WO2015092602A1 - Topical pharmaceutical composition of a retinoid - Google Patents
Topical pharmaceutical composition of a retinoid Download PDFInfo
- Publication number
- WO2015092602A1 WO2015092602A1 PCT/IB2014/066652 IB2014066652W WO2015092602A1 WO 2015092602 A1 WO2015092602 A1 WO 2015092602A1 IB 2014066652 W IB2014066652 W IB 2014066652W WO 2015092602 A1 WO2015092602 A1 WO 2015092602A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- forming polymers
- retinoid
- microspheres
- microcapsules
- benzoyl peroxide
- Prior art date
Links
- 150000004492 retinoid derivatives Chemical class 0.000 title claims abstract description 142
- 239000012049 topical pharmaceutical composition Substances 0.000 title claims abstract description 69
- 239000004005 microsphere Substances 0.000 claims abstract description 185
- 239000003094 microcapsule Substances 0.000 claims abstract description 127
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims abstract description 114
- 239000004342 Benzoyl peroxide Substances 0.000 claims abstract description 113
- 235000019400 benzoyl peroxide Nutrition 0.000 claims abstract description 113
- 238000000034 method Methods 0.000 claims abstract description 96
- 230000008569 process Effects 0.000 claims abstract description 62
- 238000002360 preparation method Methods 0.000 claims abstract description 56
- 208000002874 Acne Vulgaris Diseases 0.000 claims abstract description 15
- 206010000496 acne Diseases 0.000 claims abstract description 15
- 229920000642 polymer Polymers 0.000 claims description 167
- 239000000203 mixture Substances 0.000 claims description 115
- 239000006185 dispersion Substances 0.000 claims description 77
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 72
- 239000011247 coating layer Substances 0.000 claims description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 49
- 239000000839 emulsion Substances 0.000 claims description 48
- -1 poly(acryl) Polymers 0.000 claims description 41
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 claims description 32
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 31
- 239000008346 aqueous phase Substances 0.000 claims description 30
- 229960001727 tretinoin Drugs 0.000 claims description 30
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 27
- 239000011248 coating agent Substances 0.000 claims description 27
- 238000000576 coating method Methods 0.000 claims description 27
- 239000003381 stabilizer Substances 0.000 claims description 26
- 238000002156 mixing Methods 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- 239000012074 organic phase Substances 0.000 claims description 16
- 235000011187 glycerol Nutrition 0.000 claims description 13
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 12
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- 229920001661 Chitosan Polymers 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000002202 Polyethylene glycol Substances 0.000 claims description 9
- OGQICQVSFDPSEI-UHFFFAOYSA-N Zorac Chemical compound N1=CC(C(=O)OCC)=CC=C1C#CC1=CC=C(SCCC2(C)C)C2=C1 OGQICQVSFDPSEI-UHFFFAOYSA-N 0.000 claims description 9
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 claims description 9
- 229920001223 polyethylene glycol Polymers 0.000 claims description 9
- 229960000565 tazarotene Drugs 0.000 claims description 9
- 235000020945 retinal Nutrition 0.000 claims description 8
- 239000011604 retinal Substances 0.000 claims description 8
- NCYCYZXNIZJOKI-OVSJKPMPSA-N retinal group Chemical group C\C(=C/C=O)\C=C\C=C(\C=C\C1=C(CCCC1(C)C)C)/C NCYCYZXNIZJOKI-OVSJKPMPSA-N 0.000 claims description 8
- NCYCYZXNIZJOKI-UHFFFAOYSA-N vitamin A aldehyde Natural products O=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-UHFFFAOYSA-N 0.000 claims description 8
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 7
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 7
- 239000000194 fatty acid Substances 0.000 claims description 7
- 229930195729 fatty acid Natural products 0.000 claims description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 6
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 229920002678 cellulose Polymers 0.000 claims description 6
- 239000001913 cellulose Substances 0.000 claims description 6
- 239000000600 sorbitol Substances 0.000 claims description 6
- 235000010356 sorbitol Nutrition 0.000 claims description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 6
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 claims description 5
- 239000004359 castor oil Substances 0.000 claims description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 5
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 5
- SHGAZHPCJJPHSC-ZVCIMWCZSA-N 9-cis-retinoic acid Chemical compound OC(=O)/C=C(\C)/C=C/C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-ZVCIMWCZSA-N 0.000 claims description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 4
- 229920002307 Dextran Polymers 0.000 claims description 4
- 229920002472 Starch Polymers 0.000 claims description 4
- 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 4
- 229960002916 adapalene Drugs 0.000 claims description 4
- 229960001445 alitretinoin Drugs 0.000 claims description 4
- 229930002945 all-trans-retinaldehyde Natural products 0.000 claims description 4
- NMJJFJNHVMGPGM-UHFFFAOYSA-N butyl formate Chemical compound CCCCOC=O NMJJFJNHVMGPGM-UHFFFAOYSA-N 0.000 claims description 4
- HQMNCQVAMBCHCO-DJRRULDNSA-N etretinate Chemical compound CCOC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)C=C(OC)C(C)=C1C HQMNCQVAMBCHCO-DJRRULDNSA-N 0.000 claims description 4
- 229960002199 etretinate Drugs 0.000 claims description 4
- 229960005280 isotretinoin Drugs 0.000 claims description 4
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims description 4
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 claims description 4
- 230000002207 retinal effect Effects 0.000 claims description 4
- 229960003471 retinol Drugs 0.000 claims description 4
- 235000020944 retinol Nutrition 0.000 claims description 4
- 239000011607 retinol Substances 0.000 claims description 4
- 239000008107 starch Substances 0.000 claims description 4
- 235000019698 starch Nutrition 0.000 claims description 4
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 claims description 4
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 4
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- 108010010803 Gelatin Proteins 0.000 claims description 3
- 150000001252 acrylic acid derivatives Chemical class 0.000 claims description 3
- 150000004665 fatty acids Chemical class 0.000 claims description 3
- 239000008273 gelatin Substances 0.000 claims description 3
- 229920000159 gelatin Polymers 0.000 claims description 3
- 235000019322 gelatine Nutrition 0.000 claims description 3
- 235000011852 gelatine desserts Nutrition 0.000 claims description 3
- 150000002632 lipids Chemical class 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims description 2
- RMOUBSOVHSONPZ-UHFFFAOYSA-N Isopropyl formate Chemical compound CC(C)OC=O RMOUBSOVHSONPZ-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- HDSBZMRLPLPFLQ-UHFFFAOYSA-N Propylene glycol alginate Chemical compound OC1C(O)C(OC)OC(C(O)=O)C1OC1C(O)C(O)C(C)C(C(=O)OCC(C)O)O1 HDSBZMRLPLPFLQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000000129 anionic group Chemical group 0.000 claims description 2
- 229940043232 butyl acetate Drugs 0.000 claims description 2
- MSZJEPVVQWJCIF-UHFFFAOYSA-N butylazanide Chemical compound CCCC[NH-] MSZJEPVVQWJCIF-UHFFFAOYSA-N 0.000 claims description 2
- 125000002091 cationic group Chemical group 0.000 claims description 2
- IWYBVQLPTCMVFO-UHFFFAOYSA-N ethyl 2,2-dichloroacetate Chemical compound CCOC(=O)C(Cl)Cl IWYBVQLPTCMVFO-UHFFFAOYSA-N 0.000 claims description 2
- GZKHDVAKKLTJPO-UHFFFAOYSA-N ethyl 2,2-difluoroacetate Chemical compound CCOC(=O)C(F)F GZKHDVAKKLTJPO-UHFFFAOYSA-N 0.000 claims description 2
- VCYZVXRKYPKDQB-UHFFFAOYSA-N ethyl 2-fluoroacetate Chemical compound CCOC(=O)CF VCYZVXRKYPKDQB-UHFFFAOYSA-N 0.000 claims description 2
- 229940093499 ethyl acetate Drugs 0.000 claims description 2
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 claims description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- 150000008040 ionic compounds Chemical class 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 claims description 2
- HKMLRUAPIDAGIE-UHFFFAOYSA-N methyl 2,2-dichloroacetate Chemical compound COC(=O)C(Cl)Cl HKMLRUAPIDAGIE-UHFFFAOYSA-N 0.000 claims description 2
- CSSYKHYGURSRAZ-UHFFFAOYSA-N methyl 2,2-difluoroacetate Chemical compound COC(=O)C(F)F CSSYKHYGURSRAZ-UHFFFAOYSA-N 0.000 claims description 2
- RJBYSQHLLIHSLT-UHFFFAOYSA-N methyl 2-fluoroacetate Chemical compound COC(=O)CF RJBYSQHLLIHSLT-UHFFFAOYSA-N 0.000 claims description 2
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 2
- 235000010409 propane-1,2-diol alginate Nutrition 0.000 claims description 2
- 239000000770 propane-1,2-diol alginate Substances 0.000 claims description 2
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 2
- 229940080818 propionamide Drugs 0.000 claims description 2
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 claims description 2
- 229940090181 propyl acetate Drugs 0.000 claims description 2
- 108090000623 proteins and genes Proteins 0.000 claims description 2
- 102000004169 proteins and genes Human genes 0.000 claims description 2
- 239000001993 wax Substances 0.000 claims 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 claims 1
- 229920002554 vinyl polymer Polymers 0.000 claims 1
- 239000013047 polymeric layer Substances 0.000 abstract description 4
- 239000000243 solution Substances 0.000 description 88
- 239000008213 purified water Substances 0.000 description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- 238000003756 stirring Methods 0.000 description 18
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 16
- 239000001856 Ethyl cellulose Substances 0.000 description 16
- 235000019325 ethyl cellulose Nutrition 0.000 description 16
- 229920001249 ethyl cellulose Polymers 0.000 description 16
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 description 10
- 229960000878 docusate sodium Drugs 0.000 description 10
- 239000002245 particle Substances 0.000 description 10
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 10
- 229960004063 propylene glycol Drugs 0.000 description 10
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 10
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 9
- 235000013772 propylene glycol Nutrition 0.000 description 9
- 235000010413 sodium alginate Nutrition 0.000 description 9
- 239000000661 sodium alginate Substances 0.000 description 9
- 229940005550 sodium alginate Drugs 0.000 description 9
- 229920002125 Sokalan® Polymers 0.000 description 8
- 239000011148 porous material Substances 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000003002 pH adjusting agent Substances 0.000 description 6
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 5
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 229920000136 polysorbate Polymers 0.000 description 5
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical class [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 4
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 239000004014 plasticizer Substances 0.000 description 4
- 238000000710 polymer precipitation Methods 0.000 description 4
- 210000003491 skin Anatomy 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 241000186427 Cutibacterium acnes Species 0.000 description 3
- 229920003134 Eudragit® polymer Polymers 0.000 description 3
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 3
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- 239000004166 Lanolin Substances 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 235000019438 castor oil Nutrition 0.000 description 3
- 229960001484 edetic acid Drugs 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 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 3
- 238000000265 homogenisation Methods 0.000 description 3
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 3
- SHGAZHPCJJPHSC-XFYACQKRSA-N isotretinoin Chemical compound OC(=O)/C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-XFYACQKRSA-N 0.000 description 3
- 229940039717 lanolin Drugs 0.000 description 3
- 235000019388 lanolin Nutrition 0.000 description 3
- 229920000609 methyl cellulose Polymers 0.000 description 3
- 235000010981 methylcellulose Nutrition 0.000 description 3
- 239000001923 methylcellulose Substances 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- 229930002330 retinoic acid Natural products 0.000 description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 238000001694 spray drying Methods 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- XDOFQFKRPWOURC-UHFFFAOYSA-N 16-methylheptadecanoic acid Chemical compound CC(C)CCCCCCCCCCCCCCC(O)=O XDOFQFKRPWOURC-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-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
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 239000004322 Butylated hydroxytoluene Substances 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
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 229920002907 Guar gum Polymers 0.000 description 2
- 206010020649 Hyperkeratosis Diseases 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- SHGAZHPCJJPHSC-UHFFFAOYSA-N Panrexin Chemical compound OC(=O)C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- 239000004141 Sodium laurylsulphate Substances 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- ZFOZVQLOBQUTQQ-UHFFFAOYSA-N Tributyl citrate Chemical compound CCCCOC(=O)CC(O)(C(=O)OCCCC)CC(=O)OCCCC ZFOZVQLOBQUTQQ-UHFFFAOYSA-N 0.000 description 2
- UYXTWWCETRIEDR-UHFFFAOYSA-N Tributyrin Chemical compound CCCC(=O)OCC(OC(=O)CCC)COC(=O)CCC UYXTWWCETRIEDR-UHFFFAOYSA-N 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 150000001242 acetic acid derivatives Chemical class 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 229940023476 agar Drugs 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 235000010418 carrageenan Nutrition 0.000 description 2
- 229920001525 carrageenan Polymers 0.000 description 2
- 239000000679 carrageenan Substances 0.000 description 2
- 229940113118 carrageenan Drugs 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 2
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 2
- 229940031578 diisopropyl adipate Drugs 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000003349 gelling agent Substances 0.000 description 2
- 229940075507 glyceryl monostearate Drugs 0.000 description 2
- 239000001087 glyceryl triacetate Substances 0.000 description 2
- 235000013773 glyceryl triacetate Nutrition 0.000 description 2
- 150000002334 glycols Chemical class 0.000 description 2
- 235000010417 guar gum Nutrition 0.000 description 2
- 239000000665 guar gum Substances 0.000 description 2
- 229960002154 guar gum Drugs 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 239000003906 humectant Substances 0.000 description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- XUGNVMKQXJXZCD-UHFFFAOYSA-N isopropyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000314 lubricant Substances 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
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 150000002734 metacrylic acid derivatives Chemical class 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- 235000019271 petrolatum Nutrition 0.000 description 2
- 229920000058 polyacrylate Polymers 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 210000002374 sebum Anatomy 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N squalane Chemical compound CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 229920001059 synthetic polymer Polymers 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 229960002622 triacetin Drugs 0.000 description 2
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 2
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 1
- MEJYDZQQVZJMPP-ULAWRXDQSA-N (3s,3ar,6r,6ar)-3,6-dimethoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan Chemical compound CO[C@H]1CO[C@@H]2[C@H](OC)CO[C@@H]21 MEJYDZQQVZJMPP-ULAWRXDQSA-N 0.000 description 1
- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-N 0.000 description 1
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 description 1
- HBXWUCXDUUJDRB-UHFFFAOYSA-N 1-octadecoxyoctadecane Chemical compound CCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCC HBXWUCXDUUJDRB-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- 239000000263 2,3-dihydroxypropyl (Z)-octadec-9-enoate Substances 0.000 description 1
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- DBHODFSFBXJZNY-UHFFFAOYSA-N 2,4-dichlorobenzyl alcohol Chemical compound OCC1=CC=C(Cl)C=C1Cl DBHODFSFBXJZNY-UHFFFAOYSA-N 0.000 description 1
- ILCOCZBHMDEIAI-UHFFFAOYSA-N 2-(2-octadecoxyethoxy)ethanol Chemical compound CCCCCCCCCCCCCCCCCCOCCOCCO ILCOCZBHMDEIAI-UHFFFAOYSA-N 0.000 description 1
- FKOKUHFZNIUSLW-UHFFFAOYSA-N 2-Hydroxypropyl stearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(C)O FKOKUHFZNIUSLW-UHFFFAOYSA-N 0.000 description 1
- NLMKTBGFQGKQEV-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-hexadecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO NLMKTBGFQGKQEV-UHFFFAOYSA-N 0.000 description 1
- JKXYOQDLERSFPT-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-octadecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO JKXYOQDLERSFPT-UHFFFAOYSA-N 0.000 description 1
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 description 1
- QCDWFXQBSFUVSP-UHFFFAOYSA-N 2-phenoxyethanol Chemical compound OCCOC1=CC=CC=C1 QCDWFXQBSFUVSP-UHFFFAOYSA-N 0.000 description 1
- JMFLYAQVWMIMKC-UHFFFAOYSA-N 3-(2-aminoethylamino)propane-1,1,1,3-tetrol Chemical compound NCCNC(O)CC(O)(O)O JMFLYAQVWMIMKC-UHFFFAOYSA-N 0.000 description 1
