JP7258478B2 - Aqueous composition containing isopropylmethylphenol - Google Patents

Description

The present invention relates to an aqueous composition containing isopropylmethylphenol having broad-spectrum fungicidal action. More specifically, an aqueous composition prepared so that the addition recovery rate of isopropylmethylphenol is 90 to 110% and the amount of isopropylmethylphenol added can be accurately quantified in the addition recovery test conducted during product quality control. Regarding. The invention also relates to a method of improving spike recovery for aqueous compositions containing isopropylmethylphenol. Furthermore, the present invention relates to an addition recovery test method for an aqueous composition containing isopropylmethylphenol.

Isopropyl methylphenol (hereinafter simply referred to as "IPMP") has a wide antibacterial spectrum, is highly safe, and is an antibacterial agent (bactericide) with a low environmental impact. wound disinfectants, ointments, etc.), active ingredients of quasi-drugs (e.g., hand soaps, hair-growth tonics, deodorants [deodorants], antiperspirants, medicinal cosmetics, toothpastes, etc.), and preservatives of cosmetics, etc. It is widely used as a drug. However, since IPMP has extremely low solubility in water and high crystallinity, there is a problem that it tends to precipitate in an aqueous composition. On the other hand, since ethanol is highly soluble, it is conceivable to use ethanol to solubilize IPMP in water. Some are restricted. Moreover, it is known that when a surfactant is blended in order to solubilize IPMP in water, the antibacterial activity of IPMP may be inhibited depending on the type of surfactant. For this reason, it is generally considered difficult to apply IPMP to aqueous compositions containing a large amount of water.

Therefore, various methods have been studied and proposed for easily and stably dissolving IPMP in water while suppressing the deterioration of its antibacterial activity. As one method, in Patent Document 1, IPMP is mixed with a diol having 3 to 6 carbon atoms in a specific ratio, a polyethylene hydrogenated castor oil having an average addition mole number of ethylene oxide of 30 to 120 mol, and water. A concentrated antibacterial agent composition has been proposed, according to which it is stated that poorly water-soluble IPMP can be stably blended into any aqueous composition without crystal precipitation.

JP 2017-114823 A

The present inventors have found that an aqueous composition containing IPMP, particularly an aqueous composition containing IPMP and a diol having 3 to 6 carbon atoms in order to increase the solubility in water, is required for pharmaceuticals and quasi-drugs. As a result of carrying out an addition recovery test, it was found that there was a problem that the known amount of the compounded IPMP could not be accurately measured (decrease in addition recovery rate).

Accordingly, an object of the present invention is to provide a method for solving the problem of a decrease in addition recovery rate for an aqueous composition containing IPMP and a diol having 3 to 6 carbon atoms. Specifically, for an aqueous composition containing IPMP and a diol having 3 to 6 carbon atoms, an aqueous composition prepared so that the addition recovery rate of IPMP is 90 to 110% and the amount of IPMP added can be accurately quantified. The purpose is to provide goods. Another object of the present invention is to provide a method for improving the addition recovery of an aqueous composition containing IPMP. A further object of the present invention is to provide a test method for addition and recovery of an aqueous composition containing IPMP.

The inventors of the present invention have made intensive studies to solve the above problems, and found that IPMP can be obtained by blending an aqueous composition containing IPMP and a diol having 3 to 6 carbon atoms with silicic anhydride. It was found that the problem of the decrease in addition recovery rate was improved, and the addition recovery rate of IPMP was 90 to 110%, and the amount of IPMP added could be accurately quantified. The present invention has been completed through further studies based on such findings, and includes the following embodiments.

(I) IPMP-Containing Aqueous Composition (I-1) An aqueous composition containing IPMP, a diol having 3 to 6 carbon atoms, and silicic anhydride.
(I-2) The aqueous composition according to (I-1), which further contains a thickening agent.
(I-3) The aqueous composition according to (I-1) or (I-2), wherein the addition recovery rate of IPMP is in the range of 90 to 110%.
(I-4) The aqueous composition according to any one of (I-1) to (I-3), which is a pharmaceutical or quasi-drug.
(I-5) The aqueous composition according to any one of (I-1) to (I-4), which is an aqueous composition for addition and recovery tests.

(II) Method for improving the addition recovery rate of an IPMP-containing aqueous composition (II-1) A method for improving the addition recovery rate of IPMP for an aqueous composition containing IPMP and a diol having 3 to 6 carbon atoms, comprising IPMP and The above method, comprising the step of blending silicic anhydride in addition to the diol having 3 to 6 carbon atoms to prepare the aqueous composition.
(II-2) The method for improving addition recovery rate according to (II-1), wherein the aqueous composition further contains a thickening agent.
(II-3) The method for improving addition recovery rate according to (II-1) or (II-2), wherein the aqueous composition is a drug or a quasi-drug.
(II-4) The method for improving the addition recovery rate according to any one of (II-1) to (II-3), wherein the addition recovery rate of IPMP is adjusted to be in the range of 90 to 110%.

(III) Addition and recovery test method for IPMP-containing aqueous composition (III-1) Addition and recovery test method for IPMP in an aqueous composition containing IPMP and a diol having 3 to 6 carbon atoms, An addition and recovery test method characterized by using an aqueous composition containing silicic anhydride in addition to IPMP and a diol having 3 to 6 carbon atoms.
(III-2) The addition and recovery test method according to (III-1), wherein the aqueous composition further contains a thickening agent.
(III-3) The addition and recovery test method according to (III-1) or (III-2), wherein the aqueous composition is a drug or quasi-drug.

