EP0879044A1 - Vernis a ongles antifongique et methode associee - Google Patents
Vernis a ongles antifongique et methode associeeInfo
- Publication number
- EP0879044A1 EP0879044A1 EP96903559A EP96903559A EP0879044A1 EP 0879044 A1 EP0879044 A1 EP 0879044A1 EP 96903559 A EP96903559 A EP 96903559A EP 96903559 A EP96903559 A EP 96903559A EP 0879044 A1 EP0879044 A1 EP 0879044A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- griseofulvin
- nail lacquer
- lacquer composition
- nail
- weight percent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000004922 lacquer Substances 0.000 title claims abstract description 55
- 238000000034 method Methods 0.000 title claims abstract description 13
- 230000001716 anti-fugal effect Effects 0.000 title abstract 2
- IIUZTXTZRGLYTI-UHFFFAOYSA-N Dihydrogriseofulvin Natural products COC1CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 IIUZTXTZRGLYTI-UHFFFAOYSA-N 0.000 claims abstract description 76
- UXWOXTQWVMFRSE-UHFFFAOYSA-N Griseoviridin Natural products O=C1OC(C)CC=C(C(NCC=CC=CC(O)CC(O)C2)=O)SCC1NC(=O)C1=COC2=N1 UXWOXTQWVMFRSE-UHFFFAOYSA-N 0.000 claims abstract description 76
- DDUHZTYCFQRHIY-UHFFFAOYSA-N Negwer: 6874 Natural products COC1=CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-UHFFFAOYSA-N 0.000 claims abstract description 76
- 229960002867 griseofulvin Drugs 0.000 claims abstract description 76
- DDUHZTYCFQRHIY-RBHXEPJQSA-N griseofulvin Chemical compound COC1=CC(=O)C[C@@H](C)[C@@]11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-RBHXEPJQSA-N 0.000 claims abstract description 76
- 239000000203 mixture Substances 0.000 claims abstract description 71
- 239000000725 suspension Substances 0.000 claims abstract description 15
- 230000000843 anti-fungal effect Effects 0.000 claims abstract description 11
- 239000003960 organic solvent Substances 0.000 claims description 17
- 208000015181 infectious disease Diseases 0.000 claims description 12
- 239000000375 suspending agent Substances 0.000 claims description 9
- 239000000440 bentonite Substances 0.000 claims description 7
- 229910000278 bentonite Inorganic materials 0.000 claims description 7
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical group O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 claims description 7
- 241001465754 Metazoa Species 0.000 claims description 4
- 239000000020 Nitrocellulose Substances 0.000 claims description 4
- 229920001220 nitrocellulos Polymers 0.000 claims description 4
- 210000000282 nail Anatomy 0.000 abstract description 62
- 239000002904 solvent Substances 0.000 abstract description 27
- 210000004905 finger nail Anatomy 0.000 abstract description 4
- 210000004906 toe nail Anatomy 0.000 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 239000010409 thin film Substances 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 19
- 230000000699 topical effect Effects 0.000 description 11
- 229940121375 antifungal agent Drugs 0.000 description 8
- 239000003429 antifungal agent Substances 0.000 description 8
- 241000233866 Fungi Species 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- 238000009835 boiling Methods 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000003086 colorant Substances 0.000 description 4
- RRAFCDWBNXTKKO-UHFFFAOYSA-N eugenol Chemical compound COC1=CC(CC=C)=CC=C1O RRAFCDWBNXTKKO-UHFFFAOYSA-N 0.000 description 4
- 239000000049 pigment Substances 0.000 description 4
- 239000004014 plasticizer Substances 0.000 description 4
- 210000003491 skin Anatomy 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 206010017533 Fungal infection Diseases 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 208000031888 Mycoses Diseases 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 206010061304 Nail infection Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- NPBVQXIMTZKSBA-UHFFFAOYSA-N Chavibetol Natural products COC1=CC=C(CC=C)C=C1O NPBVQXIMTZKSBA-UHFFFAOYSA-N 0.000 description 2
- 241000723346 Cinnamomum camphora Species 0.000 description 2
- NIQCNGHVCWTJSM-UHFFFAOYSA-N Dimethyl phthalate Chemical compound COC(=O)C1=CC=CC=C1C(=O)OC NIQCNGHVCWTJSM-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 239000005770 Eugenol Substances 0.000 description 2
