MXPA00009631A - An acidified composition for topical treatment of nail and skin conditions - Google Patents
An acidified composition for topical treatment of nail and skin conditionsInfo
- Publication number
- MXPA00009631A MXPA00009631A MXPA/A/2000/009631A MXPA00009631A MXPA00009631A MX PA00009631 A MXPA00009631 A MX PA00009631A MX PA00009631 A MXPA00009631 A MX PA00009631A MX PA00009631 A MXPA00009631 A MX PA00009631A
- Authority
- MX
- Mexico
- Prior art keywords
- active agent
- nail
- hcl
- acidified
- group
- Prior art date
Links
- 210000000282 Nails Anatomy 0.000 title claims abstract description 193
- 239000000203 mixture Substances 0.000 title claims abstract description 171
- 210000003491 Skin Anatomy 0.000 title claims abstract description 83
- 230000000699 topical Effects 0.000 title abstract description 20
- 239000003814 drug Substances 0.000 claims description 136
- 239000003795 chemical substances by application Substances 0.000 claims description 73
- 239000002966 varnish Substances 0.000 claims description 67
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 61
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 57
- 239000002904 solvent Substances 0.000 claims description 56
- 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 claims description 49
- 229960005040 Miconazole Nitrate Drugs 0.000 claims description 49
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 48
- 229920000642 polymer Polymers 0.000 claims description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 37
- 235000019441 ethanol Nutrition 0.000 claims description 32
- -1 traconazole Chemical compound 0.000 claims description 28
- VHVPQPYKVGDNFY-TUJWMRSMSA-N 2-[(2S)-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-TUJWMRSMSA-N 0.000 claims description 22
- 229960004308 ACETYLCYSTEINE Drugs 0.000 claims description 22
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 claims description 22
- 229960004130 itraconazole Drugs 0.000 claims description 22
- 201000010099 disease Diseases 0.000 claims description 21
- 239000000443 aerosol Substances 0.000 claims description 20
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 20
- 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 18
- 229960004022 clotrimazole Drugs 0.000 claims description 18
- 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 18
- 239000003429 antifungal agent Substances 0.000 claims description 16
- 229960002509 miconazole Drugs 0.000 claims description 16
- 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 claims description 14
- 239000002535 acidifier Substances 0.000 claims description 14
- 229960002722 terbinafine Drugs 0.000 claims description 14
- XMAYWYJOQHXEEK-OZXSUGGESA-N 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 12
- 229920001577 copolymer Polymers 0.000 claims description 12
- 229960004125 ketoconazole Drugs 0.000 claims description 12
- CERQOIWHTDAKMF-UHFFFAOYSA-N methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 12
- 229920000058 polyacrylate Polymers 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 239000011780 sodium chloride Substances 0.000 claims description 12
- LEZWWPYKPKIXLL-UHFFFAOYSA-N Econazole Chemical compound C1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 LEZWWPYKPKIXLL-UHFFFAOYSA-N 0.000 claims description 11
- 229960003913 Econazole Drugs 0.000 claims description 11
- ZFMITUMMTDLWHR-UHFFFAOYSA-N Loniten Chemical compound NC1=[N+]([O-])C(N)=CC(N2CCCCC2)=N1 ZFMITUMMTDLWHR-UHFFFAOYSA-N 0.000 claims description 11
- 229960003632 Minoxidil Drugs 0.000 claims description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 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 description 7
- 150000002148 esters Chemical class 0.000 claims description 7
- 229960002867 griseofulvin Drugs 0.000 claims description 7
- ABJKWBDEJIDSJZ-UHFFFAOYSA-N Butenafine Chemical compound C=1C=CC2=CC=CC=C2C=1CN(C)CC1=CC=C(C(C)(C)C)C=C1 ABJKWBDEJIDSJZ-UHFFFAOYSA-N 0.000 claims description 6
- 229960002433 Cysteine Drugs 0.000 claims description 6
- XUJNEKJLAYXESH-REOHCLBHSA-N L-cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 6
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 6
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 6
- 229960002962 butenafine Drugs 0.000 claims description 6
- 235000018417 cysteine Nutrition 0.000 claims description 6
- AEMRFAOFKBGASW-UHFFFAOYSA-N glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 6
- OEOLOEUAGSPDLT-UHFFFAOYSA-N (2,6-diamino-4-piperidin-1-ylpyrimidin-1-ium-1-yl) sulfate Chemical compound NC1=[N+](OS([O-])(=O)=O)C(N)=CC(N2CCCCC2)=N1 OEOLOEUAGSPDLT-UHFFFAOYSA-N 0.000 claims description 5
- MQHLMHIZUIDKOO-AYHJJNSGSA-N Amorolfine Chemical compound C1=CC(C(C)(C)CC)=CC=C1CC(C)CN1C[C@@H](C)O[C@@H](C)C1 MQHLMHIZUIDKOO-AYHJJNSGSA-N 0.000 claims description 5
- 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 5
- 229960003204 amorolfine Drugs 0.000 claims description 5
- 229960004884 fluconazole Drugs 0.000 claims description 5
- 229960000841 minoxidil sulfate Drugs 0.000 claims description 5
- 239000011118 polyvinyl acetate Substances 0.000 claims description 5
- 229920002689 polyvinyl acetate Polymers 0.000 claims description 5
- 229960003071 Bacitracin Drugs 0.000 claims description 4
- 108010001478 Bacitracin Proteins 0.000 claims description 4
- 229960001950 Benzethonium Chloride Drugs 0.000 claims description 4
- UREZNYTWGJKWBI-UHFFFAOYSA-M Benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 claims description 4
- 229920002301 Cellulose acetate Polymers 0.000 claims description 4
- SCKYRAXSEDYPSA-UHFFFAOYSA-N Ciclopirox Chemical compound ON1C(=O)C=C(C)C=C1C1CCCCC1 SCKYRAXSEDYPSA-UHFFFAOYSA-N 0.000 claims description 4
- MINDHVHHQZYEEK-HBBNESRFSA-N MUPIROCIN Chemical compound C[C@H](O)[C@H](C)[C@@H]1O[C@H]1C[C@@H]1[C@@H](O)[C@@H](O)[C@H](C\C(C)=C\C(=O)OCCCCCCCCC(O)=O)OC1 MINDHVHHQZYEEK-HBBNESRFSA-N 0.000 claims description 4
- 229960003128 Mupirocin Drugs 0.000 claims description 4
- PGBHMTALBVVCIT-VCIWKGPPSA-N Neomycin Chemical compound N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CN)O2)N)O[C@@H]1CO PGBHMTALBVVCIT-VCIWKGPPSA-N 0.000 claims description 4
- 229940053050 Neomycin Sulfate Drugs 0.000 claims description 4
- 108010093965 Polymyxin B Proteins 0.000 claims description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 4
- XEFQLINVKFYRCS-UHFFFAOYSA-N Triclosan Chemical compound OC1=CC(Cl)=CC=C1OC1=CC=C(Cl)C=C1Cl XEFQLINVKFYRCS-UHFFFAOYSA-N 0.000 claims description 4
- FRPZMMHWLSIFAZ-UHFFFAOYSA-N Undecylenic acid Chemical compound OC(=O)CCCCCCCCC=C FRPZMMHWLSIFAZ-UHFFFAOYSA-N 0.000 claims description 4
- CLKOFPXJLQSYAH-ABRJDSQDSA-N bacitracin A Chemical compound C1SC([C@@H](N)[C@@H](C)CC)=N[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]1C(=O)N[C@H](CCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2N=CNC=2)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCCCC1 CLKOFPXJLQSYAH-ABRJDSQDSA-N 0.000 claims description 4
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims description 4
- 229960002685 biotin Drugs 0.000 claims description 4
- 235000020958 biotin Nutrition 0.000 claims description 4
- 239000011616 biotin Substances 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 4
- 229960004313 naftifine Drugs 0.000 claims description 4
- 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 claims description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 229960005266 polymyxin B Drugs 0.000 claims description 4
- 229920000024 polymyxin B Polymers 0.000 claims description 4
- 229960004880 tolnaftate Drugs 0.000 claims description 4
- 229960003500 triclosan Drugs 0.000 claims description 4
- 229960002703 undecylenic acid Drugs 0.000 claims description 4
- VQOXZBDYSJBXMA-NQTDYLQESA-N (1S,3R,4E,6E,8E,10E,14E,16E,18S,19R,20R,21S,25R,27R,29R,32R,33R,35S,37S,38R)-3-[(2R,3S,4S,5S,6R)-4-amino-3,5-dihydroxy-6-methyloxan-2-yl]oxy-19,25,27,29,32,33,35,37-octahydroxy-18,20,21-trimethyl-23-oxo-22,39-dioxabicyclo[33.3.1]nonatriaconta-4,6,8,10,14, 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/CC/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)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 claims description 3
- SVDOODSCHVSYEK-IFLJXUKPSA-N (4S,4aR,5S,5aR,6S,12aR)-4-(dimethylamino)-1,5,6,10,11,12a-hexahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide;hydron;chloride Chemical compound Cl.C1=CC=C2[C@](O)(C)[C@H]3[C@H](O)[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O SVDOODSCHVSYEK-IFLJXUKPSA-N 0.000 claims description 3
- YCIHPQHVWDULOY-FMZCEJRJSA-N (4S,4aS,5aS,6S,12aR)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide;hydrochloride Chemical compound Cl.C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O YCIHPQHVWDULOY-FMZCEJRJSA-N 0.000 claims description 3
