WO2020004192A1

WO2020004192A1 - Aqueous composition containing isopropyl methylphenol

Info

Publication number: WO2020004192A1
Application number: PCT/JP2019/024350
Authority: WO
Inventors: 正彦小森園; 信哉宅見
Original assignee: 小林製薬株式会社
Priority date: 2018-06-28
Filing date: 2019-06-19
Publication date: 2020-01-02
Also published as: JP2020002058A; TWI816813B; JP7258478B2; TW202000235A

Abstract

[Problem] To provide an aqueous composition prepared such that the added amount of isopropyl methylphenol can be determined accurately at an addition recovery rate of 90-110% for isopropyl methylphenol in an addition recovery test. [Solution] This aqueous composition contains isopropyl methylphenol, a diol having 3-6 carbon atoms, and an anhydrous silicate.

Description

Aqueous composition containing isopropylmethylphenol

The present invention relates to an aqueous composition containing isopropylmethylphenol having a wide range of bactericidal action. More specifically, in an addition recovery test performed during product quality control, 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 determined. About. The present invention also relates to a method for improving the recovery rate of an aqueous composition containing isopropylmethylphenol. Further, the present invention relates to a test method for adding and recovering an aqueous composition containing isopropylmethylphenol.

Isopropyl methylphenol (hereinafter simply referred to as “IPMP”) has high safety in addition to a broad antibacterial spectrum, and is an antibacterial agent (bactericide) with a low environmental load. Active ingredients of, for example, wound disinfectants, ointments, etc., and quasi-drugs (eg, hand soaps, hair-growing tonics, deodorants [deodorants], antiperspirants, medicated cosmetics, toothpastes, etc.), and preservatives of cosmetics, etc. It is widely used as an agent and the like. However, since IPMP has extremely low solubility in water and high crystallinity, there is a problem that IPMP easily precipitates in an aqueous composition. On the other hand, since ethanol is highly soluble, it is conceivable to use ethanol to solubilize IPMP in water, but the use of ethanol is contraindicated or the amount of ethanol is contraindicated for some drugs, quasi-drugs, and cosmetics. Some are restricted. It is also known that if a surfactant is added to solubilize IPMP in water, the antibacterial activity of IPMP may be inhibited depending on the type of the surfactant. For this reason, it is generally considered that IPMP is difficult to apply to an aqueous composition containing a large amount of water.

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

JP 2017-14823 A

The present inventors have sought an aqueous composition containing IPMP, particularly an aqueous composition containing a diol having 3 to 6 carbon atoms together with IPMP in order to enhance solubility in water, in pharmaceuticals and quasi-drugs. As a result of the addition recovery test, it was found that there was a problem that the known amount of the blended IPMP could not be measured accurately (the reduction in the addition recovery rate).

Accordingly, an object of the present invention is to provide a method for solving the problem of a decrease in the addition recovery rate of 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, the aqueous composition prepared so that the IPMP addition recovery rate is 90 to 110% and the amount of IPMP added can be accurately determined. The purpose is to provide things. Another object of the present invention is to provide a method for improving the recovery rate of an aqueous composition containing IPMP. Still another object of the present invention is to provide a method for testing the recovery of an aqueous composition containing IPMP.

The present inventors have made intensive studies to solve the above-mentioned problems, and found that the aqueous composition containing IPMP and a diol having 3 to 6 carbon atoms was further mixed with silicic anhydride to obtain IPMP. It has been found that the problem of a decrease in the addition recovery rate has been improved, and that the addition recovery rate of IPMP is 90 to 110%, and that the amount of IPMP added can be accurately determined. The present invention has been completed by further study based on such knowledge, 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), further comprising a thickener.
(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 of (I-1) to (I-3), which is a pharmaceutical or a quasi drug.
(I-5) The aqueous composition according to any one of (I-1) to (I-4), which is an aqueous composition for an addition recovery test.

