US20210161143A1 - Disinfectant composition - Google Patents
Disinfectant composition Download PDFInfo
- Publication number
- US20210161143A1 US20210161143A1 US17/258,579 US201917258579A US2021161143A1 US 20210161143 A1 US20210161143 A1 US 20210161143A1 US 201917258579 A US201917258579 A US 201917258579A US 2021161143 A1 US2021161143 A1 US 2021161143A1
- Authority
- US
- United States
- Prior art keywords
- olanexidine
- antiseptic
- formulation
- gluconate
- bactericidal
- 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.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 140
- 239000000645 desinfectant Substances 0.000 title abstract description 19
- 229950001187 olanexidine Drugs 0.000 claims abstract description 107
- 230000002421 anti-septic effect Effects 0.000 claims abstract description 62
- LIJONMBDWKFOLT-IFWQJVLJSA-N 1-[n'-[(3,4-dichlorophenyl)methyl]carbamimidoyl]-2-octylguanidine;(2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanoic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.CCCCCCCCN=C(N)NC(N)=NCC1=CC=C(Cl)C(Cl)=C1 LIJONMBDWKFOLT-IFWQJVLJSA-N 0.000 claims abstract description 49
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 98
- ZZQMUJGZCZTLQD-UHFFFAOYSA-N olanexidine Chemical compound CCCCCCCCN=C(N)NC(N)=NCC1=CC=C(Cl)C(Cl)=C1 ZZQMUJGZCZTLQD-UHFFFAOYSA-N 0.000 claims description 59
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 35
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 21
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 43
- 238000001228 spectrum Methods 0.000 abstract description 9
- 230000002500 effect on skin Effects 0.000 abstract description 3
- 230000002708 enhancing effect Effects 0.000 abstract description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 59
- 238000009472 formulation Methods 0.000 description 56
- 239000000126 substance Substances 0.000 description 45
- 238000010790 dilution Methods 0.000 description 41
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- 230000003253 viricidal effect Effects 0.000 description 24
- -1 polyhexamethylene Polymers 0.000 description 23
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 22
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 19
- 239000002609 medium Substances 0.000 description 19
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 17
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 14
- PHOQVHQSTUBQQK-SQOUGZDYSA-N D-glucono-1,5-lactone Chemical compound OC[C@H]1OC(=O)[C@H](O)[C@@H](O)[C@@H]1O PHOQVHQSTUBQQK-SQOUGZDYSA-N 0.000 description 13
- 235000012209 glucono delta-lactone Nutrition 0.000 description 13
- 239000000182 glucono-delta-lactone Substances 0.000 description 13
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- 230000000694 effects Effects 0.000 description 9
- 241000893980 Microsporum canis Species 0.000 description 8
- 241000187478 Mycobacterium chelonae Species 0.000 description 8
- 241000186365 Mycobacterium fortuitum Species 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
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- 239000004471 Glycine Substances 0.000 description 7
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- VAZJLPXFVQHDFB-UHFFFAOYSA-N 1-(diaminomethylidene)-2-hexylguanidine Polymers CCCCCCN=C(N)N=C(N)N VAZJLPXFVQHDFB-UHFFFAOYSA-N 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
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Images
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
- A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
- A01N47/40—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides
- A01N47/42—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides containing —N=CX2 groups, e.g. isothiourea
- A01N47/44—Guanidine; Derivatives thereof
-
- 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
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P1/00—Disinfectants; Antimicrobial compounds or mixtures thereof
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
Definitions
- the present invention relates to an antiseptic composition (disinfectant composition) containing olanexidine gluconate and having a broader bactericidal spectrum.
- Olanexidine chemical name 1-(3,4-dichlorobenzyl)-5-octylbiguanide
- Olanexidine gluconate has sufficient water solubility, a broad bactericidal spectrum, demonstrates a bactericidal effect in a short time, further sustains such an effect for an extended period of time, and is highly safe, thereby to be useful as a medical disinfectant (Patent Document 1).
- Dermal bactericidal disinfectants containing olanexidine gluconate have good efficacy on various bacteria which are considered as normal bacteria on skin and enveloped viruses, while substantially have no efficacy on feline calicivirus which has no envelope (Non-patent Document 1). For this reason, in the fields such as medical and nursing, and food and drink industries, olanexidine gluconate-containing disinfectants having more efficacies with a broader bactericidal spectrum are in demand.
- Olanexidine belongs to monobiganide-based compounds which have 1 biganide structure.
- Examples of the disinfectant having the same biganide structure representatively include chlorhexidine, which is a bisbiganide-based compound, and polyhexamethylene biguanide, which is a polybiganide-based compound.
- Chlorhexidine is a bisbiganide-based compound having 2 biganide structures in a molecule. As with olanexidine, chlorhexidine is hardly water-soluble and becomes soluble in the form of gluconate, for the reason of which it is mainly used in the form of chlorhexidine gluconate as a pharmaceutical product (Non-patent Document 2). Chlorhexidine gluconate, as with olanexidine gluconate, shows a viricidal action on enveloped viruses, while having no efficacy on non-enveloped viruses (Non-patent Document 3).
- chlorhexidine gluconate is stable at pH 4 to 6.5 and is known to cause precipitation when a dilute aqueous solution is basic of pH 8 or more and cause no difference in the bactericidal efficacies even when pH is increased (Patent Document 2, Non-patent Document 2, and Non-patent Document 4).
- polyhexamethylene biganide classified as a polybiganide-based compound, is a polymer of hexamethylene biganide having 1 biganide structure in a unit.
- Polyhexamethylene biganide is extremely easily soluble in water and has a broad bactericidal spectrum, for the reason of which a mild acidic solution thereof is commonly available as a low toxic sterilizing agent (Non-patent Documents 5 and 6).
- Non-patent Document 7 commercial polyhexamethylene biganide disinfectants are reported as having viricidal activities on non-enveloped viruses (Non-patent Document 7) and further reported as increasing bactericidal efficacy and viricidal efficacy when pH is further increased (Non-patent Document 4 and Patent Documents 3 and 4).
- An object of the present invention is to provide an antiseptic composition with a more extended applicable range by further enhancing the efficacy of olanexidine gluconate, which has been used as a highly safe dermal bactericidal disinfectant, and extending bactericidal spectrum.
- Non-patent Document 1 Conventional bactericides containing olanexidine gluconate were formulated to be pH (Non-patent Document 1) because compositions applied to skins are generally mildly acidic according to pH (pH 4 to 7) of skins and olanexidine deposits in the form of a free compound when neutralized with an alkaline aqueous solution (Patent Document 1), however, the present inventors intentionally prepared a basic solution of olanexidine gluconate to test activities thereof and found that bactericidal efficacies are not only unexpectedly enhanced but efficacies are demonstrated on non-enveloped viruses against which a mildly acidic formulation thereof had substantially no efficacy. Further, the present inventors confirmed that further addition of a surfactant to a basic solution containing olanexidine gluconate enhances the stability. The present invention is based on the above findings.
- the present invention is as follows.
- a disinfectant usable in the fields such as medical and nursing, and food and drink industries and having higher efficacy with a broader bactericidal spectrum can be produced.
- FIG. 1 is a chart showing bactericidal powers of olanexidine gluconate-containing compositions (pH 5, 8 to 10) of Example 1 against Mycobacterium fortuitum JCM 6387.
- FIG. 2 is a chart showing bactericidal powers of olanexidine gluconate-containing compositions (pH 5, 8 to 10) of Example 1 against Mycobacterium chelonae JCM 6388.
- FIG. 3 is a chart showing bactericidal powers of olanexidine gluconate-containing compositions (pH 5, 8 to 10) of Example 1 against Microsporum canis NBRC 32464.
- FIG. 4 is a chart showing viricidal (phage) activities of olanexidine gluconate-containing compositions (pH 5, 7 to 12) of Example 2 on phage.
- FIG. 5 is a chart showing a viricidal (phage) activity of ethanol-containing olanexidine formulation of Example 3 on phage.
- the present invention relates to an antiseptic composition which comprises olanexidine gluconate and is basic.
- Being basic used herein may be any composition of pH being more than 7 but examples include, in view of toxicity and a bactericidal activity to skins, pH being more than 7 to 12, pH being more than 7 to 11.5, pH being more than 7 to 11, pH being more than 7 to 10.5, and pH being more than 7 to 10; preferably pH 7.5 to 12, pH 7.5 to 11.5, pH 7.5 to 11, pH 7.5 to 10.5, and pH 7.5 to 10; more preferably pH 8 to 11.5, pH 8 to 11, pH 8 to 10.5, pH 8 to 10; further preferably pH 8.5 to 11.5, pH 8.5 to 11, pH 8.5 to 10.5, and pH 8.5 to 10; and furthermore preferably pH 9 to 12, pH 9 to 11.5, pH 9 to 11, pH 9 to 10.5, and pH 9 to 10.
