention comprises at least one fatty phase, or oily phase, solubilizing or dispersing retinoid.
- retinoids are soluble in various solvents, including oily solvents.
- the preferred retinoid according to the invention adapalene
- the adapalene has the particularity of being insoluble in all the solvents that can be used for retinoids.
- the adapalene must be dispersed, and more particularly in the fatty phase of the present invention.
- the following oily phase of the phenol derivative and the following oily or dispersant phase of the retinoid may, but need not be, the same fatty substances.
- the composition comprises at least one subsequent oily phase of the phenolic-derived pharmaceutical active agent, in particular hydroquinone or rucinol and at least one oily dispersant phase of adapalene.
- vegetable oils such as castor oil, sweet almond oil sold by Sictia or sesame oil sold by CPF;
- silicone oils such as cyclomethicone sold under the name ST-Cyclomethicone 5NF by Dow Corning or Dimethicone sold under the name Q7 9120 silicon fluid by Dow Corning;
- mineral oils such as Marcol 152 or Primol 352 sold by Esso;
- triglycerides such as Caprylic / Caprique Triglycerides sold under the name Miglyol 812 N by IMCD, or derivatives such as PEG-8 caprylic capric triglycerides sold under the name Labrasol by Gattefossé;
- esters such as the Octyl Dodecyl Myristate sold under the name MOD by Gattefossé, the C12-C15 alkyl benzoate sold under the name Tegosoft TN by Goldschmit or the cetearyl isononanoate sold under the name Cetiol SN PH by Cognis or else diisopropyl adipate sold under the name Crodamol DA by the company Croda; Guerbet alcohols such as octyldodecanol sold under the name Eutanol G by Cognis;
- PPG-15 Stearyl ether sold under the name Arlamol E by the company Croda; - and their mixtures.
- the oily solvents of the phenol derivative and more particularly hydroquinone or rucinol, PPG-15 stearyl ether or any other ether or derivatives, diisopropyl adipate or any other ester or derivatives or triglycerides as caprylic capric triglycerides or their derivatives or a mixture of these compounds.
- the composition according to the invention more particularly comprises a mixture of solvents.
- the solvent mixture will consist of at most 15% (by weight relative to the total weight of the composition) of ethers-derived solvent. In the composition according to the invention, this amount of solvent, combined with the other new solvents present, is sufficient to solubilize the desired concentrations of active ingredients and to obtain stable preparations.
- the retinoid and more particularly adapalene triglycerides such as capric capric triglycerides or their derivatives, will be chosen.
- oil phase and / or dispersant active comprises at least one solvent and / or oily dispersant of the active and / or lipophilic surfactant.
- Lipophilic surfactant more particularly means:
- polyoxyethylenated castor oil derivatives for example the PEG-35 castor oil marketed in particular under the name Cremophor EL by BASF.
- polyoxyethylenated derivatives of fatty acid esters for example PEG-8 caprylic capric triglycerides marketed under the name LABRASOL by Gattefossé.
- the amount of the following fat phase and / or dispersant in the composition according to the invention is generally between 5% and 99%, preferably from 10 to 98% by weight relative to the total weight of the composition. According to a particular embodiment, the compositions according to the invention do not contain alcoholic or glycolic solvents.
- composition according to the invention may further comprise at least one lipophilic gelling agent or thickener according to the desired viscosity.
- lipophilic gelling agent or thickener are used in the present invention as “viscosity adjusters”:
- lipophilic thickeners or gelling agents are meant compounds, especially chosen from waxes, hydrogenated oils and fatty acid esters.
- wax is generally meant a lipophilic compound, solid at room temperature (25 ° C.), with a reversible solid / liquid state change, having a melting point of greater than or equal to 30 ° C. and up to at 200 ° C. and in particular up to 120 ° C.
- useful waxes mention may be made of carnauba wax, microcrystalline waxes, beeswax marketed under the name White Cerabeil by Barlocher, glyceryl behenate, its derivatives such as glyceryl monobhenenate, glyceryl dibenenate, tribehenine or a mixture thereof, such as the product marketed under the name Compritol 888 by Gattefossé, or else candelilla wax.
- Hydrogenated oil is understood to mean the oils obtained by catalytic hydrogenation of animal or vegetable oils having linear or branched C 8 -C 32 fatty chains.
- hydrogenated jojoba oil isomérz jojoba oil such as trans isomerized partially hydrogenated jojoba oil manufactured or marketed by Desert Whale under the trade reference ISO-JOJOBA-50 ® , hydrogenated sunflower oil, hydrogenated castor oil, marketed in particular under the name of Cutina HR by Cognis, polyoxyethylenated castor oil sold in particular under the name Cremophor EL by BASF, hydrogenated coconut oil and hydrogenated lanolin oil; preferably, the hydrogenated castor oil will be used.
- the amount of lipophilic thickeners or gelling agents in the composition according to the invention is generally between 1 and 40% by weight relative to the total weight of the composition, preferably between 5 and 30%.
- the composition according to the invention may contain an elastomer.
- elastomer is intended to mean any polyorganosiloxane elastomer, namely any chemically crosslinked siloxane polymer which has viscoelastic properties, such as especially and preferably, Elastomer 10 marketed by Dow Corning.
- the amount of elastomer of high molecular weight in the composition according to the invention is generally between 0% and 40%, preferably from 0 to 20% by weight relative to the total weight of the composition.
- composition according to the invention may also comprise another surfactant, and / or at least one binder.
- the surfactants used are preferably nonionic surfactants, used for example, but not exclusively, to facilitate the incorporation of certain constituents such as glycols into the oily phase of the composition.
- glyceryl and optionally polyethylene glycol esters such as the mixture of glyceryl stearate and PEG-100 stearate, sold under the name Arlacel 165 by Uniqema, the mixture glyceryl stearate and PEG-75 stearate, sold under the name Gelot 64 by Gattefossé, glyceryl stearate sold under the name Cutina GMSV by Cognis; emulsifying waxes, such as the self-emulsifying wax sold under the name of Polawax NF by Croda, or the PEG-8 beeswax sold under the name of Apifil by Gattefossé; polysorbate 80 sold under the name Tween 80 by Uni
- the composition may optionally comprise at least one binder.
- binders that can be used include magnesium stearate sold by Brenntag, corn starch sold by Roquette, talc sold by WCD, cholesterol sold by Croda or silica sold by Degussa.
- the binders can be used in an amount of between 0.1 and 30% by weight, preferably between 1 and 20% by weight.
- composition according to the invention may also contain additives that those skilled in the art will choose according to the desired effect.
- additives for example, taken alone or in combination:
- vitamins such as vitamin PP or niacinamide
- soothing or anti-irritant agents such as the PPG-12 / SMDI copolymer sold by the company Bertek pharmaceuticals under the trade name Polyolprepolymer-2 or also glycyrrhetinic acid or its derivatives such as, for example, enoxolone sold by the Cognis company;
- moisturizing or humectant agents mention may be made, for example, of sugars and derivatives, of glycols, of glycerine, of sorbitol; - lecitins, cholesterol;
- preservatives such as paraben methyl sold under the name Nipagin M by Clariant, propyl paraben sold under the name Nipasol by Clariant, or phenoxyethanol sold under the name phenoxetol by Clariant;
- acids or bases such as citric acid, sodium citrate, triethanolamine, aminomethylpropanol, sodium hydroxide, diisopropanolamine;
- composition according to the invention comprises, by weight relative to the total weight:
- the composition according to the invention comprises, by weight relative to the total weight: 0.01 to 10% of at least one phenolic derivative drug, preferably hydroquinone or rucinol, 0.0001 to 1% of a retinoid, preferably adapalene, 1% to 99% of a oily phase following and / or dispersing pharmaceutical active ingredients,
- at least one phenolic derivative drug preferably hydroquinone or rucinol
- a retinoid preferably adapalene
- composition according to the invention comprises, by weight relative to the total weight:
- binder 0 to 20% of binder (s), 0 to 10% of additives.
- compositions according to the invention may be in the various known galenic forms which the person skilled in the art will adapt to the particular use of the composition.
- compositions according to the invention are preferably formulated for topical application.
- topical means an external application on the skin or mucous membranes.
- compositions may be in any dosage form normally used for topical administration.
- US Pharmacopoeia USP32-NF27 - Chap. 1 151- Pharmaceutical Dosage Forms
- European European
- Semi-solid preparations for cutaneous application or as defined in the trees of US Food and Drug Administration (FDA) decision CDER Data Standards Manual Definitions for topical
- the invention may therefore be in liquid, semi-solid, pasty or solid form and, more particularly, in the form of ointments, oily solutions, dispersions of the lotion type that may be biphasic, serum, anhydrous or lipophilic gels, powders, soaked swabs, syndets, wipes, sprays, foams, sticks, shampoos, compresses, washing bases, emulsions of liquid or semi-liquid consistency of the type oil in glycol or glycol in oil, a microemulsion, suspensions or semi-liquid or solid emulsions of the white or
- the anhydrous composition according to the invention is preferably an ointment.
- Ointment according to the invention means a particular composition as defined in the American or European pharmacopoeia mentioned above.
- the FDA thus defines the ointment as a semi-solid composition comprising, as a carrier, less than 20% water and volatile compounds and more than 50% hydrocarbons, waxes, or polyol. In some cases, when volatile levels are important such compositions may be called creams (American Food and Drug Administration (FDA) decision tree).
- FDA American Food and Drug Administration
- the American Pharmacopoeia defines an ointment as a product whose base is a vehicle that can belong to the following 4 classes: hydrocarbon base or absorbent base or water-washable base or water-soluble base.
- the ointment according to the invention and the American pharmacopoeia belongs to the class of hydrocarbon-based ointments.
- the European Pharmacopoeia defines ointment as a single-phase composition in which liquids or solids can be dispersed.
- the ointment according to the invention is a thick composition at room temperature, which comprises between 80 and 98% by weight relative to the total weight of the composition of hydrophobic compounds distinct from petroleum jelly.
- Such compounds are chosen in particular from liquid oils alone or as a mixture, said oils possibly being volatile or nonvolatile hydrocarbons, esters, vegetable oils and / or silicone oils which can be gelled by lipophilic compounds which are solid at temperature.
- a flow threshold measurement may be performed to characterize the finished product.
- a HAAKE rheometer of type VT550 with a measurement mobile SVDIN was used for the measurement of the flow threshold.
- the rheograms are produced at 25 ° C in the imposed speed of 0 to 100 s "1.
- the viscosity values are given to the shear values of 4 s" 1, 20s "1 100s” 1 ( ⁇ ).
- flow threshold ⁇ 0 expressed in Pascal
- ⁇ is meant the force required (minimum shear stress) to overcome Van der Waals cohesive forces and cause flow.
- the composition is an anhydrous pharmaceutical or cosmetic composition of ointment type comprising:
- An active phase consisting of a first active phase comprising the phenolic derivative and at least one solvent of the phenolic derivative, and a second active phase, comprising the retinoid and at least one solvent and / or retinoid dispersant; an inactive phase containing at least one fatty phase thickener and optionally an additional lipophilic thickener, and / or at least one oil, and / or at least one lipophilic surfactant, and / or a binder, and / or an elastomer and / or any optional additive.
- the composition comprises:
- An active phase consisting of a first active phase comprising hydroquinone or rucinol and at least one oily solvent of hydroquinone, and a second active phase, comprising adapalene and at least one oily dispersant of adapalene; an inactive phase containing at least one fatty phase thickener selected from behenate glyceryl and derivatives, at least one elastomer and optionally an additional lipophilic thickener, and / or at least one oil, and / or at least one lipophilic surfactant, and / or a binder, and / or any optional additive.
- the invention also relates to the use of the composition thus obtained as a medicament. More particularly, the composition can be used to prepare a medicament for the treatment and prevention of hyperpigmentary disorders such as melasma, chloasma, lentigines, senile lentigo, vitiligo, freckles, post-inflammatory hyperpigmentations. due to abrasion, burning, scarring, dermatitis, contact allergy; nevi, hyperpigmentations with genetic determinism, hyperpigmentations of metabolic or medicinal origin, melanomas or any other hyperpigmentary lesions.
- hyperpigmentary disorders such as melasma, chloasma, lentigines, senile lentigo, vitiligo, freckles, post-inflammatory hyperpigmentations.
- hyperpigmentary disorders such as melasma, chloasma, lentigines, senile lentigo, vitiligo, frec
- compositions according to the invention also find application in the cosmetics field, in particular in the protection against the harmful aspects of the sun, for preventing and / or for combating photoinduced or chronological aging of the skin and superficial body growths.
- the invention also relates to a non-therapeutic cosmetic treatment method for embellishing the skin and / or improving its surface appearance, characterized in that a composition is applied to the skin and / or its integuments. comprising adapalene and at least one depigmenting agent.
- the depigmenting composition characterized in that it comprises hydroquinone or rucinol and adapalene in the fatty phase, has an improved depigmenting efficiency compared to a composition containing the same active ingredients incorporated in the phase. aqueous and / or alcoholic and / or glycolic composition.
