AU2005209647B2 - Deep penetrating antimicrobial compositions - Google Patents
Deep penetrating antimicrobial compositions Download PDFInfo
- Publication number
- AU2005209647B2 AU2005209647B2 AU2005209647A AU2005209647A AU2005209647B2 AU 2005209647 B2 AU2005209647 B2 AU 2005209647B2 AU 2005209647 A AU2005209647 A AU 2005209647A AU 2005209647 A AU2005209647 A AU 2005209647A AU 2005209647 B2 AU2005209647 B2 AU 2005209647B2
- Authority
- AU
- Australia
- Prior art keywords
- composition
- alcohol
- chloride
- weight
- percent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
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- 239000000203 mixture Substances 0.000 claims description 147
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 88
- 230000000845 anti-microbial effect Effects 0.000 claims description 64
- 235000019441 ethanol Nutrition 0.000 claims description 45
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 34
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 30
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 24
- 239000004094 surface-active agent Substances 0.000 claims description 24
- 229960000686 benzalkonium chloride Drugs 0.000 claims description 21
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 20
- -1 cationic quaternary ammonium compound Chemical class 0.000 claims description 20
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 18
- 235000011187 glycerol Nutrition 0.000 claims description 16
- 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 13
- 229960001950 benzethonium chloride Drugs 0.000 claims description 13
- IXOCGRPBILEGOX-UHFFFAOYSA-N 3-[3-(dodecanoylamino)propyl-dimethylazaniumyl]-2-hydroxypropane-1-sulfonate Chemical compound CCCCCCCCCCCC(=O)NCCC[N+](C)(C)CC(O)CS([O-])(=O)=O IXOCGRPBILEGOX-UHFFFAOYSA-N 0.000 claims description 12
- 239000004599 antimicrobial Substances 0.000 claims description 12
- 229960003333 chlorhexidine gluconate Drugs 0.000 claims description 12
- YZIYKJHYYHPJIB-UUPCJSQJSA-N chlorhexidine gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.C1=CC(Cl)=CC=C1NC(=N)NC(=N)NCCCCCCNC(=N)NC(=N)NC1=CC=C(Cl)C=C1 YZIYKJHYYHPJIB-UUPCJSQJSA-N 0.000 claims description 12
- YMKDRGPMQRFJGP-UHFFFAOYSA-M cetylpyridinium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 YMKDRGPMQRFJGP-UHFFFAOYSA-M 0.000 claims description 11
- 229960001927 cetylpyridinium chloride Drugs 0.000 claims description 11
- ARIWANIATODDMH-UHFFFAOYSA-N rac-1-monolauroylglycerol Chemical compound CCCCCCCCCCCC(=O)OCC(O)CO ARIWANIATODDMH-UHFFFAOYSA-N 0.000 claims description 11
- VAZJLPXFVQHDFB-UHFFFAOYSA-N 1-(diaminomethylidene)-2-hexylguanidine Polymers CCCCCCN=C(N)N=C(N)N VAZJLPXFVQHDFB-UHFFFAOYSA-N 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 10
- 229940074046 glyceryl laurate Drugs 0.000 claims description 10
- 229940123208 Biguanide Drugs 0.000 claims description 8
- 229920002413 Polyhexanide Polymers 0.000 claims description 8
- 229960002788 cetrimonium chloride Drugs 0.000 claims description 6
- WOWHHFRSBJGXCM-UHFFFAOYSA-M cetyltrimethylammonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+](C)(C)C WOWHHFRSBJGXCM-UHFFFAOYSA-M 0.000 claims description 6
- 230000003750 conditioning effect Effects 0.000 claims description 6
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 239000000758 substrate Substances 0.000 claims description 6
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 claims description 5
- 229960003260 chlorhexidine Drugs 0.000 claims description 5
- 229940008099 dimethicone Drugs 0.000 claims description 5
- 239000004205 dimethyl polysiloxane Substances 0.000 claims description 5
- 235000013870 dimethyl polysiloxane Nutrition 0.000 claims description 5
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 claims description 5
- 229920001296 polysiloxane Polymers 0.000 claims description 5
- WJLVQTJZDCGNJN-UHFFFAOYSA-N Chlorhexidine hydrochloride Chemical compound Cl.Cl.C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 WJLVQTJZDCGNJN-UHFFFAOYSA-N 0.000 claims description 2
- RARSHUDCJQSEFJ-UHFFFAOYSA-N p-Hydroxypropiophenone Chemical compound CCC(=O)C1=CC=C(O)C=C1 RARSHUDCJQSEFJ-UHFFFAOYSA-N 0.000 claims description 2
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 claims 5
- 230000000249 desinfective effect Effects 0.000 claims 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 claims 1
- 229940050410 gluconate Drugs 0.000 claims 1
- 238000009472 formulation Methods 0.000 description 80
- 150000003904 phospholipids Chemical class 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 230000009467 reduction Effects 0.000 description 20
- 229960005323 phenoxyethanol Drugs 0.000 description 15
- QCDWFXQBSFUVSP-UHFFFAOYSA-N 2-phenoxyethanol Chemical compound OCCOC1=CC=CC=C1 QCDWFXQBSFUVSP-UHFFFAOYSA-N 0.000 description 14
- 239000003205 fragrance Substances 0.000 description 14
- 239000002736 nonionic surfactant Substances 0.000 description 14
- 238000012360 testing method Methods 0.000 description 13
- 239000003093 cationic surfactant Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- XEFQLINVKFYRCS-UHFFFAOYSA-N Triclosan Chemical compound OC1=CC(Cl)=CC=C1OC1=CC=C(Cl)C=C1Cl XEFQLINVKFYRCS-UHFFFAOYSA-N 0.000 description 10
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 10
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- 229960004063 propylene glycol Drugs 0.000 description 10
- 210000003491 skin Anatomy 0.000 description 10
- 229960003500 triclosan Drugs 0.000 description 10
- 241000894006 Bacteria Species 0.000 description 9
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 9
- 239000002280 amphoteric surfactant Substances 0.000 description 9
- 125000002091 cationic group Chemical group 0.000 description 9
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 9
- 244000005700 microbiome Species 0.000 description 9
- 238000005187 foaming Methods 0.000 description 8
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 8
- 210000000245 forearm Anatomy 0.000 description 7
- BOUCRWJEKAGKKG-UHFFFAOYSA-N n-[3-(diethylaminomethyl)-4-hydroxyphenyl]acetamide Chemical compound CCN(CC)CC1=CC(NC(C)=O)=CC=C1O BOUCRWJEKAGKKG-UHFFFAOYSA-N 0.000 description 7
- BARWIPMJPCRCTP-CLFAGFIQSA-N oleyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCCOC(=O)CCCCCCC\C=C/CCCCCCCC BARWIPMJPCRCTP-CLFAGFIQSA-N 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 229930003799 tocopherol Natural products 0.000 description 7
- 239000011732 tocopherol Substances 0.000 description 7
- 229960001295 tocopherol Drugs 0.000 description 7
- 235000010384 tocopherol Nutrition 0.000 description 7
- 239000003945 anionic surfactant Substances 0.000 description 6
- 230000001186 cumulative effect Effects 0.000 description 6
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 6
- 229960004592 isopropanol Drugs 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 102000004196 processed proteins & peptides Human genes 0.000 description 6
- DMWVYCCGCQPJEA-UHFFFAOYSA-N 2,5-bis(tert-butylperoxy)-2,5-dimethylhexane Chemical compound CC(C)(C)OOC(C)(C)CCC(C)(C)OOC(C)(C)C DMWVYCCGCQPJEA-UHFFFAOYSA-N 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- MRUAUOIMASANKQ-UHFFFAOYSA-N cocamidopropyl betaine Chemical compound CCCCCCCCCCCC(=O)NCCC[N+](C)(C)CC([O-])=O MRUAUOIMASANKQ-UHFFFAOYSA-N 0.000 description 5
- PUAQLLVFLMYYJJ-UHFFFAOYSA-N 2-aminopropiophenone Chemical compound CC(N)C(=O)C1=CC=CC=C1 PUAQLLVFLMYYJJ-UHFFFAOYSA-N 0.000 description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical class C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 4
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- UKHVLWKBNNSRRR-ODZAUARKSA-M dowicil 200 Chemical compound [Cl-].C1N(C2)CN3CN2C[N+]1(C\C=C/Cl)C3 UKHVLWKBNNSRRR-ODZAUARKSA-M 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 150000004665 fatty acids Chemical class 0.000 description 4
- 210000004905 finger nail Anatomy 0.000 description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- 241000228245 Aspergillus niger Species 0.000 description 3
- BYMMIQCVDHHYGG-UHFFFAOYSA-N Cl.OP(O)(O)=O Chemical compound Cl.OP(O)(O)=O BYMMIQCVDHHYGG-UHFFFAOYSA-N 0.000 description 3
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 3
- 244000011376 Leptospermum laevigatum Species 0.000 description 3
- 235000017865 Leptospermum laevigatum Nutrition 0.000 description 3
- NVNLLIYOARQCIX-MSHCCFNRSA-N Nisin Chemical compound N1C(=O)[C@@H](CC(C)C)NC(=O)C(=C)NC(=O)[C@@H]([C@H](C)CC)NC(=O)[C@@H](NC(=O)C(=C/C)/NC(=O)[C@H](N)[C@H](C)CC)CSC[C@@H]1C(=O)N[C@@H]1C(=O)N2CCC[C@@H]2C(=O)NCC(=O)N[C@@H](C(=O)N[C@H](CCCCN)C(=O)N[C@@H]2C(NCC(=O)N[C@H](C)C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCSC)C(=O)NCC(=O)N[C@H](CS[C@@H]2C)C(=O)N[C@H](CC(N)=O)C(=O)N[C@H](CCSC)C(=O)N[C@H](CCCCN)C(=O)N[C@@H]2C(N[C@H](C)C(=O)N[C@@H]3C(=O)N[C@@H](C(N[C@H](CC=4NC=NC=4)C(=O)N[C@H](CS[C@@H]3C)C(=O)N[C@H](CO)C(=O)N[C@H]([C@H](C)CC)C(=O)N[C@H](CC=3NC=NC=3)C(=O)N[C@H](C(C)C)C(=O)NC(=C)C(=O)N[C@H](CCCCN)C(O)=O)=O)CS[C@@H]2C)=O)=O)CS[C@@H]1C NVNLLIYOARQCIX-MSHCCFNRSA-N 0.000 description 3
