WO2013035837A1 - Method for suppressing decrease in viscosity of aqueous liquid agent - Google Patents

Method for suppressing decrease in viscosity of aqueous liquid agent Download PDF

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Publication number
WO2013035837A1
WO2013035837A1 PCT/JP2012/072877 JP2012072877W WO2013035837A1 WO 2013035837 A1 WO2013035837 A1 WO 2013035837A1 JP 2012072877 W JP2012072877 W JP 2012072877W WO 2013035837 A1 WO2013035837 A1 WO 2013035837A1
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Prior art keywords
pharmaceutically acceptable
acceptable salt
acid
viscosity
pranoprofen
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PCT/JP2012/072877
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French (fr)
Japanese (ja)
Inventor
根本　夫規子
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千寿製薬株式会社
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Application filed by 千寿製薬株式会社 filed Critical 千寿製薬株式会社
Priority to RU2014113392/15A priority Critical patent/RU2598721C2/en
Priority to CN201280043160.3A priority patent/CN103796653B/en
Priority to JP2013532668A priority patent/JP6376550B2/en
Priority to KR1020147008749A priority patent/KR20140059276A/en
Publication of WO2013035837A1 publication Critical patent/WO2013035837A1/en

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • 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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention generally relates to suppression of viscosity reduction in an aqueous solution of a high molecular polysaccharide, and particularly relates to suppression of viscosity reduction in an aqueous liquid preparation containing hyaluronic acid or a pharmaceutically acceptable salt thereof.
  • Hyaluronic acid is a linear polymer polysaccharide composed of many DN-acetylglucosamine molecules and D-glucuronic acid molecules linked alternately.
  • An aqueous solution of hyaluronic acid or a salt thereof is widely used as an aqueous liquid agent for various applications because it has high viscosity and has water retention ability.
  • an aqueous solution containing hyaluronic acid or a salt thereof when adjusted to a pH close to neutral with a buffer solution, decreases in viscosity due to degradation of hyaluronic acid during long-term storage. There is a problem that the viscosity cannot be maintained for a long time.
  • Blending one kind (Patent Document 1), blending fat-soluble vitamins to suppress the degradation of hyaluronic acid (Patent Document 2), and containing gluconic acid or a metal salt thereof (Patent Document 3) )
  • Patent Document 1 blending one kind
  • Patent Document 2 blending fat-soluble vitamins to suppress the degradation of hyaluronic acid
  • Patent Document 3 containing gluconic acid or a metal salt thereof
  • the composition of the hyaluronic acid-containing aqueous liquid preparation may be subject to various restrictions depending on the application and application method. Therefore, these conventionally known methods are sufficient to meet the need for suppressing the decrease in viscosity over time. I can't do it.
  • a liquid external preparation containing pranoprofen can be obtained by adding mucopolysaccharides such as sodium chondroitin sulfate and hyaluronic acid to such liquid external preparations.
  • mucopolysaccharides such as sodium chondroitin sulfate and hyaluronic acid
  • hyaluronic acid is added to such an aqueous liquid composition. It is known to blend sodium (Patent Document 5), but there is no mention of the viscosity of the composition in each case.
  • an object of the present invention is to provide a new means for suppressing a decrease in viscosity over time in an aqueous liquid preparation containing hyaluronic acid or a pharmaceutically acceptable salt thereof.
  • the present inventor In the process of studying for the above-mentioned purpose, the present inventor accidentally took pranoprofen or a preparation thereof against the decrease in the viscosity of an aqueous solution containing hyaluronic acid or a pharmaceutically acceptable salt thereof over time.
  • the present inventors have found that a salt that is scientifically acceptable has an action to suppress this, and have further studied to complete the present invention. That is, the present invention provides the following.
  • a method for suppressing a decrease in the viscosity of an aqueous solution containing hyaluronic acid or a pharmaceutically acceptable salt thereof, and pranoprofen or a pharmaceutically acceptable salt thereof is added to the aqueous solution
  • Viscosity reduction inhibitor for aqueous solutions comprising pranoprofen or a pharmaceutically acceptable salt thereof, wherein the aqueous solution contains hyaluronic acid or a pharmaceutically acceptable salt thereof Viscosity reduction inhibitor that is a liquid agent.
  • the presence / absence and degree of “decrease in viscosity” of the aqueous liquid is determined by the dynamics after storage compared to the kinematic viscosity of the aqueous liquid before starting storage when the aqueous liquid is stored at 60 ° C. for 4 weeks. It is evaluated by a decrease in viscosity (measured at 20.0 ° C.).
  • the suppression of the viscosity decrease of an aqueous liquid preparation containing hyaluronic acid or a pharmaceutically acceptable salt thereof is compared with the viscosity retention rate after storage for a specific period of time in the specific conditions of the aqueous liquid preparation.
  • a predetermined inhibitory component planoprofen or a pharmaceutically acceptable salt thereof or edetic acid or a pharmaceutically acceptable salt thereof.
  • the phrase “contains hyaluronic acid or a pharmaceutically acceptable salt thereof” only includes hyaluronic acid or a pharmaceutically acceptable salt of hyaluronic acid. It includes the case of containing both hyaluronic acid and a pharmaceutically acceptable salt thereof simultaneously. The same applies when “planoprofen or a pharmaceutically acceptable salt thereof is added” and “edetic acid or a pharmaceutically acceptable salt thereof is further added”.
  • the concentration of hyaluronic acid or a pharmacologically acceptable salt thereof in an aqueous solution intended to suppress viscosity reduction according to the present invention has no clear upper limit or lower limit, but is preferably 0.001 to 1.0 w / v%. This is because when the concentration of hyaluronic acid or a pharmaceutically acceptable salt thereof is lower than 0.001 w / v%, the resulting viscosity is inherently low, and viscosity is important in such aqueous solutions. This is because it has no technical meaning, and when it is higher than 1.0 w / v%, the aqueous solution becomes so viscous that it is difficult to produce, and such a drug is not practical.
  • the concentration of hyaluronic acid or a pharmaceutically acceptable salt thereof in the aqueous liquid is more preferably 0.002 to 0.5 w / v%, still more preferably 0.005 to 0.5 w / v%, More preferably, it is 0.005 to 0.3 w / v%, particularly preferably 0.02 to 0.3 w / v%, and particularly preferably 0.01 to 0.3 w / v%.
  • the molecular weight of hyaluronic acid is not particularly limited. Currently, those having a weight average molecular weight of about 400,000 to 4 million are available, and the present invention is used to suppress the decrease in viscosity of an aqueous solution containing these hyaluronic acid or a pharmaceutically acceptable salt thereof. can do.
  • sodium salt is particularly preferable as a pharmaceutically acceptable salt of hyaluronic acid, but is not limited thereto, and other examples include potassium salt, calcium salt, and magnesium salt. As mentioned.
  • concentration or “part by weight” for hyaluronic acid or a pharmacologically acceptable salt thereof is an aqueous solution containing both hyaluronic acid and a pharmaceutically acceptable salt thereof. Refers to the “concentration” or “part by weight” of hyaluronic acid and its pharmaceutically acceptable salt in total.
  • Planoprofen (chemical name: (2RS) -2- (10H-9-Oxa-1-azaanthracen-6-yl) propanoic (2RS) -2- (10H-9-oxa-1-azaanthracen-6-yl) propanoic acid) or a pharmaceutically acceptable salt thereof is a non-steroidal anti-inflammatory drug with a wide safety range .
  • pharmaceutically acceptable salts of pranoprofen include, but are not limited to, sodium and potassium salts.
  • pranoprofen and a pharmaceutically acceptable salt thereof function as an inhibitor against a decrease in viscosity over time in an aqueous liquid preparation containing hyaluronic acid or a pharmaceutically acceptable salt thereof.
  • concentration of pranoprofen or a pharmaceutically acceptable salt thereof in the aqueous liquid can be set as appropriate, but is preferably 0.001 to 1.0 w / v%. Usually, when it is higher than 1.0 w / v%, it is difficult to produce the preparation, and when it is lower than 0.001 w / v%, a sufficient viscosity stabilizing effect is not recognized.
  • the concentration of pranoprofen or a pharmaceutically acceptable salt thereof in the aqueous liquid is more preferably 0.005 to 0.5 w / v%, still more preferably 0.05 to 0.1 w / v% .
  • pranoprofen is particularly preferred.
  • concentration or “part by weight” for pranoprofen or its pharmacologically acceptable salt refers to the case where both pranoprofen and its pharmaceutically acceptable salt are formulated. “Concentration” or “parts by weight” in the sum of pranoprofen and its pharmaceutically acceptable salt.
  • edetic acid also referred to as ethylenediaminetetraacetic acid
  • a pharmaceutically acceptable salt thereof When edetic acid (also referred to as ethylenediaminetetraacetic acid) or a pharmaceutically acceptable salt thereof is used in combination with pranoprofen or a pharmaceutically acceptable salt thereof, the effect of suppressing the decrease in viscosity in the case of pranoprofen alone is exhibited.