- RZRNAYUHWVFMIP-GDCKJWNLSA-N 3-oleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-GDCKJWNLSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- QZCLKYGREBVARF-UHFFFAOYSA-N Acetyl tributyl citrate Chemical compound CCCCOC(=O)CC(C(=O)OCCCC)(OC(C)=O)CC(=O)OCCCC QZCLKYGREBVARF-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- XMSXQFUHVRWGNA-UHFFFAOYSA-N Decamethylcyclopentasiloxane Chemical compound C[Si]1(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O1 XMSXQFUHVRWGNA-UHFFFAOYSA-N 0.000 description 1
- MQIUGAXCHLFZKX-UHFFFAOYSA-N Di-n-octyl phthalate Natural products CCCCCCCCOC(=O)C1=CC=CC=C1C(=O)OCCCCCCCC MQIUGAXCHLFZKX-UHFFFAOYSA-N 0.000 description 1
- PYGXAGIECVVIOZ-UHFFFAOYSA-N Dibutyl decanedioate Chemical compound CCCCOC(=O)CCCCCCCCC(=O)OCCCC PYGXAGIECVVIOZ-UHFFFAOYSA-N 0.000 description 1
- YUXIBTJKHLUKBD-UHFFFAOYSA-N Dibutyl succinate Chemical compound CCCCOC(=O)CCC(=O)OCCCC YUXIBTJKHLUKBD-UHFFFAOYSA-N 0.000 description 1
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 1
- 229920002148 Gellan gum Polymers 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 229920000569 Gum karaya Polymers 0.000 description 1
- 108010076876 Keratins Proteins 0.000 description 1
- 102000011782 Keratins Human genes 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- 229920000161 Locust bean gum Polymers 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- FSVCELGFZIQNCK-UHFFFAOYSA-N N,N-bis(2-hydroxyethyl)glycine Chemical compound OCCN(CCO)CC(O)=O FSVCELGFZIQNCK-UHFFFAOYSA-N 0.000 description 1
- 206010033733 Papule Diseases 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 229920002675 Polyoxyl Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 229920001219 Polysorbate 40 Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 239000004373 Pullulan Substances 0.000 description 1
- 229920001218 Pullulan Polymers 0.000 description 1
- 235000019484 Rapeseed oil Nutrition 0.000 description 1
- 206010037888 Rash pustular Diseases 0.000 description 1
- 241000934878 Sterculia Species 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- OENHQHLEOONYIE-UKMVMLAPSA-N all-trans beta-carotene Natural products CC=1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C OENHQHLEOONYIE-UKMVMLAPSA-N 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000000305 astragalus gummifer gum Substances 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 239000011648 beta-carotene Substances 0.000 description 1
- TUPZEYHYWIEDIH-WAIFQNFQSA-N beta-carotene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2=CCCCC2(C)C TUPZEYHYWIEDIH-WAIFQNFQSA-N 0.000 description 1
- 235000013734 beta-carotene Nutrition 0.000 description 1
- 229960002747 betacarotene Drugs 0.000 description 1
- BJQHLKABXJIVAM-UHFFFAOYSA-N bis(2-ethylhexyl) phthalate Chemical compound CCCCC(CC)COC(=O)C1=CC=CC=C1C(=O)OCC(CC)CCCC BJQHLKABXJIVAM-UHFFFAOYSA-N 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- CDQSJQSWAWPGKG-UHFFFAOYSA-N butane-1,1-diol Chemical compound CCCC(O)O CDQSJQSWAWPGKG-UHFFFAOYSA-N 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229960001777 castor oil Drugs 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000007765 cera alba Substances 0.000 description 1
- 239000007766 cera flava Substances 0.000 description 1
- 229940073669 ceteareth 20 Drugs 0.000 description 1
- 229940073642 ceteareth-30 Drugs 0.000 description 1
- 229940056318 ceteth-20 Drugs 0.000 description 1
- 229940082500 cetostearyl alcohol Drugs 0.000 description 1
- 229960002798 cetrimide Drugs 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- WOWHHFRSBJGXCM-UHFFFAOYSA-M cetyltrimethylammonium chloride Chemical class [Cl-].CCCCCCCCCCCCCCCC[N+](C)(C)C WOWHHFRSBJGXCM-UHFFFAOYSA-M 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 description 1
- 229960002227 clindamycin Drugs 0.000 description 1
- 238000005354 coacervation Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 229920006037 cross link polymer Polymers 0.000 description 1
- 229940086555 cyclomethicone Drugs 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- SOROIESOUPGGFO-UHFFFAOYSA-N diazolidinylurea Chemical compound OCNC(=O)N(CO)C1N(CO)C(=O)N(CO)C1=O SOROIESOUPGGFO-UHFFFAOYSA-N 0.000 description 1
- 229960001083 diazolidinylurea Drugs 0.000 description 1
- 229960002097 dibutylsuccinate Drugs 0.000 description 1
- 229960004698 dichlorobenzyl alcohol Drugs 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- IEPRKVQEAMIZSS-AATRIKPKSA-N diethyl fumarate Chemical compound CCOC(=O)\C=C\C(=O)OCC IEPRKVQEAMIZSS-AATRIKPKSA-N 0.000 description 1
- VKNUORWMCINMRB-UHFFFAOYSA-N diethyl malate Chemical compound CCOC(=O)CC(O)C(=O)OCC VKNUORWMCINMRB-UHFFFAOYSA-N 0.000 description 1
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 1
- 229940075557 diethylene glycol monoethyl ether Drugs 0.000 description 1
- 229940008099 dimethicone Drugs 0.000 description 1
- 239000004205 dimethyl polysiloxane Substances 0.000 description 1
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 1
- 229940113088 dimethylacetamide Drugs 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- STVZJERGLQHEKB-UHFFFAOYSA-N ethylene glycol dimethacrylate Chemical compound CC(=C)C(=O)OCCOC(=O)C(C)=C STVZJERGLQHEKB-UHFFFAOYSA-N 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 230000003325 follicular Effects 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 235000021588 free fatty acids Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000010492 gellan gum Nutrition 0.000 description 1
- 239000000216 gellan gum Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229960005150 glycerol Drugs 0.000 description 1
- 229940075529 glyceryl stearate Drugs 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229920001600 hydrophobic polymer Polymers 0.000 description 1
- ZCTXEAQXZGPWFG-UHFFFAOYSA-N imidurea Chemical compound O=C1NC(=O)N(CO)C1NC(=O)NCNC(=O)NC1C(=O)NC(=O)N1CO ZCTXEAQXZGPWFG-UHFFFAOYSA-N 0.000 description 1
- 229940113174 imidurea Drugs 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229940074928 isopropyl myristate Drugs 0.000 description 1
- 229940075495 isopropyl palmitate Drugs 0.000 description 1
- 235000010494 karaya gum Nutrition 0.000 description 1
- 239000000231 karaya gum Substances 0.000 description 1
- 229940039371 karaya gum Drugs 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 235000010420 locust bean gum Nutrition 0.000 description 1
- 239000000711 locust bean gum Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000004200 microcrystalline wax Substances 0.000 description 1
- 235000019808 microcrystalline wax Nutrition 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- RZRNAYUHWVFMIP-UHFFFAOYSA-N monoelaidin Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-UHFFFAOYSA-N 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- JXTPJDDICSTXJX-UHFFFAOYSA-N n-Triacontane Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC JXTPJDDICSTXJX-UHFFFAOYSA-N 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 210000000282 nail Anatomy 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229960000292 pectin Drugs 0.000 description 1
- 125000002081 peroxide group Chemical group 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 229960005323 phenoxyethanol Drugs 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229940044519 poloxamer 188 Drugs 0.000 description 1
- 229920001992 poloxamer 407 Polymers 0.000 description 1
- 229940044476 poloxamer 407 Drugs 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 description 1
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229940101027 polysorbate 40 Drugs 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 229940055019 propionibacterium acne Drugs 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 208000029561 pustule Diseases 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 210000004927 skin cell Anatomy 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- BTURAGWYSMTVOW-UHFFFAOYSA-M sodium dodecanoate Chemical compound [Na+].CCCCCCCCCCCC([O-])=O BTURAGWYSMTVOW-UHFFFAOYSA-M 0.000 description 1
- 229940082004 sodium laurate Drugs 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 229940032094 squalane Drugs 0.000 description 1
- 229940098760 steareth-2 Drugs 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000010965 sucrose esters of fatty acids Nutrition 0.000 description 1
- 239000001959 sucrose esters of fatty acids Substances 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000000194 supercritical-fluid extraction Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229960004906 thiomersal Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 235000019149 tocopherols Nutrition 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- WEAPVABOECTMGR-UHFFFAOYSA-N triethyl 2-acetyloxypropane-1,2,3-tricarboxylate Chemical compound CCOC(=O)CC(C(=O)OCC)(OC(C)=O)CC(=O)OCC WEAPVABOECTMGR-UHFFFAOYSA-N 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
- QUEDXNHFTDJVIY-UHFFFAOYSA-N γ-tocopherol Chemical class OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/327—Peroxy compounds, e.g. hydroperoxides, peroxides, peroxyacids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
Definitions
- the present invention relates to topical pharmaceutical compositions comprising microspheres or microcapsules of a retinoid, wherein said microspheres or microcapsules are further coated with a polymeric layer.
- the present invention also relates to topical pharmaceutical compositions comprising said coated microspheres or microcapsules of a retinoid in combination with benzoyl peroxide. It also relates to processes for the preparation of the topical pharmaceutical compositions and a method of treating acne by administering the topical pharmaceutical compositions.
- Acne vulgaris is a common inflammatory skin disorder which affects the majority of the teenage population, as well as some adults.
- acne There are several causes for the development of acne. These include excessive sebum production, hyperkeratosis of the follicular epithelium, and proliferation of Propionibacterium acnes (P. acnes). These factors are primarily responsible for hyperkeratosis of the follicle lining, including retention of keratin and sebum, as well as the free fatty acid by-products of P. acnes metabolization which can lead to inflamed acne papules and pustules.
- Retinoids are biologically active chemical compounds related to vitamin A and have been traditionally used for decades for the treatment of acne. These include tretinoin, retinol, retinal, isotretinoin, alitretinoin, tazarotene, adapalene, retinaldehyde, and etretinate.
- tretinoin also known as dll-trans retinoic acid or vitamin A acid
- Tretinoin is commercially available in the form of creams, gels, and solutions. All of these compositions quickly release tretinoin, thereby necessitating frequent administration. Further, the quick release of tretinoin from these compositions causes irritation leading to patient noncompliance.
- Retin-A Micro ® a controlled-release formulation of tretinoin, is based on a system of porous microspheres prepared by using methyl methacrylate and glycol dimethacrylate cross- polymer.
- the polymeric beads have a network of pores that retain tretinoin within the pores, permitting controlled-release of tretinoin depending upon the pore size.
- U.S. Patent No. 5,955,109 discloses a topical pharmaceutical composition for the delivery of tretinoin comprising: (a) solid particles composed of a cross-linked copolymer of monoethylenically unsaturated monomers and polyethylenically unsaturated monomers, wherein said particles contain a continuous non-collapsible network of pores open to the exterior of said particles, and (b) an impregnant comprising tretinoin retained inside said pores in an amount effective to promote skin repair, wherein retention of said tretinoin inside said pores reduces irritancy of the composition.
- U.S. Patent Nos. 4,690,825, 5, 145,675, 5,135,740, 5,316,774, and 5,879,716 also disclose such polymeric beads based upon the use of synthetic polymers for making microspheres.
- U.S. Patent No. 8,053,000 discloses substantially non-porous polymeric microspheres of tretinoin comprising a hydrophobic polymer, i.e., ethyl cellulose, and a plasticizer.
- the microparticles have surface pores, internal pores, or both, but have substantially no internal porosity connecting with the surface.
- U.S. Publication No. 2011/0166101 discloses substantially porous microspheres of tretinoin comprising ethyl cellulose without the inclusion of a plasticizer.
- the formulations disclosed in the prior art run the risk of the retinoid leaching out of the microspheres during storage.
- the free retinoid upon contact with the skin surface, could cause irritation leading to patient non-compliance.
- the present invention teaches topical pharmaceutical compositions of a retinoid comprising microspheres or microcapsules of a retinoid, wherein said microspheres or microcapsules are further coated with a polymeric layer.
- the topical pharmaceutical compositions of the present invention can be combined with benzoyl peroxide in order to further enhance the efficacy of the compositions.
- the additional coating on said microspheres or microcapsules minimizes the problem of incompatibility between a retinoid and benzoyl peroxide and results in stable compositions.
- the present invention provides topical pharmaceutical compositions of a retinoid comprising microspheres or microcapsules of a retinoid, wherein said microspheres or microcapsules are coated with a polymeric layer.
- the compositions of the present invention comprise non-porous microspheres or microcapsules which are free of any leaching problems and which provide end users with a more compliant formulation.
- It further provides topical pharmaceutical compositions comprising said microspheres or microcapsules of a retinoid in combination with benzoyl peroxide.
- the additional coating on said microspheres or microcapsules overcomes the problem of incompatibility between a retinoid and benzoyl peroxide and results in stable compositions. It also provides processes of preparation of said topical pharmaceutical compositions and a method of treating acne by administering said topical pharmaceutical compositions.
- a first aspect of the present invention provides a topical pharmaceutical composition of a retinoid comprising:
- microspheres comprising a retinoid and one or more microsphere-forming polymers
- a second aspect of the present invention provides a topical pharmaceutical composition of a retinoid comprising:
- microcapsules comprising a retinoid and one or more microcapsule-forming polymers
- a third aspect of the present invention provides a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:
- composition of a retinoid comprising:
- microspheres comprising a retinoid and one or more microsphere- forming polymers
- a fourth aspect of the present invention provides a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:
- composition of a retinoid comprising:
- microcapsules comprising a retinoid and one or more microcapsule- forming polymers
- a fifth aspect of the present invention provides a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:
- microspheres comprising a retinoid and one or more microsphere- forming polymers
- microcapsules comprising benzoyl peroxide and one or more
- microcapsule-forming polymers
- a sixth aspect of the present invention provides a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:
- microspheres comprising a retinoid and one or more microsphere- forming polymers
- microspheres comprising benzoyl peroxide and one or more
- a seventh aspect of the present invention provides a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:
- microcapsules comprising a retinoid and one or more microcapsule- forming polymers
- microcapsules comprising benzoyl peroxide and one or more
- microcapsule-forming polymers
- An eighth aspect of the present invention provides a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:
- microcapsules comprising a retinoid and one or more microcapsule- forming polymers
- microspheres comprising benzoyl peroxide and one or more
- the retinoid is selected from the group comprising tretinoin, retinol, retinal, isotretinoin, alitretinoin, tazarotene, adapalene, retinaldehyde, and etretinate.
- the retinoid is tretinoin.
- the microsphere-forming polymers, microcapsule-forming polymers, or coat-forming polymers are selected from the group comprising cellulose derivatives e.g., ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl cellulose, and sodium carboxymethyl cellulose; acrylates e.g., methacrylates, polyacrylates, and methacrylic acid and methyl methacrylate copolymers such as Eudragit ® L 100; polyoxyethylene-polyoxypropylene copolymers; gums e.g., alginic acid, sodium alginate, carrageenan, gellan gum, and guar gum; propylene glycol alginate; chitosan; starch; dextran; gelatin; polyvinyl pyrrolidone; polyethylene glycol; polyethylene oxide; polyvinyl alcohol; lipids; fatty acids; waxes;
- cellulose derivatives e.g.
- the microsphere-forming polymer is ethyl cellulose and microcapsule-forming polymer or coat-forming polymer is chitosan, sodium alginate, or an acrylate.
- a ninth aspect of the present invention provides a kit for dispensing a topical pharmaceutical composition of a retinoid and benzoyl peroxide, wherein the kit comprises:
- a first compartment comprising a composition of a retinoid comprising:
- microspheres comprising a retinoid and one or more microsphere- forming polymers
- a tenth aspect of the present invention provides a kit for dispensing a topical pharmaceutical composition of a retinoid and benzoyl peroxide, wherein the kit comprises:
- a first compartment comprising a composition of a retinoid comprising:
- microcapsules comprising a retinoid and one or more microcapsule- forming polymers
- the second compartment comprises benzoyl peroxide in free-form, in the form of microcapsules, or in the form of microspheres.