(II) Method for Improving Addition / Recovery Rate of IPMP-Containing Aqueous Composition (II-1) A method for improving the IPMP addition / recovery rate of an aqueous composition containing IPMP and a diol having 3 to 6 carbon atoms, the method comprising: The above method, comprising a step of preparing an aqueous composition by blending silicic anhydride in addition to the diol having 3 to 6 carbon atoms.
(II-2) The method according to (II-1), wherein the aqueous composition further contains a thickener.
(II-3) The method 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 recovery of addition according to any of (II-1) to (II-3), wherein the recovery of addition of IPMP is in the range of 90 to 110%.

(III) Addition / recovery test method of IPMP-containing aqueous composition (III-1) This is a method of adding / recovering 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 recovery test according to (III-1), wherein the aqueous composition further contains a thickener.
(III-3) The addition and recovery test method according to (III-1) or (III-2), wherein the aqueous composition is a drug or a quasi drug.

According to the IPMP-containing aqueous composition of the present invention, the method for improving the recovery of addition, and the method for testing the recovery of addition, the recovery of the IPMP added and blended is measured with high accuracy of as high as 90 to 110% in the recovery of addition. Becomes possible.

(I) IPMP-Containing Aqueous Composition The aqueous composition of the present invention (hereinafter, simply referred to as “the present 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 having a needle-like crystal form with a chemical name of 3-methyl-4-isopropylphenol. It has a wide range of antibacterial and antifungal spectrums (O-157, MRSA, Serratia, Trichophyton, etc.), and has a bactericidal effect against various germicidal, yeast, and mold fungi, as well as low odor, low taste, and low odor. Because of its irritation and non-sensitizing properties, it is widely used as a bactericide, antibacterial agent, or preservative in pharmaceuticals and quasi-drugs, as well as cosmetics and daily necessities. IPMP is commercially available (for example, Osaka Chemical Co., Ltd.), and is sold as a product that can be easily blended with an aqueous product, "BIOSOL (registered trademark) -LIQUID" (manufactured by Osaka Chemical Co., Ltd.). Can also be used.

The ratio of the IPMP contained in the present aqueous composition is such that the target aqueous composition exhibits a desired antibacterial effect (including a bactericidal effect and an antiseptic effect), and the type of the aqueous composition, its use, In addition, it can be appropriately set according to the purpose of adding IPMP (the expected effect of IPMP). For example, the range is 0.001 to 2% by mass, preferably 0.01 to 1% by mass, and more preferably 0.05 to 0.5% by mass.

(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 one carboxylic acid is used for every two carbon atoms of the chain aliphatic hydrocarbon. It is a compound having a structure in which each hydroxyl group is substituted. 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 C3 to C6 diols can be used alone or in any combination of two or more.

The ratio of the C3-6 diol contained in the present aqueous composition is an amount that makes IPMP solubilized in water without impairing the antibacterial effect of IPMP in the target aqueous composition, and exhibits the effects of the present invention. It may be in the range, for example, it can be appropriately selected and set from the range of 0.1 to 50% by mass. The preferred range is 1 to 20% by mass, more preferably 5 to 15% by mass.

(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, scale-like, spindle-like, etc.), particle size (fog-like, fine-particle, pigment grade, etc.), particle structure (porous, non-porous, etc.), Either one can be used. Preferably, a porous non-hollow spherical silica anhydride having a particle diameter of 7.0 to 10.0 μm can be exemplified.

