WO1996030011A1 - Topical antimycotic compositions - Google Patents
Topical antimycotic compositions Download PDFInfo
- Publication number
- WO1996030011A1 WO1996030011A1 PCT/US1996/004390 US9604390W WO9630011A1 WO 1996030011 A1 WO1996030011 A1 WO 1996030011A1 US 9604390 W US9604390 W US 9604390W WO 9630011 A1 WO9630011 A1 WO 9630011A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- nail
- composition
- dimethyl sulfoxide
- pharmaceutical composition
- epinychium
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 49
- 230000000699 topical effect Effects 0.000 title abstract description 5
- 230000001857 anti-mycotic effect Effects 0.000 title description 2
- 239000002543 antimycotic Substances 0.000 title description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 125
- 239000003429 antifungal agent Substances 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims abstract description 21
- 229940121375 antifungal agent Drugs 0.000 claims abstract description 17
- 238000011282 treatment Methods 0.000 claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 241000233866 Fungi Species 0.000 claims abstract description 5
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 4
- 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 4
- 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 4
- 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 4
- 229960002867 griseofulvin Drugs 0.000 claims abstract 4
- 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 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 206010017533 Fungal infection Diseases 0.000 claims description 7
- 208000031888 Mycoses Diseases 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 claims description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 claims description 6
- 229960003942 amphotericin b Drugs 0.000 claims description 6
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 claims description 5
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 claims description 5
- 229960004413 flucytosine Drugs 0.000 claims description 5
- -1 heptaene polyene Chemical class 0.000 claims description 5
- 229960004125 ketoconazole Drugs 0.000 claims description 5
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 229960004022 clotrimazole Drugs 0.000 claims description 4
- 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 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 229960004884 fluconazole Drugs 0.000 claims description 4
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 claims description 4
- 229960004130 itraconazole Drugs 0.000 claims description 4
- 238000004806 packaging method and process Methods 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 239000012049 topical pharmaceutical composition Substances 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 3
- MPIPASJGOJYODL-SFHVURJKSA-N (R)-isoconazole Chemical compound ClC1=CC(Cl)=CC=C1[C@@H](OCC=1C(=CC=CC=1Cl)Cl)CN1C=NC=C1 MPIPASJGOJYODL-SFHVURJKSA-N 0.000 claims description 2
- OCAPBUJLXMYKEJ-UHFFFAOYSA-N 1-[biphenyl-4-yl(phenyl)methyl]imidazole Chemical compound C1=NC=CN1C(C=1C=CC(=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 OCAPBUJLXMYKEJ-UHFFFAOYSA-N 0.000 claims description 2
- LEZWWPYKPKIXLL-UHFFFAOYSA-N 1-{2-(4-chlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound C1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 LEZWWPYKPKIXLL-UHFFFAOYSA-N 0.000 claims description 2
- BYBLEWFAAKGYCD-UHFFFAOYSA-N Miconazole Chemical compound ClC1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 BYBLEWFAAKGYCD-UHFFFAOYSA-N 0.000 claims description 2
- 229960002206 bifonazole Drugs 0.000 claims description 2
- 229960003913 econazole Drugs 0.000 claims description 2
- 229960004849 isoconazole Drugs 0.000 claims description 2
- 239000003120 macrolide antibiotic agent Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229960002509 miconazole Drugs 0.000 claims description 2
- 229960003483 oxiconazole Drugs 0.000 claims description 2
- QRJJEGAJXVEBNE-MOHJPFBDSA-N oxiconazole Chemical compound ClC1=CC(Cl)=CC=C1CO\N=C(C=1C(=CC(Cl)=CC=1)Cl)\CN1C=NC=C1 QRJJEGAJXVEBNE-MOHJPFBDSA-N 0.000 claims description 2
- 150000003558 thiocarbamic acid derivatives Chemical class 0.000 claims description 2
- 230000003442 weekly effect Effects 0.000 claims 2
- 208000010195 Onychomycosis Diseases 0.000 abstract description 14
- 201000005882 tinea unguium Diseases 0.000 abstract description 9
- 238000011321 prophylaxis Methods 0.000 abstract description 6
- 210000000282 nail Anatomy 0.000 description 28
- 239000000243 solution Substances 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 8
- 210000004905 finger nail Anatomy 0.000 description 6
- 208000015181 infectious disease Diseases 0.000 description 6
- 210000004906 toe nail Anatomy 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- LVYLCBNXHHHPSB-UHFFFAOYSA-N 2-hydroxyethyl salicylate Chemical compound OCCOC(=O)C1=CC=CC=C1O LVYLCBNXHHHPSB-UHFFFAOYSA-N 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
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- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- DOMXUEMWDBAQBQ-WEVVVXLNSA-N terbinafine Chemical compound C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 DOMXUEMWDBAQBQ-WEVVVXLNSA-N 0.000 description 2
- HFVMEOPYDLEHBR-UHFFFAOYSA-N (2-fluorophenyl)-phenylmethanol Chemical compound C=1C=CC=C(F)C=1C(O)C1=CC=CC=C1 HFVMEOPYDLEHBR-UHFFFAOYSA-N 0.000 description 1
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N 1-Heptene Chemical class CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 1