- compositions of a retinoid and benzoyl peroxide are applied concomitantly or sequentially onto a surface of a subject's body.
- An eleventh aspect of the present invention provides a method of treating acne by administering a topical pharmaceutical composition of a retinoid comprising:
- microspheres comprising a retinoid and one or more microsphere-forming polymers; and (b) a coating layer over said microspheres comprising one or more coat-forming polymers.
- a twelfth aspect of the present invention provides a method of treating acne by administering a topical pharmaceutical composition of a retinoid comprising:
- microcapsules comprising a retinoid and one or more microcapsule-forming polymers
- a thirteenth aspect of the present invention provides a method of treating acne by administering a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:
- composition of a retinoid comprising:
- microspheres comprising a retinoid and one or more microsphere- forming polymers
- a fourteenth aspect of the present invention provides a method of treating acne by administering a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:
- composition of a retinoid comprising:
- microcapsules comprising a retinoid and one or more microcapsule- forming polymers
- the benzoyl peroxide is present in free-form, in the form of microcapsules, or in the form of microspheres.
- the topical pharmaceutical composition is co-administered with one or more additional drugs used to treat acne.
- a fifteenth aspect of the present invention provides a process for the preparation of a topical pharmaceutical composition of a retinoid comprising: (i) forming microspheres of a retinoid by using one or more microsphere-forming polymers; and
- the process comprises:
- step (ii) dissolving a retinoid into the solution of step (i);
- step (iv) admixing the solution of step (ii) with the solution of step (iii) to form an emulsion
- step (v) homogenizing the emulsion of step (iv) using a homogenizer to form
- step (vi) coating the microspheres of step (v) with one or more coat-forming polymers to obtain coated microspheres.
- a sixteenth aspect of the present invention provides a process for the preparation of a topical pharmaceutical composition of a retinoid comprising:
- the process comprises:
- step (ii) dispersing a retinoid into the solution of step (i);
- step (iii) homogenizing the dispersion of step (ii) using a homogenizer
- step (iv) mixing one or more microcapsule-forming polymers into the homogenized dispersion of step (iii) to form microcapsules;
- step (v) coating the microcapsules of step (iv) with one or more coat-forming polymers to obtain coated microcapsules.
- a seventeenth aspect of the present invention provides a process for the preparation of a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising a first composition of a retinoid and a second composition of benzoyl peroxide, wherein the process for the preparation of the first composition comprises the steps of: (i) forming microspheres of a retinoid by using one or more microsphere-forming polymers; and
- microcapsule-forming polymers
- the process for the preparation of the first composition comprises the steps of:
- step (ii) dissolving a retinoid into the solution of step (i);
- step (iv) admixing the solution of step (ii) with the solution of step (iii) to form an emulsion
- step (v) homogenizing the emulsion of step (iv) using a homogenizer to form
- step (vi) coating the microspheres of step (v) with one or more coat-forming polymers to obtain coated microspheres;
- step (ii) dispersing benzoyl peroxide into the solution of step (i);
- step (iii) homogenizing the dispersion of step (ii) using a homogenizer
- step (iv) mixing one or more microcapsule-forming polymers into the homogenized dispersion of step (iii) to form microcapsules;
- step (v) optionally coating the microcapsules of step (iv) with one or more coat- forming polymers to obtain coated microcapsules.
- An eighteenth aspect of the present invention provides a process for the preparation of a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising a first composition of a retinoid and a second composition of benzoyl peroxide, wherein the process for the preparation of the first composition comprises the steps of: (i) forming microspheres of a retinoid by using one or more microsphere-forming polymers; and
- the process for the preparation of a first composition comprises the steps of:
- step (ii) dissolving a retinoid into the solution of step (i);
- step (iv) admixing the solution of step (ii) with the solution of step (iii) to form an emulsion
- step (v) homogenizing the emulsion of step (iv) using a homogenizer to form
- step (vi) coating the microspheres of step (v) with one or more coat-forming polymers to obtain coated microspheres;
- step (ii) dissolving benzoyl peroxide into the solution of step (i);
- step (iv) admixing the solution of step (ii) with the solution of step (iii) using a
- step (v) optionally coating the microspheres of step (iv) with one or more coat-forming polymers to obtain coated microspheres.
- a nineteenth aspect of the present invention provides a process for the preparation of a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising a first composition of a retinoid and a second composition of benzoyl peroxide, wherein the process for the preparation of the first composition comprises the steps of:
- microcapsule-forming polymers
- the process for the preparation of the first composition comprises the steps of:
- step (ii) dispersing a retinoid into the solution of step (i);
- step (iii) homogenizing the dispersion of step (ii) using a homogenizer
- step (iv) mixing one or more microcapsule-forming polymers into the homogenized dispersion of step (iii) to form microcapsules;
- step (v) coating the microcapsules of step (iv) with one or more coat-forming polymers to obtain coated microcapsules;
- step (ii) dispersing benzoyl peroxide into the solution of step (i);
- step (iii) homogenizing the dispersion of step (ii) using a homogenizer
- step (iv) mixing one or more microcapsule-forming polymers into the homogenized dispersion of step (iii) to form microcapsules;
- step (v) optionally coating the microcapsules of step (iv) with one or more coat- forming polymers to obtain coated microcapsules.
- a twentieth aspect of the present invention provides a process for the preparation of a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising a first composition of a retinoid and a second composition of benzoyl peroxide, wherein the process for the preparation of the first composition comprises the steps of: (i) forming microcapsules of a retinoid by using one or more microcapsule- forming polymers; and
- the process for the preparation of the first composition comprises the steps of:
- step (ii) dispersing a retinoid into the solution of step (i);
- step (iii) homogenizing the dispersion of step (ii) using a homogenizer
- step (iv) mixing one or more microcapsule-forming polymers into the homogenized dispersion of step (iii) to form microcapsules;
- step (v) coating the microcapsules of step (iv) with one or more coat-forming polymers to obtain coated microcapsules;
- step (ii) dissolving benzoyl peroxide into the solution of step (i);
- step (iv) admixing the solution of step (ii) with the solution of step (iii) using a
- step (v) optionally coating the microspheres of step (iv) with one or more coat-forming polymers to obtain coated microspheres.
- topical refers to a composition meant for application to the skin, nail, or mucosal tissue.
- retinoid refers to chemical compounds related to vitamin
- retinoids include tretinoin, retinol, retinal, isotretinoin, alitretinoin, tazarotene, adapalene, retinaldehyde, and etretinate.
- the retinoid used in the present invention is tretinoin.
- the term "tretinoin,” as used herein, refers to all-trans retinoic acid or vitamin A acid. Chemically, tretinoin is 3,7-dimethyl-9-(2,6,6-trimethyl-l-cyclohexen-l-yl)-2,4,6,8- nonatetraenoic acid. It further includes its salts, polymorphs, enantiomers, hydrates, solvates, prodrugs, chelates, and complexes.
- benzoyl peroxide refers to a peroxide consisting of two benzoyl groups joined by a peroxide group. Hydrous benzoyl peroxide may also be used. Benzoyl peroxide used in the present invention is present in free-form, in the form of microcapsules, or in the form of microspheres.
- free-form refers to the benzoyl peroxide present in the composition not intimately embedded, encapsulated, entrapped, or encased in a polymeric carrier, and is present in the composition in direct contact with the composition carrier.
- Suitable additional drugs used to treat acne are selected from the group comprising antibiotics e.g., tetracycline, erythromycin, and clindamycin; salicylic acid; sulfur; resorcinol; and combinations thereof.
- microspheres or microcapsules of the present invention can be of any shape e.g., spherical, oblong, or ellipsoidal.
- microsphere refers to a matrix system in which a retinoid or benzoyl peroxide is dissolved or dispersed throughout the polymer matrix.
- the microspheres of the present invention have a D 90 value in a range of from about 0.01 ⁇ to about 1000 ⁇ , particularly in a range of from about 0.1 ⁇ to about 500 ⁇ , and more particularly in a range of from about 1 ⁇ to about 200 ⁇ .
- microcapsule refers to a system comprising a retinoid or benzoyl peroxide surrounded by a polymeric shell.
- the microcapsules of the present invention have a D 90 value in a range of from about 0.01 ⁇ to about 1000 ⁇ , particularly in a range of from about 0.1 ⁇ to about 500 ⁇ , and more particularly in a range of from about 1 ⁇ to about 200 ⁇ .
- D 90 refers to a diameter for which 90% of the
- microspheres or microcapsules have diameters equal to or smaller than that diameter.
- the diameter of the microspheres or microcapsules can be determined using laser diffraction particle size analyzers such as a Malvern ® instrument; electrical conductance instruments such as a Coulter counter; sieve analyzers; optical microscopes; sedimentation analyzers; and other known methods in the art.
- the D 90 value is determined by using a Malvern ® instrument.
- stabilizers are used as suspending agents that help to prevent the aggregation of the microspheres or microcapsules.
- Stabilizers used in the present invention can be selected from the group comprising cationic, anionic, or non-ionic compounds. Specific examples of stabilizers include cetyltrimethylammonium bromide; cetyltrimethylammonium chloride; polyvinyl alcohol; cellulose derivatives e.g.,
- carboxymethyl cellulose polyvinyl pyrrolidone; sorbitan derivatives e.g., polysorbate 80; sodium lauryl sulphate; docusate sodium; lecithin; polyoxyethylene-castor oil derivatives; and mixtures thereof.
- organic phase includes all organic solvents. Suitable examples of organic solvents are alcohols such as methanol, ethanol, and isopropyl alcohol; chlorinated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, methyl dichloroacetate, ethyl chloroacetate, ethyl dichloroacetate, and ethylene dichloride;
- fluorinated hydrocarbons such as methyl fluoroacetate, methyl difluoroacetate, ethyl fluoroacetate, and ethyl difluoroacetate; acetates such as ethyl acetate, propyl acetate, isopropyl acetate, and butyl acetate; formates such as methyl formate, ethyl formate, isopropyl formate, propyl formate, and butyl formate; anhydrides such as maleic anhydride, acetic anhydride, propionic anhydride, and phosphoric anhydride; amides such as acetamide, propionamide, and butylamide; acetone; acetonitrile; tetrahydrofuran; and mixtures thereof.
- fluorinated hydrocarbons such as methyl fluoroacetate, methyl difluoroacetate, ethyl fluoroacetate, and ethyl difluoro
- aqueous phase includes water and all water-miscible solvents.
- water-miscible solvents include glycerin; sorbitol; glycols e.g., polyethylene glycol and propylene glycol; and mixtures thereof.
- the aqueous phase is selected from the group comprising water, glycerin, sorbitol, polyethylene glycol, propylene glycol, and mixtures thereof.
- microspheres or microcapsules of the present invention can be prepared by any suitable technique known in the art. Most commonly used techniques include
- microspheres of the present invention are preferably prepared by a
- the retinoid or benzoyl peroxide and one or more microsphere-forming polymers are first dissolved into an organic phase. Further, a stabilizer is mixed in an aqueous phase. These two phases are admixed together to form an emulsion. This emulsion is then homogenized using a homogenizer to form the microspheres.
- the retinoid or benzoyl peroxide can be dissolved in an organic phase which is added into an aqueous phase to form the emulsion. This emulsion is then homogenized using a homogenizer to form the microspheres.
- the microcapsules of the present invention are preferably prepared by a polymer precipitation process.
- a stabilizer is first mixed in an aqueous phase.
- the retinoid or benzoyl peroxide is dispersed in said aqueous phase and is homogenized using a homogenizer.
- One or more microcapsule-forming polymers are then mixed into the homogenized dispersion.
- the pH of the dispersion is then adjusted using a pH-adjusting agent such that the microcapsule-forming polymers are precipitated over retinoid or benzoyl peroxide particles to form the
- microcapsules Alternatively, the retinoid or benzoyl peroxide is dispersed in an aqueous phase and is homogenized using a homogenizer. One or more microcapsule-forming polymers are then mixed into the homogenized dispersion. The pH of the dispersion is then adjusted using a pH-adjusting agent such that the microcapsule-forming polymers are precipitated over retinoid or benzoyl peroxide particles to form the microcapsules.
- microspheres or microcapsules can be separated from the emulsion/dispersion by any suitable technique known in the art. Suitable techniques include filtration, centrifugation, decantation, dialysis, and evaporation. The preferred technique is filtration.
- the separated microspheres or microcapsules can be dried by any suitable technique known in the art. Suitable techniques include distillation, spray drying, lyophilization, oven drying, fluidized bed drying, rota-evaporation using a rotavapor, and combinations thereof.
- microspheres or microcapsules of the present invention can be coated with a coating layer comprising one or more coat-forming polymers.
- the coating can be performed by a technique such as polymer precipitation in which one or more coat-forming polymers are coated onto the microspheres or microcapsules.
- the coat-forming polymers are dissolved or dispersed in an organic or aqueous phase to form the solution or dispersion.
- the microspheres or microcapsules are then dispersed into the solution or dispersion of the coat-forming polymers.
- the pH of the dispersion is then adjusted using a pH adjusting agent such that the coat-forming polymers are precipitated over the microspheres or microcapsules to form the coated microspheres or microcapsules.
- Suitable pH-adjusting agents are selected from the group comprising organic or inorganic acids, e.g., citric acid, acetic acid, fumaric acid, tartaric acid, phosphoric acid, and hydrochloric acid; organic or inorganic bases, e.g. , sodium hydroxide, potassium hydroxide, and ammonium hydroxide; tertiary amines, e.g., triethanolamine and tetrahydroxypropyl ethylendiamine; and buffers, e.g., phosphate buffer and acetate buffer.
- organic or inorganic acids e.g., citric acid, acetic acid, fumaric acid, tartaric acid, phosphoric acid, and hydrochloric acid
- organic or inorganic bases e.g. , sodium hydroxide, potassium hydroxide, and ammonium hydroxide
- tertiary amines e.g., triethanolamine and tetrahydroxypropyl ethyl
- one or more coat-forming polymers are dissolved or dispersed in an organic or aqueous phase along with one or more coating additives to form the solution or dispersion.
- This solution/dispersion is then coated onto microspheres or microcapsules using any suitable methods such as spray drying and fluidized bed coating.
- Coating additives may be selected from the group consisting of plasticizers, binders, lubricants, and coloring agents.
- Suitable plasticizers are selected from the group consisting of triethyl citrate, dibutyl sebacate, acetylated triacetin, tributyl citrate, glycerol tributyrate, monoglyceride, rapeseed oil, olive oil, sesame oil, acetyl tributyl citrate, acetyl triethyl citrate, glycerin, sorbitol, diethyl oxalate, diethyl phthalate, diethyl malate, diethyl fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, and mixtures thereof.
- Suitable binders are selected from the group consisting of methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and mixtures thereof.
- Suitable lubricants are selected from the group consisting of colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, white beeswax, and mixtures thereof.
- Coloring agents includes any FDA approved color for topical use.
- microspheres of the present invention may also comprise pre-formed microspheres, such as silica microspheres, in which the retinoid or benzoyl peroxide can be impregnated. These microspheres can be further coated with a coating layer comprising one or more coat-forming polymers.
- the microspheres and/or microcapsules of the present invention can be dispersed in a suitable pharmaceutical composition to allow for ease of topical application.
- the pharmaceutical composition of the present invention possesses good spreadability.
- the pharmaceutical composition can be aqueous-based or non-aqueous based.
- the pharmaceutical composition of the present invention can be in the form of an ointment, a cream, a lotion, an oil, a solution, an emulsion, a gel, a paste, an aerosol, a powder, or a foam.
- the pharmaceutical composition may comprises one or more pharmaceutically acceptable excipients selected from the group comprising gelling agents, preservatives, surfactants, chelating agents, pH-adjusting agents, humectants, antioxidants, permeation- enhancers, emulsifiers, solvents, and mixtures thereof.