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

(4) The Aqueous Composition The aqueous composition of the present invention contains the IPMP, C3-6 diol, and silicic anhydride in an aqueous solvent in a dissolved, dispersed, or emulsified state. Here, water can be used as the aqueous solvent. The water may be any water used in the preparation of pharmaceuticals, quasi-drugs or cosmetics, and for example, purified water, distilled water, physiological saline, sterilized water, or the like 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 components (eg, solubility and dispersibility), formulation characteristics (eg, viscosity, osmotic pressure, pH), formulation, and dosage form. 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 components)
The present aqueous composition may contain methylpolysiloxane as a component for solubilizing IPMP in addition to the above-mentioned C3-6 diol. The mixing ratio of methylpolysiloxane in the present aqueous composition may be within a range that does not hinder the antibacterial effect of IPMP of the target aqueous composition and exerts the effects of the present invention. % Can be appropriately selected and set. The range is preferably 0.5 to 10% by mass, more preferably 1 to 5% by mass.

In addition, the present aqueous composition does not interfere with the antibacterial effect of IPMP, and as long as it does not interfere with the effect of the present invention, depending on its use and form, various pharmaceuticals, quasi-drugs, etc. Components and additives can be appropriately selected and used together to form a formulation. For example, thickeners, surfactants, tonicity agents, buffers, pH adjusters, chelating agents, fragrances or fresheners, preservatives, stabilizers, solubilizers commonly used in the preparation of solutions and the like And various additives such as a base. In addition, vitamins; amino acids; high molecular compounds such as saccharides, gums, and polysaccharides; cellulose or derivatives thereof, or salts thereof, can also be formulated. Examples of these additives include the following components, for example. However, in the present aqueous composition, all of these components are 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 adduct of ethylenediamine (eg, poloxamine); POE (20) sorbitan monolaurate (polysorbate 20), POE (20) sorbitan monooleate (polysorbate 80), POE such as polysorbate 60 Sorbitan fatty acid esters; POE (60) hardened castor oil such as hardened castor oil; POE (9) POE alkyl ethers such as lauryl ether; POE (20) POP (4 POE · POP alkyl ethers such as cetyl ether; POE (10) POE alkylphenyl ethers such as nonyl phenyl ether; POE (10) POE alkylphenyl ethers such as nonyl phenyl ether and the like. The numbers in parentheses indicate the number of moles added.

Isotonizing agents: for example, sodium bisulfite, 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 and the like.

Buffers: known borate buffers (boric acid and salts thereof (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), citrate 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 adjuster: 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 a salt thereof can also be used in the form of a hydrate.

Fragrances or fresheners: for example, camphor, geraniol, borneol, menthol, rhubarb, fennel oil, cauliflower oil, cool mint oil, spearmint oil, peppermint oil, peppermint oil, peppermint oil, bergamot oil, eucalyptus oil, rose oil and the like. These may be d-form, l-form or dl-form.

Preservatives: alkyl diaminoethyl glycine hydrochloride, sodium benzoate, chlorhexidine gluconate, chlorobutanol, sodium dehydroacetate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol Phenoxyethanol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide, etc.), Gloquil (trade name, manufactured by Rhodia) and the like.

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

Solubilizers and 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, and the like.

Saccharides: for example, glucose, fructose, galactose, mannose, ribose, allose, ribulose, arabinose, xylose, lyxose, deoxyribose, maltose, trehalose, sucrose, cellobiose, glucobiose, bicyanose, rutinose, lactose, pullulan, lactulose, raffinose, maltitol , Stachyose, cyclodextrin, xylitol, sorbitol, mannitol and the like.

High molecular compounds such as gums and polysaccharides: for example, gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guaiac oil, quince seed, dalman gum, tragacanth, benzoin gum, locust bean gum, casein, agar, alginic acid, dextrin, dextran , Carrageenan, gelatin, collagen, pectin, starch, polygalacturonic acid, chitin and its derivatives, chitosan and its derivatives, elastin, heparin, heparinoid, heparin sulfate, heparan sulfate, hyaluronic acid, chondroitin sulfate, ceramide, polyvinyl alcohol (complete, Or partially saponified), polyvinylpyrrolidone, polyvinyl methacrylate, polyacrylic acid, carboxyvinyl polymer, polyethyleneimine, ribonucleic acid, Such Kishiribo nucleic acids, and the like pharmaceutically acceptable salts.