- AFNXATANNDIXLG-SFHVURJKSA-N 1-[(2R)-2-[(4-chlorophenyl)methylsulfanyl]-2-(2,4-dichlorophenyl)ethyl]imidazole Chemical compound C1=CC(Cl)=CC=C1CS[C@H](C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 AFNXATANNDIXLG-SFHVURJKSA-N 0.000 claims description 3
- HUADITLKOCMHSB-AVQIMAJZSA-N 2-butan-2-yl-4-[4-[4-[4-[[(2S,4R)-2-(2,4-difluorophenyl)-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(C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3O[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 HUADITLKOCMHSB-AVQIMAJZSA-N 0.000 claims description 3
- 229940025660 Anthralin Drugs 0.000 claims description 3
- 229960000686 Benzalkonium Chloride Drugs 0.000 claims description 3
- SWLMUYACZKCSHZ-UHFFFAOYSA-N Butoconazole Chemical compound C1=CC(Cl)=CC=C1CCC(SC=1C(=CC=CC=1Cl)Cl)CN1C=NC=C1 SWLMUYACZKCSHZ-UHFFFAOYSA-N 0.000 claims description 3
- LWQQLNNNIPYSNX-UROSTWAQSA-N Calcipotriol Chemical compound C1([C@H](O)/C=C/[C@@H](C)[C@@H]2[C@]3(CCCC(/[C@@H]3CC2)=C\C=C\2C([C@@H](O)C[C@H](O)C/2)=C)C)CC1 LWQQLNNNIPYSNX-UROSTWAQSA-N 0.000 claims description 3
- 229940064701 Corticosteroid nasal preparations for topical use Drugs 0.000 claims description 3
- 229960001334 Corticosteroids Drugs 0.000 claims description 3
- NUZWLKWWNNJHPT-UHFFFAOYSA-N Dithranol Chemical compound C1C2=CC=CC(O)=C2C(=O)C2=C1C=CC=C2O NUZWLKWWNNJHPT-UHFFFAOYSA-N 0.000 claims description 3
- DBEPLOCGEIEOCV-WSBQPABSSA-N Finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 claims description 3
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 claims description 3
- RWSXRVCMGQZWBV-WDSKDSINSA-N Glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 claims description 3
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- 229960003258 Hexylresorcinol Drugs 0.000 claims description 3
- WFJIVOKAWHGMBH-UHFFFAOYSA-N Hexylresorcinol Chemical compound CCCCCCC1=CC=C(O)C=C1O WFJIVOKAWHGMBH-UHFFFAOYSA-N 0.000 claims description 3
- 229960004452 Methionine Drugs 0.000 claims description 3
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- 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 3
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- UFUVLHLTWXBHGZ-MGZQPHGTSA-N [(2R,3R,4S,5R,6R)-6-[(1S,2S)-2-chloro-1-[[(2S,4R)-1-methyl-4-propylpyrrolidine-2-carbonyl]amino]propyl]-4,5-dihydroxy-2-methylsulfanyloxan-3-yl] dihydrogen phosphate Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](OP(O)(O)=O)[C@@H](SC)O1 UFUVLHLTWXBHGZ-MGZQPHGTSA-N 0.000 claims description 3
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- HZAXFHJVJLSVMW-UHFFFAOYSA-N ethanolamine Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 3
- VEVFSWCSRVJBSM-HOFKKMOUSA-N ethyl 4-[4-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OCC)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 VEVFSWCSRVJBSM-HOFKKMOUSA-N 0.000 claims description 3
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- 229960002518 gentamicin Drugs 0.000 claims description 3
- RTIAQOLKVLAEAU-UHFFFAOYSA-N hexan-3-yl acetate Chemical compound CCCC(CC)OC(C)=O RTIAQOLKVLAEAU-UHFFFAOYSA-N 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- 229960000988 nystatin Drugs 0.000 claims description 3
- 229960003483 oxiconazole Drugs 0.000 claims description 3
- 229960003742 phenol Drugs 0.000 claims description 3
- 229960002607 sulconazole Drugs 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 3
- 229960000580 terconazole Drugs 0.000 claims description 3
- 229960004989 tetracycline hydrochloride Drugs 0.000 claims description 3
- 229940083878 topical for treatment of hemorrhoids and anal fissures Corticosteroids Drugs 0.000 claims description 3
- QYAPHLRPFNSDNH-LYNLVHCPSA-N (4S,4aS,6S,12aR)-7-chloro-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide;hydrochloride Chemical compound Cl.C1=CC(Cl)=C2[C@](O)(C)C3C[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O QYAPHLRPFNSDNH-LYNLVHCPSA-N 0.000 claims description 2
- CATSNJVOTSVZJV-UHFFFAOYSA-N 2-Heptanone Chemical compound CCCCCC(C)=O CATSNJVOTSVZJV-UHFFFAOYSA-N 0.000 claims description 2
- 229920002284 Cellulose triacetate Polymers 0.000 claims description 2
- 229960003185 Chlortetracycline Hydrochloride Drugs 0.000 claims description 2
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Abstract
This invention relates to a method for topical treatment of human nail and skin diseases, including fungal infections, bacterial infections, and psoriatic infections. In addition, this invention relates to a method of treating the general condition of human nails including their strength, rate of growth and appearance. More particularly, the invention relates to an acidified composition and methods of using said composition. Still further the invention relates to an acidified lacquer useful in treating human nails and skin.
Description
ACIDIFIED COMPOSITION FOR THE TOPICAL TREATMENT OF NAIL AND SKIN CONDITIONS
FIELD OF THE INVENTION
This invention relates to a method for the topical treatment of human nail and skin diseases, including fungal infections, bacterial infections and psoriatic infections. Furthermore, this invention relates to a method for treating the general condition of human nails including their resistance, growth rate and appearance. More particularly, the invention relates to an acidified composition and methods for using said composition. In addition, the invention relates to an acidified lacquer useful for treating human nails and skin.
BACKGROUND OF THE INVENTION
Onychomycosis is a fungal disease of human nails. The symptoms of this disease are separated nail plates, thickened, hardened and rough. This is caused by any of a number of organisms and is particularly prevalent in the elderly. Fungal infections are typically treated by the topical application of antifungal agents and / or oral administration of antifungal agents. Unlike other fungal infections, there is no topical treatment for onychomycosis that has been approved by the United States Food and Drug Administration. It is desirable to treat this disease topically because of the potential for side effects that have been associated with some of the oral treatment regimens. One reason for the absence of a topical treatment is that in this disease, the symptomatic thickened nail plate prevents topical agents from reaching the site of infection. The target sites for the treatment of onychomycosis reside in the nail plate, nail bed and nail matrix, as described in figure 1. It has been shown that if the barrier the nail is modified, reduces or eliminates , topical treatment with antifungal drugs is effective to stop onychomycosis. For example, both miconazole and ketoconazole have been shown to be effective in treating topical onychomycosis after the removal of the nail. However, many consumers would certainly prefer a less dramatic treatment for fungal infections of the nails than the removal of the nail. The nail plate is thick, hard, dense and represents a formidable barrier for drugs to be able to penetrate a therapeutically necessary amount. Although the material of the nails is similar to the stratum corneum of the skin, which derives from the epidermis, it is mainly composed of hard keratin, which is highly disulfide-bound, and is approximately 100 times thicker than the stratum corneum. In order to be able to deliver a sufficient amount of drug within the nail plate, the permeability of the nail plate to the drug must be increased. This is particularly true in fungal diseases in which a thickened nail plate is a common symptom of the disease. In a study of onychomycosis, the small toenails of the patients measured 5 mm and the nails of the large toes measured 9 mm. When compared with uninfected nail sizes of 0.5 mm for small toe finger nails and 1.5 mm for large toe nails, the infected nail presents a formidable barrier to topical treatment. Nail plates have a high sulfur content in the form of disulfide bonds. The patent of E.U.A. 5,696,164 (Sun et al., 1997) describes the use of amino compounds containing thio and its derivatives (ie, sulfhydryl-containing amino acids), such as cysteine and N-acetyl cysteine, and urea to increase the permeability of the drug in a nail plate, breaking the disulfide bonds in the keratin of the nail to increase the penetration of the drug into and through the nail. It was shown that a significant increase in the topical delivery of the drug through the nail was achieved. European patent application EP 503988 A1 (1992) describes a composition for treating onychomycosis, comprising nail penetration agents, such as glycols, glycol ethers, dimethyl sulfoxide, caprolactane and other hydrophilic compounds to facilitate the penetration of fungicides from allylamine in the nail.
