JP6376550B2 - Method for inhibiting viscosity reduction of aqueous liquid preparation - Google Patents

Description

  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 high-molecular polysaccharide composed of many DN-acetylglucosamine molecules and D-glucuronic acid molecules bonded 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.

  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.

  On the other hand, pain and itching appearing in affected areas such as the eye and nasal cavity due to pranoprofen-containing liquid external preparations 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.

Japanese Patent Laid-Open No. 10-072376 JP 2004-359629 A International Publication No. 2008/050776 Pamphlet JP 2005-289899 A JP 2010-132608 A

  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.

  In the process of studying for the above-mentioned purpose, the present inventor accidentally took pranoprofen or a preparation thereof against the temporal decrease in the viscosity of an aqueous liquid preparation containing hyaluronic acid or a pharmaceutically acceptable salt thereof. 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) 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.
(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 composition 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 liquids, comprising pranoprofen or a pharmaceutically acceptable salt thereof, wherein the aqueous liquid contains hyaluronic acid or a pharmaceutically acceptable salt thereof Viscosity reduction inhibitor that is a liquid.

  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.

  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.).

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

  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”.

  The concentration of hyaluronic acid or a pharmacologically acceptable salt thereof in an aqueous solution intended to suppress a decrease in viscosity according to the present invention has no clear upper limit or lower limit, but 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%, still More preferably, it is 0.005-0.3 w / v%, Most preferably, it is 0.02-0.3 w / v%, Especially preferably, it is 0.01-0.3 w / v%.

  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 a decrease in viscosity of an aqueous solution containing these hyaluronic acid or a pharmaceutically acceptable salt thereof. can do.

  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.

  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.

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 range of safety . Examples of pharmaceutically acceptable salts of pranoprofen include, but are not limited to, sodium and potassium salts.

  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 solution 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 appropriately set, 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.

  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.

  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 1-4 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.

  In the present invention, the concentration of edetic acid or a pharmaceutically acceptable salt thereof in the aqueous liquid preparation can be appropriately set, but is preferably 0.0005 to 0.3 w / v%, more preferably 0.00. It is 001-0.2 w / v%, More preferably, it is 0.002-0.1 w / v%, Most preferably, it is 0.005-0.08 w / v%.

  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.

  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. What is necessary is just to carry out by the compounding ratio of a weight part, More preferably, 0.02-10 weight part, More preferably, 0.03-0.5 weight part.

  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.

  Examples of buffering agents include, but are not limited to, phosphate buffer, borate buffer, citrate buffer, tartaric acid buffer, acetate buffer and amino acids.

  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.

  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.

  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.

  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.

  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.

  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.

  Examples of the refreshing agent include, but are not limited to, l-menthol, borneol, camphor, and eucalyptus oil.

  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; and anticholinesterase agents such as neostigmine methyl sulfate may be included.

  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 sorbic 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, and hesperidin are not limited thereto.

  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.

  In the present invention, the pH of the aqueous liquid preparation is not particularly limited as long as it is within a range that is acceptable for a biological site intended for administration, but is usually 4.5 to 9.0, preferably 6.0 to 6.0. It is 8.0, More preferably, it is 7.0-8.0.

  EXAMPLES 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.

  In the following examples, pranoprofen is pranoprofen (Pharmacopoeia) manufactured by API Corporation, and edetate disodium hydrate is edetate sodium hydrate manufactured by Kanto Chemical Co., Ltd. Each thing (the pharmacopoeia) was used.

According to each formulation shown in Tables 1-7, an aqueous liquid preparation containing sodium hyaluronate (weight average molecular weight 1,040,000, Seikagaku Corporation) was prepared. The pH of each aqueous solution was 7.5. Each aqueous solution was dispensed and sealed in a 15 mL container made of polyethylene terephthalate (PET, grade RT543), 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. 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.

2. Viscosity reduction inhibitory effect of pranoprofen and edetic acid sodium salt As shown in Table 2 below, prepared aqueous solutions of formulations 4 and 5 corresponding to formulations 1 and 2 further blended with sodium salt of edetic acid Then, it was 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.

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 influence 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 0.01w / 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.

  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). 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, stored at 60 ° C. for 4 weeks, and the viscosity retention rates were compared. As a result, as shown in Tables 4 to 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.

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 case of the aqueous solution of the same sodium hyaluronate concentration), the sodium salt of edetic acid alone did not show the effect of suppressing the viscosity decrease.

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) 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 liquid was measured in the same manner as in each of the above Examples, the viscosity retention was calculated, and the results were compared.

  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.

  As described above, it was found that the decrease in viscosity over time of an aqueous solution containing sodium hyaluronate was 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.

  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 (7)

A method for suppressing a decrease in viscosity over time of an aqueous solution containing hyaluronic acid or a pharmaceutically acceptable salt thereof,
Blending pranoprofen or a pharmaceutically acceptable salt thereof with the aqueous solution;
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 0.05 to 0.1 w / v%. To be done, and
Planoprofen or a pharmaceutically acceptable salt thereof is added 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. A method characterized by: Planoprofen or a pharmaceutically acceptable salt thereof is blended at a blending ratio of 0.17 to 5 parts by weight with respect to 1 part by weight of hyaluronic acid or a pharmaceutically acceptable salt thereof. The method of claim 1, characterized by: The method of claim 1 or 2 , wherein the pharmaceutically acceptable salt of hyaluronic acid is sodium hyaluronate. The method according to any one of claims 1 to 3 , wherein edetic acid or a pharmaceutically acceptable salt thereof is further added to the aqueous solution. The method of claim 4 , wherein the pharmaceutically acceptable salt of edetic acid is the sodium salt of edetic acid. The method according to any one of claims 1 to 5 , wherein the concentration of hyaluronic acid 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 claims 1 to 6 , wherein the aqueous liquid preparation is an eye drop.