- anhydrous compositions according to the invention are obtained by those skilled in the art using a conventional and known method of mixing the phases.
- the manufacturing process may include the following steps:
- the preferred solvents are Crodamol DA, Arlamol E and Labrasol, which give hydroquinone good chemical and physical stability (macroscopic observation of the color), coupled with a good solubilizing effect.
- the use of such solvents may therefore make it possible to dispense with any use of antioxidants.
- Cremophor EL may be used in limited quantities to help solubilize hydroquinone, but preferably alongside a solvent stabilizing hydroquinone, such as for example Miglyol.
- compositions according to the invention were made.
- physical stability is measured by macroscopic and microscopic observation of the formulation at room temperature, at 4 ° C and at room temperature.
- Chemical stability is measured by assaying the assets by external calibration in
- PHASE A In the beaker form introduce Glyceryl behenate and Cetearyl isononanoate. Bring the mixture to 85 ° C with slow stirring. Maintain agitation and heating until perfectly homogeneous. Stop heating and maintain agitation.
- phase E At 40 ° C maximum, add phase E while maintaining agitation. Then add phase F.
- Macroscopic appearance firm ointment, white
- Macroscopic appearance glossy white ointment
- Example 4 Efficiency test of the depigmenting activity of a composition according to the invention.
- Example 2 The composition of Example 2 is compared in a depigmenting activity measurement test on the tail of the mouse, to the composition below:
- Figure 1 show that at the same concentrations of active ingredients, the composition according to Example 2 of the present invention with adaplene dispersed in the fatty phase and hydroquinone solubilized in the fatty phase shows a depigmenting activity greater than the composition in which the adapalene and hydroquinone are solubilized and / or dispersed in the aqueous / alcoholic phase of a gel.
Abstract
The present invention relates to a novel anhydrous depigmenting composition especially for topical application, comprising, within the fatty phase, a solubilized phenolic derivative and a retinoid as pharmaceutical active agents, to the method for the preparation thereof and to the dermatological use thereof.
Description
COMPOSITIONS DEPIG M ENTANTES ANHYDRES COMPRENANT, AU SEIN DE LA PHASE GRASSE UN DERIVE PHENOLIQUE SOLUBILISE ET UN RETINOIDE ANHYDROUS DEPIG COMPOSITIONS COMPRISING, WITHIN THE FATTY PHASE, A SOLUBILIZED PHENOLIC DERIVATIVE AND A RETINOID
La présente invention se rapporte à une nouvelle composition dépigmentante cosmétique ou pharmaceutique caractérisée en ce qu'elle comprend, à titre d'actifs pharmaceutiques, ,un rétinoide et un dérivé phénolique solubilisé dans la phase grasse, pour une application topique, et à son procédé de préparation et à son utilisation en dermatologie.The present invention relates to a new cosmetic or pharmaceutical depigmenting composition characterized in that it comprises, as pharmaceutical active ingredients, a retinoid and a phenolic derivative solubilized in the fatty phase, for a topical application, and to its process preparation and its use in dermatology.
Parmi les agents thérapeutiques préconisés dans le traitement de l'hyperpigmentation cutanée, les dérivés phénoliques et plus particulièrement les polyphénols, depuis des décennies, parmi les actifs les plus efficaces. L'utilisation thérapeutique de ces agents résulte de l'observation de dépigmentations cutanées chez des ouvriers de l'industrie du caoutchouc où certains de ces produits sont utilisés comme antioxydants. Depuis, de nombreuses études n'ont fait que confirmer leur efficacité seuls ou associés à d'autres dépigmentants [Jorge L.Sanchez, M. D. and Miguel Vazquez, M. D International Journal of Dermatology Jan-Feb 1982 vol 21 p55 58]. Ils apparaissent ainsi comme des actifs pratiquement incontournables dans le traitement de l'hyperpigmentation et sont de ce fait présents dans de nombreux produits commerciaux.Among the therapeutic agents recommended in the treatment of cutaneous hyperpigmentation, phenolic derivatives and more particularly polyphenols, for decades, among the most effective assets. The therapeutic use of these agents results from the observation of skin depigmentation in workers in the rubber industry where some of these products are used as antioxidants. Since then, numerous studies have only confirmed their efficacy alone or in combination with other depigmenting agents [Jorge L. Sanchez, M.D. and Miguel Vazquez, M. International Journal of Dermatology Jan.-Feb 1982 vol 21 p55 58]. They thus appear as virtually inescapable assets in the treatment of hyperpigmentation and are therefore present in many commercial products.
Parmi les dérivés phénoliques, les polyphénols tel l'hydroquinone sont les actifs pharmaceutique les plus utilisés. L'hydroquinone a fait l'objet du dépôt de diverses demandes de brevet, et en particulier le brevet US 3,856,934 où l'hydroquinone est en association avec l'acide rétinoique et d'un corticoïde comme composition dépigmentante.Among the phenolic derivatives, polyphenols such as hydroquinone are the most used pharmaceutical active ingredients. Hydroquinone has been the subject of various patent applications, and in particular US Pat. No. 3,856,934, in which hydroquinone is in combination with retinoic acid and a corticosteroid as depigmenting composition.
Le rucinol ou lucinol, ou encore le 4-butyl-résorcinol est également un actif pharmaceutique dérivé phénolique, de type polyphénols, commercialisé comme agent éclaircissant des taches brunes liées aux troubles de la pigmentation (produit Iklen ®).Rucinol or lucinol, or 4-butyl-resorcinol is a phenol derivative pharmaceutical active agent, polyphenol type marketed as agent for lightening brown spots related to pigmentation disorders (product Iklen ®).
Mais dans la majorité des cas, l'hydroquinone, le rucinol ou leurs sels ou leurs dérivés sont solubilisés dans la phase aqueuse de la préparation.But in most cases, hydroquinone, rucinol or their salts or their derivatives are solubilized in the aqueous phase of the preparation.
Il est connu qu'un certain nombre de principes actifs présentant une activité thérapeutique intéressante sont sensibles à l'oxydation et subissent notamment une dégradation chimique conduisant à une perte sensible de leur activité en présence d'eau.
L'incorporation d'un dérivé phénolique comme l'hydroquinone ou le rucinol, présente donc, dans ce type de préparation aqueuse, un inconvénient majeur. En effet, on observe souvent la dégradation des formulations contenant des dérivés phénoliques tels que l'hydroquinone ou le rucinol, seuls ou en association avec d'autres principes actifs. Ces actifs sont effectivement connus pour leur grande sensibilité à l'oxydation et à la chaleur entraînant une diminution de l'efficacité, un brunissement rapide des formulations et pouvant mener même à une demixtion de la formulation. De plus, pour accélérer leur solubilisation, les dérivés phénoliques tels que l'hydroquinone ou le rucinol, sont souvent exposés à la chaleur au cours de la phase de réalisation de la composition, notamment dans les émulsions classiques, phénomène qui amorce et accélère le phénomène de brunissement.It is known that a certain number of active ingredients having a therapeutic activity of interest are sensitive to oxidation and in particular undergo chemical degradation leading to a significant loss of their activity in the presence of water. The incorporation of a phenol derivative such as hydroquinone or rucinol, therefore has, in this type of aqueous preparation, a major disadvantage. Indeed, the degradation of formulations containing phenolic derivatives such as hydroquinone or rucinol, alone or in combination with other active principles, is often observed. These active agents are actually known for their high sensitivity to oxidation and heat leading to a decrease in the effectiveness, a rapid browning of the formulations and which can even lead to a demixtion of the formulation. In addition, to accelerate their solubilization, phenol derivatives such as hydroquinone or rucinol, are often exposed to heat during the embodiment phase of the composition, especially in conventional emulsions, a phenomenon that initiates and accelerates the phenomenon. browning.
Dans l'art antérieur, des agents réducteurs sont utilisés pour combattre cette dégradation, en particulier les sulfites, quasi incontournables. Cependant ces antioxydants présentent un certain nombre d'inconvénients comme des problèmes d'irritation cutanée, d'odeur au niveau des formulations ou de déstabilisation de la formule lié à une perte de viscosité.In the prior art, reducing agents are used to combat this degradation, in particular sulfites, which are almost unavoidable. However, these antioxidants have a number of disadvantages such as skin irritation problems, odor in the formulations or destabilization of the formula related to a loss of viscosity.
Un autre inconvénient dû à la présence des dérivés phénoliques tels que l'hydroquinone, seule ou en association avec d'autres agents actifs dans la composition, est leur fort pouvoir irritant.Another disadvantage due to the presence of phenol derivatives such as hydroquinone, alone or in combination with other active agents in the composition, is their high irritancy.
L'hydroquinone de par son pouvoir irritant à concentration élevée peut engendrer des hypermélanoses post-inflammmatoires et des phénomènes d'ochronosis.Hydroquinone because of its high concentration of irritating effect can cause post-inflammatory hypermelanosis and ochronosis phenomena.
Des irritations locales et des dermatites peuvent se développer après une utilisation prolongée d'hydroquinone à haute concentration [« N-acetyl4S cysteaminylphénol as a new type of depigmenting agent » Jimbow K. Arch. Dermatol. 1991 Oct ; 127 (10): 1528- 1534].Local irritations and dermatitis may develop after prolonged use of high concentration hydroquinone ["N-acetyl4S cysteaminylphenol as a new type of depigmenting agent" Jimbow K. Arch. Dermatol. 1991 Oct; 127 (10): 1528-1534].
Le traitement à l'hydroquinone peut s'accompagner d'une irritation qui peut conduire à une hyperpigmentation post-inflammatoire. L'incidence de l'irritation dépend de la concentration en hydroquinone. Cette dernière est assez importante pour les concentrations à 10% et diminue fortement pour les préparations dosées à 5% et serait
pratiquement nulle à la concentration de 2% [« Les agents chimiques dépigmentants » JP. Ortonne Ann. Dermatol. Venerol.1986,1 13 :733-736].Treatment with hydroquinone may be accompanied by irritation that may lead to post-inflammatory hyperpigmentation. The incidence of irritation depends on the concentration of hydroquinone. The latter is quite important for the 10% concentrations and strongly decreases for the 5% virtually zero at 2% concentration ["Depigmenting Chemicals" JP. Ortonne Ann. Dermatol. Venerol. 1986, 13: 733-736].
La galénique choisie peut donc jouer un rôle prépondérant dans la minimisation de ces effets.The galenic chosen can therefore play a leading role in minimizing these effects.
Par conséquent, pour éviter la présence de sulfites et limiter l'utilisation d'antioxydants responsables d'irritation, il convient de formuler les dérivés phénoliques et en particulier l'hydroquinone sous forme solubilisée dans des huiles permettant la formulation de compositions parfaitement anhydres.Therefore, to avoid the presence of sulfites and limit the use of antioxidants responsible for irritation, it is appropriate to formulate phenol derivatives and in particular hydroquinone solubilized form in oils for the formulation of perfectly anhydrous compositions.
Dans les compositions anhydres décrites dans l'art antérieur, l'hydroquinone est en général solubilisée dans des solvants alcooliques ou glycoliques avant d'être incorporé au reste de la préparation anhydre. C'est le cas notamment dans la demande de brevet US 2006/0120979 décrit une composition comprenant de l'hydroquinone et une base anhydre constituée d'un solvant anhydre et d'un véhicule siliconé de haut poids moléculaire. L'hydroquinone est dans ce cas solubilisée dans un solvant de préférence sélectionné dans le groupe des alcools monohydriques (tels que l'isopropanol), des alcools dihydriques (tels que les glycols), des alcools trihydriques (comme le glycerol). Ces compositions ne contiennent pas de sulfites mais nécessitent des antioxydants lipophiles en quantité assez importante. En effet, l'hydroquinone dans un tel milieu subit tout de même une dégradation, moins marquée que dans l'eau mais suffisamment importante pour nécessiter la présence d'antioxydants lipophiles dans des proportions allant jusqu'à 1 % de la composition.In the anhydrous compositions described in the prior art, hydroquinone is generally solubilized in alcoholic or glycol solvents before being incorporated in the rest of the anhydrous preparation. This is particularly the case in US patent application 2006/0120979 describes a composition comprising hydroquinone and an anhydrous base consisting of an anhydrous solvent and a high molecular weight silicone vehicle. The hydroquinone is in this case solubilized in a solvent preferably selected from the group of monohydric alcohols (such as isopropanol), dihydric alcohols (such as glycols), trihydric alcohols (such as glycerol). These compositions do not contain sulphites but require lipophilic antioxidants in a fairly large amount. Indeed, the hydroquinone in such a medium undergoes any degradation, less marked than in water but sufficiently important to require the presence of lipophilic antioxidants in proportions of up to 1% of the composition.