Nail polish, also known as coating, luster, enamel and / or nail varnish, is a popular form of nail care products. A nail lacquer containing drug is the most convenient and most acceptable method of nail treatment for treating nail diseases such as onychomycosis and nails affected by psoriasis. As described above, it is essential to have a nail lacquer containing drug that is capable of delivering a drug or drugs within and through the nail in a therapeutically sufficient amount. In addition, the drug-containing lacquer should not be irritating to the skin tissue adjacent to the nail. The drug in the lacquer formulations must be stable enough to meet the two-year shelf life normally required for a pharmaceutical product. Nail lacquers containing therapeutic agents have been known in the past. For example, the patent of E.U.A. No. 4,957,730 (1990) a nail varnish containing a water-insoluble film-forming substance and an antifungal compound. The patent of E.U.A. 5,120,530 (1992) discloses an antifungal nail varnish containing amorolfine in a quaternary ammonium acrylic copolymer. The water-insoluble film former is a copolymerized material of acrylic acid esters and methacrylic acid esters having a low content of quaternary ammonium groups. The patent of E.U.A. 5,264, 206 (1993) describes a nail lacquer with antifungal activity, which contains an antifungal agent and water-soluble film formers including polyvinyl acetate, a copolymer of polyvinyl acetate and acrylic acid, copolymers of vinyl acetate and crotonic acid, monoalkyl maleate, etc. The patent of E.U.A. 5,346,692 (1994) describes a nail lacquer for treating onychomycosis comprising a film-forming agent, an antimycotic active substance and urea, whereby the antinychotic agent and urea are released from the lacquer when the lacquer is applied. A preferred formulation comprises cellulose derivatives as a film former, clotrimazole as the antifungal agent, dibutyl phthalate as a plasticizer, and a mixture of acetone and ethanol as the solvent. The patent of E.U.A. 5,487,776 (1996) discloses a nail lacquer composition which forms a water permeable film containing griseofulvin when the organic solvent system is evaporated, wherein a portion of the griseofulvin is in solution and a portion of the griseofulvin is present as a colloidal suspension. The European patent solution EP 515312 A2 (1992) discloses a nail lacquer containing terbinafine or its hydrochloric acid salt as an antifungal agent, solvents and a polymeric film former consisting of dibutyl phthalate, paraloid A-21 acrylic resin , polyvinyl acetate, etc. However, these patents and publications mention very little, if any, information that refers to the increased penetration of the nail of drugs in these descriptions. Despite these cases, however, simply placing a drug in a conventional lacquer formulation without any means to increase penetration through the nail will not be possible to achieve the desired therapeutic goal. This is particularly true with some classes of antifungal medications, particularly azoles and imidazoles. These drugs are commonly quite insoluble and therefore it is difficult to prepare topical formulations of these drugs. In addition, it is known that many topical formulations of imidazole have been extremely irritating. Furthermore, when onychomycosis is treated, once the nail fungus is removed, the uninfected replacement nails grow relatively slowly. Thus, it can take six months for nails of uninfected hands, and 12 to 18 months for uninfected toenails to grow and replace discolored and / or deformed nails. Preferably, a topical product for the treatment of nail diseases, such as onychomycosis, is not only effective to eliminate fungi, but to shorten the waiting period for the healthy nail to grow. The patent of E.U.A. 4,927,626 (1990) describes the topical application of minoxidil to increase hoof growth in animals, including human nails. However, neither describes nor suggests how to supply minoxidil through the nail. The recurrence rate of onychomycosis is relatively high for patients who have been treated and considered "cured." Since certain people are more prone to onychomycosis, prophylactic products, such as a drug-containing lacquer, are desirable to prevent the re-occurrence of onychomycosis.
Apart from the antifungal diseases (sic) associated with the nails, there are antifungal diseases (sic) associated with human skin. A particular source of infection is the feet, in which diseases associated with the sérpigo, commonly known as athlete's foot, prevail. There are a number of commercial treatments for this disease that contain miconazole nitrate as the active ingredient. However, despite these commercial products, a formulation that would be able to provide a greater percentage of the active ingredient than commercial products would be useful. Therefore, an object of the present invention is to prepare a drug containing composition which is capable of delivering a drug or drugs in and through human nails and skin in a therapeutically sufficient amount. Furthermore, an object of this invention is to prepare a composition that adheres to the nail and skin for a prolonged period of time. Moreover, an object of the invention is to prepare a composition that does not irritate human skin. A further object of the invention is to prepare a lacquer containing said composition. In addition, the lacquer-containing composition should not be irritating to the skin tissue adjacent to the nail. Moreover, the composition and lacquer must have the counter life necessary for a pharmaceutical product.
BRIEF DESCRIPTION OF THE INVENTION
The present invention provides an acidified composition for treating diseases of the nails and skin such as onychomycosis, psoriatic nails, skin psoriasis, versicolor, pedicel, foot soaking tub, jock rash and athlete's foot. Particularly, the invention includes an acidified composition comprising at least one active agent, at least one acidulant and at least one volatile solvent. In addition, the invention includes a method for treating human nails or skin infected by diseases by topically applying 1) an acidified composition comprising at least one acidulant, at least one volatile solvent and at least one active agent or 2) a composition of acidified lacquer comprising at least one acidulant, at least one volatile solvent, at least one active agent and at least one polymer film former. Moreover, the invention includes a method for improving and promoting healthy human nails and skin by topically applying 1) an acidified composition comprising at least one acidulant, at least one volatile solvent and at least one active agent or 2) a composition of acidified lacquer comprising at least one acidulant, at least one volatile solvent, at least one active agent and at least one polymer film former. In addition, the invention contemplates an acidified lacquer composition comprising at least one active agent, at least one acidifier, at least one volatile solvent and at least one polymer film former.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an illustration of the target sites for the treatment of onychomycosis. Figure 2 is a graph of the drug separation results for miconazole nitrate lacquer formulations. Figure 3 is a graph of the drug separation results for itraconazole lacquer formulations. Figure 4 is a graph of the permeation profiles for miconazole nitrate. Figure 5 is a graph of the permeability of miconazole nitrate lakes. Figure 6 is a graph comparing the amount of miconazole nitrate retained on the skin using different formulations of miconazole nitrate. Figure 7 shows the relative content of miconazole in the epidermis, dermis and receptor media.
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to an acidified composition comprising at least one active agent, at least one acidulant, at least one volatile solvent and at least one active agent. As used herein, the term "acidulant" refers to substances that are liquids that have an apparent pH of <; 1, or solids that have a pKa < 5. Apparent pH is the pH reading measured by glass pH electrode. Preferred acidulants are 37% HCl, 10% HCl, sulfuric acid, o-phosphoric acid, nitric acid, acetic acid, L (+) - lactic acid, salicylic acid and glycolic acid. Particularly preferred acidulants are 37% HCl and 10% HCl. If the total weight of the composition acidifies is 100 parts, the acidulant should represent about 0.05 to about 50% w / w (w / w = weight / weight), preferably about 0.1 to about 10%, most preferably about 0.5. % to approximately 5%. The term "volatile solvent" refers to liquid substances that evaporate more quickly than water. The volatile solvent does not have to be anhydrous but must have less than 30%, preferably less than 10% and more preferably less than 2% water. Examples of such solvents include but are not limited to ethyl alcohol, isopropyl alcohol, ethyl acetate, butyl acetate, acetone and mixtures thereof. Volatile solvents which are preferred are ethyl alcohol, isopropyl alcohol, ethyl acetate and butyl acetate. If the total weight of the acidified composition is 100 parts, preferably the volatile solvent represents 90-98% w / w. As used herein, the term "active agents" refers to drugs for treating diseased nails, nutrients or conditioners for nails that can be used to improve damaged nails or keep them healthy, and nail growth promoters that can be used on damaged nails. or healthy All of the above-mentioned types of active agents can be used to treat the tissue surrounding the nail, and skin whether the tissue is healthy or diseased. Active agents include but are not limited to antifungal drugs used to treat onychomycosis and athlete's foot, antibiotics (or antiseptics) for bacterial infection of the nails, tissue surrounding the nails and other human tissues, and antipsoriatic drugs for the treatment of psoriatic nail and skin. Examples of antifungal drugs include but are not limited to miconazole, econazole, ketoconazole, itraconazole, fluconazole, bifoconazole, terconazole, butoconazole, thioconazole, oxiconazole, sulconazole, saperconazole, clotrimazole, undecylenic acid, halogenoprogina, butenafine, tolnaftate, nystatin, cyclopirox olamine, terbinafine, amorolfine, naftifine, elubiol, griseofulvin and their pharmaceutically acceptable salts. The antifungal drugs that are preferred are an azole, an allylamine or a mixture thereof. The azoles that are preferred are selected from the group consisting of itraconazole, ketoconazole, miconazole, econazole, fluconazole, voriconazole, clotrimazole, butenafine, undecylenic acid, clioquinol and their pharmaceutically acceptable salts. The allylamines that are preferred are selected from the group consisting of terbinafine, naftifine and mixture thereof. Examples of antibiotics (or antiseptics) include but are not limited to mupirocin, neomycin sulfate, bacitracin, polymyxin B, / -ofloxacin, tetracyclines (chlortetracycline hydrochloride, oxytetracycline hydrochloride and tetracycline hydrochloride), clindamycin phosphate, gentamicin sulfate , benzalkonium chloride, benzethonium chloride, hexylresorcinol, methylbenzethonium chloride, phenol, quaternary ammonium compounds, triclocarbon, triclosan, tea tree oil, and pharmaceutically acceptable salts. Antibiotics and antiseptics that are preferred include mupirocin, neomycin, neomycin sulfate, bacitracin, polymyxin B, / -ofloxacin, tetracyclines, benzalkonium chloride, benzethonium chloride, triclocarbon and triclosan. Examples of antipsoriatic drugs include but are not limited to corticosteroids (e.g., betamethasone dipropionate, betamethasone valerate, clobetasol propionate, diflorasone diacetate, halogen beta propionate, amcinonide, deoximetasone, fluocinonide, fluocinolone acetonide, halcinonide, triamcinolone acetate , hydrocortisone, hydrocortisone verlerate, hydrocortisone butyrate, aclometasone dipropionate, flurandrenolide, mometasone furoate, methylprednisolone acetate), calcipotriene and anthralin. Preferred anti-psoriatic drugs include betamethasone dipropionate, betamethasone valerate and clobetasol propionate.