- Suitable gelling agents are selected from the group comprising carboxyvinyl polymers, e.g., Carbopol ® 980, Carbopol ® 974P, Carbopol ® 97 IP, and Carbopol ® 934P; natural gums, e.g., karaya gum, locust bean gum, guar gum, xanthan gum, arabic gum, tragacanth gum, carrageenan, pectin, agar, alginic acid, and sodium alginate; cellulose derivatives, e.g., hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl cellulose, and sodium carboxymethyl cellulose; acrylates, e.g., methacrylates and polyacrylates; alginic acid-propylene glycol ester; polyoxyethylene-polyoxypropylene copolymers; polyvinyl pyrrolidone; polyethylene glycol; polyethylene oxide; poly
- Suitable preservatives are selected from the group comprising methyl-, ethyl-, propyl-, or butyl-esters of hydroxy benzoic acid or sodium salts thereof, benzoic acid, sodium benzoate, chlorhexedine, benzalkonium chloride, 2-phenoxyethanol, cetrimide, potassium sorbate, benzyl alcohol, imidurea, dichlorobenzyl alcohol, thiomersal, diazolidinylurea, and mixtures thereof.
- Suitable surfactants are selected from the group comprising polyethoxylated fatty acid esters, polyoxyethylene sorbitan esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene-polyoxypropylene glycol, sorbitan esters, sodium lauryl sulphate, docusate sodium, nonooxynol, glyceryl monostearate, and mixtures thereof.
- Suitable chelating agents are selected from the group comprising
- ethylenediaminetetraacetic acid or derivatives or salts thereof e.g. , disodium edetate
- dihydroxyethyl glycine dihydroxyethyl glycine
- glucamine acids, e.g., citric acid, tartaric acid, gluconic acid, and phosphoric acid; and mixtures thereof.
- Suitable humectants or emollients are selected from the group comprising propylene glycol, glycerin, butylene glycol, sorbitol, triacetin, cyclomethicone, dimethicone copolyol, caprylic/capric triglyerides, castor oil, ceteareth-20, ceteareth-30, ceteth-20, cetostearyl alcohol, cetyl alcohol, cocoa butter, diisopropyl adipate, glycerin, glyceryl monooleate, glyceryl monostearate, glyceryl stearate, isopropyl myristate, isopropyl palmitate, lanolin, lanolin alcohol, hydrogenated lanolin, liquid paraffins, linoleic acid, mineral oil, oleic acid, white petrolatum, polyethylene glycol, polyoxyethylene glycol fatty alcohol ethers, polyoxypropylene 15 stearyl
- Suitable antioxidants include butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium metabisulfite, ascorbic acid, propyl gallate, thiourea, tocopherols, beta-carotene, and mixtures thereof.
- Suitable permeation-enhancers are selected from the group comprising sulfoxides, e.g., dimethyl sulfoxide (DMSO); ethers, e.g.,diethylene glycol monoethyl ether (e.g., Transcutol ® ); surfactants, e.g., sodium laurate, sodium lauryl sulfate, polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80; alkyl glycosides; alcohols, e.g., ethanol, propanol, and benzyl alcohol; fatty acids, e.g., lauric acid, oleic acid, valeric acid, and isostearic acid; fatty acid esters, e.g., isopropyl myristate and isopropyl palmitate; polyols or esters thereof, e.g., propylene glycol, ethylene glycol, glycerol, butanedio
- Suitable emulsifiers are selected from the group comprising tri-block copolymers, e.g., Poloxamer 407, Poloxamer 188; polyoxyl stearates, e.g., poly oxyethylene-20 stearate (Myrj ® 49); polysorbates, e.g., Tween ® 80, Tween ® 60 and Tween ® 20; sorbitan fatty acid esters, e.g., Span ® 60 or Span ® 80; polyoxyethylene alkyl ethers, e.g., Brij ® 97;
- tri-block copolymers e.g., Poloxamer 407, Poloxamer 188
- polyoxyl stearates e.g., poly oxyethylene-20 stearate (Myrj ® 49)
- polysorbates e.g., Tween ® 80, Tween ® 60 and Tween ® 20
- polyoxyethylene alkylphenyl ethers polyoxyethylene alkylphenyl ethers; sucrose fatty acid esters; and mixtures thereof.
- Suitable solvents are selected from the group comprising water; alcohols, e.g., methanol, ethanol, isopropyl alcohol, and higher alcohols; glycerin; sorbitol; glycols, e.g., polyethylene glycol and propylene glycol; tetrahydrofuran; liquid petrolatum; ether;
- petroleum ether aromatics, e.g., benzene and toluene; alkanes, e.g., pentane, hexane, and heptane; ketones, e.g., acetone and methyl ethyl ketone; chlorinated hydrocarbons e.g., chloroform, carbon tetrachloride, methylene chloride, and ethylene dichloride; acetates, e.g., ethyl acetate; lipids, e.g., isopropyl myristate, diisopropyl adipate, and mineral oil; and mixtures thereof.
- aromatics e.g., benzene and toluene
- alkanes e.g., pentane, hexane, and heptane
- ketones e.g., acetone and methyl ethyl ketone
- pH-adjusting agents well known in the art can be used, including, for example, NaOH, acetic acid, hydrochloric acid, etc.
- Any suitable pH-adjusting agents well known in the art can be used, including, for example, NaOH, acetic acid, hydrochloric acid, etc.
- the following examples represent various embodiments according to the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention.
- step 3 The solution of step 1 was added into the solution of step 2 to form an emulsion.
- step 3 The emulsion of step 3 was homogenized using a homogenizer to form microspheres.
- microsphere dispersion The microsphere dispersion.
- step 6 was added into the microsphere dispersion of step 5.
- step 7 The pH of the dispersion of step 7 was adjusted to 3.0 using a hydrochloric acid solution to obtain coated microspheres.
- step 3 The solution of step 1 was added into the solution of step 2 to form an emulsion.
- step 3 The emulsion of step 3 was homogenized using a homogenizer to form microspheres.
- microsphere dispersion The microsphere dispersion.
- step 6 was added to the microsphere dispersion of step 5.
- step 7 The pH of the dispersion of step 7 was adjusted to 3.0 using a hydrochloric acid solution to obtain coated microspheres.
- step 8 The coated microspheres of step 8 were filtered and dried.
- step 3 The solution of step 1 was added into the solution of step 2 to form an emulsion.
- step 3 The emulsion of step 3 was homogenized using a homogenizer to form microspheres.
- microsphere dispersion The microsphere dispersion.
- step 6 Chitosan was added to purified water acidified with a hydrochloric acid solution. 7. The solution of step 6 was added into the microsphere dispersion of step 5.
- step 7 The pH of the dispersion of step 7 was adjusted to 7.0 using a sodium hydroxide solution to obtain coated microspheres.
- step 3 The solution of step 1 was added into the solution of step 2 to form an emulsion.
- step 3 The emulsion of step 3 was homogenized using a homogenizer to form microspheres.
- microsphere dispersion The microsphere dispersion.
- step 6 Chitosan was added to purified water acidified with a hydrochloric acid solution. 7. The solution of step 6 was added into the microsphere dispersion of step 5.
- step 7 The pH of the dispersion of step 7 was adjusted to 7.0 using sodium hydroxide solution to obtain coated microspheres.
- step 8 The coated microspheres of step 8 were filtered and dried.
- Benzoyl peroxide was dispersed into the solution of step 2, and the mixture was homogenized using a homogenizer.
- step 3 The dispersion of step 3 was filtered to obtain benzoyl peroxide particles.
- step 4 The benzoyl peroxide particles of step 4 were redispersed into the solution of step 5 and stirred.
- step 7 was added into the dispersion of step 6.
- step 8 The pH of the dispersion of step 8 was adjusted to 7.0 using a sodium hydroxide solution to obtain coated microcapsules.
- step 3 The dispersion of step 2 was dried in a rotavapor to obtain tazarotene loaded silica microspheres.
- step 3 The tazarotene loaded silica microspheres of step 3 were dispersed into the solution of step 4.
- step 5 The dispersion of step 5 was spray dried to obtain coated microspheres.
- step 3 The solution of step 1 was added into the solution of step 2 to form an emulsion.
- step 4 The emulsion of step 3 was homogenized using a homogenizer to form microspheres. 5. The dichloromethane from the emulsion of step 4 was evaporated to form a microsphere dispersion.
- step 6 was added into the microsphere dispersion of step 5.
- step 7 The pH of the dispersion of step 7 was adjusted to 7.0 using a sodium hydroxide solution to obtain coated microspheres.
- step 8 The coated microspheres of step 8 were filtered and dried.
- step 3 The solution of step 1 was added into the solution of step 2 to form an emulsion. 4. The emulsion of step 3 was homogenized using a homogenizer to form microspheres.
- microsphere dispersion The microsphere dispersion.
- step 6 was added into the microsphere dispersion of step 5.
- step 7 The pH of the dispersion of step 7 was adjusted to 7.0 using a sodium hydroxide solution to obtain coated microspheres.
- step 3 The solution of step 1 was added into the solution of step 2 to form an emulsion.
- step 3 The emulsion of step 3 was homogenized using a homogenizer to form microspheres.
- microsphere dispersion The microsphere dispersion.
- step 6 was added into the microsphere dispersion of step 5.
- step 7 The pH of the dispersion of step 7 was adjusted to 3.0 using a hydrochloric acid solution to obtain coated microspheres.
- step 8 The coated microspheres of step 8 were filtered and dried.
- step 3 The solution of step 1 was added into the solution of step 2 to form an emulsion. 4. The emulsion of step 3 was homogenized using a homogenizer to form microspheres.
- microsphere dispersion The microsphere dispersion.
- step 6 was added into the microsphere dispersion of step 5.
- step 7 The pH of the dispersion of step 7 was adjusted to 3.0 using a hydrochloric acid solution to obtain coated microspheres.
- step 8 The coated microspheres of step 8 were filtered and dried.
- step 3 The dispersion of step 3 was filtered to obtain benzoyl peroxide particles.
- step 4 The benzoyl peroxide particles of step 4 were redispersed in purified water.
- step 6 The solution of step 6 was added into the dispersion of step 5. 8.
- the pH of the dispersion of step 7 was adjusted to 7.0 using a sodium hydroxide solution to obtain coated microcapsules.
- step 3 The solution of step 1 was added into the solution of step 2 to form an emulsion.
- step 3 The emulsion of step 3 was homogenized using a homogenizer to form microspheres.
- microsphere dispersion The microsphere dispersion.
- step 5 The dispersion of step 5 was added into the solution of step 6.
- step 7 The dispersion of step 7 was spray dried to obtain coated microspheres.
- step 3 The solution of step 1 was added into the solution of step 2 to form an emulsion.
- step 3 The emulsion of step 3 was homogenized using a homogenizer to form microspheres.
- microsphere dispersion The microsphere dispersion.
- step 6 was added into the microsphere dispersion of step 5.
- step 8 The coated microspheres of step 8 were filtered and dried.
- Microspheres of tretinoin obtained from Examples 1-3, microspheres of benzoyl peroxide obtained from Example 4, and microcapsules of benzoyl peroxide obtained from Example 5 were incorporated either separately or in combination into a gel composition as described in Examples 14-16 provided below.
- Purified water was divided into three portions.
- Carbopol ® 974P was dispersed into the third portion of purified water.
- step 7 The dispersions of step 3 and step 5 were added into the dispersion of step 6 while stirring.
- step 7 The pH of the dispersion of step 7 was adjusted to 5.5 with a sodium hydroxide solution.
- Purified water was divided into three portions.
- Hydroxyethyl cellulose was dispersed into the third portion of purified water.
- Carbopol ® 974P was dispersed into the second portion of propylene glycol.
- Tretinoin microspheres were dispersed in glycerin.
- step 3 was added into the carbopol dispersion of step 4 while
- step 5 was added into the dispersion of step 6.
Abstract
The present invention relates to topical pharmaceutical compositions comprising microspheres or microcapsules of a retinoid, wherein said microspheres or microcapsules are further coated with a polymeric layer. The present invention also relates to topical pharmaceutical compositions comprising said coated microspheres or microcapsules of a retinoid in combination with benzoyl peroxide. It also relates to processes for the preparation of said topical pharmaceutical compositions and a method of treating acne by administering said topical pharmaceutical compositions.
Description
TOPICAL PHARMACEUTICAL COMPOSITION OF A RETINOID
Field of the Invention
The present invention relates to topical pharmaceutical compositions comprising microspheres or microcapsules of a retinoid, wherein said microspheres or microcapsules are further coated with a polymeric layer. The present invention also relates to topical pharmaceutical compositions comprising said coated microspheres or microcapsules of a retinoid in combination with benzoyl peroxide. It also relates to processes for the preparation of the topical pharmaceutical compositions and a method of treating acne by administering the topical pharmaceutical compositions.
Background of the Invention
Acne vulgaris is a common inflammatory skin disorder which affects the majority of the teenage population, as well as some adults. There are several causes for the development of acne. These include excessive sebum production, hyperkeratosis of the follicular epithelium, and proliferation of Propionibacterium acnes (P. acnes). These factors are primarily responsible for hyperkeratosis of the follicle lining, including retention of keratin and sebum, as well as the free fatty acid by-products of P. acnes metabolization which can lead to inflamed acne papules and pustules.
Retinoids are biologically active chemical compounds related to vitamin A and have been traditionally used for decades for the treatment of acne. These include tretinoin, retinol, retinal, isotretinoin, alitretinoin, tazarotene, adapalene, retinaldehyde, and etretinate. Among these, tretinoin, also known as dll-trans retinoic acid or vitamin A acid, treats acne by stimulating the turnover of skin cells and clearing the skin of plugged follicles. Tretinoin is commercially available in the form of creams, gels, and solutions. All of these compositions quickly release tretinoin, thereby necessitating frequent administration. Further, the quick release of tretinoin from these compositions causes irritation leading to patient noncompliance.
Retin-A Micro®, a controlled-release formulation of tretinoin, is based on a system of porous microspheres prepared by using methyl methacrylate and glycol dimethacrylate cross- polymer. The polymeric beads have a network of pores that retain tretinoin within the pores, permitting controlled-release of tretinoin depending upon the pore size.
U.S. Patent No. 5,955,109 discloses a topical pharmaceutical composition for the delivery of tretinoin comprising: (a) solid particles composed of a cross-linked copolymer of
monoethylenically unsaturated monomers and polyethylenically unsaturated monomers, wherein said particles contain a continuous non-collapsible network of pores open to the exterior of said particles, and (b) an impregnant comprising tretinoin retained inside said pores in an amount effective to promote skin repair, wherein retention of said tretinoin inside said pores reduces irritancy of the composition. U.S. Patent Nos. 4,690,825, 5, 145,675, 5,135,740, 5,316,774, and 5,879,716 also disclose such polymeric beads based upon the use of synthetic polymers for making microspheres.
The use of synthetic polymers for making microspheres is not always preferred. Polymers of natural origin or chemically modified natural polymers such as cellulose derivatives e.g., ethyl cellulose, provide a useful and environmentally -friendly alternative to the formulators.
U.S. Patent No. 8,053,000 discloses substantially non-porous polymeric microspheres of tretinoin comprising a hydrophobic polymer, i.e., ethyl cellulose, and a plasticizer. The microparticles have surface pores, internal pores, or both, but have substantially no internal porosity connecting with the surface.
U.S. Publication No. 2011/0166101 discloses substantially porous microspheres of tretinoin comprising ethyl cellulose without the inclusion of a plasticizer.
The formulations disclosed in the prior art run the risk of the retinoid leaching out of the microspheres during storage. The free retinoid, upon contact with the skin surface, could cause irritation leading to patient non-compliance. Thus, there remains a need for an improved topical pharmaceutical composition of a retinoid which does not leach out of the microspheres and results in improved patient compliance. The present invention teaches topical pharmaceutical compositions of a retinoid comprising microspheres or microcapsules of a retinoid, wherein said microspheres or microcapsules are further coated with a polymeric layer. Also, the topical pharmaceutical compositions of the present invention can be combined with benzoyl peroxide in order to further enhance the efficacy of the compositions. The additional coating on said microspheres or microcapsules minimizes the problem of incompatibility between a retinoid and benzoyl peroxide and results in stable compositions.