Dans le brevet US 4,466,955, sont également décrites des compositions de type anhydre contenant de l'Hydroquinone. Les solvants utilisés sont uniquement des solvants de type éthers d'acides gras polyalkoxylés (dérivés de PPO ou de PEO). D'autre part, ces solvants doivent être utilisés à une concentration importantes comprise entre 30 - 60 % (de préférence 40 - 45 %) et en aucun cas en dessous, afin de parvenir à solubiliser entre 2 - 10 % d'hydroquinone. Par ailleurs, malgré le choix de ces solvants, une dégradation de l'hydroquinone est observée si un refroidissement rapide n'est pas effectué. Par ailleurs, il est précisé que la température de chauffe de la phase
contenant l'hydroquinone ne doit pas être supérieure à 45°C. Ceci amène donc des contraintes de procédés de fabrication importantes.In US Pat. No. 4,466,955, anhydrous compositions containing Hydroquinone are also described. The solvents used are only polyalkoxylated fatty acid ether solvents (PPO or PEO derivatives). On the other hand, these solvents must be used at a high concentration of between 30-60% (preferably 40-45%) and in no case below, in order to solubilize between 2 - 10% of hydroquinone. Moreover, despite the choice of these solvents, degradation of hydroquinone is observed if rapid cooling is not performed. In addition, it is specified that the heating temperature of the phase containing hydroquinone must not exceed 45 ° C. This brings constraints of important manufacturing processes.
L'un des buts de la présente invention est ici de solubiliser le dérivé phénolique dans un solvant huileux dans lequel l'actif est à la fois soluble et stable et dans lequel il est alors possible d'envisager l'incorporation de l'actif dans des procédés de fabrication qui nécessitent des étapes de chauffage sans avoir d'impact sur la stabilité de l'actif.One of the aims of the present invention is here to solubilize the phenolic derivative in an oily solvent in which the active agent is both soluble and stable and in which it is then possible to envisage the incorporation of the active ingredient into manufacturing processes that require heating steps without having an impact on the stability of the asset.
Un autre but de la présente invention est de proposer une composition pharmaceutique anhydre destinée à une application topique présentant une stabilité prolongée, permettant une libération optimisée s actifs tout en étant très bien tolérée.Another object of the present invention is to provide an anhydrous pharmaceutical composition intended for topical application having a prolonged stability, allowing optimized release active while being very well tolerated.
La présente invention se rapporte donc à une nouvelle composition stable anhydre, notamment pour une application topique, comprenant un dérivé phénolique de type polyphénols solubilisé et un rétinoide dans la phase grasse.The present invention thus relates to a novel anhydrous stable composition, especially for topical application, comprising a solubilized polyphenol phenol derivative and a retinoid in the fatty phase.
La composition selon l'invention, de par sa composition anhydre garantit à la fois une excellente stabilité et innocuité de la composition.The composition according to the invention, by virtue of its anhydrous composition, guarantees both excellent stability and harmlessness of the composition.
L'objet de la présente invention est une composition, pharmaceutique anhydre comprenant un actif pharmaceutqiue de type dérivé phénolique, et notamment de type polyphénols, et caractérisée en ce que ledit dérivé phénolique est solubilisé dans la phase grasse.The object of the present invention is an anhydrous pharmaceutical composition comprising a phenolic derivative-type pharmacological active agent, and in particular of the polyphenol type, and characterized in that the said phenolic derivative is solubilized in the fatty phase.
Par actif pharmaceutique de type dérivé phénolique selon l'invention, on peut citer à titre non limitatif les polyphénols et plus particulièrement l'hydroquinone, le rucinol ou lucinol et leurs sels, le 4-hydroxyanisol, le monoethyl éther d'hydroquinone et le monobenzylether d'hydroquinone. De préférence, on utilise l'hydroquinone, ou le rucinol et ses sels. Par sel de rucinol, on entend notamment des sels formés avec une base pharmaceutiquement acceptable, notamment un base minérale telle que la soude, la potasse, et l'ammoniaque ou une base organique telle que la lysine, l'arginine, la N- Méthyl-glucamine, mais également les sels formés avec des aminés grasses telle que la dioctylamine, l'aminométhyl propanil et la stéarylamine.By phenolic derivative-type pharmaceutical active agent according to the invention, mention may be made, without limitation, of polyphenols and more particularly hydroquinone, rucinol or lucinol and their salts, 4-hydroxyanisol, hydroquinone monoethyl ether and monobenzyl ether. hydroquinone. Preferably, hydroquinone, or rucinol and its salts are used. The term "rucinol salt" is intended especially to mean salts formed with a pharmaceutically acceptable base, in particular a mineral base such as sodium hydroxide, potassium hydroxide and ammonia, or an organic base such as lysine, arginine or N-methyl. -glucamine, but also the salts formed with fatty amines such as dioctylamine, aminomethyl propanil and stearylamine.
De préférence, on utilise l'hydroquinone ou le rucinol.
Avantageusement, la quantité de dérivé phénolique est de 0,01 à 10% en poids par rapport au poids total de la composition, de préférence de 0,1 à 6% en poids et plus particulièrement de 0,1 à 5% en poids.Preferably, hydroquinone or rucinol is used. Advantageously, the amount of phenol derivative is from 0.01 to 10% by weight relative to the total weight of the composition, preferably from 0.1 to 6% by weight and more particularly from 0.1 to 5% by weight.
La composition selon l'invention comprend à titre de second actif pharmaceutique, un rétinoide.The composition according to the invention comprises, as a second pharmaceutical active ingredient, a retinoid.
Par rétinoïde, on entend tout composé se liant aux récepteurs (récepteurs aux acides rétinoique (RARs) et/ou des récepteurs rétinoiques X (RXRs)) ainsi que leurs précurseurs et dérivés.By retinoid is meant any compound binding to receptors (retinoic acid receptors (RARs) and / or retinoic receptors X (RXRs)) as well as their precursors and derivatives.
Les rétinoïdes pouvant être utilisés dans le cadre de l'invention comprennent notamment l'acide tout-trans rétinoïque ou trétinoïne, l'acide 13-cis-rétinoïque ou isotrétinoïne, l'acitrétine, l'acide arotinoïque, le rétinol, le tazarotène, le rétinaldéhyde, l'etrétinate et les composés protégés dans les demandes de brevet EP 0 199 636, US 4,666,941 , US 4,581 ,380, EP 0 210 929, EP 0 232 199, EP 0 260 162, EP 0 292 348, EP 0 325 540, EP 0 359 621 , EP 0 409 728, EP 0 409 740, EP 0 552 282, EP 0 584 191 , EP 0 514 264, EP 0 514 269, EP 0 661 260, EP 0 661 258, EP 0 658 553, EP 0 679 628, EP 0 679 631 , EP 0 679 630, EP 0 708 100, EP 0 709 382, EP 0 722 928, EP 0 728 739, EP 0 732 328, EP 0 740 937, EP 0 776 885, EP 0 776 881 , EP 0 823 903, EP 0 832 057, EP 0 832 081 , EP 0 816 352, EP 0 826 657, EP 0 874 626, EP 0 934 295, EP 0 915 823, EP 0 882 033, EP 0 850 909, EP 0 879 814, EP 0 952 974, EP 0 905 1 18, EP 0 947 496, W098/56783, W099/10322, W099/50239, W099/65872, WO2006/066978, et notamment l'acide 6-(3-(1-adamantyl)-4-méthoxyphényl)-2- naphtoïque (adapalène) et son ester méthylique, les composés protégés dans la demande de brevet WO2006/066978 tel que l'acide 3"-tert-butyl-4'-(2-hydroxy-ethoxy)- 4"-pyrrolidin-1-yl-[1 ,1 ';3',1 "]terphenyl-4-carboxylique, les composés de la demande de brevet WO2007066041 dont l'acide 2-hydroxy-4-[3-hydroxy-3-(5,6,7,8-tétrahydro- 5,5,8,8-tétraméthyl-2-naphtyl)-1-propynyl]benzoique ou l'un de ses énantiomères, les composés de la demande de brevet WO 05/56516 dont l'acide 4'-(4-isopropylamino- butoxy)-3'-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-biphenyl-4- carboxylique, les composés de la demande de brevet WO2005056510 dont l'acide 4-{3- hydroxy-3-[4-(2-éthoxy-ethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl]- prop-1-ynyl}-benzoïque, les composés de la demande de brevet WO2005037772 dont l'acide 4-[2-(3-tert-butyl-4-diethylamino-phenyl)-2-hydroxyimino-ethoxy]-2-hydroxy- benzoïque.
En particulier, on préférera l'adapalène ainsi que ses sels, et l'acide 3"-tert-butyl- 4'-(2-hydroxy-ethoxy)-4"-pyrrolidin-1-yl-[1 ,1 ';3',1 "]terphenyl-4-carboxylique.The retinoids that can be used in the context of the invention include in particular all-trans retinoic acid or tretinoin, 13-cis-retinoic acid or isotretinoin, acitretin, arotinoic acid, retinol, tazarotene, retinaldehyde, etretinate and the compounds protected in patent applications EP 0 199 636, US 4,666,941, US 4,581,380, EP 0 210 929, EP 0 232 199, EP 0 260 162, EP 0 292 348, EP 0 325 540, EP 0 359 621, EP 0 409 728, EP 0 409 740, EP 0 552 282, EP 0 584 191, EP 0 514 264, EP 0 514 269, EP 0 661 260, EP 0 661 258, EP 0 658,553, EP 0 679 628, EP 0 679 631, EP 0 679 630, EP 0 708 100, EP 0 709 382, EP 0 722 928, EP 0 728 739, EP 0 732 328, EP 0 740 937, EP 0 776,885, EP 0 776 881, EP 0 823 903, EP 0 832 057, EP 0 832 081, EP 0 816 352, EP 0 826 657, EP 0 874 626, EP 0 934 295, EP 0 915 823, EP 0 882,033, EP 0 850 909, EP 0 879 814, EP 0 952 974, EP 0 905 18, EP 0 947 496, WO98 / 56783, WO99 / 10322, WO99 / 50239, WO99 / 6587. 2, WO2006 / 066978, and in particular 6- (3- (1-adamantyl) -4-methoxyphenyl) -2-naphthoic acid (adapalene) and its methyl ester, the compounds protected in the patent application WO2006 / 066978 that 3 "-tert-butyl-4 '- (2-hydroxyethoxy) -4" -pyrrolidin-1-yl- [1,1', 3 ', 1 "] terphenyl-4-carboxylic acid, compounds of Patent Application WO2007066041 including 2-hydroxy-4- [3-hydroxy-3- (5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) - 1-propynyl] benzoic acid or one of its enantiomers, the compounds of the patent application WO 05/56516 including 4 '- (4-isopropylamino-butoxy) -3' - (5,5,8,8 tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl) -biphenyl-4-carboxylic acid, the compounds of the patent application WO2005056510, including 4- {3- hydroxy-3- [4- (2-Ethoxy-ethoxy) -5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl] -prop-1-ynyl} -benzoic acid, the compounds of the application for Patent WO2005037772 including 4- [2- (3-tert-butyl-4-diethylamino-phenyl) -2-hydroxyimino-ethoxy] -2-h benzoic acid. In particular, adapalene and its salts are preferred, and 3 "-tert-butyl-4 '- (2-hydroxyethoxy) -4" -pyrrolidin-1-yl- [1, 1'; 3 ', 1 "] terphenyl-4-carboxylic acid.
Par sels de l'adapalène, on entend notamment les sels formés avec une base pharmaceutiquement acceptable, notamment des bases minérales telles que la soude, la potasse et l'ammoniaque ou des bases organiques telles que la lysine, l'arginine, la N-méthyl-glucamine, et les sels formés avec des aminés grasses telles que la dioctylamine et la stéarylamine. Par précurseurs de rétinoïdes, on entend leurs précurseurs biologiques immédiats ou substrats, ainsi que leurs précurseurs chimiques.Suitable salts of adapalene are in particular salts formed with a pharmaceutically acceptable base, in particular mineral bases such as sodium hydroxide, potassium hydroxide and aqueous ammonia or organic bases such as lysine, arginine, N- methylglucamine, and salts formed with fatty amines such as dioctylamine and stearylamine. By retinoid precursors are meant their immediate biological precursors or substrates, as well as their chemical precursors.
Par dérivés des rétinoïdes, on entend aussi bien leurs dérivés métaboliques que leurs dérivés chimiques.Derivatives of retinoids include both their metabolic derivatives and their chemical derivatives.
De préférence, la composition comprend une quantité d'agent rétinoide comprise entre 0,0001 et 1 % en poids par rapport au poids total de la composition, de préférence comprise entre 0,001 et 0,3%, encore plus préférentiellement comprise entre 0,01 et 0,1 % en poids.Preferably, the composition comprises an amount of retinoid agent of between 0.0001 and 1% by weight relative to the total weight of the composition, preferably between 0.001 and 0.3%, even more preferably between 0.01. and 0.1% by weight.
La présente invention se rapporte donc à une nouvelle composition stable anhydre, notamment pour une application topique, comprenant au sein d'une phase grasse, un rétinoide et un dérivé phénolique solubilisé.The present invention thus relates to a new anhydrous stable composition, especially for topical application, comprising within a fatty phase, a retinoid and a solubilized phenol derivative.
La composition selon l'invention, de par sa nature anhydre garantit à la fois une excellente stabilité et innocuité de la composition.The composition according to the invention, by its anhydrous nature guarantees both excellent stability and harmlessness of the composition.