- 108010053775 Nisin Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 206010041925 Staphylococcal infections Diseases 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
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- 230000002421 anti-septic effect Effects 0.000 description 3
- 229940027983 antiseptic and disinfectant quaternary ammonium compound Drugs 0.000 description 3
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- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 230000002209 hydrophobic effect Effects 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
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- 125000001095 phosphatidyl group Chemical group 0.000 description 3
- 125000001453 quaternary ammonium group Chemical group 0.000 description 3
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- NKZMCHIKTDEJNP-UHFFFAOYSA-N zinc;oxygen(2-);propane-1,2,3-triol Chemical compound [O-2].[Zn+2].OCC(O)CO NKZMCHIKTDEJNP-UHFFFAOYSA-N 0.000 description 3
- OSDLLIBGSJNGJE-UHFFFAOYSA-N 4-chloro-3,5-dimethylphenol Chemical compound CC1=CC(O)=CC(C)=C1Cl OSDLLIBGSJNGJE-UHFFFAOYSA-N 0.000 description 2
- DITDKJOHAAZUGD-UHFFFAOYSA-N 4-methyl-1,3-dioxolan-2-one;propane-1,2-diol Chemical compound CC(O)CO.CC1COC(=O)O1 DITDKJOHAAZUGD-UHFFFAOYSA-N 0.000 description 2
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N Betaine Natural products C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 2
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- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 2
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- QWZLBLDNRUUYQI-UHFFFAOYSA-M Methylbenzethonium chloride Chemical compound [Cl-].CC1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 QWZLBLDNRUUYQI-UHFFFAOYSA-M 0.000 description 2
- KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical compound C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
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- 230000001476 alcoholic effect Effects 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- CBTVGIZVANVGBH-UHFFFAOYSA-N aminomethyl propanol Chemical compound CC(C)(N)CO CBTVGIZVANVGBH-UHFFFAOYSA-N 0.000 description 2
- 125000000129 anionic group Chemical group 0.000 description 2
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- 125000004432 carbon atom Chemical group C* 0.000 description 2
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- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
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- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
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- FJLUATLTXUNBOT-UHFFFAOYSA-N 1-Hexadecylamine Chemical compound CCCCCCCCCCCCCCCCN FJLUATLTXUNBOT-UHFFFAOYSA-N 0.000 description 1
- GKQHIYSTBXDYNQ-UHFFFAOYSA-M 1-dodecylpyridin-1-ium;chloride Chemical compound [Cl-].CCCCCCCCCCCC[N+]1=CC=CC=C1 GKQHIYSTBXDYNQ-UHFFFAOYSA-M 0.000 description 1
- CPKVUHPKYQGHMW-UHFFFAOYSA-N 1-ethenylpyrrolidin-2-one;molecular iodine Chemical compound II.C=CN1CCCC1=O CPKVUHPKYQGHMW-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical class C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- DJMUYABFXCIYSC-UHFFFAOYSA-N 1H-phosphole Chemical compound C=1C=CPC=1 DJMUYABFXCIYSC-UHFFFAOYSA-N 0.000 description 1
- XFOQWQKDSMIPHT-UHFFFAOYSA-N 2,3-dichloro-6-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CC=C(Cl)C(Cl)=N1 XFOQWQKDSMIPHT-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- OBWBSSIUKXEALB-UHFFFAOYSA-N 2-aminoethanol;2-hydroxypropanamide Chemical compound NCCO.CC(O)C(N)=O OBWBSSIUKXEALB-UHFFFAOYSA-N 0.000 description 1
- SOANRMMGFPUDDF-UHFFFAOYSA-N 2-dodecylaniline Chemical compound CCCCCCCCCCCCC1=CC=CC=C1N SOANRMMGFPUDDF-UHFFFAOYSA-N 0.000 description 1
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- 229940083122 ganglion-blocking antiandrenergic bisquaternary ammonium compound Drugs 0.000 description 1
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- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- ACGUYXCXAPNIKK-UHFFFAOYSA-N hexachlorophene Chemical compound OC1=C(Cl)C=C(Cl)C(Cl)=C1CC1=C(O)C(Cl)=CC(Cl)=C1Cl ACGUYXCXAPNIKK-UHFFFAOYSA-N 0.000 description 1
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
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- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000007903 penetration ability Effects 0.000 description 1
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
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- 229920000573 polyethylene Chemical class 0.000 description 1
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- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
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- MILWSGRFEGYSGM-UHFFFAOYSA-N propane-1,2-diol;propane-1,2,3-triol Chemical compound CC(O)CO.OCC(O)CO MILWSGRFEGYSGM-UHFFFAOYSA-N 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
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- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
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- 230000008313 sensitization Effects 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- LLKGTXLYJMUQJX-UHFFFAOYSA-M sodium;3-[2-carboxyethyl(dodecyl)amino]propanoate Chemical compound [Na+].CCCCCCCCCCCCN(CCC(O)=O)CCC([O-])=O LLKGTXLYJMUQJX-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 150000003445 sucroses Chemical class 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000003784 tall oil Substances 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- UWHCKJMYHZGTIT-UHFFFAOYSA-N tetraethylene glycol Chemical compound OCCOCCOCCOCCO UWHCKJMYHZGTIT-UHFFFAOYSA-N 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- YUYCVXFAYWRXLS-UHFFFAOYSA-N trimethoxysilane Chemical compound CO[SiH](OC)OC YUYCVXFAYWRXLS-UHFFFAOYSA-N 0.000 description 1
- 150000003673 urethanes Chemical class 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
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- 239000011709 vitamin E Substances 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N31/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic oxygen or sulfur compounds
- A01N31/08—Oxygen or sulfur directly attached to an aromatic ring system
- A01N31/16—Oxygen or sulfur directly attached to an aromatic ring system with two or more oxygen or sulfur atoms directly attached to the same aromatic ring system
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N31/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic oxygen or sulfur compounds
- A01N31/02—Acyclic compounds
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Agronomy & Crop Science (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Dentistry (AREA)
- General Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Environmental Sciences (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Cosmetics (AREA)
Description
P/00/011 Regulation 3.2
AUSTRALIA
Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Invention Title: Deep penetrating antimicrobial compositions The following statement is a full description of this invention, including the best method of performing it known to us: 004613743 lA DEEP PENETRATING ANTIMICROBIAL COMPOSITIONS a BACKGROUND OF THE INVENTION 1. Field of the Invention This invention is related to antimicrobial compositions D 5 which provide instant and long-lasting antimicrobial activity.
2. Related Art
OD
2 SThe normal skin flora consists of both resident and transient populations of bacteria. It is thought that O chronic exposure to pathogenic organisms in a hospital environment can lead to their becoming part of the resident flora of the stratum corneum. In a healthcare O setting, nosocomial infections are mostly spread through the more loosely-attached transient flora. Most Stransient organisms can be rinsed away mechanically by simple handwashing with a non-antimicrobial soap. In surgical environments, it is also critical to reduce the resident populations of bacteria, which are frequently pathogenic. The dramatic reduction of these deeper and more adherent bacteria requires potent antiseptics, or Is chemical disinfection. Residual efficacy depends on penetration, release and retention of antimicrobial agents into the stratum corneum to prevent recolonization of bacteria.
The most commonly used active ingredients in today's surgical scrubs are chlorhexidine gluconate (CHG) and iodophors, such as povidone-iodine(PVP- Iodine). CHG exhibits broad-spectrum antimicrobial activity and extended antimicrobial persistence, by binding to young epithelial cells for an extended time.
While considered to be generally safe, allergic reactions do occur. The antimicrobial activity of PVP- Iodine is also quite good, but its persistence is poor, and is easily inactivated by blood and organic JJM-510 3 materials. The oxidizing nature of iodine also leads to dthe typical harshness of iodophor types of scrubs.
