Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
  • A61L2/16—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
  • A61L2/18—Liquid substances or solutions comprising solids or dissolved gases
• • 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
  • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
  • A01N25/02—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing liquids as carriers, diluents or solvents
• • 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
• • 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
  • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
  • A61P27/04—Artificial tears; Irrigation solutions
• • 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
  • A61P31/02—Local antiseptics

Definitions

• the present invention relates to a germicidal solution, and more particularly to a germicidal solution exhibiting an excellent germicidal effect or an antiseptic effect, which can be advantageously used as an ophthalmic solution, a germicidal solution for contact lenses, a preservative for cosmetics, and the like. . Background technology
• contact lens solutions include, in addition to detergent components for removing dirt such as proteins and eye oils derived from eye fluids and adhering to contact lenses, bacteria as well as bacteria.
• a bactericide component is included to prevent contamination by microorganisms and power plants.
• Japanese Patent Application Laid-Open No. 10-198989 discloses that polyhexa, a biguanide bactericide, is used as a solution for contact lenses having an excellent bactericidal effect and having eye safety. It has been proposed to use methylene biguanide with a non-ionic tonicity agent such as glycerin-propylene glycol, In Japanese Patent Application Laid-Open No. 11-249807, non-ionic isotonic polypolyester is used as a contact lens liquid agent that has an excellent disinfecting effect and is sufficiently safe for the eyes. It has been proposed to use it together with an agent and / or an amino acid, and by adopting those liquid agent compositions, the sterilization effect of the contact lens liquid could be certainly improved, but the characteristics of the liquid could be improved. Still have room for improvement. Disclosure of the invention
• the present invention has been made in view of such circumstances, and the problem to be solved is to minimize the toxicity to living organisms as much as possible, while ensuring sufficient safety. It is another object of the present invention to provide a germicidal solution capable of realizing an excellent bactericidal effect or an antiseptic effect.
• the inventors of the present invention have conducted intensive studies to solve such a problem, and as a result, the germicidal solution containing a germicide is generally included in the germicidal solution to adjust its osmotic pressure.
• the bactericide is originally possessed by a strong electrolyte such as sodium chloride, or an inorganic salt-based buffer such as phosphoric acid and its salt, which is used to adjust the pH of the germicidal solution, and has high electrical conductivity.
• the present invention has been completed on the basis of such findings, and the gist of the present invention is to provide a sterilizing solution containing at least one or more germicides in 0.1 ml / l.
• the L aqueous solution contains an isotonic agent having an electric conductivity of 50 OmS / m or less, and the concentration of sodium chloride in the sterilizing solution is adjusted to be 0 to 0.2% by weight, and phosphoric acid is added. And a salt thereof, each of which has been adjusted to have a total concentration of 0 to 0.5% by weight.
• the concentration of sodium chloride and the total concentration of phosphoric acid and its salts are made as small as possible, the bactericidal ability of the bactericide is reduced. Therefore, even if the concentration of the bactericide component in the germicidal solution is kept low, a high bactericidal effect or an antiseptic effect can be advantageously obtained. This also makes it possible to further improve the safety of the living body.
• an electric conductivity of 0.1 lmo 1 / L aqueous solution is 50 O m S / m or less.
• the tonicity agent has an electric conductivity of 100 mS / m or less in its 0.1 mol / L aqueous solution. Therefore, it is possible to exhibit even more excellent bactericidal efficacy.
• the tonicity agent is a nonionic tonicity agent composed of at least one of sugar and reducing sugar. Sorbitol, mannitol, glucose, xylitol, inositol, fructose, sucrose, or trehalose are preferably used as such nonionic isotonic dandruff.
• the isotonic agent trimethylglycine, panthenol, creatinine, tranexamic acid, nicotinic acid amide, urea, triethanolamine, N At least one compound selected from the group consisting of N, dimethylacetamide and ethylene carbonate is advantageously used.
• a biguanide-based or quaternary ammonium salt-based bactericide be used as the bactericide.
• the bactericidal effect or the antiseptic effect can be exerted at a very high level.
• the isotonic agent has an osmotic pressure of 5 OmO sm / kg or more in its 0.1 Imo1 / L aqueous solution. It is desirable that the amount of the tonicity agent added be kept low.
• the germicidal solution according to the present invention desirably has an osmotic pressure of 25 OmO sm / kg or more, whereby the problem of irritation to eyes, skin, etc. can be advantageously avoided. You will get.
• the germicidal agent is contained in a ratio of 0.001 to 0.1% by weight, By adopting such a configuration, the safety of the sterilizing solution can be assured at a very high level.
• a germicidal solution for contact lenses is also a gist thereof. It is.