According to the IPMP-containing aqueous composition, the method for improving the addition recovery rate, and the method for the addition recovery test of the present invention, the addition recovery rate of the added IPMP can be measured with high accuracy of 90 to 110% in the addition recovery test. becomes possible.

(I) IPMP-Containing Aqueous Composition The aqueous composition of the present invention (hereinafter simply referred to as "this aqueous composition") is characterized by containing IPMP, a diol having 3 to 6 carbon atoms, and silicic anhydride. and

(1) IPMP
IPMP is an isomer of thymol, a compound with the chemical name 3-methyl-4-isopropylphenol with a needle-like crystalline form. It has a wide range of antibacterial and antifungal spectrum (O-157, MRSA, Serratia, Trichophyton, etc.), and exhibits bactericidal effects against various sterilizations, yeasts, and molds. Due to its irritating and non-sensitizing properties, it is widely used as a disinfectant, antibacterial agent, or antiseptic in pharmaceuticals, quasi-drugs, cosmetics, and daily necessities. IPMP is commercially available (for example, Osaka Kasei Co., Ltd.), and is sold as a product that can be easily incorporated into aqueous products, "BIOSOL (registered trademark)-LIQUID" (manufactured by Osaka Kasei Co., Ltd.). can also be used.

The ratio of IPMP contained in the present aqueous composition is within the range in which the present aqueous composition of interest exhibits the desired antibacterial effect (including bactericidal effect and antiseptic effect), the type of the present aqueous composition, its use, And it can be appropriately set according to the purpose of adding IPMP (efficacy and effect expected from IPMP). For example, a range of 0.001 to 2% by mass, preferably 0.01 to 1% by mass, more preferably 0.05 to 0.5% by mass can be exemplified.

(2) C3-6 diol A diol having 3 to 6 carbon atoms (hereinafter referred to as "C3-6 diol") has 3 to 6 carbon atoms and has one for every two carbon atoms of the chain aliphatic hydrocarbon. It is a compound with a structure in which hydroxyl groups are substituted one by one. Specifically, 1,2-propanediol, 1,3-propanediol, 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, 1,2-pentanediol, 1,5 -Pentanediol, 1,2-hexanediol, 1,6-hexanediol, dipropylene glycol and the like. Preferred are 1,3-butanediol, 1,2-pentanediol and dipropylene glycol, and more preferred is 1,3-butanediol. These diols having 3 to 6 carbon atoms can be used singly or in combination of two or more.

The proportion of the C3-6 diol contained in the present aqueous composition is an amount that allows IPMP to be solubilized in water without hindering the antibacterial effect of the IPMP in the subject aqueous composition, and the effect of the present invention is exhibited. Any range is acceptable, for example, it can be appropriately selected and set from the range of 0.1 to 50% by mass. A range of preferably 1 to 20% by mass, more preferably 5 to 15% by mass can be exemplified.

(3) Silicic Anhydride Silicic anhydride is an oxide of silicon called silicon dioxide or silica. Regardless of its shape (spherical, needle-like, plate-like, irregular shape, scale-like, spindle-like, etc.), particle size (fumed, fine particle, pigment grade, etc.), particle structure (porous, non-porous, etc.), Either one can be used. Porous non-hollow spherical anhydrous silicic acid having a particle size of 7.0 to 10.0 μm is preferably used.

The ratio of silicic anhydride contained in the present aqueous composition may be within a range that does not interfere with the antibacterial effect of IPMP in the subject aqueous composition and that exhibits the effects of the present invention. It can be appropriately selected and set within the range of 20% by mass. A range of preferably 0.1 to 5% by mass, more preferably 0.2 to 1% by mass can be exemplified.

(4) Aqueous Composition The aqueous composition of the present invention contains the IPMP, C3-6 diol, and silicic anhydride dissolved, dispersed, or emulsified in an aqueous solvent. Water can be mentioned as an aqueous solvent here. Water may be used for preparation of pharmaceuticals, quasi-drugs or cosmetics, and for example, purified water, distilled water, physiological saline, sterilized water, etc. can be used without limitation. The content of the aqueous solvent in the present aqueous composition is appropriately determined according to the stability of the ingredients (solubility, dispersibility, etc.), formulation properties (viscosity, osmotic pressure, pH, etc.), formulation shape, administration form, etc. can be set. The range is usually 50 to 99% by mass, preferably 60 to 95% by mass, more preferably 70 to 90% by mass.

(other ingredients)
The present aqueous composition may contain methylpolysiloxane in addition to the aforementioned C3-6 diol as a component that solubilizes IPMP. The proportion of methylpolysiloxane in the present aqueous composition may be within a range that does not interfere with the antibacterial effect of IPMP in the subject aqueous composition and that exhibits the effects of the present invention, for example 0.1 to 20 mass. It can be appropriately selected and set from the range of %. A range of preferably 0.5 to 10% by mass, more preferably 1 to 5% by mass can be exemplified.