There are only two Category I active ingredients specifically mentioned in the monograph for Surgical Hand Scrubs (21CFR 333.414 Vol. 59, No. 116), alcohol O and iodine.
The most safe, rapid-acting and broad spectrum antimicrobial is undoubtedly alcohol. It chemically dissolves and disrupts cell walls of both gram positive and negative bacteria. It's residual activity is extremely limited but the log 0 lo reduction of bacteria is so severe that populations cannot reestablish themselves for several hours after application. Currently, alcoholic hand disinfection is more universally used in surgical wards in Europe than in the United States.
Because of its strong antiseptic action and reasonably good skin tolerance when properly formulated, high alcoholic products are also becoming well accepted in the as shown by the recent surge of popularity of antiseptic hand gels in the consumer and healthcare provider markets.
Accordingly, there is a need for an efficacious, convenient, surgical handwash, which will exhibit excellent instantaneous antibacterial kill as well as persistent antimicrobial activity equal to or surpassing the6current state of the art. The improved antimicrobial composition should be achieved without the JJM-510 004613743 4 S known drawbacks and disadvantages such as requiring a lengthy S surgical scrub application procedure, requiring use of scrub brushes which are harsh to the skin due to mechanical abrasion; being drying to the skin; causing the possibility of allergic reaction such as with CHG; or causing the possibility of irritation or sensitization particularly when using CHG or iodophors.
\O
Cl That is, improved antimicrobial compositions should be non- C irritating, moisturizing, and should leave a protective barrier C 10 on the skin after washing, possibly extending to latex protein blocking ability. Acceptability of such a product would be superior to surgeons and health care workers and thus increase compliance with handwashing protocols. The invention (product) is intended to replace traditional pre-operative scrubs containing CHG, hexachlorophene, iodophors, and parachlorometaxylenol (chloroxylenol).
SUMMARY OF THE INVENTION This invention relates to an antimicrobial composition comprising: a) an alcohol b) an effective amount of a cationic quaternary ammonium compound; c) an effective amount of phenoxy ethanol; d) an effective amount of a surfactant system, the system comprising surfactants other than anionic surfactants; and e) optionally a biguanide compound.
004613743 o In one embodiment, the cationic quaternary ammonium compound S is selected from the group consisting of benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride and mixtures
C/)
thereof, with the surfactant system being a mixture of nonionic, and cationic surfactants and optionally amphoteric surfactants, and with the optional biguanide compound present.
Desirably, the compositions of the invention further Ci comprise an effective amount of a compatible skin conditioning system, the system comprising of skin conditioners and Ci 10 percutaneous enhancers such as glycerin, phenylethyl dimethicone, silicone quaternary compounds LAMBENT QUAT AD, available from Lambent Technologies), and propylene glycol.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION The present invention is directed to antimicrobial compositions comprising a blend of antimicrobial agents and a particular combination of surfactants, the surfactant not including any anionic surfactants.
V-6eCq The compositions of the present invention have Sshown excellent antimicrobial efficacy in both alcohol- Scontaining and non-alcohol containing systems.
In a preferred embodiment, the antimicrobial compositions of this invention contain alcohol and such \0 alcohol-containing compositions have extremely high 0 antimicrobial effectiveness even when used as a wash-off [V product. Thus, despite the inclination of those skilled in the art that the wash-off nature of a product is a disadvantage due the active antimicrobial being rinsed away, the compositions of this invention appear to compensate for loss of active antimicrobial due to rinsing by providing enhanced penetrating and depositing properties.
The antimicrobial components of the present invention contain an effective amount of cationic quaternary ammonium compounds, and a surfactant system of nonionic, cationic, and optionally amphoteric surfactants, and desirably a biguanide compound.
Examples of cationic quaternary ammonium compounds include benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride, polymeric ammonium chloride, and bisquaternary ammonium compounds.
Examples of biguanide compounds include chlorhexidine or its--derivatives, such as chlorhexidine gluconate, chlorhexidine digluconate, chlorhexidine JJM-510 7diacetate, chlorhexidine dihydrochloride and polyhexamethylene biguanide.
Other optional antimicrobial compounds include, alkyl pyridinium salts such as cetylpyridinium chloride; antimicrobial polypeptides such as Nisin (34 amino acid peptide) and of different families such as.amphiphilic Cysteine containing beta sheet peptides (Defensins), Cysteine-Disulfide ring peptides (Cyclic dodecapeptide, Ranlexin, Brevinins), Amphiphilic alpha-helix peptides (Magainins, Cecropins), linear peptides with one or two predominant amino acids, Mammalian and Avian disulfidelinked antimicrobial molecules (Human neutrophil peptide, Human defensin, Neutrophil peptide, Macrophage is cationic peptide and beta-defensins).
Preferred antimicrobial compounds include benzalkonium chloride and/or benzethonium chloride, polyhexamethylene biguanide, phenoxyethanol, propylene glycol, Coco PG-dimonium chloride phosphate (phospholipid CDM), chlorhexidine gluconate and/or cetyl-pyridinium chloride.
The effective amounts of the foregoing antimicrobial agents will typically be in the following weight ranges, but to those skilled in the art variation in the following ranges may occur but with the benefits of this invention still being achieved: benzalkonium chloride. .typically 0.02 to preferably 0.05 to most preferably 0.05 to 0.15%, benzethonium JJM-510 8- Cl chloride typically 0.02 to preferably 0.02 to most preferably 0.05 to 0.12 polyhexamethylene biguanide typically 0.01 to preferably 0.02 to 0 most preferably 0.03 to 0.5 %;phenoxyethanol typically 0.1 to preferably 0.2 to most preferably 0.5 to propylene glycol typically 0.1 ID to 40%, preferably 1.0 to 20.0%, most preferably 5.0 to S15.0%; Coco-PG dimonuim chloride phosphate typically 0.1 Sto preferably 0.2 to most preferably 0.5 to and cetylpyridinium chloride typically 0.01 to Cl preferably 0.02 to 0.35%, most preferably 0.05 to 0.3%.
In addition to the foregoing antimicrobial agents, the following optional antimicrobial agents may be used: (Dowcil-200) typically 0.1 to Boregeamidoprophyl phosphatidyl PG-Dimonium Chloride (Phospholipid GLA) typically 0.1 to Coco PGdimonuim chloride phosphate (Phospholipid CDM) typically 0.1 to triclosan typically 0.1 to chlorhexidine gluconate typically 0.01 to polyhexamethylenebiguanide hydrochloride typically 0.02 to 5% and methylbenzethonium chloride typically 0.05 to by weight.
The surfactant system useful in this invention is comprised of amphoteric, nonionic, and cationic surfactants. Each of these surfactants are typically present in the antimicrobial system of this inventi-on-- JJM-510 O9 Cl ranging from 0.1 to 15, preferably 0.1 to 8, most O preferably 0.2 to 5% by weight.
Examples of suitable amphoteric surfactants include those related or derived from betaines such as amine betaines and amido betaines. Also useful amphoteric surfactants include glycinate and/or imidazole 0 derivatives such as coco-imidazoline mono-carboxylate Cl ln and/or dicarboxylate. Preferred amphoteric sufactants for use with this invention include hydroxysultaine, cocamidropropyl betaine, and sodium lauriminodipropionate, and disodium lauroamphodiacetate.
Nonionic surfactants are neutral molecules without any charge, and these compounds are very mild with poor foaming properties. Non-ionic compounds diminish surface tension and dissolve in water quite easily, but not in same way as common salt. They are equally soluble in oil, which is important in producing emulsions. In the presence of water, they do not' form simple solutions, they form complexes known as hydrates. Applications for nonionics include solubilization and for cationics, conditioning. Examples Alkyl phenol ethoxylates, fatty acid dialkanolmides, fatty acid monoalkanolamides, fatty acid ethoxylates, fatty alcohol ethoxylates, fatty amine ethoxylates, substituted phenol ethoxylates, vegetable oil ethoxylates, polyalkylglycosides, sucrose esters and glyceryl laurate.
JJM-510 10 1 Generally, preferred nonionic surfactants include condensation products of one or more alkylene oxide groups with an organic hydrophobic compound, such as an 0 aliphatic or alkyl aromatic compound. Exemplary nonionic surfactants based upon polyethoxylated, polyproproxylated, or polyglyceroxylated alcohols, ND alkylphenols, or fatty acids.
V3 Further specific examples of nonionic surfactants 0o include, for example, alkyl phenoxypolyethoxy ethanols having alkyl groups from about 7 to 18 carbon atoms and from about 6 to about 60 oxyethylene units such as, for example, heptyl phenoxypolyethoxyethanols, ethylene oxide derivatives of long chained carboxylic acids such is as lauric acid, myristic acid, palmitic acid, oleic acid, and the like, or mixtures of acids such as those found in tall oil containing from about 6 to oxyethylene units; ethylene oxide condensates of longchained alcohols such as octyl, decyl, lauryl, or cetyl alcohols containing from 6 to 60 oxyethylene units; ethylene oxide condensates of long-chain or branched chain amines such as dodecyl amine, hexadecyl amine, and octadecyl amine, containing from about 6 to oxyetheylene units; and block copolymers of ethylene oxide sections combined with one of more hydrophobic propylene oxide sections.