- UVMRYBDEERADNV-UHFFFAOYSA-N Pseudoeugenol Natural products COC1=CC(C(C)=C)=CC=C1O UVMRYBDEERADNV-UHFFFAOYSA-N 0.000 description 2
- 208000002474 Tinea Diseases 0.000 description 2
- 241001045770 Trichophyton mentagrophytes Species 0.000 description 2
- 239000010775 animal oil Substances 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229960000846 camphor Drugs 0.000 description 2
- 229930008380 camphor Natural products 0.000 description 2
- 239000004927 clay Substances 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 239000002537 cosmetic Substances 0.000 description 2
- 210000004207 dermis Anatomy 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
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229960002217 eugenol Drugs 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000002538 fungal effect Effects 0.000 description 2
- KWLMIXQRALPRBC-UHFFFAOYSA-L hectorite Chemical compound [Li+].[OH-].[OH-].[Na+].[Mg+2].O1[Si]2([O-])O[Si]1([O-])O[Si]([O-])(O1)O[Si]1([O-])O2 KWLMIXQRALPRBC-UHFFFAOYSA-L 0.000 description 2
- 229910000271 hectorite Inorganic materials 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- FUSNMLFNXJSCDI-UHFFFAOYSA-N tolnaftate Chemical compound C=1C=C2C=CC=CC2=CC=1OC(=S)N(C)C1=CC=CC(C)=C1 FUSNMLFNXJSCDI-UHFFFAOYSA-N 0.000 description 2
- 229960004880 tolnaftate Drugs 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- MCCACAIVAXEFAL-UHFFFAOYSA-N 1-[2-(2,4-dichlorophenyl)-2-[(2,4-dichlorophenyl)methoxy]ethyl]imidazole;nitric acid Chemical compound O[N+]([O-])=O.ClC1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 MCCACAIVAXEFAL-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- GEGSSUSEWOHAFE-UHFFFAOYSA-N 2-(4-chlorphenoxy)-ethanol Chemical compound OCCOC1=CC=C(Cl)C=C1 GEGSSUSEWOHAFE-UHFFFAOYSA-N 0.000 description 1
- QCDWFXQBSFUVSP-UHFFFAOYSA-N 2-phenoxyethanol Chemical compound OCCOC1=CC=CC=C1 QCDWFXQBSFUVSP-UHFFFAOYSA-N 0.000 description 1
- LWVQQAOGNZFJRA-UHFFFAOYSA-N 3,4-dibromo-1,1,2,2,3-pentachlorocyclohexane Chemical compound ClC1(Cl)CCC(Br)C(Cl)(Br)C1(Cl)Cl LWVQQAOGNZFJRA-UHFFFAOYSA-N 0.000 description 1
- AWVDYRFLCAZENH-UHFFFAOYSA-N 3-phenoxypropan-1-ol Chemical compound OCCCOC1=CC=CC=C1 AWVDYRFLCAZENH-UHFFFAOYSA-N 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 208000007163 Dermatomycoses Diseases 0.000 description 1
- 241001480035 Epidermophyton Species 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- 241001480037 Microsporum Species 0.000 description 1
- 241000893980 Microsporum canis Species 0.000 description 1
- 208000010195 Onychomycosis Diseases 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 206010040880 Skin irritation Diseases 0.000 description 1
- YSMRWXYRXBRSND-UHFFFAOYSA-N TOTP Chemical group CC1=CC=CC=C1OP(=O)(OC=1C(=CC=CC=1)C)OC1=CC=CC=C1C YSMRWXYRXBRSND-UHFFFAOYSA-N 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- 241000223238 Trichophyton Species 0.000 description 1
- 241001459572 Trichophyton interdigitale Species 0.000 description 1
- 241000223229 Trichophyton rubrum Species 0.000 description 1
- 241000893966 Trichophyton verrucosum Species 0.000 description 1
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
- MHYWEVWYJLSASA-UHFFFAOYSA-N acetic acid;triethyl 2-hydroxypropane-1,2,3-tricarboxylate Chemical compound CC(O)=O.CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC MHYWEVWYJLSASA-UHFFFAOYSA-N 0.000 description 1
- 125000005233 alkylalcohol group Chemical group 0.000 description 1
- 229940072049 amyl acetate Drugs 0.000 description 1
- PGMYKACGEOXYJE-UHFFFAOYSA-N anhydrous amyl acetate Natural products CCCCCOC(C)=O PGMYKACGEOXYJE-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001857 anti-mycotic effect Effects 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 229940030999 antipsoriatics Drugs 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940073609 bismuth oxychloride Drugs 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229960004022 clotrimazole Drugs 0.000 description 1
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 201000003929 dermatomycosis Diseases 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- FBSAITBEAPNWJG-UHFFFAOYSA-N dimethyl phthalate Natural products CC(=O)OC1=CC=CC=C1OC(C)=O FBSAITBEAPNWJG-UHFFFAOYSA-N 0.000 description 1
- 229960001826 dimethylphthalate Drugs 0.000 description 1