When the active agents are nail growth promoters, said agents include but are not limited to minoxidil, minoxidil sulfate, retinoids, cysteine and acetylcysteine, methionine, glutathione, biotin, finasteride and ethokinin, as well as pharmaceutically acceptable salts of these compounds. Preferred nail growth promoters are minoxidil, minoxidil sulfate, retinoids, cysteine and acetylcysteine. Particularly preferred nail growth promoters are 2% minoxidil, 2% minoxidil sulfate, and 0.1% retinol. When the active agents include nutrients, these include but are not limited to vitamins, amino acids and their derivatives. Examples of said agent include but are not limited to vitamin B complex; thiamine, nicotinic acid, biotin, pantothenic acid, choline riboflavin, vitamin B6, vitamin B-2, pyroxydine, inositol, carnitine, ascorbic acid, ascorbyl palmitate, vitamin A, vitamin K, vitamin E, vitamin D, cysteine and N-acetylcysteine, herbal extracts and their derivatives. When active agents include conditioners for nails, these include but are not limited to compounds containing minerals, flavonoids and retinoids. These conditioners for nails improve the general conditions of the nails, such as reinforcement of the nails to prevent them from splintering and breaking, and to beautify the nails. Examples of such agents include but are not limited to calcium pantothenate, calcium carbonate and calcium gluconate. Examples of retinoids include but are not limited to retinol (vitamin A alcohol), retinal (vitamin A aldehyde), retinyl acetate, ethynyl palpitate, retinoic acid, 9-cis-retinoic acid and 13-cis-retinoic acid. When the retinoids are the active agents, the concentration of retinoids is from about 0.01% to about 0.5%, preferably about 0.5 to about 0.1%. Examples of flavonoids include but are not limited to naringenin, quercetin, catechins (eg, epigallocatechin gallate), theaflavins, robustalflavone, hinoquiflavone, amentoflavone, agatisflavone, volkensiflavone, moreloflavone, rhusflavanone and succedangeaflavanone. Above all, the preferred active agents are miconazole nitrate, itraconazole, econazole nitrate, ketoconazole, clotrimazole and terbinafine. If the total weight of the acidified composition is 100 parts, the active agent is present at about 0.05% to about 10% w / w, preferably about 0.1% to about 5%, most preferably about 0.5% to about 2% . Apart from the acidulant, the volatile solvent and the active agent, the compositions of this invention may include other substances, such as preservatives, cosmetic additives, antioxidants, chelating agents and pigment flakes. Examples of such agents include but are not limited to benzoic acid, benzyl alcohol (as a preservative), glycerol, propylene glycol as an emollient, butylated hydroxytoluene, butylated hydroxyanisole, ascorbic acid, ascorbyl palmitate, N-acetylcysteine as an antioxidant, citric acid, edetic acid and its sodium salts as a chelating agent.
An example of a typical acidified composition comprises 1% clotrimazole as an active agent, 0.1% concentrated HCl (37% by weight HCl) as an acidulant and 98.7% ethyl alcohol as a volatile solvent. An example of a topical formulation containing this composition comprises 1% clotrimazole as an active agent, 0.1% concentrated HCl (37% by weight HCl) as an acidulant, 0.1% butylated hydroxytoluene as an antioxidant, 0.1% citric acid and 98.7%. % ethyl alcohol as a volatile solvent. The invention includes an acidified lacquer composition comprising at least one active agent, at least one acidifier, at least one volatile solvent and at least one polymeric film former. The terms active agent, acidulant and volatile solvent have their meanings mentioned above. The acidulant should be present at about 0.05 to 10% w / w, preferably about 0.1% to about 5%, most preferably about 0.5% to about 2%. The volatile solvent should preferably be present from about 70 to about 98% w / w. The active agent should be present from about 0.05% to 10 w / w, preferably from about 0.1% to about 5%, more preferably from about 0.5% to about 2%. As defined herein, the term "lacquer" refers to a liquid substance that typically dries to form a continuous or non-continuous film by evaporating the solvent.
As defined herein, the term "polymeric film former" is a polymer that can be added to a volatile solvent and other substances to form a polymer solution that can be applied to the skin to form a film. Examples of polymer film formers include but are not limited to acrylic copolymers / acrylic polymers (such as Carboset® or Avalure® polymers made by BF Goodrich); methacrylic acid polymers and their esters (such as Eudragit® series S, L, RS and RL polymers, made by Rohm Pharma); cellulose polymers, nitrocellulose, methyl cellulose, ethyl cellulose, cellulose acetates (such as cellulose triacetate, cellulose acetate butyrate); nylon, polyvinyl acetate, polyvinyl acetate phthalate, formaldehyde resin and mixtures of the polymers mentioned above. The polymeric film formers that are preferred are selected from the group consisting of acrylic copolymers / acrylic polymers (such as Carboset® or Avalure® polymers made by BF Goodrich); methacrylic acid polymers and their esters (such as Eudragit® series S, L, RS and RL polymers made by Rohm Pharma). The lacquers may have different viscosities. The viscosity of the lacquer refers to the thickness of the film that will be left on a surface once the volatile solvent has evaporated. If a thick, viscous lacquer is desired, which will deposit a thin and thick film on a surface, the concentration of the polymer film former should be from about 0.1% to about 30%, preferably about 0.5% to about 15% of the total composition. If a thin lacquer that will deposit a thin film on a surface is desired, the concentration of the polymer film former should be from about 0.1% to about 15%, preferably about 0.5% to about 5.0% of the total composition. The acidified lacquers of the invention may have other additives such as plasticizers (to preserve the bending ability of film formers), non-volatile drug solubilizers, cosmetic additives and pharmaceutical additives. When non-volatile drug plasticizers and solubilizers are used, examples of these substances include but are not limited to phthalate esters (eg, dibutyl phthalate), citrate esters, triacetin, isopropyl myristate, N-methyl-2- pyrrolidone, fatty acids and esters of fatty acid, propylene glycol, butylene glycol, hexylene glycol, propylene carbonate, polypropylene glycol, methoxypolyethylene glycol, polyethylene glycol, glycerin. When plasticizers are used they preferably represent about 0.001 to about 10% by weight of the total composition. Pharmaceutical additives include but are not limited to antioxidants and chelating agents. Examples of antioxidants include but are not limited to butylated hydroxytoluene, butylated hydroxyanisole, ascorbic acid, ascorbyl palmitate, N-acetylcysteine. Examples of chelating agents include but are not limited to citric acid, edetic acid and its sodium salts. Cosmetic additives include, but are not limited to, coloring agents, fragrances, pigments, as well as silica powders, zinc oxide and titanium oxide. A typical acidified lacquer composition comprises 1% clotrimazole as an active agent, 0.1% concentrated HCL (37% by weight HCl) as an acidulant, 15% acrylic polymer (Carboset® 525 or Avalure® AC 315) as a film former. and 43% ethyl alcohol and 40% ethyl acetate as volatile solvents. Typical topical formulation containing the acidified lacquer composition comprises 1% clotrimazole as active agent, 0.1% concentrated HCl (37% by weight HCl) as an acidulant, 15% acrylic polymer (Carboset® 525 or Avalure® AC 315 ) as a film former, 0.7% isopropyl myristate as a non-volatile drug solubilizer, 0.1% of butylated hydroxytoluene as an antioxidant, 0.1% citric acid and 43% ethyl alcohol and 40% ethyl acetate as volatile solvents. A typical formulation containing the acidified lacquer composition that can be used to treat onychomycosis, comprises about 0.5 to about 3% of an antifungal drug as an active agent, about 0.1% to about 1% concentrated HCl (37% HCl) by weight) as an acidulant, approximately 15% acrylic polymer (Carboset® 525 or Avalure® AC 315) as a polymer film former, 1% isopropyl myristate as a non-volatile solvent, 0.1% butylated hydroxytoluene as an antioxidant, 0.1% of citric acid and 37% ethyl alcohol and 42.3% - 42.7% ethyl acetate as volatile solvents.