Examples of cationic surfactants include, for example, lauryl pyridinium-chloride, cetyldimethyl amine JJM-510 II C( acetate, and alkyldimethylbenzylammonium chloride, in Swhich the alkyl group has from 8 to 18 carbon atoms.
0 Other useful cationic surfactants include aliphatic fatty amines and their derivatives, homologues of aromatic amines having fatty chains dodecylaniline, fatty amides derived from aliphatic diamines, fatty C amides derived from disubstituted amines, quaternary
B
n ammonium compounds, amides derived from aminoalcohols and their quaternary ammonium derivatives, quaternary ammonium bases derived from fatty amides of disubstituted diamines, quaternary ammonium bases of the benzimidazolines, basic compounds of pyridinium and its derivatives, quaternary ammonium compound of betaine, dimethylphenylbenzyl ammonium chloride, urethanes or basic salts of ethylene diamine, polyethylene diamines and their quaternary ammonium compounds.
A particularly useful mixture of surfactants comprise from about 0.1 to about 10% active weight of cocamidopropyl hydroxysultaine (amphoteric surfactant), from about 0.1 to about 10% active weight of polyalkylglycoside (preferably Plantaren 2000 from Henkel), nonionic surfactant, and from about 0.1 to about 10 by active weight of PPG-40 diethylmonium chloride (Preferably Emcol CC-42 from Witco Chem. Co.), cationic surfactant.
The mixture of-amphoteric, nonionic, and cationic surfactants of this invention have been shown to be JJM-510 12 compatible with high alcohol and low water systems, OC thereby resulting.in a stable formulation.
The alcohol used with the composition of this invention is typically present in an amount ranging from about 20 to about 80%, preferably 40 to 80%, most O preferably 60 to 70% by volume of the composition. The Salcohols useful in the present invention include ethyl ln alcohol, iso-propyl alcohol, n-propyl alcohol and combinations thereof. Ethyl alcohol may be used as the only alcohol or the alcohol may be a mixture from about to 70% by volume ethyl alcohol, from about 10 to by volume iso-propyl alcohol, and from about 10 to 70 by volume n-propyl alcohol.
Other materials may be added to the compositions of this invention to improve such characteristics as skin conditioning and moisturization of the compositions.
Thus, humectants such as glycerin, antiinflammatory/anti-irritants such as isolene (C.
2
-C
18 diglycerides), anchoring agents, conditioners such as phenylethyl dimethicone (Silsoft PEDM from Witco OSi), silicone quaternary compound Lambent Quat AD from Lambent Technologies, A Petroferm Company), cetrimonuim chloride, and glyceryl laurate. Glyceryl laurate (a nonionic surfactant) in addition to contributing to conditioning and penetration of the antimicrobial compositions disclosed herein, also acts as a foam JJM-510 -13 Cl Typically, these additional agents may be present in the compositions of this invention according to the following amounts: glycerin from about 0.1 to about by weight, phenylethyl dimethicone from about 0.01 to s about 0.5% by weight, silicone quaternium, 8 from about 0.1 to about 5% by weight, cetrimonium chloride from IND about 0.2. to about 5% by weight and glyceryl laurate from about 0.5% to about 10% by weight of the composition of this invention.
The antimicrobial compositions of the present invention are effective in controlling microorganisms when an effective amount of the composition is topically applied to a substrate or location, such as the hands., acne sites, patient prepping sites, or injection site for catheters, etc. The amount applied to be effective depends upon such environmental factors as the length of application, the amount of contact of the antimicrobial composition and the substrate, the condition of substrate normal or dry skin) as well temperature and evaporation rates. Those with skill in the art will readily be able to determine the effective level necessary to control the microorganisms. .Typically, from about 0.5 to about 10 milliliters, preferably from about 1.0 to about 9, and most preferably from about to about 5 milliliters of the antimicrobial composition is applied. This amount of the antimicrobial composition if found to be effective, to provide a loglo reduction of or more in the microbe population. Also,-. thj,arnq.=,t JJM- 510 005088249 14 00 O is enough to exhibit residual and cumulative antimicrobial effects on resident skin flora.
The present invention can also be prepared as an emulsion
\O
using techniques well known in the art, see for example US Patent s No. 5,308,890. The active ingredients, excipients, etc., may be emulsified with amphoteric, cationic, and nonionic surfactants in
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S the amounts previously noted.
EXAMPLES
Cl The following examples are illustrative of the present .0 invention and are not intended to limit the invention to the following compositions. Unless noted to the contrary, all percentages presented in this application are understood to be weight percent.
The following formulations were applied to the skin following a modified surgical scrub procedure identified and described as Scrub procedure One in co-pending, commonly assigned U.S. patent Application No. 09/460013, entitled "Novel Skin Disinfection Procedures" the disclosure of which is hereby incorporated by reference. The formulations were subsequently tested by the methods hereinafter described for antimicrobial effectiveness.
Scrub Procedure One [Dry application, rub, dry application, rub, wet, lather, rinse] Step 1.1: Volunteers' fingernails are checked to determined if they. are <1.0 mm free edge. If not, they are clipped. Remove all jewelry from hands and arms.
Step 1.2: Subjects wet their hands including two-thirds s of forearms under running tap water 40 2 0 C for seconds. Clean under fingernails and around the cuticle u area with a nail cleaner. Rinse fingernails, cuticles, and hands.
V) Step 1.3: Subjects dry hands thoroughly with paper 010 towels.
Step 1.4: Dispense into the subject's hands 5 ml of the assigned test article. Subjects are to distribute the material over all surfaces of the hands and lower twothirds of the forearms taking care not to lose the substance.
Step 1.5: The material is vigorously rubbed over the hands and lower two-thirds of the forearms. Particular attention is paid to the nails, cuticles and interdigital spaces. Note: This step is performed over a period of approximately one-minute.
Step 1.6: Dispense a second 5 ml aliquot of the test article in the subject's cupped hands.
Subjects are to distribute it over all the surfaces of the hands and lower one-third of the forearm, taking care not to lose the substance.
Step 1.7: Repeat the treatment procedure described in step 1.5 except limit the scrub to the hands and lower one-third of the forearms. (An additional one minute of rubbing time) JJM-510 0D 16 C Steo 1.8: Subjects wet hands under tap by passing hands Sone or two times through water.
Step 1.9: The test article is vigorously rubbed over 0 the hands and lower one-third of the forearms paying particular attention to the finger nail region. Note: this lathering step is performed over a period of one IN minute.
SStep 1.10: Rinse each hand and forearm separately for Sone minute per hand and shake to remove excess water.
010 Step 1.11: Proceed with antimicrobial effectiveness testing.
Total Rubbing/Lathering time: 3 minutes.
The following compositions were used in the 1s formulations hereinafter described: AMP 95 is a mixture of 2-amino-2-methyl-l-propanol, 2- (methylamino)-2-methyl-l-propanol and water in a ratio of from about 90:5:5, commercially available from Angus Chemical Company.
ACRITAMER® 505E. a polyvinyl carboxy polymer crosslinked with ethers of pentaerythritol, R.I.T.A available from Crystal Lake, IL.
AMPHOTERGE K-2, coco imidazoline dicarboxylate, available from Lonza.
ESS 9090C is a-fragrance, available from Givuan-Roure Corporation.
JJM-510 17 CERAPHYL 28 is a mixture of cetyl alcohol and cetyl lactate, a waxy solid commercially available for ISP Van O Dyk Inc.
CERAPHYL 41 is a mixture of C 12
C
1 s alcohol lactates, -O available from ISP Van Dyk Inc.
SCETIOL HE- PEG-7 glyceryl cocoate, from Henkel.
COSMOCIL CQ is polyhexamethylene biguanide, available Cl from Zeneca.
DISODIUM EDTA, available from Dow Chemical as Versene NA.
DOW CORNING® 580 wax is a mixture of stearoxy trimethoxy silane and stearyl alcohol.
DOWICIL 200, quaternium 15, Dow Chemical.
EMCOL CC42- PPG-40 dimonium chloride, or quaternium 21, available from Witco Corp.
GERMABEN II is a mixture comprised of diazolindinyl urea (about methyl paraben (about propyl paraben (about and propylene glycol (about available from Sutton Laboratories.
JJM-510 -18 G. -ERNALL PLUS is a *mixture of diazolidinyl urea (about 9996), '3-Iodo-pr-opynylbuty2.carbamate available from Sutton Laboratories.
s INCRONECTAINT LAIYEA- a mixture of acetamide monoethanolamine, arnd lactamide monoethanolamine (Croda) LEXOREZ 100 is a saturated crosslinked hydroxy functional; polyester, comprised of glycerin, diethylene :L 0 glycol, adilpate crosslinked polymer, which is a viscous, hydrophobic liquid at room temperature and is dispersible in many lipids and emollients.
LEXQU.AT AMG-IS, isostearamidopropyl PG dimonium chloride is (Inolex Chemical Company) MACKAM CBS-5OG, cocamidopropyl hydroxysultaine, (McIntyre) MEARLMAID OL contains isopropyl alcohol, guanine, and Polysorbate 80 (Engelhard).
