HRP20030559A2 - Stabilized brivudine topical formulations containing metal oxide pigments - Google Patents
Stabilized brivudine topical formulations containing metal oxide pigments Download PDFInfo
- Publication number
- HRP20030559A2 HRP20030559A2 HR20030559A HRP20030559A HRP20030559A2 HR P20030559 A2 HRP20030559 A2 HR P20030559A2 HR 20030559 A HR20030559 A HR 20030559A HR P20030559 A HRP20030559 A HR P20030559A HR P20030559 A2 HRP20030559 A2 HR P20030559A2
- Authority
- HR
- Croatia
- Prior art keywords
- brivudine
- iron oxide
- oxide
- titanium dioxide
- pharmaceutical preparation
- Prior art date
Links
- 229960001169 brivudine Drugs 0.000 title claims description 44
- ODZBBRURCPAEIQ-PIXDULNESA-N helpin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(\C=C\Br)=C1 ODZBBRURCPAEIQ-PIXDULNESA-N 0.000 title claims description 44
- 239000000049 pigment Substances 0.000 title claims description 15
- 229910044991 metal oxide Inorganic materials 0.000 title claims description 8
- 150000004706 metal oxides Chemical class 0.000 title claims description 8
- 239000012049 topical pharmaceutical composition Substances 0.000 title claims description 3
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 42
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 39
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims description 28
- 239000006071 cream Substances 0.000 claims description 25
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 24
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 23
- 239000004408 titanium dioxide Substances 0.000 claims description 19
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 18
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 14
- -1 polyoxyethylene monostearate Polymers 0.000 claims description 13
- 230000000699 topical effect Effects 0.000 claims description 12
- 229940057995 liquid paraffin Drugs 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 9
- 239000000741 silica gel Substances 0.000 claims description 9
- 229910002027 silica gel Inorganic materials 0.000 claims description 9
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 claims description 8
- 239000003871 white petrolatum Substances 0.000 claims description 8
- 241000700588 Human alphaherpesvirus 1 Species 0.000 claims description 7
- 238000009472 formulation Methods 0.000 claims description 7
- 239000011787 zinc oxide Substances 0.000 claims description 7
- 241000701085 Human alphaherpesvirus 3 Species 0.000 claims description 6
- 239000000839 emulsion Substances 0.000 claims description 6
- 239000000017 hydrogel Substances 0.000 claims description 6
- SZVJSHCCFOBDDC-UHFFFAOYSA-N iron(II,III) oxide Inorganic materials O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 claims description 6
- 235000019271 petrolatum Nutrition 0.000 claims description 6
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 5
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 5
- 229940082500 cetostearyl alcohol Drugs 0.000 claims description 5
- 239000004205 dimethyl polysiloxane Substances 0.000 claims description 5
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 claims description 5
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 claims description 5
- NJESAXZANHETJV-UHFFFAOYSA-N 4-methylsalicylic acid Chemical compound CC1=CC=C(C(O)=O)C(O)=C1 NJESAXZANHETJV-UHFFFAOYSA-N 0.000 claims description 4
- 239000005662 Paraffin oil Substances 0.000 claims description 4
- 239000013543 active substance Substances 0.000 claims description 4
- 208000015181 infectious disease Diseases 0.000 claims description 4
- 229940075579 propyl gallate Drugs 0.000 claims description 4
- 235000010388 propyl gallate Nutrition 0.000 claims description 4
- 239000000473 propyl gallate Substances 0.000 claims description 4
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 claims description 4
- ODZBBRURCPAEIQ-DJLDLDEBSA-N Brivudine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C=CBr)=C1 ODZBBRURCPAEIQ-DJLDLDEBSA-N 0.000 claims description 2
- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical compound O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 claims description 2
- LDHBWEYLDHLIBQ-UHFFFAOYSA-M iron(3+);oxygen(2-);hydroxide;hydrate Chemical compound O.[OH-].[O-2].[Fe+3] LDHBWEYLDHLIBQ-UHFFFAOYSA-M 0.000 claims description 2
- 229940083037 simethicone Drugs 0.000 claims description 2
- 229960004063 propylene glycol Drugs 0.000 claims 9
- 235000013772 propylene glycol Nutrition 0.000 claims 9
- WTFXARWRTYJXII-UHFFFAOYSA-N iron(2+);iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[O-2].[Fe+2].[Fe+3].[Fe+3] WTFXARWRTYJXII-UHFFFAOYSA-N 0.000 claims 5
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 claims 5
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 claims 5
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims 4
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 claims 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims 4
- 229940045860 white wax Drugs 0.000 claims 4
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 claims 3
- 239000001593 sorbitan monooleate Substances 0.000 claims 3
- 229940035049 sorbitan monooleate Drugs 0.000 claims 3
- 235000011069 sorbitan monooleate Nutrition 0.000 claims 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims 2