A typical formulation containing the acidified lacquer composition that can be used to treat versicolor, psoriasis, sterigo, plantar floor of the feet, Jock rash and athlete's foot comprises about 0.5 to about 3% of an antifungal drug as an active agent , about 0.1 to about 1% concentrated HCl (37% by weight HCl) as an acidulant, 3% acrylic polymer (Carboset® 525 or Avalure® AC 315) as a polymeric film former, 1% myristate sopropyl as a non-volatile solvent, 0.1% of butylated hydroxytoluene as an antioxidant, 0.1% of citric acid and 67% of ethyl alcohol and 24.3% - 24.7% of ethyl acetate as volatile solvents. The antifungal drugs in the above examples can be selected from at least one of the following: clotrimazole, miconazole, terbinafine, amorolfine, cyclopirox olamine, tolnaftate, fluconazole, econazole, ketocoanzole, itraconazole, butenafine and their pharmaceutically acceptable salts. The invention includes a method for treating human nails infected by diseases or human skin infected by diseases by applying topically 1) an acidified composition comprising at least one acidulant, at least one volatile solvent and at least one active agent or 2) a acidified lacquer composition comprising at least one acidulant, at least one volatile solvent, at least one active agent and at least one polymer film former. The terms acidulant, volatile solvent, active agent, lacquer and polymer film were defined above.
The term "nail" means the corneal skin plate on the dorsal surface of the far end of a finger or toe. Figure 1 is a schematic diagram showing the basic anatomical structure of the human nail and its surrounding tissues. The treatment contemplated by this invention is designed to deliver an active agent to the nail plate (the stratum corneum nail) and the nail bed (the modified area of the epidermis below the nail, on which the nail plate). the nail slides as it grows) through the nail plate. Desirably, the active agent is also administered concurrently to the nail matrix (the proximal portion of the nail bed from which growth proceeds most) and the nail bed through the skin of the eponychium (commonly called the cuticle) and the hyponychium (thickened epidermis below the free distant end of the nail). The term "applying" refers to any method for physically transferring the acidified composition to the nail and the skin. Such methods include but are not limited to painting the composition or lacquer on the surface of the skin; spray the composition or lacquer using a spray pump and combine the composition or lacquer with a propellant to be sprayed on the skin as an aerosol. The term "aerosol" refers to systems consisting of "pressurized packages" with compressed gases or liquified gases as propellants. Examples of compressed gases are nitrogen and compressed air. Examples of liquid gas propellants are propane, isobutane, n-butane, dimethyl ether and mixtures thereof.
The preferred propellants are dimethyl ether and a mixture of dimethyl ether and one or more hydrocarbon propellants. The preferred weight ratio of dimethyl ether to the hydrocarbon propellants varies from more than or equal to about 3: 2 (> 3.2) respectively. Typically for the treatment of nail diseases, the composition or lacquer is initially applied once or twice a day and can be reduced once or twice a week depending on the intensity and recurrence of the underlying infection. As used herein, the term "disease" refers to fungal diseases, bacterial diseases and psoriasis. Fungal diseases of the human nail that can be treated according to the invention include but are not limited to "onychomycosis". This disease is typically caused by an infection of Epidermophyton floccosum, various species of Trichophyton, such as T. rubrum and T. mentagrophytes, or yeast, such as Candida albicans or fungi. Fungal diseases of human skin that can be treated according to the invention include but are not limited to the diseased portions of the skin surrounding a nail, especially the eponychium, i.e., the skin tissue on the nail matrix. This application allows the antifungal drug and nail growth promoters to be absorbed into the eponychium and subsequently into the nail matrix. This is particularly beneficial, as the growth of the nail accelerates, a little antifungal drug is incorporated into the growing healthy nail to prevent reinfection by fungi. In addition to onychomycosis, fungal skin diseases such as versicolor, pedicle, psoriasis, athlete's foot, plantar foot soak, Jock rash may be treated using the methods and compositions of this invention. Typically these skin diseases are caused by fungi such as Trichophyton rubrum, T. mentagrophytes and Epidermophyton floccosum. Typically the treatment regimen for fungal infections of the skin using the acidified composition or acidified lacquer may be once or twice a day, preferably once a day, with a duration of less than one week to four weeks, preferably equal or less than two weeks. The topical treatment of the invention can be used in combination with a systemic treatment. For example, an antifungal drug, such as, traconazole, terbinafine, griseofulvin or other antifungal drugs can be administered orally over a period of time. This period of time may be concurrently during the complete topical treatment regimen, or concurrently during a portion (usually the final phase) of the topical treatment regimen, or after topical treatment. The invention includes a method for treating healthy human nails or skin by applying topically 1) an acidified composition comprising at least one acidifier, at least one volatile solvent and at least one active agent or 2) an acidified lacquer composition that it comprises at least one acidulant, at least one volatile solvent, at least one active agent and at least one polymer film former. Since the acidified composition and the acidified lacquer of the invention are not irritant, they can be used prophylactically to prevent infections. When used in this way, the acidified lacquer and the acidified composition can be applied once or twice a month. Typically the prophylactic treatment regimen for fungal infections of the nail and skin using the acidified composition or acidified lacquer may vary from once to twice a week to once or twice a month, with the shorter inter-treatment interval for the skin and more long for the nail. To illustrate the invention, the following examples are included. These examples do not limit the invention. They try to suggest a method to carry out the invention. Those familiar with the treatment of human nails and skin can find other methods for practicing the invention. However, those methods are considered within the scope of this invention.
EXAMPLES
As demonstrated in the following examples, several experiments were carried out in an effort to satisfy the need for a suitable topical therapeutic product: (1) increased drug delivery; (2) non-irritant to human tissues involved; (3) suitable drug stability and (4) convenient to use. It has been shown that the uptake of antifungal drugs in human nails could be significantly increased by using the acidified lacquer compositions described (Example 3, Table 4). In addition, it has been shown that even greater drug uptake is obtained when the nails are pretreated with penetration enhancers (example 5, table 6), followed by the use of the acidified lacquer compositions. It was also demonstrated that the substantivity in the skin of an antifungal drug against washing, as well as the penetration of the drug into the skin, increased dramatically when the described acid lacquer composition was used, compared to commercial products (example 9, figures 6 and 7).
EXAMPLE 1 Acidification to increase the uptake of drug in human nail
To evaluate the effect of concentrated acids on the solubility in miconazole nitrate, 0.5% or 1.0% of the following acids were added to a liquid containing 2% miconazole nitrate and ethyl alcohol until the
100% The percentages are all in weight throughout the text. The tests were carried out at 22% with mixing.
As shown in table 1, among the different acids tested for acidification of nail varnish, including concentrated hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, lactic acid and glycolic acid, only concentrated HCl and sulfuric acid concentrated to a lesser degree, they can completely solubilize miconazole nitrate in ethyl alcohol. As used herein, complete solubilization means that the resulting mixture produces a clear solution. Furthermore, as can be seen in Table 1, this phenomenon of complete solubilization only occurred with concentrated hydrochloric acid and, to a lesser degree, with concentrated sulfuric acid, but not with the other acids tested. TABLE 1 Solubility in miconazole nitrate
• Sources, grades and pH measurements (with a glass electrode after 1 minute) of the concentrated acids.
Acidulant pH reading
** It becomes a clear solution when heated to 32 ° C.
EXAMPLE 2 Drug uptake of acidified solutions in human nail clippings
To evaluate the effect of concentrated acids on the uptake of miconazole nitrate in human nail, an experiment was carried out as follows. A part of the acidulant (listed in Table 2) was added to a glass bottle containing a liquid comprising two parts of miconazole nitrate and 97 parts of ethyl alcohol (denatured, 200 strength). A known weight of human nail clippings was placed in the bottle, which was then sealed. The nail separation experiment was carried out at 32 ° C for 24 hours with mixing. At the end of the experiment, the nail clippings were carefully washed with alcohol to remove the drug bound to the surface. The miconazole nitrate content of the nail clippings was analyzed by high pressure liquid chromatography (CLAP) and the results were tabulated in table 2. It can be seen that the miconazole nitrate uptake of the acidified solutions was increased approximately 9 times using 1% hydrochloric acid or sulfuric acid; and 2 to 3 times using the other acids tested.
TABLE 2
EXAMPLE 3 Drug uptake of acidified lacquer formulations on human nail clippings
Nail separation studies were carried out to evaluate the nail uptake of a drug by dipping human nail clippings in various lacquer formulations for 48 hours at 32 ° C with constant agitation. At the end of the experiment, the drug content in the nail clippings was analyzed by CLAP after washing the drug bound to the surface. The nail varnish formulations used in the drug separation studies are shown in Table 3. The lacquer formulations contained miconazole nitrate or traconazole, with and without concentrated hydrochloric acid. The results of drug separation in the nail are shown in table 4, figure 2 (miconazole nitrate) and figure 3 (itraconazole). The number in the bars of the figures is the ratio of increase, which is equal to the content of drug for nails treated with a lacquer containing HCl, divided between the content of drug for nails treated with a lacquer added without added HCl of the same concentration of drug. As can be observed, an increase of 12 to 33 times in the pick up of drug in the nail was achieved with the miconazole nitrate lacquers, and an increase of 38 to 57 times with the lacquers of itraconazole. These results clearly show that the acidified nail lacquer compositions significantly increased the penetration of the antimyotic drugs miconazole nitrate and itraconazole into the nail.
E 3
The compositions of the lacquer formulations containing miconazole nitrate or itraconazole used in the nail uptake experiments and in the primary dermal irritation test (in% by weight).