  • edetic acid or a pharmaceutically acceptable salt thereof include, but are not limited to, sodium salt and potassium salt. Particularly preferred is the sodium salt of edetic acid.
  • Edetic acid forms a salt with 1 to 4 sodium ions. Any salt can be used as long as the pH of the aqueous solution is adjusted to a desired level, but disodium edetate is preferred in terms of handling convenience.
  • edetic acid or a pharmaceutically acceptable salt thereof has a viscosity reduction inhibitory effect exhibited by pranoprofen in a state where it is blended with hyaluronic acid or a pharmaceutically acceptable salt thereof together with pranoprofen.
  • the concentration of edetic acid or a pharmaceutically acceptable salt thereof in the aqueous liquid can be appropriately set, but is preferably 0.0005 to 0.3 w / v%, more preferably 0. It is 001 to 0.2 w / v%, more preferably 0.002 to 0.1 w / v%, particularly preferably 0.005 to 0.08 w / v%.
  • pranoprofen or a pharmaceutically acceptable salt thereof is preferably added in an amount of 0.05 to 1 part by weight of hyaluronic acid or a pharmaceutically acceptable salt thereof in an aqueous solution.
  • the mixing ratio may be 25 parts by weight, more preferably 0.1 to 20 parts by weight, still more preferably 0.15 to 10 parts by weight, and particularly preferably 0.17 to 5 parts by weight.
  • the formulation of edetic acid or a pharmaceutically acceptable salt thereof is preferably 0.01 to 16 with respect to 1 part by weight of hyaluronic acid or a pharmaceutically acceptable salt thereof in an aqueous solution. It may be carried out at a blending ratio of parts by weight, more preferably 0.02 to 10 parts by weight, still more preferably 0.03 to 0.5 parts by weight.
  • the aqueous liquid preparation of the present invention may be other than buffers, pH adjusters, tonicity agents, solubilizers, preservatives, viscous bases, edetic acid or salts thereof, as desired. Additives widely used in chelating agents, cooling agents and other aqueous liquids may be further blended.
  • buffer examples include, but are not limited to, phosphate buffer, borate buffer, citrate buffer, tartaric acid buffer, acetate buffer and amino acids.
  • pH regulators include hydrochloric acid, boric acid, aminoethylsulfonic acid, epsilon-aminocaproic acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, sodium carbonate , Borax, triethanolamine, monoethanolamine, diisopropanolamine, sulfuric acid, phosphoric acid, polyphosphoric acid, propionic acid, oxalic acid, gluconic acid, fumaric acid, lactic acid, tartaric acid, malic acid, succinic acid, gluconolactone, Although ammonium acetate etc. are mentioned, it is not limited to these.
  • isotonic agents include sugars such as sorbitol, glucose, mannitol, cyclodextrin, polyhydric alcohols such as glycerin, propylene glycol, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, Examples include 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, and boric acid. It is not limited to these.
  • solubilizers include polyoxyethylene sorbitan monooleate, polyoxyethylene hydrogenated castor oil, nonionic surfactants such as tyloxapol and pluronic, and polyhydric alcohols such as glycerol and macrogol. It is not limited to.
  • preservatives include quaternary ammonium salts such as alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, methyl paraoxybenzoate, ethyl paraoxybenzoate, paraoxybenzoate
  • quaternary ammonium salts such as alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, methyl paraoxybenzoate, ethyl paraoxybenzoate, paraoxybenzoate
  • paraoxybenzoates such as propyl acid and butyl paraoxybenzoate, benzyl alcohol, phenethyl alcohol, sorbic acid, thimerosal, chlorobutanol, and sodium dehydroacetate.
  • viscous bases examples include water-soluble polymers such as polyvinylpyrrolidone, polyethylene glycol, and polyvinyl alcohol, and celluloses such as hydroxyethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, and sodium carboxymethylcellulose. It is not limited.
  • chelating agents other than edetic acid or its salts include citric acid, polyphosphoric acid, hexametaphosphoric acid, metaphosphoric acid, ascorbic acid, succinic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1-hydroxyethane-1,1- Examples include, but are not limited to, diphosphonic acid and the like, and pharmaceutically acceptable salts thereof.
  • cooling agents include, but are not limited to, l-menthol, borneol, camphor, and eucalyptus oil.
  • the aqueous liquid further includes a vasoconstrictor such as naphazoline and its salts (hydrochloride, nitrate), tetrahydrozoline hydrochloride, phenylephrine hydrochloride, epinephrine and its hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride; glycyrrhizin Anti-inflammatory agents such as dipotassium acid, allantoin, and ⁇ -aminocaproic acid; vitamins; amino acids; anticholinesterase agents such as neostigmine methylsulfate, and the like may be included.
  • a vasoconstrictor such as naphazoline and its salts (hydrochloride, nitrate), tetrahydrozoline hydrochloride, phenylephrine hydrochloride, epinephrine and its hydrochloride, ephedrine hydrochloride, methylep
  • vitamins include vitamins such as retinal, retinol, retinoic acid, carotene, dehydroretinal, lycopene, thiamine, thiamine disulfide, dicetiamine, octothiamine, chicotiamine, bisbutiamine, bisbenchamine, prosultiamine, Benfotiamine, fursultiamine, riboflavin, flavin adenine dinucleotide, pyridoxine, pyridoxine hydrochloride, pyridoxal, hydroxocobalamin, cyanocobalamin, methylcobalamin, deoxyadenocobalamin, folate, tetrahydrofolate, dihydrofolate, nicotinic acid, nicotinamide, nicoti Nickel alcohol, pantothenic acid, panthenol, biotin, choline, inositol and other vitamin Bs, ascorbic acid and its derivatives, Vitamin Cs
  • amino acids examples include leucine, isoleucine, valine, methionine, threonine, alanine, phenylalanine, tryptophan, lysine, glycine, asparagine, aspartic acid, serine, glutamine, glutamic acid, proline, tyrosine, cysteine, histidine, ornithine, hydroxyproline , Hydroxylysine, glycylglycine, and aminoethylsulfonic acid (taurine), but are not limited thereto.
  • the pH of the aqueous liquid preparation is not particularly limited as long as it is within the range acceptable for the biological site intended for administration, but it is usually 4.5 to 9.0, preferably 6.0 to It is 8.0, more preferably 7.0 to 8.0.
  • pranoprofen is pranoprofen (Pharmacopoeia) manufactured by API Corporation
  • edetate disodium hydrate is sodium edetate hydrate manufactured by Kanto Chemical Co., Ltd. Each thing (the pharmacopoeia) was used.
  • aqueous solutions containing sodium hyaluronate (weight average molecular weight 1,040,000, Seikagaku Corporation) were prepared.
  • the pH of each aqueous solution was 7.5.
  • Each aqueous solution was dispensed and sealed in a 15 mL polyethylene terephthalate (PET, grade RT543) container, and stored at 60 ° C. for 4 weeks.
  • PET polyethylene terephthalate
  • the viscosity (kinematic viscosity) of each aqueous solution was determined according to the “Viscosity Measurement Method ⁇ 2.53>, Method 1 Capillary Viscometer Method” of the General Test Method of Japan (Fifteenth Revision).
  • Viscosity retention (%) (kinematic viscosity after storage-1) / (kinematic viscosity before storage-1) ⁇ 100
  • Viscosity reduction inhibitory effect by pranoprofen As seen in Table 1, compared with pranoprofen-free aqueous solution containing sodium hyaluronate in Formula 3, pranoprofen was added to pranoprofen at 0.05 and 0.1 w / v, respectively. In the aqueous liquid preparations of Formulations 1 and 2, which correspond to those formulated with%, the decrease in viscosity over time was remarkably suppressed.
  • Viscosity reduction inhibitory effect by pranoprofen and sodium salt of edetic acid As shown in Table 2 below, preparation of aqueous solutions of formulations 4 and 5 corresponding to formulations 1 and 2 further blended with sodium salt of edetic acid And stored at 60 ° C. for 4 weeks, and the viscosity retention was compared. As a result, it was found that the combined use of sodium edetic acid made the suppression of viscosity decrease even more remarkable.
  • Formulas 4 and 5 corresponding to those with the addition of 0.01% w / v of Japanese show a high viscosity retention because the combination of pranoprofen and sodium salt of edetic acid has some synergistic effect. This is probably due to the fact that it occurred.
  • Viscosity reduction inhibitory effect at various sodium hyaluronate concentrations According to the formulations shown in Tables 4 to 6 below, an aqueous solution in which the concentration of sodium hyaluronate was changed, an aqueous solution containing pranoprofen, and a plano Aqueous solutions containing prophene and disodium edetate hydrate were prepared and stored at 60 ° C. for 4 weeks, and the viscosity retention was compared.
  • the viscosity retention of the aqueous solutions of formulations 15 and 16 was substantially the same as the viscosity retention of the aqueous solutions of formulations 1 and 4, and the change from borate buffer to phosphate buffer was Neither the effect of pranoprofen alone, the combination of pranoprofen and sodium edetate, or the sodium salt of edetic acid alone had any substantial effect on the viscosity-inhibiting effect.
  • Table 8 shows the measurement results of the viscosity retention with and without pranoprofen in aqueous liquids containing sodium hyaluronate at concentrations of 0.001, 0.002, or 0.005 w / v%.
  • the viscosity retention of the aqueous liquid formulation containing pranoprofen is remarkably higher than that without pranoprofen.
  • the present invention is useful as a new means for suppressing a decrease in viscosity over time in an aqueous liquid preparation containing hyaluronic acid or a pharmaceutically acceptable salt thereof.