- 239000004166 Lanolin Substances 0.000 claims 2
- 229960000541 cetyl alcohol Drugs 0.000 claims 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims 2
- 229940039717 lanolin Drugs 0.000 claims 2
- 235000019388 lanolin Nutrition 0.000 claims 2
- 235000019359 magnesium stearate Nutrition 0.000 claims 2
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 claims 2
- 239000004147 Sorbitan trioleate Substances 0.000 claims 1
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 claims 1
- 235000021355 Stearic acid Nutrition 0.000 claims 1
- 235000011037 adipic acid Nutrition 0.000 claims 1
- 150000001279 adipic acids Chemical class 0.000 claims 1
- 235000014113 dietary fatty acids Nutrition 0.000 claims 1
- GPLRAVKSCUXZTP-UHFFFAOYSA-N diglycerol Chemical compound OCC(O)COCC(O)CO GPLRAVKSCUXZTP-UHFFFAOYSA-N 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 239000000194 fatty acid Substances 0.000 claims 1
- 229930195729 fatty acid Natural products 0.000 claims 1
- 150000004665 fatty acids Chemical class 0.000 claims 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 claims 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 claims 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims 1
- 235000019337 sorbitan trioleate Nutrition 0.000 claims 1
- 229960000391 sorbitan trioleate Drugs 0.000 claims 1
- 239000008117 stearic acid Substances 0.000 claims 1
- LADGBHLMCUINGV-UHFFFAOYSA-N tricaprin Chemical compound CCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCC)COC(=O)CCCCCCCCC LADGBHLMCUINGV-UHFFFAOYSA-N 0.000 claims 1
- VLPFTAMPNXLGLX-UHFFFAOYSA-N trioctanoin Chemical compound CCCCCCCC(=O)OCC(OC(=O)CCCCCCC)COC(=O)CCCCCCC VLPFTAMPNXLGLX-UHFFFAOYSA-N 0.000 claims 1
- 229960004150 aciclovir Drugs 0.000 description 10
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 10
- 239000003443 antiviral agent Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 5
- 208000004898 Herpes Labialis Diseases 0.000 description 4
- 206010067152 Oral herpes Diseases 0.000 description 4
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 description 4
- 241000700605 Viruses Species 0.000 description 4
- 229960001179 penciclovir Drugs 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 241001529453 unidentified herpesvirus Species 0.000 description 4
- 230000000840 anti-viral effect Effects 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- JGUMTYWKIBJSTN-UHFFFAOYSA-N 2-ethylhexyl 4-[[4,6-bis[4-(2-ethylhexoxycarbonyl)anilino]-1,3,5-triazin-2-yl]amino]benzoate Chemical compound C1=CC(C(=O)OCC(CC)CCCC)=CC=C1NC1=NC(NC=2C=CC(=CC=2)C(=O)OCC(CC)CCCC)=NC(NC=2C=CC(=CC=2)C(=O)OCC(CC)CCCC)=N1 JGUMTYWKIBJSTN-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 208000009889 Herpes Simplex Diseases 0.000 description 2
- 208000029433 Herpesviridae infectious disease Diseases 0.000 description 2
- 239000004904 UV filter Substances 0.000 description 2
- 108020005202 Viral DNA Proteins 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- AGBQKNBQESQNJD-UHFFFAOYSA-N lipoic acid Chemical compound OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 238000001782 photodegradation Methods 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 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 description 1
- MXHRCPNRJAMMIM-SHYZEUOFSA-N 2'-deoxyuridine Chemical class C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 MXHRCPNRJAMMIM-SHYZEUOFSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 208000007514 Herpes zoster Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 208000036142 Viral infection Diseases 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
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000000991 chicken egg Anatomy 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- XACKNLSZYYIACO-DJLDLDEBSA-N edoxudine Chemical compound O=C1NC(=O)C(CC)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XACKNLSZYYIACO-DJLDLDEBSA-N 0.000 description 1
- 239000003344 environmental pollutant Substances 0.000 description 1
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical class OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 1
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 239000008309 hydrophilic cream Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 235000019136 lipoic acid Nutrition 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 230000000176 photostabilization Effects 0.000 description 1
- 231100000719 pollutant Toxicity 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 229960002663 thioctic acid Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000007442 viral DNA synthesis Effects 0.000 description 1
- 230000009385 viral infection Effects 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
Classifications
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
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Description
Ovaj izum odnosi se na stabilizirane farmaceutske pripravke koji sadrže antivirusni brivudin za topički tretman infekcija uzrokovanih virusom herpesa. Infekcije virusom herpesa mogu biti uzrokovane raznim herpes virusima, a najuobičajeniji su virus herpes simpleks i virus varicella-zoster. Također postoje mnogi životinjski virusi herpesa.