Cellulose or a derivative thereof or a salt thereof: for example, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxyethylcellulose, nitrocellulose and the like.

The present aqueous composition does not impair the antibacterial effect of IPMP and various components other than the above components depending on the purpose and use (efficacy) of the present aqueous composition as long as the effects of the present invention are not impaired. (Including a pharmacologically active component and a physiologically active component). Types of such components are not particularly limited, and include, for example, whitening components; moisturizing components; vitamins; peptides or derivatives thereof; amino acids or derivatives thereof; cell activating components; anti-aging components; An anti-inflammatory component or an astringent component; an antihistamine component or an anti-allergic component; a decongestant component; a local anesthetic component;

Whitening ingredients: placenta; arbutin; kojic acid; ellagic acid; phytic acid; tranexamic acid; lucinol; Ferulic acid, ferulic acid salt; glabridine; ascorbic acid derivatives such as ascorbic acid, ascorbate and ascorbic acid 2-glucoside; vitamins such as tocopherol acetate, tocopherol derivative, vitamin A or derivatives thereof, pantothenic acid or derivatives thereof; polyphenols And plant extracts having a whitening effect.

Examples of the moisturizing component include polyhydric alcohols other than C3-6 diols such as glycerin, polyethylene glycol and diglycerin trehalose; sodium hyaluronate, heparin-like substance, chondroitin sulfate, collagen, elastin, keratin, chitin, chitosan and the like. High molecular compounds; amino acids such as glycine, aspartic acid and arginine; natural moisturizing factors such as sodium lactate, urea and sodium pyrrolidone carboxylate; lipids such as ceramide, cholesterol and phospholipids; plant extracts such as chamomile extract and hamamelis extract; .

Vitamins: For example, riboflavin, flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetra-butyrate, riboflavin 5'-sodium phosphate esters, vitamin B ₂ such as riboflavin tetra nicotinate; nicotinic acid, nicotinic Acid amides, nicotinic acids such as dl-α-tocopherol nicotinate, benzyl nicotinate, methyl nicotinate, β-butoxyethyl nicotinate, 1- (4-methylphenyl) ethyl nicotinate; methyl hesperidin, ergocalciferol, kore Vitamin D such as calciferol; Vitamin K such as filoquinone and farnoquinone; γ-oryzanol, dibenzoylthiamine, dibenzoylthiamine hydrochloride, thiamine hydrochloride, thiaminecet Hydrochloride, thiamine thiocyanate, thiamine lauryl hydrochloride, thiamine nitrate, thiamine monophosphate, thiamine lysine salt, thiamine triphosphate, thiamine monophosphate ester phosphate, thiamine monophosphate ester, thiamine diphosphate ester, thiamine diphosphate Vitamin B ₁ such as acid ester hydrochloride, thiamine triphosphate, thiamine triphosphate monophosphate; vitamin B ₆ such as pyridoxine hydrochloride, pyridoxine acetate, pyridoxal hydrochloride, 5′-pyridoxal phosphate, pyridoxamine hydrochloride; cyanocobalamin , hydroxocobalamin, vitamin B ₁₂ such as deoxyadenosyl cobalamin; folic acid, folic acid such as pteroylglutamic acid; pantothenate, sodium pantothenate, calcium pantothenate, Pantote Alcohol (panthenol), D-pantethene, D-pantethine, coenzyme A, pantothenic acids such as pantothenyl ethyl ether; biotins such as biotin and bioticin; ascorbic acid, ascorbate, and 2-glucoside ascorbic acid Vitamin Cs; vitamin Es such as tocopherol acetate and tocopherol derivatives; vitamin A or its derivatives; and vitamin-like agents such as carnitine, ferulic acid, α-lipoic acid and orotic acid.