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Abstract

Disclosed is a novel means for suppressing decrease over time in the viscosity of an aqueous liquid agent which contains hyaluronic acid or a pharmaceutically acceptable salt thereof. The means includes a method for suppressing decrease in the viscosity of an aqueous liquid agent which contains hyaluronic acid or a pharmaceutically acceptable salt thereof, and this method is characterized by blending pranoprofen or a pharmaceutically acceptable salt thereof into the aqueous liquid agent.

Description

水性液剤の粘度低下抑制方法Method for inhibiting viscosity reduction of aqueous liquid preparation
　本発明は，一般的には高分子多糖類の水溶液における粘性低下の抑制に関し，特に，ヒアルロン酸又はその薬剤学的に許容し得る塩を含有する水性液剤における粘度低下の抑制に関する。 The present invention generally relates to suppression of viscosity reduction in an aqueous solution of a high molecular polysaccharide, and particularly relates to suppression of viscosity reduction in an aqueous liquid preparation containing hyaluronic acid or a pharmaceutically acceptable salt thereof.
　ヒアルロン酸は，Ｄ－Ｎ－アセチルグルコサミン分子とＤ－グルクロン酸分子が交互に多数結合して構成された，直鎖状の高分子多糖である。ヒアルロン酸又はその塩の水溶液は，高い粘性を有しており，保水力もあること等から，種々の用途の水性液剤に広く用いられている。しかしながら，ヒアルロン酸又はその塩を含有する水溶液は，緩衝液で中性付近のｐＨに調整された場合，長期間の保存中にヒアルロン酸が分解される等の理由で粘度が低下することが知られており，粘度を長期間維持できないという問題があった。 Hyaluronic acid is a linear polymer polysaccharide composed of many DN-acetylglucosamine molecules and D-glucuronic acid molecules linked alternately. An aqueous solution of hyaluronic acid or a salt thereof is widely used as an aqueous liquid agent for various applications because it has high viscosity and has water retention ability. However, it is known that an aqueous solution containing hyaluronic acid or a salt thereof, when adjusted to a pH close to neutral with a buffer solution, decreases in viscosity due to degradation of hyaluronic acid during long-term storage. There is a problem that the viscosity cannot be maintained for a long time.
　ヒアルロン酸含有水性液剤の粘度の経時的低下を抑制する方法としては，そのような水性液剤に，粘度安定化剤としてポリオール，ポリカルボン酸，ポリカルボン酸塩及び糖質よりなる群から選ばれる少なくとも１種を配合すること（特許文献１），ヒアルロン酸の分解を抑制するために脂溶性ビタミン類を配合すること（特許文献２），及びグルコン酸又はその金属塩を含有させること（特許文献３）が，それぞれ知られている。しかしながら，用途や適用方法等によっては，ヒアルロン酸含有水性液剤の組成に様々な制約がかかり得るため，これら従来知られている方法のみでは，粘度の経時的低下の抑制という必要性には十分対応し切れない。 As a method for suppressing the time-dependent decrease in the viscosity of the hyaluronic acid-containing aqueous solution, at least selected from the group consisting of polyols, polycarboxylic acids, polycarboxylates and sugars as viscosity stabilizers in such aqueous solutions. Blending one kind (Patent Document 1), blending fat-soluble vitamins to suppress the degradation of hyaluronic acid (Patent Document 2), and containing gluconic acid or a metal salt thereof (Patent Document 3) ) Are known. However, the composition of the hyaluronic acid-containing aqueous liquid preparation may be subject to various restrictions depending on the application and application method. Therefore, these conventionally known methods are sufficient to meet the need for suppressing the decrease in viscosity over time. I can't do it.
　他方，プラノプロフェン含有の液状外用剤により眼部や鼻腔内等の患部に出現する痛みと痒みが，コンドロイチン硫酸ナトリウムやヒアルロン酸等のムコ多糖類をそのような液状外用剤に配合することで軽減できること（特許文献４），及びプラノプロフェン等種々の薬物について，これを含有する水性液状組成物の長期保存時における異物の析出を防止するために，そのような水性液状組成物にヒアルロン酸ナトリウムを配合すること（特許文献５）が知られているが，それぞれの場合について，組成物の粘度に関する言及はない。 On the other hand, pain and itching appearing in affected areas such as the eye and nasal cavity due to a liquid external preparation containing pranoprofen can be obtained by adding mucopolysaccharides such as sodium chondroitin sulfate and hyaluronic acid to such liquid external preparations. In order to prevent the precipitation of foreign substances during long-term storage of an aqueous liquid composition containing various drugs such as pranoprofen, which can be reduced (Patent Document 4), hyaluronic acid is added to such an aqueous liquid composition. It is known to blend sodium (Patent Document 5), but there is no mention of the viscosity of the composition in each case.
特開平１０－０７２３７６号公報Japanese Patent Laid-Open No. 10-072376 特開２００４－３５９６２９号公報JP 2004-359629 A 国際公開第２００８／０５０７７６号パンフレットInternational Publication No. 2008/050776 Pamphlet 特開２００５－２８９８９９号公報JP 2005-289899 A 特開２０１０－１３２６０８号公報JP 2010-132608 A
　上記の背景において，本発明の目的は，ヒアルロン酸又はその薬剤学的に許容し得る塩を含有する水性液剤における粘度の経時的低下を抑制するための新たな手段を提供することである。 In the above background, an object of the present invention is to provide a new means for suppressing a decrease in viscosity over time in an aqueous liquid preparation containing hyaluronic acid or a pharmaceutically acceptable salt thereof.
　上記目的に向けた検討の過程で，本発明者は偶然にも，ヒアルロン酸又はその薬剤学的に許容し得る塩を含有する水性液剤の粘度の経時的低下に対し，プラノプロフェン又はその製剤学的に許容し得る塩にこれを抑制する作用があることを見出し，更に検討を重ねて本発明を完成させた。すなわち，本発明は以下を提供するものである。 In the process of studying for the above-mentioned purpose, the present inventor accidentally took pranoprofen or a preparation thereof against the decrease in the viscosity of an aqueous solution containing hyaluronic acid or a pharmaceutically acceptable salt thereof over time. The present inventors have found that a salt that is scientifically acceptable has an action to suppress this, and have further studied to complete the present invention. That is, the present invention provides the following.
　（１）ヒアルロン酸又はその薬剤学的に許容し得る塩を含有する水性液剤の粘度低下を抑制する方法であって，該水性液剤にプラノプロフェン又はその薬剤学的に許容し得る塩を配合することを特徴とする方法。
　（２）ヒアルロン酸の薬剤学的に許容し得る塩がヒアルロン酸ナトリウムである，上記１の方法。
　（３）該水性液剤にエデト酸又はその薬剤学的に許容し得る塩を更に配合することを特徴とする，上記１又は２の方法。
　（４）エデト酸の薬剤学的に許容し得る塩がエデト酸のナトリウム塩である，上記３の方法。
　（５）該水性液剤におけるヒアルロン酸又はその薬剤学的に許容し得る塩の濃度が０．００１～１．０ｗ／ｖ％である，上記１ないし４の何れかの方法。
　（６）プラノプロフェン又はその薬剤学的に許容し得る塩の配合が，該水性液剤におけるプラノプロフェン又はその薬剤学的に許容し得る塩の濃度が０．００１～１．０ｗ／ｖ％となるように行われるものである，上記１ないし５の何れかの方法。
　（７）プラノプロフェン又はその薬剤学的に許容し得る塩の配合が，ヒアルロン酸又はその薬剤学的に許容し得る塩の１重量部に対して０．０５～２５重量部の配合比で行われるものである，上記１ないし６の何れかの方法。
　（８）該水性液剤が点眼剤である，上記１ないし７の何れかの方法。
　（９）水性液剤用粘度低下抑制剤であって，プラノプロフェン又はその薬剤学的に許容し得る塩からなり，該水性液剤がヒアルロン酸又はその薬剤学的に許容し得る塩を含有する水性液剤である，粘度低下抑制剤。 (1) A method for suppressing a decrease in the viscosity of an aqueous solution containing hyaluronic acid or a pharmaceutically acceptable salt thereof, and pranoprofen or a pharmaceutically acceptable salt thereof is added to the aqueous solution A method characterized by:
(2) The method according to 1 above, wherein the pharmaceutically acceptable salt of hyaluronic acid is sodium hyaluronate.
(3) The method according to 1 or 2 above, wherein edetic acid or a pharmaceutically acceptable salt thereof is further added to the aqueous liquid preparation.
(4) The method according to 3 above, wherein the pharmaceutically acceptable salt of edetic acid is sodium salt of edetic acid.
(5) The method according to any one of 1 to 4 above, wherein the concentration of hyaluronic acid or a pharmaceutically acceptable salt thereof in the aqueous liquid is 0.001 to 1.0 w / v%.
(6) The formulation of pranoprofen or a pharmaceutically acceptable salt thereof is such that the concentration of pranoprofen or a pharmaceutically acceptable salt thereof in the aqueous liquid is 0.001 to 1.0 w / v%. The method according to any one of 1 to 5 above, which is carried out so that