Virus tipa herpes simpleks 1 uzrokuje mukokutanu infekciju oralne šupljine koja vodi latentnom prisustvu virusa i ponovnom pojavljivanju tegoba herpes labialis (sore). Mada su sve pojave herpes labialis blage, oni često uzrokuju psihološke poremećaje kao i fizičku nelagodu i mogu prerasti u ozbiljne slučajeve. Kako kod hepres labialis postoji rizik da se prenese, postoji potreba za učinkovitim antivirusnim tretmanom tih bolesti.
Postoje brojna antivirusna sredstva kao što je acilovir, famaciklovir, penciklovir, brivudin itd. koji su aktivni u tretmanu humanih infekcija virusom herpesa. Kada se pojavljuje lokalizirana manifestacija virusnih infekcija, topički tretman može biti preferiran.
Većina aktivnih antivirusnih sredstava, tj. aciklovir, penciklovir, famaciklovir, brivudin itd. imaju slične kemijske karakteristike, u stvari, njihove strukture sliče purinskim i pirimidinskim bazama koje čine nukleinske kiseline. Antivirusna aktivnosti tih nukleozidnih analoga je zasnovana na inihibiciji sinteze virusne DNA. Oni se fosforiliranju u inficiranoj stanici enzimima koje kodira virus, te se oni ugrade kao "lažno blokirajući" u virusnu DNA ili inhibiraju virusnu DNA izravno.
Brivudin, (E)-5-(2-bromvinil)-2'-deoksiuridin je moćno antivirusno sredstvo za tretman infekcija uzrokovanih virusom varicalla zoster (VZV) i virusom herpes simpleks tip 1 (HSV-01). Njegova in vitro učinkovitost prema VZV vrsti je bolja od učinkovitosti aciklovira i peniciklovira [srednja IC50 u 13 kliničkih VZV sojeva: 0.001 μg/mL (bruvidin), 0.2 μg/mL (aciklovir), te 0.91 μg/mL (penciklovir)] (Andrei G., Snoeck R., Reymen D. Eur. J. Clin. Microbio. Infect.; 14;318-319; 1995).
Nadalje, brivudin je jaki inhibitor replikacije HSV-1 s dobrom in vitro učinkovitosti u odnosu na aciklovir i peniciklovir: u 23 klinička HSV-1 soja je pokazano da je bribudin skoro dva puta učiknovitiji od aciklovira [srednja IC50: 0.52 μg/mL (bruvidin) prema 0.92 μg/mL (aciklovir)] (Andrei G., Snoeck R., Goubao P. Eur. J. Clin. Microbio. Infect.; 11; 143-151; 1992). U dva slična testa u grupi od 20 klinički izoliranih slučajeva je penciklovir pokazao srednju IC50 od 0.6 μg/mL (Wienberg A., Bate B. J. Masters H. B. Antimicrob. Agents Chemother.; 36; 2037-2038; 1992).
Ranija istraživanja uglavnom provedena s HSV-1 vrstama su pokazala da čak i niže IC50 brivudina, a između 0.004 μg/mL i 0.2 μg/mL (ovisno o vrsti virusa i stanici sustava) (De Clercq E., Descpams J., Verhelst G., J. Infect. Dis., 141;563-574; 1980; De Clercq E., Antimicrob. Agents Chemorher.; 21; 661-663; 1982).
Nekoliko patenata pokazuje kako se pripravlja farmaceutski pripravak koji sadrži antivirusno sredstvo:
GB1,5233,865 opisuje nekoliko primjera korisnih za davanje aciklovira putem različitih kutanih putova davanja: oralnim, parenteralnim, okularnim ili topičkin putem;
EP44543 navodi određene kutane putove davanja i opisuje nekoliko formulacija aciklovira pogodnih za primjenu na koži, kao što su vodene kreme ili neke emulzije ulje/voda.
EP948332 opisuje farmaceutske formulacije pogodne za davanje topičkim aplikatorom koji sadrži aciklovir sam ili s vitaminom A za tretman hepres labialis;
EP809498 opisuje farmaceutske pripravke koji sadrže antivirusno sredstvo, među kojima su aciklovir ili Brivudin, a povezano s antiupalnim glikokortikoidima.
DE3706421 prikazuje farmaceutski pripravak za topički tretman virusa gerpesa, a koji sadrži 5-etil-2'deoksiuridin i ureu;
EP72137 se odnosi na određene derivate 3-metil-5-halovinil-deoksiurina za tretman herpes simpleks ili varicella zoster;
EP104066, EP95292, EP95294 prikazuju derivat 2'-deoksiuridina za topički i sistemski tretman virusa;
GB1601020 prvi prijavljuje brivudin, njegovu sintezu i upotrebu u tretmanu herpes simpleks, a različitim putovima.