- the composition of the present invention is an aqueous solution.
- the “disinfection” and “bactericidal” mean to kill bacteria, fungi
- any known pH adjuster can be used to adjust the pH, but examples include a basic solution such as sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium carbonate, and potassium carbonate, of which sodium hydroxide is preferable.
- the composition of the present invention is optionally prepared using a basic buffer, and examples of the buffer used include a boric acid-sodium carbonate buffer, a CAPS-NaOH buffer, a Bicine-NaOH buffer, a Glycine-NaOH buffer, a Tricine-NaOH buffer, a HEPPS-NaOH buffer, a TAPS-NaOH buffer, a Bicine-NaOH buffer, and a HEPES-NaOH buffer.
- the concentration of olanexidine gluconate is not particularly limited as long as it has sufficient bactericidal efficacy, but examples include 0.01 to 20% (W/V), preferably 0.1 to 10% (W/V), and more preferably 0.5 to 5% (W/V).
- examples of such a concentration include 0.01 to 10% (W/V), preferably 0.1 to 7% (W/V), more preferably 0.5 to 5% (W/V), and further preferably 0.5 to 3% (W/V).
- a composition of the present invention has more promoted bactericidal activities on filamentous fungi and acid-fast bacteria, particularly bacteria of the genus Microsporum and bacteria of the genus Mycobacterium. Further, the present composition also has good viricidal activities even on non-enveloped viruses, particularly viruses of the family Caliciviridae (viruses of the genus Norovirus ), against which the conventional olanexidine gluconate-containing disinfectants failed to inactivate.
- a composition of the present invention further optionally contains an antiseptic alcohol to potentiate bactericidal activities and impart quick-dryness.
- the antiseptic alcohol herein preferably include ethanol and isopropyl alcohol, and examples of the antiseptic alcohol concentration include 10 to 85% (V/V), 20 to 85% (V/V), 30 to 85% (V/V), 40 to 85% (V/V), 50 to 85% (V/V), 10 to 80% (V/V), 20 to 80% (V/V), 30 to 80% (V/V), 40 to 80% (V/V), 50 to 80% (V/V), 10 to 70% (V/V), 20 to 70% (V/V), 30 to 70% (V/V), 40 to 70% (V/V), and 50 to 70% (V/V).
- a composition of the present invention may not substantially contain an antiseptic alcohol.
- Containment of the antiseptic alcohol enables to prepare a quick-drying disinfectant having both potentiating effects of bactericidal activities due to the antiseptic alcohol and sustained effects of bactericidal activities due to olanexidine gluconate. Further, as bactericidal activities are potentiated due to the antiseptic alcohol, a concentration of olanexidine gluconate can be reduced. Examples of the concentration ratio of the olanexidine gluconate to the antiseptic alcohol include 1:400 to 1:20, preferably 1:300 to 1:30, and more preferably 1:200 to 1:40.
- a composition of the present invention can further contain a known bactericide.
- the bactericide include a benzalkonium salt such as benzalkonium chloride and benzalkonium alkyl phosphate, benzethonium chloride, triclosan, isopropyl methylphenol, cetylpyridinium chloride, resorcin, trichlorocarbanilide, chlorhexidine hydrochloride, chlorhexidine gluconate, polyhexamethylene biganide, sodium hypochlorite, hydrogen peroxide, povidone iodine, and iodine tincture.
- These bactericides are optionally used singly or 2 or more may be used in combination.
- a composition of the present invention can further contain a known solubilizer.
- the solubilizer include a nonionic surfactant, an ionic surfactant, ethylenediamine, sodium benzoate, nicotinamide, cyclodextrin, ethanol, benzyl alcohol, and propylene glycol.
- the ionic surfactant preferably include an alkyl dimethylamine oxide such as an oleyl dimethylamine oxide, a stearyl dimethylamine oxide, a palmityl dimethylamine oxide, a myristyl dimethylamine oxide, a lauryl dimethylamine oxide, and a coconut oil alkyl dimethylamine oxide, of which a lauryl dimethylamine oxide is preferable.
- nonionic surfactant examples include a sorbitan fatty acid ester, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene alkyl ether, a polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene polyoxypropylene glycol, a polyglyceryl fatty acid ester, a polyoxyethylene hydrogenated castor oil, and a sucrose fatty acid ester, of which polyoxyethylene polyoxypropylene glycol, a polyoxyethylene alkyl ether, and a polyoxyethylene polyoxypropylene alkyl ether are preferable.
- polyoxyethylene polyoxypropylene glycol examples include polyoxyethylene(42) polyoxypropylene(67) glycol (Pluronic (R) P-123), polyoxyethylene(54) polyoxypropylene(39) glycol (Pluronic (R) P-85), polyoxyethylene(196) polyoxypropylene (67) glycol (Pluronic (R) F-127), polyoxyethylene(3) polyoxypropylene(17) glycol (Pluronic (R) L-31), polyoxyethylene(20) polyoxypropylene(20) glycol (Pluronic (R) L-44), polyoxyethylene(120) polyoxypropylene(40) glycol (Pluronic (R) F-87), and polyoxyethylene(160) polyoxypropylene(30) glycol (Pluronic (R) F-68), of which polyoxyethylene(20) polyoxypropylene(20) glycol (Pluronic (R) L-44) is preferable.
- polyoxyethylene alkyl ether examples include a polyoxyethylene cetylether, a polyoxyethylene oleyl ether, and a polyoxyethylene lauryl ether (lauromacrogol), with a polyoxyethylene lauryl ether (lauromacrogol) being particularly preferable.
- polyoxyethylene polyoxypropylene alkyl ether examples include a polyoxyethylene(20) polyoxypropylene(4) cetylether, a polyoxyethylene(30) polyoxypropylene(6) decyltetradecyl ether, a polyoxyethylene(25) polyoxypropylene(25) lauryl ether, with a polyoxyethylene(20) polyoxypropylene(4) cetylether being particularly preferable.
- the concentration of a solubilizer may be a concentration which prevents olanexidine gluconate from precipitating and does not reduce the bactericidal activity and is usually determined in accordance with a concentration of olanexidine gluconate within a concentration range of 0.1 to 30% (W/V).
- a composition of the present invention optionally contains an anti-inflammatory agent, a moisturizer, an emollient agent, a touch improver, and a thickener.
- anti-inflammatory agent examples include a licorice extract, glycyrrhetinic acid, dipotassium glycyrrhizinate, stearyl glycyrrhetinate, tocopherol acetate, allantoin, and an aloe extract.
- Example of the moisturizer include an amino acid, a fatty acid ester, pyrrolidone carboxylic acid, sodium pyrrolidone carboxylate, sodium lactate, hyaluronic acid, sodium hyaluronate, N-cocoyl-L-arginine ethyl ester-DL-pyrrolidone carboxylate, urea, sorbitol, trehalose, 1,3-butylene glycol, propylene glycol, poloxamer (Pluronic (R) F-68, etc.), and glycerin.
- a fatty acid ester pyrrolidone carboxylic acid, sodium pyrrolidone carboxylate, sodium lactate, hyaluronic acid, sodium hyaluronate, N-cocoyl-L-arginine ethyl ester-DL-pyrrolidone carboxylate, urea, sorbitol, trehalose, 1,3-butylene glyco
- emollient examples include a fatty acid ester such as isopropyl myristate, isopropyl palmitate, isopropyl stearate, isobutyl oleate, and isobutyl maleate, and 1 fatty acid ester singly or 2 or more of these can be contained.
- a fatty acid ester such as isopropyl myristate, isopropyl palmitate, isopropyl stearate, isobutyl oleate, and isobutyl maleate, and 1 fatty acid ester singly or 2 or more of these can be contained.
- Examples of the touch improver include a silicone-based compound such as dimethylpolysiloxane and cyclic silicone.
- the thickener examples include a cellulose derivative such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydrophobic hydroxypropyl methylcellulose, methyl cellulose, and carboxymethyl cellulose, a (meth)acrylic acid base copolymer, polyvinyl alcohol, polyvinylpyrrolidone, a methyl vinyl ether-maleic anhydride copolymer, polyacrylamide, alginic acid, sodium alginate, propylene glycol alginate, gelatin, a gum arabic, a gum tragacanth, a locust bean gum, a guar gum, a tamarind gum, a xanthan gum, a gellan gum, and carrageenan.