- QISOBCMNUJQOJU-UHFFFAOYSA-N 4-bromo-1h-pyrazole-5-carboxylic acid Chemical compound OC(=O)C=1NN=CC=1Br QISOBCMNUJQOJU-UHFFFAOYSA-N 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- SAIKULLUBZKPDA-UHFFFAOYSA-N Bis(2-ethylhexyl) amine Chemical compound CCCCC(CC)CNCC(CC)CCCC SAIKULLUBZKPDA-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 241000518994 Conta Species 0.000 description 1
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- 206010028980 Neoplasm Diseases 0.000 description 1
- 241000228143 Penicillium Species 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000012871 anti-fungal composition Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 229940049638 carbomer homopolymer type c Drugs 0.000 description 1
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- 239000003795 chemical substances by application Substances 0.000 description 1
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- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
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- 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
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- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- 238000004508 fractional distillation Methods 0.000 description 1
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- 230000008014 freezing Effects 0.000 description 1
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- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 description 1
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- XUGNVMKQXJXZCD-UHFFFAOYSA-N isopropyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- 229960004313 naftifine Drugs 0.000 description 1
- OZGNYLLQHRPOBR-DHZHZOJOSA-N naftifine Chemical compound C=1C=CC2=CC=CC=C2C=1CN(C)C\C=C\C1=CC=CC=C1 OZGNYLLQHRPOBR-DHZHZOJOSA-N 0.000 description 1
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- 150000007524 organic acids Chemical class 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- BWMISRWJRUSYEX-SZKNIZGXSA-N terbinafine hydrochloride Chemical compound Cl.C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 BWMISRWJRUSYEX-SZKNIZGXSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
- A61K8/4946—Imidazoles or their condensed derivatives, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K31/33—Heterocyclic compounds
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
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- 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
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/46—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur
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- 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
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q3/00—Manicure or pedicure preparations
Definitions
- the invention relates to certain methods and compositions for the treatment of onychomycoses (i.e. fungal infections of the toenail or fingernail).
- onychomycoses i.e. fungal infections of the toenail or fingernail.
- Subjects who are immunocompromised are especially susceptible to such infections. Diabetes, drug (e.g. cancer chemotherapy) therapy, AIDS, and other disease states can immunocompromise a subject, and the occurrence of onychomycoses in these groups of people is greater than the population as a whole.
- Griseofiilvin is one oral antifungal agent that is produced by, for example, Penicillium griseofurvum Dierck or Penicillinm jaczewski Zal. (see, e.g. U.S. Patent 3,607,656 to Laine et al., patented Sept. 21, 1971).
- DMSO has been studied to assess how it might influence permeation through the human nail. Walters et al. "Solvent Effects on Nail Permeation", Journal of Pharmacy & Pharmacology. 37:771-775 (1985). DMSO was found to retard permeation rates of model molecules such as methanol and hexanol. Id. A need exists for a once daily, relatively cost-effective therapy for effectively treating toenail or fingernail fungal infections in a way that does not necessarily involve avulsion or debridement of the affected nail or nails.
- an effective treatment for onychomycosis which need not involve avulsion of the nail.
- the treatment involves topically applying an antifungal agent dissolved in a dimethyl sulfoxide solution, on a regular basis, to the nail and to the nail's epinychium.
- the antifungal agent is present in the composition in at least a minimum inhibitory concentration for the antirnycotic agent for the particular fungus when the antifungal agent is dissolved in DMSO.
- the composition is applied to the infected nail and epinychium on a no more than once daily basis, and the infected nail need not necessarily be removed by avulsion or debridement.
- the invention thus includes a method of treating or preventing onychomycosis, associated pharmaceutical compositions for treating or preventing onychomycosis (especially ones conta ing dimethyl sulfoxide and from about 0.1 % to about 10% by weight griseofiilvin), and methods of making the pharmaceutical compositions.
- Antifungal agents include both fungistatic compounds (i.e. such compounds merely inhibit the growth of the fungus without killing it) and fungicidal compounds.
- Specific antifungal agents include flucytosine (also known as 5-fluorocytosine in amounts generally ranging from lmg/ml to lOmg/ml by weight of the composition), griseofiilvin, polyene macrolide antibiotics, especially the heptaenes (e.g.