Peptide or derivative thereof: For example, keratin-decomposed peptide, hydrolyzed keratin, collagen, fish-derived collagen, atelocollagen, gelatin, elastin, elastin-decomposed peptide, collagen-degraded peptide, hydrolyzed collagen, hydroxypropylammonium chloride-hydrolyzed collagen, elastin-degraded peptide , Conchiolin degrading peptide, hydrolyzed conchiolin, silk proteolytic peptide, hydrolyzed silk, lauroyl hydrolyzed silk sodium, soybean proteolytic peptide, hydrolyzed soybean protein, wheat protein, wheat proteolytic peptide, hydrolyzed wheat protein, casein degradable peptide , And acylated peptides (palmitoyl oligopeptide, palmitoyl pentapeptide, palmitoyl tetrapeptide, etc.).

Amino acids or derivatives thereof: for example, betaine (trimethylglycine), proline, hydroxyproline, arginine, lysine, serine, glycine, alanine, phenylalanine, β-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 and the like.

Cell activating component: for example, amino acids such as γ-aminobutyric acid and ε-aminoproic acid; vitamins such as retinol, thiamine, riboflavin, pyridoxine hydrochloride, pantothenic acids; α-hydroxy acids such as glycolic acid and lactic acid; tannin Flavonoids; saponins;

Anti-aging components: for example, pangamic acid, kinetin, ursolic acid, sphingosine derivatives, silicon, silicic acid, N-methyl-L-serine, mevalonolactone and the like.

Components for promoting blood circulation: for example, plants (for example, Panax ginseng, Ashitaba, Arnica, Ginkgo, Fennel, Emmeso, Dutch oak, chamomile, Roman chamomile, Carrot, Gentian, burdock, Hawthorn, Shiitake, Seize, Senkyu, Assembly, Thyme, Choji And glucosyl, components derived from ,, chimpanzees, peppers, cucumber, tonin, spruce, carrots, garlic, butcher bloom, buttons, marronnier, melissa, yuzu, yokunin, rosemary, rosehip, peach, apricot, walnut, corn, etc .; Hesperidin and the like.

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

Anti-inflammatory or astringent components: for example, zinc sulfate, zinc lactate, zinc paraphenolsulfonate, zinc oxide, dipotassium glycyrrhizinate, allantoin, indomethacin, lysozyme chloride, silver nitrate, sodium azulene sulfonate, diclofenac sodium, bromfenac sodium , Lysozyme chloride, piroxicam and the like.

Antihistamine or antiallergic components: for example, acitazanolast, amlexanox, ibudilast, tazanolast, tranilast, isotipendyl, dipheterol, diphenylpyrazine, triprolidine, tripelenamine, tondylamine, promethazine, methdilazine, carbinoxamine, alimemazine, hydromethazine, hydromethazine, hydromethazine, promethazine Oxatomide, mequitazine, terfenadine, epinastine, astemizole, ebastine, cetirizine, loratadine, fexofenadine (fexofenadine), suplatast, diphenhydramine hydrochloride, revocabastine hydrochloride, ketotifen fumarate, sodium cromoglicate, potassium pemiroclolate, pemiloclolate Pheniramine, emedastine fumarate, fumarate Clemastine acid, azelastine hydrochloride, iproheptin hydrochloride, olopatadine hydrochloride and the like.

Decongestant: 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-form, l-form or dl-form.

