JP2001508062A - 医薬品の経皮浸透用ヒドロアルコール組成物 - Google Patents
医薬品の経皮浸透用ヒドロアルコール組成物Info
- Publication number
- JP2001508062A JP2001508062A JP53090298A JP53090298A JP2001508062A JP 2001508062 A JP2001508062 A JP 2001508062A JP 53090298 A JP53090298 A JP 53090298A JP 53090298 A JP53090298 A JP 53090298A JP 2001508062 A JP2001508062 A JP 2001508062A
- Authority
- JP
- Japan
- Prior art keywords
- composition
- group
- alkyl
- emulsifier
- carbon atoms
- 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
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 213
- 239000003814 drug Substances 0.000 title claims description 69
- 230000035515 penetration Effects 0.000 title description 20
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 223
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 78
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 52
- 238000000034 method Methods 0.000 claims abstract description 27
- 230000037317 transdermal delivery Effects 0.000 claims abstract description 22
- 230000001737 promoting effect Effects 0.000 claims abstract description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 120
- 125000000217 alkyl group Chemical group 0.000 claims description 84
- -1 alkyl phosphates Chemical class 0.000 claims description 43
- 229940079593 drug Drugs 0.000 claims description 40
- 125000003342 alkenyl group Chemical group 0.000 claims description 28
- 150000002148 esters Chemical class 0.000 claims description 28
- 239000002562 thickening agent Substances 0.000 claims description 26
- 239000002904 solvent Substances 0.000 claims description 25
- 125000004434 sulfur atom Chemical group 0.000 claims description 20
- 125000001165 hydrophobic group Chemical group 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 15
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol group Chemical group OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 238000002156 mixing Methods 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 11
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 11
- 238000001816 cooling Methods 0.000 claims description 9
- 239000006210 lotion Substances 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 125000005907 alkyl ester group Chemical group 0.000 claims description 8
- 150000001412 amines Chemical group 0.000 claims description 8
- 229920000223 polyglycerol Polymers 0.000 claims description 8
- 229910019142 PO4 Inorganic materials 0.000 claims description 7
- 125000005233 alkylalcohol group Chemical group 0.000 claims description 7
- 229920001577 copolymer Polymers 0.000 claims description 7
- 230000001186 cumulative effect Effects 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 235000021317 phosphate Nutrition 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 239000002202 Polyethylene glycol Substances 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 229920001223 polyethylene glycol Polymers 0.000 claims description 6
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 5
- 125000000129 anionic group Chemical group 0.000 claims description 5
- 125000004185 ester group Chemical group 0.000 claims description 5
- 150000005846 sugar alcohols Polymers 0.000 claims description 5
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 claims description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 4
- 239000011575 calcium Substances 0.000 claims description 4
- 229910052791 calcium Inorganic materials 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 150000002500 ions Chemical class 0.000 claims description 4
- 229910052744 lithium Inorganic materials 0.000 claims description 4
- 239000011777 magnesium Substances 0.000 claims description 4
- 229910052749 magnesium Inorganic materials 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 claims description 3
- 125000003368 amide group Chemical group 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 238000005119 centrifugation Methods 0.000 claims description 3
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims description 3
- 150000003904 phospholipids Chemical class 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 125000003158 alcohol group Chemical group 0.000 claims description 2
- 150000003973 alkyl amines Chemical group 0.000 claims description 2
- 125000005599 alkyl carboxylate group Chemical group 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 230000004907 flux Effects 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 claims description 2
- 239000008177 pharmaceutical agent Substances 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 2
- 239000011877 solvent mixture Substances 0.000 claims 2
- JNYAEWCLZODPBN-UHFFFAOYSA-N 2-(1,2-dihydroxyethyl)oxolane-3,4-diol Polymers OCC(O)C1OCC(O)C1O JNYAEWCLZODPBN-UHFFFAOYSA-N 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 125000001033 ether group Chemical group 0.000 claims 1
- 239000012875 nonionic emulsifier Substances 0.000 claims 1
- JNYAEWCLZODPBN-CTQIIAAMSA-N sorbitan Polymers OCC(O)C1OCC(O)[C@@H]1O JNYAEWCLZODPBN-CTQIIAAMSA-N 0.000 claims 1
- 125000000547 substituted alkyl group Chemical group 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 2
- 238000012377 drug delivery Methods 0.000 abstract 1
- 238000013271 transdermal drug delivery Methods 0.000 abstract 1
- 238000002844 melting Methods 0.000 description 43
- 230000008018 melting Effects 0.000 description 43
- 210000003491 skin Anatomy 0.000 description 31
- 239000000839 emulsion Substances 0.000 description 27
- 239000003974 emollient agent Substances 0.000 description 21
- 150000001298 alcohols Chemical class 0.000 description 19
- 239000003795 chemical substances by application Substances 0.000 description 16
- 239000000047 product Substances 0.000 description 15
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 14
- 150000003839 salts Chemical class 0.000 description 14
- 150000002430 hydrocarbons Chemical group 0.000 description 13
- 230000002209 hydrophobic effect Effects 0.000 description 13
- 239000007788 liquid Substances 0.000 description 13
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 12
- 239000012071 phase Substances 0.000 description 12
- 239000001993 wax Substances 0.000 description 12