(7) The compounding ratio of pranoprofen or a pharmaceutically acceptable salt thereof is 0.05 to 25 parts by weight with respect to 1 part by weight of hyaluronic acid or a pharmaceutically acceptable salt thereof. The method according to any one of 1 to 6 above, which is performed.
(8) The method according to any one of 1 to 7 above, wherein the aqueous liquid preparation is an eye drop.
(9) Viscosity reduction inhibitor for aqueous solutions, comprising pranoprofen or a pharmaceutically acceptable salt thereof, wherein the aqueous solution contains hyaluronic acid or a pharmaceutically acceptable salt thereof Viscosity reduction inhibitor that is a liquid agent.
　上記構成になる本発明によれば，ヒアルロン酸又はその薬剤学的に許容し得る塩を含有する水性液剤の経時的な粘度低下を抑制して長期間の保存でも粘度を安定に維持するための，新たな手段を提供することができる。 According to the present invention having the above-described configuration, it is possible to stably maintain the viscosity even during long-term storage by suppressing the decrease in viscosity over time of the aqueous liquid preparation containing hyaluronic acid or a pharmaceutically acceptable salt thereof. , Can provide new means.
　なお本発明において，水性液剤の「粘度の低下」の有無及び程度は，水性液剤を６０℃で４週間静置保存した場合における，保存開始前の水性液剤の動粘度と比較した保存後の動粘度（２０．０℃にて測定）の低下により評価される。 In the present invention, the presence / absence and degree of “decrease in viscosity” of the aqueous liquid is determined by the dynamics after storage compared to the kinematic viscosity of the aqueous liquid before starting storage when the aqueous liquid is stored at 60 ° C. for 4 weeks. It is evaluated by a decrease in viscosity (measured at 20.0 ° C.).
　本発明において，ヒアルロン酸又はその薬剤学的に許容し得る塩を含有する水性液剤の粘度低下の抑制は，当該水性液剤の特定条件での特定期間保存後の粘度保持率に比して，これに所定の抑制成分（プラノプロフェン若しくはその薬剤学的に許容し得る塩又はこれに加えエデト酸若しくはその薬剤学的に許容し得る塩）を更に配合してなる水性液剤の同一条件での同一期間の保存後の粘度保持率の方が高いことにより確認される。ここに，粘度保持率は，次式で規定される値である。
　粘度保持率（％）＝（保存後の動粘度－１）／（保存前の動粘度－１）×１００ In the present invention, the suppression of the viscosity decrease of an aqueous liquid preparation containing hyaluronic acid or a pharmaceutically acceptable salt thereof is compared with the viscosity retention rate after storage for a specific period of time in the specific conditions of the aqueous liquid preparation. The same under the same conditions of an aqueous liquid preparation further comprising a predetermined inhibitory component (planoprofen or a pharmaceutically acceptable salt thereof or edetic acid or a pharmaceutically acceptable salt thereof) This is confirmed by the higher viscosity retention after storage of the period. Here, the viscosity retention is a value defined by the following equation.
Viscosity retention (%) = (kinematic viscosity after storage-1) / (kinematic viscosity before storage-1) × 100
　本発明において，「ヒアルロン酸又はその薬剤学的に許容し得る塩を含有する」というときは，ヒアルロン酸又はヒアルロン酸の薬剤学的に許容し得る塩の何れか一方のみを含有する場合のみならず，ヒアルロン酸及びその薬剤学的に許容し得る塩の双方を同時に含有する場合を包含する。「プラノプロフェン又はその薬剤学的に許容し得る塩を配合」，及び「エデト酸又はその薬剤学的に許容し得る塩を更に配合」というときも同様である。 In the present invention, the phrase “contains hyaluronic acid or a pharmaceutically acceptable salt thereof” only includes hyaluronic acid or a pharmaceutically acceptable salt of hyaluronic acid. It includes the case of containing both hyaluronic acid and a pharmaceutically acceptable salt thereof simultaneously. The same applies when “planoprofen or a pharmaceutically acceptable salt thereof is added” and “edetic acid or a pharmaceutically acceptable salt thereof is further added”.
　本発明により粘度低下を抑制しようとする水性液剤中のヒアルロン酸又はその薬理学的に許容し得る塩の濃度には，明確な上限や下限はないが，好ましくは０．００１～１．０ｗ／ｖ％である。これは，ヒアルロン酸又はその薬剤学的に許容し得る塩の濃度が０．００１ｗ／ｖ％より低いときはそれにより得られる粘度がもともと僅かであり，そのような水性液剤においては粘度が重要な技術的意味を持たないこと，及び１．０ｗ／ｖ％より高いときは水性液剤が製造困難な程に高粘度となり，そのような薬剤は実用性に乏しいことによる。水性液剤中のヒアルロン酸又はその薬剤学的に許容し得る塩の濃度は，より好ましくは０．００２～０．５ｗ／ｖ％，更に好ましくは０．００５～０．５ｗ／ｖ％，なおも更に好ましくは０．００５～０．３ｗ／ｖ％，特に好ましくは０．０２～０．３ｗ／ｖ％，取り分け好ましくは０．０１～０．３ｗ／ｖ％である。 The concentration of hyaluronic acid or a pharmacologically acceptable salt thereof in an aqueous solution intended to suppress viscosity reduction according to the present invention has no clear upper limit or lower limit, but is preferably 0.001 to 1.0 w / v%. This is because when the concentration of hyaluronic acid or a pharmaceutically acceptable salt thereof is lower than 0.001 w / v%, the resulting viscosity is inherently low, and viscosity is important in such aqueous solutions. This is because it has no technical meaning, and when it is higher than 1.0 w / v%, the aqueous solution becomes so viscous that it is difficult to produce, and such a drug is not practical. The concentration of hyaluronic acid or a pharmaceutically acceptable salt thereof in the aqueous liquid is more preferably 0.002 to 0.5 w / v%, still more preferably 0.005 to 0.5 w / v%, More preferably, it is 0.005 to 0.3 w / v%, particularly preferably 0.02 to 0.3 w / v%, and particularly preferably 0.01 to 0.3 w / v%.
　本発明において，ヒアルロン酸の分子量については特に限定はない。現在，重量平均分子量がおよそ４０万～４００万のものが入手可能であり，本発明は，これらのヒアルロン酸又はその薬剤学的に許容し得る塩を含有する水性液剤の粘度低下の抑制に使用することができる。 In the present invention, the molecular weight of hyaluronic acid is not particularly limited. Currently, those having a weight average molecular weight of about 400,000 to 4 million are available, and the present invention is used to suppress the decrease in viscosity of an aqueous solution containing these hyaluronic acid or a pharmaceutically acceptable salt thereof. can do.
　本発明において，ヒアルロン酸の薬剤学的に許容し得る塩として特に好ましいのはナトリウム塩であるが，これに限定されず，他にも，例えば，カリウム塩，カルシウム塩，マグネシウム塩が，好ましい塩として挙げられる。 In the present invention, sodium salt is particularly preferable as a pharmaceutically acceptable salt of hyaluronic acid, but is not limited thereto, and other examples include potassium salt, calcium salt, and magnesium salt. As mentioned.
　なお，本発明において，ヒアルロン酸又はその薬理学的に許容し得る塩について「濃度」又は「重量部」というときは，ヒアルロン酸とその薬剤学的に許容し得る塩の双方を含有する水性液剤については，ヒアルロン酸とその薬剤学的に許容し得る塩との合計での「濃度」又は「重量部」をいう。 In the present invention, the term “concentration” or “part by weight” for hyaluronic acid or a pharmacologically acceptable salt thereof is an aqueous solution containing both hyaluronic acid and a pharmaceutically acceptable salt thereof. Refers to the “concentration” or “part by weight” of hyaluronic acid and its pharmaceutically acceptable salt in total.
　プラノプロフェン（化学名：(2RS)-2-(10H-9-Oxa-1-azaanthracen-6-yl)propanoic
acid；(2RS)-2-(10H-9-オキサ-1-アザアントラセン-6-イル)プロパン酸）又はその薬剤学的に許容し得る塩は，安全域の広い非ステロイド抗炎症薬である。プラノプロフェンの薬剤学的に許容される塩の例としては，ナトリウム塩及びカリウム塩が挙げられるが，これらに限定されない。 Planoprofen (chemical name: (2RS) -2- (10H-9-Oxa-1-azaanthracen-6-yl) propanoic
(2RS) -2- (10H-9-oxa-1-azaanthracen-6-yl) propanoic acid) or a pharmaceutically acceptable salt thereof is a non-steroidal anti-inflammatory drug with a wide safety range . Examples of pharmaceutically acceptable salts of pranoprofen include, but are not limited to, sodium and potassium salts.