Antibacterial or bactericidal components: For example, alkyl polyaminoethyl glycine, polyhexamethylene biguanide, chlorhexidine hydrochloride, chlorhexidine gluconate, aminodeoxykanamycin sulfate, kanamycin sulfate, gentamicin sulfate, sisomicin sulfate, streptomycin sulfate, tobramycin, micronomycin sulfate, clonomycin sulfate Ramphenicol, sulfamethoxazole, sulfisoxazole, sulfamethoxazole sodium, sulfisoxazole diethanolamine, sulfisoxazole monoethanolamine, sodium sulfisomethol, sodium sulfisomidine , Tetracycline hydrochloride, oxytetracycline hydrochloride, ofloxacin, norfloxacin, levofloxacin, lomefloxacin hydrochloride, salt Ciprofloxacin sulbenicin sodium, cefmenoxime hydrochloride, benzylpenicillin potassium, berberine sulfate, berberine chloride, colistin metasulfonate sodium, erythromycin, erythromycin lactobionate, 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 ( Name, produced by Rhodia, for example, Glokill PQ), poly [oxyethylene (dimethyliminio) ethylene - (dimethyliminio) ethylene dichloride], etc..

Local anesthetic components: for example, oxybuprocaine hydrochloride, cocaine hydrochloride, cornecaine hydrochloride, dibucaine hydrochloride, tetracaine hydrochloride, diethylaminoethyl parabutylaminobenzoate hydrochloride, piperokine hydrochloride, procaine hydrochloride, proparacaine hydrochloride, hexothiocaine hydrochloride, lidocaine hydrochloride and the like.

Steroid ingredients: For example, dexamethasone, hydrocortisone, fluorometholone, prednisolone, methylprednisolone, hydroxymesterone, hydrocortisone caproate, prednisolone caproate, cortisone acetate, hydrocortisone acetate, prednisolone acetate, dexamethasone sodium metasulfobenzoate, dexamethasone sodium sodium , Dexamethasone sodium phosphate, triamcinolone acetonide, betamethasone sodium phosphate, dexamethasone sodium metasulfobenzoate, methylprednisolone and the like.

The amounts of these components can be selected according to the purpose and use of the present aqueous composition, and are, for example, in the range of about 0 to 20% by mass, preferably about 0.0011 to 10% by mass based on the entire aqueous composition. You can choose from.

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

(Usage and form)
The present aqueous composition is not particularly limited as long as it exhibits the effects of the present invention, but can be widely used as a drug or a quasi-drug based on the antibacterial action of IPMP. The usage can be used according to a standard method according to the purpose, formulation form, and administration route of the present aqueous composition. The form of the present aqueous composition can be a liquid or semi-solid agent (sol or gel) by mixing water at 50% by mass or more, but is preferably a liquid or gel (gel). These preparations are prepared by a conventional method, and in this case, in addition to the above-mentioned components, conventional additives (thickeners, gums, etc. in the case of gels) corresponding to the preparations may be used. it can. The liquid agent may be a homogeneous solution or a suspension (dispersion, emulsion), or a composition used by mixing or dissolving.

(Production method)
The present 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 in a sterile environment, and washed and sterilized. It can be manufactured by aseptically filling a container. The above-mentioned (other components) can be appropriately compounded depending on the purpose and the form of the present aqueous composition. For example, when the present aqueous composition is prepared as a gel (gel), the aqueous composition can be prepared by blending the above-mentioned thickener to form a gel according to a standard method.

The aqueous composition is characterized in that the IPMP recovery rate in the recovery test is in the range of 90 to 110%. Preferably, the IPMP addition recovery rate is in the range of 95 to 105%. For pharmaceuticals or quasi-drugs, the spike recovery test is an important test to control and assure the quality of manufactured products. The IPMP addition recovery rate is defined as the amount of IPMP in the aqueous composition (product) obtained as a result of conducting a recovery test for IPMP on an aqueous composition (product) to which a known amount of IPMP has been added. , A percentage (%) of the known amount of IPMP added and blended in the production of the aqueous composition (product), and can be determined from the following equation.