- a cellulose derivative such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydrophobic hydroxypropyl methylcellulose, methyl cellulose, and carboxymethyl cellulose
- a (meth)acrylic acid base copolymer polyvin
- a composition of the present invention can preferably be used for the purpose of disinfecting the instrument surfaces of medical instruments, cookware, and nursing equipment, and skin surfaces such as hands and fingers.
- a composition of the present invention is optionally used as soaked in paper, cloth, non-woven fabric, cotton swab, or absorbent cotton, or as filled in an applicator for application, or in the form of a rubbing agent or a scrubbing agent, but a composition of the present invention is preferably used as a rubbing agent.
- the rubbing agent herein means a quick-drying rubbing-type formulation
- the scrubbing agent means a formulation obtained by mixing a bactericide/disinfectant and a surfactant having detergency.
- an amount usually used per disinfection is 1 to 5 ml, preferably 1.5 to 4.5 ml, more preferably 2 to 4 ml, and further preferably 2.5 to 3.5 ml, and examples of the number of times used per day include, in view of dermal toxicity, within 100 times, preferably within 80 times, more preferably within 60 times, and further preferably within 40 times.
- Substance to be tested 1 Name: Olanexidine formulation pH 5 Composition: Olanexidine gluconate 1.5% (W/V) Pluronic L-44 1.08% (W/V) pH Adjuster (sodium hydroxide, glucono- ⁇ -lactone) qs Pure water qs pH 5 (2) Substance to be tested 2 Name: Olanexidine formulation pH 8 Composition: Olanexidine gluconate 1.5% (W/V) Pluronic L-44 1.08% (W/V) HEPES 0.1% (W/V) pH Adjuster (sodium hydroxide, glucono- ⁇ -lactone) qs Pure water qs pH 8 (3) Substance to be tested 3 Name: Olanexidine formulation pH 9 Composition: Olanexidine gluconate 1.5% (W/V) Pluronic L-44 4.08% (W/V) Glycine 0.1% (W/V) pH Adjuster (sodium hydroxide, glucono- ⁇ -lactone) qs Pure water qs
- test microorganisms filamentous fungus Microsporum canis NBRC 32464, acid-fast bacteria Mycobacterium chelonae JCM 6388 and Mycobacterium fortuitum JCM 6387 were used.
- Each of the test microorganisms was cultured on the 7H10 plate ( Mycobacterium chelonae and Mycobacterium fortuitum ) or the SAB plate ( Microsporum canis ), and then suspended in distilled water to prepare test microorganism solutions of McFarland No.1 ( Mycobacterium chelonae and Mycobacterium fortuitum ) or of McFarland No.5 ( Microsporum canis ).
- the mixing ratio of the reaction solution to the neutralizer is 1:99 and the smear amount is 100 ⁇ L, because of which the minimum limit of detection of a viable cell count is 1000 CFU/mL (3 in common logarithm value). Further, with Microsporum canis, the mixing ratio of the reaction solution to the neutralizer is 1:9 and the smear amount is 100 ⁇ L, because of which the minimum limit of detection of a viable cell count is 100 CFU/mL (2 in common logarithm value). When a colony was not detected, the minimum limit of detection was adopted and LR is indicated with a sign of inequality “>”.
- Bacteriophage MS2 is known to be resistant to disinfectants and is used for an alternative test such as the norovirus killing action of disinfectants. For this reason, viricidal effects of the olanexidine formulations prepared by changing pH and a commercial disinfectant on a virus were evaluated by a test using bacteriophage MS2.
- Substance to be tested 1 Name: Olanexidine formulation pH 5 Composition: Olanexidine gluconate 1.5% (W/V) Pluronic L-44 1.08% (W/V) pH Adjuster (sodium hydroxide, glucono- ⁇ -lactone) qs Pure water qs pH 5 (2) Substance to be tested 2 Name: Olanexidine formulation pH 7 Composition: Olanexidine gluconate 1.5% (W/V) Pluronic L-44 1.08% (W/V) HEPES 0.1% (W/V) pH Adjuster (sodium hydroxide, glucono- ⁇ -lactone) qs Pure water qs pH 7 (3) Substance to be tested 3 Name: Olanexidine formulation pH 8 Composition: Olanexidine gluconate 1.5% (W/V) Pluronic L-44 1.08% (W/V) HEPES 0.1% (W/V) pH Adjuster (sodium hydroxide, glucono- ⁇ -lactone) qs Pure water qs
- a phage solution prepared to about 6 ⁇ 10 12 PFU/mL in accordance with a routine method was used.
- Phage titer was calculated using the following (Equation 1).
- a titer (PFU/mL) was converted to common logarithm (log 10 PFU/mL) and indicated to the first decimal place by rounding off. When a titer (PFU/mL) was 1 or less, its common logarithm value was 0.
- the viricidal (phage) action was evaluated by a Log 10 reduction value.
- LR is indicated to the first decimal place by rounding off. Note that when a titer (common logarithm value) of the test substance after acted was 0, LR is indicated as “>(A ⁇ 3)” because the phage titer has the minimum limit of detection of 3 ⁇ log 10 .
- Evaluation results on the viricidal actions of the test substances are shown in Table 4 and FIG. 4 .
- the olanexidine formulation at pH 5 did not substantially show the viricidal action, and the viricidal action of the olanexidine formulation at pH 7 was equal to 70% ethanol used as the control substance, whereas the olanexidine formulations with the pH changed to basic tended to have larger LR as pH increased.
- the formulations at pH 8 or more had an LR of 3 or higher at 60 seconds and the formulation at pH 8.5 or more had an LR of 3 or higher at 30 seconds thereby to meet a requirement for the viricidal action of an ideal disinfectant of LR 3 or higher.
- a basic solution of olanexidine gluconate was revealed to have a practical viricidal activity and such a viricidal activity is intensified as pH increases.
- ethanol was added to a basic olanexidine formulation of pH 9.5 to evaluate a viricidal effect by a test using bacteriophage MS2 for the purpose of confirming the quick-dryness imparting effect and the potentiating effect of the bactericidal activity by an antiseptic alcohol to a basic olanexidine formulation.
- Viricidal effects were evaluated by the method using the bacteriophage MS2 described in the above Example 2, 2-1 and 2-2. Note that a phage solution prepared to about 4 ⁇ 10 12 PFU/mL was used.
- Evaluation results on viricidal actions of the test substances are shown in Table 6 and FIG. 5 .
- the above results showed that the viricidal action increases in a concentration dependent manner of olanexidine gluconate even in the basic olanexidine formulation containing ethanol whereby the viricidal action by olanexidine gluconate is not impeded even when ethanol is added to impart quick-dryness.
- the basic olanexidine formulation containing ethanol has a higher viricidal action compared with a basic olanexidine formulation which does not contain ethanol, for the reason of which the ethanol-containing basic olanexidine formulation showed to have a practical viricidal action even when an olanexidine gluconate concentration is reduced.
- composition of the present invention when used, can produce an olanexidine gluconate-containing disinfectant having an improved bactericidal spectrum and an effect on non-enveloped viruses and is thus highly useful in the fields such as medical and nursing, and food and drink industries.
Abstract
Description
- The present invention relates to an antiseptic composition (disinfectant composition) containing olanexidine gluconate and having a broader bactericidal spectrum.
- Olanexidine, chemical name 1-(3,4-dichlorobenzyl)-5-octylbiguanide, is a compound with a high bactericidal activity. Olanexidine gluconate has sufficient water solubility, a broad bactericidal spectrum, demonstrates a bactericidal effect in a short time, further sustains such an effect for an extended period of time, and is highly safe, thereby to be useful as a medical disinfectant (Patent Document 1). Dermal bactericidal disinfectants containing olanexidine gluconate have good efficacy on various bacteria which are considered as normal bacteria on skin and enveloped viruses, while substantially have no efficacy on feline calicivirus which has no envelope (Non-patent Document 1). For this reason, in the fields such as medical and nursing, and food and drink industries, olanexidine gluconate-containing disinfectants having more efficacies with a broader bactericidal spectrum are in demand.
- Olanexidine belongs to monobiganide-based compounds which have 1 biganide structure. Examples of the disinfectant having the same biganide structure representatively include chlorhexidine, which is a bisbiganide-based compound, and polyhexamethylene biguanide, which is a polybiganide-based compound.