　本発明において，プラノプロフェン及びその薬剤学的に許容し得る塩は，ヒアルロン酸又はその薬剤学的に許容し得る塩を含有する水性液剤における経時的な粘度低下に対する抑制剤として機能する。水性液剤中のプラノプロフェン又はその薬剤学的に許容し得る塩の濃度は適宜設定することができるが，好ましくは０．００１～１．０ｗ／ｖ％である。通常，１．０ｗ／ｖ％より高いと製剤の製造が困難であり，０．００１ｗ／ｖ％より低いと十分な粘度安定化効果が認められないためである。水性液剤中のプラノプロフェン又はその薬剤学的に許容し得る塩の濃度は，より好ましくは０．００５～０．５ｗ／ｖ％，更に好ましくは０．０５～０．１ｗ／ｖ％である。また，プラノプロフェン又はその薬剤学的に許容し得る塩のうち，特に好ましいのはプラノプロフェンである。 In the present invention, pranoprofen and a pharmaceutically acceptable salt thereof function as an inhibitor against a decrease in viscosity over time in an aqueous liquid preparation containing hyaluronic acid or a pharmaceutically acceptable salt thereof. The concentration of pranoprofen or a pharmaceutically acceptable salt thereof in the aqueous liquid can be set as appropriate, but is preferably 0.001 to 1.0 w / v%. Usually, when it is higher than 1.0 w / v%, it is difficult to produce the preparation, and when it is lower than 0.001 w / v%, a sufficient viscosity stabilizing effect is not recognized. The concentration of pranoprofen or a pharmaceutically acceptable salt thereof in the aqueous liquid is more preferably 0.005 to 0.5 w / v%, still more preferably 0.05 to 0.1 w / v% . Of the pranoprofen and pharmaceutically acceptable salts thereof, pranoprofen is particularly preferred.
　なお，プラノプロフェン又はその薬理学的に許容し得る塩について「濃度」又は「重量部」というときは，プラノプロフェンとその薬剤学的に許容し得る塩の双方を配合する場合については，プラノプロフェンとその薬剤学的に許容し得る塩との合計での「濃度」又は「重量部」をいう。 The term “concentration” or “part by weight” for pranoprofen or its pharmacologically acceptable salt refers to the case where both pranoprofen and its pharmaceutically acceptable salt are formulated. “Concentration” or “parts by weight” in the sum of pranoprofen and its pharmaceutically acceptable salt.
　エデト酸（エチレンジアミン四酢酸ともいう）又はその薬剤学的に許容し得る塩は，プラノプロフェン又はその薬剤学的に許容し得る塩と併用すると，プラノプロフェン単独の場合の粘度低下抑制効果を更に増強することを，本発明者は見出した。エデト酸又はその薬剤学的に許容し得る塩の例としては，ナトリウム塩及びカリウム塩が挙げられるが，これらに限定されない。特に好ましいのは，エデト酸のナトリウム塩である。エデト酸は１～４個のナトリウムイオンとの塩を形成する。水性液剤のｐＨを所望のレベルに調整する限り，何れの塩も使用できるが，エデト酸二ナトリウムが，取り扱いの便という点で好ましい。なお，エデト酸又はその薬剤学的に許容し得る塩は，プラノプロフェンと共にヒアルロン酸又はその薬剤学的に許容し得る塩に配合されている状態で，プラノプロフェンが奏する粘度低下抑制効果を更に増強するように作用するものであることから，本発明において，これら各成分をどのような順序で配合して水性液剤とするかは問わない。 When edetic acid (also referred to as ethylenediaminetetraacetic acid) or a pharmaceutically acceptable salt thereof is used in combination with pranoprofen or a pharmaceutically acceptable salt thereof, the effect of suppressing the decrease in viscosity in the case of pranoprofen alone is exhibited. The inventor has found further enhancement. Examples of edetic acid or a pharmaceutically acceptable salt thereof include, but are not limited to, sodium salt and potassium salt. Particularly preferred is the sodium salt of edetic acid. Edetic acid forms a salt with 1 to 4 sodium ions. Any salt can be used as long as the pH of the aqueous solution is adjusted to a desired level, but disodium edetate is preferred in terms of handling convenience. It should be noted that edetic acid or a pharmaceutically acceptable salt thereof has a viscosity reduction inhibitory effect exhibited by pranoprofen in a state where it is blended with hyaluronic acid or a pharmaceutically acceptable salt thereof together with pranoprofen. In this invention, it does not ask | require what order these ingredients are mix | blended in order to make an aqueous liquid agent.
　本発明において，水性液剤中のエデト酸又はその薬剤学的に許容し得る塩の濃度は適宜設定することができるが，好ましくは，０．０００５～０．３ｗ／ｖ％，より好ましくは０．００１～０．２ｗ／ｖ％，更に好ましくは０．００２～０．１ｗ／ｖ％，特に好ましくは０．００５～０．０８ｗ／ｖ％である。 In the present invention, the concentration of edetic acid or a pharmaceutically acceptable salt thereof in the aqueous liquid can be appropriately set, but is preferably 0.0005 to 0.3 w / v%, more preferably 0. It is 001 to 0.2 w / v%, more preferably 0.002 to 0.1 w / v%, particularly preferably 0.005 to 0.08 w / v%.
　本発明において，プラノプロフェン又はその薬剤学的に許容し得る塩の配合は，水性液剤中のヒアルロン酸又はその薬剤学的に許容し得る塩の１重量部に対し，好ましくは０．０５～２５重量部，より好ましくは０．１～２０重量部，更に好ましくは０．１５～１０重量部，特に好ましくは０．１７～５重量部の配合比で行えばよい。 In the present invention, pranoprofen or a pharmaceutically acceptable salt thereof is preferably added in an amount of 0.05 to 1 part by weight of hyaluronic acid or a pharmaceutically acceptable salt thereof in an aqueous solution. The mixing ratio may be 25 parts by weight, more preferably 0.1 to 20 parts by weight, still more preferably 0.15 to 10 parts by weight, and particularly preferably 0.17 to 5 parts by weight.
　本発明において，エデト酸又はその薬剤学的に許容し得る塩の配合は、水性液剤中のヒアルロン酸又はその薬剤学的に許容し得る塩の１重量部に対し，好ましくは０．０１～１６重量部，より好ましくは０．０２～１０重量部，更に好ましくは０．０３～０．５重量部の配合比で行えばよい。 In the present invention, the formulation of edetic acid or a pharmaceutically acceptable salt thereof is preferably 0.01 to 16 with respect to 1 part by weight of hyaluronic acid or a pharmaceutically acceptable salt thereof in an aqueous solution. It may be carried out at a blending ratio of parts by weight, more preferably 0.02 to 10 parts by weight, still more preferably 0.03 to 0.5 parts by weight.
　本発明の水性液剤には，本発明の効果を妨げない限り，所望により，緩衝剤，ｐＨ調整剤，等張化剤，溶解補助剤，防腐剤，粘性基剤，エデト酸又はその塩以外のキレート剤，清涼化剤その他水性液剤に広く用いられる添加剤を更に配合されていてもよい。 As long as the effect of the present invention is not hindered, the aqueous liquid preparation of the present invention may be other than buffers, pH adjusters, tonicity agents, solubilizers, preservatives, viscous bases, edetic acid or salts thereof, as desired. Additives widely used in chelating agents, cooling agents and other aqueous liquids may be further blended.
　緩衝剤の例としては，リン酸緩衝剤，ホウ酸緩衝剤，クエン酸緩衝剤，酒石酸緩衝剤，酢酸緩衝剤及びアミノ酸が挙げられるが，これらに限定されない。 Examples of buffer include, but are not limited to, phosphate buffer, borate buffer, citrate buffer, tartaric acid buffer, acetate buffer and amino acids.
　ｐＨ調節剤の例としては，塩酸，ホウ酸，アミノエチルスルホン酸，イプシロン－アミノカプロン酸，クエン酸，酢酸，水酸化ナトリウム，水酸化カリウム，水酸化カルシウム，水酸化マグネシウム，炭酸水素ナトリウム，炭酸ナトリウム，ホウ砂，トリエタノールアミン，モノエタノールアミン，ジイソプロパノールアミン，硫酸，リン酸，ポリリン酸，プロピオン酸，シュウ酸，グルコン酸，フマル酸，乳酸，酒石酸，リンゴ酸，コハク酸，グルコノラクトン，酢酸アンモニウム等が挙げられるが，これらに限定されない。 Examples of pH regulators include hydrochloric acid, boric acid, aminoethylsulfonic acid, epsilon-aminocaproic acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium bicarbonate, sodium carbonate , Borax, triethanolamine, monoethanolamine, diisopropanolamine, sulfuric acid, phosphoric acid, polyphosphoric acid, propionic acid, oxalic acid, gluconic acid, fumaric acid, lactic acid, tartaric acid, malic acid, succinic acid, gluconolactone, Although ammonium acetate etc. are mentioned, it is not limited to these.
　等張化剤の例としては，ソルビトール，グルコース，マンニトール，シクロデキストリン等の糖類，グリセリン，プロピレングリコール等の多価アルコール類，リン酸水素二ナトリウム，リン酸二水素ナトリウム，リン酸二水素カリウム，亜硫酸水素ナトリウム，亜硫酸ナトリウム，塩化カリウム，塩化カルシウム，塩化ナトリウム，塩化マグネシウム，酢酸カリウム，酢酸ナトリウム，炭酸水素ナトリウム，炭酸ナトリウム，チオ硫酸ナトリウム，硫酸マグネシウム等の塩類，及びホウ酸が挙げられるが，これらに限定されない。 Examples of isotonic agents include sugars such as sorbitol, glucose, mannitol, cyclodextrin, polyhydric alcohols such as glycerin, propylene glycol, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, Examples include 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, and boric acid. It is not limited to these.
　溶解補助剤の例としては，ポリオキシエチレンソルビタンモノオレエート，ポリオキシエチレン硬化ヒマシ油，チロキサポール，プルロニック等の非イオン性界面活性剤，グリセロール，マクロゴール等の多価アルコールが挙げられるが，これらに限定されない。 Examples of solubilizers include polyoxyethylene sorbitan monooleate, polyoxyethylene hydrogenated castor oil, nonionic surfactants such as tyloxapol and pluronic, and polyhydric alcohols such as glycerol and macrogol. It is not limited to.