- DWNAQMUDCDVSLT-UHFFFAOYSA-N diphenyl phthalate Chemical compound C=1C=CC=C(C(=O)OC=2C=CC=CC=2)C=1C(=O)OC1=CC=CC=C1 DWNAQMUDCDVSLT-UHFFFAOYSA-N 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000000855 fungicidal effect Effects 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 230000001408 fungistatic effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008233 hard water Substances 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- -1 isopropyl alcohols Chemical class 0.000 description 1
- 229940119170 jojoba wax Drugs 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000010445 mica Substances 0.000 description 1
- 229910052618 mica group Inorganic materials 0.000 description 1
- 229960005040 miconazole nitrate Drugs 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- BWOROQSFKKODDR-UHFFFAOYSA-N oxobismuth;hydrochloride Chemical compound Cl.[Bi]=O BWOROQSFKKODDR-UHFFFAOYSA-N 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
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 1
- 229920002037 poly(vinyl butyral) polymer Polymers 0.000 description 1
- 229920001225 polyester resin Polymers 0.000 description 1
- 239000004645 polyester resin Substances 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 229940032159 propylene carbonate Drugs 0.000 description 1
- 230000036556 skin irritation Effects 0.000 description 1
- 231100000475 skin irritation Toxicity 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 210000000434 stratum corneum Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000004308 thiabendazole Substances 0.000 description 1
- 229960004546 thiabendazole Drugs 0.000 description 1
- 235000010296 thiabendazole Nutrition 0.000 description 1
- WJCNZQLZVWNLKY-UHFFFAOYSA-N thiabendazole Chemical compound S1C=NC(C=2NC3=CC=CC=C3N=2)=C1 WJCNZQLZVWNLKY-UHFFFAOYSA-N 0.000 description 1
- 201000004647 tinea pedis Diseases 0.000 description 1
- 201000005882 tinea unguium Diseases 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- XZZNDPSIHUTMOC-UHFFFAOYSA-N triphenyl phosphate Chemical compound C=1C=CC=CC=1OP(OC=1C=CC=CC=1)(=O)OC1=CC=CC=C1 XZZNDPSIHUTMOC-UHFFFAOYSA-N 0.000 description 1
- 239000002966 varnish Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Definitions
- the present invention is directed to a nail lacquer containing an anti-fungal effective amount of griseofulvin.
- nail lacquer compositions contain film-forming compounds and organic solvents. Depending on the organic solvent, the griseofulvin may be soluble or somewhat soluble at ambient temperatures in such solvent. Thus, the griseofulvin may be in solution in the nail lacquer, partially in solution and partially suspended in the nail lacquer, or be totally suspended in the nail lacquer. When the griseofulvin is partially or totally suspended in the nail lacquer, the nail lacquer should also contain a suspending agent such as bentonite.
- a suspending agent such as bentonite.
- the fingernails and toenails are susceptible to dermatophytic infections which are caused by the invasion of fungi into the nails of human beings and other animals.
- fungi such as T. rubrum, Microsporum Canis, T. mentagrophytum, T. interdigitale, and other known fungi that can cause these types of infections.
- the treatment of these infections typically involves administering one or more known types of antifungal agents, e.g., griseofulvin, clotrimazole, miconazole nitrate and thiabendazole, either orally or topically depending on the particular anti-fungal agent used.
- griseofulvin may be administered when the dermatophytic infection has not been successfully treated with the topical application of other antifungal agents.
- infections of the nails The general rule is that, if not treated very early, these infections progress to become chronic and are essentially not responsive to any form of therapy, except on some occasions, to prolonged administration of orally administered griseofulvin and a few other new antifungal agents.
- griseofulvin due to their insolubility and associated poor adsorption from the gastrointestinal tract, have to be administered in relatively large doses, for long periods of time, sometimes extending for more than one year, and have a series of undesirable side effects.