- amphotericin B the imidazole derivatives such as ticonazole, clotrimazole, econazole, oxiconazole, isoconazole, and miconazole
- imidazole derivatives such as ticonazole, clotrimazole, econazole, oxiconazole, isoconazole, and miconazole
- bifonazole U.S. Patent 4,118,487 to criz et al., patented Oct. 3, 1978
- itraconazole U.S.
- thiocarbamic acid derivatives such as tolnaftate
- terbinafine forms of which are available from Sandoz under the trade designation LAMASIL
- pharmaceutically acceptable salts e.g. acid addition salts
- pharmaceutically acceptable acid addition salts include salts of inorganic acids such as sulfuric, nitric, phosphoric, and preferably hydrochloric acid, as well as organic acids such as acetic, propionic, succinic, fumaric, maleic, citric, tartaric, cinnamic, lactic, mandelic, and ethanedisulfonic acid.
- the salts may be made by reacting the free base of the particular antifungal agent with the chosen acid in a stoichiometric ratio in an appropriate solvent.
- the DMSO to be incorporated into the inventive compositions is preferably of a purified grade (i.e. not a technical grade), which means that it should be sufficiently purified so that it does not cause any untoward reaction or injury to the body of the subject from contaminants and the like.
- a purified grade i.e. not a technical grade
- Various methods of purifying technical grade DMSO are known (see, e.g. U.S. Patent 3,358,036), and include fractional distillation, solvent extraction, and freezing.
- Concentrations of DMSO incorporated into the topical pharmaceutical compositions of the invention will preferably be of greater than 90% (e.g. 100%) strength.
- solutions containing at least about 50 % DMSO along with a minor amount of a pharmaceutically acceptable diluent such as ethanol, n-propanol, isopropanol, propylene glycol, or glycerol.
- solutions containing more than 50% DMSO by weight as a solvent for the composition are "dimethyl sulfoxide solutions”.
- Dimethyl sulfoxide solutions containing greater than 90% DMSO may cause some skin drying and irritation.
- the amount of diluent should be chosen so as not to interfere with the solubility of the particular antifungal agent.
- the dimethyl sulfoxide solution preferably contains, by weight, from 80% to 100% dimethyl sulfoxide.
- Concentrations of the antifungal agents in the composition will of course vary dependent on the antifungal agent and (possibly) salt used. Concentrations will preferably be at least at high as the respective compound or compounds' minimum inhibitory concentration ("MIC") for fungi, and more preferably at least as great as the respective compound or compounds' minimum fungicidal concentration ("MFC”) in DMSO.
- the antifungal compositions will be present in the inventive compositions in an amount varying from 0.1 to 50 weight percent, preferably 1 to 10 weight percent, of the total composition.
- compositions may also contain pharmaceutical necessities such as thickening agents and preservatives.
- the invention also includes the use of the components of the herein described compositions (e.g. dimethyl sulfoxide solution and antimycotic agent or agents) in the manufacture of a medicament for the treatment or prophylaxis of onychomycoses. Once made, the composition may be used to treat or prophylax against onychomycosis.
- a method of treating a fungal infection of a nail, without avulsing the nail includes topically applying to the nail and to the nail's epinychium, on a regular basis (e.g. one to three times a week, although for convenience's sake, it may be applied on a more frequent e.g. daily basis), a composition comprising an antimycotic agent dissolved in a dimethyl sulfoxide solution. The antimycotic agent is present in the composition at an MIC for the antimycotic agent.
- composition may be accomplished by eye-dropper, Q- TrP -like swab, brush (e.g. such as a nail polish brush, aerosol, atomizer, dipping, a nail-sized transdermal drug delivery pad containing the two compounds, and equivalent structure.
- brush e.g. such as a nail polish brush, aerosol, atomizer, dipping, a nail-sized transdermal drug delivery pad containing the two compounds, and equivalent structure.
- the treated area may (but need not) be occluded by subsequent application of a bandage, tape, cotton, or nail cap.
- Prophylaxis will be especially of the nails adjacent to fungally infected nails.
- the composition need not be applied as often (e.g. once to three times a week).
- Typical candidates for prophylaxis include the elderly and patients suffering from HIN, diabetes, peripheral vascular disease, or undergoing immunosuppressive therapy.
- Packaging for the composition will typically include a glass or other inert container for the composition as well as one of the aforementioned applicators and instructions for using the composition either to treat onychomycosis or prevent its occurrence.
- This packaging may further include material to occlude the nail after treatment or prophylaxis.