　防腐剤の例としては，塩酸アルキルジアミノエチルグリシン，安息香酸ナトリウム，エタノール，塩化ベンザルコニウム，塩化ベンゼトニウム，塩化セチルピリジニウム等の第四級アンモニウム塩類，パラオキシ安息香酸メチル，パラオキシ安息香酸エチル，パラオキシ安息香酸プロピル，パラオキシ安息香酸ブチル等のパラオキシ安息香酸エステル類，ベンジルアルコール，フェネチルアルコール，ソルビン酸，チメロサール，クロロブタノール，デヒドロ酢酸ナトリウムが挙げられるが，これらに限定されない。 Examples of preservatives include quaternary ammonium salts such as alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, methyl paraoxybenzoate, ethyl paraoxybenzoate, paraoxybenzoate Examples include, but are not limited to, paraoxybenzoates such as propyl acid and butyl paraoxybenzoate, benzyl alcohol, phenethyl alcohol, sorbic acid, thimerosal, chlorobutanol, and sodium dehydroacetate.
　粘性基剤の例としては，ポリビニルピロリドン，ポリエチレングリコール，ポリビニルアルコール等の水溶性高分子，ヒドロキシエチルセルロース，メチルセルロース，ヒドロキシプロピルメチルセルロース，ヒドロキシプロピルセルロース，カルボキシメチルセルロースナトリウム等のセルロース類が挙げられるが，これらに限定されない。 Examples of viscous bases include water-soluble polymers such as polyvinylpyrrolidone, polyethylene glycol, and polyvinyl alcohol, and celluloses such as hydroxyethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, and sodium carboxymethylcellulose. It is not limited.
　エデト酸又はその塩以外のキレート剤の例としては，クエン酸，ポリリン酸，ヘキサメタリン酸，メタリン酸，アスコルビン酸，コハク酸，トリヒドロキシメチルアミノメタン，ニトリロトリ酢酸，１－ヒドロキシエタン－１，１－ジホスホン酸等，及びそれらの薬剤学的に許容し得る塩類が挙げられるが，これらに限定されない。 Examples of chelating agents other than edetic acid or its salts include citric acid, polyphosphoric acid, hexametaphosphoric acid, metaphosphoric acid, ascorbic acid, succinic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1-hydroxyethane-1,1- Examples include, but are not limited to, diphosphonic acid and the like, and pharmaceutically acceptable salts thereof.
　清涼化剤の例としては，ｌ－メントール，ボルネオ－ル，カンフル，ユーカリ油が挙げられるが，これらに限定されない。 Examples of cooling agents include, but are not limited to, l-menthol, borneol, camphor, and eucalyptus oil.
　本発明において，水性液剤には，必要に応じ更に，ナファゾリン及びその塩（塩酸塩，硝酸塩），塩酸テトラヒドロゾリン，塩酸フェニレフリン，エピネフリン及びその塩酸塩，塩酸エフェドリン，塩酸メチルエフェドリン等の血管収縮剤；グリチルリチン酸二カリウム，アラントイン，ε－アミノカプロン酸等の消炎剤；ビタミン類；アミノ酸類；メチル硫酸ネオスチグミン等の抗コリンエステラーゼ剤等が配合されていてもよい。 In the present invention, if necessary, the aqueous liquid further includes a vasoconstrictor such as naphazoline and its salts (hydrochloride, nitrate), tetrahydrozoline hydrochloride, phenylephrine hydrochloride, epinephrine and its hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride; glycyrrhizin Anti-inflammatory agents such as dipotassium acid, allantoin, and ε-aminocaproic acid; vitamins; amino acids; anticholinesterase agents such as neostigmine methylsulfate, and the like may be included.
　ビタミン類の例としては，レチナール，レチノール，レチノイン酸，カロチン，デヒドロレチナール，リコピンなどのビタミンA類，チアミン，チアミンジスルフィド，ジセチアミン，オクトチアミン，シコチアミン，ビスイブチアミン，ビスベンチアミン，プロスルチアミン，ベンフォチアミン，フルスルチアミン，リボフラビン，フラビンアデニンジヌクレオチド，ピリドキシン，塩酸ピリドキシン，ピリドキサール，ヒドロキソコバラミン，シアノコバラミン，メチルコバラミン，デオキシアデノコバラミン，葉酸，テトラヒドロ葉酸，ジヒドロ葉酸，ニコチン酸，ニコチン酸アミド，ニコチニックアルコール，パントテン酸，パンテノール，ビオチン，コリン，イノシトールなどのビタミンＢ類，アスコルビン酸及びその誘導体，エリソルビン酸及びその誘導体などのビタミンＣ類，エルゴカルシフェロール，コレカルシフェロール，ヒドロキシコレカルシフェロール，ジヒドロキシコレカルシフェロール，ジヒドロタキステロールなどのビタミンＤ類，トコフェロール及びその誘導体（例えば，酢酸トコフェロール），ユビキノン誘導体などのビタミンＥ類，カルニチン，フェルラ酸，γ－オリザノール，オロチン酸，ルチン，エリオシトリン，ヘスペリジンなどのその他のビタミン類が挙げられるが，これらに限定されない。 Examples of vitamins include vitamins such as retinal, retinol, retinoic acid, carotene, dehydroretinal, lycopene, thiamine, thiamine disulfide, dicetiamine, octothiamine, chicotiamine, bisbutiamine, bisbenchamine, prosultiamine, Benfotiamine, fursultiamine, riboflavin, flavin adenine dinucleotide, pyridoxine, pyridoxine hydrochloride, pyridoxal, hydroxocobalamin, cyanocobalamin, methylcobalamin, deoxyadenocobalamin, folate, tetrahydrofolate, dihydrofolate, nicotinic acid, nicotinamide, nicoti Nickel alcohol, pantothenic acid, panthenol, biotin, choline, inositol and other vitamin Bs, ascorbic acid and its derivatives, Vitamin Cs such as resorbic acid and its derivatives, ergocalciferol, cholecalciferol, hydroxycholecalciferol, dihydroxycholecalciferol, vitamin Ds such as dihydrotachysterol, tocopherol and its derivatives (for example, tocopherol acetate), ubiquinone Other vitamins such as vitamin E such as derivatives, carnitine, ferulic acid, γ-oryzanol, orotic acid, rutin, eriocitrin, hesperidin are not limited thereto.
　アミノ酸類の例としては，ロイシン，イソイロイシン，バリン，メチオニン，トレオニン，アラニン，フェニルアラニン，トリプトファン，リジン，グリシン，アスパラギン，アスパラギン酸，セリン，グルタミン，グルタミン酸，プロリン，チロシン，システイン，ヒスチジン，オルニチン，ヒドロキシプロリン，ヒドロキシリジン，グリシルグリシン，アミノエチルスルホン酸（タウリン）が挙げられるがこれらに限定されない。 Examples of amino acids include leucine, isoleucine, valine, methionine, threonine, alanine, phenylalanine, tryptophan, lysine, glycine, asparagine, aspartic acid, serine, glutamine, glutamic acid, proline, tyrosine, cysteine, histidine, ornithine, hydroxyproline , Hydroxylysine, glycylglycine, and aminoethylsulfonic acid (taurine), but are not limited thereto.
　本発明において，水性液剤のｐＨは，投与を意図する生体部位に許容される範囲内にあればよく，特に限定されないが，通常は４．５～９．０であり，好ましくは６．０～８．０であり，より好ましくは７．０～８．０である。 In the present invention, the pH of the aqueous liquid preparation is not particularly limited as long as it is within the range acceptable for the biological site intended for administration, but it is usually 4.5 to 9.0, preferably 6.0 to It is 8.0, more preferably 7.0 to 8.0.
　以下，実施例を挙げて本発明を更に具体的に説明するが，本発明がそれらの実施例により限定されることは意図しない。 Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not intended to be limited by these examples.
　なお，以下の各実施例において，プラノプロフェンとしては株式会社エーピーアイ　コーポレ―ション製プラノプロフェン（局方）を，エデト酸二ナトリウム水和物としては関東化学株式会社製エデト酸ナトリウム水和物（局方）を，それぞれ使用した。 In each of the following examples, pranoprofen is pranoprofen (Pharmacopoeia) manufactured by API Corporation, and edetate disodium hydrate is sodium edetate hydrate manufactured by Kanto Chemical Co., Ltd. Each thing (the pharmacopoeia) was used.
　表１～７に示す各処方に従い，ヒアルロン酸ナトリウム（重量平均分子量１，０４０，０００，生化学工業株式会社）含有の水性液剤を調製した。各水性液剤のｐＨは７．５とした。各水性液剤を，１５ｍＬ容量のポリエチレンテレフタレート（ＰＥＴ，グレードＲＴ５４３）製容器に１５ｍＬずつ分注して密封し，６０℃にて４週間保存した。保存前及び保存後に，各水性液剤の粘度（動粘度）を，日局（第十五改正）一般試験法の「粘度測定法＜２．５３＞，第１法　毛細管粘度計法」に従い，ウベローデ粘度計を用いて２０．０℃にて測定し，「粘度保持率（％）」を，次の式により算出した。
　粘度保持率（％）＝（保存後の動粘度－１）／（保存前の動粘度－１）×１００ In accordance with the formulations shown in Tables 1 to 7, aqueous solutions containing sodium hyaluronate (weight average molecular weight 1,040,000, Seikagaku Corporation) were prepared. The pH of each aqueous solution was 7.5. Each aqueous solution was dispensed and sealed in a 15 mL polyethylene terephthalate (PET, grade RT543) container, and stored at 60 ° C. for 4 weeks. Before and after storage, the viscosity (kinematic viscosity) of each aqueous solution was determined according to the “Viscosity Measurement Method <2.53>, Method 1 Capillary Viscometer Method” of the General Test Method of Japan (Fifteenth Revision). It measured at 20.0 degreeC using the viscometer, and "viscosity retention (%)" was computed by the following formula.
Viscosity retention (%) = (kinematic viscosity after storage-1) / (kinematic viscosity before storage-1) × 100
　１．プラノプロフェンによる粘度低下抑制効果
　表１に見られるように，処方３のプラノプロフェン不含のヒアルロン酸ナトリウム含有水性液剤に較べ，これにプラノプロフェンをそれぞれ０．０５及び０．１ｗ／ｖ％配合したものに相当する処方１及び２の水性液剤では，経時的な粘度低下が顕著に抑制された。 1. Viscosity reduction inhibitory effect by pranoprofen As seen in Table 1, compared with pranoprofen-free aqueous solution containing sodium hyaluronate in Formula 3, pranoprofen was added to pranoprofen at 0.05 and 0.1 w / v, respectively. In the aqueous liquid preparations of Formulations 1 and 2, which correspond to those formulated with%, the decrease in viscosity over time was remarkably suppressed.
Figure JPOXMLDOC01-appb-T000001
  
