WO2020004192A1 - Composition aqueuse contenant du méthylphénol d'isopropyle - Google Patents

Composition aqueuse contenant du méthylphénol d'isopropyle Download PDF

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Publication number
WO2020004192A1
WO2020004192A1 PCT/JP2019/024350 JP2019024350W WO2020004192A1 WO 2020004192 A1 WO2020004192 A1 WO 2020004192A1 JP 2019024350 W JP2019024350 W JP 2019024350W WO 2020004192 A1 WO2020004192 A1 WO 2020004192A1
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Prior art keywords
aqueous composition
ipmp
acid
addition
sodium
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Japanese (ja)
Inventor
正彦 小森園
信哉 宅見
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Kobayashi Pharmaceutical Co Ltd
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Kobayashi Pharmaceutical Co Ltd
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    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • 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.
  • IPMP Isopropyl methylphenol
  • bactericide an antibacterial agent
  • 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.
  • IPMP has extremely low solubility in water and high crystallinity, there is a problem that IPMP easily precipitates in an aqueous composition.
  • 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.
  • 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.
  • IPMP aqueous composition containing IPMP
  • a diol having 3 to 6 carbon atoms together with IPMP in order to enhance solubility in water, in pharmaceuticals and quasi-drugs.
  • 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.
  • IPMP-containing aqueous composition 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%.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 ⁇ m 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • vitamins; amino acids; high molecular compounds such as saccharides, gums, and polysaccharides; cellulose or derivatives thereof, or salts thereof can also be formulated.
  • 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.
  • 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 alkylphenylene
  • 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. .
  • ethylenediaminetetraacetic acid ethylenediaminetetraacetic acid
  • EDDA ethylenediaminediacetic acid
  • DTPA diethylenetriaminepentaacetic acid
  • HEDTA N- (2-hydroxyethyl) ethylenediaminetriacetic acid
  • HIDA N- (2-hydroxyethyl) iminodiacetic acid
  • 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, polyethylenei
  • 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.
  • a pharmacologically active component and a physiologically active component 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.
  • the moisturizing component examples 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; .
  • polyhydric alcohols other than C3-6 diols such as glycerin, polyethylene glycol and diglycerin trehalose; sodium hyaluronate, heparin-like substance, chondroitin sulfate, collagen, elastin,
  • 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- ⁇ -tocopherol nicotinate, benzyl nicotinate, methyl nicotinate, ⁇ -butoxyethyl nicotinate, 1- (4-methylphenyl) ethyl nicotinate; methyl hesperidin, ergocalciferol, kore Vitamin D such as calciferol; Vitamin K such as filoquinone and farnoquinone; ⁇ -oryzanol, dibenzoylthiamine, di
  • 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, ⁇ -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, ⁇ -aminobutyric acid, ⁇ -amino- ⁇ -hydroxy Butyric acid, ⁇ -aminovaleric acid, epsilon aminocaproic acid, carnitine, carnosine, creatine and the like.
  • betaine trimethylglycine
  • proline for example, betaine (trimethylglycine
  • arginine proline
  • Cell activating component for example, amino acids such as ⁇ -aminobutyric acid and ⁇ -aminoproic acid; vitamins such as retinol, thiamine, riboflavin, pyridoxine hydrochloride, pantothenic acids; ⁇ -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.
  • plants for example, Panax ginseng, Ashitaba, Arnica, Ginkgo, Fennel, Emmeso, Dutch oak, chamomile, Roman chamomile, Carrot, Gentian, burdock, Hawthorn, Shiitake, Seize,
  • 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 fuma
  • Decongestant For example, ⁇ -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, levof
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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%.
  • 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.
  • IPMP addition recovery rate (%) (amount of IPMP obtained as test result / known amount of added IPMP) ⁇ 100
  • the present invention also relates to a method for improving IPMP addition / recovery rate of an aqueous composition containing IPMP.
  • 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.
  • the target aqueous composition may contain other components.
  • methylpolysiloxane is further added. May be blended.
  • the target aqueous composition has a gel (gel) shape, the above-mentioned thickener, gum, and the like can be added.
  • 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).
  • 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.
  • the recovery rate of the IPMP addition was compared.
  • 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.
  • 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.
  • the target aqueous composition may contain other components.
  • methylpolysiloxane is further added. May be blended.
  • the target aqueous composition has a gel (gel) shape, the above-mentioned thickener, gum, and the like can be added.
  • 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).
  • 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.
  • % 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.).
  • 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.
  • 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
  • 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%

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Abstract

Le problème décrit par la présente invention est de fournir une composition aqueuse préparée de telle sorte que la quantité ajoutée de méthylphénol d'isopropyle peut être déterminée avec précision à un taux de récupération d'addition de 90 à 110 % pour le méthylphénol d'isopropyle dans un test de récupération d'addition. La solution selon l'invention porte sur une composition aqueuse qui contient du méthylphénol d'isopropyle, un diol ayant 3 à 6 atomes de carbone, et un silicate anhydre.
PCT/JP2019/024350 2018-06-28 2019-06-19 Composition aqueuse contenant du méthylphénol d'isopropyle Ceased WO2020004192A1 (fr)

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