- Chlorhexidine is a bisbiganide-based compound having 2 biganide structures in a molecule. As with olanexidine, chlorhexidine is hardly water-soluble and becomes soluble in the form of gluconate, for the reason of which it is mainly used in the form of chlorhexidine gluconate as a pharmaceutical product (Non-patent Document 2). Chlorhexidine gluconate, as with olanexidine gluconate, shows a viricidal action on enveloped viruses, while having no efficacy on non-enveloped viruses (Non-patent Document 3). Further, chlorhexidine gluconate is stable at
pH 4 to 6.5 and is known to cause precipitation when a dilute aqueous solution is basic ofpH 8 or more and cause no difference in the bactericidal efficacies even when pH is increased (Patent Document 2, Non-patentDocument 2, and Non-patent Document 4). - On the other hand, polyhexamethylene biganide, classified as a polybiganide-based compound, is a polymer of hexamethylene biganide having 1 biganide structure in a unit. Polyhexamethylene biganide is extremely easily soluble in water and has a broad bactericidal spectrum, for the reason of which a mild acidic solution thereof is commonly available as a low toxic sterilizing agent (Non-patent
Documents 5 and 6). Further, commercial polyhexamethylene biganide disinfectants are reported as having viricidal activities on non-enveloped viruses (Non-patent Document 7) and further reported as increasing bactericidal efficacy and viricidal efficacy when pH is further increased (Non-patentDocument 4 andPatent Documents 3 and 4). -
- [Patent Document 1] Japanese unexamined Patent Application Publication No. 2005-289959
- [Patent Document 2] Japanese unexamined Patent Application Publication No. 2007-217394
- [Patent Document 3] Japanese unexamined Patent Application Publication No. 2007-045732
- [Patent Document 4] Japanese unexamined Patent Application Publication No. 2017-171606
-
- [Non-patent Document 1] Attached document “Olanexidine solution 1.5%
antiseptic applicator 10 mL/25 mL” (August, 2015 Revised) - [Non-patent Document 2] Pharmaceutical Product Interview Form “Clorhexidine gluconate solution” (July, 2010 Revised)
- [Non-patent Document 3] Clin Microbiol Rev.; 12(1): 147-179 (January, 1999)
- [Non-patent Document 4] Skin Pharmacol Physiol.; 28(3): 147-158 (2015)
- [Non-patent Document 5] Scientific Committee on Consumer Safety “Opinion on the safety of poly(hexamethylene) biguanide hydrochloride (PHMB)” (July, 2015)
- [Non-patent Document 6] VANTOCIL IB Antimicrobial Technical information materials
- [Non-patent Document 7] Website “Arch Chemicals Reports that Studies Confirm that Vantocil (™) Product Controls Norovirus, a Leading Cause of Acute Gastroenteritis” (https://www.businesswire.com/news/home/20060113005294/en/Arch-Chemicals-Reports-Studies-Confirm-Vantocil-™)
- An object of the present invention is to provide an antiseptic composition with a more extended applicable range by further enhancing the efficacy of olanexidine gluconate, which has been used as a highly safe dermal bactericidal disinfectant, and extending bactericidal spectrum.
- The present inventors continued extensive studies to solve the above object. Conventional bactericides containing olanexidine gluconate were formulated to be pH (Non-patent Document 1) because compositions applied to skins are generally mildly acidic according to pH (
pH 4 to 7) of skins and olanexidine deposits in the form of a free compound when neutralized with an alkaline aqueous solution (Patent Document 1), however, the present inventors intentionally prepared a basic solution of olanexidine gluconate to test activities thereof and found that bactericidal efficacies are not only unexpectedly enhanced but efficacies are demonstrated on non-enveloped viruses against which a mildly acidic formulation thereof had substantially no efficacy. Further, the present inventors confirmed that further addition of a surfactant to a basic solution containing olanexidine gluconate enhances the stability. The present invention is based on the above findings. - More specifically, the present invention is as follows.
- (1) An antiseptic composition comprising olanexidine gluconate, wherein the antiseptic composition is basic.
- (2) The antiseptic composition according to (1), having a pH within a range from 8 to 11.
- (3) The antiseptic composition according to (1) or (2), wherein a concentration of olanexidine gluconate is 0.01 to 20% (W/V).
- (4) The antiseptic composition according to any one of (1) to (3), comprising water and/or an antiseptic alcohol.
- (5) The antiseptic composition according to (4), wherein a concentration of the antiseptic alcohol concentration is 10 to 85% (V/V).
- (6) The antiseptic composition according to (4) or (5), wherein the antiseptic alcohol is selected from ethanol and isopropyl alcohol.
- (7) A rubbing agent comprising the antiseptic composition according to any one of (1) to (6).
- According to a composition of the present invention, a disinfectant usable in the fields such as medical and nursing, and food and drink industries and having higher efficacy with a broader bactericidal spectrum can be produced.
-
FIG. 1 is a chart showing bactericidal powers of olanexidine gluconate-containing compositions (pH -
FIG. 2 is a chart showing bactericidal powers of olanexidine gluconate-containing compositions (pH -
FIG. 3 is a chart showing bactericidal powers of olanexidine gluconate-containing compositions (pH -
FIG. 4 is a chart showing viricidal (phage) activities of olanexidine gluconate-containing compositions (pH -
FIG. 5 is a chart showing a viricidal (phage) activity of ethanol-containing olanexidine formulation of Example 3 on phage. - The present invention relates to an antiseptic composition which comprises olanexidine gluconate and is basic. Being basic used herein may be any composition of pH being more than 7 but examples include, in view of toxicity and a bactericidal activity to skins, pH being more than 7 to 12, pH being more than 7 to 11.5, pH being more than 7 to 11, pH being more than 7 to 10.5, and pH being more than 7 to 10; preferably pH 7.5 to 12, pH 7.5 to 11.5, pH 7.5 to 11, pH 7.5 to 10.5, and pH 7.5 to 10; more preferably
pH 8 to 11.5,pH 8 to 11,pH 8 to 10.5,pH 8 to 10; further preferably pH 8.5 to 11.5, pH 8.5 to 11, pH 8.5 to 10.5, and pH 8.5 to 10; and furthermore preferablypH 9 to 12,pH 9 to 11.5,pH 9 to 11,pH 9 to 10.5, andpH 9 to 10. Note that the composition of the present invention is an aqueous solution. Further, in the present Description, the “disinfection” and “bactericidal” mean to kill bacteria, fungi and/or viruses. - Any known pH adjuster can be used to adjust the pH, but examples include a basic solution such as sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium carbonate, and potassium carbonate, of which sodium hydroxide is preferable. Further, the composition of the present invention is optionally prepared using a basic buffer, and examples of the buffer used include a boric acid-sodium carbonate buffer, a CAPS-NaOH buffer, a Bicine-NaOH buffer, a Glycine-NaOH buffer, a Tricine-NaOH buffer, a HEPPS-NaOH buffer, a TAPS-NaOH buffer, a Bicine-NaOH buffer, and a HEPES-NaOH buffer.
- The concentration of olanexidine gluconate is not particularly limited as long as it has sufficient bactericidal efficacy, but examples include 0.01 to 20% (W/V), preferably 0.1 to 10% (W/V), and more preferably 0.5 to 5% (W/V). When the antiseptic alcohol to be described later is used concurrently, examples of such a concentration include 0.01 to 10% (W/V), preferably 0.1 to 7% (W/V), more preferably 0.5 to 5% (W/V), and further preferably 0.5 to 3% (W/V).
- A composition of the present invention has more promoted bactericidal activities on filamentous fungi and acid-fast bacteria, particularly bacteria of the genus Microsporum and bacteria of the genus Mycobacterium. Further, the present composition also has good viricidal activities even on non-enveloped viruses, particularly viruses of the family Caliciviridae (viruses of the genus Norovirus), against which the conventional olanexidine gluconate-containing disinfectants failed to inactivate.
- A composition of the present invention further optionally contains an antiseptic alcohol to potentiate bactericidal activities and impart quick-dryness. Examples of the antiseptic alcohol herein preferably include ethanol and isopropyl alcohol, and examples of the antiseptic alcohol concentration include 10 to 85% (V/V), 20 to 85% (V/V), 30 to 85% (V/V), 40 to 85% (V/V), 50 to 85% (V/V), 10 to 80% (V/V), 20 to 80% (V/V), 30 to 80% (V/V), 40 to 80% (V/V), 50 to 80% (V/V), 10 to 70% (V/V), 20 to 70% (V/V), 30 to 70% (V/V), 40 to 70% (V/V), and 50 to 70% (V/V). A composition of the present invention may not substantially contain an antiseptic alcohol. Containment of the antiseptic alcohol enables to prepare a quick-drying disinfectant having both potentiating effects of bactericidal activities due to the antiseptic alcohol and sustained effects of bactericidal activities due to olanexidine gluconate. Further, as bactericidal activities are potentiated due to the antiseptic alcohol, a concentration of olanexidine gluconate can be reduced. Examples of the concentration ratio of the olanexidine gluconate to the antiseptic alcohol include 1:400 to 1:20, preferably 1:300 to 1:30, and more preferably 1:200 to 1:40.