N. mic. Miconazole nitrate Itra. Itraconazole HCl conc. Concentrated hydrochloric acid, 37% IPM Isopropyl myristate EtOH Ethyl alcohol, 200 strength, denatured CBST525 Carboset® 525, acrylic copolymer, BF Goodrich Ac. Et. Ethyl Acetate Acidified lacquer formulations demonstrated increased drug uptake in human nail clippings. Nail uptake experiments (fingernail separation) were carried out in triplicate (n = 3). The concentrations of drug in the nail were the average value (PROM) with the corresponding standard deviation (STD). The increase ratio of nail uptake of a drug was calculated by dividing the content of drug for nails treated with the acidified lacquer formulation of a particular drug concentration, between the content of drug for nails treated with a non-acidified lacquer containing the same concentration of drug.
E 4
EXAMPLE 4 Skin Irritation Test
In spite of the extremely strong acidity of the lacquer formulations, to the surprise of the inventors, the nail varnish formulations do not irritate the skin. A standard test for skin irritation, called "the Modified Draize Rabbit Primary Skin Irritation Test" (PDI), was used to evaluate lacquers for acidified nails. The test procedures are described briefly as follows. The test skin sites of the white albino rabbits of New Zealand were left free of fur. Abrasion was done on the skin on each test skin site using the bearded type of a sterile 20 gauge hypodermic needle in a "cat" game pattern. The nail lacquer was applied to the prepared skin test site. The observation was made by an expert scientist in twenty-four hours, and again in seventy-two hours, to verify any signs of skin irritation, including erythema, eschar, and edema formation. A scoring system was used to grade the skin irritation observed: varying from the lowest score, 0 (non-irritant) to the highest score, 8 (severely irritating). The acidified lacquer formulations tested for PDI include Nos. 3-2, 3-3 and 3-9 (e 3). All the acidified lacquers obtained the "light" PDI score. Another skin irritation test, called the "Cumulative Skin Irritation Test" (CSI), was also carried out using the New Zealand White albino rabbits. The lacquers for acidified nails were applied to the intact skin previously freed from fur (ie without previous skin abrasion) twice a week for two and a half weeks. Prior to the application of each lacquer, the dry nail lacquer was first removed from the test skin using an alcohol swab containing 70% isopropyl alcohol. Again, all the test results were smooth (e 5). The irritation potential of the acidified varnish formulation was also evaluated in human volunteers. The nail varnish was applied to the ventral skin of the forearm of three volunteers for 24 hours. There was no sign of skin irritation. In a volunteer, the application of varnish was continued once a day for two weeks. Prior to each application of varnish, the dried nail varnish was first removed from the test skin using an alcohol swab containing 70% isopropyl alcohol. Again, no signs of skin irritation were observed. It should be noted that the acidity of nail varnishes is extremely high. Due to the anhydrous nature of nail varnishes, any direct pH measurement does not have its normal meaning. However, to put the matter in perspective, consider the fact that the pH value of 0.1 N HCl is pH 1.0, while the HCl content in nail varnishes tested in this study was up to five times higher than HCl 0.1 N. The fact that a topical formulation containing such a high content of a strong acid still remains soft to the skin, is something truly surprising and completely unexpected.
TABLE 5 The compositions of varnish formulations containing either miconazole nitrate or itraconazole used in the cumulative skin irritation test (in% by weight), and the results of the test
Mic. N .: miconazole nitrate Itra: Itraconazole Conc. HCl: concentrated hydrochloric acid, 37% IPM: isopropyl myristate Ascor. P: ascorbyl palmitate Eth. Ac: ethyl acetate EtOH: ethyl alcohol, 200 proof, denatured CBST: Carboset® 525, acrylic copolymer
EXAMPLE 5 Absorption of the drug in nail clippings that have been pretreated with penetration enhancers
It has been demonstrated that nail penetration enhancers such as N-acetylcysteine (NAC) promote the penetration of drugs through the human nail when a formulation contains the penetration enhancer and the drug (see US patent No. 5,696,164). The invention describes a new method of incrementation using NAC for the topical delivery of drugs in the nail. The essence of the new method of increase is a pretreatment of nails with penetration enhancer or enhancers in the nail before the application of a formulation containing active agent. The active agent can be of therapeutic or cosmetic value. Optionally, the pretreatment formulation containing enhancers is also constituted by active agents for therapeutic and cosmetic purposes. To demonstrate this methodology, the experiments were conducted as follows. Human nail clippings of known weight were immersed in a pretreatment formulation containing NAC, urea and distilled water of certain concentrations at 32 ° C under mixing for a period (for example, 24 hours). At the end of the pretreatment procedure, the degree of nail expansion was determined by weighing the nail clippings after being dried by contact with a paper towel.
Then a drug absorption experiment was carried out by immersing the pretreated nail clippings in the acidified antifungal varnish formulations at 32 ° C under constant mixing for 48 hours. The basic composition of the acidified formulations of itraconazole varnish, and the drug absorption procedures of the nail (i.e. partitioning into the nail) were the same as described in the previous sections. Table 6 shows the results of the nail expansion after pretreatment, and the absorption of itraconazole in the pretreated nail clippings. In general, drug absorption increased as a result of pretreatment with nail penetration enhancers. The hierarchy of the increaser with different pretreatment conditions are as follows: urea alone < NAC only < NAC plus urea. Pre-treatment with urea alone showed a more than limited increase in drug absorption, whereas NAC was only more effective. A combination of NAC and urea, on the other hand, showed a definite synergistic effect in the increase of drug absorption. For example, pretreatment with 20% urea alone resulted in 4.7 mg of drug per gram of nail; pretreatment with 10% NAC only resulted in 15.45 mg of drug per gram of nail. In marked contrast, pretreatment with 10% NAC and 20% urea resulted in 28.46 mg of drug per gram of nail. The synergistic increase of two enhancers for the absorption of drugs in the nail has an important and practical implication: it allows the use of a minimum amount of an enhancer which could be irritating to the skin at a high concentration, such as NAC. It should be noted that, in Table 6, the ratio of drug absorption increase in the nail means to compare the effect of the pretreatment only. Acid varnishes containing drug were used in all experiments, and absorption data from the non-pretreated nail was used as the reference mark. On the other hand, a comparison can also be made between a non-acidic varnish of a certain drug concentration in a non-pretreated nail absorption experiment (as shown in Table 4) and an acidified varnish with the same concentration of drug in a pretreatment experiment (as shown in table 6). Therefore another set of increment ratio data can be calculated: for 1% traconazole varnish, there is a 463 fold increase in drug absorption in the nail; for 2% traconazole varnish, there is an increase of 826 times; and for a varnish with 5% itraconazole there is an increase of 759 times, when the nail has been pretreated with 10% NAC and 10% urea. This shows that the power of combination enhancement (ie, acidified varnish and pretreatment) for the delivery of drugs to the nail is notorious.
TABLE 6 Absorption of drug in human nails from acid varnish with itraconazole after pre-treatment with nail penetration enhancers. All experiments were conducted in triplicate (n = 3)
* The increment ratio is defined as: the drug content in the pretreated nail divided by the drug content in the unpretreated nail after immersing it in a nail varnish with the same concentration of drug.
EXAMPLE 6 Permeation of the drug in and toward the human nail plate
Experiments were conducted to evaluate the penetration of drugs through human nails. The experimental procedures are briefly described as follows: (1) human nail plates were mounted in modified Franz diffusion cells. (2) a nail enhancer formulation containing 10% NAC and 20% urea was placed in the donor cells to pre-treat the nail plate for 24 hours. (3) after the pretreatment formulations were removed from the donor cells, varnish formulations containing 2% or 5% miconazole nitrate were applied to the nail plate in the donor cells. At the end of a week from the beginning of the pre-treatment of the nail, the nail varnishes were removed with swabs with ethanol. Steps (2) and (3) were repeated for 3 more weeks. The experiment was conducted in triplicate for a total period of 3 weeks at 32 ° C (avg + std., N = 3). The effect of occlusive conditions against non-occlusive conditions was evaluated by covering the selected donor cells with an occlusive polymer film after allowing sufficient time for the varnish to dry. The occlusion test was used to mimic the condition frequently caused by the "overcoat" layers of another nail varnish. The amount of drug permeated through the nail plate was determined by analyzing the receptor fluid by HPLC. The concentration of drug in the nail plate was determined. The permeation results of the nail were tabulated in table 7 and plotted in figure 4. The permeation profiles in figure 4 show that the miconazole nitrate from the nail varnishes passed through the skin plate in quite quickly, especially for those nail plates that had been pretreated with nail penetration enhancers (ie, comparing # 1-4 with # 5). As can be seen from FIG. 5 and FIG. 7, the acid nail varnishes supplied miconazole nitrate in and to the nail plates even without the aid of nail penetration enhancers. Pretreatment with NAC and urea significantly increased drug permeation through the nail. The varnish containing a higher concentration of drug delivered more drug through the nail. The occlusive condition further increased the permeation of the drug from the varnish containing the drug. Occlusive conditions can be easily achieved by multiple coatings of the drug-containing varnish, or by "overcoating" another varnish, or by applying an occlusive cover, such as an adhesive-coated polymeric adhesive strip of predetermined properties, such as a certain range of permeabilities to humidity and gas.
TABLE 7 Penetration of drug in and through the human nail plate
'Composition similar to 4-1 but with a lower drug concentration.