Par composition « anhydre », on entend une composition comprenant une quantité d'eau inférieure ou égale à 5% en poids par rapport au poids total de la composition.By "anhydrous" composition is meant a composition comprising a quantity of water less than or equal to 5% by weight relative to the total weight of the composition.
Dans un mode préféré selon l'invention, la composition ne contient pas d'eau.In a preferred embodiment according to the invention, the composition does not contain water.
Par composition stable, on entend une composition stable chimiquement et physiquement. Par stabilité chimique, on entend notamment qu'aucune dégradation de l'actif n'est constatée dans le temps et à des températures comprises entre 4 et 400C.
Par stabilité physique, on entend notamment que les compositions ne présentent pas de modification d'aspect macroscopique en particulier de couleur ni d'aspect microscopique sans évolution de viscosité dans le temps et à des températures comprises entre 4 et 400C. Optionnellement, une mesure du seuil d'écoulement peut-être réalisée afin de caractériser le produit fini.By stable composition is meant a chemically and physically stable composition. By chemical stability is meant in particular that no degradation of the active is observed over time and at temperatures between 4 and 40 ° C. By physical stability, it is meant in particular that the compositions do not exhibit a macroscopic appearance modification in particular of color or of microscopic appearance without evolution of viscosity with time and at temperatures between 4 and 40 ° C. Optionally, a Flow threshold measurement can be carried out to characterize the finished product.
Pour la mesure du seuil d'écoulement, un rhéomètre HAAKE de type VT550 avec un mobile de mesure SVDIN a été utilisé.For the measurement of the flow threshold, a HAAKE rheometer of type VT550 with a measurement mobile SVDIN was used.
Les rhéogrammes sont réalisés à 25°C et en vitesse imposée de 0 à 100s"1. Les valeurs de viscosité sont données aux valeurs de cisaillement de 4 s"1, 20s"1, 100s"1 (γ). Par seuil d'écoulement (τ0 exprimé en Pascal) on entend la force nécessaire (contrainte de cisaillement minimum) pour vaincre les forces de cohésion de type Van der Waals et provoquer l'écoulement.The rheograms are produced at 25 ° C and imposed speed from 0 to 100 s "1. The viscosity values are given to the shear values of 4 s" 1, 20s "1 100s" 1 (γ). By flow threshold (τ 0 expressed in Pascal) is meant the force required (minimum shear stress) to overcome Van der Waals cohesive forces and cause flow.
Dans l'ensemble de la présente demande, par température ambiante, on entend une température comprise entre 20 et 300C.Throughout the present application, ambient temperature means a temperature between 20 and 30 ° C.
Le caractère anhydre de la composition selon l'invention permet d'éviter l'instabilité du dérivé phénolique en particulier son oxydation en milieu aqueux. Dans une telle formulation l'utilisation de sulfites indispensables pour la stabilisation de l'hydroquinone en milieu aqueux n'est donc plus nécessaire. Par conséquent, dans un mode préféré selon l'invention, la composition ne contient pas de sulfites et contient une quantité d'antioxydants strictement inférieure à 0.3% et préférentiellement inférieure à 0.2% en poids par rapport au poids total de la composition. Les anti-oxydants utilisables selon l'invention sont préférentiellement des antioxydants tels que la vitamine E et ses dérivés, comme le DL alpha Tocopherol ou l'acétate de tocopherol de Roche ; la vitamine C et ses dérivés, comme l'Ascorbyl Palmitate de Roche, le Butylhydroxytoluene vendu sous le nom de Nipanox BHT par Clariant.The anhydrous nature of the composition according to the invention makes it possible to avoid the instability of the phenol derivative, in particular its oxidation in an aqueous medium. In such a formulation the use of sulphites essential for the stabilization of hydroquinone in an aqueous medium is no longer necessary. Therefore, in a preferred embodiment according to the invention, the composition does not contain sulfites and contains an amount of antioxidants strictly less than 0.3% and preferably less than 0.2% by weight relative to the total weight of the composition. The antioxidants that can be used according to the invention are preferably antioxidants such as vitamin E and its derivatives, such as DL alpha Tocopherol or Roche tocopherol acetate; vitamin C and its derivatives, such as Roche's Ascorbyl Palmitate, butylhydroxytoluene sold under the name Nipanox BHT by Clariant.
La composition selon l'invention comprend au moins une phase grasse suivante, ou phase huileuse suivante, du composé de la famille des dérivés phénoliques, et de préférence l'hydroquinone ou le rucinol.
La composition selon l'invention comprend au moins une phase grasse, ou phase huileuse, solubilisante ou dispersante du rétinoide.The composition according to the invention comprises at least one subsequent fatty phase, or the following oily phase, of the compound of the family of phenolic derivatives, and preferably hydroquinone or rucinol. The composition according to the invention comprises at least one fatty phase, or oily phase, solubilizing or dispersing retinoid.
En effet, la plupart des rétinoides sont solubles dans différents solvants, y compris des solvant huileux. Cependant, le rétinoide préféré selon l'invention, l'adapalène, présente la particularité d'être insoluble dans la totalité des solvants utilisables pour les rétinoides. Dans toute composition et notamment dans la présente invention, l'adapalène doit donc être dispersé, et plus particulièrement dans la phase grasse de la présente invention.Indeed, most retinoids are soluble in various solvents, including oily solvents. However, the preferred retinoid according to the invention, adapalene, has the particularity of being insoluble in all the solvents that can be used for retinoids. In any composition and especially in the present invention, the adapalene must be dispersed, and more particularly in the fatty phase of the present invention.
La phase huileuse suivante du dérivé phénolique et la phase huileuse suivante ou dispersante du rétinoide, peut, mais n'est pas obligatoirement constituée par les mêmes corps gras.The following oily phase of the phenol derivative and the following oily or dispersant phase of the retinoid may, but need not be, the same fatty substances.
Dans un mode préféré selon l'invention, la composition comprend au moins une phase huileuse suivante de l'actif pharmaceutique dérivé phénolique, notamment l'hydroquinone ou le rucinol et au moins une phase huileuse dispersante de l'adapalène.In a preferred embodiment according to the invention, the composition comprises at least one subsequent oily phase of the phenolic-derived pharmaceutical active agent, in particular hydroquinone or rucinol and at least one oily dispersant phase of adapalene.
Comme constituants de la phase suivante et/ou dispersante huileuse, on entend notamment :As constituents of the following phase and / or oily dispersant is meant in particular:
- des huiles végétales, comme l'huile de ricin, l'huile d'amande douce vendue par Sictia ou l'huile de sésame vendue par CPF ;vegetable oils, such as castor oil, sweet almond oil sold by Sictia or sesame oil sold by CPF;
- des huiles silicones comme la cyclométhicone vendue sous le nom de ST- Cyclomethicone 5NF par Dow Corning ou la Dimethicone vendue sous le nom de Q7 9120 silicon fluid par Dow corning ;silicone oils such as cyclomethicone sold under the name ST-Cyclomethicone 5NF by Dow Corning or Dimethicone sold under the name Q7 9120 silicon fluid by Dow Corning;
- des huiles minérales, comme le Marcol 152 ou le Primol 352 vendu par Esso ;mineral oils, such as Marcol 152 or Primol 352 sold by Esso;
- le perhydrosqualène ;perhydrosqualene;
- des triglycérides comme les Triglycérides Caprylique / Caprique vendus sous le nom de Miglyol 812 N par IMCD, ou dérivés comme le PEG-8 caprylic capric triglycérides vendu sous le nom Labrasol par Gattefossé ;triglycerides such as Caprylic / Caprique Triglycerides sold under the name Miglyol 812 N by IMCD, or derivatives such as PEG-8 caprylic capric triglycerides sold under the name Labrasol by Gattefossé;
- des esters, comme l'Octyl Dodecyl Myristate vendu sous le nom de MOD par Gattefossé, le C12-C15 Alkyl benzoate vendu sous le nom de Tegosoft TN par Goldschmit ou l'Isononanoate de cétéaryle vendu sous le nom de Cetiol SN PH par Cognis ou encore le diisopropyl adipate vendu sous le nom de Crodamol DA par la société Croda ;
- les alcools de Guerbet comme l'octyldodécanol vendu sous le nom de Eutanol G par Cognis ;esters, such as the Octyl Dodecyl Myristate sold under the name MOD by Gattefossé, the C12-C15 alkyl benzoate sold under the name Tegosoft TN by Goldschmit or the cetearyl isononanoate sold under the name Cetiol SN PH by Cognis or else diisopropyl adipate sold under the name Crodamol DA by the company Croda; Guerbet alcohols such as octyldodecanol sold under the name Eutanol G by Cognis;
- les éthers et dérivés comme le PPG-15 Stearyl ether vendu sous le nom d'Arlamol E par la société Croda ; - et leurs mélanges.ethers and derivatives such as PPG-15 Stearyl ether sold under the name Arlamol E by the company Croda; - and their mixtures.
De préférence, on choisira comme solvants huileux du dérivé phénolique, et plus particulièrement de l'hydroquinone ou du rucinol, le PPG-15 stearyl éther ou tout autre éther ou dérivés, le diisopropyl adipate ou tout autre ester ou dérivés ou encore les triglycérides comme les caprylic capric triglycérides ou leurs dérivés ou un mélange de ces composés. La composition selon l'invention comprend plus particulièrement un mélange de solvants. De façon préférentielle, le mélange de solvants sera constitué au maximum de 15% (en poids par rapport au poids total de la composition) de solvant de type dérivés d'éthers. Dans la composition selon l'invention, cette quantité de solvant, combinée aux autres solvants nouveaux présents est suffisante pour solubiliser les concentrations recherchées d'actif et obtenir des préparations stables.Preferably, the oily solvents of the phenol derivative, and more particularly hydroquinone or rucinol, PPG-15 stearyl ether or any other ether or derivatives, diisopropyl adipate or any other ester or derivatives or triglycerides as caprylic capric triglycerides or their derivatives or a mixture of these compounds. The composition according to the invention more particularly comprises a mixture of solvents. Preferably, the solvent mixture will consist of at most 15% (by weight relative to the total weight of the composition) of ethers-derived solvent. In the composition according to the invention, this amount of solvent, combined with the other new solvents present, is sufficient to solubilize the desired concentrations of active ingredients and to obtain stable preparations.
De préférence, on choisira comme dispersants huileux du rétinoïde et plus particulièrement d'adapalène, les triglycérides comme les caprylic capric triglycérides ou leurs dérivés.Preferably, as oily dispersants, the retinoid and more particularly adapalene, triglycerides such as capric capric triglycerides or their derivatives, will be chosen.
La phase huileuse suivante et/ou dispersante de l'actif comprend au moins un solvant et/ou dispersant huileux de l'actif et/ou un tensioactif lipophile.The following oil phase and / or dispersant active comprises at least one solvent and / or oily dispersant of the active and / or lipophilic surfactant.
Par tensioactif lipophile, on entend plus particulièrement :Lipophilic surfactant more particularly means:
Les dérivés d'huile de ricin polyoxyéthylénés comme par exemple le PEG-35 castor oil commercialisée notamment sous le nom de Cremophor EL par BASF. Les dérivés polyoxyéthylénés d'esters d'acides gras comme par exemple le PEG-8 caprylic capric triglycérides commercialisé sous le nom de LABRASOL par Gattefossé.The polyoxyethylenated castor oil derivatives, for example the PEG-35 castor oil marketed in particular under the name Cremophor EL by BASF. The polyoxyethylenated derivatives of fatty acid esters, for example PEG-8 caprylic capric triglycerides marketed under the name LABRASOL by Gattefossé.
La quantité de phase grasse suivante et/ou dispersante dans la composition selon l'invention est généralement comprise entre 5% et 99%, préférentiellement de 10 à 98% en poids par rapport au poids total de la composition.
Selon un mode de réalisation particulier, les compositions selon l'invention ne contiennent pas de solvants alcooliques ou glycoliques.The amount of the following fat phase and / or dispersant in the composition according to the invention is generally between 5% and 99%, preferably from 10 to 98% by weight relative to the total weight of the composition. According to a particular embodiment, the compositions according to the invention do not contain alcoholic or glycolic solvents.
La composition selon l'invention peut comprendre en outre au moins un gélifiant ou épaississant lipophile selon la viscosité souhaitée. En effet, ces composés sont utilisés dans la présente invention comme « ajusteurs de viscosité » :The composition according to the invention may further comprise at least one lipophilic gelling agent or thickener according to the desired viscosity. Indeed, these compounds are used in the present invention as "viscosity adjusters":
Par épaississants ou gélifiants lipophiles selon l'invention, on entend des composés, notamment choisis parmi les cires, les huiles hydrogénées, les esters d'acides gras.By lipophilic thickeners or gelling agents according to the invention is meant compounds, especially chosen from waxes, hydrogenated oils and fatty acid esters.
