RU2598721C2 - Method for suppressing decrease in viscosity of aqueous liquid agent - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry, means for suppressing decrease over time 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, where concentration of hyaluronic acid or a pharmaceutically acceptable salt in the aqueous solution is 0.001~1.0 % and where addition of pranoprofena or its pharmaceutically acceptable salt is performed so, that concentration of hyaluronic acid or a pharmaceutically acceptable salt in the aqueous solution is 0.001~1.0 %.

EFFECT: invention ensures maintenance of stable viscosity liquid aqueous agent, which contains hyaluronic acid or a pharmaceutically acceptable salt thereof, due to suppression of reducing viscosity for a long time.

7 cl, 8 tbl

Description

FIELD OF THE INVENTION

[0001] The invention generally relates to inhibiting a decrease in the viscosity of an aqueous solution of a macromolecular polysaccharide and, in particular, inhibiting a decrease in the viscosity of a liquid aqueous preparation containing hyaluronic acid or a pharmaceutically acceptable salt thereof.

BACKGROUND

[0002] Hyaluronic acid is a linear macromolecular polysaccharide formed by a large number of D-N-acetylglucosamine and D-glucuronic acid molecules that are connected to each other in turn. Due to their high viscosity and moisture retention properties, aqueous solutions containing hyaluronic acid or its salt are widely used in liquid aqueous preparations for various applications. However, it is known that the viscosity of an aqueous solution containing hyaluronic acid or its salt, if the pH of the solution is brought to a neutral region, will decrease during long-term storage for some reason, for example, as a result of decomposition of hyaluronic acid and, therefore, the disadvantage of such a solution is that that he cannot maintain his viscosity for a long time.

[0003] Several methods are known to suppress the decrease in viscosity of liquid aqueous preparations containing hyaluronic acid over time, namely, adding at least one compound selected from the group consisting of polyols, polycarboxylic acids, polycarboxylic acid salts and saccharides to such liquid aqueous preparations. , as a stabilizer (patent document 1); adding a fat-soluble vitamin to suppress the decomposition of hyaluronic acid (Patent Document 2) and adding glucuronic acid or its salt to the metal (Patent Document 3), respectively. However, since there may be various restrictions on the composition of a liquid aqueous preparation containing hyaluronic acid, depending on its applications or methods of use, these traditional methods do not fully meet the requirements of suppressing a decrease in viscosity over time.

[0004] On the other hand, it is known that pain and pruritus can be alleviated at sites of exposure, such as the eye or nasal cavity, caused by a pranoprofen-containing liquid pharmaceutical preparation for external use by adding mucopolysaccharides, for example chondroitin sulfate or hyaluronic acid (patent document 4); and that sodium hyaluronate is added to liquid aqueous compositions containing one of various drugs, for example, pranoprofen, in order to prevent the precipitation of foreign substances during their long-term storage (patent document 5). However, nothing is mentioned about the viscosity of any of these compositions.

PROTOTYPE DOCUMENTS

PATENT DOCUMENTS

[0005] Patent Document 1: JP Publication of Patent Application No. H10-072376.

Patent Document 2: JP Publication of Patent Application No. 2004-359629.

Patent Document 3: WO No. 2008/050776.

Patent Document 4: JP Publication of Patent Application No. 2005-289899.

Patent Document 5: JP Publication of Patent Application No. 2010-132608.

SUMMARY OF THE INVENTION

PROBLEMS TO BE SOLVED BY THE INVENTION

[0006] In contrast to the aforementioned premises, the present invention has as its purpose, the provision of new means of suppressing a decrease in the viscosity of a liquid aqueous preparation containing hyaluronic acid or a pharmaceutically acceptable salt thereof over time.

MEANS FOR SOLVING PROBLEMS

[0007] In a study regarding the above objective, the applicant unexpectedly discovered that pranoprofen or a pharmaceutically acceptable salt thereof has activity to suppress the decrease in viscosity of a liquid aqueous preparation containing hyaluronic acid or a pharmaceutically acceptable salt thereof over time, and carried out the present invention by carrying out an additional study. Thus, the present invention relates to the following.