- A composition of the present invention can further contain a known bactericide. Examples of the bactericide include a benzalkonium salt such as benzalkonium chloride and benzalkonium alkyl phosphate, benzethonium chloride, triclosan, isopropyl methylphenol, cetylpyridinium chloride, resorcin, trichlorocarbanilide, chlorhexidine hydrochloride, chlorhexidine gluconate, polyhexamethylene biganide, sodium hypochlorite, hydrogen peroxide, povidone iodine, and iodine tincture. These bactericides are optionally used singly or 2 or more may be used in combination.
- A composition of the present invention can further contain a known solubilizer. Examples of the solubilizer include a nonionic surfactant, an ionic surfactant, ethylenediamine, sodium benzoate, nicotinamide, cyclodextrin, ethanol, benzyl alcohol, and propylene glycol. Examples of the ionic surfactant preferably include an alkyl dimethylamine oxide such as an oleyl dimethylamine oxide, a stearyl dimethylamine oxide, a palmityl dimethylamine oxide, a myristyl dimethylamine oxide, a lauryl dimethylamine oxide, and a coconut oil alkyl dimethylamine oxide, of which a lauryl dimethylamine oxide is preferable. Examples of the nonionic surfactant include a sorbitan fatty acid ester, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene alkyl ether, a polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene polyoxypropylene glycol, a polyglyceryl fatty acid ester, a polyoxyethylene hydrogenated castor oil, and a sucrose fatty acid ester, of which polyoxyethylene polyoxypropylene glycol, a polyoxyethylene alkyl ether, and a polyoxyethylene polyoxypropylene alkyl ether are preferable. Examples of the polyoxyethylene polyoxypropylene glycol include polyoxyethylene(42) polyoxypropylene(67) glycol (Pluronic (R) P-123), polyoxyethylene(54) polyoxypropylene(39) glycol (Pluronic (R) P-85), polyoxyethylene(196) polyoxypropylene (67) glycol (Pluronic (R) F-127), polyoxyethylene(3) polyoxypropylene(17) glycol (Pluronic (R) L-31), polyoxyethylene(20) polyoxypropylene(20) glycol (Pluronic (R) L-44), polyoxyethylene(120) polyoxypropylene(40) glycol (Pluronic (R) F-87), and polyoxyethylene(160) polyoxypropylene(30) glycol (Pluronic (R) F-68), of which polyoxyethylene(20) polyoxypropylene(20) glycol (Pluronic (R) L-44) is preferable. Examples of the polyoxyethylene alkyl ether include a polyoxyethylene cetylether, a polyoxyethylene oleyl ether, and a polyoxyethylene lauryl ether (lauromacrogol), with a polyoxyethylene lauryl ether (lauromacrogol) being particularly preferable. Further, examples of the polyoxyethylene polyoxypropylene alkyl ether include a polyoxyethylene(20) polyoxypropylene(4) cetylether, a polyoxyethylene(30) polyoxypropylene(6) decyltetradecyl ether, a polyoxyethylene(25) polyoxypropylene(25) lauryl ether, with a polyoxyethylene(20) polyoxypropylene(4) cetylether being particularly preferable. The concentration of a solubilizer may be a concentration which prevents olanexidine gluconate from precipitating and does not reduce the bactericidal activity and is usually determined in accordance with a concentration of olanexidine gluconate within a concentration range of 0.1 to 30% (W/V).
- A composition of the present invention optionally contains an anti-inflammatory agent, a moisturizer, an emollient agent, a touch improver, and a thickener.
- Examples of the anti-inflammatory agent include a licorice extract, glycyrrhetinic acid, dipotassium glycyrrhizinate, stearyl glycyrrhetinate, tocopherol acetate, allantoin, and an aloe extract.
- Example of the moisturizer include an amino acid, a fatty acid ester, pyrrolidone carboxylic acid, sodium pyrrolidone carboxylate, sodium lactate, hyaluronic acid, sodium hyaluronate, N-cocoyl-L-arginine ethyl ester-DL-pyrrolidone carboxylate, urea, sorbitol, trehalose, 1,3-butylene glycol, propylene glycol, poloxamer (Pluronic (R) F-68, etc.), and glycerin.
- Examples of the emollient include a fatty acid ester such as isopropyl myristate, isopropyl palmitate, isopropyl stearate, isobutyl oleate, and isobutyl maleate, and 1 fatty acid ester singly or 2 or more of these can be contained.
- Examples of the touch improver include a silicone-based compound such as dimethylpolysiloxane and cyclic silicone.
- Examples of the thickener include a cellulose derivative such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydrophobic hydroxypropyl methylcellulose, methyl cellulose, and carboxymethyl cellulose, a (meth)acrylic acid base copolymer, polyvinyl alcohol, polyvinylpyrrolidone, a methyl vinyl ether-maleic anhydride copolymer, polyacrylamide, alginic acid, sodium alginate, propylene glycol alginate, gelatin, a gum arabic, a gum tragacanth, a locust bean gum, a guar gum, a tamarind gum, a xanthan gum, a gellan gum, and carrageenan.
- A composition of the present invention can preferably be used for the purpose of disinfecting the instrument surfaces of medical instruments, cookware, and nursing equipment, and skin surfaces such as hands and fingers. A composition of the present invention is optionally used as soaked in paper, cloth, non-woven fabric, cotton swab, or absorbent cotton, or as filled in an applicator for application, or in the form of a rubbing agent or a scrubbing agent, but a composition of the present invention is preferably used as a rubbing agent. The rubbing agent herein means a quick-drying rubbing-type formulation, and the scrubbing agent means a formulation obtained by mixing a bactericide/disinfectant and a surfactant having detergency. Note that when a composition of the present invention is used for disinfecting fingers of both hands, an amount usually used per disinfection is 1 to 5 ml, preferably 1.5 to 4.5 ml, more preferably 2 to 4 ml, and further preferably 2.5 to 3.5 ml, and examples of the number of times used per day include, in view of dermal toxicity, within 100 times, preferably within 80 times, more preferably within 60 times, and further preferably within 40 times.
- Hereinafter, the present invention will be described more specifically in reference to examples, but technical ranges of the present invention are not limited thereto.
-
- 1. Bactericidal Power Against Fungi and Non-Tuberculous Mycobacteria
- Bactericidal power of olanexidine gluconate containing-compositions (pH5, 8 to 10) against filamentous fungi and non-tuberculous mycobacteria, which are known to cause infections, was evaluated by Time-kill test.
- 1-1 Test Material and Method
- 1-1-1 Test Substances
-
(1) Substance to be tested 1 Name: Olanexidine formulation pH 5 Composition: Olanexidine gluconate 1.5% (W/V) Pluronic L-44 1.08% (W/V) pH Adjuster (sodium hydroxide, glucono-δ-lactone) qs Pure water qs pH 5 (2) Substance to be tested 2 Name: Olanexidine formulation pH 8 Composition: Olanexidine gluconate 1.5% (W/V) Pluronic L-44 1.08% (W/V) HEPES 0.1% (W/V) pH Adjuster (sodium hydroxide, glucono-δ-lactone) qs Pure water qs pH 8 (3) Substance to be tested 3 Name: Olanexidine formulation pH 9 Composition: Olanexidine gluconate 1.5% (W/V) Pluronic L-44 4.08% (W/V) Glycine 0.1% (W/V) pH Adjuster (sodium hydroxide, glucono-δ-lactone) qs Pure water qs pH 9 (4) Substance to be tested 4 Name: Olanexidine formulation pH 10 Composition: Olanexidine gluconate 1.5% (W/V) Pluronic L-44 16.08% (W/V) Glycine 0.1% (W/V) pH Adjuster (sodium hydroxide, glucono-δ-lactone) qs Pure water qs pH 10 (5) Control substance Name: Base pH 10 Composition: Pluronic L-44 1.08% (W/V) Glycine 0.1% (W/V) pH Adjuster (sodium hydroxide, glucono-δ-lactone) qs Pure water qs pH 10 - 1-1-2 Medium
- (1) 7H10 Plate
- To 19 g of Difco Middlebrook 7H10 Agar (product number: 262710, manufactured by Becton, Dickinson and Company), 5 mL of glycerol (product number: 070-04941, manufactured by Wako Pure Chemical Industries, Ltd.) and 900 mL of pure water were added and stirred. The medium was steam-sterilized under pressure (121° C., 20 minutes). After sterilization, the medium was taken out from the pressure steam sterilizer, cooled to 50 to 55° C. with stirring, and subsequently 100 mL of BBL Middlebrook OADC Enrichment (product number: 212240, manufactured by Becton, Dickinson and Company) was added and stirred. About 20 mL each of the agar, before set, was dispensed in petri dishes and allowed to be solidified.