MIRATAINE CB cocamidopropyl betaine (Rhone-Poulenc) NATROSOL 250 HHR hydroxyethylcellulose (Agualon, Div.
Of Hercules).
NISIN, a 34 amino acid polypeptide, sold as Ambicin by" Applied Microbiology, JiM-510 -19 ORANGE ZEST B FRAGRANCE, a blend of oily volatile compounds, sold by Firmenich, Inc.
PEG-7 Glyceryl Cocoate (see Cetiol HE) PEO-1 polyethylene glycol, 21,000 M.W. INCI: PHOS'POLIP:D CDM is cocophosphatidyl (PG) -dimonium chloride, a co-synthetic, phospholipid available from Mona Industries, Inc.
PHOSPHOLIPID GLA borageamidopropyl phosphatidyl PGdirnonium chloride (Mona).
PHOSPOLIPID PTC is cocamidopropyl phosphatidyl PGdimoniJumn chloride, available form Mona Industries.
PLANTAREN 2000 is decyl polyglucose, available from Henkel /Cospha.
!0 SILSOFT PEDM is phenylethyl dimenthicone, available from Witco Cooperation, Osi Specialties,,Inc.
SEAFOAM 143.258/GGE, fragrance available from Firmenich, Inc.
TOCOPHEROL (dl-alpha-tocopherol), Vitamin E, available from Roche Vitamins and Fine Chemicals.
TRICLOSAN 2, 4, 4'-trichloro-2-hydoxydiphenyl ether.
JiM -510 20 4 ULTREZ® 10 a carbomer polymer, available from BF SGoodrich, Cleveland Ohio, and disclosed in US patent S004,598, the contents of which are incorporated by reference in its entirety.
VAROX 270 lauramine oxide, 30% active of 70% C12, available from Witco.
EXAMPLE 1 This is a comparative example to demonstrate the shortcoming of using antimicrobial systems containing anionic surfactants ammonium laureth sulfate) in terms forming formulations of long-lasting 6 hours) antimicrobial effectiveness.
Formulation 1-1: Ethanol 62% D.I. Water Zinc Oxide Glycerin PEG-7 Glyceryl Cocoate Lexorez 100 Silsoft A- 843 Lexquat AMG-IS Incromectant LAMEA Tocopherol Ceraphyl 41 Natrosol 250 HHR PEO-1 Seafoam fragrance (0.15%),Plantaren 2000 Ammonium Laureth Sulfate EtOH (53.1% Phenoxyethanol Benzalkonium Chloride [50% solution] Germall Plus Germaben II Phospholipid CDM Phospholipid GLA Formulation 1-2 (w/triclosan) Ethanol Water Zinc Oxide Glycerin JJM-510 S- 21 Cetiol HE Lexorez 100 Silsoft Ad) 843 Lexquat AMG-IS Incromectant LAMEA Tocopherol Ceraphyl 41 Natrosol O 250 HHR PEO-1 Seafoam fragrance (0.15%),Plantaren 2000 Ammonium Laureth Sulfate EtOH (46.2% Phenoxyethanol
\O
Benzalkonium Chloride [50% solution] Germall Plus Germaben II Phospholipid CDM n Phospholipid GLA Triclosan Formulation 1-3 Australian Tea Tree Oil): Ethanol 62% D.I. Water Zinc Oxide Glycerin Cetiol HE Lexorez 100 Silsoft A-843 Lexquat AMG-IS Incromectant LAMEA Tocopherol Ceraphyl 41 Natrosol 250 HHR PEO-1 Seafoam fragrance (0.15%),Plantaren 2000 Ammonium Laureth Sulfate EtOH (53.1% Phenoxyethanol Benzalkonium Chloride [50% solution] Germall Plus Germaben II Phospholipid CDM Phospholipid GLA Australian Tea Tree Oil The pH of the preceding formulations was adjusted with phosphoric acid to The results of antimicrobial effectiveness of the foregoing formulations are summarized in TABLE 1 in -terms of the cumulative and persistent activity for 1, 2, and 5 days at 0 and 6 hours as measured by the log 10 JJM-510 -22 CA reductions. Briefly, the logo reduction test method is conducted on subjects selected from a group of volunteers who have refrained from using any antimicrobials for at least two weeks prior to initiation of the test. Sufficient number of subjects are selected from this group on the basis of high NO initial bacteria count, 1 X 10 s per hand as determined by Sbaseline measurements of the bacteria on their hands.
The selected subjects perform a simulated surgical handwash under the supervision of an individual competent in aseptic technique. One hand is sampled after the surgical handwash and the other hand after 6 hours. The difference between the base line and the is recovered organisms after surgical hand wash gives the antimicrobial effectiveness of test formulations.
Those with skill in the art will appreciate that the compositions with higher log 0 l reduction value indicates improved efficacy. The loglo reduction is the difference in the initial bacterial counts and the count recovered after each treatment.
TABLE 1 Time 0 hr 6 hr 0 hr 6 hr 0 hr 6 hr Formulation 1-1 1-1 1-2 1-2 1-3 1-3 Day 1 0.58 -0.1 0.68 -0.15 0.59 0.38 Day 2 0.52 -0.25 0.89 -0.0008 1.01 1.05 Day 5 1.13 0.30 1.02 0.56 1.60 1.79 JJM-510 -23 Cq Cumulative activity of the tested formulations was e( evaluated by comparing the logio reductions achieved at 0 hours on day 1 to the loglo reductions achieved at 0 hours on day 2 and 5. The paired test" results of these comparisons indicated significantly more antimicrobial activity on days 2 and 5 at 0 hours \O compared to day 1 at 0 hours for Formulation 1-3.
Significantly more antimicrobial activity was indicated Vn on day 5 but not day 2 at 0 hours compared to day 1 at 0 hours for Formulation 1-1 and Formulation 1-2. Those with skill in the art will appreciate that the test" is a statistical method used to compare the test material from the control to establish the significance at 0.05 level of significance. This compares the differences between means of the two distributions divided by the flux about those means. This then is the value for that difference. The larger the value the greater the probability that the two means are different because they come from distinct rather than just random sampling chance.
Mathematically speaking values become large as: 1) the difference between the two means gets larger; and 2) the flux about the mean (standard deviations) get smaller.
However, the low log 0 reductions and weak persistent activity of all tested formulations, which fall well short of FDA requirements--for -a surgical scrub, are believed to be attributed to inactivation of JJM-510 24 the antimicrobial compositions, by the highfoaming anionic-based surfactant system, the ammonium laureth sulfate. Thus, the foregoing formulations do not provide an adequate solution to the s problem of providing long-lasting antimicrobial effectiveness.
EXAMPLE 2 In view of the results of Example 1, the following formulations free of anionic surfactants were screened o0 for in vivo antimicrobial efficacy both at 0 Time and 6 Hours (to test for cumulative or residual effects).
Formulation 2-1: EtOH (61.8% W/W or 70% D.I.
Water Mirataine CB (6.0 Glycerin, Amphoterge K-2 HC 1 N Cetiol HE Zinc Oxide Lexorez 100 Silsoft A-843 Ceraphyl 41 Natrosol 250 HHR PEO-1 Seafoam fragrance Varox 270 Phenoxyethanol Benzalkonium Chloride [50% solution] Germall Plus Germaben II Phospholipid CDM Phospholipid GLA Propylene Glycol and Propylene carbonate Formulation 2-2: EtOH (52.9% W/W or 60 Isopropyl alcohol (4.38 W/W or 5 n-Propyl alcohol 49 w/w or 5 D.I. Water Mirataine CB Glycerin Amphoterge K-2 HC1 1 N Cetiol HE (.10%JL,.._Z.inc Oxide Lexorez 100 Silsoft A-843 Tocopherol JJM-510 Ceraphyl 41 Natrosol 250 HR PEO-1 Seafoam fragrance Varox 270 Phenoxyethanol Berizalkoniun Chloride Solutionl G-errnall Plus Gerrnaben II s Phospholipid CDM Phospholipid GLA Propylene Glycol and Propylene IND carbonate Formulation 2-3 (w/Triclosan): EtOH (48.42% W/W or :LO Isopropyl alcohol (8.76 W/W or 10 v/v) 1 n-Propyl alcohol (4.48 w/w or 5 v/v) 1 D.I. Water (18.51%), Mirataine CB (6.0 Glycerin Amphoterge K-2 Ed1 1 N Cetiol HE Zinc oxide Lexorez 100 Silsoft A-843 Tocopherol Ceraphyl. 41 Natrosol 250 HER PEO-1 Seafoam fragrance Varox.270 Phenoxyethanol Benzalkonium Chloride [50% solution] Germall Plus Germaben 11 Phospholipid CDM Phospholipid GLA Propylene Glycol Propylene carbonate and Triclosan Formulation 2-4 (w/Triclosan Australian Tee Tree Oil): EtOH (48.42% W/W or 55 v/v) 1 Isopropyl. alcohol (8.76 W/W or 10 n-Propyl alcohol (4.48 w/w or 5 v/v), D.I. Water Mirataine CB (6.0 Glycerin Amphoterge K-2 HCl 1 N Cetiol HE Lexorez 100 Silsoft A-843 Tocopherol Natrosol. 250 HER JJm- 510 -26- CI PEO-1 Orange Zest fragrance 1 Varox 270 Phenoxyethanol Benzalkonium r Chloride [50% solution] Germall Plus Germaben II Phospholipid CDM Phospholipid GLA Propylene Glycol Propylene carbonate Australian tea tree oil and triclosan (1.0
CN
V The results of the antimicrobial efficiency for the foregoing formulations are summarized in TABLE 2.