EXAMPLE 7 Skin permeation experiment
To assess whether the drug-containing varnish formulation can be used to deliver drug to the skin, a skin permeation study was conducted by applying a varnish formulation containing 2% miconazole nitrate to a solvent evaporated in a short period of time. , and that leaves a uniform polymer film on the skin. Table 8 tabulates the compositions of the formulations tested for nail varnish. A commercial cream product containing 2% miconazole nitrate (Micatin cream) was also tested for comparison. The amount of miconazole nitrate that penetrates through the skin and reaches the receptor was analyzed by HPLC. The drug content in the skin, that is, that was retained in the dermis, was also determined by HPLC. The results in Table 9 and Figure 5 show that miconazole nitrate was indeed able to diffuse out of the varnish layer and penetrate through the human skin. All varnishes containing miconazole nitrate supplied more drug in the skin. A comparison of formulations numbers 7-3 with 7-4 show that a higher HCl content in the varnish produced a higher skin permeation of the drug, indicating that the acid acted as a penetration enhancer in this situation. Depending on the polymer content, the acidified formulations can be formulated as varnishes or as a spray and aerosol.
A varnish formulation has relatively high polymer contents and forms a polymeric film after being applied. On the other hand, a formulation with low polymer content can be sprayed by a manually operated pump, or driven by compressed or liquefied gases, i.e. in the form of liquid spray or aerosol. In fact, one of the formulations (ie, No. 4-3) in Table 5 tested for skin irritation is specifically formed as a liquid spray. This contained only 0.5% Carboset® 525 as a polymer film former instead of 15% polymer in the other varnishes. After being applied to the skin with a spray pump, this formulation formed an almost invisible single layer on the skin test site.
TABLE 8 The compositions of varnish formulations containing miconazole nitrate used in the study of skin permeation (in% by weight).
TABLE 9 Results of miconazole nitrate permeation in the skin from acidified varnish formulations (prom ± std., N = 3)
EXAMPLE 8 Stability of the drug in acidified varnish
To evaluate the stability of the drug in the acidified varnish formulations, tests of accelerated stability of known drugs at elevated temperature during certain periods were carried out (a method widely applied in the pharmaceutical industry). The stability results for the tested formulations (eg, formulations 4-1, 4-3, 3-8 and 3-9) indicate that the drug formulations are stable in acidified varnishes, and that they will satisfy the shelf life of two years required This is surprising since it is well known that the presence of a strong acid generally causes drug decompositions through degradation reactions induced in acid medium.
EXAMPLE 9 Miconazole Nitrate Enhanced Substance to the Skin by the Present Invention
The purpose of this experiment was to examine the substantivity towards the skin of the antimagic drug miconazole nitrate from a liquid spray formulation as an example of the present invention. This liquid spray (hereafter the spray formulation) was compared with two commercial products for the treatment of athlete's foot, which contains the same drug and concentration as the spray formulation. In the United States, topical antifungal products containing 2% miconazole nitrate for the treatment of athlete's foot require an application regimen of twice daily and a duration of 4 weeks. If the substantivity made the skin of miconazole nitrate can be improved (ie the retention of drug in the skin is increased), a safer product towards the patient can be elaborated with a much less frequent dosing regimen and a duration of much shorter therapy. In vitro skin permeation tests combined with a washing procedure were conducted using dermatomized human cadaver skin mounted on Franz diffusion cells (n = 6). The three formulations tested were the spray formulation, the Micatin® cream (hereinafter referred to as formula A) and the liquid spray aerosol Lotrimin® (hereinafter referred to as formula B). Table 10 shows all the compositions of the preparations tested.
TABLE 10 Compositions of the tested preparations
To start the experiment, a test formulation was applied to the surface of the skin to form a thin layer. A washing procedure was conducted at 0.5, 12 or 24 hours, to mimic the normal shower / bath procedure by washing the surface of the skin with 5 ml of warm water (32 ° C). At the end of the 24-hour permeation test, the miconazole nitrate retained on the surface of the skin was removed with methanol swabs, and the epidermis was separated from the dermis. The drug content in washing liquids, methanol, epidermis, dermis and receptor medium swabs were analyzed by HPLC. As shown in Figure 6, approximately 62-81% miconazole nitrate was found retained on the surface of the skin after washing. In contrast, the drug retained on the surface for the cream of formula A was less than 9%, and for aerosol of formula B less than 0.6%. The order rank of miconazole nitrate in the samples treated with the spray formulation is as follows: retained on the surface (swabs with methanol) »washing liquids >epidermis > dermis > fluid receptor. On the other hand, the rank order for the cream of formula A and formula B is: washing liquids »retained on the surface > epidermis > derm¡s > receiving fluid. The different exposure times before washing have no marked effect on substantivity results. The data confirm that the spray formulation does in fact provide a substantivity of drug superior to the skin, as opposed to the cream and commercial aerosol formulations. The significantly increased drug retention on the surface of the skin by the spray formulation should allow a less frequent dosing regimen than current products, and thus improve patient acceptance. Figure 7 shows the relative content of miconazole in the epidermis, dermis and receptor medium. As can be observed in the figure, the concentrations of miconazole in the epidermis and dermis from the spray formulation were several times higher than those for the cream of formula A and the aerosol of formula B. The content of drug in the fluid receiver was very low. The epidermis is the white tissue for treatment for athlete's foot. A higher concentration of antifungal drug in the epidermis could ensure the complete elimination of pathogenic dermatophytes which should allow a reduction in the frequency of dosing (for example, from twice a day to once a day) and the duration of treatment (for example, from four weeks to one or two weeks). There is a general tendency to increase the penetration of drug into the skin with prolonged skin exposure times before washing with the cream of formula A and the aerosol of formula B. Interestingly, for spray formulation, penetration of miconazole nitrate in the skin was reduced as the time of exposure before washing was increased. This was probably due to the drying effect of the volatile solvents in the substantially anhydrous spray formulation. The release of drug from the binding film should be prevented when the surface of the skin is very dry.
After the washing procedure, the residual moisture content should facilitate drug release and, therefore, increased skin penetration of the drug. Because the dermatophytes that cause athlete's foot tend to prevail in an environment with high humidity, the release of single drug activated by moisture from the formulation and the spray should be beneficial for foot athlete treatment. Based on the amount of miconazole nitrate washed or retained on the skin between the three formulations tested, it could be concluded that the new spray formulation has miconazole nitrate developed to provide superior substantivity to the skin over the two commercial products tested (ie say, cream of formula A and spray liquid in spray of formula B). The significantly increased drug retention on the surface of the skin for the spray formulation should allow a less frequent dosing regimen than current products, and thus improve patient acceptance. In addition, miconazole can be delivered several times more to the skin by spray formulation as opposed to commercial products. Because the epidermis is the target tissue for the treatment of athlete's foot, a higher concentration of antifungal drug in the epidermis would ensure the complete elimination of the pathogenic dermatophytes. These findings confirmed that the present invention resulted in a better topical antifungal product for the treatment of athlete skin, which is safer to the patient with a reduced dosage frequency and duration of treatment, and is probably more effective than commercial products currently available with the same antifungal drug.
EXAMPLE 10 Composition of acidified spray varnish
The liquid composition "spray formulation" in Example 9 (as shown in Table 10) was made aerosol following known procedures using dimethyl ether and a mixture of dimethyl ether with n-butane. The aerosol compositions and results are shown in Table 11. The physical appearances of the resulting aerosols were observed through transparent aerosol packages.
TABLE 11 Miconazole nitrate aerosol lacquer and the resulting aerosols
The attached aerosol varnish compositions are preferably aerosols with uniformity of suitable content, while composition 3 is less desirable since precipitation probably causes non-uniform deposition of the drug during application, and could also result in malfunctioning of the composition. aerosol spray valve when plugging the hole.
EXAMPLE 11 Drug Partition Studies with Various Concentrations of Acidifying Agent
Drug partition studies were conducted to evaluate the acidity of the formulation in the miconazole nitrate portion in the nail from 9 nail varnish formulations. All formulations contain the same concentration of drug (2% miconazole nitrate), but different amounts of modified from acidity, ie, concentrated HCl (37% HCl) 2%, 1.5%, 1%, 0.5% and 0%, or concentrated NaOH solution (10% NaOH in distilled water) 0.5%, 1%, 1.5%, and 2%. The rest of the formulations include 1% isopropyl myristate, 40% ethyl acetate, 15% Carboset® 525 and ethyl alcohol up to 100%. All the indicated percentages are by weight). The experiments were conducted in triplicate, and the experimental procedures were the same as those described in example 3. The resulting contents of the drug in nails are tabulated in the following table. The increase ratio refers to the ratio of drug content in the nail from a varnish containing an acid modifier to that of a varnish that contains no acid modifier (ie formulation No. 5). It can be seen that both HCl and NaOH increased drug absorption in the nail. The degree of increase in drug absorption is much greater with HCl. The highest drug absorption was presented with 0.5% concentrated HCl, followed by 1% concentrated HCl.
TABLE 12
Claims (25)
1. - An acidified composition comprising at least one active agent, at least one acidifying agent and at least one volatile solvent.
2. The composition according to claim 1, further characterized in that said at least one acidulating agent is selected from the group consisting of 37% HCl, 10% HCl, sulfuric acid, o-phosphoric acid, nitric acid, acetic acid, L (+) - lactic acid, salicylic acid and glycolic acid.