• the concentration of the germicide added to the solution can be kept low in order to exert the desired germicidal effect. From the fact that it can be obtained, even if the disinfection (disinfection) treatment by dipping the contact lens or the soft contact lens is performed for a long time, the adsorption of the disinfectant on the surface of the contact lens or the soft contact lens is practical.
• the germicidal solution according to the present invention is mainly composed of water, in which a predetermined isotonic agent is contained together with a bactericide, and further, the content of sodium chloride which inhibits the bactericidal ability of such a bactericide, By making the total content of phosphoric acid and its salts zero or as small as possible, the bactericidal effect can be exerted extremely effectively. It has various features.
• a bactericidal solution conventionally used as a tonicity agent is generally used. It is desirable not to allow any strong electrolyte such as sodium chloride and sodium chloride to be contained therein. Even if sodium chloride or the like is contained, the concentration should be 0.2% by weight (w / w%). However, as described above, when the sodium salt concentration is set to 0 to 0.2% by weight, the osmotic pressure of the sterilizing solution becomes too low.
• the electrical conductivity of the 0.1 mo 1 / L aqueous solution is 50 O m S Zm or less, preferably 300 M S / m or less, more preferably 100 in A tonicity agent of SZm or less will be used.
• the electrical conductivity of the tonicity agent in a 0.1 lmo 1 ZL aqueous solution exceeds 50 OmS / m, the disinfecting ability of the disinfectant is impaired and sufficient disinfecting effect is obtained. This is because they cannot be realized and the desired bactericidal effect cannot be obtained.
• any one that satisfies the above conditions and has high safety can be used.
• Nonionic isotonic agents for sugars and reducing sugars trimethylglycine, panthenol, creatinine, tranexamic acid, nicotinamide, urea, triethanolamine, N, N-dimethylacetamide and ethylene Carbonate and the like can be mentioned, and at least one or more compounds are appropriately selected and used from them.
• such a tonicity agent reduces the change in the lens size during the immersion treatment of the contact lens, and has a feature that does not cause any problem such as swelling.
• nonionic tonicity agent for the sugar and reducing sugar
• sorbitol, mannitol, glucose, xylitol , Inositol, fructose, sucrose or trehalose are preferred.
• these tonicity agents are used to adjust the osmotic pressure of the sterilizing solution, such as inorganic salts of strong electrolytes, such as sodium chloride and saline rim.
• the germicidal solution according to the present invention when using the germicidal solution according to the present invention, usually taking into account physiological osmotic pressure so as not to cause irritation to eyes, skin, etc., it is usually from 250 to 400 It is added and contained so as to be in a range substantially equal to the physiological osmotic pressure of about m ⁇ s mZkg, and is generally 0.5 to 7.0% by weight (w / w%), preferably At a concentration of 1.0 to 5.0% by weight (w / w%), it will be contained in the sterilizing solution. If the content of the tonicity agent is too small, the osmotic pressure of the sterilizing solution will be low. .
• a tonicity agent usually, in order to prevent the amount of addition from becoming excessive, in a 0.1 lmo 1 / L aqueous solution, 5 O mO smkg or more, more preferably, 8 O mO smkg or more.
• Those having an osmotic pressure of mO sm / kg or more are particularly preferably used. However, if the osmotic pressure is too low, the amount of the tonicity agent required to achieve the desired osmotic pressure increases, which hinders the bactericidal action of the bactericide.
• the solution may become susceptible to reduction in the bactericidal effect, and may cause problems such as solubility problems such as precipitation or insolubility of the tonicity agent, increase in cost, and a decrease in feel due to increased viscosity. This is because there is a risk of causing a change in the properties of the material.
• bactericidal agent which has excellent germicidal properties and is suitable for contact lenses (eye and skin) and which is less likely to cause allergies or other obstacles is desirable.
• appropriate ones are selected and used alone or in combination of two or more.
• an organic nitrogen-based disinfectant having an excellent disinfecting or preservative effect is desirably used.
• the use of a biguanide-based fungicide or a quaternary ammonium salt-based fungicide is particularly recommended.
• Examples of the biguanide-based bactericide include polyhexamethylenebi. Examples thereof include guanide (PHMB) and a biguanide polymer represented by the following structural formula (I).
• PHMB guanide
• I a biguanide polymer represented by the following structural formula (I).
• Examples of the quaternary ammonium salt fungicides include tetraalkylammonium salts such as alkyltrimethylammonium chloride, and octadecyldimethyl.
• Alkyl ammonium salts such as trialkyl benzyl ammonium salts such as benzyl ammonium chloride; quaternary salts of alkyl hydroxyalkyl imidazoline represented by hydroxyethyl alkyl imidazo link;
• cationic surfactants such as alkylisoquinolinium salts represented by lysoquinolinium bromide; alkylpyridinium salts; amidoamines, the following structural formulas (II) to (I) V), a quaternary ammonium polymer, a condensate of a diamine and a dihalogen compound as disclosed in Japanese Patent No. 2550036, Japanese Patent Application Laid-Open No. And polycationic compounds disclosed in JP-A-512145, JP-A-11-249087, etc., and benzalkonium halides.