CN
TABLE 2 Mean LOGIo Reduction Formulation Sampling Period 2-1 0.48 2-2 0.39 0 Hour, Day 1 2-3 0.25 2-4 0.28 Referring to TABLE 2, it was surprising that none of these formulations met the FDA requirement for 1 Log 10 reduction even for zero time on day 1. Although not reported in Table 2, the formulations containing Triclosan, Formulations 2-3 and 2-4, showed greater cumulative activity than the others at days 2 and 5. Thus, simple elimination of anionic surfactants did not appear the only factor affecting antimicrobial activity. Since poor 0 hour results were achieved for i*"....f..mulations 2-1 to 2-4, the 6 hour results are not reported.
JJM-510 27 EXAMPLE 3 In view of the results of Examples 1 and 2 and in order to more quickly receive and evaluate results, it was decided to perform in vitro evaluations of various combinations of surfactants and antimicrobials.
The in vitro time kill study was conducted with 9 microorganisms by evaluating the loglo reductions of bacterial counts using 8 log 0 bacterial inoculation into each test product. All subsequent time-kill studies for the brushless scrub were conducted under this protocol.
The microorganisms (ATCC and clinical isolates) tested are identified in the following tables by both the commonly used descriptive names of the microorganisms and by the ATCC identification numbers.
The previously referenced formulations, Formulations 2-1, 2-2, 2-3 and 2-4, as well as alcoholcontaining Formulations 2-5 and 2-6 were evaluated by this time-kill method. Formulation 2-5 contained ethyl alcohol 49.1%, isopropyl alcohol n-propyl alcohol and water 37.5% based on W/W% and Formulation 2-6 contained simply 70% V/V% ethanol in water. TABLE 3 represents the results of the antimicrobial efficacy of the foregoing formulations in terms of logio and percentage bacterial kill.
JJM-510 2005209647 09 Sep 2005 28 TABLE 3 Microorganisms (ATCC Formulation Exposure A. niger C. albicans E.faecalis E. Faeciun E. Coli P. aeruginosa S. aureus S. aureus S. epiderimidis Time (M#16404) (#10231) (VRE-CI) (VRE.-CI) (18739) (N9027) (16538) (MRSA-CI) (1112228) Iss 3.6119 6.2135 6.4141 6.2613 6.2577 6.2122 6.6232 6.5185 6.2148 99.9756% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 4.4491 6.2135 6.4141 6.2613 6.2577 6.2122 6.6232 6.5185 6.2148 2-1 99.9964% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% Im 5.0512 6.2135 6.4141 6.2613 6.2577 6.2122 6.6232 6.5185 6.2148 99.9991% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99,9999% 99.9999% 99.99990% 5.0512 6.2135 6.4141 6.2613 6.2577 6.2122 6.6232 6.5185 6.2148 99.9991% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.99990% Is 3.2187 6.2135 6.4141 6.2613 6.2577 6.2122 6.6232 6.5185 6.2148 99.9396% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 4.6533 6.2135 64141 6.2613 6.2577 6.2122 6.6232 6.5185 6.2148 99.9978% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 2-2 I m 5.0512 6.2135 6.4141 6,2613 6.2577 6.2122 6.6232 6.5185 6.2148 99.9991% 99.9999%0 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999%0 99.9999% 5.0512 6.2135 6.4141 6.2613 6.2577 6.2122 6.6232. 6.5185 6.2148 99.9991% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% )9,9999% ISs 2.7178 6.2135 6.4141 6.2613 6.2577 6.2122 6.6232 6.5185 6.2148 99.8084% 99.9999% 99.9999% 99.99990/0 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 3.8082 6.2135 6.4141 6.2613 6.2577 6.2122 6.6232 6.5185 6.2148 99.9844% 99.9999% 99-9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 2-3 Im 5.0512 6.2135 6.4141 6.2613 6.2577 6.2122 6.6232 6.5185 6.2148 1 99.9991% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% Sm 5.0512 6.2135 6.4141 6.2613 6.2577 6.2122 6.6232 6.5185 6.2148 1 99.9991% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% JJM-510 2005209647 09 Sep 2005 29 TABLE 3 (Con't).
Microorganisms (ATCC Formulation Exposure A. niger C. albicans E.faecalis E.faecitm E. Coli P. aeruginosa S. aureus S. aureus S. epidermidis Time (116404) (N#10231 (VRE-CO) (VRE-CI) (#8739) (119027) (116538) (MRSA-CI) (11228) 2.9273 6.2135 2.6544 6.2613 6.2577 6.2122 6.6232 6.5185 6.2148 99.8818% 99.9999% 99.7784% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 3.9209 6.2135 6.4141 6.2613 6.2577 6.2122 6.6232 6.5185 6.2148 2-4 30s 99.9880% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.99996/. 99.9999% 99.9999% 5.0512 6.2135 6.4141 6.2613 6.2577 6.2122 6.6232 6.5185 6.2148 1 i 99.9991% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99,9999% 99.9999% 99.9999% 5.0512 6.2135 6.4141 6.2613 6.2577 6.2122 6.6232 6.5185 6.2148 _51_ 99.9991% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.99990/0 99.9999% 99.9999% 3.5964 6.2135 6.4141 6.2613 6.2577 6.2122 6.6232 6.5185 6.2148 99.9747% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 5.0512 6.2135 6,4141 6.2613 6.2577 6.2122 6.6232 6.5185 6.2148 30s 99.9991% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 5.0512 6.2135 6.4141 6.2613 6.2577 6.2122 6.6232 6.5185 6.2148 Im 99.9991% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 5.0512 6.2135 .6.4141 6.2613 6.2577 6.2122 6.6232 6.5185 6.2148 Sm 99.9991% 99.9999% 99,9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 3.2767 6.2135 6.4141 6.2613 6.2577 6.2122 6.6232 6.5185 6.2148 99.9471% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 4.0512 6.2135 6.4141 6.2613 6.2577 6.2122 6.6232 6.5185 6,2148 2-6 99.9911% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% Im 5.0512 6,2135 6.4141 6.2613 6.2577 6.2122 6.6232 6.51,85 6.2148 99.9991% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 5.0512 6.2135 6.4141 6,2613 6.2577 6.2122 6.6232 6.5185 6.2149 99.9991% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% JJM-510 0 30 CO Referring to TABLE 3, it is clear that log 10
Q,
reductions at 15 seconds were from 5 to 6 across the board for these formulations, except in the case of the 0 microorganism A. niger (ATCC #16404), in which the loglo s reduction which was typically 3 for all formulations measured at 15 seconds. The kill was overwhelming in ND these formulations due to the presence of alcohol S(typically 6 log in 15 and differences between them V) were lost.
EXAMPLE 4 Based on the results of Example 3 and in an attempt to isolate the effectiveness of antimicrobial systems without alcohol the following in vitro samples submitted were in an aqueous base only, and contained no alcohol.
In the Formulation 4 series, a common antimicrobial base was combined with three surfactant variations. The base contained Benzalkonium Chloride (0.09% active), Benzethonium Chloride (0.09% active), Phenoxyethanol Phospholipid CDM Propylene Glycol Glycerin and water. Formulation 4-1 contained Ammonium Laureth Sulfate(2%), an anionic surfactant, and 0.1% Cetylpyridinium Chloride additionally. Formulation 4-2 contained the base plus Cocamidopropyl Hydroxysultaine (Mackam CBS 50G, and Cetylpyridinium Chloride Formulation 4-3 contained the base plus PPG-40 Diethylmonium Chloride (Emcol CC42, and Cetylpyridinium Chloride wa.s noticed that version Formulation 4-1 formed a precipitate. It is likely due to the incompatibility JJM-510 31 of the cationic quaternary compounds (Benzalkonium Chloride, Benzethonium Chloride, Cetylpyridinium Chloride) with the anionic Ammonium Laureth Sulfate.
Formulations 4-2 and 4-3 remained clear. Results of the s antimicrobial efficiency of the foregoing formulations are presented in TABLE 4.