Niti u jednom slučaju informacija dobivena o poznatim farmaceutskim pripravcima nije korisna za pripravu stabilnog farmaceutskog pripravka brivudina za topičko davanje.
Brivudin se, u stvari, pokazao posebno nestabilan u uvjetima koje se normalno koriste za topičke pripravke. Pod tim uvjetima je nađeno da brivudin podliježe fotoraspadanju što smanjuje koncentraciju aktivne tvari, smanjuje konačni efekt tretmana, a utvrđivanje su i značajne lokalne iritacije koje mogu spriječiti upotrebu farmaceutskog pripravka. Raspadanje brivudina je istraživano prema ICH (International Conference on Harmonazation) uputama CPMP/ICH/279/95. Neraspakirani uzorci bruvidina koji ne sadrže stabilizator su osvijetljeni 9.6 sati intenzitetom od 49/5 W/m2 (doza: 475 Wh/m2). Sadržaj brivudina se smanjuje od oko 100% do oko 79% nakon iradijacije. U isto vrijeme su uzorci pokazali povećanje poznatih i nepoznatih onečišćenja za oko 30%.
Pogodni fotostabilizator uz sprečavanje raspadanja mora imati važne karakteristike kao što je odsutnost toksičnosti u rasponu korištenih koncentracija, nepostojanje neželjene biološke aktivnosti, mala cijena, pogodna fizičko-kemijske svojstva za industrijsko rukovanje, te ne postojanje kemijske interakcije s ostalim sastojcima formulacije.
Mnogi su se fotostabilizatori pokazali neučinkovitim u stabiliziranju topičkog pripravka brivudina. Nadalje, znanje koje potječe od formulacija i antivirusnih sredstava brivudina nije pomoglo u rješavanju problema fotodegeneracije brivudina u topičkim farmaceutskim pripravcima.
Iznenađujuće, nađeno je da se problem može riješiti upotrebom pogodnih količina pigmenata koji su tip metlanih oksida.
Istraživanja fotostablilizatora su provedena kapsuliranjem aktivne tvari u ciklodekstrinskim kompleksima (npr. α-, β-, γ-ciklodekstrinski kompleksi) ili dodavanjem različitih stabilizatora. Korišteni su poznati fotostabilizatori kao što su antioksidanski (npr. propilgalat, alfa-liponska kiselina) kemijski UV-filteri (npr. oktil-triazon) i pigmenti (titanov dioksid, cinkov oksid, željezov oksid, žuti).
Učinkovitost fotostabilizatora je testirana određivanjem sadržaja brivudina nakon 2 sata iradijacije s UV-lampom (doza od 1 MED [minimalna doza koja izaziva eritem, 24.8 WH/m2, UVA-svjetlo]. UVA-svjetlo je primjenjeno izravno na kremu bez prethodnog pakiranja. Što je veći sadržaj nepromijenjenog brivudina nakon iradijacije, to je veća fotostabilnost.
Bez fotostabilizatora je sadržaj brivudina smanjen nakon iradijacije na oko 40% početne koncentracije (100% odgovora koncentraciji od 5% w/w brivudina u testiranoj formulaciji). Kapsuliranjem brivudina u ciklodekstrinske komplekse i dodatkom antioksidansa (propilgalat, 0.02% w/w) ili kemijskog UV-filtera (oktil-triazon, 5% w/w) je rezultiralo sadržajem brivudina između 30% i 60% početne koncentracije. Bolji rezultati se, iznenađujuće, mogu dobiti s pigmentima kao što je titanov oksid, željezov oksid ili cinkov oksid. Titanov oksid pri koncentraciji od 20% w/w rezultira s oko 85% konačnog sadržaja brivudina.
Iz tih rezultata se može zaključiti da su fotostabilizatori metalnih oksida znatno učinkovitiji u sprječavanju fotodegeneracije brivudina.
Prema tome, cilj izuma su topički pripravci brivudina stabilizirani prema fotoraspadanju pomoću pigmenata koji su tipa metalnog oksida. Preferirani pigmenti su titanov dioksid i željezov oksid. Titanov dioksid ima bijelu boju, dok je željezov oksid žut, čime se dobiva žuto obojena krema. Željezov oksid se također može uspješno koristiti kao sredstvo za bojanje bijele kreme koja sadrži titanov dioksid. Ovakvi pigmenti se mogu koristiti sami ili u kombinaciji.
Koncentracije pigmenata koje mogu izazvati efekt fotostablilizacije se mogu mijenjati od 10 do 50% po masi pripravka, preferirano od 15 do 35%, preferiranije od 20 do 30% w/w. Sadržaj brivudina je obično u rasponu od 0.3 do 8%, preferirano od 0.5 do 5% w/w.