Figure JPOXMLDOC01-appb-T000001
  
２．プラノプロフェンとエデト酸のナトリウム塩による粘度低下抑制効果
　下の表２に見られるとおり，処方１及び２に更にエデト酸のナトリウム塩を配合したものに相当する処方４及び５の水性液剤を調製し，６０℃にて４週間保存して，粘度保持率を比較した。その結果，エデト酸のナトリウム塩の併用により粘度低下の抑制が一層顕著となることが判明した。 2. Viscosity reduction inhibitory effect by pranoprofen and sodium salt of edetic acid As shown in Table 2 below, preparation of aqueous solutions of formulations 4 and 5 corresponding to formulations 1 and 2 further blended with sodium salt of edetic acid And stored at 60 ° C. for 4 weeks, and the viscosity retention was compared. As a result, it was found that the combined use of sodium edetic acid made the suppression of viscosity decrease even more remarkable.
Figure JPOXMLDOC01-appb-T000002
  
Figure JPOXMLDOC01-appb-T000002
  
　３．エデト酸のナトリウム塩自体の粘度低下抑制効果の有無の検討
　ヒアルロン酸ナトリウム含有水性液剤の粘度低下に対するエデト酸のナトリウム塩自体の影響を調べるため，次の表３に処方３Ｅで示す水性液剤（プラノプロフェン不含の上記処方３にエデト酸二ナトリウム水和物０．０１ｗ／ｖ％を加えたものに相当する）を調製し，上記と同様に６０℃にて４週間保存した後，粘度保持率を測定し，その結果を処方３につき上記で既に得られている結果と比較した。 3. Examination of whether or not the sodium salt of edetic acid itself has the effect of suppressing the decrease in viscosity In order to investigate the effect of sodium salt of edetic acid itself on the decrease in viscosity of the sodium hyaluronate-containing aqueous solution, Corresponding to the above formulation 3 containing edetate disodium hydrate 0.01 w / v%), and stored for 4 weeks at 60 ° C. The rate was measured and the results were compared with the results already obtained for Formula 3 above.
Figure JPOXMLDOC01-appb-T000003
  
Figure JPOXMLDOC01-appb-T000003
  
　表３に見られるように，プラノプロフェン不含の処方３に比べ，これにエデト酸二ナトリウム水和物０．０１ｗ／ｖ％を添加したものに相当する処方３Ｅでは，粘度保持率が低下しており，エデト酸のナトリウム塩自体には，単独でのヒアルロン酸ナトリウム含有水性液剤の粘度低下を抑制する効果は認められなかった。それにも拘わらず，既に表２に示したようにプラノプロフェン０．１ｗ／ｖ％を含有するがエデト酸のナトリウム塩を含有しない前記の処方１及び４に比べ，これらにエデト酸二ナトリウム水和物０．０１ｗ／ｖ％を添加したものにそれぞれ相当する処方４及び５が高い粘度保持率を示しているのは，プラノプロフェンとエデト酸のナトリウム塩との組合せにより，何らかの相乗効果が生じたことによるものと考えられる。 As can be seen in Table 3, the viscosity retention is reduced in the formulation 3E corresponding to the addition of 0.01 w / v% edetate disodium hydrate compared to the formulation 3 containing no pranoprofen. Therefore, the sodium salt of edetic acid itself did not show the effect of suppressing the decrease in the viscosity of the aqueous solution containing sodium hyaluronate alone. Nevertheless, as shown in Table 2, edetate disodium water was added to the above formulations 1 and 4 which contained pranoprofen 0.1 w / v% but not sodium edetate. Formulas 4 and 5 corresponding to those with the addition of 0.01% w / v of Japanese show a high viscosity retention because the combination of pranoprofen and sodium salt of edetic acid has some synergistic effect. This is probably due to the fact that it occurred.
　４．種々のヒアルロン酸ナトリウム濃度における粘度低下抑制効果
　下の表４～６に示す処方に従って，ヒアルロン酸ナトリウムの濃度を変化させた水性液剤に対し，これにプラノプロフェンを配合した水性液剤，更に，プラノプロフェン及びエデト酸二ナトリウム水和物を配合した水性液剤をそれぞれ調製し，６０℃にて４週間保存して，粘度保持率を比較した。その結果，表４～６に見られるように，何れのヒアルロン酸ナトリウム濃度についても，プラノプロフェンによる粘度低下の顕著な抑制効果，及びエデト酸のナトリウム塩の併用による更に顕著な抑制効果が，共に確認された。 4). Viscosity reduction inhibitory effect at various sodium hyaluronate concentrations According to the formulations shown in Tables 4 to 6 below, an aqueous solution in which the concentration of sodium hyaluronate was changed, an aqueous solution containing pranoprofen, and a plano Aqueous solutions containing prophene and disodium edetate hydrate were prepared and stored at 60 ° C. for 4 weeks, and the viscosity retention was compared. As a result, as shown in Tables 4-6, for any sodium hyaluronate concentration, there is a remarkable inhibitory effect on the decrease in viscosity by pranoprofen, and a more remarkable inhibitory effect by the combined use of sodium salt of edetic acid. Both were confirmed.
Figure JPOXMLDOC01-appb-T000004
  