- orally administered griseofulvin there is concern that the oral use of griseofulvin includes a risk of toxicity. It is generally believed that this risk may be reduced if griseofulvin could be successfully topically administered.
- the topical administration of griseofulvin has been hindered by the lack of a suitable carrier, since griseofulvin cannot be topically applied and absorbed through the dermis in its natural solid or powder state.
- griseofulvin is insoluble in water and only slightly soluble in common solvents, such as dimethylsulfoxide, dimethylformamide and acetone which are typically used as pharmaceutical carriers.
- common solvents such as dimethylsulfoxide, dimethylformamide and acetone which are typically used as pharmaceutical carriers.
- the following articles which discuss the topical application of griseofulvin using various carrier systems are aimed at the skin surface rather than the nails.
- Topical griseofulvin therapy of that which is called tinea pedis by Goldman, et al., ASMC Dermato Venerologica, line 39, page 454-460 (1959);
- the activity of various topical griseofulvin preparations and the appearance of oral griseofulvin in the stratum corneum by Knight, British Journal of Dermatology, Vol.
- the highly volatile solvents e.g. acetone
- the oily solvents or ointment carriers even when demonstrated as potentially effective as carriers, typically were applied in relatively excessive amounts leaving an oily residue even after the lapse of an extended period of time.
- Topical griseofulvin compositions are also disclosed in U.S. Patent No. 3,899,578, issued to Bird, et al., August 12, 1975.
- the disclosed compositions are comprised of griseofulvin dissolved in various high boiling, volatile solvents, e.g. propylene carbonate, di ethylphthalate, 3 phenoxypropanol, 4-chlorophenoxyethanol, phenoxyethanol, phenylethanol, eugenol and benzyl alcohol.
- Benzyl alcohol in combination with dimethyl phthalate, propylene carbonate or eugenol are disclosed as preferred solvent carriers.
- the composition may be diluted with ethanol, n-propanol, isopropanol, propylene glycol or glycerol.
- the disclosed compositions would be generally classified as a gel, ointment or paste due to the large amount of the low volatile solvent used in their preparation.
- these compositions will leave an oily residue for a considerable amount of time after application. It is believed that griseofulvin is solubilized in the oily layer of the composition and will rub off on the clothing or upon washing and thus will not be absorbed to any great extent by the skin.
- U.S. Patent No. 4,820,724 also discloses a griseofulvin composition for topical application to the skin.
- the solvent carrier system disclosed in this patent is a mixture of a fugitive solvent having a boiling point of less than 110°C and a delivery solvent having a boiling point of greater than 120°C.
- the delivery systems described in this patent are effective in promoting the absorption of griseofulvin through the skin; however, the delivery systems are easy to remove accidentally and therefore are not convenient to use.
- compositions for application to or treatment of nails including nail polishes, nail polish removers, nail oil emulsions, and the like have been developed.
- U.S. Patent No. 3,382,151 describes an aqueous- based, formaldehyde-containing composition which can be applied to fingernails to strengthen them against cracking and splitting. The patent further discloses that the product possesses aseptic properties, curing some inflammation of the matrix of the nail and killing fungi which occasionally infect nails.
- U.S. Patent No. 4,250,164 describes a nail polish composition, which has added thereto an anti-psoriasis effective amount of a topical steroid effective against psoriasis.
- 2,799,613 describes the use of dibromo- pentachlorocyclohexane as a topical fungicide and bactericide and also discloses including it as an ingredient of nail polish.
- Certain oil-containing compositions have been disclosed as being useful as nail and cuticle conditioners or softeners.
- U.S. Patent No. 2,765,257 indicates that sulfonated mineral oil acts as an effective cuticle softener; while sulfonated animal and vegetable oils are not effective.
- Other prior art e.g., U.S. Patent No. 4,286,609, has disclosed the soaking of fingertips in a hot, aqueous emulsion of vegetable and animal oils to moisturize, smooth and soften the surface of the nails and the tissue surrounding the nails.
- U.S. Patent No. 4,810,498 refers to nail oil composition consisting of a cosmetic oil containing jojoba oil and tolnaftate. This substance is prescribed to treat fungal infections in nails, particular sculptured nails, known for their propensity to become contaminated. This type of formulation, although potentially effective if applied frequently has the difficulty that it has an oily texture which will only display its properties while present on the nail, and is easily removed by rubbing or when hands are washed with detergents.