Test klorioalantonske membrane pilećeg jajeta (HET/CAM test) je izveden da se odredi mogućnost iradijacije formulacije s komercijalnim titanovim dioksidom (25%w/w). Test je izveden nakon 2 sata iradijacije s UV-lampom pri 5 MED (124 Wh/m2, UV-svjetlo). UV svjetlo je primijenjeno direktno na kremu bez prethodnog pakiranja. U ovim testovima tolerancije je krema bez pigmenta ocjenjena kao "umjereno iritirajuća" dok je krema koja sadrži pigment ocjenjena kao "blago iritirajuća". Rezultati iznenađujuće pokazuju da titanov dioksid ne povećava samo fotostabilnost nego također smanjuje mogućnost iritacije.
Prema izumu, preferirane topički pripravci su u obliku O/W ili W/O kreme, lipogela, hidrogela ili stika.
Općenito, farmaceutski pripravci koji sadrže brivudin za topičko davanje se mogu pripraviti prema poznatim metodama, primjerice opisanom u Remingtons's Pharmaceutical Science, 17th ed. Mack Publishing Company, Waston, PA (1985). Prema tom primjeru se O/W krema može pripraviti slijedeći postupak od tri koraka koji sadrži tvorbu emulzije, dodatak prigmenta i dodatak aktivne tvari.
Primjeri
Primjer 1: O/W krema
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Ekscipijensi koji tvore uljnu fazu (tekuće parafinsko ulje, polioksietilen-monostearat, cetostearilni alkohol, bijeli vazelin, polidimetilsiloksan, simetikon) su taljeni pri temperaturi između 75 °C i 80 °C. Hidrofilna baza kreme (limunska kiselina 20%, pročišćena voda, propilen-glikol [dio količine], benzalkonij-klorid, 4-metilhidroksibenzoat) su zagrijavani posebno pri temperaturi između 75 °C i 80 °C. Obje faze su spojene u prethodno zagrijanom spremniku farmaceutskog homegenizatora. Smjesa je miješana pri temperaturi između 75 °C i 80 °C pri niskom tlaku. U bazu kreme su dodani ekscipijensi: titanov dioksid, glicerol i silikegel. Smjesa je miješana i homogenizirana pri temperaturi između 75 °C i 80 °C pri niskom tlaku. Tada se krema može ohladiti do sobne temperature održavajući miješanje pri niskom tlaku.
Brivudin je dispergiran u propilen-glikolu (preostala količina). Ta disperzija je dodana u kremu. Smjesa je miješana i homogenizirana pri temperaturi između 20 °C i 30 °C pri niskom tlaku.
Krema je čuvana od svjetla u zatvorenom spremniku do daljnjeg procesuiranja.
Primjer 2: formulacija stika
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Primjer 3: lipogel
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Primjer 4: W/O emulzija
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Primjer 5: hidrogel
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Primjer 6: W/O emulzija
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Primjer 7: hidrogel
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Primjer 8: lipogel
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Primjer 9: O/W krema
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Primjer 10: O/W krema
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Ekscipijensi koji tvore uljnu fazu (tekuće parafinsko ulje, polioksietilen-monostearat, cetostearilni alkohol, bijeli vazelin, polidimetilsiloksan) su taljeni pri temperaturi između 75 °C i 80 °C. Hidrofilna baza kreme (limunska kiselina 20%, pročišćena voda, propilen-glikol [dio količine], su zagrijavani posebno pri temperaturi između 75 °C i 80 °C. Obje faze su spojene u prethodno zagrijanom spremniku farmaceutskog homegenizatora. Smjesa je miješana pri temperaturi između 75 °C i 80 °C pri niskom tlaku. U bazu kreme su dodani ekscipijensi: titanov dioksid, željezov oksid žut, željezov oksid crn, željezov oksid crven, glicerol i silikegel. Smjesa je miješana i homogenizirana pri temperaturi između 75 °C i 80 °C pri niskom tlaku. Tada se krema može ohladiti do sobne temperature održavajući miješanje pri niskom tlaku.
Brivudin je dispergiran u propilen-glikolu (preostala količina). Ta disperzija je dodan u kremu. smjesa je miješana i homogenizirana pri temperaturi između 20 °C i 30 °C pri niskom tlaku.
Krema je čuvana od svjetla u zatvorenom spremniku do daljnjeg procesuiranja.
Claims (13)
1. Stabiliziran topički farmaceutski pripravak, naznačeno time da sadrži brivudin ((E)-5-(2-bromvinil)-2'-deoksiuridin) kao aktivnu tvar i jedan ili više pigmenata koji su metalni oksidi u koncentraciji od 10% do 50% w/w, skupa s farmaceutski prihvatljivim ekscipijensima.
2. Farmaceutski pripravak prema patentnom zahtjevu 1, naznačeno time da je koncentracija metalnog oksida od 15% do 35% w/w.