Summary of the Invention
The present invention provides topical pharmaceutical compositions of a retinoid comprising microspheres or microcapsules of a retinoid, wherein said microspheres or microcapsules are coated with a polymeric layer. The compositions of the present invention
comprise non-porous microspheres or microcapsules which are free of any leaching problems and which provide end users with a more compliant formulation. It further provides topical pharmaceutical compositions comprising said microspheres or microcapsules of a retinoid in combination with benzoyl peroxide. The additional coating on said microspheres or microcapsules overcomes the problem of incompatibility between a retinoid and benzoyl peroxide and results in stable compositions. It also provides processes of preparation of said topical pharmaceutical compositions and a method of treating acne by administering said topical pharmaceutical compositions.
Numerous other aspects are provided in accordance with these and other aspects of the invention. Other features and aspects of the present invention will become more fully apparent from the following detailed description and the appended claims.
Detailed Description of the Invention
A first aspect of the present invention provides a topical pharmaceutical composition of a retinoid comprising:
(a) microspheres comprising a retinoid and one or more microsphere-forming polymers; and
(b) a coating layer over said microspheres comprising one or more coat-forming polymers.
A second aspect of the present invention provides a topical pharmaceutical composition of a retinoid comprising:
(a) microcapsules comprising a retinoid and one or more microcapsule-forming polymers; and
(b) a coating layer over said microcapsules comprising one or more coat-forming polymers.
A third aspect of the present invention provides a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:
(a) a composition of a retinoid comprising:
(i) microspheres comprising a retinoid and one or more microsphere- forming polymers; and
(ii) a coating layer over said microspheres comprising one or more coat- forming polymers; and
(b) benzoyl peroxide in free-form.
A fourth aspect of the present invention provides a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:
(a) a composition of a retinoid comprising:
(i) microcapsules comprising a retinoid and one or more microcapsule- forming polymers; and
(ii) a coating layer over said microcapsules comprising one or more coat- forming polymers; and
(b) benzoyl peroxide in free-form.
A fifth aspect of the present invention provides a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:
(a) a first composition of a retinoid comprising:
(i) microspheres comprising a retinoid and one or more microsphere- forming polymers; and
(ii) a coating layer over said microspheres comprising one or more coat- forming polymers; and
(b) a second composition of benzoyl peroxide comprising:
(i) microcapsules comprising benzoyl peroxide and one or more
microcapsule-forming polymers; and
(ii) an optional coating layer over said microcapsules comprising one or more coat-forming polymers.
A sixth aspect of the present invention provides a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:
(a) a first composition of a retinoid comprising:
(i) microspheres comprising a retinoid and one or more microsphere- forming polymers; and
(ii) a coating layer over said microspheres comprising one or more coat- forming polymers; and
(b) a second composition of benzoyl peroxide comprising:
(i) microspheres comprising benzoyl peroxide and one or more
microsphere-forming polymers; and
(ii) an optional coating layer over said microspheres comprising one or more coat-forming polymers.
A seventh aspect of the present invention provides a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:
(a) a first composition of a retinoid comprising:
(i) microcapsules comprising a retinoid and one or more microcapsule- forming polymers; and
(ii) a coating layer over said microcapsules comprising one or more coat- forming polymers; and
(b) a second composition of benzoyl peroxide comprising:
(i) microcapsules comprising benzoyl peroxide and one or more
microcapsule-forming polymers; and
(ii) an optional coating layer over said microcapsules comprising one or more coat-forming polymers.
An eighth aspect of the present invention provides a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:
(a) a first composition of a retinoid comprising:
(i) microcapsules comprising a retinoid and one or more microcapsule- forming polymers; and
(ii) a coating layer over said microcapsules comprising one or more coat- forming polymers; and
(b) a second composition of benzoyl peroxide comprising:
(i) microspheres comprising benzoyl peroxide and one or more
microsphere-forming polymers; and
(ii) an optional coating layer over said microspheres comprising one or more coat-forming polymers.
According to one embodiment of the above aspects, the retinoid is selected from the group comprising tretinoin, retinol, retinal, isotretinoin, alitretinoin, tazarotene, adapalene, retinaldehyde, and etretinate. In a preferred embodiment, the retinoid is tretinoin.
According to another embodiment of the above aspects, the microsphere-forming polymers, microcapsule-forming polymers, or coat-forming polymers are selected from the group comprising cellulose derivatives e.g., ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl cellulose, and sodium carboxymethyl cellulose; acrylates e.g., methacrylates, polyacrylates, and methacrylic acid and methyl methacrylate copolymers such as Eudragit® L 100; polyoxyethylene-polyoxypropylene
copolymers; gums e.g., alginic acid, sodium alginate, carrageenan, gellan gum, and guar gum; propylene glycol alginate; chitosan; starch; dextran; gelatin; polyvinyl pyrrolidone; polyethylene glycol; polyethylene oxide; polyvinyl alcohol; lipids; fatty acids; waxes;
proteins e.g., albumin and collagen; poly(acryl) dextran; poly(acryl) starch; and mixtures thereof. In a preferred embodiment, the microsphere-forming polymer is ethyl cellulose and microcapsule-forming polymer or coat-forming polymer is chitosan, sodium alginate, or an acrylate.
A ninth aspect of the present invention provides a kit for dispensing a topical pharmaceutical composition of a retinoid and benzoyl peroxide, wherein the kit comprises:
(a) a first compartment comprising a composition of a retinoid comprising:
(i) microspheres comprising a retinoid and one or more microsphere- forming polymers; and
(ii) a coating layer over said microspheres comprising one or more coat- forming polymers; and
(b) a second compartment comprising benzoyl peroxide.
A tenth aspect of the present invention provides a kit for dispensing a topical pharmaceutical composition of a retinoid and benzoyl peroxide, wherein the kit comprises:
(a) a first compartment comprising a composition of a retinoid comprising:
(i) microcapsules comprising a retinoid and one or more microcapsule- forming polymers; and
(ii) a coating layer over said microcapsules comprising one or more coat- forming polymers; and
(b) a second compartment comprising benzoyl peroxide.
According to one embodiment of the above aspects, the second compartment comprises benzoyl peroxide in free-form, in the form of microcapsules, or in the form of microspheres.
According to another embodiment of the above aspects, the compositions of a retinoid and benzoyl peroxide are applied concomitantly or sequentially onto a surface of a subject's body.
An eleventh aspect of the present invention provides a method of treating acne by administering a topical pharmaceutical composition of a retinoid comprising:
(a) microspheres comprising a retinoid and one or more microsphere-forming polymers; and
(b) a coating layer over said microspheres comprising one or more coat-forming polymers.
A twelfth aspect of the present invention provides a method of treating acne by administering a topical pharmaceutical composition of a retinoid comprising:
(a) microcapsules comprising a retinoid and one or more microcapsule-forming polymers; and
(b) a coating layer over said microcapsules comprising one or more coat-forming polymers.
A thirteenth aspect of the present invention provides a method of treating acne by administering a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:
(a) a composition of a retinoid comprising:
(i) microspheres comprising a retinoid and one or more microsphere- forming polymers; and
(ii) a coating layer over said microspheres comprising one or more coat- forming polymers; and
(b) benzoyl peroxide.
A fourteenth aspect of the present invention provides a method of treating acne by administering a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:
(a) a composition of a retinoid comprising:
(i) microcapsules comprising a retinoid and one or more microcapsule- forming polymers; and
(ii) a coating layer over said microcapsules comprising one or more coat- forming polymers; and
(b) benzoyl peroxide.
According to one embodiment of the above aspects, the benzoyl peroxide is present in free-form, in the form of microcapsules, or in the form of microspheres.
According to another embodiment of the above aspects, the topical pharmaceutical composition is co-administered with one or more additional drugs used to treat acne.
A fifteenth aspect of the present invention provides a process for the preparation of a topical pharmaceutical composition of a retinoid comprising:
(i) forming microspheres of a retinoid by using one or more microsphere-forming polymers; and
(ii) applying a coating layer over said microspheres comprising one or more coat- forming polymers.
According to one embodiment of the above aspect, the process comprises:
(i) dissolving one or more microsphere-forming polymers in a suitable organic phase;
(ii) dissolving a retinoid into the solution of step (i);
(iii) mixing a stabilizer in an aqueous phase;
(iv) admixing the solution of step (ii) with the solution of step (iii) to form an emulsion;
(v) homogenizing the emulsion of step (iv) using a homogenizer to form
microspheres; and
(vi) coating the microspheres of step (v) with one or more coat-forming polymers to obtain coated microspheres.
A sixteenth aspect of the present invention provides a process for the preparation of a topical pharmaceutical composition of a retinoid comprising:
(i) forming microcapsules of a retinoid by using one or more microcapsule- forming polymers; and
(ii) applying a coating layer over said microcapsules comprising one or more coat- forming polymers.
According to one embodiment of the above aspect, the process comprises:
(i) mixing a stabilizer in an aqueous phase;
(ii) dispersing a retinoid into the solution of step (i);
(iii) homogenizing the dispersion of step (ii) using a homogenizer;
(iv) mixing one or more microcapsule-forming polymers into the homogenized dispersion of step (iii) to form microcapsules; and
(v) coating the microcapsules of step (iv) with one or more coat-forming polymers to obtain coated microcapsules.
A seventeenth aspect of the present invention provides a process for the preparation of a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising a first composition of a retinoid and a second composition of benzoyl peroxide, wherein the process for the preparation of the first composition comprises the steps of:
(i) forming microspheres of a retinoid by using one or more microsphere-forming polymers; and
(ii) applying a coating layer over said microspheres comprising one or more coat- forming polymers; and
wherein the process for the preparation of the second composition comprises the steps of:
(i) forming microcapsules of benzoyl peroxide by using one or more
microcapsule-forming polymers; and
(ii) optionally applying a coating layer over said microcapsules comprising one or more coat-forming polymers.
According to one embodiment of the above aspect, the process for the preparation of the first composition comprises the steps of:
(i) dissolving one or more microsphere-forming polymers in a suitable organic phase;
(ii) dissolving a retinoid into the solution of step (i);
(iii) mixing a stabilizer in an aqueous phase;
(iv) admixing the solution of step (ii) with the solution of step (iii) to form an emulsion;
(v) homogenizing the emulsion of step (iv) using a homogenizer to form
microspheres; and
(vi) coating the microspheres of step (v) with one or more coat-forming polymers to obtain coated microspheres; and
wherein the process for the preparation of the second composition comprises the steps of:
(i) mixing a stabilizer in an aqueous phase;
(ii) dispersing benzoyl peroxide into the solution of step (i);
(iii) homogenizing the dispersion of step (ii) using a homogenizer;
(iv) mixing one or more microcapsule-forming polymers into the homogenized dispersion of step (iii) to form microcapsules; and
(v) optionally coating the microcapsules of step (iv) with one or more coat- forming polymers to obtain coated microcapsules.
An eighteenth aspect of the present invention provides a process for the preparation of a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising a first composition of a retinoid and a second composition of benzoyl peroxide, wherein the process for the preparation of the first composition comprises the steps of:
(i) forming microspheres of a retinoid by using one or more microsphere-forming polymers; and
(ii) applying a coating layer over said microspheres comprising one or more coat- forming polymers; and
wherein the process for the preparation of the second composition comprises the steps of:
(i) forming microspheres of benzoyl peroxide by using one or more microsphere- forming polymers; and
(ii) optionally applying a coating layer over said microspheres comprising one or more coat-forming polymers.
According to one embodiment of the above aspect, the process for the preparation of a first composition comprises the steps of:
(i) dissolving one or more microsphere-forming polymers in a suitable organic phase;
(ii) dissolving a retinoid into the solution of step (i);
(iii) mixing a stabilizer in an aqueous phase;
(iv) admixing the solution of step (ii) with the solution of step (iii) to form an emulsion;
(v) homogenizing the emulsion of step (iv) using a homogenizer to form
microspheres; and
(vi) coating the microspheres of step (v) with one or more coat-forming polymers to obtain coated microspheres; and
wherein the process for the preparation of a second composition comprises the steps of:
(i) dissolving one or more microsphere-forming polymers in a suitable organic phase;
(ii) dissolving benzoyl peroxide into the solution of step (i);
(iii) mixing a stabilizer in an aqueous phase;
(iv) admixing the solution of step (ii) with the solution of step (iii) using a
homogenizer to form microspheres; and
(v) optionally coating the microspheres of step (iv) with one or more coat-forming polymers to obtain coated microspheres.
A nineteenth aspect of the present invention provides a process for the preparation of a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising a first
composition of a retinoid and a second composition of benzoyl peroxide, wherein the process for the preparation of the first composition comprises the steps of:
(i) forming microcapsules of a retinoid by using one or more microcapsule- forming polymers; and
(ii) applying a coating layer over said microcapsules comprising one or more coat- forming polymers; and
wherein the process for the preparation of the second composition comprises the steps of:
(i) forming microcapsules of benzoyl peroxide by using one or more
microcapsule-forming polymers; and
(ii) optionally applying a coating layer over said microcapsules comprising one or more coat-forming polymers.
According to one embodiment of the above aspect, the process for the preparation of the first composition comprises the steps of:
(i) adding a stabilizer in an aqueous phase;
(ii) dispersing a retinoid into the solution of step (i);
(iii) homogenizing the dispersion of step (ii) using a homogenizer;
(iv) mixing one or more microcapsule-forming polymers into the homogenized dispersion of step (iii) to form microcapsules; and
(v) coating the microcapsules of step (iv) with one or more coat-forming polymers to obtain coated microcapsules; and
wherein the process for the preparation of a second composition comprises the steps of:
(i) adding a stabilizer in an aqueous phase;
(ii) dispersing benzoyl peroxide into the solution of step (i);
(iii) homogenizing the dispersion of step (ii) using a homogenizer;
(iv) mixing one or more microcapsule-forming polymers into the homogenized dispersion of step (iii) to form microcapsules; and
(v) optionally coating the microcapsules of step (iv) with one or more coat- forming polymers to obtain coated microcapsules.
A twentieth aspect of the present invention provides a process for the preparation of a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising a first composition of a retinoid and a second composition of benzoyl peroxide, wherein the process for the preparation of the first composition comprises the steps of:
(i) forming microcapsules of a retinoid by using one or more microcapsule- forming polymers; and
(ii) applying a coating layer over said microcapsules comprising one or more coat- forming polymers; and
wherein the process for the preparation of the second composition comprises the steps of:
(i) forming microspheres of benzoyl peroxide by using one or more microsphere- forming polymers; and
(ii) optionally applying a coating layer over said microspheres comprising one or more coat-forming polymers.
According to one embodiment of the above aspect, the process for the preparation of the first composition comprises the steps of:
(i) mixing a stabilizer in an aqueous phase;
(ii) dispersing a retinoid into the solution of step (i);
(iii) homogenizing the dispersion of step (ii) using a homogenizer;
(iv) mixing one or more microcapsule-forming polymers into the homogenized dispersion of step (iii) to form microcapsules; and
(v) coating the microcapsules of step (iv) with one or more coat-forming polymers to obtain coated microcapsules; and
wherein the process for the preparation of a second composition comprises the steps of:
(i) dissolving one or more microsphere-forming polymers in a suitable organic phase;
(ii) dissolving benzoyl peroxide into the solution of step (i);
(iii) dissolving a stabilizer in an aqueous phase;
(iv) admixing the solution of step (ii) with the solution of step (iii) using a
homogenizer to form microspheres; and
(v) optionally coating the microspheres of step (iv) with one or more coat-forming polymers to obtain coated microspheres.
The term "topical," as used herein, refers to a composition meant for application to the skin, nail, or mucosal tissue.
The term "retinoid," as used herein, refers to chemical compounds related to vitamin
A. Specific examples of retinoids include tretinoin, retinol, retinal, isotretinoin, alitretinoin, tazarotene, adapalene, retinaldehyde, and etretinate. In particular, the retinoid used in the present invention is tretinoin.
The term "tretinoin," as used herein, refers to all-trans retinoic acid or vitamin A acid. Chemically, tretinoin is 3,7-dimethyl-9-(2,6,6-trimethyl-l-cyclohexen-l-yl)-2,4,6,8- nonatetraenoic acid. It further includes its salts, polymorphs, enantiomers, hydrates, solvates, prodrugs, chelates, and complexes.