In addition, the present aqueous composition can be used for pharmaceuticals, quasi-drugs, etc., depending on its application and form, provided that it does not interfere with the antibacterial effect of IPMP and does not interfere with the effects of the present invention. Ingredients and additives can be appropriately selected and used in combination to formulate formulations. For example, thickening agents, surfactants, tonicity agents, buffering agents, pH adjusting agents, chelating agents, flavoring agents or cooling agents, preservatives, stabilizers, solubilizers commonly used in the preparation of liquid formulations, etc. , various additives such as bases. In addition, vitamins; amino acids; polymer compounds such as saccharides, gums and polysaccharides; Examples of these additives include the following components. However, in the present aqueous composition, these components are all optional components and may not be blended. That is, the aqueous composition of the present invention can be produced without containing all or any one or more of the following components.

Thickeners: For example, carboxyvinyl polymer, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, alginic acid, polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone, macrogol, sodium chondroitin sulfate, and the like.

Surfactants: glycine-type amphoteric surfactants, such as alkyldiaminoethylglycine; for example, polyoxyethylene (POE)-polyoxypropylene (POP) block copolymers (eg, poloxamer 407, poloxamer 235, poloxamer 188, etc.); Polyoxyethylene-polyoxypropylene block copolymer adducts of ethylenediamine (e.g. poloxamines); POE such as POE (20) sorbitan monolaurate (polysorbate 20), POE (20) sorbitan monooleate (polysorbate 80), polysorbate 60, etc. Sorbitan fatty acid esters; POE hydrogenated castor oils such as POE (60) hydrogenated castor oil; POE alkyl ethers such as POE (9) lauryl ether; POE/POP alkyl ethers such as POE (20) POP (4) cetyl ether POE alkylphenyl ethers such as POE(10) nonylphenyl ether; POE alkylphenyl ethers such as POE(10) nonylphenyl ether; Numbers in parentheses indicate the number of added moles.

Tonicity agent: for example, sodium hydrogen sulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium hydrogen carbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, dihydrogen phosphate sodium, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glycerin, propylene glycol, etc.

Buffers: known borate buffers (boric acid and its salts (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.)), phosphate buffers (disodium hydrogen phosphate, phosphorus sodium dihydrogen acid, potassium dihydrogen phosphate), carbonate buffer (sodium hydrogen carbonate, sodium carbonate), citric acid buffer (citric acid, sodium citrate), acetate buffer (acetic acid, potassium acetate, sodium acetate), Good buffers (MES, MOPS, PIPES, HEPES, BES, TES, etc.) and the like.

pH adjusters: hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, boric acid, aminoethylsulfonic acid, epsilon-aminocaproic acid, acetic acid, propionic acid, oxalic acid, gluconic acid, fumaric acid, lactic acid, citric acid, tartaric acid, malic acid , succinic acid, gluconolactone, ammonium acetate, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium hydrogen carbonate, sodium carbonate, triethanolamine, monoethanolamine, diisopropanolamine, triisopropanolamine, etc. .

Chelating agents: ethylenediaminetetraacetic acid (EDTA), ethylenediaminediacetic acid (EDDA), diethylenetriaminepentaacetic acid (DTPA), N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA), N-(2-hydroxyethyl)iminodiacetic acid (HIDA), ascorbic acid, citric acid, phytic acid, polyphosphoric acid, metaphosphoric acid, succinic acid, tartaric acid, or salts thereof (alkali metal salts such as sodium). Ethylenediaminetetraacetic acid or its salt can also be used in the form of a hydrate.

Fragrance or cooling agent: For example, camphor, geraniol, borneol, menthol, ryuno, fennel oil, cinnamon oil, cool mint oil, spearmint oil, mint water, mint oil, peppermint oil, bergamot oil, eucalyptus oil, rose oil, and the like. These may be d-, l- or dl-isomers.

Preservatives: Alkyldiaminoethylglycine hydrochloride, sodium benzoate, chlorhexidine gluconate, chlorobutanol, sodium dehydroacetate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, oxyquinoline sulfate, phenethyl alcohol , phenoxyethanol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide, etc.), Glokill (trade name, manufactured by Rhodia), and the like.

Stabilizers: dibutylhydroxytoluene, trometamol, sodium formaldehyde sulfoxylate (Rongalit), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, etc.

Solubilizers, bases: octyldodecanol, olive oil, sesame oil, potassium bromide, soybean oil, camellia oil, corn oil, rapeseed oil, cottonseed oil, paraffin, castor oil, plastibase, peanut oil, lanolin, petrolatum, propylene glycol, etc.

Sugars: such as glucose, fructose, galactose, mannose, ribose, allose, ribulose, arabinose, xylose, lyxose, deoxyribose, maltose, trehalose, sucrose, cellobiose, glucobiose, vicianose, rutinose, lactose, pullulan, lactulose, raffinose, maltitol , stachyose, cyclodextrin, xylitol, sorbitol, mannitol, etc.

Polymer compounds such as gums and polysaccharides: for example, gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guaiac butter, quince seed, dalman gum, tragacanth, benzoin gum, locust bean gum, casein, agar, alginic acid, dextrin, dextran , galrageenan, gelatin, collagen, pectin, starch, polygalacturonic acid, chitin and its derivatives, chitosan and its derivatives, elastin, heparin, heparinoids, heparin sulfate, heparan sulfate, hyaluronic acid, chondroitin sulfate, ceramide, polyvinyl alcohol (complete, or partially saponified products), polyvinylpyrrolidone, polyvinyl methacrylate, polyacrylic acid, carboxyvinyl polymer, polyethyleneimine, ribonucleic acid, deoxyribonucleic acid, and pharmaceutically acceptable salts thereof.