- EXAMPLE I A composition comprising 660 mg of ultramicrosize griseofiilvin dissolved in 30 ml DMSO was made. 2 tablets of FULNICI ⁇ TM P/G 330 griseofiilvin USP (available from Schering Corporation of Kenilworth, ⁇ J, USA) were ground and dissolved in 30 ml of 99% DMSO. EXAMPLE ⁇
- EXAMPLE I The composition of EXAMPLE I was applied daily to the top of the nail and the epinychium of ten subjects ranging in age from 25 to 70 years old, all of whom were suffering from onychomycoses. Beneficial results were seen in all patients in 3 to 4 weeks. All new nail growth was noted to be fungus-free. No relapses were seen after one year.
- EXAMPLE m A composition comprising 200 mg of fluconazole dissolved in 30 ml DMSO was made. 4 tablets (50 mg each) of DIFLUCANTM fluconazole USP (available from Roerig Division of Pfizer Labs, of New York, NY, USA) were ground and dissolved in 30 ml of DMSO.
- DIFLUCANTM fluconazole USP available from Roerig Division of Pfizer Labs, of New York, NY, USA
- composition of EXAMPLE in was applied daily to the top of the nail and the epinychium of five subjects suffering from onychomycosis. Beneficial results were seen in all patients in three weeks.
- a composition containing 750 mg of flucytosine dissolved in 30 ml DMSO is made by dissolving the contents of three 250 mg capsules of ANCOBONTM flucytosine USP (available from Roche Labs, of Nutley, NJ, USA) into 30 ml of DMSO (density 1.0955 g/ml).
- EXAMPLE VI A composition containing 200 mg of amphotericin B dissolved in 30 ml DMSO is made by dissolving the already lyophilized contents of 4 vials of FUNGIZONETM Intravenous amphotericin B USP (available from Apothecon of Princeton, NJ, USA) in 30 ml of DMSO.
- EXAMPLE VH A composition containing 200 mg of itraconazole dissolved in 30 ml DMSO is made by dissolving the contents of two 100 mg capsules of SPORANAXTM itraconazole USP (available from Janssen Pharmaceutica of Titusville, NJ, USA) into 30 ml of DMSO.
- EXAMPLE VIE A composition containing 400 mg of ketoconazole dissolved in 30 ml DMSO is made by crushing two 200 mg tablets of NIZORALTM ketoconazole USP (available from Janssen Pharmaceutica of Titusville, NJ, USA) and dissolving the crushed tablets into 30 ml of DMSO.
- EXAMPLE LX A composition containing 1000 mg of clotrimazole dissolved in 30 ml DMSO is made by dissolving 1000 mg of clotrimazole USP into 30 ml of DMSO.
- EXAMPLE X The composition of EXAMPLE Vm is placed into a brown glass bottle having a brush associated with its lid. Instructions for once daily use of the composition are included on a label associated with the bottle.
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Abstract
An effective treatment and prophylaxis for onychomycosis is described involving the regular topical application of an antifungal agent dissolved in a dimethyl sulfoxide solution to the nail and to the nail's epinychium. The antifungal agent is present in the composition in at least a minimum inhibitory concentration for the antimycotic agent for the particular fungus when the antifungal agent is dissolved in DMSO. The composition may be applied to the nail and epinychium on a daily or less frequent basis, and the infected nail need not be removed. Also described are methods of treating or preventing onychomycosis, associated pharmaceutical compositions for treating or preventing onychomycosis (especially ones containing dimethyl sulfoxide and from 2 to 10 % by weight griseofulvin), and methods of making the pharmaceutical compositions.
Description
TOPICAL ANTI YCOTIC COMPOSITIONS
Technical Field. The invention relates to certain methods and compositions for the treatment of onychomycoses (i.e. fungal infections of the toenail or fingernail).
Background Art. Fungal infections of the fingernails and toenails are a bane to the person who suffers from them. The infection variably spreads from nail to nail. The infection is unsightly, and, in some instances, it evolves from a superficial infection of the nails to a life-threatening systemic infection. It can also lead to secondary bacterial" infections. Occasionally the person's leg needs to be amputated.
Subjects who are immunocompromised are especially susceptible to such infections. Diabetes, drug (e.g. cancer chemotherapy) therapy, AIDS, and other disease states can immunocompromise a subject, and the occurrence of onychomycoses in these groups of people is greater than the population as a whole.
Current treatment usually involves completely removing ("avulsing") the affected nail, and treating the patient with oral antifungal agents ("antifungals or antimycotics"). However this treatment is believed to have nearly a 100% relapse rate within five years.
Griseofiilvin is one oral antifungal agent that is produced by, for example, Penicillium griseofurvum Dierck or Penicillinm jaczewski Zal. (see, e.g. U.S. Patent 3,607,656 to Laine et al., patented Sept. 21, 1971).