Par cire, on entend d'une manière générale un composé lipophile, solide à température ambiante (25 0C), à changement d'état solide / liquide réversible, ayant un point de fusion supérieur ou égal à 30 0C pouvant aller jusqu'à 200 0C et notamment jusqu'à 120 0C. Comme cires utilisables, on peut citer la cire de carnauba, les cires microcristallines, la cire d'abeille commercialisée sous le nom de Cerabeil blanche par Barlocher, le béhénate de glycéryle, ses dérivés comme le monobéhénate de glycéryle, le dibénénate de glycéryle, la tribéhénine ou leur mélange comme celui commercialisé sous la dénomination Compritol 888 par Gattefossé, ou encore la cire de candellila.By wax is generally meant a lipophilic compound, solid at room temperature (25 ° C.), with a reversible solid / liquid state change, having a melting point of greater than or equal to 30 ° C. and up to at 200 ° C. and in particular up to 120 ° C. As useful waxes, mention may be made of carnauba wax, microcrystalline waxes, beeswax marketed under the name White Cerabeil by Barlocher, glyceryl behenate, its derivatives such as glyceryl monobhenenate, glyceryl dibenenate, tribehenine or a mixture thereof, such as the product marketed under the name Compritol 888 by Gattefossé, or else candelilla wax.
Par huile hydrogénée, on entend les huiles obtenues par hydrogénation catalytique d'huiles animales ou végétales ayant des chaînes grasses, linéaires ou ramifiées, en C8-C32. Parmi celles-ci, on peut notamment citer l'huile de jojoba hydrogénée, l'huile de jojoba isomérisée telle que l'huile de jojoba partiellement hydrogénée isomérisée trans fabriquée ou commercialisée par la société Désert Whale sous la référence commerciale ISO-JOJOBA-50®, l'huile de tournesol hydrogénée, l'huile de ricin hydrogénée, commercialisée notamment sous le nom de Cutina HR par Cognis, l'huile de ricin polyoxyéthyléné commercialisée notamment sous le nom de Cremophor EL par BASF, l'huile de coprah hydrogénée et l'huile de lanoline hydrogénée ; de préférence, on utilisera l'huile de ricin hydrogénée. Comme esters d'acides gras utilisables, on peut citer la lanoline vendue notamment sous le nom de Medilan par Croda, les glycéryl esters d'acides gras vendus sous le nom de Gelucire par Gattefossé, les glycérides hydrogénés de coco vendus sous le nom d'Akosoft 36 par Karlshamns, ou encore le monostéarate de diéthylène glycol ou de propylène glycol vendus respectivement sous le nom d'Hydrine ou de Monostéol par Gattefossé.
La quantité d'épaississants ou gélifiants lipophiles dans la composition selon l'invention est généralement comprise entre 1 et 40% en poids par rapport au poids total de la composition, de préférence comprise entre 5 et 30%.Hydrogenated oil is understood to mean the oils obtained by catalytic hydrogenation of animal or vegetable oils having linear or branched C 8 -C 32 fatty chains. Among these, there may be mentioned hydrogenated jojoba oil, isomérisée jojoba oil such as trans isomerized partially hydrogenated jojoba oil manufactured or marketed by Desert Whale under the trade reference ISO-JOJOBA-50 ® , hydrogenated sunflower oil, hydrogenated castor oil, marketed in particular under the name of Cutina HR by Cognis, polyoxyethylenated castor oil sold in particular under the name Cremophor EL by BASF, hydrogenated coconut oil and hydrogenated lanolin oil; preferably, the hydrogenated castor oil will be used. As fatty acid esters that may be used, mention may be made of lanolin sold in particular under the name of Medilan by Croda, the glyceryl esters of fatty acids sold under the name of Gelucire by Gattefossé, the hydrogenated glycerides of coconut sold under the name of Akosoft 36 by Karlshamns, or the monostearate of diethylene glycol or propylene glycol sold respectively under the name Hydrine or Monosteol by Gattefosse. The amount of lipophilic thickeners or gelling agents in the composition according to the invention is generally between 1 and 40% by weight relative to the total weight of the composition, preferably between 5 and 30%.
La composition selon l'invention peut contenir un élastomère. On entend par élastomère, tout élastomère polyorganosiloxane, à savoir tout polymère de siloxane chimiquement réticulé qui présente des propriétés viscoélastiques comme notamment et de façon préférée, l'Elastomer 10 commercialisé par Dow Corning. La quantité d'élastomère de haut poids moléculaire dans la composition selon l'invention est généralement comprise entre 0% et 40%, préférentiellement de 0 à 20% en poids par rapport au poids total de la composition.The composition according to the invention may contain an elastomer. The term "elastomer" is intended to mean any polyorganosiloxane elastomer, namely any chemically crosslinked siloxane polymer which has viscoelastic properties, such as especially and preferably, Elastomer 10 marketed by Dow Corning. The amount of elastomer of high molecular weight in the composition according to the invention is generally between 0% and 40%, preferably from 0 to 20% by weight relative to the total weight of the composition.
Optionnellement, la composition selon l'invention peut également comprendre un autre tensioactif, et/ou au moins un liant.Optionally, the composition according to the invention may also comprise another surfactant, and / or at least one binder.
Les tensioactifs utilisés sont de préférence des tensioactifs non ioniques, utilisés par exemple, mais non exclusivement, pour faciliter l'incorporation de certains constituants comme les glycols dans la phase huileuse de la composition. Parmi les tensioactifs utilisables selon l'invention, on peut citer les esters de glycéryle et éventuellement de polyéthylène glycol, tels que le mélange de stéarate de glycéryle et de PEG-100 stéarate, vendu sous le nom d'Arlacel 165 par Uniqema, le mélange de stéarate de glycéryle et de PEG-75 stéarate, vendu sous le nom de Gelot 64 par Gattefossé, le stéarate de glycéryle vendu sous le nom de Cutina GMSV par Cognis ; les cires émulsionnantes, telles que la cire autoémulsionnante vendue sous le nom de Polawax NF par Croda, ou la cire d'abeille PEG-8 vendue sous le nom d'Apifil par Gattefossé ; le polysorbate 80 vendu sous le nom de Tween 80 par Uniqema ; l'huile de ricin et dérivés comme par exemple l'huile de ricin polyoxyethylénée de BASF vendu sous le nom commercial de crémophor EL, ou encore le mélange de stéarate de glycérol et de PEG-2 stéarate, vendu sous le nom de Sedefos 75 par Gattefossé. De préférence, on utilisera le Polysorbate 80. La quantité de tensioactifs est comprise entre 0,1 et 20% en poids, de préférence entre 1 et 10% en poids.The surfactants used are preferably nonionic surfactants, used for example, but not exclusively, to facilitate the incorporation of certain constituents such as glycols into the oily phase of the composition. Among the surfactants that may be used according to the invention, mention may be made of glyceryl and optionally polyethylene glycol esters, such as the mixture of glyceryl stearate and PEG-100 stearate, sold under the name Arlacel 165 by Uniqema, the mixture glyceryl stearate and PEG-75 stearate, sold under the name Gelot 64 by Gattefossé, glyceryl stearate sold under the name Cutina GMSV by Cognis; emulsifying waxes, such as the self-emulsifying wax sold under the name of Polawax NF by Croda, or the PEG-8 beeswax sold under the name of Apifil by Gattefossé; polysorbate 80 sold under the name Tween 80 by Uniqema; castor oil and derivatives such as BASF polyoxyethylenated castor oil sold under the trade name of Cremophor EL, or the mixture of glycerol stearate and PEG-2 stearate, sold under the name Sedefos 75 by Gattefossé. Preferably, Polysorbate 80 will be used. The amount of surfactants is between 0.1 and 20% by weight, preferably between 1 and 10% by weight.
La composition peut optionnellement comprendre au moins un liant. Parmi les liants utilisables, on peut citer le stéarate de magnésium vendu par Brenntag, l'amidon de maïs vendu par Roquette, le talc vendu par WCD, le cholestérol vendu par Croda ou
la silice vendue par Degussa.The composition may optionally comprise at least one binder. Among the binders that can be used include magnesium stearate sold by Brenntag, corn starch sold by Roquette, talc sold by WCD, cholesterol sold by Croda or silica sold by Degussa.
Les liants peuvent être utilisés en quantité comprise entre 0.1 et 30% en poids, de préférence entre 1 et 20% en poids.The binders can be used in an amount of between 0.1 and 30% by weight, preferably between 1 and 20% by weight.
La composition selon l'invention peut également contenir des additifs que l'homme de l'art choisira en fonction de l'effet recherché.The composition according to the invention may also contain additives that those skilled in the art will choose according to the desired effect.
Parmi les additifs on peut citer en exemple, pris seuls ou combinés :Among the additives, for example, taken alone or in combination:
- des vitamines telles que la vitamine PP ou niacinamide ;vitamins such as vitamin PP or niacinamide;
- des agents apaisants ou anti-irritants, tels que le PPG-12/SMDI copolymer vendu par la société Bertek pharmaceuticals sous le nom commercial de Polyolprepolymer-2 ou encore de l'acide glycyrrhetinique ou ses dérivés comme par exemple l'Enoxolone vendu par la société Cognis ;soothing or anti-irritant agents, such as the PPG-12 / SMDI copolymer sold by the company Bertek pharmaceuticals under the trade name Polyolprepolymer-2 or also glycyrrhetinic acid or its derivatives such as, for example, enoxolone sold by the Cognis company;
- des agents hydratants ou humectants : on peut citer par exemple des sucres et dérivés, des glycols, de la glycérine, du sorbitol ; - des lécitines, du cholestérol ;moisturizing or humectant agents: mention may be made, for example, of sugars and derivatives, of glycols, of glycerine, of sorbitol; - lecitins, cholesterol;
- des conservateurs, tels le methyl paraben vendu sous le nom de Nipagin M par Clariant, le propyl paraben vendu sous le nom de Nipasol par Clariant, ou encore le phenoxyethanol vendu sous le nom de phenoxetol par Clariant ;preservatives, such as paraben methyl sold under the name Nipagin M by Clariant, propyl paraben sold under the name Nipasol by Clariant, or phenoxyethanol sold under the name phenoxetol by Clariant;
- des acides ou bases tels que l'acide citrique, le sodium citrate, la triethanolamine, l'aminométhylpropanol, le sodium hydroxyde, la diisopropanolamine ;acids or bases such as citric acid, sodium citrate, triethanolamine, aminomethylpropanol, sodium hydroxide, diisopropanolamine;
- autres additifs permettants de conférer à la dite préparation des propriétés spécifiques.other additives making it possible to confer on the said preparation specific properties.
Préférentiellement, la composition selon l'invention comprend, en poids par rapport au poids total :Preferably, the composition according to the invention comprises, by weight relative to the total weight:
0,01 à 10% d'au moins un actif pharmaceutique dérivé phénolique,0.01 to 10% of at least one phenolic derivative drug,
0,0001 à 1 % d'au moins un rétinoide,0.0001 to 1% of at least one retinoid,
0.05% à 99% d'une phase huileuse suivante et/ou dispersante des actifs pharmaceutiques,0.05% to 99% of an oily phase following and / or dispersing pharmaceutical active ingredients,
0 à 50% de gélifiants ou épaississants lipophiles supplémentaires, - 0 à 20% d'additifs.0 to 50% additional lipophilic gelling agents or thickeners, 0 to 20% additives.
Plus préférentiellement, la composition selon l'invention comprend, en poids par rapport au poids total :
0,01 à 10% d'au moins un actif pharmaceutique dérivé phénolique, de préférence l'hydroquinone ou le rucinol, 0,0001 à 1 % d'un rétinoide, de préférence l'adapalène, 1 % à 99% d'une phase huileuse suivante et/ou dispersante des actifs pharmaceutiques,More preferentially, the composition according to the invention comprises, by weight relative to the total weight: 0.01 to 10% of at least one phenolic derivative drug, preferably hydroquinone or rucinol, 0.0001 to 1% of a retinoid, preferably adapalene, 1% to 99% of a oily phase following and / or dispersing pharmaceutical active ingredients,
1 à 40% de gélifiants ou épaississants lipophiles supplémentaires, 0 à 20% de tensioactifs,1 to 40% of additional lipophilic gelling agents or thickeners, 0 to 20% of surfactants,
- 0 à 30% de liant(s),0 to 30% of binder (s),
- 0 à 10% d'additifs.0 to 10% of additives.
Encore plus préférentiellement, la composition selon l'invention comprend, en poids par rapport au poids total :Even more preferentially, the composition according to the invention comprises, by weight relative to the total weight:
0,01 à 5% d'hydroquinone ou de rucinol,0.01 to 5% hydroquinone or rucinol,
- 0,001 à 0.3% d'adapalène, - 1 % à 98% d'une phase huileuse suivante des actifs pharmaceutiques,0.001 to 0.3% of adapalene, 1% to 98% of an oily phase following pharmaceutical active ingredients,
10 à 25% de béhénate de glycéryle, 0 à 10% de tensioactifs,10 to 25% of glyceryl behenate, 0 to 10% of surfactants,
- 0 à 20% de liant(s), - 0 à 10% d'additifs.0 to 20% of binder (s), 0 to 10% of additives.