3. The composition according to claim 1, further characterized in that said at least one acidulating agent is 37% HCl or 10% HCl.
4. The composition according to claim 1, further characterized in that said at least one volatile solvent is selected from an element of the group consisting of ethyl alcohol, isopropyl alcohol, ethyl acetate, butyl acetate and acetone.
5. The composition according to claim 1, further characterized in that said at least one volatile solvent is selected from the group consisting of ethyl alcohol, isopropyl alcohol, or ethyl acetate.
6. The composition according to claim 1, further characterized in that said at least one active agent is selected from the group consisting of miconazole, econazole, ketoconazole, traconazole, fluconazole, bifoconazole, terconazole, butoconazole, thioconazole, oxiconazole, sulconazole, saperconazole, clotrimazole, butenafine, undecylenic acid, haloprogine, tolnaftate, nystatin, cyclopirox olamine, terbinafine, amorolfine, naftifine, elubiol, griseofulvin, corticosteroids, calcipotriene, anthralin, minoxidil, minoxidil sulfate, retinoids, cysteine and acetyl cysteine, methionine, glutathione biotin, finasteride and ethocin, tea tree oil, mupirocin, neomycin sulfate, bacitracin, polymyxin B, l-ofloxacin, chlortetracycline hydrochloride, oxytetracycline hydrochloride, tetracycline hydrochloride, clindamycin phosphate, gentamicin sulfate, benzalkonium, benzethonium chloride, hexylresorcinol, methylbenzethonium chloride, phenol, compound quaternary ammonium, trichlorocarbon, triclosan and pharmaceutically acceptable salts thereof.
7. The composition according to claim 1, further characterized in that said at least one active agent is minoxidil, and further comprises at least one active agent that is selected from the group consisting of miconazole, itraconazole, econazole, ketoconazole, clotrimazole, butenifine, terbinafine and pharmaceutically acceptable salts thereof.
8. - An acidified varnish composition comprising at least one active agent, at least one acidifying agent, at least one volatile solvent and at least one polymer film former.
9. The acidified varnish composition according to claim 8, further characterized in that said at least one polymeric film former is selected from the group consisting of copolymers of acrylic acid / acrylic acid polymers, methacrylic acid polymers, esters of polymers of methacrylic acid, cellulose polymers, nitrocellulose, methylcellulose, ethylcellulose, cellulose acetates, cellulose triacetate, cellulose acetate butyrate, nylon, polyvinyl acetate, polyvinyl acetate phthalate and formaldehyde resin.
10. The acidified varnish composition according to claim 9, further characterized in that said at least one active agent is present at a concentration from about 0.1% to about 5%; said at least one acidifying agent is present at a concentration from about 0.1% to about 5%; said at least one volatile solvent is present at a concentration of from about 70% to about 95%; and said at least one polymer film former is present at a concentration of at least 0.1% up to about 15%.
11. The composition according to claim 10, further characterized in that said at least one active agent is selected from the group consisting of miconazole, econazole, ketoconazole, itraconazole, fluconazole, bifoconazole, terconazole, butoconazole, thioconazole, oxiconazole, sulconazole, saperconazole, clotrimazole, butenafine, undecylenic acid, haloprogin , tolnaftate, nystatin, ciclopirox olamine, terbinafine, amorolfine, naftifine, elubiol, griseofulvin, corticosteroids, calcipotriene, anthralin, minoxidil, minoxidil sulfate, retinoids, cysteine and acetyl cysteine, methionine, glutathione, biotin, finasteride and ethocin, tree oil tea, mupirocin, neomycin sulfate, bacitracin, polymyxin B, l-ofloxacin, chlorotetracycline hydrochloride, oxytetracycline hydrochloride, tetracycline hydrochloride, clindamycin phosphate, gentamicin sulfate, benzalkonium chloride, benzethonium chloride, hexylresorcinol, methylbenzethonium, phenol, quaternary ammonium compounds, trichlorocarbon, triclosan and s pharmaceutically acceptable alcohols thereof.
12. The acidified varnish composition according to claim 8, further characterized in that said at least one active agent is minoxidil, and further comprises at least one active agent that is selected from the group consisting of miconazole, itraconazole, econazole , ketoconazole, clotrimazole, butenifine, terbinafine and pharmaceutically acceptable salts thereof; said at least one acidulating agent is 37% HCl or 10% HCl; said at least one volatile solvent is selected from the group consisting of ethyl alcohol, isopropyl alcohol or ethyl acetate; and said at least one polymeric film former is selected from the group consisting of copolymers of acrylic acid / acrylic acid polymers, methacrylic acid polymers and the esters of methacrylic acid polymers.
13. An acidified varnish composition comprising about 1% 37% HCl, about 2% miconazole nitrate, about 70% ethyl alcohol, about 22% ethyl acetate and about 3% an acrylic polymer.
14. An acidified varnish composition comprising about 1% 37% HCl, about 2% miconazole nitrate, about 40% ethyl alcohol, about 22% ethyl acetate and about 15% an acrylic polymer.
15. The acidified varnish composition according to claim 8, further characterized in that said at least one active agent that is about 0.5% up to about 2% of an antifungal drug, said at least one acidifying agent is about 0.1% to about 1% 37% HCl, said at least one nonvolatile solvent is about 40% ethyl alcohol and about 42% to about 44% ethyl acetate, and said at least one polymeric film former is about 15% of an acrylic polymer.
16. The acidified varnish composition according to claim 8, further characterized in that said at least one active agent is about 0.5% up to about 2% of an antifungal drug, said at least one acidifying agent is about 0. 1% to about 1% 37% HCl, said at least one nonvolatile solvent is about 70% ethyl alcohol and about 23% up to about 24% ethyl acetate and said at least one polymeric film former it is about 3% of an acrylic polymer.
17. The use of an acidified composition comprising 1) at least one acidifying agent, at least one volatile solvent, and at least one active agent; or 2) an acidified varnish composition comprising at least one acidifying agent, at least one volatile solvent, at least one active agent and at least one polymeric film former to make a medicament for the treatment of nails or skin of human infected with disease.
18. The use of claim 17, wherein said at least one acidifying agent is about 1% 37% HCl; said at least one active agent is from about 0.5% to about 3% and is selected from the group consisting of miconazole, itraconazole, econazole, ketoconazole, clotrimazole, butenifine, terbinafine and pharmaceutically acceptable salts thereof; said at least one volatile solvent is from about 40 to about 70% ethyl alcohol and from about 23% to about 24% ethyl acetate; and said polymer film former is from about 3% to about 15% of an acrylic polymer.
19. - The use of claim 17, wherein said at least one acidulating agent is about 1% 37% HCl, said at least one active agent is from about 1% to 2% miconazole nitrate, said at minus one volatile solvent is from about 40 to about 70% ethyl alcohol and from about 23% to about 24% ethyl acetate; and said polymer film former is from about 3% to about 15% of an acrylic polymer.
20. The use of claim 17, wherein said at least one active agent is minoxidil, and further comprises at least one active agent that is selected from the group consisting of miconazole, itraconazole, econazole, ketoconazole, clotrimazole, butenifine. , terbinafine and pharmaceutically acceptable salts thereof; said at least one acidulating agent is 37% HCl or 10% HCl; said at least one volatile solvent is selected from the group consisting of ethyl alcohol, isopropyl alcohol or ethyl acetate; and said at least one polymeric film former is selected from the group consisting of copolymers of acrylic acid / acrylic acid polymers, methacrylic acid polymers and the esters of methacrylic acid polymers.
21. The use of claim 17, wherein said medicament comprising said composition or said varnish is applied as an aerosol.
22. - The use of 1) an acidified composition comprising at least one acidifying agent, at least one volatile solvent and at least one active agent; or 2) an acidified varnish composition comprising at least one acidifying agent, at least one volatile solvent, at least one active agent and at least one polymeric film former for the manufacture of a medicament for improving and promoting nails and healthy human skin.
23. The use of claim 22, wherein said at least one active agent is minoxidil, and further comprises at least one active agent that is selected from the group consisting of miconazole, traconazole, econazole, ketoconazole, clotrimazole, butenifine, terbinafine and pharmaceutically acceptable salts thereof; said at least one acidulating agent is 37% HCl or 10% HCl; said at least one volatile solvent is selected from the group consisting of ethyl alcohol, isopropyl alcohol or ethyl acetate; and said at least one polymeric film former is selected from the group consisting of copolymers of acrylic acid / acrylic acid polymers, methacrylic acid polymers and the esters of methacrylic acid polymers.
24. The use of claim 22, wherein said at least one active agent is selected from the group consisting of miconazole, itraconazole, econazole, ketoconazole, clotrimazole, butenafine, terbinafine and pharmaceutically acceptable salts thereof; said at least one acidulating agent is 37% HCl or 10% HCl; said at least one volatile solvent is selected from the group consisting of ethyl alcohol, isopropyl alcohol or ethyl acetate; and said at least one polymeric film former is selected from the group consisting of copolymers of acrylic acid / acrylic acid polymers, methacrylic acid polymers and the esters of methacrylic acid polymers.
25. The use of claim 22, wherein said medicament comprising said composition or said varnish is applied as an aerosol.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US60/080,116 | 1998-03-31 |
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MXPA00009631A true MXPA00009631A (en) | 2002-06-05 |
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