[Equation 1]
IPMP addition recovery rate (%) = (amount of IPMP obtained as test result / known amount of added IPMP) × 100

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

Specifically, the present invention relates to a method for improving the recovery rate of IPMP for 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. And a step of preparing an aqueous composition by adding silicic acid anhydride in addition to the above. The types and proportions of IPMP, diol having 3 to 6 carbon atoms, silicic anhydride, and aqueous solvent added to and mixed with the aqueous composition are as described in (I) above, and are incorporated herein by reference. can do. Further, as described in (I), the target aqueous composition may contain other components. For example, as a component for increasing the solubility of IPMP in water, methylpolysiloxane is further added. May be blended. When the target aqueous composition has a gel (gel) shape, the above-mentioned thickener, gum, and the like can be added.

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

According to the method of the present invention, for an aqueous composition containing IPMP and a diol having 3 to 6 carbon atoms, the recovery rate of addition of IPMP is improved, and more preferably, it is determined as a quality standard for pharmaceuticals or quasi-drugs. It is possible to satisfy the required addition recovery rate (90 to 110%). The method of obtaining the recovery rate of addition of IPMP is as described in (I).

Whether or not the recovery rate of IPMP addition was improved by the method of the present invention is determined by comparing the recovery rate of IPMP addition and recovery of an aqueous composition containing IPMP and a diol having 3 to 6 carbon atoms with or without the addition of silicic anhydride. Can be implemented. 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 above test sample except that silicic anhydride was not added For the (control sample), the recovery rate of the IPMP addition was compared. When the recovery rate of the IPMP addition of the test sample became closer to the reference “100%” than the recovery rate of the IPMP addition of the control sample, the recovery rate of the IPMP addition was increased. It can be determined that it has improved. More preferably, by adding silicic anhydride, the recovery rate of the IPMP addition outside the range of 90 to 110% (less than 90% or more than 110%) is reduced to the range of 90 to 110%. In addition, when it is close to “100%” and falls within the range of 95 to 105%, it can be determined that the IPMP-containing recovery rate of the IPMP-containing aqueous composition has been improved by the addition of the silicic anhydride, and It can be provided as a product conforming to the quality of quasi-drugs.

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

The types and proportions of IPMP, diol having 3 to 6 carbon atoms, silicic anhydride, and aqueous solvent added to and mixed with the aqueous composition are as described in (I) above, and are incorporated herein by reference. can do. Further, as described in (I), the target aqueous composition may contain other components. For example, as a component for increasing the solubility of IPMP in water, methylpolysiloxane is further added. May be blended. When the target aqueous composition has a gel (gel) shape, the above-mentioned thickener, gum, and the like can be added.

According to the addition and recovery test method of the present invention, since the addition and recovery of IPMP is improved for the aqueous composition 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 as an IPMP-containing aqueous composition, particularly as a drug or a quasi-drug. The method of obtaining the recovery rate of addition of IPMP is as described in (I). The addition recovery test method performed on the IPMP-containing aqueous composition will be described in detail in Experimental Examples described later.

Hereinafter, the configuration and effects of the present invention will be described in detail with reference to examples, but the examples are only 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. Further, unless otherwise specified, production and experiments were performed under normal pressure (atmospheric pressure) and normal temperature (25 ° C.).

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

(1) Test method (1-1) Preparation of sample (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 having a purity (depending on the density) of 94.8 to 95.8 vol% (the same applies hereinafter).
(B) Preparation of Standard Solution About 40 mg of IPMP for quantification was precisely weighed, and ethanol (95) was added to make exactly 100 mL, which was used as a standard stock solution. 5 mL of this standard stock solution was accurately measured, and 5 mL of the internal standard solution was accurately added thereto, and ethanol (95) was added to make exactly 50 mL, which was used as a standard solution.
(C) Preparation of Sample Solution Each component described in Table 1 was weighed out at that ratio, and all components were dissolved by stirring and mixing to prepare test samples (Example 1, Comparative Example 1). The test sample was mixed well, accurately weighing about 2 g, accurately adding 5 mL of the internal standard solution, and adding ethanol (95) to make exactly 50 mL. This was irradiated with ultrasonic waves for 10 minutes, and filtered with a membrane filter (pore size: 0.45 μm, “ACRODISC 25 mm” manufactured by Pall Corporation) to obtain a sample solution.