La composition anhydre selon l'invention peut se présenter sous les différentes formes galéniques connues que l'homme du métier adaptera à l'utilisation particulière de la composition. Les compositions selon l'invention sont de préférence formulées pour une application par voie topique.The anhydrous composition according to the invention may be in the various known galenic forms which the person skilled in the art will adapt to the particular use of the composition. The compositions according to the invention are preferably formulated for topical application.
Par voie topique, on entend une application externe sur la peau ou les muqueuses.By topical means an external application on the skin or mucous membranes.
Les compositions peuvent se présenter sous toutes les formes galéniques normalement utilisées pour une administration par voie topique. A titre d'exemple non limitatif des compositions telles que décrites aux pharmacopées américaines (USP32-NF27 - Chap 1 151- Pharmaceutical Dosage Forms) ou européennes (Edition 6.3 - Chapitre Préparations semi-solides pour application cutanée ou telles que définies dans les arbres de décision de la « Food and Drug Administration » américaine (FDA) (CDER Data Standards Manual Définitions for topical dosage Forms). Les compositions selon
l'invention peuvent donc se présenter sous forme liquide, semi-solide, pâteuse ou solide et, plus particulièrement, sous forme d'onguents, de solutions huileuses, de dispersions du type lotion éventuellement biphasée, de sérum, de gels anhydres ou lipophiles, de poudres, de tampons imbibés, de syndets, de lingettes, de sprays, de mousses, de sticks, de shampoings, de compresses, de bases lavantes, d'émulsions de consistance liquide ou semi-liquide du type huile dans glycol ou glycol dans huile, d'une microémulsion, de suspensions ou émulsions semi-liquide ou solide du type crème blanche ou colorée, émulsions multiples ou inverses, gel ou pommade, de suspensions de microsphères ou nanosphères ou de vésicules lipidiques ou polymériques, ou de microcapsules, micro- ou nanoparticules ou de patchs polymériques ou gélifiés permettant une libération contrôlée.The compositions may be in any dosage form normally used for topical administration. By way of nonlimiting example of the compositions as described in the US Pharmacopoeia (USP32-NF27 - Chap. 1 151- Pharmaceutical Dosage Forms) or European (Edition 6.3 - Chapter Semi-solid preparations for cutaneous application or as defined in the trees of US Food and Drug Administration (FDA) decision (CDER Data Standards Manual Definitions for topical the invention may therefore be in liquid, semi-solid, pasty or solid form and, more particularly, in the form of ointments, oily solutions, dispersions of the lotion type that may be biphasic, serum, anhydrous or lipophilic gels, powders, soaked swabs, syndets, wipes, sprays, foams, sticks, shampoos, compresses, washing bases, emulsions of liquid or semi-liquid consistency of the type oil in glycol or glycol in oil, a microemulsion, suspensions or semi-liquid or solid emulsions of the white or colored cream type, multiple or inverse emulsions, gel or ointment, suspensions of microspheres or nanospheres or of lipid or polymeric vesicles, or microcapsules, micro or nanoparticles or polymeric or gelled patches allowing controlled release.
La composition anhydre selon l'invention est de préférence un onguent. Par onguent selon l'invention, on entend une composition notamment telle que définie dans les pharmacopées Américaine ou Européennes mentionnées plus haut. La FDA définit ainsi l'onguent comme une composition semi-solide comprenant, en tant que véhicule, moins de 20% d'eau et de composés volatiles et plus de 50% d'hydrocarbones, de cires, ou de polyol. Dans certains cas, lorsque les teneurs en volatiles sont importantes de telles compositions peuvent s'appeler des crèmes (Arbre de décision de la « Food and Drug Administration » américaine (FDA)). La Pharmacopée Américaine définit un onguent comme un produit dont la base est un véhicule pouvant appartenir aux 4 classes suivantes : base hydrocarbone ou base absorbante ou base lavable à l'eau ou base soluble dans l'eau. De préférence, l'onguent, selon l'invention et la pharmacopée américaine appartient à la classe des onguents à base hydrocarbone. La pharmacopée européenne définit l'onguent comme une composition monophase dans lequel peuvent être dispersés des liquides ou des solides.The anhydrous composition according to the invention is preferably an ointment. Ointment according to the invention means a particular composition as defined in the American or European pharmacopoeia mentioned above. The FDA thus defines the ointment as a semi-solid composition comprising, as a carrier, less than 20% water and volatile compounds and more than 50% hydrocarbons, waxes, or polyol. In some cases, when volatile levels are important such compositions may be called creams (American Food and Drug Administration (FDA) decision tree). The American Pharmacopoeia defines an ointment as a product whose base is a vehicle that can belong to the following 4 classes: hydrocarbon base or absorbent base or water-washable base or water-soluble base. Preferably, the ointment according to the invention and the American pharmacopoeia belongs to the class of hydrocarbon-based ointments. The European Pharmacopoeia defines ointment as a single-phase composition in which liquids or solids can be dispersed.
De façon préférentielle, l'onguent selon l'invention est une composition épaisse à température ambiante, qui comprend entre 80 et 98% en poids par rapport au poids total de la composition de composés hydrophobes distincts de la vaseline. De tels composés sont notamment choisis parmi des huiles liquides seules ou en mélange, lesdites huiles pouvant être des hydrocarbures, des esters, des huiles végétales et/ou des huiles silicones, volatiles ou non volatiles, pouvant être gélifiés par des composés lipophiles solides à température ambiante tels que des cires, des beurres, des esters d'acides gras.
Optionnellement, une mesure du seuil d'écoulement peut-être réalisée afin de caractériser le produit fini.Preferably, the ointment according to the invention is a thick composition at room temperature, which comprises between 80 and 98% by weight relative to the total weight of the composition of hydrophobic compounds distinct from petroleum jelly. Such compounds are chosen in particular from liquid oils alone or as a mixture, said oils possibly being volatile or nonvolatile hydrocarbons, esters, vegetable oils and / or silicone oils which can be gelled by lipophilic compounds which are solid at temperature. such as waxes, butters, esters of fatty acids. Optionally, a flow threshold measurement may be performed to characterize the finished product.
Pour la mesure du seuil d'écoulement, un rhéomètre HAAKE de type VT550 avec un mobile de mesure SVDIN a été utilisé. Les rhéogrammes sont réalisés à 25°C, en vitesse imposée de 0 à 100s"1. Les valeurs de viscosité sont données aux valeurs de cisaillement de 4 s"1, 20s"1, 100s"1 (γ). Par seuil d'écoulement (τ0 exprimé en Pascal) on entend la force nécessaire (contrainte de cisaillement minimum) pour vaincre les forces de cohésion de type Van der Waals et provoquer l'écoulement.For the measurement of the flow threshold, a HAAKE rheometer of type VT550 with a measurement mobile SVDIN was used. The rheograms are produced at 25 ° C in the imposed speed of 0 to 100 s "1. The viscosity values are given to the shear values of 4 s" 1, 20s "1 100s" 1 (γ). By flow threshold (τ 0 expressed in Pascal) is meant the force required (minimum shear stress) to overcome Van der Waals cohesive forces and cause flow.
Dans un mode préféré selon l'invention, la composition est une composition pharmaceutique ou cosmétique anhydre de type onguent comprenant :In a preferred embodiment according to the invention, the composition is an anhydrous pharmaceutical or cosmetic composition of ointment type comprising:
Une phase active, constituée d'une première phase active comprenant le dérivé phénolique et au moins un solvant du dérivé phénolique, et une seconde phase active, comprenant le rétinoide et au moins un solvant et/ou dispersant du rétinoide ; une phase non active contenant au moins un épaississant de phase grasse et optionnellement un épaississant lipophile supplémentaire, et/ou au moins une huile, et/ou un au moins un tensioactif lipophile, et/ou un liant, et/ou un élastomère et/ou tout additif optionnel.An active phase, consisting of a first active phase comprising the phenolic derivative and at least one solvent of the phenolic derivative, and a second active phase, comprising the retinoid and at least one solvent and / or retinoid dispersant; an inactive phase containing at least one fatty phase thickener and optionally an additional lipophilic thickener, and / or at least one oil, and / or at least one lipophilic surfactant, and / or a binder, and / or an elastomer and / or any optional additive.
Dans un mode plus particulièrement préféré selon l'invention, la composition comprend :In a more particularly preferred embodiment according to the invention, the composition comprises:
Une phase active, constituée d'une première phase active comprenant l'hydroquinone ou le rucinol et au moins un solvant huileux de l'hydroquinone, et une seconde phase active, comprenant l'adapalène et au moins un dispersant huileux de l'adapalène ; une phase non active contenant au moins un épaississant de phase grasse choisi parmi le glycéryle de béhénate et dérivés, au moins un élastomère et optionnellement un épaississaint lipophile supplémentaire, et/ou au moins une huile, et/ou un au moins un tensioactif lipophile, et/ou un liant, et/ou tout additif optionnel.An active phase, consisting of a first active phase comprising hydroquinone or rucinol and at least one oily solvent of hydroquinone, and a second active phase, comprising adapalene and at least one oily dispersant of adapalene; an inactive phase containing at least one fatty phase thickener selected from behenate glyceryl and derivatives, at least one elastomer and optionally an additional lipophilic thickener, and / or at least one oil, and / or at least one lipophilic surfactant, and / or a binder, and / or any optional additive.
L'invention a également pour objet l'utilisation de la composition ainsi obtenue comme médicament.
Plus particulièrement, la composition peut être utilisée pour préparer un médicament destiné au traitement et à la prévention des désordres hyperpigmentaires tels que le melasma, le chloasma, les lentigines, le lentigo sénile, le vitiligo, les taches de rousseur, les hyperpigmentations post-inflammatoires dues à une abrasion, une brûlure, une cicatrice, une dermatose, une allergie de contact; les nevi, les hyperpigmentations à déterminisme génétique, les hyperpigmentations d'origine métabolique ou médicamenteuse, les mélanomes ou toutes autres lésions hyperpigmentaires.The invention also relates to the use of the composition thus obtained as a medicament. More particularly, the composition can be used to prepare a medicament for the treatment and prevention of hyperpigmentary disorders such as melasma, chloasma, lentigines, senile lentigo, vitiligo, freckles, post-inflammatory hyperpigmentations. due to abrasion, burning, scarring, dermatitis, contact allergy; nevi, hyperpigmentations with genetic determinism, hyperpigmentations of metabolic or medicinal origin, melanomas or any other hyperpigmentary lesions.
Les compositions selon l'invention trouvent également une application dans le domaine cosmétique, en particulier dans la protection contre les aspects néfastes du soleil, pour prévenir et/ou pour lutter contre le vieillissement photo-induit ou chronologique de la peau et des phanères.The compositions according to the invention also find application in the cosmetics field, in particular in the protection against the harmful aspects of the sun, for preventing and / or for combating photoinduced or chronological aging of the skin and superficial body growths.
L'invention porte également sur un procédé de traitement cosmétique non thérapeutique d'embellissement de la peau et/ou d'amélioration de son aspect de surface, caractérisé par le fait que l'on applique sur la peau et/ou ses phanères une composition comprenant de l'adapalène et au moins un agent dépigmentant.The invention also relates to a non-therapeutic cosmetic treatment method for embellishing the skin and / or improving its surface appearance, characterized in that a composition is applied to the skin and / or its integuments. comprising adapalene and at least one depigmenting agent.
Dans un mode préféré selon l'invention, la composition dépigmentante caractérisée en ce qu'elle comprend l'hydroquinone ou le rucinol et l'adapalène en phase grasse, présente une efficacité dépigmentante améliorée comparée à une composition contenant les mêmes actifs incorporés dans la phase aqueuse et/ou alcoolique et/ou glycolique de la composition.In a preferred embodiment according to the invention, the depigmenting composition, characterized in that it comprises hydroquinone or rucinol and adapalene in the fatty phase, has an improved depigmenting efficiency compared to a composition containing the same active ingredients incorporated in the phase. aqueous and / or alcoholic and / or glycolic composition.
Les exemples ci-dessous permettent d'illustrer l'efficacité de compositions particulières selon l'invention.The examples below make it possible to illustrate the effectiveness of particular compositions according to the invention.
Les compositions anhydres selon l'invention sont obtenues par l'homme de l'art en utilisant un procédé classique et connu de mélange des phases.The anhydrous compositions according to the invention are obtained by those skilled in the art using a conventional and known method of mixing the phases.
Le procédé de fabrication peut notamment comprendre les étapes suivantes :The manufacturing process may include the following steps:
Préparation des phases actives en incorporant les actifs pharmaceutiques dans leurs solvants et/ou dispersants huileux, au moyen si nécessaire de chauffage.
Préparation de la ou des phases non actives.Preparation of the active phases by incorporating the pharmaceutical active ingredients into their oily solvents and / or dispersants, by means of heating if necessary. Preparation of the non-active phase (s)
Incorporation des phases actives et non actives sous agitation.Incorporation of the active and non-active phases with stirring.