3. Farmaceutski pripravak prema patentnom zahtjevu 2, naznačeno time da je koncentracija metalnog oksida od 20% do 30% w/w.
4. Farmaceutski pripravak prema bilo kojem od prethodnih patentnih zahtjeva, naznačeno time da je pigment odabran iz skupine koju čine: titanov dioksid, željezov oksid, cinkov oksid.
5. Farmaceutski pripravak prema patentnom zahtjevu 4, naznačeno time da željezov oksid jeste žut, crven ili crn.
6. Farmaceutski pripravak prema patentnim zahtjevima 4-5, naznačeno time da pigment jeste titanov dioksid ili željezov oksid žut.
7. Farmaceutski pripravak prema bilo kojem od prethodnih patentnih zahtjeva, naznačeno time da sadrži 0.3-8% brivudina.
8. Farmaceutski pripravak prema patentnom zahtjevu 7, naznačeno time da sadrži 0.5-5% brivudina.
9. Farmaceutski pripravak prema bilo kojem od prethodnih patentnih zahtjeva, naznačeno time da je u obliku (O/W ili W/O) kreme, stika, lipogela, hidrogela.
10. Farmaceutski pripravak prema patentnom zahtjevu 9, naznačeno time da je odabran iz skupine koju čine:
i) O/W krema koja sadrži: brivudin 1%, titanov dioksid 25%, aluminijev oksid 1.6%, silikagel 0.1%, glicerol 0.4%, simetikon 0.5%, stearinsku kiselinu 1.9%, propilen-glikol 15, bijeli vazelin 9%, polioksietilen-monostearat 2%, cetostearilni alkohol 1.5%, limunsku kiselinu (20%) 0.6%, 4-metilhidroksibenzoat 0.15%, benzalkonij-klorid 0.2%, polidimetilsiloksan 0.2%, vodu do 100%;
ii) formulacija za stik koja sadrži: brivudin 5%, titanov dioksid 20%, glicerol-monostearat 10%, glicerolni ester masnih kiselina C10-C18 0.1%, propilen-glikol 15%, triglicerid kaprilne kiseline, triglicerid kapronske kiseline 15%, bijeli vosak 4%, ester diglicerola i kaprilne, kapronske, izostearinske, adipinske kiseline 11%;
iii) lipogel koji sadrži: brivudin 5%, tekući parafin 34%, izopropil-miristat 25%, silikagel 6.25%, sorbitan-monooleat 3%, titanov dioksid 16.25%, aluminijev oksid 5.125%, žuti željezov oksid 2.1%, crveni željezov oksid 0.6%, crni željezov oksid 0.3%, glicerol 2.375%,
iv) W/O emulzija koja sadrži: brivudin 0.5%, cinkov oksid 10%, titanov dioksid 10%, tekući parafin 15%, propilen-glikol 8%, bijeli vazelin 6%, lanolin 5%, sorbitan monooleat 3%, bijeli vosak 1.5%, cinkov stearat 1.0%, magnezijev stearat 1.0%, 4-metilhidroksibenzoat 0.15%, benzalkonij-klorid 0.2%, propil-galat 0.02%, limunsku kiselinu (20%) 0.6%, vodu do 100%,
v) hidrogel koji sadrži: brivudin 5%, titanov dioksid 21.25%, aluminijev oksid 1.25%, silikagel 0.125%, glicerol 2.375%, željezov oksid, žut 3.25%, crveni željezov oksid 1.25%, crni željezov oksid 0.5%, propilen-glikol 20%, tekući parafin 5%, izopropil-miristat 5%, cetilni alkohol 3%, polioksietil-monostearat 0.8%, hidroksietilcelulozu 0.3%, limunsku kiselinu q.s., vodu do 100%,
vi) W/O emulzija koja sadrži: brivudin 5%, titanov dioksid 22.5%, tekući parafin 15%, propilen-gliko 10.5%, bijeli vazelin 6%, lanolin 5%, sorbitan monooleat 3%, bijeli vosak 1.5%, cinkov stearat 1.0%, magnezijev stearat 1.0%, 4-metilhidroksibenzoat 0.15%, benzalkonij-klorid 0.2%, propil-galat 0.02%, vodu do 100%,
vii) hidrogel koji sadrži: brivudin 1%, titanov dioksid 27%, propilen-glikol 15%, silikagel 0.125%, tekući parafin 5%, izopropil-miristat 5%, cetilni alkohol 3%, polioksietil-monostearat 0.8%, hidroksietilceluloza 0.3%, benzalkonijev klorid 0.2%, limunsku kiselinu q.s., vodu do 100%,
viii) lipogel koji sadrži: brivudin 2%, žuti željezov oksid 0.75%, crveni željezov oksid 0.15%, crni željezov oksid 0.1%, izopropil-miristat 5%, titanov dioksid 15%, tekući parafin 15%, propilen-glikol 15%, bijeli vazelin 12%, cinkov oksid 5%, silikagel 5%, sorbiran-trioleat 3%, bijeli vosak 3%;