Topical compositions containing griseofiilvin have been described. For example, U.S. Patent 3,524,916 to Mima et al. (Aug. 18. 1970) describes griseofiilvin dissolved in ethylene glycol monosalicylate solution for treating athlete's foot, by topically applying the solution. U.S. Patent 3,899,578 to Bird et al. (Aug. 12, 1975) describes a topical griseofiilvin composition for treating fungal skin infections comprising, for example, griseofiilvin, dimethyl phthalate, and benzyl alcohol. U.S. Patents 3,932,653 (Jan. 13, 1976) and 4,039,664 (Aug. 2, 1977) both to Stoughton et al. describe methods for topically administering griseofiilvin to a human. U.S. Patent 3,981,996 to Leigh (Sept. 21, 1976) describes a skin cream having a continuous hydrophobic medium in which there is dispersed
an inert water-insoluble powder, the particles of which carry absorbed thereon an aqueous solution or dispersion of medicament emulsion.
For treating onychomycoses specifically, unspecified solutions of unspecified antimycotic agents are mentioned in U.S. Patent 5,263,206 to Bonn et al. (Nov. 23, 1993). However these solutions are described as requiring application to the nails several times a day. Furthermore the treatment associated with these solutions was also described as including applications of dressings at night. Such therapy is difficult for someone to follow, and this therapy is described as being unsuccessful. A gel containing dimethyl sulfoxide ("DMSO"), urea, ethanol, water, isopropyl palmitate, carbomer-940, di(2-ethylhexyl)amine, and griseofiilvin is disclosed in EXAMPLE 17 of U.S. Patent 4,296,104 to Herschler (Oct. 20, 1981). Methods of treating toenails and fingernails with undergrowing fungal infections are described in EXAMPLES 14 through 20 of this U.S. patent. In all of the described methods however, the affected nails were removed (e.g. by forcep urging) during the treatment with the DMSO containing composition.
Under the best of circumstances, having one's fingernail or toenail removed is not a pleasant experience. The removal can be painful. The sensitive skin underlying the nail is left exposed and unprotected until the fingernail or toenail grows back. When the nail finally does grow back, no guarantee exists that it will not be deformed.
DMSO has been studied to assess how it might influence permeation through the human nail. Walters et al. "Solvent Effects on Nail Permeation", Journal of Pharmacy & Pharmacology. 37:771-775 (1985). DMSO was found to retard permeation rates of model molecules such as methanol and hexanol. Id. A need exists for a once daily, relatively cost-effective therapy for effectively treating toenail or fingernail fungal infections in a way that does not necessarily involve avulsion or debridement of the affected nail or nails.
Disclosure of Invention Surprisingly, an effective treatment for onychomycosis which need not involve avulsion of the nail. The treatment involves topically applying an antifungal agent dissolved in a dimethyl sulfoxide solution, on a regular basis, to the nail and to the nail's epinychium. The antifungal agent is present in the composition in at
least a minimum inhibitory concentration for the antirnycotic agent for the particular fungus when the antifungal agent is dissolved in DMSO. The composition is applied to the infected nail and epinychium on a no more than once daily basis, and the infected nail need not necessarily be removed by avulsion or debridement. The invention thus includes a method of treating or preventing onychomycosis, associated pharmaceutical compositions for treating or preventing onychomycosis (especially ones conta ing dimethyl sulfoxide and from about 0.1 % to about 10% by weight griseofiilvin), and methods of making the pharmaceutical compositions.
Best Mode for Carrying Out the Invention Antifungal agents, as used herein, include both fungistatic compounds (i.e. such compounds merely inhibit the growth of the fungus without killing it) and fungicidal compounds. Specific antifungal agents include flucytosine (also known as 5-fluorocytosine in amounts generally ranging from lmg/ml to lOmg/ml by weight of the composition), griseofiilvin, polyene macrolide antibiotics, especially the heptaenes (e.g. amphotericin B), the imidazole derivatives such as ticonazole, clotrimazole, econazole, oxiconazole, isoconazole, and miconazole (see, e.g. U.S. Patent 3,717,655 to Godefroi et al., patented Feb. 20, 1973 and U.S. Patent 3,839,574 also to Godefroi et al., patented Oct. 1, 1974), bifonazole (U.S. Patent 4,118,487 to Regel et al., patented Oct. 3, 1978), itraconazole (U.S. Patent 4,267,179 to Heeres et al., patented May 12, 1981), naftifine (U.S. Patent 4,282,251 to Berney, patented Aug. 4, 1981), ketoconazole (U.S. Patent 4,335,125 to Heeres et al., patented June 15, 1982), ketoconazole derivatives (U.S. Patent 4,789,587 to Le Clef et al., patented Dec. 6, 1988), fluconazole (U.S. Patent 4,404,216 to Richardson, patented Sep. 13, 1983), thiocarbamic acid derivatives (such as tolnaftate), terbinafine (forms of which are available from Sandoz under the trade designation LAMASIL), and the pharmaceutically acceptable salts (e.g. acid addition salts) thereof. Examples of pharmaceutically acceptable acid addition salts include salts of inorganic acids such as sulfuric, nitric, phosphoric, and preferably hydrochloric acid, as well as organic acids such as acetic, propionic, succinic, fumaric, maleic, citric, tartaric, cinnamic, lactic, mandelic, and ethanedisulfonic acid. The salts may
be made by reacting the free base of the particular antifungal agent with the chosen acid in a stoichiometric ratio in an appropriate solvent.