L'homme de l'art adaptera les procédés de fabrication aux types de compositions et ingrédients choisis.Those skilled in the art will adapt the manufacturing processes to the types of compositions and ingredients chosen.
Les exemples de formulations ci-dessous permettent d'illustrer les compositions selon l'invention, sans toutefois en limiter la portée. Les quantités des constituants sont exprimées en % en poids par rapport au poids total de la composition.The examples of formulations below make it possible to illustrate the compositions according to the invention, without however limiting the scope thereof. The amounts of the constituents are expressed in% by weight relative to the total weight of the composition.
Exemple 1 : ETUDE DE SOLUBILITE / STABILITE DES ACTIFSExample 1: SOLUBILITY / STABILITY STUDY OF ASSETS
a) Solubilités et stabilités de l'hydroquinone dans des huiles solvantes et tensioactifs lipophilesa) Solubilities and Stabilities of Hydroquinone in Solvent and Lipophilic Surfactant Oils
> Solubilités de l'hydroquinone> Solubilities of hydroquinone
Le tableau ci-dessus permet d'identifier quels sont les solvants les plus solubilisants de l'actif pour un choix optimum des ingrédients de la composition. Cependant, le choix du solvant se fera également sur la base des résultats de stabilité de l'hydroquinone dans ces solvants. Un compromis entre solubilité et stabilité doit être obtenu si besoin au moyen d'un
mélange de solvants.The table above makes it possible to identify which are the most solubilizing solvents of the active ingredient for an optimum choice of the ingredients of the composition. However, the choice of the solvent will also be based on the stability results of hydroquinone in these solvents. A compromise between solubility and stability must be achieved if necessary by means of a solvent mixture.
> Stabilité de l'hydroquinone dans des huiles solvantes et tensioactifs lipophiles> Stability of hydroquinone in solvent oils and lipophilic surfactants
Technique de dosage par HPLC contre substance de référence. Le temps initial (TO) est considéré à 100%.Assay technique by HPLC against reference substance. The initial time (TO) is considered 100%.
Le tableau ci-dessus permet d'évaluer la stabilité de l'hydroquinone dans les différents solubilisants identifiés auparavant.The table above makes it possible to evaluate the stability of hydroquinone in the different solubilizers identified previously.
Ainsi, on peut en déduire que les solvants préférés sont le Crodamol DA , l'Arlamol E et le Labrasol qui confèrent à l'hydroquinone une bonne stabilité chimique et physique (observation macroscopique de la couleur), couplées à un bon effet solubilisant. L'utilisation de tels solvants peut donc permettre de s'affranchir de toute utilisation d'antioxydants.Thus, it can be deduced that the preferred solvents are Crodamol DA, Arlamol E and Labrasol, which give hydroquinone good chemical and physical stability (macroscopic observation of the color), coupled with a good solubilizing effect. The use of such solvents may therefore make it possible to dispense with any use of antioxidants.
On peut noter que malgré une forte solubilité de l'hydroquinone dans le Cremophor EL, elle montre une instabilité macroscopique mise en évidence par un brunissement s'accentuant avec le temps et la température. Le Cremophor EL pourra être utilisé en quantité limitée pour aider à la solubilisation de l'hydroquinone, mais de préférence aux côtés d'un solvant stabilisant l'hydroquinone, comme par exemple le Miglyol.It can be noted that despite the high solubility of hydroquinone in Cremophor EL, it shows a macroscopic instability highlighted by a browning accentuating with time and temperature. Cremophor EL may be used in limited quantities to help solubilize hydroquinone, but preferably alongside a solvent stabilizing hydroquinone, such as for example Miglyol.
b) Solubilités et stabilités du rucinol dans des huiles solvantes et tensioactifs lipophilesb) Solubilities and Stabilities of Rucinol in Solvent and Lipophilic Surfactant Oils
> Solubilités du Rucinol> Solubilities of Rucinol
Solubilités du Rucinol
Solubilities of Rucinol
L'étude de solubilité réalisée a montrée que le rucinol présente une très bonne solubilité dans tous les solvants testés. Cependant, le choix du solvant optimal se fera également sur la base des résultats de stabilité du rucinol dans ces solvants.The solubility study carried out has shown that rucinol has a very good solubility in all the solvents tested. However, the choice of the optimal solvent will also be based on the stability results of rucinol in these solvents.
> Stabilité du rucinol dans des huiles solvantes et tensioactifs lipophiles> Stability of rucinol in solvent oils and lipophilic surfactants
Technique de dosage par HPLC contre substance de référence. Le temps initial (TO) est considéré à 100%Assay technique by HPLC against reference substance. The initial time (TO) is considered 100%
Le tableau ci-dessus permet d'évaluer la stabilité du Rucinol dans les solubilisants identifiés auparavant lors de l'étude de solubilité.The above table is used to evaluate the stability of Rucinol in solubilizers previously identified in the solubility study.
Sur la base de ces résultats les compositions suivantes selon l'invention ont été réalisées.
Pour toutes les formulations, la stabilité physique est mesurée par une observation macroscopique et microscopique de la formulation à température ambiante, à 4°C et àOn the basis of these results the following compositions according to the invention were made. For all formulations, physical stability is measured by macroscopic and microscopic observation of the formulation at room temperature, at 4 ° C and at room temperature.
400C après 1 mois, 2 mois, et optionnellement 3 mois et 6 mois.40 0 C after 1 month, 2 months, and optionally 3 months and 6 months.
A température ambiante, l'observation macroscopique permet de garantir l'intégrité physique des produits et l'observation microscopique permet de vérifier qu'il n'y a pas recristallisation de l'actif solubilisé.At room temperature, macroscopic observation makes it possible to guarantee the physical integrity of the products and the microscopic observation makes it possible to verify that there is no recrystallization of the solubilized active agent.
A 4°C, l'observation microscopique vérifie la non-recristallisation des actifs solubilisés.At 4 ° C., the microscopic observation verifies the non-recrystallization of the solubilized active agents.
A 400C, l'observation macroscopique vérifie l'intégrité du produit fini.At 40 ° C., the macroscopic observation verifies the integrity of the finished product.
La stabilité chimique est mesurée par dosage des actifs par étalonnage externe enChemical stability is measured by assaying the assets by external calibration in
HPLC et les résultats sont exprimés en % de recouvrement par rapport à la valeur théorique.HPLC and the results are expressed as% recovery from the theoretical value.
Exemple 2 :Example 2
Mode opératoire des exemples 2 et 3:Procedure of Examples 2 and 3
PHASE A :
Dans le bêcher formulaire introduire le Glyceryl behenate et le Cetearyl isononanoate. Porter le mélange à 85°C sous agitation lente. Maintenir l'agitation et le chauffage jusqu'à parfaite homogénéité. Arrêter le chauffage et maintenir l'agitation.PHASE A: In the beaker form introduce Glyceryl behenate and Cetearyl isononanoate. Bring the mixture to 85 ° C with slow stirring. Maintain agitation and heating until perfectly homogeneous. Stop heating and maintain agitation.
PHASE B :PHASE B:
Dans un bêcher annexe, solubiliser la part minoritaire d'hydroquinone ou de rucinol dans le Caprylic Capric triglycérides sous agitation magnétique et en chauffant à 75°C environ. Disperser sous agitation l'adapalène dans le mélange précédent.In an auxiliary beaker, solubilize the minor portion of hydroquinone or rucinol in Caprylic Capric triglycerides with magnetic stirring and heating to about 75 ° C. Disperse with stirring the adapalene in the previous mixture.
PHASE C :PHASE C:
Dans un bêcher annexe, solubiliser le DL alpha Tocopherol et l'Ascorbyl palmitate et la deuxième part d' hydroquinone ou de rucinol dans le PPG-15 Stearyl éther sous agitation magnétique en chauffant à 75°C environ.In an auxiliary beaker, solubilize DL alpha Tocopherol and Ascorbyl palmitate and the second part of hydroquinone or rucinol in PPG-15 Stearyl ether with magnetic stirring by heating to about 75 ° C.
PHASE D :PHASE D:
Dans un bêcher annexe, solubiliser la troisième part d' hydroquinone ou de rucinol dans PEG-8 Caprylic capric triglycérides sous agitation magnétique et en chauffant à 75°C environ.In an auxiliary beaker, solubilize the third part of hydroquinone or rucinol in PEG-8 Caprylic capric triglycerides with magnetic stirring and heating to about 75 ° C.
PHASE E :PHASE E:
Dans un bêcher annexe, disperser l'adapalène dans une part de Caprylic Capric triglycérides sous agitation.In an auxiliary beaker, disperse the adapalene in one part Caprylic Capric triglyceride with stirring.
PHASE F :PHASE F:
Dans un récipient annexe, peser le ST Elastomer 10.In an additional container, weigh the ST Elastomer 10.
Mélange :Mixed :
A 75°C environ, ajouter la phase B bien homogénéisée sous agitation.At about 75 ° C., add the well-mixed phase B with stirring.
A 55°C environ, ajouter les phases C et D et bien homogénéiser sous agitation.At about 55 ° C., add the phases C and D and mix well with stirring.
A 400C maximum, ajouter la phase E tout en maintenant l'agitation.
Puis additionner la phase F.At 40 ° C maximum, add phase E while maintaining agitation. Then add phase F.
Laisser refroidir sous agitation jusqu'à 35°C environ.Cool with stirring to about 35 ° C.
Spécifications à TOj.Specifications at TOj.
Aspect macroscopique : onguent ferme, blancMacroscopic appearance: firm ointment, white
Aspect microscopique : absence de cristaux d'hydroquinone - adapalène en dispersion (observé en fluorescence), cristaux < 2.5 à 5 μm.Microscopic appearance: absence of hydroquinone crystals - adapalene in dispersion (observed in fluorescence), crystals <2.5 to 5 μm.
Stabilité physique :Physical stability:
Stabilité chimique:Chemical stability:
^Hydroquinone^ Hydroquinone
^Adapalène : ^ Adapalene:
Exemple 3 :Example 3
Spécifications à TO :Specifications at TO:
Aspect macroscopique : onguent blanc brillantMacroscopic appearance: glossy white ointment
Aspect microscopique : absence de cristaux de rucinol - adapalène en dispersionMicroscopic appearance: absence of crystals of rucinol - adapalene in dispersion
(observé en fluorescence), cristaux < 2.5 à 5 μm.(observed in fluorescence), crystals <2.5 to 5 μm.
Profil Haake (4s 1 /20s 1 /100s 1): 126/84/109
Stabilité physique :Haake Profile (4s 1 / 20s 1 / 100s 1 ): 126/84/109 Physical stability:
Stabilité chimique:Chemical stability:
^Rucinol :^ Rucinol:
^Adapalène :^ Adapalene:
Exemple 4 : Test d'efficacité de l'activité dépigmentante d'une composition selon l'invention.Example 4: Efficiency test of the depigmenting activity of a composition according to the invention.
La composition de l'exemple 2 est comparée dans un test de mesure d'activité dépigmentante sur la queue de souris, à la composition ci-après :The composition of Example 2 is compared in a depigmenting activity measurement test on the tail of the mouse, to the composition below:
Résultats : La Figure 1 montrent qu'aux mêmes concentrations d'actifs, la composition selon l'exemple 2 de la présente invention avec adaplène dispersé en phase grasse et hydroquinone solubilisé en phase grasse montre une activité dépigmentante supérieure à la composition dans laquelle l'adapalène et l'hydroquinone sont solubilisés et/ou dispersés en phase aqueuse/alcoolique d'un gel.
Results: Figure 1 show that at the same concentrations of active ingredients, the composition according to Example 2 of the present invention with adaplene dispersed in the fatty phase and hydroquinone solubilized in the fatty phase shows a depigmenting activity greater than the composition in which the adapalene and hydroquinone are solubilized and / or dispersed in the aqueous / alcoholic phase of a gel.
Claims
1. Composition pharmaceutique anhydre comprenant : a. un dérivé phénolique, choisi parmi l'hydroquinone, le rucinol ou lucinol et leurs sels, le 4-hydroxyanisol, le monoethyl éther d'hydroquinone et le monobenzylether d'hydroquinone. b. un rétinoide, caractérisée en ce que le dérivé phénolique et le rétinoide sont solubilisés et/ou dispersés dans la phase grasse de la composition.An anhydrous pharmaceutical composition comprising: a. a phenol derivative, chosen from hydroquinone, rucinol or lucinol and their salts, 4-hydroxyanisol, hydroquinone monoethyl ether and hydroquinone monobenzyl ether. b. a retinoid, characterized in that the phenolic derivative and the retinoid are solubilized and / or dispersed in the fatty phase of the composition.
2. Composition selon la revendication 1 , caractérisée en ce que le dérivé phénolique est solubilisé dans au moins une phase grasse de la composition.2. Composition according to claim 1, characterized in that the phenolic derivative is solubilized in at least one fatty phase of the composition.
3. Composition selon l'une des revendications 1 à 2 , caractérisée en ce que le rétinoide est solubilisé dans au moins une phase grasse de la composition.3. Composition according to one of claims 1 to 2, characterized in that the retinoid is solubilized in at least one fatty phase of the composition.