[0008] (1) A method for suppressing a decrease in the viscosity of a liquid aqueous preparation comprising hyaluronic acid or a pharmaceutically acceptable salt thereof, comprising adding pranoprofen or a pharmaceutically acceptable salt thereof to the liquid aqueous preparation.

(2) The method of the preceding claim 1, wherein the pharmaceutically acceptable salt of hyaluronic acid is sodium hyaluronate.

(3) The method according to the above 1 or 2, further comprising adding edetic acid or a pharmaceutically acceptable salt thereof.

(4) The method according to the above 3, wherein the pharmaceutically acceptable salt of edetic acid is the sodium salt of edetic acid.

(5) The method according to one of the above claims 1 to 4, wherein the concentration of hyaluronic acid or a pharmaceutically acceptable salt thereof is 0.001-1.0% w / v.

(6) The method according to one of the preceding claims 1 to 5, wherein the addition of pranoprofen or a pharmaceutically acceptable salt thereof is performed such that the concentration of pranoprofen or its pharmaceutically acceptable salt in a liquid aqueous preparation is 0.001-1.0% w / v .

(7) The method according to one of the above claims 1 to 6, wherein the addition of pranoprofen or a pharmaceutically acceptable salt thereof is carried out in such a way that its ratio in combination corresponds to 0.05-25 parts by weight. on 1 part wt. hyaluronic acid or a pharmaceutically acceptable salt thereof.

(8) The method according to one of the preceding claims 1 to 7, wherein the liquid aqueous preparation is eye drops.

(9) An agent for suppressing a decrease in viscosity of a liquid aqueous preparation, wherein said agent contains pranoprofen or a pharmaceutically acceptable salt thereof, and where the liquid aqueous preparation is a liquid aqueous preparation containing hyaluronic acid or a pharmaceutically acceptable salt thereof.

EFFECT OF THE INVENTION

[0009] The present invention described above relates to new means for maintaining a stable viscosity of a liquid aqueous preparation containing hyaluronic acid or a pharmaceutically acceptable salt thereof, by suppressing a decrease in viscosity of the preparation over time, even if it is stored for a long time.

MODE FOR CARRYING OUT THE INVENTION

[0010] In the present invention, the presence and degree of “viscosity reduction” of a liquid aqueous preparation is estimated by the reduction in the kinematic viscosity (measured at 20 ° C) of the liquid aqueous preparation after its static storage for 4 weeks at 60 ° C compared with the kinematic viscosity of the liquid aqueous drug before storage.

[0011] In the present invention, the inhibition of lowering the viscosity of a liquid aqueous preparation containing hyaluronic acid or a pharmaceutically acceptable salt thereof is detected by the fact that, compared with the degree of preservation of the viscosity of the liquid aqueous preparation after being kept under specific conditions for a certain period of time, a higher degree viscosity preservation demonstrates a liquid aqueous preparation, optionally containing (compared with the previous) one or more predefined inhibitory components ntov (pranoprofen or a pharmaceutically acceptable salt thereof, or a combination of edetic acid or a pharmaceutically acceptable salt thereof) after storage under the same conditions and for the same time period. The expression "degree of conservation of viscosity" here means a value determined by the following formula:

The degree of conservation of viscosity (%) = (kinematic viscosity after storage-1) / (kinematic viscosity before storage - 1) × 100

[0012] In the present invention, the expression "containing hyaluronic acid or a pharmaceutically acceptable salt thereof" is not limited to the case where only hyaluronic acid or only the pharmaceutically acceptable salt of hyaluronic acid is contained, but also includes the case when both compounds, hyaluronic acid and its pharmaceutically acceptable salt at the same time. The same applies to the terms “addition of pranoprofen or a pharmaceutically acceptable salt thereof” and “additional addition of edetic acid or a pharmaceutically acceptable salt thereof”.