The DMSO to be incorporated into the inventive compositions is preferably of a purified grade (i.e. not a technical grade), which means that it should be sufficiently purified so that it does not cause any untoward reaction or injury to the body of the subject from contaminants and the like. Various methods of purifying technical grade DMSO are known (see, e.g. U.S. Patent 3,358,036), and include fractional distillation, solvent extraction, and freezing.
Concentrations of DMSO incorporated into the topical pharmaceutical compositions of the invention will preferably be of greater than 90% (e.g. 100%) strength. However, also of use are solutions containing at least about 50 % DMSO along with a minor amount of a pharmaceutically acceptable diluent, such as ethanol, n-propanol, isopropanol, propylene glycol, or glycerol. As used herein, solutions containing more than 50% DMSO by weight as a solvent for the composition are "dimethyl sulfoxide solutions". Dimethyl sulfoxide solutions containing greater than 90% DMSO may cause some skin drying and irritation. The amount of diluent should be chosen so as not to interfere with the solubility of the particular antifungal agent. The dimethyl sulfoxide solution preferably contains, by weight, from 80% to 100% dimethyl sulfoxide. Concentrations of the antifungal agents in the composition will of course vary dependent on the antifungal agent and (possibly) salt used. Concentrations will preferably be at least at high as the respective compound or compounds' minimum inhibitory concentration ("MIC") for fungi, and more preferably at least as great as the respective compound or compounds' minimum fungicidal concentration ("MFC") in DMSO. As a general statement, the antifungal compositions will be present in the inventive compositions in an amount varying from 0.1 to 50 weight percent, preferably 1 to 10 weight percent, of the total composition.
The compositions may also contain pharmaceutical necessities such as thickening agents and preservatives. The invention also includes the use of the components of the herein described compositions (e.g. dimethyl sulfoxide solution and antimycotic agent or agents) in the manufacture of a medicament for the treatment or prophylaxis of onychomycoses.
Once made, the composition may be used to treat or prophylax against onychomycosis. A method of treating a fungal infection of a nail, without avulsing the nail, includes topically applying to the nail and to the nail's epinychium, on a regular basis (e.g. one to three times a week, although for convenience's sake, it may be applied on a more frequent e.g. daily basis), a composition comprising an antimycotic agent dissolved in a dimethyl sulfoxide solution. The antimycotic agent is present in the composition at an MIC for the antimycotic agent.
Application of the composition may be accomplished by eye-dropper, Q- TrP -like swab, brush (e.g. such as a nail polish brush, aerosol, atomizer, dipping, a nail-sized transdermal drug delivery pad containing the two compounds, and equivalent structure.
Afterwards, the treated area may (but need not) be occluded by subsequent application of a bandage, tape, cotton, or nail cap.
Prophylaxis, according to the invention, will be especially of the nails adjacent to fungally infected nails. Typically for prophylaxis, the composition need not be applied as often (e.g. once to three times a week). Typical candidates for prophylaxis include the elderly and patients suffering from HIN, diabetes, peripheral vascular disease, or undergoing immunosuppressive therapy.
Packaging for the composition will typically include a glass or other inert container for the composition as well as one of the aforementioned applicators and instructions for using the composition either to treat onychomycosis or prevent its occurrence. This packaging may further include material to occlude the nail after treatment or prophylaxis.
The invention is further explained by the following illustrative EXAMPLES:
EXAMPLES
EXAMPLE I A composition comprising 660 mg of ultramicrosize griseofiilvin dissolved in 30 ml DMSO was made. 2 tablets of FULNICIΝ™ P/G 330 griseofiilvin USP (available from Schering Corporation of Kenilworth, ΝJ, USA) were ground and dissolved in 30 ml of 99% DMSO.