4. Composition selon l'une des revendications 1 à 2 caractérisée en ce que le rétinoide est dispersé dans au moins une phase grasse de la composition.4. Composition according to one of claims 1 to 2 characterized in that the retinoid is dispersed in at least one fatty phase of the composition.
5. Composition selon l'une des revendications 1 à 4, caractérisée en ce que la phase grasse comprend une phase huileuse suivante du dérivé phénolique.5. Composition according to one of claims 1 to 4, characterized in that the fatty phase comprises a following oil phase of the phenolic derivative.
6. Composition selon l'une des revendications 1 à 5, caractérisée en ce que la phase huileuse suivante du dérivé phénolique comprend un solvant huileux et/ou un tensioactif lipophile.6. Composition according to one of claims 1 to 5, characterized in that the following oily phase of the phenolic derivative comprises an oily solvent and / or a lipophilic surfactant.
7. Composition selon l'une des revendications 1 à 3, caractérisée en ce que la phase huileuse suivante est choisi parmi les esters et dérivés, les éthers et dérivés les caprylic capric triglycérides.7. Composition according to one of claims 1 to 3, characterized in that the following oily phase is selected from esters and derivatives, ethers and derivatives caprylic capric triglycerides.
8. Composition selon l'une des revendications 1 à 4, caractérisée en ce que la tensioactif lipophile est le PEG-8 Caprylic Capric triglycéride..8. Composition according to one of claims 1 to 4, characterized in that the lipophilic surfactant is PEG-8 Caprylic Capric triglyceride.
9. Composition selon la revendication 1 à 4, caractérisée en ce qu'elle comprend une phase huileuse dispersante du rétinoide. 9. Composition according to claim 1 to 4, characterized in that it comprises an oily dispersant phase of the retinoid.
10. Composition selon l'une des revendications 1 à 9, caractérisée en ce que la phase huileuse suivante dispersante du rétinoide comprend les triglycérides capric-caprylique.10. Composition according to one of claims 1 to 9, characterized in that the following oily phase dispersant retinoid comprises capric-caprylic triglycerides.
1 1. Composition selon l'une des revendications 1 à 10, caractérisée en ce qu'elle comprend également au moins un épaississant, ou gélifiant, lipophile .1. Composition according to one of claims 1 to 10, characterized in that it also comprises at least one thickener, or gelling agent, lipophilic.
12. Composition selon l'une des revendications 1 à 1 1 , caractérisée en ce qu'elle comprend également au moins un corps gras supplémentaire.12. Composition according to one of claims 1 to 1 1, characterized in that it also comprises at least one additional fatty substance.
13. Composition selon l'une des revendications 1 à 12 caractérisé en ce que le rétinoide est l'adapalène.13. Composition according to one of claims 1 to 12 characterized in that the retinoid is adapalene.
14. Composition selon la revendication 1 , caractérisé en ce qu'adapalène est compris entre 0.0001 et 1% en poids par rapport au poids total de la composition.14. Composition according to claim 1, characterized in that adapalene is between 0.0001 and 1% by weight relative to the total weight of the composition.
15. Composition selon la revendication 1 , caractérisé en ce que qu'adapalène est compris entre 0.001 % et 0.3% en poids par rapport au poids total de la composition15. Composition according to claim 1, characterized in that adapalene is between 0.001% and 0.3% by weight relative to the total weight of the composition.
16. Composition selon l'une des revendications 1 à 9, caractérisée en ce que le dérivé phénolique est l'hydroquinone16. Composition according to one of claims 1 to 9, characterized in that the phenolic derivative is hydroquinone
17. Composition selon l'une des revendications 1 à 8, caractérisée en ce que le dérivé phénolique est présent en quantité comprise entre 0,00001 et 10%.17. Composition according to one of claims 1 to 8, characterized in that the phenol derivative is present in an amount between 0.00001 and 10%.
18. . Composition selon l'une des revendications 1 à 8, caractérisée en ce que le dérivé phénolique est présent en quantité comprise entre 0,001 et 6%.18.. Composition according to one of Claims 1 to 8, characterized in that the phenol derivative is present in an amount of between 0.001 and 6%.
19. Composition selon l'une des revendications précédentes caractérisée en ce qu'elle ne contient pas de solvant alcoolique ou glycolique.19. Composition according to one of the preceding claims characterized in that it does not contain alcoholic or glycolic solvent.
20. Composition selon l'une des revendications précédentes, caractérisée en ce que l'épaississant lipophile est le glycéryle de béhénate et/ou ses dérivés. 20. Composition according to one of the preceding claims, characterized in that the lipophilic thickener is behenyl glyceryl and / or its derivatives.
21. Composition selon l'une des revendications précédentes, caractérisée en ce qu'elle comprend un élastomère organopolysiloxane.21. Composition according to one of the preceding claims, characterized in that it comprises an organopolysiloxane elastomer.
22. Composition selon l'une des revendications 1 à 21 , à titre de médicament.22. Composition according to one of claims 1 to 21, as a medicament.
23. Utilisation d'une composition selon l'une des revendications 1 à 13 pour préparer un médicament destiné au traitement et/ou à la prévention des désordres hyperpigmentaires tels que le melasma, le chloasma, les lentigines, le lentigo sénile, le vitiligo, les taches de rousseur, les hyperpigmentations postinflammatoires dues à une abrasion, une brûlure, une cicatrice, une dermatose, une allergie de contact; les nevi, les hyperpigmentations à déterminisme génétique, les hyperpigmentations d'origine métabolique ou médicamenteuse, les mélanomes ou toutes autres lésions hyperpigmentaires.23. Use of a composition according to one of claims 1 to 13 for preparing a medicament for the treatment and / or prevention of hyperpigmentary disorders such as melasma, chloasma, lentigines, senile lentigo, vitiligo, freckles, post-inflammatory hyperpigmentations due to abrasion, burning, scarring, dermatitis, contact allergy; nevi, hyperpigmentations with genetic determinism, hyperpigmentations of metabolic or medicinal origin, melanomas or any other hyperpigmentary lesions.
24. Utilisation d'une composition selon l'une des revendications 1 à 13 pour préparer un médicament destiné à la protection contre les aspects néfastes du soleil, pour prévenir et/ou pour lutter contre le vieillissement photo-induit ou chronologique de la peau et des phanère 24. Use of a composition according to one of claims 1 to 13 for preparing a medicament for protection against the harmful aspects of the sun, for preventing and / or for combating photo-induced or chronological aging of the skin and dander
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US5755308P | 2008-05-30 | 2008-05-30 | |
PCT/FR2009/051040 WO2009156679A1 (en) | 2008-05-30 | 2009-06-02 | Anhydrous depigmenting compositions comprising, within the fatty phase, a solubilized phenolic derivative and a retinoid |
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EP2291180A1 true EP2291180A1 (en) | 2011-03-09 |
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EP09769520A Withdrawn EP2291180A1 (en) | 2008-05-30 | 2009-06-02 | Anhydrous depigmenting compositions comprising, within the fatty phase, a solubilized phenolic derivative and a retinoid |
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US (1) | US20110319491A1 (en) |
EP (1) | EP2291180A1 (en) |
JP (1) | JP2011521936A (en) |
KR (1) | KR20110014242A (en) |
CN (1) | CN102099022A (en) |
AU (1) | AU2009264015A1 (en) |
CA (1) | CA2723313A1 (en) |
MX (1) | MX2010012753A (en) |
RU (1) | RU2010153985A (en) |
WO (1) | WO2009156679A1 (en) |
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WO2011135090A1 (en) * | 2010-04-29 | 2011-11-03 | Galderma Research & Development | Method for treating scars with adapalene 0.3% |
FR2991180B1 (en) * | 2012-06-01 | 2014-06-13 | Galderma Res & Dev | EMULSION - FREE EMULSION - TYPE TOPICAL COMPOSITIONS BASED ON STABILIZING PARTICLES. |
FR2991174B1 (en) * | 2012-06-01 | 2014-12-26 | Galderma Res & Dev | DERMATOLOGICAL COMPOSITION COMPRISING OLEOSOMES AND RETINOIDS, PROCESS FOR PREPARING SAME AND USE THEREOF |
FR2991172A1 (en) * | 2012-06-01 | 2013-12-06 | Galderma Res & Dev | TOPICAL PHARMACEUTICAL COMPOSITIONS COMPRISING MICROCAPSULES |
WO2017062029A1 (en) * | 2015-10-09 | 2017-04-13 | Ecstasy LLC | Anhydrous depigmenting compositions comprising phenolic compounds |
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US4466955A (en) * | 1982-06-09 | 1984-08-21 | Germaine Monteil Cosmetiques Corporation | Skin bleaching stick containing hydroquinone |
JP2622955B2 (en) * | 1986-07-29 | 1997-06-25 | エイボン プロダクツ インコ−ポレイテツド | Anhydrous cosmetics |
LU87410A1 (en) * | 1988-12-20 | 1990-07-10 | Cird | COSMETIC OR PHARMACEUTICAL COMPOSITION CONTAINING POLYMERIC OR FATTY BODY MICROSPHERES CHARGED WITH AT LEAST ONE ACTIVE PRODUCT |
US5093360A (en) * | 1989-04-07 | 1992-03-03 | Yu Ruey J | Retinal, derivatives and their therapeutic use |
AR003918A1 (en) * | 1995-01-11 | 1998-09-30 | Mary Kay Cosmetics Inc | NEW COSMETIC COMPOSITIONS CONTAINING TOPIC RELEASE SYSTEMS FOR DERMATOLOGICALLY ACTIVE, POLAR AGENTS. |
SK173699A3 (en) * | 1997-06-20 | 2000-07-11 | Mary Kay Inc | Cosmetic composition containing a whitening agent and an exfoliant |
US6110449A (en) * | 1999-06-14 | 2000-08-29 | The Procter & Gamble Company | Anhydrous antiperspirant cream compositions improved perfume longevity |
US20030072724A1 (en) * | 1999-12-16 | 2003-04-17 | Maibach Howard I. | Topical pharmaceutical composition to treat hyperpigmentation of the skin |
US20020022040A1 (en) * | 2000-07-10 | 2002-02-21 | The Proctor & Gamble Company | Methods of enhancing delivery of oil-soluble skin care actives |
US20020193321A1 (en) * | 2000-12-12 | 2002-12-19 | Mohan Vishnupad | Dual dispenser for aesthitically acceptable delivery of anhydrous skin treatment compositions |
GB0301577D0 (en) * | 2003-01-23 | 2003-02-26 | Edko Pazarlama Tanitim Ltd Sti | Topical pharmaceutical and/or cosmetic dispense systems |
WO2005044219A1 (en) * | 2003-10-31 | 2005-05-19 | The Procter & Gamble Company | Skin care composition containing dehydroacetic acid and skin care actives |
WO2006003992A1 (en) * | 2004-06-30 | 2006-01-12 | The Nisshin Oillio Group, Ltd. | Liquid ester composition and cosmetic preparation containing the same |
US20060110415A1 (en) * | 2004-11-22 | 2006-05-25 | Bioderm Research | Topical Delivery System for Cosmetic and Pharmaceutical Agents |
US20060120979A1 (en) * | 2004-12-02 | 2006-06-08 | Joel Rubin | Skin care composition comprising hydroquinone and a substantially anhydrous base |
FR2915682B1 (en) * | 2007-05-04 | 2009-07-03 | Galderma Res & Dev | DERMATOLOGICAL AND COSMETIC DEPIGMENTING COMPOSITIONS, PROCESSES FOR THEIR PREPARATION, AND USES THEREOF |
-
2009
- 2009-06-02 CA CA2723313A patent/CA2723313A1/en not_active Abandoned
- 2009-06-02 AU AU2009264015A patent/AU2009264015A1/en not_active Abandoned
- 2009-06-02 CN CN2009801203388A patent/CN102099022A/en active Pending
- 2009-06-02 RU RU2010153985/15A patent/RU2010153985A/en not_active Application Discontinuation
- 2009-06-02 WO PCT/FR2009/051040 patent/WO2009156679A1/en active Application Filing
- 2009-06-02 EP EP09769520A patent/EP2291180A1/en not_active Withdrawn
- 2009-06-02 KR KR1020107029557A patent/KR20110014242A/en not_active Application Discontinuation
- 2009-06-02 US US12/994,900 patent/US20110319491A1/en not_active Abandoned
- 2009-06-02 MX MX2010012753A patent/MX2010012753A/en not_active Application Discontinuation
- 2009-06-02 JP JP2011511073A patent/JP2011521936A/en active Pending
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Title |
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See references of WO2009156679A1 * |
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MX2010012753A (en) | 2010-12-21 |
KR20110014242A (en) | 2011-02-10 |
WO2009156679A1 (en) | 2009-12-30 |
US20110319491A1 (en) | 2011-12-29 |
CN102099022A (en) | 2011-06-15 |
JP2011521936A (en) | 2011-07-28 |
CA2723313A1 (en) | 2009-12-30 |
RU2010153985A (en) | 2012-07-10 |
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