- U.S. Patent No. 4,957,730 described a nail varnish comprising a water insoluble film forming substance and a series of antimycotic compounds derived from a l-hydroxy-2- pyridone structure.
- the present invention provides a method and composition for application of griseofulvin to the nail surface, which will adhere tenaciously and yet continue to deliver the active anti ⁇ fungal compound (griseofulvin) into and through the nail.
- the present invention is predicated upon the surprising discovery that when griseofulvin is added to a nail lacquer and the nail lacquer is applied to the toenails and/or fingernails, the griseofulvin is effective in preventing and/or alleviating dermatophytic infections of the nails to which the anti-fungal nail lacquer is applied.
- the nail lacquer of the present invention includes, at a minimum, an organic film former which is in solution in a solvent system of one or more biocompatible organic solvents which, upon application to the nails, evaporate, leaving a relatively hard water permeable film.
- organic film former which is in solution in a solvent system of one or more biocompatible organic solvents which, upon application to the nails, evaporate, leaving a relatively hard water permeable film.
- film-forming compounds and solvent systems therefor are well known in the art and no detailed exemplification thereof is deemed necessary.
- the film-forming compounds are those which form a film which is relatively hard and strong, such film- forming compounds including polymers and copolymers of vinyl acetate, polymers and copolymers of acrylic or methacrylic acid (e.g., polymethyl methacrylate) polyvinylacytel and polyvinylbutyrals.
- a particular preferred film-forming compound is nitrocellulose, either alone or in combination with one or more of the other film- forming compounds mentioned above.
- Physiologically acceptable solvent systems which will dissolve the film-forming compounds mentioned above, are known in the art and include either alone or in combination lower alkyl alcohols such as ethyl, butyl and isopropyl alcohols, aromatic solvents such as benzyl alcohol, and butyl, ethyl, and amyl acetate.
- the solvent system preferably contains a combination of organic solvents, at least one of the organic solvents having a boiling point of below about 100°C (e.g. between 40°C or 50°C and 100°C) and at least one organic solvent having a boiling point above 100°C (e.g. 110°C - 200°C) .
- nail lacquer compositions also include a plasticizer to render the film more elastic.
- Plasticizers are also generally known in the cosmetic art and includes camphor, dibutyldioctyl and diphenyl phthalate and tricresyl and triphenyl phosphate.
- ingredients of the nail lacquer include, if desired, colorants and pigments such as titanium oxide, mica, bismuth oxychloride, etc. If insoluble colorants and pigments are used, then a suspending agent such as bentonite should also be in the nail lacquer composition in order to prevent settling out of such insoluble colorants and pigments.
- the amount of solvent in the nail lacquer composition of the present invention should, of course, be sufficient to solubilize and dissolve the film-forming compounds. Generally speaking, the amount of film-forming compound, relative to the organic solvent system, is relatively small. For example, the weight rate of film former to organic solvent will range from 1:3 to 1:10.
- the film- forming solution i.e. the film former and organic solvent system
- the amount thereof will be relatively minor compared to the amount of film former.
- the weight ratio of fil - forming compound to plasticizer will be between about 5:1 to 20:1.
- a suspending agent should also be present in the nail composition if an insoluble colorant or pigment is used and, in addition, if griseofulvin is present in an amount greater than that which is dissolved in the organic solvents of the nail lacquer composition.
- the amount of suspending agent is not critical and will generally be present in amounts of from 1 to 10 weight percent.
- the amount of griseofulvin in the nail lacquer compositions of the present invention is generally between about 0.5 weight percent and 10 weight percent with a preferred amount being between about 2 weight percent and 8 weight percent with a most preferred amount being between about 2 weight percent and 5 weight percent.
- the griseofulvin is present in an amount of between about 1.5 or 2 weight percent and 3 weight percent, the remaining portion of the griseofulvin is undissolved and suspended in the nail lacquer composition.
- a suspending agent such as an organic clay (e.g., bentonite) is added, which allows the griseofulvin to remain in the nail lacquer composition as a colloidal suspension.
- a portion of the griseofulvin be in solution and a portion of the griseofulvin be in suspension.
- a portion of the griseofulvin be in solution and a portion of the griseofulvin be in suspension.
- the griseofulvin leaches out of the nail lacquer to exert its' fungistatic effects.
- Small filter paper discs impregnated with the lacquer and allowed to dry, when placed on culture dishes containing T.