JJM-510 2005209647 09 Sep 2005 32 Formulation 4-1 4-2 4-2A 4-3 TABLE 4 Time Mcroorganisrns (ATCG 11) Aniger -E -alblcns E--fae-colis -E.faeciunrt coi P. aeruginosa -aureus S. areuss S. epiderinidis 1116404 (110231)- v jKi -cI (VRE (118739) (/1H9027) _(116538) _MRSA Cl /12 lis 0.0000 0.3843 0.2030 0.1203 0.1242 0.3445 0.2432 0.3040 0.4848 m 0.0000% 58.7269% 37.3451% 24.2009% 24.8649% 54.7619% 42.8846% 50.3448% 67.2549% liii 0.00 0306.83 01363 061711 0.580.3163 0.3040 0.6701 0.0000% 52.1561% __3983/ 26.9406% 32.5676% 65.1515% 51,7308% 50.3448% 78.6275% 0.0000 1.5703 6.4510 6.0394 6.5682 4:Z5063 6.7160 6.0364 6.4065 0.00% 9.10% 9.99% 99.9999% 99.9999% 99.9969% 99.99990% 99.9999% 99.9999% Im 0.0000 3.6663 6.4510 6.0394 6.5682 95;.5185 6.7160 6.6385 6.4065 0.0000% 99.9784% 99.9999% 99.9999% 99.9999% 999% 9999% 99.9999% 99.9999% Iss 0.0000 2.166 6.8482 6.3570 -6.2844 6.8228 6.K9004 6.8543 6.7672 d 0.0000% 99.0375% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% Im 0.0000 5.3980 6.8482 6.3570 6.2844 6.8228 6.9004 6.8543 6,7672 0.0000% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% 99.9999% Is 0.0000 1.5837 6.45 10 6.0394 6.5682 6.3636 6.7160 6.6385 6.4065 0.0000 732% 99.99% 99999999% 99% 9999 99.9999% 99.9999% 99.9999% Im 0.0000 4.3531 6.4510 6.34 6.5682 6.3636 6.10 6.35646 0.0000% 999956% 99.9999% 99.9999% 99.9999% 99.9999 L 99999% 99.9999% .99.9999% JJM -510 33 d Referring to TABLE 4, it is clear that Formulation 4-1 exhibited very poor antimicrobial activity in the 0 time-kill studies compared to Formulations 4-2 and 4-3, confirming the likely inactivation of the cationic antimicrobials.
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SThese results suggest the complete compatibility and possible enhancement of the antimicrobial system by Cocamidopropyl Hydroxysultaine and PPG-40 Dimonium Chloride at 2.0% levels.
To improve foaming and mildness, a.third surfactant was tested in Formulation 4-2A, Plantaren 2000 (polyalkylglycoside) substituting this surfactant for Cocamidopropyl Hydroxysultaine in Formulation 4-2 The results showed excellent activity for this formula as well, with no apparent suppression of the antimicrobials. (See TABLE 4).
At this point we had three viable surfactants compatible with our antimicrobial system, Plantaren 2000 a non-ionic), Cocamidopropyl Hydroxysultaine (an amphoteric), and PPG-40 Dimonium Chloride (a cationic).
The combination of the three was found to give good foaming and lather.
EXAMPLE This example investigates the effect of pH on the antimicrobial systems of this invention. Up to this JJM-510 34 point, all formulas tested were in the pH 6-7 range. A 1 new formulation, Formulation 5-1 was made which contained the previously mentioned antimicrobial system, o of Formulation 4-2 plus Nisin Disodium EDTA a surfactant system consisting of Plantaren 2000 (nonionic) and Mackam CBS-50G (amphoteric), and pH
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0 adjuster Glycolic Acid (0.19% of a 70% solution). The C- pH of this batch was C- 10 The time-kill efficacy results for this formula showed weak activity. The log 10 reductions were less than 1 for many of the microorganisms at the 15 second interval. This implied that there was no benefit and probably deleterious effects on efficacy from low pH is with this antimicrobial system. We also attempted a high pH formula, Formulation 5-2, contained the following based on weight Deionized water 97%; PEG-4 cellulose benzalkonium chloride 0.18%; Benzethonium chloride 0.09%; Cocamidopropyl Hydroxysultaine with the pH adjusted to 8.3 with NaOH. The efficacy at this pH was also weaker than at the apparent optimum pH of approximately 7. As we had seen excellent efficacy results from formulas of pH approximately 7, we decided to make that the target pH.
In addition, this is the pH where this particular system with these surfactants and antimicrobials is most stable, requiring no adjustment. Thus, best antimicrobial performance would be expected in pH ranges around 7, most likely from about 5.5 to about 8.
JJM-510 35 EXAMPLE 6 C Now that we had identified an excellent surfactant system by in vitro testing (the Plantaren 2000, O Cocamidopropyl Hydroxysultaine, and PPG-40 Dimonium Chloride combination), it was decided to test some variations on this theme, using an in vivo scrub study
\O
N with two more formulations, Formulations 6-1 and 6-2.
Formulation 6-1 contained EtOH (26.5% W/W or 30% V/V), n-Propyl Alcohol (25.1% W/W or 28% Triclosan D.I. Water Opacifier-295 (Morton), Hydroxypropylcellulose Plantaren 2000 Cocamidopropyl Hydroxysultaine -Mackam CBS50G Diethylmonium Chloride-Emcol CC42 Benzalkonium Chloride [50% solution] is Benzethonium Chloride ,Phenoxyethanol Phospholipid CDM Phospholipid GLA Cetrimonium Chloride (0.86% of 29% sol.), Dowicil 200 Cetylpyridinium Chloride Glycerin Propylene Glycol fragrance Formulation 6-2 contained the same composition as Formulation 6-1 except that Formulation 6-2 is a high glycerin formula high-alcohol (65% V/V-active levels), and low water formula and whereas Formulation 6-1 is a mixed alcohol formula (total of 58% V/V, or an inactive level), and the glycerin has been reduced to Also tested in this study was Prevacare Antimicrobial Hand Gel (Lot No. P8-006), Healthpo.int.'s Triseptin Surgical Scrub, and pure ethanol at 70% V/V.
JJM-510 36 Only 1st day results at 0 time were evaluated and are shown in Table 6.
TABLE 6 Mean LOGlo Reduction Formulation Sampling Period 6-1 1.18 6-2 1.24 Antimicrobial Hand Gel 1.40 Ethanol) Surgical Scrub 0 Hour, Day 1 Ethanol) Ethanol 70% 0.95 The results of Table 6 indicate that all the formulations met the FDA surgical scrub requirement for l-loglo reduction in bacteria at zero time with the exception of Ethanol These were the first formulas tested in vivo which met the FDA requirements for rapid kill. This confirmed the compatibility of this particular surfactant mixture with the antimicrobial mixture. In-the presence of alcohol, this combination met the surgical scrub requirements when utilizing a double-dry application, lather, and rinse method.
Also, notable from these results is that the formula did not have statistically significant gains in activity from the presence of-Trielosan, at least at 0 time. The cumulative efficacy effects of each formula JJM-510 37 are unknown from this study which only evaluated 0 time results.
EXAMPLE 7 In an effort to further increase the antimicrobial efficacy of the formula and the moisturization, further adjustments to the formula were made.
The improved formula is as follows: Formulation 7-1: i0 EtOH (62.25% W/W or 70% D.I. Water Glyceryl Laurate Isolene Silsoft PEDM Mearlmaid OL Hydroxypropylcellulose Plantaren 2000 Cocamidopropyl Hydroxysultaine -Mackam CBS50G PPG-40 Diethylmonium Chloride-Emcol CC42 Benzalkonium Chloride [50% solution] Benzethonium Chloride Phenoxyethanol Phospholipid CDM Phospholipid GLA Cetrimonium Chloride (0.86% of 29% sol.), Dowicil 200 Cetylpyridinium Chloride Glycerin Propylene Glycol and fragrance Silsoft PEDM and Isolene both contribute to appearance and feel. They are both partially soluble in a hydroalcoholic system forming droplets, which help the opacity and lotion-like appearance of the product.
Glyceryl Laurate was added at 1.0% to enhance the foaming and trans-dermal penetration abilities of the formula. The Phosphol.ipid.CDM and Benzalkonium Chloride were also increased in this formula to enhance efficacy JJM-510 38 and moisturization. Isolene and Phospholipid CDM also have anti-irritant benefits to compensate for increases in the Benzalkonium Chloride levels. Logo 0 reduction data is shown in Table 7 for Formulation 7-1 for both 0 hour and 6 hours.
TABLE 7 Formulation Loglo at 0 hours Log 0 l at 6 hours 7-1 1.41 0.84 o0 Thus, the results of Table 7 show extremely improved logo 1 reductions at both 0 hour and 6 hour compared to the measured properties of previously tested formulations that do not contain the claimed elements of this invention most notably the formulations of Table 1.
EXAMPLE 8 Two more formulations (Formulations 8-1 and 8-2) were evaluated. Formulation 8-2's surfactant system consisted of only cationic and nonionic surfactants.