ix) O/W krema koja sadrži: brivudin 5%, cinkov oksid 10%, titanov oksid 10%, aluminijev oksid 0.6%, silikagel 0.032%, glicerol 0.1%, žuti željezov oksid 2.6%, crveni željezov oksid 1%, crni željezov oksid 0.4%, propilen-glikol 20%, bijeli vazelin 10%, tekuće parafinsko ulje 6%, polioksietilen-monostearat 3%, cetostearilni alkohol 2%, limunsku kiselinu 20% 0.6%, polidimetilsiloksan 0.5%, vodu do 100%;
x) O/W krema koja sadrži: brivudin 2%, titanov oksid 21.27%, aluminijev oksid 1.38%, silikagel 0.07%, glicerol 0.28%, žuti željezov oksid 1.4%, crveni željezov oksid 0.4%, crni željezov oksid 0.2%, propilen-glikol 20%, bijeli vazelin 9%, tekuće parafinsko ulje 5%, polioksietilen-monostearat 3%, cetostearilni alkohol 2%, limunsku kiselinu (20%) 0.8%, polidimetilsiloksan 0.3%, vodu do 100%,
11. Farmaceutski pripravak prema bilo kojem od prethodnih patentnih zahtjeva, naznačeno time da je za topički tretman infekcije uzrokovane virusom varicella zoster, te virusom herpes simpleks tipa 1.
12. Upotreba pigmenata koji su metalni oksidi kao fotostablizatora, naznačeno time da je za topičku formulaciju.
13. Upotreba prema patentnom zahtjevu 12, naznačeno time da su jedan ili više pigmenata odabranih od skupine koju čine titanov dioksid, željezov oksid, cinkov oksid.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP01100968 | 2001-01-17 | ||
| PCT/EP2002/000163 WO2002056913A2 (en) | 2001-01-17 | 2002-01-10 | Stabilized brivudine topical formulations containing metal oxide pigments |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20030559A2 true HRP20030559A2 (en) | 2005-06-30 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HR20030559A HRP20030559A2 (en) | 2001-01-17 | 2003-07-10 | Stabilized brivudine topical formulations containing metal oxide pigments |
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| JP (1) | JP2004519460A (hr) |
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| BG (1) | BG107988A (hr) |
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| CA (1) | CA2434743A1 (hr) |
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| EE (1) | EE200300322A (hr) |
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| UA (1) | UA80673C2 (hr) |
| WO (1) | WO2002056913A2 (hr) |
| YU (1) | YU57103A (hr) |
| ZA (1) | ZA200305437B (hr) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102005046769A1 (de) * | 2005-09-29 | 2007-04-05 | Berlin-Chemie Ag | Lichtstabile, brivudinhaltige pharmazeutische Formulierung zur Behandlung von Augenherpes (Herpes Ophthalmicus) |
| FR2936706B1 (fr) * | 2008-10-08 | 2010-12-17 | Oreal | Composition cosmetique contenant un derive de dibenzoylmethane et un compose dithiolane ; procede de photostabilisation du derive de dibenzoylmethane |
| JP5591128B2 (ja) * | 2009-01-29 | 2014-09-17 | 大日本住友製薬株式会社 | 内核を有する口腔内崩壊錠 |
| EP3272346A4 (en) * | 2015-03-19 | 2018-08-01 | Daiichi Sankyo Company, Limited | Solid preparation containing colorant |
| CN104988791A (zh) * | 2015-06-25 | 2015-10-21 | 广东义晟实业有限公司 | 一种抗病毒添加剂及添加该添加剂的胶水和uv漆 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0072137A1 (en) * | 1981-08-01 | 1983-02-16 | Beecham Group Plc | Antiviral deoxyuridine compounds |
| HU196038B (en) * | 1987-08-07 | 1988-09-28 | Mta Koezponti Kemiai Kutato In | Process for producing antiherpetic pharmaceutics for external use, containing 5-isopropyl-2'-beta-deoxy-uridine |
| DE4122337A1 (de) * | 1991-07-05 | 1993-01-14 | Cedona Pharm Bv | Pharmazeutische zubereitung |
| FR2737118B1 (fr) * | 1995-07-28 | 1997-09-05 | Oreal | Composition dermatologique ou pharmaceutique, procede de preparation et utilisation |