Cellulose or derivatives thereof or salts thereof: for example, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxyethylcellulose, nitrocellulose and the like.

The present aqueous composition may contain various components in addition to the above components, depending on the purpose and application (efficacy) of the present aqueous composition, as long as it does not interfere with the antibacterial effect of IPMP and does not interfere with the effects of the present invention. (including pharmacologically active ingredients and physiologically active ingredients) can be contained in combination. The types of such ingredients are not particularly limited, and include, for example, whitening ingredients; moisturizing ingredients; vitamins; peptides or derivatives thereof; amino acids or derivatives thereof; Anti-inflammatory or astringent ingredients; anti-histamine or anti-allergic ingredients; decongestant ingredients; local anesthetic ingredients;

Whitening ingredients: placenta; arbutin; kojic acid; ellagic acid; phytic acid; tranexamic acid; rucinol; Ferulic acid, ferulate; glabridin; ascorbic acid, ascorbate, ascorbic acid derivatives such as ascorbic acid 2-glucoside; vitamins such as tocopherol acetate, tocopherol derivatives, vitamin A or derivatives thereof, pantothenic acid or derivatives thereof; polyphenols and plant extracts with whitening action.

Examples of moisturizing ingredients include polyhydric alcohols other than C3-6 diols, such as glycerin, polyethylene glycol, and diglycerin trehalose; Polymer compounds; amino acids such as glycine, aspartic acid and arginine; natural moisturizing factors such as sodium lactate, urea and sodium pyrrolidonecarboxylate; lipids such as ceramide, cholesterol and phospholipids; plant extracts such as chamomile extract and hamamelis extract .

Vitamins: For example, vitamin _B2s such as riboflavin, flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, riboflavin 5'-phosphate sodium, riboflavin tetranicotinate; nicotinic acid, nicotine nicotinic acids such as acid amides, dl-α-tocopherol nicotinate, benzyl nicotinate, methyl nicotinate, β-butoxyethyl nicotinate, 1-(4-methylphenyl)ethyl nicotinate; methylhesperidin, ergocalciferol, cholesterol vitamin D such as calciferol; vitamin K such as phylloquinone and farnoquinone; γ-oryzanol, dibenzoylthiamine, dibenzoylthiamine hydrochloride, thiamine hydrochloride, thiamine cetyl hydrochloride, thiamine thiocyanate, thiamine lauryl hydrochloride Thiamine nitrate, thiamine monophosphate, thiamine lysine salt, thiamine triphosphate, thiamine monophosphate phosphate, thiamine monophosphate, thiamine diphosphate, thiamine diphosphate hydrochloride, thiamine triphosphate, thiamine triphosphate Vitamin B ₁ types such as ester monophosphate; Vitamin B ₆ types such as pyridoxine hydrochloride, pyridoxine acetate, pyridoxal hydrochloride, 5'-pyridoxal phosphate, pyridoxamine hydrochloride; Vitamin B ₁₂ such as cyanocobalamin, hydroxocobalamin, deoxyadenosylcobalamin folic acid, folic acid such as pteroylglutamic acid; pantothenic acid, sodium pantothenate, calcium pantothenate, pantothenyl alcohol (panthenol), D-panthesaine, D-pantethine, coenzyme A, pantothenyl ethyl ether pantothenic acids; biotins such as biotin and biotisine; vitamins C such as ascorbic acid, ascorbate, ascorbic acid 2-glucoside; vitamins E such as tocopherol acetate and tocopherol derivatives; vitamin A or derivatives thereof; vitamin-like agents such as acid, α-lipoic acid, orotic acid, and the like.

Peptides or derivatives thereof: for example, keratinolytic peptides, hydrolyzed keratin, collagen, fish-derived collagen, atelocollagen, gelatin, elastin, elastinolytic peptides, collagenolytic peptides, hydrolyzed collagen, hydroxypropylammonium chloride hydrolyzed collagen, elastinolytic peptides , conchiolin hydrolyzed peptide, hydrolyzed conchiolin, silk proteolytic peptide, hydrolyzed silk, lauroyl hydrolyzed silk sodium, soybean proteolytic peptide, hydrolyzed soy protein, wheat protein, wheat proteolytic peptide, hydrolyzed wheat protein, casein hydrolyzed peptide , and acylated peptides (palmitoyl oligopeptides, palmitoyl pentapeptides, palmitoyl tetrapeptides, etc.).

Amino acids or derivatives thereof: e.g. betaine (trimethylglycine), proline, hydroxyproline, arginine, lysine, serine, glycine, alanine, phenylalanine, beta-alanine, threonine, glutamic acid, sodium glutamate, magnesium glutamate, glutamine, asparagine, aspartic acid , sodium aspartate, potassium aspartate, magnesium aspartate, calcium aspartate, magnesium-potassium aspartate mixture, cystine, methionine, leucine, isoleucine, valine, histidine, taurine, γ-aminobutyric acid, γ-amino-β-hydroxy Butyric acid, γ-aminovaleric acid, epsilon aminocaproic acid, carnitine, carnosine, creatine, etc.

Cell activation components: amino acids such as γ-aminobutyric acid and ε-aminoproic acid; vitamins such as retinol, thiamine, riboflavin, pyridoxine hydrochloride, and pantothenic acids; α-hydroxy acids such as glycolic acid and lactic acid; tannins flavonoids; saponins; and Photosensitizer No. 301, and the like.