- the invention is directed to a composition which is comprised of at least 0.1 weight percent griseofulvin in a clear lacquer which is essentially similar in composition to that used to manicure nails.
- This composition can be topically applied to the infected sites (nails and surrounding tissue) which exhibits signs of fungal infection.
- the invention is further directed to methods of making and using the composition, considering that the drug remains in solution and/or suspension for prolonged periods of time.
- the griseofulvin containing lacquer Once the griseofulvin containing lacquer is applied to the nail it rapidly hardens and forms a water permeable film containing the griseofulvin following the evaporation of the solvent system. This not only concentrates the griseofulvin at or near the site where it is needed, but it is believed facilitates the transport of the active compound through the patient's nail. Thus not only does the nail lacquer composition of this invention provide a means for applying a concentrated amount of an active compound but also promotes transport of the compound through the nail. It should be noted that the above discussion concerning the mechanism of absorption is merely a theory based on observed facts and should not be taken in any manner to limit the scope of the invention.
- the nail lacquer composition may be prepared by admixing the solvents, film former and active compound in a suitable manner which assures the solubilization and/or suspension of the griseofulvin in the solvents.
- composition may be applied to the affected area by any suitable means.
- this composition of the invention may be used to treat various types of dermatophytic infections.
- this composition may be used to treat the various dermatophytid infections, and nail infections caused by fungi (Onychomycosis) .
- These types of infections may be caused by numerous fungi, e.g., those classified under the genera: trichophyton, microsporum or epidermophyton.
- the antifungal agent griseofulvin used to treat fungal infections in accordance with this embodiment of the invention is represented by the following general formula: Compound Parts by Weight
- the resulting composition is topically applied directly to the infected site. After application the solvents quickly dissipate by evaporation, due to the body temperature of the patient, leaving as a residue a thin water soluble film on the affected area.
- the composition may be applied to the affected area by any satisfactory means, such as a small brush, cotton swab or spatula, being the most satisfactory.
- the effective amount of the composition applied to the infected area is such to provide a thin layer of the residue after evaporation of the solvents.
- the precise amount of the composition is not critical, however, excessive application will not be beneficial.
- Removal of the lacquer should be accomplished periodically by using a suitable solvent (usually every 2-4 days) . This could be achieved with any nail polish remover available commercially, or preferably a mixture of acetone-plant or animal tissue oil (9:1) containing 1% griseofulvin in solution. This maintains the levels of drug in the tissue and the oil prevents the nails from becoming brittle, a problem which is particularly prevalent in individuals suffering from such infections.
- this composition ensures that the griseofulvin remains in the lacquer for a sufficient enough time on the patient's nail to allow for absorption of the griseofulvin. Furthermore, the topical application of griseofulvin using this composition allows a several order of magnitude reduction in the amount of griseofulvin given the patient in comparison with oral administration. This reduces the potential risks associated with the oral administration of griseofulvin as discussed above and the potential of skin irritation caused by the solvent.
Landscapes
- Cosmetics (AREA)
- Medicinal Preparation (AREA)
Abstract
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002243566A CA2243566A1 (fr) | 1994-03-17 | 1996-01-18 | Laque antifongique pour ongles et methode connexe |
PCT/US1996/000710 WO1997025962A1 (fr) | 1994-03-17 | 1996-01-18 | Vernis a ongles antifongique et methode associee |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0879044A1 true EP0879044A1 (fr) | 1998-11-25 |
EP0879044A4 EP0879044A4 (fr) | 1999-03-31 |
Family
ID=25680381
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP96903559A Withdrawn EP0879044A4 (fr) | 1996-01-18 | 1996-01-18 | Vernis a ongles antifongique et methode associee |
Country Status (1)
Country | Link |
---|---|
EP (1) | EP0879044A4 (fr) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1989008442A1 (fr) * | 1988-03-11 | 1989-09-21 | Seton Products Limited | Preparations topiques |
-
1996
- 1996-01-18 EP EP96903559A patent/EP0879044A4/fr not_active Withdrawn
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1989008442A1 (fr) * | 1988-03-11 | 1989-09-21 | Seton Products Limited | Preparations topiques |
Non-Patent Citations (1)
Title |
---|
See also references of WO9725962A1 * |
Also Published As
Publication number | Publication date |
---|---|
AU4760796A (en) | 1997-08-11 |
AU707437B2 (en) | 1999-07-08 |
EP0879044A4 (fr) | 1999-03-31 |
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