Figure JPOXMLDOC01-appb-T000004
  
Figure JPOXMLDOC01-appb-T000005
  
Figure JPOXMLDOC01-appb-T000005
  
Figure JPOXMLDOC01-appb-T000006
  
Figure JPOXMLDOC01-appb-T000006
  
　５．粘度抑制効果に対する緩衝剤の変更の影響の有無の検討
　処方１及び４における緩衝剤をリン酸緩衝液に変更したものである表７の処方１５及び１６と，処方１６からプラノプロフェンを除いたものである処方１７に従って，水性液剤をそれぞれ調製し，６０℃にて４週間保存して，粘度保持率を調べた。その結果，処方１５及び１６の水性液剤の粘度保持率は，処方１及び４の水性液剤の粘度保持率と実質的に同等であり，ホウ酸緩衝剤からリン酸緩衝剤に変更したことは，プラノプロフェン単独，プラノプロフェンとエデト酸のナトリウム塩との併用，及びエデト酸のナトリウム塩単独の何れが奏する粘度低下抑制効果にも，実質的影響を与えなかった。
　また，エデト酸のナトリウム塩は含有するがプラノプロフェンを含有しないものである処方１７の水性液剤の粘度保持率は，２５％と小さく，粘度低下抑制成分を含まない処方３（ホウ酸緩衝剤。ヒアルロン酸ナトリウム濃度は同一）の水性液剤での値２９％との比較からは，エデト酸のナトリウム塩単独での粘度低下抑制効果は認められなかった。 5. Examination of the effect of changing the buffering agent on the viscosity suppression effect Formulations 15 and 16 in Table 7 in which the buffering agent in Formulations 1 and 4 was changed to phosphate buffer, and pranoprofen were excluded from Formulation 16 Aqueous liquid preparations were respectively prepared according to the formulation 17 and stored at 60 ° C. for 4 weeks, and the viscosity retention rate was examined. As a result, the viscosity retention of the aqueous solutions of formulations 15 and 16 was substantially the same as the viscosity retention of the aqueous solutions of formulations 1 and 4, and the change from borate buffer to phosphate buffer was Neither the effect of pranoprofen alone, the combination of pranoprofen and sodium edetate, or the sodium salt of edetic acid alone had any substantial effect on the viscosity-inhibiting effect.
In addition, the viscosity retention of the aqueous solution of Formulation 17 that contains sodium salt of edetic acid but does not contain pranoprofen is as low as 25%, and Formula 3 (Boric Acid Buffer In comparison with the value of 29% in the aqueous solution of the same concentration of sodium hyaluronate), the sodium salt of edetic acid alone did not show the effect of suppressing the decrease in viscosity.
Figure JPOXMLDOC01-appb-T000007
  
Figure JPOXMLDOC01-appb-T000007
  
　６．低濃度ヒアルロン酸水性液剤におけるプラノプロフェンによる粘度低下抑制効果の確認
　次の表８に示す各処方に従い，上記処方例より低濃度領域でヒアルロン酸ナトリウム（重量平均分子量３，２２０，０００，キューピー株式会社製ヒアルロンサンＨＡ－ＱＳＥ）を含有する水性液剤を調製した。各水性液剤のｐＨは７．５とした。上記の各実施例と同様に，各水性液剤を，１５ｍＬ容量のポリエチレンテレフタレート（ＰＥＴ）製容器に１５ｍＬずつ分注して密封し，６０℃にて４週間保存した。保存前及び保存後に，各水性液剤の粘度（動粘度）を，上記各実施例と同様にして測定し，粘度保持率を算出し，結果を比較した。 6). Confirmation of Viscosity Reduction Inhibition Effect by Planoprofen in Low Concentration Hyaluronic Acid Aqueous Solution According to each formulation shown in the following Table 8, sodium hyaluronate (weight average molecular weight 3,220,000, cupy stock in lower concentration region than the above formulation example) An aqueous solution containing Hyaluronic Sun HA-QSE (manufactured by company) was prepared. The pH of each aqueous solution was 7.5. In the same manner as in the above Examples, each aqueous solution was dispensed and sealed in a 15 mL polyethylene terephthalate (PET) container, and stored at 60 ° C. for 4 weeks. Before and after storage, the viscosity (kinematic viscosity) of each aqueous solution was measured in the same manner as in each of the above Examples, the viscosity retention rate was calculated, and the results were compared.
Figure JPOXMLDOC01-appb-T000008
  
Figure JPOXMLDOC01-appb-T000008
  
　表８は，ヒアルロン酸ナトリウムを０．００１，０．００２，又は０．００５ｗ／ｖ％の各濃度で含有する水性液剤において，プラノプロフェンの配合の有無での粘度保持率の測定結果を示しており，これら何れのヒアルロン酸ナトリウム濃度の群でも，プラノプロフェン不含のものに比べプラノプロフェンを配合した水性液剤の粘度保持率が，顕著に高い。 Table 8 shows the measurement results of the viscosity retention with and without pranoprofen in aqueous liquids containing sodium hyaluronate at concentrations of 0.001, 0.002, or 0.005 w / v%. In any of these groups of sodium hyaluronate concentrations, the viscosity retention of the aqueous liquid formulation containing pranoprofen is remarkably higher than that without pranoprofen.
　以上のとおり，ヒアルロン酸ナトリウム含有の水性液剤の経時的な粘度低下は，プラノプロフェンの配合によって，ヒアルロン酸の分子量の大小に関わりなく顕著に抑制されることが判明した。またこれに更にエデト酸のナトリウム塩を配合することにより，抑制が一層顕著になることも判明した。また，種々のヒアルロン酸ナトリウム濃度において，プラノプロフェンの配合，及びプラノプロフェンとエデト酸のナトリウム塩との併用により，水性液剤の粘度低下に対する優れた抑制効果の得られること，及び緩衝剤の種類による影響を受けないことが，それぞれ確認された。 As described above, it has been found that the decrease in viscosity over time of an aqueous liquid containing sodium hyaluronate is significantly suppressed by the incorporation of pranoprofen regardless of the molecular weight of hyaluronic acid. In addition, it was also found that the suppression becomes even more remarkable by adding edetic acid sodium salt. In addition, at various sodium hyaluronate concentrations, the combination of pranoprofen and the combined use of pranoprofen and sodium edetate can provide an excellent inhibitory effect on the viscosity reduction of aqueous solutions, and It was confirmed that they were not affected by type.
　本発明は，ヒアルロン酸又はその薬剤学的に許容し得る塩を含有する水性液剤における粘度の経時的低下を抑制するための新たな手段として有用である。 The present invention is useful as a new means for suppressing a decrease in viscosity over time in an aqueous liquid preparation containing hyaluronic acid or a pharmaceutically acceptable salt thereof.

Claims (9)

  1. 　ヒアルロン酸又はその薬剤学的に許容し得る塩を含有する水性液剤の粘度低下を抑制する方法であって，該水性液剤にプラノプロフェン又はその薬剤学的に許容し得る塩を配合することを特徴とする方法。 A method for suppressing a decrease in viscosity of an aqueous liquid preparation containing hyaluronic acid or a pharmaceutically acceptable salt thereof, comprising adding pranoprofen or a pharmaceutically acceptable salt thereof to the aqueous liquid preparation. Feature method.
  2. 　ヒアルロン酸の薬剤学的に許容し得る塩がヒアルロン酸ナトリウムである，請求項１の方法。 2. The method of claim 1, wherein the pharmaceutically acceptable salt of hyaluronic acid is sodium hyaluronate.
  3. 　該水性液剤にエデト酸又はその薬剤学的に許容し得る塩を更に配合することを特徴とする，請求項１又は２の方法。 The method according to claim 1 or 2, wherein edetic acid or a pharmaceutically acceptable salt thereof is further added to the aqueous liquid.
  4. 　エデト酸の薬剤学的に許容し得る塩がエデト酸のナトリウム塩である，請求項３の方法。 The method of claim 3, wherein the pharmaceutically acceptable salt of edetic acid is the sodium salt of edetic acid.
  5. 　該水性液剤におけるヒアルロン酸又はその薬剤学的に許容し得る塩の濃度が０．００１～１．０ｗ／ｖ％である，請求項１ないし４の何れかの方法。 The method according to any one of claims 1 to 4, wherein the concentration of hyaluronic acid or a pharmaceutically acceptable salt thereof in the aqueous liquid is 0.001 to 1.0 w / v%.
  6. 　プラノプロフェン又はその薬剤学的に許容し得る塩の配合が，該水性液剤におけるプラノプロフェン又はその薬剤学的に許容し得る塩の濃度が０．００１～１．０ｗ／ｖ％となるように行われるものである，請求項１ないし５の何れかの方法。 The formulation of pranoprofen or a pharmaceutically acceptable salt thereof is such that the concentration of pranoprofen or a pharmaceutically acceptable salt thereof in the aqueous solution is 0.001 to 1.0 w / v%. 6. The method according to any one of claims 1 to 5, wherein the method is performed as follows.
  7. 　プラノプロフェン又はその薬剤学的に許容し得る塩の配合が，ヒアルロン酸又はその薬剤学的に許容し得る塩の１重量部に対して０．０５～２５重量部の配合比で行われるものである，請求項１ないし６の何れかの方法。 Planoprofen or a pharmaceutically acceptable salt thereof is mixed at a mixing ratio of 0.05 to 25 parts by weight with respect to 1 part by weight of hyaluronic acid or a pharmaceutically acceptable salt thereof. The method according to claim 1, wherein:
  8. 　該水性液剤が点眼剤である，請求項１ないし７の何れかの方法。 The method according to any one of claims 1 to 7, wherein the aqueous liquid preparation is an eye drop.
  9. 　水性液剤用粘度低下抑制剤であって，プラノプロフェン又はその薬剤学的に許容し得る塩からなり，該水性液剤がヒアルロン酸又はその薬剤学的に許容し得る塩を含有する水性液剤である，粘度低下抑制剤。 Viscosity reduction inhibitor for aqueous solutions, comprising pranoprofen or a pharmaceutically acceptable salt thereof, wherein the aqueous solution contains hyaluronic acid or a pharmaceutically acceptable salt thereof , Viscosity reduction inhibitor.
PCT/JP2012/072877 2011-09-07 2012-09-07 Method for suppressing decrease in viscosity of aqueous liquid agent WO2013035837A1 (en)

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