Antiaging ingredients: For example, pangamic acid, kinetin, ursolic acid, sphingosine derivatives, silicon, silicic acid, N-methyl-L-serine, mevalonolactone and the like.

Ingredients promoting blood circulation: for example, plants (e.g., Panax ginseng, Angelica keiskei, Arnica, Ginkgo biloba, Fennel, Trifolium serrata, Holland oak, Chamomile, Roman chamomile, Carrot, Gentian, Burdock, Hawthorn, Shiitake, Juniper, Nemaria, Japanese juniper, Thyme, Clove , chimp, capsicum, toki, tokin, spruce, carrot, garlic, butcher bloom, botan, horse chestnut, melissa, yuzu, coix seed, rosemary, rosehip, peach, apricot, walnut, corn, etc.); and glucosyl such as hesperidin.

Keratin softening ingredients: for example, urea, salicylic acid, glycolic acid, fruit acid, phytic acid, sulfur and the like.

Anti-inflammatory or astringent ingredients: e.g. zinc sulfate, zinc lactate, zinc paraphenolsulfonate, zinc oxide, dipotassium glycyrrhizinate, allantoin, indomethacin, lysozyme chloride, silver nitrate, sodium azulene sulfonate, sodium diclofenac, sodium bromfenac , lysozyme chloride, piroxicam, etc.

antihistamine or antiallergic ingredients: e.g. acitazanolast, amlexanox, ibudilast, tazanolast, tranilast, isothipendyl, dipheterol, diphenylpyraline, triprolidine, tripelennamine, tonzilamine, promethazine, methdilazine, carbinoxamine, alimemazine, promethazine, mebhydroline, phenetazine, Oxatomide, mequitazine, terfenadine, epinastine, astemizole, ebastine, cetirizine, loratadine, fexofenadine, suplatast, diphenhydramine hydrochloride, levocabastine hydrochloride, ketotifen fumarate, sodium cromoglycate, potassium pemirolast, chlor maleate Pheniramine, emedastine fumarate, clemastine fumarate, azelastine hydrochloride, iproheptine hydrochloride, olopatadine hydrochloride, and the like.

Decongestant components: For example, α-adrenergic agonists, specifically epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, epinephrine bitartrate, naphazoline nitrate, and the like. These may be d-, l- or dl-isomers.

Antibacterial or bactericidal ingredients: e.g. alkylpolyaminoethylglycine, polyhexamethylenebiguanide, chlorhexidine hydrochloride, chlorhexidine gluconate, aminodeoxykanamycin sulfate, kanamycin sulfate, gentamicin sulfate, sisomycin sulfate, streptomycin sulfate, tobramycin, micronomycin sulfate, chlorine Ramphenicol, Sulfamethoxazole, Sulfisoxazole, Sulfamethoxazole Sodium, Sulfisoxazole Diethanolamine, Sulfisoxazole Monoethanolamine, Sulfisomethazole Sodium, Sulfisomidine Sodium , tetracycline hydrochloride, oxytetracycline hydrochloride, ofloxacin, norfloxacin, levofloxacin, lomefloxacin hydrochloride, ciprofloxacin hydrochloride sulbenicin sodium, cefmenoxime hydrochloride, benzylpenicillin potassium, berberine sulfate, berberine chloride, colistin sodium methasulfonate, erythromycin, lactobionic acid erythromycin, kitasamycin, spiramycin, fradiomycin sulfate, polymyxin sulfate, dibekacin, amikacin, amikacin sulfate, acyclovir, iododeoxycytidine, idoxuridine, cyclocytidine, cytosine arabinoside, trifluorothymidine, bromodeoxyuridine, Polyvinyl alcohol iodine, iodine, amphotericin B, isoconazole, econazole, clotrimazole, nystatin, pimaricin, fluorocytosine, miconazole, acrinol, polydronium chloride, Glokill (trade name, manufactured by Rhodia, for example, Glokill PQ), poly[oxyethylene (dimethyliminio)ethylene-(dimethyliminio)ethylene dichloride] and the like.

Local anesthetic ingredients: for example, oxybuprocaine hydrochloride, cocaine hydrochloride, cornecaine hydrochloride, dibucaine hydrochloride, tetracaine hydrochloride, diethylaminoethyl parabutylaminobenzoate hydrochloride, pipelocaine hydrochloride, procaine hydrochloride, proparacaine hydrochloride, hexothocaine hydrochloride, lidocaine hydrochloride, and the like.

Steroid components: e.g. dexamethasone, hydrocortisone, fluorometholone, prednisolone, methylprednisolone, hydroxymesterone, hydrocortisone caproate, prednisolone caproate, cortisone acetate, hydrocortisone acetate, prednisolone acetate, dexamethasone sodium metasulfobenzoate, dexamethasone sodium sulfate , dexamethasone sodium phosphate, triamcinolone acetonide, betamethasone sodium phosphate, dexamethasone sodium metasulfobenzoate, methylprednisolone and the like.

The blending amount of these components can be selected according to the purpose and application of the present aqueous composition, and is, for example, in the range of 0 to 20% by mass, preferably about 0.0011 to 10% by mass, relative to the entire aqueous composition. You can choose from

(pH)
The present aqueous composition is preferably adjusted to a pH range of 5 to 8 due to the antibacterial activity of IPMP. More preferably, the pH is about 5-7.