- (2) SAB Plate
- To 65 g of a Sabouraud agar medium “Nissui” (product number: 05701, manufactured by NISSUI PHARMACEUTICAL CO., LTD.), 1000 mL of pure water was added and stirred. The medium was steam-sterilized under pressure (121° C., 20 minutes). About 20 mL each of the agar, before set, was dispensed in petri dishes and allowed to be solidified.
- (3) SABLP Plate
- To 73 g of a Sabouraud-Dextrose LP Agar medium “DAIGO” (product code: 392-01875, manufactured by NIHON PHARMACEUTICAL CO., LTD.), 1000 mL of pure water was added and stirred. The medium was steam-sterilized under pressure (121° C., 20 minutes). About 20 mL each of the agar, before set, was dispensed in petri dishes and allowed to be solidified.
- 1-1-3 Neutralizer
- To about 800 mL of distilled water, 100 g of polysorbate 80, 5.0 g of a sodium thiosulfate hydrate, 0.4 g of potassium dihydrogen phosphate, 1 mL of Triton X-100, 10.1 g of disodium hydrogen phosphate anhydrous, and 11.7 g of soy lecithin were added and stirred. Further, 10.0 g of Tamol (R) NN8906 was added, and heated and stirred until dissolved. After dissolution, a 1 mol/L sodium hydroxide solution was added to adjust pH to 7.8 to 7.9. Distilled water was added until the total amount was 1000 mL, and then steam-sterilization under pressure was carried out.
- 1-1-4 Test Microorganisms
- For test microorganisms, filamentous fungus Microsporum canis NBRC 32464, acid-fast bacteria Mycobacterium chelonae JCM 6388 and Mycobacterium fortuitum JCM 6387 were used. Each of the test microorganisms was cultured on the 7H10 plate (Mycobacterium chelonae and Mycobacterium fortuitum) or the SAB plate (Microsporum canis), and then suspended in distilled water to prepare test microorganism solutions of McFarland No.1 (Mycobacterium chelonae and Mycobacterium fortuitum) or of McFarland No.5 (Microsporum canis).
- 1-2 Bactericidal Power Evaluation Test
- 1-2-1 Measurement of Initial Viable Cell Counts (Mycobacterium chelonae and Mycobacterium fortuitum)
- (1) To 3 mL of distilled water, 150 μL of the test microorganism solution was added and mixed.
- (2) Immediately, 50 μL of the bacterium mixture was added to 4.95 mL of the neutralizer and mixed. The mixture was prepared to be a 102-fold dilution.
- (3) 0.3 mL of the 102-fold dilution was added to 2.7 mL of the neutralizer to dilute 10 times. Dilution was further repeated by the same operation to produce 10-fold dilution series (3 stages in total from 102- to 104-fold dilutions).
- (4) 100 μL each of the 102- to 104-fold dilutions was dispensed onto the 7H10 plate and smeared. Steps (2) to (4) were carried out within 30 minutes.
- (5) The smear plate was inverted and the cells were cultured until a colony count can be carried out.
- (6) The colonies grown in the smear plate were visually counted and the number of colonies was multiplied by a dilution factor to calculate a viable cell count (CFU/mL). However, the smear plates in which the number of colonies is too numerous to distinguish colonies from each other were defined as TNTC (too numerous to count) and not counted.
- 1-2-2 Measurement of Viable Cell Count After the Test Substances Acted (Mycobacterium chelonae and Mycobacterium fortuitum)
- (1) To 3 mL of the test substance, 150 μL of the test microorganism solution was added and mixed. Using this mixture as a reaction solution, the reaction was carried out at room temperature.
- (2) After allowing the reaction to proceed for a predetermined period of time, 50 μL of the reaction solution was extracted, to which 4.95 mL of the neutralizer was added and mixed. This mixture was prepared to be a 102-fold dilution.
- (3) 0.3 mL of the 102-fold dilution was added to 2.7 mL of the neutralizer to dilute 10 times. Dilution was further repeated by the same operation to produce 10-fold dilution series (3 stages in total from 102- to 104-fold dilutions).
- (4) 100 μL each of the 102- to 104-fold dilutions was dispensed onto the 7H10 plate and smeared.
- (5) The smear plate was inverted and the cells were cultured until a colony count can be carried out.
- (6) The colonies grown in the smear plate were visually counted and the number of colonies was multiplied by a dilution factor to calculate a viable cell count (CFU/mL).
- 1-2-3 Measurement of Initial Viable Cell Count (Microsporum canis)
- (1) To 3 mL of distilled water, 150 μL of the test microorganism solution was added and mixed.
- (2) Immediately, 500 μL of the microorganism mixture solution was added to 4.5 mL of the neutralizer and mixed. This mixture was prepared to be a 101-fold dilution.
- (3) 0.3 mL of the 101-fold dilution was added to 2.7 mL of the neutralizer to dilute 10 times. Dilution was further repeated by the same operation to produce 10-fold dilution series (3 stages in total from 101- to 103-fold dilutions).
- (4) 100 μL each of the 101- to 103-fold dilutions was dispensed onto the SABLP plate and smeared. Steps (2) to (4) were carried out within 30 minutes.
- (5) The smear plate was inverted and the cells were cultured until a colony count can be carried out.
- (6) The colonies grown in the smear plate were visually counted and the number of colonies was multiplied by a dilution factor to calculate a viable cell count (CFU/mL). However, the smear plates in which the number of colonies is too numerous to distinguish colonies from each other were defined as TNTC and not counted.
- 1-2-4 Measurement of Viable Cell Count After the Test Substance Acted (Microsporum canis)
- (1) To 3 mL of the test substance, 150 μL of the test microorganism solution was added and mixed. Using this mixture as a reaction solution, the reaction was carried out at room temperature.
- (2) After allowing the reaction to proceed for a predetermined period of time, 500 μL of the reaction solution was extracted, to which 4.5 mL of the neutralizer was added and mixed. This mixture was prepared to be a 101-fold dilution.
- (3) 0.3 mL of the 101-fold dilution was added to 2.7 mL of the neutralizer to dilute 10 times. Dilution was further repeated by the same operation to produce 10-fold dilution series (3 stages in total from 101- to 103-fold dilutions).
- (4) 100 μL each of the 101- to 103-fold dilutions was dispensed onto the SABLP plate and smeared.
- (5) The smear plate was inverted and the cells were cultured until a colony count can be carried out.
- (6) The colonies grown in the smear plate were visually counted and the number of colonies was multiplied by a dilution factor to calculate a viable cell count (CFU/mL).
- 1-2-5 Calculation Formula of Log10 Reduction (LR)
-
LR=A−B - A: Average value of initial viable cell count (common logarithm value)
- B: Viable cell count after each of the test substances acted (common logarithm value)
- With Mycobacterium chelonae and Mycobacterium fortuitum, the mixing ratio of the reaction solution to the neutralizer is 1:99 and the smear amount is 100 μL, because of which the minimum limit of detection of a viable cell count is 1000 CFU/mL (3 in common logarithm value). Further, with Microsporum canis, the mixing ratio of the reaction solution to the neutralizer is 1:9 and the smear amount is 100 μL, because of which the minimum limit of detection of a viable cell count is 100 CFU/mL (2 in common logarithm value). When a colony was not detected, the minimum limit of detection was adopted and LR is indicated with a sign of inequality “>”.