- 239000000126 substance Substances 0.000 description 11
- 239000004094 surface-active agent Substances 0.000 description 11
- 230000001965 increasing effect Effects 0.000 description 10
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- 230000000845 anti-microbial effect Effects 0.000 description 9
- 229920000642 polymer Polymers 0.000 description 9
- 229920001296 polysiloxane Polymers 0.000 description 9
- 230000006870 function Effects 0.000 description 8
- 229920000570 polyether Polymers 0.000 description 8
- 239000003380 propellant Substances 0.000 description 8
- 238000010998 test method Methods 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- 239000000853 adhesive Substances 0.000 description 7
- 230000001070 adhesive effect Effects 0.000 description 7
- 239000003623 enhancer Substances 0.000 description 7
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- 239000004615 ingredient Substances 0.000 description 7
- 229960003604 testosterone Drugs 0.000 description 7
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical class 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 description 6
- 239000004721 Polyphenylene oxide Substances 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- 229930182478 glucoside Natural products 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Polymers CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 239000000080 wetting agent Substances 0.000 description 6
- HNUQMTZUNUBOLQ-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-(2-octadecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO HNUQMTZUNUBOLQ-UHFFFAOYSA-N 0.000 description 5
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 5
- 150000001335 aliphatic alkanes Chemical class 0.000 description 5
- 229960003260 chlorhexidine Drugs 0.000 description 5
- 239000002537 cosmetic Substances 0.000 description 5
- NOPFSRXAKWQILS-UHFFFAOYSA-N docosan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCO NOPFSRXAKWQILS-UHFFFAOYSA-N 0.000 description 5
- 150000002170 ethers Chemical class 0.000 description 5
- 239000000194 fatty acid Substances 0.000 description 5
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- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 4
- 239000004215 Carbon black (E152) Substances 0.000 description 4
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
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- 150000007513 acids Chemical class 0.000 description 4
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- NNPPMTNAJDCUHE-UHFFFAOYSA-N isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 description 4
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- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 4
- ARIWANIATODDMH-UHFFFAOYSA-N rac-1-monolauroylglycerol Chemical compound CCCCCCCCCCCC(=O)OCC(O)CO ARIWANIATODDMH-UHFFFAOYSA-N 0.000 description 4
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- XDOFQFKRPWOURC-UHFFFAOYSA-N 16-methylheptadecanoic acid Chemical compound CC(C)CCCCCCCCCCCCCCC(O)=O XDOFQFKRPWOURC-UHFFFAOYSA-N 0.000 description 3
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- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
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- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
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- JNMRHUJNCSQMMB-UHFFFAOYSA-N sulfathiazole Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CS1 JNMRHUJNCSQMMB-UHFFFAOYSA-N 0.000 description 1
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- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 description 1
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- JYKSTGLAIMQDRA-UHFFFAOYSA-N tetraglycerol Chemical compound OCC(O)CO.OCC(O)CO.OCC(O)CO.OCC(O)CO JYKSTGLAIMQDRA-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/781,097 US6019997A (en) | 1997-01-09 | 1997-01-09 | Hydroalcoholic compositions for transdermal penetration of pharmaceutical agents |
| US08/781,097 | 1997-01-09 | ||
| PCT/US1997/023483 WO1998030244A1 (en) | 1997-01-09 | 1997-12-23 | Hydroalcoholic compositions for transdermal penetration of pharmaceutical agents |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2001508062A true JP2001508062A (ja) | 2001-06-19 |
| JP2001508062A5 JP2001508062A5 (enExample) | 2005-09-08 |
Family
ID=25121692
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP53090298A Ceased JP2001508062A (ja) | 1997-01-09 | 1997-12-23 | 医薬品の経皮浸透用ヒドロアルコール組成物 |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US6019997A (enExample) |
| EP (1) | EP0957939B1 (enExample) |
| JP (1) | JP2001508062A (enExample) |
| AU (1) | AU738444B2 (enExample) |
| CA (1) | CA2274565C (enExample) |
| DE (1) | DE69738200T2 (enExample) |
| ES (1) | ES2293667T3 (enExample) |
| WO (1) | WO1998030244A1 (enExample) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2017508808A (ja) * | 2014-03-17 | 2017-03-30 | ジー・エフ・エス.コーポレーション.エー・ユー・エス.ピー・ティー・ワイ.エル・ティー・ディーGfs Corporation Aus Pty Ltd | 抗菌性除菌剤組成物およびその使用 |
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| EP1374847A1 (en) * | 1995-06-22 | 2004-01-02 | Minnesota Mining And Manufacturing Company | Stable hydroalcoholic compositions |
| US6623744B2 (en) * | 1995-06-22 | 2003-09-23 | 3M Innovative Properties Company | Stable hydroalcoholic compositions |
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| US20050037040A1 (en) * | 2003-08-13 | 2005-02-17 | Moshe Arkin | Topical compositions of urea and ammonium lactate |
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| JP2017508808A (ja) * | 2014-03-17 | 2017-03-30 | ジー・エフ・エス.コーポレーション.エー・ユー・エス.ピー・ティー・ワイ.エル・ティー・ディーGfs Corporation Aus Pty Ltd | 抗菌性除菌剤組成物およびその使用 |
Also Published As
| Publication number | Publication date |
|---|---|
| ES2293667T3 (es) | 2008-03-16 |
| AU738444B2 (en) | 2001-09-20 |
| DE69738200T2 (de) | 2008-07-10 |
| CA2274565C (en) | 2008-04-08 |
| CA2274565A1 (en) | 1998-07-16 |
| AU5709898A (en) | 1998-08-03 |
| US6019997A (en) | 2000-02-01 |
| EP0957939B1 (en) | 2007-10-10 |
| WO1998030244A1 (en) | 1998-07-16 |
| EP0957939A1 (en) | 1999-11-24 |
| DE69738200D1 (de) | 2007-11-22 |
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