(Usage and form)
The present aqueous composition is not particularly limited as long as it exhibits the effect of the present invention, but can be widely used as a pharmaceutical or quasi-drug based on the antibacterial action of IPMP. It can be used according to a conventional method depending on the purpose, formulation form, and administration route of the present aqueous composition. The present aqueous composition can be in the form of a liquid or semi-solid formulation (sol or gel) by blending 50% by mass or more of water, preferably a liquid formulation or a gel formulation (gel). These formulations are prepared by conventional methods, and at that time, in addition to the above-mentioned ingredients, conventional additives (thickeners, gums, etc. in the case of gels) according to the formulation may be used. can. The liquid agent may be a homogeneous solution, a suspension (dispersion, milky lotion), or a composition used by mixing or dissolving.

(Production method)
This aqueous composition can be produced by a known method, except that IPMP, C3-6 diol, silicic anhydride and an aqueous solvent are blended as described above. For example, IPMP, C3-6 diol, and silicic anhydride are dissolved or dispersed in an aqueous solvent such as distilled water or purified water, adjusted to a predetermined pH, filtered and sterilized under an aseptic environment, and washed and sterilized. It can be manufactured by aseptically filling containers. The aforementioned (other components) can be appropriately blended according to the purpose and formulation form of the present aqueous composition. For example, when the present aqueous composition is prepared as a gel, it can be prepared by blending the thickening agent described above and forming a gel according to a conventional method.

The present aqueous composition is characterized in that the IPMP addition recovery rate is in the range of 90 to 110% in the addition recovery test. Preferably, the IPMP addition recovery rate is in the range of 95 to 105%. For pharmaceuticals or quasi-drugs, the additive recovery test is an important test for controlling and assuring the quality of manufactured products. The IPMP addition recovery rate is the amount of IPMP in the aqueous composition (product) obtained as a test result by performing an addition recovery test for IPMP on an aqueous composition (product) to which a known amount of IPMP has been added. , is the percentage (%) of the known amount of IPMP added during the production of the aqueous composition (product), and can be obtained from the following formula.

[Number 1]
Addition recovery rate of IPMP (%) =
(Amount of IPMP obtained as a test result/known amount of IPMP added) x 100

(II) Method for Improving Addition Recovery Rate of IPMP-Containing Aqueous Composition The present invention also relates to a method for improving the addition recovery rate of IPMP in an aqueous composition containing IPMP.

Specifically, the present invention relates to a method for improving the addition recovery rate of IPMP in an aqueous composition containing IPMP and a diol having 3 to 6 carbon atoms, the method comprising IPMP and a diol having 3 to 6 carbon atoms. In addition, it can be implemented by having a step of preparing an aqueous composition by blending silicic anhydride. The IPMP, the diol having 3 to 6 carbon atoms, the silicic anhydride, and the aqueous solvent to be added and blended in the aqueous composition and the type and blending ratio thereof are as described in (I) above, and are incorporated herein by reference. can do. In addition, as explained in (I), the target aqueous composition may contain other components. For example, as a component for increasing the water solubility of IPMP, methylpolysiloxane may be blended. Moreover, when the target aqueous composition has a gel (gel) shape, the above-described thickening agent, gum substance, and the like can be blended.

In the method of the present invention, the IPMP-containing aqueous composition may contain a combination of various ingredients (including pharmacologically active ingredients and physiologically active ingredients) as long as the effects of the invention are not impaired. The type of such component is not particularly limited, but specific examples are as described in (I).

According to the method of the present invention, an aqueous composition containing IPMP and a diol having 3 to 6 carbon atoms can be improved in the addition recovery rate of IPMP, and more preferably, the It is possible to meet the required spike recovery (90-110%). The method for determining the addition recovery rate of IPMP is as described in (I).

Whether or not the recovery rate of IPMP addition is improved by the method of the present invention can be determined by comparing the recovery rate of IPMP addition with or without addition of silicic anhydride for an aqueous composition containing IPMP and a diol having 3 to 6 carbon atoms. can be implemented by Specifically, an aqueous composition (test sample) containing IPMP, a diol having 3 to 6 carbon atoms, and silicic anhydride, and an aqueous composition having the same composition as the test sample except that silicic anhydride is not blended. For (control sample), the IPMP addition recovery rate is compared, and when the IPMP addition recovery rate of the test sample is closer to the reference "100%" than the IPMP addition recovery rate of the control sample, the IPMP addition recovery rate is can be judged to have improved. More preferably, by blending silicic anhydride, the IPMP addition recovery rate, which was outside the range of 90 to 110% (less than 90% or more than 110%), becomes within the range of 90 to 110%. Furthermore, when it approaches "100%" and falls within the range of 95 to 105%, it can be judged that the addition of silicic anhydride has improved the IPMP addition recovery rate for the IPMP-containing aqueous composition. It can be provided as a product that meets the quality of quasi-drugs.

(III) Addition-and-recovery test method for IPMP-containing aqueous composition The present invention relates to an addition-and-recovery test method for an IPMP-containing aqueous composition. Specifically, the present invention is a test method for adding and recovering IPMP in an aqueous composition containing IPMP and a diol having 3 to 6 carbon atoms, wherein the method includes a prescribed amount of IPMP as a test sample and In addition to the diol of No. 6, it can be carried out by using an aqueous composition containing silicic anhydride.