- 1-3 Results
- The results are shown in Tables 1 to 3 and
FIGS. 1 to 3 below. -
TABLE 1 Bactericidal power against acid-fast bacterium Mycobacterium fortuitum JCM 6387 Log10 reduction (mean ± SD) Test substance 5 min (n = 3) 10 min (n = 6) 15 min (n = 3) Olanexidine 0.83 ± 0.24 1.28 ± 0.33 1.94 ± 0.26 formulation pH 5Olanexidine 2.08 ± 0.38 3.18 ± 0.25 3.40 ± 0.00 formulation pH 8Olanexidine 2.18 ± 0.28 2.51 ± 0.16 3.06 ± 0.60 formulation pH 9Olanexidine 1.67 ± 0.24 2.13 ± 0.30 2.51 ± 0.55 formulation pH 10Base pH 100.00 ± 0.02 0.02 ± 0.15 0.06 ± 0.13 -
TABLE 2 Bactericidal power against acid-fast bacterium Mycobacterium chelonae JCM 6388 Log10 reduction (mean ± SD, n = 3) Test substance 5 min 10 min 15 min Olanexidine 0.12 ± 0.38 0.24 ± 0.32 0.62 ± 0.53 formulation pH 5Olanexidine 1.62 ± 0.65 2.02 ± 0.55 2.24 ± 0.17 formulation pH 8Olanexidine 0.68 ± 0.40 1.00 ± 0.24 2.24 ± 0.17 formulation pH 9Olanexidine 0.08 ± 0.10 0.53 ± 0.42 0.94 ± 0.22 formulation pH 10Base pH 10−0.37 ± 0.23 −0.09 ± 0.22 −0.17 ± 0.20 -
TABLE 3 Bactericidal power against filamentous fungus Microsporum canis NBRC 32464 Log10 reduction (mean ± SD, n = 3) Test substance 15 sec 30 sec 60 sec Olanexidine 0.29 ± 0.04 0.44 ± 0.03 0.86 ± 0.05 formulation pH 5Olanexidine 2.23 ± 0.35 >2.57 >2.57 formulation pH 8Olanexidine 2.47 ± 0.17 >2.57 >2.57 formulation pH 9Olanexidine 2.23 ± 0.35 2.37 ± 0.35 >2.57 formulation pH 10Base pH 10−0.07 ± 0.04 0.02 ± 0.06 0.07 ± 0.03 - The above results revealed that, in all test microorganisms, bactericidal powers of the olanexidine formulations at
pH 8 to 10 are more intense than the olanexidine formulation atpH 5. Note that the bactericidal power of the olanexidine formulation atpH 10 is more reduced than the olanexidine formulation atpH 8, but this is considered that the activity was prohibited by Pluronic L-44 added as the solubilizer. -
- 2. Action of Olanexidine Formulations on Bacteriophage MS2
- Bacteriophage MS2 is known to be resistant to disinfectants and is used for an alternative test such as the norovirus killing action of disinfectants. For this reason, viricidal effects of the olanexidine formulations prepared by changing pH and a commercial disinfectant on a virus were evaluated by a test using bacteriophage MS2.
- 2-1 Test Material and Method
- 2-1-1 Test Substances
-
(1) Substance to be tested 1 Name: Olanexidine formulation pH 5 Composition: Olanexidine gluconate 1.5% (W/V) Pluronic L-44 1.08% (W/V) pH Adjuster (sodium hydroxide, glucono-δ-lactone) qs Pure water qs pH 5 (2) Substance to be tested 2 Name: Olanexidine formulation pH 7 Composition: Olanexidine gluconate 1.5% (W/V) Pluronic L-44 1.08% (W/V) HEPES 0.1% (W/V) pH Adjuster (sodium hydroxide, glucono-δ-lactone) qs Pure water qs pH 7 (3) Substance to be tested 3 Name: Olanexidine formulation pH 8 Composition: Olanexidine gluconate 1.5% (W/V) Pluronic L-44 1.08% (W/V) HEPES 0.1% (W/V) pH Adjuster (sodium hydroxide, glucono-δ-lactone) qs Pure water qs pH 8 (4) Substance to be tested 4 Name: Olanexidine formulation pH 8.5 Composition: Olanexidine gluconate 1.5% (W/V) Pluronic L-44 1.08% (W/V) L-Histidine 0.1% (W/V) pH Adjuster (sodium hydroxide, glucono-δ-lactone) qs Pure water qs pH 8.5 (5) Substance to be tested 5 Name: Olanexidine formulation pH 9 Composition: Olanexidine gluconate 1.5% (W/V) Pluronic L-44 4.08% (W/V) Glycine 0.1% (W/V) pH Adjuster (sodium hydroxide, glucono-δ-lactone) qs Pure water qs pH 9 (6) Substance to be tested 6 Name: Olanexidine formulation pH 9.5 Composition: Olanexidine gluconate 1.5% (W/V) Pluronic L-44 10.08% (W/V) Glycine 0.1% (W/V) pH Adjustor (sodium hydroxide, glucono-δ-lactone) qs Pure water qs pH 9.5 (7) Substance to be tested 7 Name: Olanexidine formulation pH 10 Composition: Olanexidine gluconate 1.5% (W/V) Pluronic L-44 16.08% (W/V) Glycine 0.1% (W/V) pH Adjustor (sodium hydroxide, glucono-δ-lactone) qs Pure water qs pH 10 (8) Substance to be tested 8 Name: Olanexidine formulation pH 12 Composition: Olanexidine gluconate 1.5% (W/V) Pluronic L-44 26.08% (W/V) L-Arginine 0.1% (W/V) pH Adjustor (sodium hydroxide, glucono-δ-lactone) qs Pure water qs pH 12 (9) Control substance Name/Abbreviated name: Antiseptic ethanol “Kenei”/70% EtOH Manufacturer and distributor: KENEI Pharmaceutical Co., Ltd. Composition: Ethanol (C2H6O) content is 76.9 to 81.4% (V/V). - 2-1-2 Medium
- (1) 702 Liquid Medium
- To 1 L of pure water, 10 g of Polypepton, 2 g of a Yeast extract, and 1 g of MgSO4.7H2O were added and steam-sterilized under pressure (121° C., 20 minutes).
- (2) Soft Agar Medium
- To 0.5 L of pure water, 5 g of Polypepton, 1 g of a Yeast extract, 0.5 g of MgSO4.7H2O, and 3.5 g of agar for a medium were added and steam-sterilized under pressure (121° C., 20 minutes).
- (3) Agar Plate
- To 64 g of a trypto-soya agar medium (SCD agar medium) “Nissui”, 1.6 L of pure water was added and stirred. The medium was steam-sterilized under pressure (121° C., 20 minutes). About 20 mL each of the agar, before set, was dispensed in petri dishes and allowed to be solidified.
- 2-1-3 Neutralizer
- To about 800 mL of distilled water, 100 g of polysorbate 80, 5.0 g of a sodium thiosulfate hydrate, 0.4 g of potassium dihydrogen phosphate, 1 mL of Triton X-100, 10.1 g of disodium hydrogen phosphate anhydrous, and 11.7 g of soy lecithin were added and stirred. Further, 10.0 g of Tamol (R) NN8906 was added, and heated and stirred until dissolved. After dissolution, a 1 mol/L sodium hydroxide solution was added to adjust pH to 7.8 to 7.9. Distilled water was added until the total amount was 1000 mL, and then steam-sterilization under pressure was carried out.
- 2-1-4 Bacteriophage and Host
- (1) Bacteriophage
- Name/Abbreviated name: Escherichia coli phage MS2/MS2 phage
- Supply source: National Institute of Technology and Evaluation Biotechnology Center (NBRC)
- NBRC No.: 102619
- (2) Host
- Name/Abbreviated name: Escherichia coli (Migula 1895) Castellani and Chalmers 1919/E. coli NBRC13965
- Supply source: NBRC
- NBRC No.: 13965
- 2-2 Test Method
- 2-2-1 Host
- E. coli NBRC 13965 preserved in a casitone medium was inoculated in 5 mL×4 of a 702 liquid medium and cultured by shaking at 35° C. overnight. The cells were added to 180 mL of the 702 liquid medium and further cultured by shaking for 3 hours to use the obtained culture by shaking as a host culture liquid.
- 2-2-2 Phage Solution
- A phage solution prepared to about 6×1012 PFU/mL in accordance with a routine method was used.
- 2-2-3 Viricidal (Phage) Test
- (1) To 475 μL of the test substance, 25 μL of the phage solution was added. Further, 25 μL of the phage solution was added to 475 μL of distilled water as a control action solution.
- (2) The action was allowed to proceed at room temperature for 30 seconds, 1 minute and 3 minutes. The control action solution only had the action time of about 3 minutes.
- (3) After the action, 50 μL of the action solution was collected and then 450 μL of the neutralizer was added and stirred. This mixture was prepared to be a 101-fold dilution.
- (4) 20 μL of each of the 101-fold dilutions was added to 180 μL of the neutralizer and stirred. This mixture was prepared to be a 102-fold dilution. Same dilution operation was repeated to produce 10-fold dilution series to 109-fold.