[0013] Although the upper or lower limits for the concentration of hyaluronic acid or its pharmaceutically acceptable salt in an aqueous liquid preparation whose suppression of viscosity reduction is contemplated by the present invention are not clear, a range of 0.001-1.0% w / v is preferred. The reason is that when the concentration of hyaluronic acid or its pharmaceutically acceptable salt is below 0.001% wt./about. the resulting initial viscosity is too low, and such viscosity does not have important technical value for a liquid aqueous preparation, and if the concentration is higher than 1.0% w / v, the resulting liquid aqueous preparation is too viscous to prepare it without difficulty, making the preparation unsuitable . The concentration of hyaluronic acid or a pharmaceutically acceptable salt thereof in a liquid aqueous preparation is more preferably 0.002-0.5% w / v, even more preferably 0.005-0.5% w / v, even more preferably 0.005-0.3 % wt./about., and most preferably 0.02-0.3% wt./about.

[0014] In the present invention, there are no particular restrictions on the molecular weight of hyaluronic acid. Hyaluronic acid having a weight average molecular weight of about 400000-4000000 is now available, the present invention can be used to suppress a decrease in the viscosity of a liquid aqueous preparation containing such hyaluronic acid or a pharmaceutically acceptable salt thereof.

[0015] Although in the present invention a particularly preferred pharmaceutically acceptable salt of hyaluronic acid is a sodium salt, this is not a limitation, and other salts such as potassium salt, calcium salt and magnesium salt are also included in the examples of preferred salts.

[0016] In addition, in the present invention, the term "concentration" or "mass fraction (s)" used with respect to hyaluronic acid or its pharmaceutically acceptable salt, if used in relation to a liquid aqueous preparation containing both substances, hyaluronic acid and its pharmaceutically acceptable salt, means "concentration" or "mass fraction (s)" of the sum of hyaluronic acid and its pharmaceutically acceptable salt.

[0017] Pranoprofen (chemical name: (2RS) -2- (10H-9-oxa-1-azaanthracene-6-yl) propanoic acid) or its pharmaceutically acceptable salt is a non-steroidal anti-inflammatory agent with a wide range of safety. Examples of pharmaceutically acceptable salts of pranoprofen include, but are not limited to, the sodium salt and potassium salt.

[0018] In the present invention, pranoprofen or a pharmaceutically acceptable salt thereof acts as an agent to suppress the decrease in viscosity of a liquid aqueous preparation of hyaluronic acid or a pharmaceutically acceptable salt thereof over time. The concentration of pranoprofen or its pharmaceutically acceptable salt in a liquid aqueous preparation can be set as required, but preferably the concentration is 0.001-1.0% wt./about. In general, if the concentration is above 1.0% w / v, the preparation of the preparation becomes difficult, whereas if the concentration is below 0.001% w / v, the resulting effect on stabilizing the viscosity is unsatisfactory. The concentration of pranoprofen or a pharmaceutically acceptable salt thereof in a liquid aqueous preparation is preferably 0.005-0.5% w / v, more preferably 0.05-0.1% w / v. Moreover, among pranoprofen or its pharmaceutically acceptable salts, pranoprofen is particularly preferred.

[0019] Furthermore, the term “concentration” or “mass fraction (s)” as used with respect to pranoprofen or a pharmaceutically acceptable salt thereof, as applied to the case where both compounds are added, pranoprofen and its pharmaceutically acceptable salt, refers to “concentration” or “mass fraction (s)” of the amount of pranoprofen and its pharmaceutically acceptable salt.

[0020] The Applicant has found that edetic acid (also known as ethylenediaminetetraacetic acid) or a pharmaceutically acceptable salt thereof in combination with pranoprofen or a pharmaceutically acceptable salt thereof further enhances the effect of suppressing viscosity reduction compared to pranoprofen used alone. Examples of edetic acid or a pharmaceutically acceptable salt thereof include, but are not limited to, sodium salt and potassium salt. Especially preferred is the edetic acid sodium salt. Edetic acid forms salts with 1-4 sodium ions. Although any of these salts can be used, if the pH of the liquid aqueous preparation is adjusted to the desired level, disodium edetate is preferred, given its ease of handling. In addition, since edetic acid or a pharmaceutically acceptable salt thereof is effective, further enhancing the effect of pranoprofen in suppressing viscosity reduction, provided that it is added to hyaluronic acid or its pharmaceutically acceptable salt along with pranoprofen, these components can be added to form a liquid aqueous preparation .