The IPMP, the diol having 3 to 6 carbon atoms, the silicic anhydride, and the aqueous solvent to be added and blended in the aqueous composition and the type and blending ratio thereof are as described in (I) above, and are incorporated herein by reference. can do. In addition, as explained in (I), the target aqueous composition may contain other components. For example, as a component for increasing the water solubility of IPMP, methylpolysiloxane may be blended. Moreover, when the target aqueous composition has a gel (gel) shape, the above-described thickening agent, gum substance, and the like can be blended.

In the method of the present invention, the IPMP-containing aqueous composition may contain a combination of various ingredients (including pharmacologically active ingredients and physiologically active ingredients) as long as the effects of the invention are not impaired. The type of such component is not particularly limited, but specific examples are as described in (I).

According to the addition recovery test method of the present invention, since the addition recovery rate of IPMP is improved for aqueous compositions containing IPMP and a diol having 3 to 6 carbon atoms, the amount of IPMP actually added can be accurately determined. It can be quantified in a reflected state, and stable quality control can be performed for the IPMP-containing aqueous composition, especially as a drug or quasi-drug. The method for determining the addition recovery rate of IPMP is as described in (I). Further, the addition and recovery test method performed on the IPMP-containing aqueous composition will be described in detail in the experimental examples described later.

The configuration and effects of the present invention will be described in detail below with reference to examples, but the examples are examples and the present invention is not limited to these examples. In the following examples, "%" means "% by mass" and "parts" means "parts by mass" unless otherwise specified. In addition, unless otherwise specified, manufacturing and experiments were carried out under normal pressure (atmospheric pressure) and normal temperature (25° C.) conditions.

Experimental Example 1 Addition and Recovery Test (Part 1)
As described below, the aqueous composition (test sample: Example 1 and Comparative Example 1, pH 6.6) described in Table 1 was subjected to an addition recovery test, and the amount of isopropylmethylphenol (IPMP) in the test sample was was analyzed (quantified).

(1) Test method (1-1) Sample preparation (a) Preparation of internal standard solution An internal standard solution was prepared using 4-methoxybenzaldehyde as an internal standard substance. Specifically, ethanol (95) was added to 7 mg of 4-methoxybenzaldehyde to make 200 mL, which was used as an internal standard solution (0.0035 w/v%). Ethanol (95) means ethanol with a purity (depending on density) of 94.8 to 95.8 vol% (same below).
(b) Preparation of standard solution About 40 mg of IPMP for quantitative determination was accurately weighed, and ethanol (95) was added to make exactly 100 mL, which was used as a standard undiluted solution. 5 mL of this standard undiluted solution was accurately weighed, 5 mL of the internal standard solution was added thereto, and ethanol (95) was added to make exactly 50 mL, which was used as the standard solution.
(c) Preparation of sample solution Each component described in Table 1 was weighed out in its ratio, and all components were stirred and mixed to dissolve to prepare a test sample (Example 1, Comparative Example 1). This test sample was thoroughly stirred, and about 2 g was accurately weighed, to which 5 mL of the internal standard solution was added accurately, and ethanol (95) was added to make exactly 50 mL. This was irradiated with ultrasonic waves for 10 minutes and filtered through a membrane filter (pore size 0.45 μm, “ACRODISC 25 mm” Pall Corporation) to obtain a sample solution.

(1-2) Quantitative method 20 μL of each of the sample solution and standard solution is subjected to liquid chromatography (HPLC) under the following conditions, and the peak area of IPMP with respect to the peak area of the internal standard for each of the sample solution and standard solution The ratio of (Q _T , Q _S ) was determined.
Q _T : Ratio of peak area of IPMP to peak area of internal standard for sample solution Q _S : Ratio of peak area of IPMP to peak area of internal standard for standard solution

(a) HPLC measurement conditions Column: Inertsi ODS-3 (4.6 mm x 250 nm, 5 µm) (GL Sciences Inc.)
Column temperature: 40° C. or constant temperature around 40° C. Mobile phase: acetonitrile/sodium lauryl sulfate diluted acetic acid (100) (1→1000) mixture (13:12). This was prepared by adding water to 2 mL of acetic acid (100) to make 2000 mL, adding 11.6 g of sodium lauryl sulfate and mixing.
Flow rate (flow velocity): Adjusted so that the retention time of IPMP was about 11 minutes.
Injection volume: 20 μL
Analysis time: 20 minutes Elution behavior: 4-methoxybenzaldehyde (internal standard substance) and IPMP are eluted in this order.

(b) Calculation of addition recovery rate From the HPLC analysis results obtained for the above sample solution, the amount of IPMP (quantitative value) obtained as a test result as the amount of IPMP contained in the sample solution was obtained, and the actual amount of IPMP as a component was determined. The addition recovery rate was calculated according to the following formula from the known amount added (blending value).
[Number 2]
Addition recovery rate of IPMP (%) = (quantitative value / blended value) × 100
Specifically, the addition recovery rate (%) can be calculated by the following formula.
(Q _T /Q _S )×(quantitative IPMP weighed amount (mg)/sample weighed amount (g)/400/IPMP compounding amount in 100 g of formulation (0.1 g in Example 1)×100

表１に示すように、無水ケイ酸を配合しない水性組成物におけるＩＰＭＰの添加回収率は非常に悪く、水性組成物中のＩＰＭＰの含有量を正確に測定することは出来なかった（比較例１）。しかし、その水性組成物中に無水ケイ酸を配合することでＩＰＭＰの添加回収率は顕著に改善することが確認された（実施例１）。 (2) Test results The results are also shown in Table 1.
In addition, when the addition recovery rate is "less than 90% or more than 110%", it is defective "x", and when it is "90% to over 110%", it is good "○", especially "95% to 105% ” was determined as the best “⊚”.