The term "benzoyl peroxide," as used herein, refers to a peroxide consisting of two benzoyl groups joined by a peroxide group. Hydrous benzoyl peroxide may also be used. Benzoyl peroxide used in the present invention is present in free-form, in the form of microcapsules, or in the form of microspheres.
The term "free-form," as used herein, refers to the benzoyl peroxide present in the composition not intimately embedded, encapsulated, entrapped, or encased in a polymeric carrier, and is present in the composition in direct contact with the composition carrier.
Suitable additional drugs used to treat acne are selected from the group comprising antibiotics e.g., tetracycline, erythromycin, and clindamycin; salicylic acid; sulfur; resorcinol; and combinations thereof.
The microspheres or microcapsules of the present invention can be of any shape e.g., spherical, oblong, or ellipsoidal.
The term "microsphere," as used herein, refers to a matrix system in which a retinoid or benzoyl peroxide is dissolved or dispersed throughout the polymer matrix. The microspheres of the present invention have a D90 value in a range of from about 0.01 μιη to about 1000 μιη, particularly in a range of from about 0.1 μιη to about 500 μιη, and more particularly in a range of from about 1 μιη to about 200 μιη.
The term "microcapsule," as used herein, refers to a system comprising a retinoid or benzoyl peroxide surrounded by a polymeric shell. The microcapsules of the present invention have a D90 value in a range of from about 0.01 μιη to about 1000 μιη, particularly in a range of from about 0.1 μιη to about 500 μιη, and more particularly in a range of from about 1 μιη to about 200 μιη.
The term "D90," as used herein, refers to a diameter for which 90% of the
microspheres or microcapsules have diameters equal to or smaller than that diameter. The diameter of the microspheres or microcapsules can be determined using laser diffraction particle size analyzers such as a Malvern® instrument; electrical conductance instruments such as a Coulter counter; sieve analyzers; optical microscopes; sedimentation analyzers; and other known methods in the art. Particularly, the D90 value is determined by using a Malvern® instrument.
The term "about," as used herein, refers to any value which lies within the range defined by a variation of up to ±10% of the value.
In the present invention, stabilizers are used as suspending agents that help to prevent the aggregation of the microspheres or microcapsules. Stabilizers used in the present invention can be selected from the group comprising cationic, anionic, or non-ionic compounds. Specific examples of stabilizers include cetyltrimethylammonium bromide; cetyltrimethylammonium chloride; polyvinyl alcohol; cellulose derivatives e.g.,
carboxymethyl cellulose; polyvinyl pyrrolidone; sorbitan derivatives e.g., polysorbate 80; sodium lauryl sulphate; docusate sodium; lecithin; polyoxyethylene-castor oil derivatives; and mixtures thereof.
The term "organic phase," as used herein, includes all organic solvents. Suitable examples of organic solvents are alcohols such as methanol, ethanol, and isopropyl alcohol; chlorinated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, methyl dichloroacetate, ethyl chloroacetate, ethyl dichloroacetate, and ethylene dichloride;
fluorinated hydrocarbons such as methyl fluoroacetate, methyl difluoroacetate, ethyl fluoroacetate, and ethyl difluoroacetate; acetates such as ethyl acetate, propyl acetate, isopropyl acetate, and butyl acetate; formates such as methyl formate, ethyl formate, isopropyl formate, propyl formate, and butyl formate; anhydrides such as maleic anhydride, acetic anhydride, propionic anhydride, and phosphoric anhydride; amides such as acetamide, propionamide, and butylamide; acetone; acetonitrile; tetrahydrofuran; and mixtures thereof.
The term "aqueous phase," as used herein, includes water and all water-miscible solvents. Examples of water-miscible solvents include glycerin; sorbitol; glycols e.g., polyethylene glycol and propylene glycol; and mixtures thereof. In certain embodiments, the aqueous phase is selected from the group comprising water, glycerin, sorbitol, polyethylene glycol, propylene glycol, and mixtures thereof.
The microspheres or microcapsules of the present invention can be prepared by any suitable technique known in the art. Most commonly used techniques include
homogenization, solvent evaporation, coacervation phase separation, spray drying, spray congealing, polymer precipitation, and supercritical fluid extraction.
The microspheres of the present invention are preferably prepared by a
homogenization process. To prepare the microspheres using a homogenization process, the retinoid or benzoyl peroxide and one or more microsphere-forming polymers are first dissolved into an organic phase. Further, a stabilizer is mixed in an aqueous phase. These
two phases are admixed together to form an emulsion. This emulsion is then homogenized using a homogenizer to form the microspheres. Alternatively, the retinoid or benzoyl peroxide can be dissolved in an organic phase which is added into an aqueous phase to form the emulsion. This emulsion is then homogenized using a homogenizer to form the microspheres.
The microcapsules of the present invention are preferably prepared by a polymer precipitation process. To prepare the microcapsules using a polymer precipitation process, a stabilizer is first mixed in an aqueous phase. Further, the retinoid or benzoyl peroxide is dispersed in said aqueous phase and is homogenized using a homogenizer. One or more microcapsule-forming polymers are then mixed into the homogenized dispersion. The pH of the dispersion is then adjusted using a pH-adjusting agent such that the microcapsule-forming polymers are precipitated over retinoid or benzoyl peroxide particles to form the
microcapsules. Alternatively, the retinoid or benzoyl peroxide is dispersed in an aqueous phase and is homogenized using a homogenizer. One or more microcapsule-forming polymers are then mixed into the homogenized dispersion. The pH of the dispersion is then adjusted using a pH-adjusting agent such that the microcapsule-forming polymers are precipitated over retinoid or benzoyl peroxide particles to form the microcapsules.
The microspheres or microcapsules can be separated from the emulsion/dispersion by any suitable technique known in the art. Suitable techniques include filtration, centrifugation, decantation, dialysis, and evaporation. The preferred technique is filtration.
The separated microspheres or microcapsules can be dried by any suitable technique known in the art. Suitable techniques include distillation, spray drying, lyophilization, oven drying, fluidized bed drying, rota-evaporation using a rotavapor, and combinations thereof.
The microspheres or microcapsules of the present invention can be coated with a coating layer comprising one or more coat-forming polymers.
The coating can be performed by a technique such as polymer precipitation in which one or more coat-forming polymers are coated onto the microspheres or microcapsules. The coat-forming polymers are dissolved or dispersed in an organic or aqueous phase to form the solution or dispersion. The microspheres or microcapsules are then dispersed into the solution or dispersion of the coat-forming polymers. The pH of the dispersion is then adjusted using a pH adjusting agent such that the coat-forming polymers are precipitated over the microspheres or microcapsules to form the coated microspheres or microcapsules.
Suitable pH-adjusting agents are selected from the group comprising organic or inorganic acids, e.g., citric acid, acetic acid, fumaric acid, tartaric acid, phosphoric acid, and hydrochloric acid; organic or inorganic bases, e.g. , sodium hydroxide, potassium hydroxide, and ammonium hydroxide; tertiary amines, e.g., triethanolamine and tetrahydroxypropyl ethylendiamine; and buffers, e.g., phosphate buffer and acetate buffer.
Alternatively, one or more coat-forming polymers are dissolved or dispersed in an organic or aqueous phase along with one or more coating additives to form the solution or dispersion. This solution/dispersion is then coated onto microspheres or microcapsules using any suitable methods such as spray drying and fluidized bed coating.
Coating additives may be selected from the group consisting of plasticizers, binders, lubricants, and coloring agents.
Suitable plasticizers are selected from the group consisting of triethyl citrate, dibutyl sebacate, acetylated triacetin, tributyl citrate, glycerol tributyrate, monoglyceride, rapeseed oil, olive oil, sesame oil, acetyl tributyl citrate, acetyl triethyl citrate, glycerin, sorbitol, diethyl oxalate, diethyl phthalate, diethyl malate, diethyl fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, and mixtures thereof.
Suitable binders are selected from the group consisting of methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and mixtures thereof.
Suitable lubricants are selected from the group consisting of colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, white beeswax, and mixtures thereof.
Coloring agents includes any FDA approved color for topical use.
The microspheres of the present invention may also comprise pre-formed microspheres, such as silica microspheres, in which the retinoid or benzoyl peroxide can be impregnated. These microspheres can be further coated with a coating layer comprising one or more coat-forming polymers.
The microspheres and/or microcapsules of the present invention can be dispersed in a suitable pharmaceutical composition to allow for ease of topical application. The pharmaceutical composition of the present invention possesses good spreadability. Further, the pharmaceutical composition can be aqueous-based or non-aqueous based.
The pharmaceutical composition of the present invention can be in the form of an ointment, a cream, a lotion, an oil, a solution, an emulsion, a gel, a paste, an aerosol, a powder, or a foam.
The pharmaceutical composition may comprises one or more pharmaceutically acceptable excipients selected from the group comprising gelling agents, preservatives, surfactants, chelating agents, pH-adjusting agents, humectants, antioxidants, permeation- enhancers, emulsifiers, solvents, and mixtures thereof.
Suitable gelling agents are selected from the group comprising carboxyvinyl polymers, e.g., Carbopol® 980, Carbopol® 974P, Carbopol® 97 IP, and Carbopol® 934P; natural gums, e.g., karaya gum, locust bean gum, guar gum, xanthan gum, arabic gum, tragacanth gum, carrageenan, pectin, agar, alginic acid, and sodium alginate; cellulose derivatives, e.g., hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl cellulose, and sodium carboxymethyl cellulose; acrylates, e.g., methacrylates and polyacrylates; alginic acid-propylene glycol ester; polyoxyethylene-polyoxypropylene copolymers; polyvinyl pyrrolidone; polyethylene glycol; polyethylene oxide; polyvinyl alcohol; silicon dioxide; polyacrylamide; and mixtures thereof.
Suitable preservatives are selected from the group comprising methyl-, ethyl-, propyl-, or butyl-esters of hydroxy benzoic acid or sodium salts thereof, benzoic acid, sodium benzoate, chlorhexedine, benzalkonium chloride, 2-phenoxyethanol, cetrimide, potassium sorbate, benzyl alcohol, imidurea, dichlorobenzyl alcohol, thiomersal, diazolidinylurea, and mixtures thereof.
Suitable surfactants are selected from the group comprising polyethoxylated fatty acid esters, polyoxyethylene sorbitan esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene-polyoxypropylene glycol, sorbitan esters, sodium lauryl sulphate, docusate sodium, nonooxynol, glyceryl monostearate, and mixtures thereof.
Suitable chelating agents are selected from the group comprising
ethylenediaminetetraacetic acid or derivatives or salts thereof, e.g. , disodium edetate;
dihydroxyethyl glycine; glucamine; acids, e.g., citric acid, tartaric acid, gluconic acid, and phosphoric acid; and mixtures thereof.
Suitable humectants or emollients are selected from the group comprising propylene glycol, glycerin, butylene glycol, sorbitol, triacetin, cyclomethicone, dimethicone copolyol, caprylic/capric triglyerides, castor oil, ceteareth-20, ceteareth-30, ceteth-20, cetostearyl alcohol, cetyl alcohol, cocoa butter, diisopropyl adipate, glycerin, glyceryl monooleate,
glyceryl monostearate, glyceryl stearate, isopropyl myristate, isopropyl palmitate, lanolin, lanolin alcohol, hydrogenated lanolin, liquid paraffins, linoleic acid, mineral oil, oleic acid, white petrolatum, polyethylene glycol, polyoxyethylene glycol fatty alcohol ethers, polyoxypropylene 15 stearyl ether, propylene glycol stearate, squalane, steareth-2, steareth- 100, stearic acid, stearyl alcohol, urea, and mixtures thereof.
Suitable antioxidants include butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium metabisulfite, ascorbic acid, propyl gallate, thiourea, tocopherols, beta-carotene, and mixtures thereof.
Suitable permeation-enhancers are selected from the group comprising sulfoxides, e.g., dimethyl sulfoxide (DMSO); ethers, e.g.,diethylene glycol monoethyl ether (e.g., Transcutol®); surfactants, e.g., sodium laurate, sodium lauryl sulfate, polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80; alkyl glycosides; alcohols, e.g., ethanol, propanol, and benzyl alcohol; fatty acids, e.g., lauric acid, oleic acid, valeric acid, and isostearic acid; fatty acid esters, e.g., isopropyl myristate and isopropyl palmitate; polyols or esters thereof, e.g., propylene glycol, ethylene glycol, glycerol, butanediol, and polyethylene glycol; amides or other nitrogenous compounds, e.g., urea, dimethyl acetamide, dimethyl formamide, 2-pyrrolidone, l-methyl-2-pyrrolidone, ethanolamine, diethanolamine, and triethanolamine; terpenes; dimethyl isosorbide; alkanones; and mixtures thereof.
Suitable emulsifiers are selected from the group comprising tri-block copolymers, e.g., Poloxamer 407, Poloxamer 188; polyoxyl stearates, e.g., poly oxyethylene-20 stearate (Myrj® 49); polysorbates, e.g., Tween® 80, Tween® 60 and Tween® 20; sorbitan fatty acid esters, e.g., Span® 60 or Span® 80; polyoxyethylene alkyl ethers, e.g., Brij® 97;
polyoxyethylene alkylphenyl ethers; sucrose fatty acid esters; and mixtures thereof.
Suitable solvents are selected from the group comprising water; alcohols, e.g., methanol, ethanol, isopropyl alcohol, and higher alcohols; glycerin; sorbitol; glycols, e.g., polyethylene glycol and propylene glycol; tetrahydrofuran; liquid petrolatum; ether;
petroleum ether; aromatics, e.g., benzene and toluene; alkanes, e.g., pentane, hexane, and heptane; ketones, e.g., acetone and methyl ethyl ketone; chlorinated hydrocarbons e.g., chloroform, carbon tetrachloride, methylene chloride, and ethylene dichloride; acetates, e.g., ethyl acetate; lipids, e.g., isopropyl myristate, diisopropyl adipate, and mineral oil; and mixtures thereof.
Any suitable pH-adjusting agents well known in the art can be used, including, for example, NaOH, acetic acid, hydrochloric acid, etc.
The following examples represent various embodiments according to the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention.
EXAMPLES
Example 1
Procedure:
1. Ethyl cellulose and tretinoin were dissolved in dichloromethane.
2. Cetyltrimethylammonium bromide was dissolved in purified water.
3. The solution of step 1 was added into the solution of step 2 to form an emulsion.
4. The emulsion of step 3 was homogenized using a homogenizer to form microspheres.
5. The dichloromethane from the emulsion of step 4 was evaporated to form the
microsphere dispersion.
6. Sodium alginate was dissolved in purified water.
7. The solution of step 6 was added into the microsphere dispersion of step 5.
8. The pH of the dispersion of step 7 was adjusted to 3.0 using a hydrochloric acid solution to obtain coated microspheres.
9. The coated microspheres of step 8 were filtered and dried.
Example 2
Procedure:
1. Ethyl cellulose and tretinoin were dissolved in dichloromethane.
2. Polyvinyl alcohol was dissolved in purified water.
3. The solution of step 1 was added into the solution of step 2 to form an emulsion.
4. The emulsion of step 3 was homogenized using a homogenizer to form microspheres.
5. The dichloromethane from the emulsion of step 4 was evaporated to form a
microsphere dispersion.
6. Sodium alginate was dissolved in purified water.
7. The solution of step 6 was added to the microsphere dispersion of step 5.
8. The pH of the dispersion of step 7 was adjusted to 3.0 using a hydrochloric acid solution to obtain coated microspheres.
9. The coated microspheres of step 8 were filtered and dried.
Example 3
1. Ethyl cellulose and tretinoin were dissolved in dichloromethane.
2. Purified water was heated and docusate sodium was dissolved in the heated water while stirring.
3. The solution of step 1 was added into the solution of step 2 to form an emulsion.
4. The emulsion of step 3 was homogenized using a homogenizer to form microspheres.
5. The dichloromethane from the emulsion of step 4 was evaporated to form a
microsphere dispersion.
6. Chitosan was added to purified water acidified with a hydrochloric acid solution. 7. The solution of step 6 was added into the microsphere dispersion of step 5.
8. The pH of the dispersion of step 7 was adjusted to 7.0 using a sodium hydroxide solution to obtain coated microspheres.