[0021] In the present invention, the concentration of edetic acid or a pharmaceutically acceptable salt thereof (although it can be set as desired) is preferably 0.0005-0.3% w / v, more preferably 0.001-0.2% w / v ., even more preferably 0.002-0.1% wt./about. and particularly preferably 0.005-0.08% w / v.

[0022] In the present invention, pranoprofen or a pharmaceutically acceptable salt thereof can be added to the combination, preferably in a ratio of 0.05-25 wt. shares, more preferably 0.1-20 wt. shares, even more preferably 0.15-10 wt. shares and particularly preferably 0.17-5 wt. shares per wt. the proportion of hyaluronic acid or its pharmaceutically acceptable salt contained in a liquid aqueous preparation.

[0023] In the present invention, edetic acid or a pharmaceutically acceptable salt thereof can be added to the combination, preferably in a ratio of 0.01-16 wt. shares, more preferably 0.02-10 wt. shares, even more preferably 0.03-0.5 wt. shares per wt. the proportion of hyaluronic acid or its pharmaceutically acceptable salt contained in a liquid aqueous preparation.

[0024] The liquid aqueous preparation of the present invention may optionally contain buffers, pH adjusting agents, isotonicity agents, dissolution promoting agents, preservatives, thickeners, chelating agents other than edetic acid or its salts, refreshing agents, and other additives commonly used in liquid aqueous preparations until they interfere with the effect of the present invention.

[0025] Examples of buffers include, but are not limited to, phosphate buffer, borate buffer, citrate buffer, tartrate buffer, acetate buffer, and amino acids.

[0026] Examples of pH adjusting agents include, but are not limited to, hydrochloric acid, boric acid, aminoethyl sulfonic acid, ε-aminocaproic acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium hydrogen carbonate, 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 slot, succinic acid, gluconolactone, ammonium acetate and the like.

[0027] Examples of isotonicity agents include, but are not limited to, saccharides such as sorbitol, glucose, mannitol, and cyclodextrin; polyols such as glycerol, propylene glycol; salts such as disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, 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.

[0028] Examples of dissolution promoting agents include, but are not limited to, nonionic surfactants such as polyoxyethylene sorbitan monooleate, polyoxyethylene hydrogenated castor oil, tyloxapol, pluronic; polyols such as glycerin, macrogol.

[0029] Examples of preservatives include, but are not limited to, alkyl diaminoethyl glycine hydrochloride, sodium benzoate, and ethanol; quaternary ammonium salts such as benzalkonium chloride, benzethonium chloride and cetyl pyridinium chloride; para-hydroxybenzoates such as methyl para-hydroxybenzoate, ethyl para-hydroxybenzoate, propyl para-hydroxybenzoate, butyl para-hydroxybenzoate; benzyl alcohol, phenylethyl alcohol, sorbic acid, thimerosal, chlorobutanol and sodium dehydroacetic acid.

[0030] Examples of thickeners include, but are not limited to, water-soluble macromolecular compounds such as polyvinylpyrrolidone, polyethylene glycol and polyvinyl alcohol; cellulose-based compounds such as hydroxyethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose and hydroxypropyl cellulose, carboxymethyl cellulose sodium.

[0031] Examples of chelating agents other than edetic acid include, but are not limited to, citric acid, polyphosphoric acid, sodium hexametaphosphate, metaphosphate, ascorbic acid, succinic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, and 1-hydroxyethane acetic acid and 1,1-hydroxyethanesulfonic acid acid and their pharmaceutically acceptable salts.

[0032] Examples of fresheners include, but are not limited to, 1-menthol, borneol, camphor, and eucalyptus oil.