EXAMPLE Π
The composition of EXAMPLE I was applied daily to the top of the nail and the epinychium of ten subjects ranging in age from 25 to 70 years old, all of whom were suffering from onychomycoses. Beneficial results were seen in all patients in 3 to 4 weeks. All new nail growth was noted to be fungus-free. No relapses were seen after one year.
EXAMPLE m A composition comprising 200 mg of fluconazole dissolved in 30 ml DMSO was made. 4 tablets (50 mg each) of DIFLUCAN™ fluconazole USP (available from Roerig Division of Pfizer Labs, of New York, NY, USA) were ground and dissolved in 30 ml of DMSO.
EXAMPLE IV
The composition of EXAMPLE in was applied daily to the top of the nail and the epinychium of five subjects suffering from onychomycosis. Beneficial results were seen in all patients in three weeks.
EXAMPLE V
A composition containing 750 mg of flucytosine dissolved in 30 ml DMSO is made by dissolving the contents of three 250 mg capsules of ANCOBON™ flucytosine USP (available from Roche Labs, of Nutley, NJ, USA) into 30 ml of DMSO (density 1.0955 g/ml).
EXAMPLE VI A composition containing 200 mg of amphotericin B dissolved in 30 ml DMSO is made by dissolving the already lyophilized contents of 4 vials of FUNGIZONE™ Intravenous amphotericin B USP (available from Apothecon of Princeton, NJ, USA) in 30 ml of DMSO.
EXAMPLE VH A composition containing 200 mg of itraconazole dissolved in 30 ml DMSO is made by dissolving the contents of two 100 mg capsules of SPORANAX™ itraconazole USP (available from Janssen Pharmaceutica of Titusville, NJ, USA) into 30 ml of DMSO.
EXAMPLE VIE A composition containing 400 mg of ketoconazole dissolved in 30 ml DMSO is made by crushing two 200 mg tablets of NIZORAL™ ketoconazole USP (available from Janssen Pharmaceutica of Titusville, NJ, USA) and dissolving the crushed tablets into 30 ml of DMSO.
EXAMPLE LX A composition containing 1000 mg of clotrimazole dissolved in 30 ml DMSO is made by dissolving 1000 mg of clotrimazole USP into 30 ml of DMSO.
EXAMPLE X The composition of EXAMPLE Vm is placed into a brown glass bottle having a brush associated with its lid. Instructions for once daily use of the composition are included on a label associated with the bottle.
Although the invention has been described with the use of various examples and preferred embodiments, these are illustrative only, and the scope of the invention is to be determined by the appended claims.
Claims
1. A method of manufacturing a medicament for treatment of a fungal infection of a nail without avulsing the nail, said treatment comprising: topically applying to the nail and to an epinychium associated with the nail, on a regular basis, a composition comprising an antimycotic agent dissolved in a dimethyl sulfoxide solution, said antimycotic agent being present in said composition in at least a minimum inhibitory concentration for the antimycotic agent.
2. The method according to claim 1 wherein the dimethyl sulfoxide solution contains, by weight, from 80% to 100% by weight dimethyl sulfoxide.
3. The method according to claim 1 wherein the composition is applied to the nail and the associated epinychium on a no more than once daily basis.
4. The method according to claim 3 wherein the composition is applied to the nail and the associated epinychium on a daily basis.
5. The method according to claim 1 wherein the antimycotic agent is selected from the group consisting of griseofiilvin, amphotericin B, ketoconazole, derivatives thereof, and mixtures thereof.
6. The method according to claim 1 further comprising occluding the nail after application of the composition.
7. A pharmaceutical composition comprising an effective amount of an antifungal agent selected from the group consisting of flucytosine, non-heptaene polyene macrolide antibiotics, ticonazole, clotrimazole, econazole, oxiconazole, isoconazole, miconazole, bifonazole, itraconazole, fluconazole, thiocarbamic acid derivatives, terijmafine, mixtures thereof, and the pharmaceutically acceptable salts and derivatives thereof dissolved in a dimethyl sulfoxide solution.
8. The pharmaceutical composition of claim 7 wherein the dimethyl sulfoxide solution contains, by weight, greater than 90% dimethyl sulfoxide.
9. The pharmaceutical composition of claim 7 wherein the antifungal agent is present in an amount greater than one milligram per milliliter of dimethyl sulfoxide solution.
10. The pharmaceutical composition of claim 7 further comprising a diluent selected from the group consisting of ethanol, n-propanol, isopropanol, propylene glycol, and glycerol.
11. A topical pharmaceutical composition comprising dimethyl sulfoxide and griseofulvin, said griseofiilvin being present in a concentration of 2% to about 10% by weight of said topical pharmaceutical composition.
12. The topical pharmaceutical composition of claim 11 wherein said griseofulvin is present in an amount of 2 % to 3 % by weight.