9. The coated microspheres of step 8 were filtered and dried. Example 4
Procedure:
1. Ethyl cellulose and benzoyl peroxide were dissolved in dichloromethane.
2. Purified water was heated and docusate sodium was dissolved in the heated water while stirring.
3. The solution of step 1 was added into the solution of step 2 to form an emulsion.
4. The emulsion of step 3 was homogenized using a homogenizer to form microspheres.
5. The dichloromethane from the emulsion of step 4 was evaporated to form a
microsphere dispersion.
6. Chitosan was added to purified water acidified with a hydrochloric acid solution.
7. The solution of step 6 was added into the microsphere dispersion of step 5.
8. The pH of the dispersion of step 7 was adjusted to 7.0 using sodium hydroxide solution to obtain coated microspheres.
9. The coated microspheres of step 8 were filtered and dried.
Example 5
Procedure:
1. Purified water was heated and docusate sodium was dissolved in the heated water while stirring.
2. Glycerin was added into the solution of step 1.
3. Benzoyl peroxide was dispersed into the solution of step 2, and the mixture was homogenized using a homogenizer.
4. The dispersion of step 3 was filtered to obtain benzoyl peroxide particles.
5. Purified water was heated and docusate sodium was dissolved in the heated water while stirring.
6. The benzoyl peroxide particles of step 4 were redispersed into the solution of step 5 and stirred.
7. Chitosan was added to purified water acidified with hydrochloric acid solution (for coating).
8. The solution of step 7 was added into the dispersion of step 6.
9. The pH of the dispersion of step 8 was adjusted to 7.0 using a sodium hydroxide solution to obtain coated microcapsules.
10. The coated microcapsules of step 9 were filtered and dried.
Example 6
Procedure:
1. Tazarotene was dissolved in dichloromethane.
2. Silica microspheres (preformed) were added into the solution of step 1 while stirring.
3. The dispersion of step 2 was dried in a rotavapor to obtain tazarotene loaded silica microspheres.
4. Eudragit® L 100 was dissolved in ethanol while stirring.
5. The tazarotene loaded silica microspheres of step 3 were dispersed into the solution of step 4.
6. The dispersion of step 5 was spray dried to obtain coated microspheres.
Example 7
Procedure:
1. Ethyl cellulose and tretinoin were dissolved in dichloromethane.
2. Purified water was heated and polyvinyl alcohol was dissolved in the heated water while stirring.
3. The solution of step 1 was added into the solution of step 2 to form an emulsion.
4. The emulsion of step 3 was homogenized using a homogenizer to form microspheres.
5. The dichloromethane from the emulsion of step 4 was evaporated to form a microsphere dispersion.
6. Chitosan was added to purified water acidified with a hydrochloric acid solution.
7. The solution of step 6 was added into the microsphere dispersion of step 5.
8. The pH of the dispersion of step 7 was adjusted to 7.0 using a sodium hydroxide solution to obtain coated microspheres.
9. The coated microspheres of step 8 were filtered and dried.
Example 8
Procedure:
1. Ethyl cellulose and benzoyl peroxide were dissolved in dichloromethane.
2. Purified water was heated and polyvinyl alcohol was dissolved in the heated water while stirring.
3. The solution of step 1 was added into the solution of step 2 to form an emulsion. 4. The emulsion of step 3 was homogenized using a homogenizer to form microspheres.
5. The dichloromethane from the emulsion of step 4 was evaporated to form a
microsphere dispersion.
6. Chitosan was added to purified water acidified with a hydrochloric acid solution.
7. The solution of step 6 was added into the microsphere dispersion of step 5.
8. The pH of the dispersion of step 7 was adjusted to 7.0 using a sodium hydroxide solution to obtain coated microspheres.
9. The coated microspheres of step 8 were filtered and dried.
Example 9
Procedure:
1. Ethyl cellulose and benzoyl peroxide were dissolved in dichloromethane.
2. Purified water was heated and polyvinyl alcohol was dissolved in the heated water while stirring.
3. The solution of step 1 was added into the solution of step 2 to form an emulsion.
4. The emulsion of step 3 was homogenized using a homogenizer to form microspheres.
5. The dichloromethane from the emulsion of step 4 was evaporated to form a
microsphere dispersion.
6. Sodium alginate was dissolved in purified water.
7. The solution of step 6 was added into the microsphere dispersion of step 5.
8. The pH of the dispersion of step 7 was adjusted to 3.0 using a hydrochloric acid solution to obtain coated microspheres.
9. The coated microspheres of step 8 were filtered and dried.
Example 10
1. Ethyl cellulose and benzoyl peroxide were dissolved in dichloromethane.
2. Cetyltrimethylammonium bromide was dissolved in purified water.
3. The solution of step 1 was added into the solution of step 2 to form an emulsion. 4. The emulsion of step 3 was homogenized using a homogenizer to form microspheres.
5. The dichloromethane from the emulsion of step 4 was evaporated to form a
microsphere dispersion.
6. Sodium alginate was dissolved in purified water.
7. The solution of step 6 was added into the microsphere dispersion of step 5.
8. The pH of the dispersion of step 7 was adjusted to 3.0 using a hydrochloric acid solution to obtain coated microspheres.
9. The coated microspheres of step 8 were filtered and dried.
Example 11
Procedure:
1. Purified water was heated and docusate sodium was dissolved in the heated water while stirring.
2. Glycerin was added into the solution of step 1.
3. Benzoyl peroxide was dispersed into the solution of step 2 and the mixture was
homogenized using a homogenizer.
4. The dispersion of step 3 was filtered to obtain benzoyl peroxide particles.
5. The benzoyl peroxide particles of step 4 were redispersed in purified water.
6. Chitosan was added to purified water acidified with a hydrochloric acid solution.
7. The solution of step 6 was added into the dispersion of step 5.
8. The pH of the dispersion of step 7 was adjusted to 7.0 using a sodium hydroxide solution to obtain coated microcapsules.
9. The coated microcapsules of step 8 were filtered and dried. Example 12
Procedure:
1. Ethyl cellulose and tazarotene were dissolved in dichloromethane.
2. Purified water was heated and polyvinyl alcohol was dissolved in the heated water while stirring.
3. The solution of step 1 was added into the solution of step 2 to form an emulsion.
4. The emulsion of step 3 was homogenized using a homogenizer to form microspheres.
5. The dichloromethane from the emulsion of step 4 was evaporated to form a
microsphere dispersion.
6. Eudragit®L 100 was dissolved in ethanol while stirring.
7. The dispersion of step 5 was added into the solution of step 6.
8. The dispersion of step 7 was spray dried to obtain coated microspheres.
Example 13
1. Ethyl cellulose and tazarotene were dissolved in dichloromethane.
2. Purified water was heated and polyvinyl alcohol was dissolved in the heated water while stirring.
3. The solution of step 1 was added into the solution of step 2 to form an emulsion.
4. The emulsion of step 3 was homogenized using a homogenizer to form microspheres.
5. The dichloromethane from the emulsion of step 4 was evaporated to form a
microsphere dispersion.
6. Sodium alginate was dissolved in purified water.
7. The solution of step 6 was added into the microsphere dispersion of step 5.
8. The pH of the dispersion of step 7 was adjusted to 3 using a hydrochloric acid
solution to obtain coated microspheres.
9. The coated microspheres of step 8 were filtered and dried.
Microspheres of tretinoin obtained from Examples 1-3, microspheres of benzoyl peroxide obtained from Example 4, and microcapsules of benzoyl peroxide obtained from Example 5 were incorporated either separately or in combination into a gel composition as described in Examples 14-16 provided below.
Example 14
Procedure:
1. Purified water was divided into three portions.
2. The first portion of purified water was heated and docusate sodium was dissolved ' the heated water while stirring.
3. Benzoyl peroxide microspheres were added into the solution of step 2.
4. Glycerin and ethylenediaminetetraacetic acid were added into the second portion of purified water.
5. Tretinoin microspheres were added into the solution of step 4.
6. Carbopol® 974P was dispersed into the third portion of purified water.
7. The dispersions of step 3 and step 5 were added into the dispersion of step 6 while stirring.
8. The pH of the dispersion of step 7 was adjusted to 5.5 with a sodium hydroxide solution.
Example 15
Procedure:
1. Purified water was divided into three portions.
2. The first portion of purified water was heated and docusate sodium was dissolved in the heated water while stirring.
3. Benzoyl peroxide microcapsules were added into the solution of step 2.
4. Glycerin and ethylenediaminetetraacetic acid were added into the second portion of purified water.
5. Tretinoin microspheres were added into the solution of step 4.
6. Hydroxyethyl cellulose was dispersed into the third portion of purified water.
7. The dispersions of step 3 and step 5 were added into the dispersion of step 6 while stirring.
Example 16
Procedure:
1. Propylene glycol was divided into two portions.
2. Docusate sodium was dissolved in the first portion of propylene glycol.
3. Benzoyl peroxide microcapsules were added into the solution of step 2.
4. Carbopol® 974P was dispersed into the second portion of propylene glycol.
5. Tretinoin microspheres were dispersed in glycerin.
6. The dispersion of step 3 was added into the carbopol dispersion of step 4 while
stirring.
7. The dispersion of step 5 was added into the dispersion of step 6.
Other Embodiments
The foregoing description discloses only exemplary embodiments of the invention. It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims. Thus, while only certain features of the invention have been illustrated and described, many modifications and changes will occur to those skilled in the art. It is therefore to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.
Claims
1. A topical pharmaceutical composition of a retinoid comprising:
(a) microspheres comprising a retinoid and one or more microsphere-forming polymers; and
(b) a coating layer over said microspheres comprising one or more coat-forming polymers.
2. A topical pharmaceutical composition of a retinoid comprising:
(a) microcapsules comprising a retinoid and one or more microcapsule-forming polymers; and
(b) a coating layer over said microcapsules comprising one or more coat-forming polymers.
3. A topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:
(a) a composition of a retinoid comprising:
(i) microspheres comprising a retinoid and one or more microsphere- forming polymers; and
(ii) a coating layer over said microspheres comprising one or more coat- forming polymers; and
(b) benzoyl peroxide in free-form.
4. A topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:
(a) a composition of a retinoid comprising:
(i) microcapsules comprising a retinoid and one or more microcapsule- forming polymers; and
(ii) a coating layer over said microcapsules comprising one or more coat- forming polymers; and
(b) benzoyl peroxide in free-form.
5. A topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:
(a) a first composition of a retinoid comprising:
(i) microspheres comprising a retinoid and one or more microsphere- forming polymers; and
(ii) a coating layer over said microspheres comprising one or more coat- forming polymers; and
(b) a second composition of benzoyl peroxide comprising:
(i) microcapsules comprising benzoyl peroxide and one or more
microcapsule-forming polymers; and
(ii) an optional coating layer over said microcapsules comprising one or more coat-forming polymers.
6. A topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:
(a) a first composition of a retinoid comprising:
(i) microspheres comprising a retinoid and one or more microsphere- forming polymers; and
(ii) a coating layer over said microspheres comprising one or more coat- forming polymers; and
(b) a second composition of benzoyl peroxide comprising:
(i) microspheres comprising benzoyl peroxide and one or more
microsphere-forming polymers; and
(ii) an optional coating layer over said microspheres with comprising one or more coat-forming polymers.
7. A topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:
(a) a first composition of a retinoid comprising:
(i) microcapsules comprising a retinoid and one or more microcapsule- forming polymers; and
(ii) a coating layer over said microcapsules comprising one or more coat- forming polymers; and
(b) a second composition of benzoyl peroxide comprising:
(i) microcapsules comprising benzoyl peroxide and one or more
microcapsule-forming polymers; and
(ii) an optional coating layer over said microcapsules comprising one or more coat-forming polymers.
8. A topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising:
(a) a first composition of a retinoid comprising:
(i) microcapsules comprising a retinoid and one or more microcapsule- forming polymers; and
(ii) a coating layer over said microcapsules comprising one or more coat- forming polymers; and
(b) a second composition of benzoyl peroxide comprising:
(i) microspheres comprising benzoyl peroxide and one or more
microsphere-forming polymers; and
(ii) an optional coating layer over said microspheres comprising one or more coat-forming polymers.
9. The topical pharmaceutical composition of claims 1 to 8, wherein the retinoid is selected from the group consisting of tretinoin, retinol, retinal, isotretinoin, alitretinoin, tazarotene, adapalene, retinaldehyde, and etretinate.
10. The topical pharmaceutical composition of claim 9, wherein the retinoid is tretinoin.
1 1. The topical pharmaceutical composition of claims 1 to 8, wherein the microsphere- forming polymers, microcapsule-forming polymers, or coat-forming polymers are selected from the group consisting of cellulose derivatives; acrylates; polyoxyethylene- polyoxypropylene copolymers; gums; propylene glycol alginate; chitosan; starch; dextran; gelatin; polyvinyl pyrrolidone; polyethylene glycol; polyethylene oxide; polyvinyl alcohol; lipids; fatty acids; waxes; proteins; poly(acryl) dextran; poly(acryl) starch; and mixtures thereof.
12. A kit for dispensing a topical pharmaceutical composition of a retinoid and benzoyl peroxide, wherein the kit comprises:
(a) a first compartment comprising a composition of a retinoid comprising:
(i) microspheres comprising a retinoid and one or more microsphere- forming polymers; and
(ii) a coating layer over said microspheres comprising one or more coat- forming polymers; and
(b) a second compartment comprising benzoyl peroxide.
13. A kit for dispensing a topical pharmaceutical composition of a retinoid and benzoyl peroxide, wherein the kit comprises:
(a) a first compartment comprising a composition of a retinoid comprising:
microcapsules comprising a retinoid and one or more microcapsule- forming polymers;and
a coating layer over said microcapsules comprising one or more coat- forming polymers; and
(b) a second compartment comprising benzoyl peroxide.
14. The kit for dispensing the topical pharmaceutical composition of claim 12 or 13, wherein the second compartment comprises benzoyl peroxide in free-form, in the form of microcapsules, or in the form of microspheres.
15. A method of treating acne by administering a topical pharmaceutical composition of any one of a composition of claims 1 to 8.
16. A process for the preparation of a topical pharmaceutical composition of a retinoid comprising:
(i) forming microspheres of a retinoid by using one or more microsphere-forming polymers; and
(ii) applying a coating layer over said microspheres comprising one or more coat- forming polymers.
17. The process for the preparation of the topical pharmaceutical composition of claim 16 comprising:
(i) dissolving one or more microsphere-forming polymers in a suitable organic phase;
(ii) dissolving a retinoid into the solution of step (i);
(iii) mixing a stabilizer in an aqueous phase;
(iv) admixing the solution of step (ii) with the solution of step (iii) to form an emulsion;
(v) homogenizing the emulsion of step (iv) using a homogenizer to form
microspheres; and
(vi) coating the microspheres of step (v) with one or more coat-forming polymers to obtain coated microspheres.
18. A process for the preparation of a topical pharmaceutical composition of a retinoid comprising:
(i) forming microcapsules of a retinoid by using one or more microcapsule- forming polymers; and
(ii) applying a coating layer over said microcapsules comprising one or more coat- forming polymers.
19. The process for the preparation of the topical pharmaceutical composition of claim 18 comprising:
(i) mixing a stabilizer in an aqueous phase;
(ii) dispersing a retinoid into the solution of step (i);
(iii) homogenizing the dispersion of step (ii) using a homogenizer;
(iv) mixing one or more microcapsule-forming polymers into the homogenized dispersion of step (iii) to form microcapsules; and
(v) coating the microcapsules of step (iv) with one or more coat-forming polymers to obtain coated microcapsules.
20. A process for the preparation of a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising a first composition of a retinoid and a second composition of benzoyl peroxide, wherein the process for the preparation of the first composition comprises the steps of:
(i) forming microspheres of a retinoid by using one or more microsphere-forming polymers; and
(ii) applying a coating layer over said microspheres comprising one or more coat- forming polymers; and
wherein the process for the preparation of the second composition comprises the steps of:
(i) forming microcapsules of benzoyl peroxide by using one or more
microcapsule-forming polymers; and
(ii) optionally applying a coating layer over said microcapsules comprising one or more coat-forming polymers.