- (5) To 100 μL of 102- to 109-fold dilutions series, 0.2 mL of the host culture liquid was added and stirred. About 5 mL of a soft agar medium preserved at about 47° C. was added, gently stirred, and then overlaid on the agar plate.
- (6) The soft agar medium, after solidified, was cultured at 35° C. overnight.
- (7) The number of plaques caused was counted.
- (8) A titer (log10 PFU/mL) was calculated using weighted average method [(Equation 1) below]. Further, a Log10 reduction was calculated.
- 2-2-5 Data Analysis
- (1) Phage Titer
- Phage titer was calculated using the following (Equation 1).
-
PFU/t=(Σc 1 +c 2 + . . . +c n) ((n 1 +n 2 ×v 2 + . . . +n n ×v n)×d) (Equation 1) - t: A dilution amount added to the plate (0.1 mL in the present test)
- c1: Total number of plaques of all plates of the minimum dilution factor countable
- c2: Total number of plaques of all plates of dilution factor after c1
- cn: Total number of plaques of all plates of the maximum dilution factor
- n1: Number of plates of c1
- n2: Number of plates of c2
- v2: Ratio of the dilution factors of c1 to c2 (10−1 in the present test)
- nn: Number of plates of cn
- vn: Ratio of the dilution factors of c1 to cn
- d: Dilution factor of c1
- A titer (PFU/mL) was converted to common logarithm (log10 PFU/mL) and indicated to the first decimal place by rounding off. When a titer (PFU/mL) was 1 or less, its common logarithm value was 0.
- (2) Log10 Reduction (LR)
- The viricidal (phage) action was evaluated by a Log10 reduction value.
-
LR=A−B - A: Average value of control action solution phage titer (common logarithm value)
- B: Phage titer of each of the test substances after acted (common logarithm value)
- LR is indicated to the first decimal place by rounding off. Note that when a titer (common logarithm value) of the test substance after acted was 0, LR is indicated as “>(A−3)” because the phage titer has the minimum limit of detection of 3−log10.
- 2-3 Results
- Evaluation results on the viricidal actions of the test substances are shown in Table 4 and
FIG. 4 . -
TABLE 4 Phage killing effect of test substances Log10 reduction Test substance 30 sec 60 sec 180 sec Olanexidine 0.6 0.9 1.2 formulation pH 5Olanexidine 1.6 2 3 formulation pH 7Olanexidine 2.3 3.1 4.3 formulation pH 8Olanexidine 3 3.6 5 formulation pH 8.5 Olanexidine 3.1 4 5.3 formulation pH 9Olanexidine 3.4 4 4.5 formulation pH 9.5 Olanexidine 3 4.1 5.2 formulation pH 10Olanexidine 7.6 8.5 >8.5 formulation pH 1270% EtOH 1.9 2.9 3.9 - The olanexidine formulation at
pH 5 did not substantially show the viricidal action, and the viricidal action of the olanexidine formulation atpH 7 was equal to 70% ethanol used as the control substance, whereas the olanexidine formulations with the pH changed to basic tended to have larger LR as pH increased. The formulations atpH 8 or more had an LR of 3 or higher at 60 seconds and the formulation at pH 8.5 or more had an LR of 3 or higher at 30 seconds thereby to meet a requirement for the viricidal action of an ideal disinfectant ofLR 3 or higher. Thus, a basic solution of olanexidine gluconate was revealed to have a practical viricidal activity and such a viricidal activity is intensified as pH increases. -
- 3. Action of Ethanol-Containing Basic Olanexidine Formulation on Bacteriophage MS2
- In the present Example, ethanol was added to a basic olanexidine formulation of pH 9.5 to evaluate a viricidal effect by a test using bacteriophage MS2 for the purpose of confirming the quick-dryness imparting effect and the potentiating effect of the bactericidal activity by an antiseptic alcohol to a basic olanexidine formulation.
- 3-1 Test Substance
- Substances to be tested 1 to 3, Comparative Example 1, and Base (control substance) were prepared by the compositions of the following Table 5.
-
TABLE 5 Amount (in g/100 mL) Substance Substance Substance to be to be to be Comparative Ingredient tested 1 tested 2 tested 3 Example 1 Base Olanexidine 1.5 1 0.5 1.5 — gluconate Pluronic L-44 1.08 0.72 0.36 1.08 1.08 Benzyl 3.5 3.5 3.5 — 3.5 alcohol Hexyldecanol 0.01 0.01 0.01 — 0.01 Pluronic F-68 1 1 1 — 1 Glycyrrhetinic 0.1 0.1 0.1 — 0.1 acid Glycine 0.1 0.1 0.1 — 0.1 Glucono-δ- qs qs qs — qs lactone Sodium qs qs qs — qs hydroxide Ethanol 70 77 83 70 70 Purified qs qs qs qs qs water pH 9.5 9.5 9.5 6.89 9.5 - Further, the following antiseptic ethanol was used as a control.
- Name: Antiseptic ethanol “Kenei”
- Manufacturer and distributor: KENEI Pharmaceutical Co., Ltd.
- Composition: Ethanol (C2H6O) content is 76.9 to 81.4% (V/V).
- 3-2 Test Method
- Viricidal effects were evaluated by the method using the bacteriophage MS2 described in the above Example 2, 2-1 and 2-2. Note that a phage solution prepared to about 4×1012 PFU/mL was used.
- 3-3 Results
- Evaluation results on viricidal actions of the test substances are shown in Table 6 and
FIG. 5 . -
TABLE 6 Log10 reduction Test substance 30 sec 60 sec Substance to be tested 1 6 6.7 (Olanexidine gluconate 1.5%) Substance to be tested 2 5.2 5.8 (Olanexidine gluconate 1.0%) Substance to be tested 3 4.4 5 (Olanexidine gluconate 0.5%) Comparative Example 1 2.6 3.5 (Olanexidine gluconate 1.5%, pH 6.89) Base 3.8 4.5 Antiseptic ethanol 2.2 3.4 - The above results showed that the viricidal action increases in a concentration dependent manner of olanexidine gluconate even in the basic olanexidine formulation containing ethanol whereby the viricidal action by olanexidine gluconate is not impeded even when ethanol is added to impart quick-dryness. Further, the basic olanexidine formulation containing ethanol has a higher viricidal action compared with a basic olanexidine formulation which does not contain ethanol, for the reason of which the ethanol-containing basic olanexidine formulation showed to have a practical viricidal action even when an olanexidine gluconate concentration is reduced. Furthermore, a practical viricidal activity (LR or higher) was not found in the ethanol-containing olanexidine formulation having pH of less than 7 (Comparative Example 1), thereby suggesting that, in the basic olanexidine formulation containing ethanol, olanexidine gluconate, ethanol, and basicity synergistically contribute to the viricidal action. Note that, in the present Example, Pluronic F-68 was added for relieving rough skin and moisturization, and no difference in the effect was found even when Pluronic F-68 was 0.5 g/100 mL.
- The composition of the present invention, when used, can produce an olanexidine gluconate-containing disinfectant having an improved bactericidal spectrum and an effect on non-enveloped viruses and is thus highly useful in the fields such as medical and nursing, and food and drink industries.
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WO2004105492A1 (en) * | 2003-05-28 | 2004-12-09 | Otsuka Pharmaceutical Co., Ltd. | Aqueous compositions for disinfection and/or sterilization |
US20100168638A1 (en) * | 2008-12-30 | 2010-07-01 | Otsuka America Pharmaceutical, Inc. | Fluid application device and method |
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CA2064664C (en) * | 1991-04-05 | 2000-01-11 | Hiroshi Ishikawa | Biguanide derivatives, manufacturing method thereof, and disinfectants containing the derivatives |
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JP4541661B2 (en) * | 2003-05-28 | 2010-09-08 | 大塚製薬株式会社 | Disinfecting and / or disinfecting composition |
DK1634589T3 (en) * | 2003-05-28 | 2011-04-18 | Otsuka Pharma Co Ltd | Aqueous olane oxidine solution, process for its preparation and disinfectant |
JP4580153B2 (en) * | 2003-06-30 | 2010-11-10 | 大塚製薬株式会社 | Disinfecting and / or disinfecting composition |
JP4526300B2 (en) | 2003-05-28 | 2010-08-18 | 大塚製薬株式会社 | Oranexidine aqueous solution, its preparation method and disinfectant |
JP4975987B2 (en) | 2005-08-09 | 2012-07-11 | 大王製紙株式会社 | Norovirus disinfectant and norovirus disinfection article |
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