• b is an integer of 1 or more;
• X— is a monovalent anion such as C1—
• c is an integer of 1 or more, and X is a monovalent anion such as C 1.
• d is an integer of 1 or more;
• X_ is a monovalent anion such as C1—
• the bactericide as described above is usually about 0.001 to 0.1% by weight (w / w%), and preferably about 0.001 to 0.01% by weight. When used in the range, a particularly effective bactericidal effect or antiseptic effect is exhibited. If the content of such a bactericide is too small, a sufficient bactericidal effect or preservative effect cannot be obtained, and if it exceeds 0.1% by weight, toxicity is increased. Thus, for example, there is a possibility that a problem may occur in terms of safety, such as adverse effects on eyes and skin, and promotion of adsorption of a bactericide to the contact lens surface.
• the germicidal solution according to the present invention instead of sodium chloride having high ionic conductivity, at least one or more kinds of predetermined isotonic agents excellent in safety '14 are used as isotonic agents. Therefore, even at a low concentration, the bactericidal ability of a biguanide bactericide, a quaternary ammonium salt bactericide, or the like can be extremely effectively expressed.
• a conventional ophthalmic solution such as a pH adjuster, a buffer, a surfactant, a chelating agent, a thickener, etc.
• Various known additives which are added to and contained in ophthalmic solutions such as a germicidal solution for lenses and liquids such as cosmetics can be appropriately selected and included at all. .
• the germicidal solution according to the present invention when used as an ophthalmic solution such as an ophthalmic solution or a germicidal solution for contact lenses or cosmetics, it may cause irritation to the eyes and skin or cause disorders.
• the pH value is adjusted to 5.0 to 8.0, especially to around 7.0.
• sodium hydroxide is used.
• PH adjuster such as potassium hydroxide, hydrochloric acid, etc. can be added.
• the above-mentioned pH adjuster is also a strong electrolyte, like sodium chloride, it is necessary to keep the amount of use as low as possible.
• the sodium chloride concentration in the sterilizing solution including the sodium chloride salt thus formed, must be set to 0.2% by weight or less, needless to say. There is no place.
• a buffer is added in addition to the pH adjuster.
• the buffering agent is appropriately selected and used from various known ones. Specifically, citrate buffer, phosphate buffer, borate buffer, carbonate buffer, tris (hydroxymethyl) aminomethane (TRIS) buffer, and furthermore, such as Bis-Tris, etc. uffer and the like can be exemplified because they are particularly safe for the eyes and can reduce the influence on contact lenses.
• the amount of the buffer added is generally about 0.01 to 2% by weight (w / w%), but exhibits relatively high ionic conductivity when dissolved in water.
• a buffer such as citric acid, phosphoric acid, or a salt thereof
• the amount of the buffer added may be reduced because the buffer may impair the sterilizing ability of the fungicide. Or as low as possible.
• the pH of the citrate buffer should be adjusted so that the total concentration of phosphoric acid and its salt is 0 to 0.5% by weight. Must be added so that the total concentration of citric acid and its salts is 0 to 0.1% by weight. If the concentration of such a buffer exceeds the above range, a strong electrolyte such as sodium chloride is used. Even if the addition amount of the bactericide is kept low, the action of the bactericide is inhibited by the buffer, so that the desired bactericidal ability cannot be sufficiently exhibited.
• a surfactant as a cleaning agent may be added to the germicidal solution according to the present invention in order to effectively exert an effect of removing dirt such as eye oil (cleaning effect).
• any conventionally known activator can be used as long as it has high safety to the living body and does not affect the contact lens material. Yes, it can be advantageously added and contained at a concentration that does not impair the effects of the present invention.
• surfactants include, for example, polyglycerin fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene-polyoxypropylene block copolymer, and polyoxyethylene 'polyoxypropyleneethylenediamine.
• Polyoxyethylene sorbitan fatty acid ester Polyoxyethylene alkylphenyl ester terformaldehyde condensate, Polyoxyethylene hydrogenated castor oil, Polyoxyethylene alkyl phenyl ether, Polyoxyethylene glycerin fatty acid ester, Polyoxyethylene sorby Polyester fatty acid ester, polyoxyethylene castor oil, polyoxyethylene sterol, polyoxyethylene hydrogenated sterol, polyoxyethylene fatty acid ester, polyoxy Ethylene-Porisai carboxymethyl propylene alkyl ethers, polyoxyethylene lanolin alcohols, polyoxyethylene alkyl ⁇ Min, polyoxyethylene alkylamine de, polyoxyethylene alkyl ether phosphoric acid, it can be mentioned polysorbate.