Formulation 8-1 contained (based on 8.15% deionized water; 62.00% Ethanol (200 proof); 5.00% Glycerin; 10.00% Propylene Glycol; 5.00% Cocamidopropyl hydroxy sultaine (50% Concentration) Mackam CBS- 1.00% Phospholipid CDM; 0.50% Phospholipid GLA; 1.20% PPG-40 Diethylmonium Chloride (Emcol CC-42) (cationic); 0.80% Hydroxypropylcellulose HXF Grade; 1.00% Phenoxyethanol; 1.50% Glyceryl Laurate (non-ionic) Monomuls 90-L12; 1.70% Cetrimonium Chloride JJM-510 -39- C< (29%-Varisoft 300); 0.20% benzalkonium chloride 0.10% Benzethonium Chloride; 0.50% Lambent Quat AD; 0.15% Fragrance (Seafoam GGE); 1.00% Cosmocil CQ (polyhexamethylene biguanide 0.05% Silsoft PEDM; 0.15% Mearlmaid OL. Formulation 8-2 contained (based on 9.83% deionized water; 62.75% Ethanol \0 (200 proof); 10.00% Propylene Glycol; 5.0% Glycerin; Phospholipid CDM; 1.5% PPG-40 Diethylmonium Cl in Chloride (Emcol CC-42); 0.80% Hydroxypropylcellulose HXF Grade; 1.0% Phenoxyethanol; 2.5% Glyceryl Laurate; Cl Cetrimonium Chloride (29%-Varisoft 300); 0.2% Benzalkonium Chloride 0.1% Benzethonium Chloride; Lambent Quat AD; 0.15% Fragrance (Seafoam GGE); Cosmocil CQ; .0.07% Silsoft PEDM; 0.100% Mearlmaid OL. Surprisingly Formulation 8-2 exhibited excellent foaming properties similar to surfactant systems containing amphoteric, nonionic, and cationic surfactants. The surprising observation was that one skilled in the art would have expected worse foaming properties due to the higher relative proportion of cationic surfactants in the system. However, no appreciable foaming differences were observed in the increased amounts of nonionic/cationic surfactant system when compared to the amphoteric/nonionic/cationic surfactant system. In fact, these observations in foaming ability and its believed correlation to skin penetration is at least borne out in the excellent antimicrobial results shown in TABLE 8 for Formulation 8-1 and compared with commercially available 4% JJM-510 S- chlorhexidine gluconate and 70% ethyl alcohol based 4 products.
STABLE 8 Log 1 0 at 0 hours Log 0 o at 6 hours Formulation 8-1 1.8 1.6 HIBILCLENS 1.6 1.9 TRISEPTIN 1.7 1.8 Formulation 8-1 was evaluated following the aforementioned new brushless surgical handwashing procedure (3 minute procedure with out a brush) that was based on surgical science and compared with conventional procedure 6 minute scrub with a brush) using 4% chlorhexidine gluconate product. Also the results were compared with a 70% alcohol based product following a 3 minute surgical scrub procedure with out a brush. To our surprise Formulation 8-1 has shown slightly better results at 0 hour and comparable activity at 6 hours.
The results clearly suggest that Formulation 8-1 has the right combination of antimicrobial ingredients at appropriate concentrations to exhibit immediate and residual antimicrobial activity against resident skin flora which is relatively hard to achieve. This level of efficacy is an important feature in brushless applications to eliminate abrasive surgical scrub procedures with brushes and to offer the same level of efficacy of bench mark products, particularly, in half time of the conventional surgical scrub procedures with a brush.
JJM-510 005088249 41 00
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O
C O It should be understood that the foregoing disclosure and description of the present invention are illustrative and explanatory thereof and various changes in the size, shape and materials as well as in the description of the preferred embodiment may be made without departing from the spirit of the invention.
As used herein, the term "comprise" and variations of the term, such as "comprising", "comprises" and "comprised", are not intended to exclude other additives, components, integers or steps.
Reference to any prior art in the specification is not, and should not be taken as, an acknowledgment, or any form of suggestion, that this prior art forms part of the common general knowledge in Australia or any other jurisdiction or that this prior art could reasonably be expected to be ascertained, understood and regarded as relevant by a person skilled in the art.
Claims (12)
- 2. The composition of claim 1 wherein the alcohol is selected from the group consisting of ethyl alcohol, isopropyl alcohol and n-propyl alcohol and mixtures thereof.
- 3. The composition of claim 2 wherein the cationic quaternary ammonium compound is selected from the group consisting of benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, cetrimonium chloride, and mixtures thereof.
- 4. The composition of any one of the preceding claims wherein alcohol is from about 30 to about 65 percent by weight; the COMS ID No: ARCS-206619 Received by IP Australia: Time 12:20 Date 2008-09-18 18/09/2008 12:20 FREEHILLS 03 15/17 0C5180373 00 -43- Sphenoxy ethanol is from about 0.1 to about 5.0 percent by )weight; the cationic quaternary ammonium compound is from 00 about 0.02 to about 2.5 percent by weight; and the surfactant system is about 0.1 to about 15 percent by s weight.
- 5. The composition of claim 3 wherein the alcohol comprises O from about 50 to about 65 weight percent of alcohol V' referenced in claim 2; the cationic quaternary ammonium Scompound comprises from about 0.01 to about 0.5 percent by weight of benzalkonium chloride and from about 0.1 to about percent by weight of benzethonium chloride; the surfactant system comprises from about 0.1 to about weight percent of glyceryl laurate, and from about 0.2 to about 5.0 weight percent of PPG-40 diethylmonium chloride.
- 6. The composition of claim 3 wherein the alcohol comprises from about 50 to about 65 weight percent of alcohol wherein the alcohol is selected from the group consisting of ethyl alcohol, isopropyl alcohol and n-propyl alcohol and mixtures thereof; the cationic quaternary ammonium compound comprises from about 0.01 to about 0.5 percent by weight of benzalkonium chloride and from about 0.01 to about percent by weight of benzethonium chloride; the surfactant system comprises from about 0.1 to about 8.0 weight percent of cocamidopropyl hydroxysultaine(50% concentration), from about 0.2 to about 5.0 weight percent of polyalkylglycoside, optionally glyceryl laurate from about 0.1 to about weight percent, and from about 0.2 to about 5.0 weight percent of PPG-40 diethylmonium chloride.
- 7. The composition of any one of the preceding claims wherein the composition contains an effective amount of a biguanide. COMS ID No: ARCS-206619 Received by IP Australia: Time 12:20 Date 2008-09-18 18/09/2008 12:21 FREEHILLS 03 16/17 005150373 00 44 e, 8. The composition of claim 7, wherein the biguanide is (1 selected from the group consisting of chlorhexidine or its 00 derivatives.
- 9. The composition of claim 7, wherein the biguanide is selected from the group consisting of chlorhexidine N gluconate, chlorhexidine digluconate, chlorhexidine O diacetate, chlorhexidine dihydrochloride and IV polyhexamethylene biguanide. CI 10. The composition of claims 7, 8 or 9 wherein the biguanide is present in an amount from about 0.01 to about 5.0 weight percent.
- 11. The composition of claim 7, wherein the biguanide is selected from the group consisting of polyhexamethylene biguanide, chlorhexidine gluconate, and mixtures thereof.
- 12. The composition of any one of the preceding claims wherein the composition contains an effective amount of skin conditioning system.
- 13. The composition of claim 12, wherein the skin conditioning system is comprised of propylene glycol, glycerin, phenylethyl dimethicone and a silicone quaternary compound.
- 14. The composition of claim 13, wherein the propylene glycol is present in an amount from about 1.0 to about 20 weight percent; glycerin in an amount from about 1.0 to about weight percent; phenyl ethyl dimethicone in an amount from about 0.01 to about 0.2 weight percent; and silicone quaternary compound in an amount from about 0.1 to about weight percent. COMS ID No: ARCS-206619 Received by IP Australia: Time 12:20 Date 2008-09-18 18/09/2008 12:21 FREEHILLS 03 17/17 005180373 00 -45 0 L 15. A method of disinfecting a substrate comprising the use of CD) V/ an effective amount of the antimicrobial composition of any 00 one of the preceding claims.
- 16. The method of claim 15, wherein the substrate is the skin. 4\ 5 17. An antimicrobial composition substantially as hereinbefore O described with reference to Examples 2 to 9. ci S18. A method of disinfecting a substrate substantially as 0 hereinbefore described with reference to the Examples 2 to 9. COMS ID No: ARCS-206619 Received by IP Australia: Time 12:20 Date 2008-09-18
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|---|---|---|---|---|
| US4464293A (en) * | 1982-04-12 | 1984-08-07 | Dobrin Robert J | Liquid cleaner-disinfectant composition for use in wiping down dental operatories |
| WO1993007250A1 (en) * | 1991-10-09 | 1993-04-15 | Novapharm Research (Australia) Pty. Ltd. | Novel skin and hand cleansing process and compositions |
| EP0930065A2 (en) * | 1998-01-20 | 1999-07-21 | Ethicon, Inc. | Alcohol based anti-microbial compositions with cosmetic appearance |
| EP0937394A1 (en) * | 1998-01-20 | 1999-08-25 | Ethicon, Inc. | Antimicrobial composition |
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2005
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4464293A (en) * | 1982-04-12 | 1984-08-07 | Dobrin Robert J | Liquid cleaner-disinfectant composition for use in wiping down dental operatories |
| WO1993007250A1 (en) * | 1991-10-09 | 1993-04-15 | Novapharm Research (Australia) Pty. Ltd. | Novel skin and hand cleansing process and compositions |
| EP0930065A2 (en) * | 1998-01-20 | 1999-07-21 | Ethicon, Inc. | Alcohol based anti-microbial compositions with cosmetic appearance |
| EP0937394A1 (en) * | 1998-01-20 | 1999-08-25 | Ethicon, Inc. | Antimicrobial composition |
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