As shown in Table 1, the addition recovery rate of IPMP in the aqueous composition containing no silicic anhydride was very poor, and the content of IPMP in the aqueous composition could not be measured accurately (Comparative Example 1 ). However, it was confirmed that addition recovery of IPMP was remarkably improved by adding silicic anhydride to the aqueous composition (Example 1).

実験例１と同様に、表２に示すように、無水ケイ酸を配合しない水性組成物におけるＩＰＭＰの添加回収率は非常に悪く、水性組成物中のＩＰＭＰの含有量を正確に測定することは出来なかった（比較例２）。しかし、その水性組成物中に無水ケイ酸を配合することでＩＰＭＰの添加回収率は顕著に改善することが確認された（実施例２～５）。 Experimental Example 2 Addition and Recovery Test (Part 2)
For the aqueous compositions described in Table 2 (test samples: Examples 2 to 5 and Comparative Example 2, pH 6.6), addition and recovery tests were performed in the same manner as in Experimental Example 1, and isopropylmethylphenol (IPMP ) was analyzed (quantified). The results are also shown in Table 2.

As in Experimental Example 1, as shown in Table 2, the addition recovery rate of IPMP in the aqueous composition containing no silicic anhydride is very poor, and it is impossible to accurately measure the content of IPMP in the aqueous composition. It was not possible (Comparative Example 2). However, it was confirmed that addition recovery of IPMP was remarkably improved by adding silicic anhydride to the aqueous composition (Examples 2 to 5).

Example 6 Gel (pH 6.6)
Isopropylmethylphenol 0.1
Silicic anhydride 0.5
Methylpolysiloxane 2.6
1,2-pentanediol 3.0
1,3-butylene glycol 5.0
L-ascorbic acid 2-glucoside 2.0
Dipotassium glycyrrhizinate 0.05
Erythritol 2.0
Heparinoid 0.1
Tocopherol acetate 0.1
Carboxy vinyl polymer 0.7
Hydroxypropyl methylcellulose 0.5
(Dimethicone/vinyl dimethicone) crosspolymer/dimethicone 0.5
Polysorbate 80 2.0
Polyoxyethylene polyoxypropylene decyltetradecyl ether 0.5
Disodium edetate 0.1
Methylparaben 0.1
Citric acid appropriate amount Sodium citrate appropriate amount Sodium hydroxide appropriate amount
Purified water Balance
Total 100.00%

Claims (4)

An aqueous composition containing isopropylmethylphenol, 5-15% by weight of a C3-C6 diol, silicic anhydride, and methylpolysiloxane:
However, excluding the following compositions (1) to (3 );
(1) A gel composition containing the following components (A) to (D):
(A) crosslinked methylpolysiloxane powder whose surface is coated with fine silica powder;
(B) a water-soluble polymer,
(C) one or more selected from monohydric to trihydric alcohols,
(D) a nonionic surfactant that is liquid or pasty at 25° C. and has an HLB of 1 to 8;
(2) Oil-in-water emulsified composition containing the following components:
Stearic acid, behenyl alcohol, cholesterol, petrolatum, squalane, dimethylpolysiloxane, lipophilic glycerin monostearate (emulsified type), sodium N-stearoyl-L-glutamate (emulsified type), dipropylene glycol, glycerin, silicic anhydride, 2-ethylhexyl paramethoxycinnamate, titanium oxide, 3-methyl-4-isopropylphenol, methylparaben, fragrance, and purified water ;
(3) An emulsified composition containing the following ingredients: titanium oxide-coated activated carbon, silica, methylpolysiloxane, isopropylmethylphenol, and 1,3-butylene glycol . 2. The aqueous composition according to claim 1, wherein the addition recovery rate of isopropylmethylphenol is in the range of 90 to 110%. A method for improving the addition recovery rate of isopropylmethylphenol for pharmaceuticals or quasi-drugs, which is an aqueous composition containing isopropylmethylphenol, 5-15% by mass of a diol having 3 to 6 carbon atoms, and methylpolysiloxane. a step of blending isopropylmethylphenol, 5 to 15% by mass of a diol having 3 to 6 carbon atoms, and methylpolysiloxane with silicic anhydride to prepare an aqueous composition ;
However, the emulsion composition containing the following ingredients is excluded from the above aqueous composition containing silicic anhydride:
Titanium oxide coated activated carbon, silica, methylpolysiloxane, isopropylmethylphenol, and 1,3-butylene glycol . A test method for adding and recovering isopropylmethylphenol in a drug or quasi-drug that is an aqueous composition containing isopropylmethylphenol, 5-15% by mass of a diol having 3 to 6 carbon atoms, and methylpolysiloxane, comprising: An aqueous composition containing silicic anhydride in addition to a specified amount of isopropylmethylphenol, 5 to 15% by mass of a diol having 3 to 6 carbon atoms, and methylpolysiloxane as a sample is used. test method ;
However, the emulsion composition containing the following ingredients is excluded from the above aqueous composition containing silicic anhydride:
Titanium oxide coated activated carbon, silica, methylpolysiloxane, isopropylmethylphenol, and 1,3-butylene glycol .