(1-2) Quantitative method 20 μL of each of the sample solution and the standard solution was 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 substance for each of the sample solution and the standard solution. Were determined (Q _T , Q _S ).
Q _T: the ratio Q S of IPMP peak area to the peak area of the internal standard for the sample _solution: the ratio of the peak area of IPMP to the peak area of the internal standard for the standard solution

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

(B) Calculation of addition recovery rate From the HPLC analysis results obtained for the sample solution, the amount (quantitative value) of IPMP obtained as a test result was determined as the amount of IPMP contained in the sample solution. From the known amount (mixing value) added, the addition recovery rate was calculated according to the following formula.
[Equation 2]
IPMP addition recovery rate (%) = (quantitative value / mixing value) × 100
Specifically, the addition recovery rate (%) can be calculated by the following equation.
(Q _T / Q _S ) × (quantity of IPMP weighed for quantification (mg) / weighed amount of sample (g) / 400 / amount of IPMP in 100 g of formulation (0.1 g in Example 1) × 100

(2) Test results The results are shown in Table 1.
The case where the addition recovery rate is “less than 90% or more than 110%” is poor “×”, and the case where the addition recovery rate is “90% to more than 110%” is good “○”, and especially “95% to 105%”. ”Was determined as the best“ ◎ ”.

As shown in Table 1, the addition and recovery 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 the addition and recovery of IPMP was significantly improved by incorporating silicic anhydride into the aqueous composition (Example 1).

Experimental Example 2 Recovery test (Part 2)
An aqueous composition described in Table 2 (test sample: Examples 2 to 5 and Comparative Example 2, pH 6.6) was subjected to an addition recovery test in the same manner as in Experimental Example 1, and isopropyl methylphenol (IPMP ) Was analyzed (quantified). The results are shown in Table 2.

Similarly to Experimental Example 1, as shown in Table 2, the addition and recovery of IPMP in an aqueous composition containing no silicic anhydride was very poor, and it was difficult to accurately measure the content of IPMP in the aqueous composition. Failed (Comparative Example 2). However, it was confirmed that the addition and recovery of IPMP was significantly improved by adding silicic anhydride to the aqueous composition (Examples 2 to 5).

Example 6 Gel (pH 6.6)
Isopropyl methyl phenol 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
Heparin analogue 0.1
Tocopherol acetate 0.1
Carboxyvinyl polymer 0.7
Hydroxypropyl methylcellulose 0.5
(Dimethicone / vinyl dimethicone) Crosspolymer / Dimethicone 0.5
Polysorbate 80 2.0
Polyoxyethylene polyoxypropylene decyl tetradecyl ether 0.5
Disodium edetate 0.1
Methyl paraben 0.1
Citric acid qs Sodium citrate qs Sodium hydroxide qs
Purified water balance <Total 100.00%

Claims

(4) An aqueous composition containing isopropylmethylphenol, a diol having 3 to 6 carbon atoms, and silicic anhydride.
2. The aqueous composition according to claim 1, wherein the recovery of the addition of isopropylmethylphenol is in the range of 90 to 110%.
A method for improving the recovery of isopropylmethylphenol by adding to an aqueous composition containing isopropylmethylphenol and a diol having 3 to 6 carbon atoms, comprising the steps of: The method as described above, comprising the step of preparing an aqueous composition by mixing
The method according to claim 3, wherein the aqueous composition is a drug or a quasi-drug.
A test method for the addition and recovery of isopropylmethylphenol in an aqueous composition containing isopropylmethylphenol and a diol having 3 to 6 carbon atoms, wherein a test sample is added to a specified amount of isopropylmethylphenol and a diol having 3 to 6 carbon atoms. And using an aqueous composition containing silicic anhydride.
The method according to claim 5, wherein the aqueous composition is a drug or a quasi-drug.