13. A combination comprising the pharmaceutical composition of claim 7, packaging for said pharmaceutical composition, said packaging including an exterior surface inscribed with instructions specifying that the pharmaceutical composition is to be applied topically to a nail infected with a fungus, and the nail's epinychium on a regular basis and an applicator.
14. A method of preventing a fungal infection in a nail, said method comprising: topically applying to the nail and an epinychium associated with the nail, on a weekly or more frequent basis, a composition comprising an antimycotic agent dissolved in a dimethyl sulfoxide solution, said antimycotic agent being present in said composition in at least a minimum fiingicidal concentration.
15. The method according to claim 14 wherein the dimethyl sulfoxide solution contains, by weight, from 80% to 100% by weight dimethyl sulfoxide.
16. The method according to claim 14 wherein the composition is applied to the nail and the associated epinychium on a no more than once weekly basis.
17. The method according to claim 14 wherein the antimycotic agent is selected from the group consisting of griseofulvin, amphotericin B, ketoconazole, derivatives thereof, and mixtures thereof.
18. The method according to claim 1 further comprising occluding the nail after applying the composition.
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US41363695A | 1995-03-30 | 1995-03-30 | |
US413,636 | 1995-03-30 |
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Cited By (6)
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GR980100028A (en) * | 1998-01-15 | 1999-09-30 | Drug Research Hellas ����� | Pharmaceutical products for local use containing fluconazole in concentrations between 0.2 % and 5 % |
WO2009071959A2 (en) * | 2007-12-04 | 2009-06-11 | Pannonpharma Gyógyszergyártó Kft. | A composition in the form of a paint tincture or lacquer to treat fungal infections containing itraconazole and a process for the preparation thereof |
US10105444B2 (en) | 2010-07-08 | 2018-10-23 | Dow Pharmaceutical Sciences, Inc. | Compositions and methods for treating diseases of the nail |
US10245257B2 (en) | 2013-11-22 | 2019-04-02 | Dow Pharmaceutical Sciences, Inc. | Anti-infective methods, compositions, and devices |
US10342875B2 (en) | 2013-10-03 | 2019-07-09 | Dow Pharmaceutical Sciences, Inc. | Stabilized efinaconazole compositions |
US10512640B2 (en) | 2008-01-03 | 2019-12-24 | Dow Pharmaceutical Sciences, Inc. | Compositions and methods for treating diseases of the nail |
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US5264206A (en) * | 1987-06-16 | 1993-11-23 | Hoechst Aktiengesellschaft | Nail lacquer with antimycotic activity, and a process for the preparation thereof |
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US5264206A (en) * | 1987-06-16 | 1993-11-23 | Hoechst Aktiengesellschaft | Nail lacquer with antimycotic activity, and a process for the preparation thereof |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GR980100028A (en) * | 1998-01-15 | 1999-09-30 | Drug Research Hellas ����� | Pharmaceutical products for local use containing fluconazole in concentrations between 0.2 % and 5 % |
WO2009071959A2 (en) * | 2007-12-04 | 2009-06-11 | Pannonpharma Gyógyszergyártó Kft. | A composition in the form of a paint tincture or lacquer to treat fungal infections containing itraconazole and a process for the preparation thereof |
WO2009071959A3 (en) * | 2007-12-04 | 2009-11-26 | Pannonpharma Gyógyszergyártó Kft. | Composition containing itraconazole |
US10512640B2 (en) | 2008-01-03 | 2019-12-24 | Dow Pharmaceutical Sciences, Inc. | Compositions and methods for treating diseases of the nail |
US11872218B2 (en) | 2008-01-03 | 2024-01-16 | Bausch Health Ireland Limited | Compositions and methods for treating diseases of the nail |
US11213519B2 (en) | 2008-01-03 | 2022-01-04 | Bausch Health Ireland Limited | Compositions and methods for treating diseases of the nail |
US10105444B2 (en) | 2010-07-08 | 2018-10-23 | Dow Pharmaceutical Sciences, Inc. | Compositions and methods for treating diseases of the nail |
US10828369B2 (en) | 2010-07-08 | 2020-11-10 | Dow Pharmaceutical Sciences, Inc. | Compositions and methods for treating diseases of the nail |
US10864274B2 (en) | 2013-10-03 | 2020-12-15 | Bausch Health Ireland Limited | Stabilized efinaconazole formulations |
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US11654139B2 (en) | 2013-11-22 | 2023-05-23 | Bausch Health Ireland Limited | Anti-infective methods, compositions, and devices |
US10245257B2 (en) | 2013-11-22 | 2019-04-02 | Dow Pharmaceutical Sciences, Inc. | Anti-infective methods, compositions, and devices |
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