21. The process for the preparation of the topical pharmaceutical composition of claim 20, wherein the process for the preparation of the first composition comprises the steps of:
(i) dissolving one or more microsphere-forming polymers in a suitable organic phase;
(ii) dissolving a retinoid into the solution of step (i);
(iii) mixing a stabilizer in an aqueous phase;
(iv) admixing the solution of step (ii) with the solution of step (iii) to form an emulsion;
(v) homogenizing the emulsion of step (iv) using a homogenizer to form
microspheres; and
(vi) coating the microspheres of step (v) with one or more coat-forming polymers to obtain coated microspheres; and
wherein the process for the preparation of the second composition comprises the steps of:
(i) mixing a stabilizer in an aqueous phase;
(ii) dispersing benzoyl peroxide into the solution of step (i);
(iii) homogenizing the dispersion of step (ii) using a homogenizer;
(iv) mixing one or more microcapsule-forming polymers into the homogenized dispersion of step (iii) to form microcapsules; and
(v) optionally coating the microcapsules of step (iv) with one or more coat- forming polymers to obtain coated microcapsules.
22. A process for the preparation of a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising a first composition of a retinoid and a second composition of benzoyl peroxide, wherein the process for the preparation of the first composition comprises the steps of:
(i) forming microspheres of a retinoid by using one or more microsphere-forming polymers; and
(ii) applying a coating layer over said microspheres comprising one or more coat- forming polymers; and
wherein the process for the preparation of the second composition comprises the steps of:
(i) forming microspheres of benzoyl peroxide by using one or more microsphere- forming polymers; and
(ii) optionally applying a coating layer over said microspheres comprising one or more coat-forming polymers.
23. The process for the preparation of the topical pharmaceutical composition of claim 22, wherein the process for the preparation of the first composition comprises the steps of:
(i) dissolving one or more microsphere-forming polymers in a suitable organic phase;
(ii) dissolving a retinoid into the solution of step (i);
(iii) mixing a stabilizer in an aqueous phase;
(iv) admixing the solution of step (ii) with the solution of step (iii) to form an emulsion;
(v) homogenizing the emulsion of step (iv) using a homogenizer to form
microspheres; and
(vi) coating the microspheres of step (v) with one or more coat-forming polymers to obtain coated microspheres; and
wherein the process for the preparation of the second composition comprises the steps of:
(i) dissolving one or more microsphere-forming polymers in a suitable organic phase;
(ii) dissolving benzoyl peroxide into the solution of step (i);
(iii) mixing a stabilizer in an aqueous phase;
(iv) admixing the solution of step (ii) with the solution of step (iii) using a
homogenizer to form microspheres; and
(v) optionally coating the microspheres of step (iv) with one or more coat-forming polymers to obtain coated microspheres.
24. A process for the preparation of a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising a first composition of a retinoid and a second composition of benzoyl peroxide, wherein the process for the preparation of the first composition comprises the steps of:
(i) forming microcapsules of a retinoid by using one or more microcapsule- forming polymers; and
(ii) applying a coating layer over said microcapsules comprising one or more coat- forming polymers; and
wherein the process for the preparation of the second composition comprises the steps of:
(i) forming microcapsules of benzoyl peroxide by using one or more
microcapsule-forming polymers; and
(ii) optionally applying a coating layer over said microcapsules comprising one or more coat-forming polymers.
25. The process for the preparation of the topical pharmaceutical composition of claim 24, wherein the process for the preparation of the first composition comprises the steps of:
(i) adding a stabilizer in an aqueous phase;
(ii) dispersing a retinoid into the solution of step (i);
(iii) homogenizing the dispersion of step (ii) using a homogenizer;
(iv) mixing one or more microcapsule-forming polymers into the homogenized dispersion of step (iii) to form microcapsules; and
(v) coating the microcapsules of step (iv) with one or more coat-forming polymers to obtain coated microcapsules; and
wherein the process for the preparation of the second composition comprises the steps of:
(i) adding a stabilizer in an aqueous phase;
(ii) dispersing benzoyl peroxide into the solution of step (i);
(iii) homogenizing the dispersion of step (ii) using a homogenizer;
(iv) mixing one or more microcapsule-forming polymers into the homogenized dispersion of step (iii) to form microcapsules; and
(v) optionally coating the microcapsules of step (iv) with one or more coat- forming polymers to obtain coated microcapsules.
26. A process for the preparation of a topical pharmaceutical composition of a retinoid and benzoyl peroxide comprising a first composition of a retinoid and a second composition of benzoyl peroxide, wherein the process for the preparation of the first composition comprises the steps of:
(i) forming microcapsules of a retinoid by using one or more microcapsule- forming polymers; and
(ii) applying a coating layer over said microcapsules comprising one or more coat- forming polymers; and
wherein the process for the preparation of the second composition comprises the steps of:
(i) forming microspheres of benzoyl peroxide by using one or more microsphere- forming polymers; and
(ii) optionally applying a coating layer over said microspheres comprising one or more coat-forming polymers.
27. The process for the preparation of the topical pharmaceutical composition of claim 26, wherein the process for the preparation of the first composition comprises the steps of:
(i) mixing a stabilizer in an aqueous phase;
(ii) dispersing a retinoid into the solution of step (i);
(iii) homogenizing the dispersion of step (ii) using a homogenizer;
(iv) mixing one or more microcapsule-forming polymers into the homogenized dispersion of step (iii) to form microcapsules; and
(v) coating the microcapsules of step (iv) with one or more coat-forming polymers to obtain coated microcapsules; and
wherein the process for the preparation of a second composition comprises the steps of:
(i) dissolving one or more microsphere-forming polymers in a suitable organic phase;
(ii) dissolving benzoyl peroxide into the solution of step (i);
(iii) dissolving a stabilizer in an aqueous phase;
(iv) admixing the solution of step (ii) with the solution of step (iii) using a
homogenizer to form microspheres; and
(v) optionally coating the microspheres of step (iv) with one or more coat-forming polymers to obtain coated microspheres.
28. The process for the preparation of the topical pharmaceutical composition of claims 17, 19, 21, 23, 25, and 27, wherein the stabilizer is selected from the group consisting of cationic, anionic, or non-ionic compounds; cellulose derivatives; sorbitan derivatives;
polyoxyethylene-castor oil derivatives; polyvinyl alcohol; polyvinyl pyyrolidone; and mixtures thereof.
29. The process for the preparation of the topical pharmaceutical composition of claims 17, 19, 21, 23, 25, and 27, wherein the organic phase is selected from the group consisting of methanol, ethanol, isopropyl alcohol, dichloromethane, chloroform, carbon tetrachloride, methyl dichloroacetate, ethyl chloroacetate, ethyl dichloroacetate, ethylene dichloride, methyl fluoroacetate, methyl difluoroacetate, ethyl fluoroacetate, ethyl difluoroacetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, methyl formate, ethyl formate, isopropyl formate, propyl formate, butyl formate, maleic anhydride, acetic anhydride, propionic anhydride, phosphoric anhydride, acetamide, propionamide, butylamide, acetone, acetonitrile, tetrahydrofuran, and mixtures thereof.
30. The process for the preparation of the topical pharmaceutical composition of claims 17, 19, 21, 23, 25, and 27, wherein the aqueous phase is selected from the group consisting of water, glycerin, sorbitol, polyethylene glycol, propylene glycol, and mixtures thereof.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN3676DE2013 | 2013-12-17 | ||
IN3676/DEL/2013 | 2013-12-17 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2015092602A1 true WO2015092602A1 (en) | 2015-06-25 |
Family
ID=52023581
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2014/066652 WO2015092602A1 (en) | 2013-12-17 | 2014-12-05 | Topical pharmaceutical composition of a retinoid |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2015092602A1 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017029665A1 (en) | 2015-08-20 | 2017-02-23 | Sol-Gel Technologies Ltd. | Compositions for topical application comprising benzoyl peroxide and adapalene |
CN109126648A (en) * | 2018-06-05 | 2019-01-04 | 青岛明月生物医用材料有限公司 | A kind of preparation and its application of chitosan and propylene glycol alginate blend microcapsule |
US10933018B2 (en) | 2015-10-30 | 2021-03-02 | Timber Pharmaceuticals Llc | Isotretinoin formulations and uses and methods thereof |
US20210113511A1 (en) * | 2017-07-12 | 2021-04-22 | Sol-Gel Technologies Ltd. | Methods and compositions for the treatment of acne |
CN116251035A (en) * | 2023-03-17 | 2023-06-13 | 深圳市护家科技有限公司 | Oily composition containing retinol and/or retinol derivatives |
Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4690825A (en) | 1985-10-04 | 1987-09-01 | Advanced Polymer Systems, Inc. | Method for delivering an active ingredient by controlled time release utilizing a novel delivery vehicle which can be prepared by a process utilizing the active ingredient as a porogen |
US5135740A (en) | 1988-04-22 | 1992-08-04 | Advanced Polymer Systems, Inc. | Porous particles in preparations involving immiscible phases |
US5145675A (en) | 1986-03-31 | 1992-09-08 | Advanced Polymer Systems, Inc. | Two step method for preparation of controlled release formulations |
US5316774A (en) | 1990-06-20 | 1994-05-31 | Advanced Polymer Systems, Inc. | Blocked polymeric particles having internal pore networks for delivering active substances to selected environments |
US5879716A (en) | 1985-12-18 | 1999-03-09 | Advanced Polymer Systems, Inc. | Methods and compositions for topical delivery of benzoyl peroxide |
US5955109A (en) | 1985-12-18 | 1999-09-21 | Advanced Polymer Systems, Inc. | Methods and compositions for topical delivery of retinoic acid |
WO2008093346A2 (en) * | 2007-02-01 | 2008-08-07 | Sol-Gel Technologies Ltd. | Compositions for topical application comprising a peroxide and retinoid |
WO2010013250A2 (en) * | 2008-07-31 | 2010-02-04 | Sol-Gel Technologies Ltd. | Microcapsules comprising active ingredients and a metal oxide shell, a method for their preparation and uses thereof |
WO2011042902A2 (en) * | 2009-10-07 | 2011-04-14 | Tagra Biotechnologies Ltd | Microcapsules comprising benzoyl peroxide and topical compositions comprising them |
US20110166101A1 (en) | 2008-08-29 | 2011-07-07 | Sun Pharma Advanced Research Company Limited | Microparticles |
US8053000B2 (en) | 2005-06-07 | 2011-11-08 | Dr. Reddy's Laboratories Limited | Compositions for drug delivery |
WO2013001536A1 (en) * | 2011-06-29 | 2013-01-03 | Sol-Gel Technologies Ltd. | Stabilized topical formulations containing core-shell microcapsules |
-
2014
- 2014-12-05 WO PCT/IB2014/066652 patent/WO2015092602A1/en active Application Filing
Patent Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4690825A (en) | 1985-10-04 | 1987-09-01 | Advanced Polymer Systems, Inc. | Method for delivering an active ingredient by controlled time release utilizing a novel delivery vehicle which can be prepared by a process utilizing the active ingredient as a porogen |
US5879716A (en) | 1985-12-18 | 1999-03-09 | Advanced Polymer Systems, Inc. | Methods and compositions for topical delivery of benzoyl peroxide |
US5955109A (en) | 1985-12-18 | 1999-09-21 | Advanced Polymer Systems, Inc. | Methods and compositions for topical delivery of retinoic acid |
US5145675A (en) | 1986-03-31 | 1992-09-08 | Advanced Polymer Systems, Inc. | Two step method for preparation of controlled release formulations |
US5135740A (en) | 1988-04-22 | 1992-08-04 | Advanced Polymer Systems, Inc. | Porous particles in preparations involving immiscible phases |
US5316774A (en) | 1990-06-20 | 1994-05-31 | Advanced Polymer Systems, Inc. | Blocked polymeric particles having internal pore networks for delivering active substances to selected environments |
US8053000B2 (en) | 2005-06-07 | 2011-11-08 | Dr. Reddy's Laboratories Limited | Compositions for drug delivery |
WO2008093346A2 (en) * | 2007-02-01 | 2008-08-07 | Sol-Gel Technologies Ltd. | Compositions for topical application comprising a peroxide and retinoid |
WO2010013250A2 (en) * | 2008-07-31 | 2010-02-04 | Sol-Gel Technologies Ltd. | Microcapsules comprising active ingredients and a metal oxide shell, a method for their preparation and uses thereof |
US20110166101A1 (en) | 2008-08-29 | 2011-07-07 | Sun Pharma Advanced Research Company Limited | Microparticles |
WO2011042902A2 (en) * | 2009-10-07 | 2011-04-14 | Tagra Biotechnologies Ltd | Microcapsules comprising benzoyl peroxide and topical compositions comprising them |
WO2013001536A1 (en) * | 2011-06-29 | 2013-01-03 | Sol-Gel Technologies Ltd. | Stabilized topical formulations containing core-shell microcapsules |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017029665A1 (en) | 2015-08-20 | 2017-02-23 | Sol-Gel Technologies Ltd. | Compositions for topical application comprising benzoyl peroxide and adapalene |
CN108024980A (en) * | 2015-08-20 | 2018-05-11 | 索尔-格尔科技有限公司 | Composition for topical application comprising benzoyl peroxide and Adapalene |
EP3337472A4 (en) * | 2015-08-20 | 2019-05-15 | Sol-Gel Technologies Ltd. | Compositions for topical application comprising benzoyl peroxide and adapalene |
US10933018B2 (en) | 2015-10-30 | 2021-03-02 | Timber Pharmaceuticals Llc | Isotretinoin formulations and uses and methods thereof |
US11471408B2 (en) | 2015-10-30 | 2022-10-18 | Timber Pharmaceuticals Llc | Isotretinoin formulations and uses and methods thereof |
US20210113511A1 (en) * | 2017-07-12 | 2021-04-22 | Sol-Gel Technologies Ltd. | Methods and compositions for the treatment of acne |
CN109126648A (en) * | 2018-06-05 | 2019-01-04 | 青岛明月生物医用材料有限公司 | A kind of preparation and its application of chitosan and propylene glycol alginate blend microcapsule |
CN116251035A (en) * | 2023-03-17 | 2023-06-13 | 深圳市护家科技有限公司 | Oily composition containing retinol and/or retinol derivatives |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5622582B2 (en) | Composition comprising at least one naphthoic acid derivative, benzoyl peroxide and at least one film former, method for its preparation and use thereof | |
WO2015092602A1 (en) | Topical pharmaceutical composition of a retinoid | |
JP5548456B2 (en) | Cream gel comprising at least one retinoid and benzoyl peroxide | |
US8603539B2 (en) | Compositions for drug delivery | |
JP5465011B2 (en) | Emulsion comprising at least one retinoid and benzoyl peroxide | |
CN113559083A (en) | Lipid microcapsules comprising a retinoid | |
JP2015518031A (en) | Retinoid-containing microcapsule, method for preparing the same, and pharmaceutical composition containing the retinoid-containing microcapsule | |
US20090191245A1 (en) | Reduced-irritant dermatological compositions comprising at least one naphthoic acid compound and benzoyl peroxide and treatment of keratinization disorders therewith | |
US10028972B2 (en) | Pharmaceutical compositions of anti-acne agents | |
US20150342920A1 (en) | Dermatological compositions comprising at least one retinoid compound, an anti-irritant compound and benzoyl peroxide | |
JP6423355B2 (en) | Composition for the treatment of rosacea | |
CA2717899A1 (en) | Stable fixed dose topical formulation | |
JP2010513424A (en) | Use of nepafenac or its derivatives for the treatment of skin lesions associated with keratinization disorders that may contain inflammatory immune allergy components | |
WO2012053014A2 (en) | Method for treatment of acne using pharmaceutical compositions of clindamycin and adapalene | |
AU2021272476A1 (en) | Compositions for delivery of bioactive agents into hair follicles | |
JP6811213B2 (en) | Composition for the treatment of rosacea | |
WO2022140467A1 (en) | Topical compositions and methods of treating skin diseases and conditions with such compositions | |
Ghosh et al. | MICROSPONGE A PROMISING CA |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 14811987 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 14811987 Country of ref document: EP Kind code of ref document: A1 |