• the amount of the surfactant added is generally about 0.001 to 5% by weight (w / w%), preferably 0.005 to 2 times. %, More preferably about 0.01 to 1% by weight.
• the added amount is too small, the obtained cleaning effect will be insufficient, and if it is too large, the cleaning effect will not change and may cause eye irritation. Because.
• a thickener may be further added to the germicidal solution according to the present invention, if necessary.
• various gums such as heteropolysaccharides, synthetic organic high molecular compounds such as polyvinyl alcohol and polyvinyl alcohol Thickening agents such as N-vinylpyrrolidone, polyethylene glycol, polypropylene glycol, polyacrylamide, and further, cellulose derivatives and starch derivatives can be used as appropriate.
• additives can be mentioned. Any conventionally known additives can be used as long as they are safe for the living body and do not adversely affect the material of the contact lens. If necessary, it can be contained in the sterilizing solution according to the present invention.
• a metal chelating agent is used to prevent metal ions such as calcium in tears from adsorbing to contact lenses, especially soft contact lenses.
• metal chelating agents include, for example, ethylenediaminetetraacetic acid (EDTA) and salts thereof, for example, ethylenediaminetetraacetic acid 'disodium (EDTA-2Na), ethylenediaminetetraacetic acid'trisodium ( EDTA-3Na) and the like.
• the amount of the metal chelating agent to be added is to be contained in the germicidal solution within a quantitative range that does not impair the action and effect of the present invention, and is generally 0.01 to 1.0% by weight. (w / w%).
• the germicidal solution according to the present invention obtained as described above is, for example, a germicidal solution for contact lenses, especially a germicidal solution for soft contact lenses, an ophthalmic solution such as eye drops, and a cosmetic. It will be suitably used as a preservative to be added.
• the contact lens removed from the eyes is placed in an appropriate container filled with the germicidal solution for contact lenses according to the present invention. Then, disinfection is performed by immersing for a predetermined time. When the contact lens is worn again, the contact lens is taken out of the solution and washed. After disinfection, the disinfected contact lens may be simply rinsed with physiological saline or the like, and the disinfecting solution is safe for eyes. However, it is also possible to take out the contact lens immersed in this sterilizing solution and put it directly on the eye as it is. Furthermore, contact lenses can be disinfected using this disinfectant solution after the contact lenses have been cleaned.
• the type of contact lens that is the target of the germicidal solution for contact lenses is not limited to any particular type.
• soft contact lenses that are classified into all types such as non-aqueous, low-aqueous, and high-aqueous , And hard contact lenses can be targeted, and the material and the like of the contact lens are not questioned when applying the contact lens sterilizing solution according to the present invention.
• the sterilizing solution for contact lenses according to the present invention can be applied particularly advantageously to soft contact lenses in which the lenses are not swelled.
• a bactericide, a tonicity agent, and a chelating agent are added to a predetermined amount of distilled water at various ratios shown in Table 1 below, so that the osmotic pressure is 29 OmO sm
• a bactericidal solution according to Experimental Examples 1 to 16 at about / kg was prepared.
• the germicide polyhexamethylene biguanide (PHMB) was used in the germicidal solution according to Experimental Examples 1 to 15, and in the germicidal solution according to Experimental Example 16: Benzalkonium chloride was used.
• the tonicity agent one having an electric conductivity and an osmotic pressure as shown in Table 2 below in the 0.1 mol / L aqueous solution was used.
• ethylenediaminetetraacetic acid '2 sodium (EDTA-2Na) was used as a chelating agent.
• the viable cell count in the sample ImL was measured by the plate dilution method using. Then, from this viable cell count, the viable cell count in the treated solution ImL was calculated, and the log reduction was calculated according to the following formula, and the results are shown in Table 3 below. Was.
• Number of bacteria reduced l og (number of viable bacteria in 1 mL of bacterial suspension immediately after preparation)
• bactericidal efficacy was evaluated from the above-mentioned log reduction value, and the results are shown in Table 3 below.
• the evaluation criteria were as follows: First when the First Criteria (related to sterilization) in ISO 147229 was satisfied, and X when not.
• the germicidal solution according to the present invention the salt concentration of sodium and the total concentration of phosphoric acid and its salts are reduced to zero or as small as possible, and lmo 1 / L aqueous solution has an electrical conductivity of 50 OmS / m or less, an isotonic agent is included as an alternative to sodium chloride. Therefore, even if the concentration of the bactericide component in the germicidal solution is kept low, a high bactericidal effect or an antiseptic effect can be advantageously obtained. Therefore, the safety for the living body can be further improved. Therefore, the germicidal solution according to the present invention can be advantageously used as an ophthalmic solution / a germicidal solution for contact lenses, a preservative for cosmetics, and the like.

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