| GB9521454D0 (en) * | 1995-10-19 | 1995-12-20 | Kappa Pharmaceuticals Ltd | Compositions for the treatment of conditions caused by herpes virus |
| US6558710B1 (en) * | 1999-06-14 | 2003-05-06 | Helen Rebecca Godfrey | Topical zinc compositions and methods of use |
| DE10162593A1 (de) * | 2001-12-19 | 2003-07-03 | Menarini Ricerche Spa | Stabilisierte topische Brivudin-Formulierungen |
-
2001
- 2001-12-24 MY MYPI20015863A patent/MY136633A/en unknown
-
2002
- 2002-01-10 WO PCT/EP2002/000163 patent/WO2002056913A2/en not_active Application Discontinuation
- 2002-01-10 AU AU2002244642A patent/AU2002244642B2/en not_active Ceased
- 2002-01-10 BR BR0206478-2A patent/BR0206478A/pt not_active IP Right Cessation
- 2002-01-10 CN CNB028037448A patent/CN1236777C/zh not_active Expired - Fee Related
- 2002-01-10 SK SK899-2003A patent/SK8992003A3/sk not_active Application Discontinuation
- 2002-01-10 RU RU2003121639/15A patent/RU2280453C2/ru not_active IP Right Cessation
- 2002-01-10 CZ CZ20031912A patent/CZ20031912A3/cs unknown
- 2002-01-10 PL PL02365741A patent/PL365741A1/xx not_active Application Discontinuation
- 2002-01-10 EE EEP200300322A patent/EE200300322A/xx unknown
- 2002-01-10 CA CA002434743A patent/CA2434743A1/en not_active Abandoned
- 2002-01-10 IL IL15693302A patent/IL156933A0/xx unknown
- 2002-01-10 HU HU0302741A patent/HUP0302741A3/hu unknown
- 2002-01-10 KR KR10-2003-7009444A patent/KR20030070109A/ko not_active Application Discontinuation
- 2002-01-10 YU YU57103A patent/YU57103A/sh unknown
- 2002-01-10 EP EP02712810A patent/EP1365772A2/en not_active Withdrawn
- 2002-01-10 JP JP2002557420A patent/JP2004519460A/ja active Pending
- 2002-01-10 MX MXPA03006307A patent/MXPA03006307A/es not_active Application Discontinuation
- 2002-01-10 US US10/466,305 patent/US20040087602A1/en not_active Abandoned
- 2002-01-16 AR ARP020100151A patent/AR035530A1/es not_active Application Discontinuation
- 2002-01-16 PE PE2002000027A patent/PE20020818A1/es not_active Application Discontinuation
- 2002-10-01 UA UA2003076388A patent/UA80673C2/uk unknown
-
2003
- 2003-06-30 MA MA27219A patent/MA26266A1/fr unknown
- 2003-07-08 TN TNPCT/EP2002/000163A patent/TNSN03036A1/fr unknown
- 2003-07-10 BG BG107988A patent/BG107988A/bg unknown
- 2003-07-10 HR HR20030559A patent/HRP20030559A2/hr not_active Application Discontinuation
- 2003-07-15 ZA ZA200305437A patent/ZA200305437B/xx unknown
- 2003-07-15 NO NO20033206A patent/NO20033206L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| PL365741A1 (en) | 2005-01-10 |
| NO20033206D0 (no) | 2003-07-15 |
| UA80673C2 (en) | 2007-10-25 |
| CN1236777C (zh) | 2006-01-18 |
| TNSN03036A1 (en) | 2005-04-08 |
| MY136633A (en) | 2008-11-28 |
| KR20030070109A (ko) | 2003-08-27 |
| CN1486185A (zh) | 2004-03-31 |
| AU2002244642B2 (en) | 2005-12-15 |
| YU57103A (sh) | 2006-08-17 |
| MA26266A1 (fr) | 2004-09-01 |
| WO2002056913A3 (en) | 2002-11-07 |
| CZ20031912A3 (cs) | 2004-01-14 |
| PE20020818A1 (es) | 2002-10-21 |
| CA2434743A1 (en) | 2002-07-25 |
| SK8992003A3 (en) | 2003-11-04 |
| US20040087602A1 (en) | 2004-05-06 |
| BR0206478A (pt) | 2003-12-30 |
| HUP0302741A3 (en) | 2007-06-28 |
| JP2004519460A (ja) | 2004-07-02 |
| EE200300322A (et) | 2003-10-15 |
| RU2280453C2 (ru) | 2006-07-27 |
| WO2002056913A2 (en) | 2002-07-25 |
| IL156933A0 (en) | 2004-02-08 |
| HUP0302741A2 (hu) | 2003-11-28 |
| ZA200305437B (en) | 2004-07-15 |
| EP1365772A2 (en) | 2003-12-03 |
| NO20033206L (no) | 2003-07-15 |
| MXPA03006307A (es) | 2003-09-16 |
| RU2003121639A (ru) | 2005-02-10 |
| AR035530A1 (es) | 2004-06-02 |
| BG107988A (bg) | 2004-09-30 |
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