[0033] In the present invention, the liquid aqueous preparation may further contain, if necessary, vasoconstrictor agents such as naphazoline and its salts (hydrochloride, nitrate), tetrahydrozolening hydrochloride, phenylephrine hydrochloride, epinephrine and its hydrochloride, ephedrine hydrochloride and methyl ephedrihydrode; anti-inflammatory agents such as dipotassium glycyrrhizinate, allantoin, ε-aminocaproic acid, vitamins; amino acids; anticholinesterases such as neostigminmethyl sulfate.

[0034] Examples of vitamins include, but are not limited to, vitamins A, such as retinal, retinol, retinoic acid, carotene, dehydroretinal, and lycopene; Witham B such as thiamin, tiamindisulfid, ditsetiamin, oktotiamin, tsikotiamin, bisibutiamin, bisbentiamin, prosultiamin, benfotiamine, fursultiamin, riboflavin, flavin adenine dinucleotide, pyridoxine, piridoksingidrohlorid, pyridoxal, hydroxocobalamin, cyanocobalamin, methylcobalamin, deoksiadenozilkobalamin, folic acid, tetrahydrofolic acid, dihydrofolic acid, nicotinic acid, nicotinamide, nicotinic alcohol, pantothenic acid, panthenol, biotin, choline and inositol; vitamins C, such as ascorbic acid and its derivatives and erythorbic acid and its derivatives; vitamins D, such as ergocalciferol, cholecalciferol, hydroxycholecalciferol and dihydrotachysterol; Vitamins E, such as tocopherol and its derivatives (e.g., tocopherol acetate) and ubiquinone derivatives; other vitamins such as carnitine, ferulic acid, γ-oryzanol, orotic acid, rutin, eriocytrin and hesperidin.

[0035] Examples of amino acids include, but are not limited to, leucine, isoleucine, valine, methionine, threonine, alanine, phenylalanine, tryptophan, lysine, glycine and asparagine, aspartic acid, serine, glutamine, glutamic acid, proline, tyrosine, cysteine, histidine, ornithine, hydroxyproline, hydroxylisine, glycyl glycine, aminoethyl sulfonic acid (taurine).

[0036] In the present invention, there is no particular limitation on the pH of a liquid aqueous preparation as long as it is acceptable for the place of use in the body. However, usually the pH is 4.5-9.0, preferably 6.0-8.0, and more preferably 7.0-8.0.

EXAMPLES

[0037] Although the present invention is described in more detail below with reference to examples, this does not mean that the present invention is limited to these examples.

[0038] Further, in the examples below, the pranoprofen used is Pranoprofen (JP Pharmacopoeia) manufactured by API Corporation, and the disodium edetate hydrate used is Sodium Edetate Hydrate (JP Pharmacopoeia) manufactured by Kanto Chemical Co., Inc., respectively.

[0039] According to the formulas shown in tables 1-7, liquid aqueous preparations are prepared containing sodium hyaluronate (weight average molecular weight 1040000, Seikagaku Corporation) industrial co., Ltd.). The pH of each liquid aqueous preparation was adjusted to 7.5. Liquid aqueous preparations (15 ml of each preparation) are distributed into 15 ml containers of polyethylene terephthalate (PET, brand RT543), the containers are corked and stored at 60 ° C for 4 weeks. Determine the viscosity (kinematic viscosity) of each liquid aqueous preparation before and after storage according to “Method I for Determining Viscosity <2.53>: Determining Viscosity with a Capillary Tubular Viscometer” by General Tests, Processes and Apparatus, Japanese Pharmacopoeia (Fifteenth Edition) at 20 ° C using a Ubbelohde type viscometer, and calculate the degree of conservation of viscosity (%) according to the following formula.

The degree of conservation of viscosity (%) = (kinematic viscosity after storage-1) / (kinematic viscosity before storage-1) × 100

[0040] 1. The inhibitory effect of pranoprofen on viscosity reduction.

As can be seen from table 1, in comparison with a liquid aqueous preparation of formula 3 containing sodium hyaluronate but not containing pranoprofen, liquid aqueous preparations of formulas 1 and 2, which are preparations containing in addition to the above 0.05 and 0.1 % wt./about. pranoprofen, respectively, show a marked suppression of viscosity reduction over time.

[0041]

Table 1 Formula (% w / v) Formula 1 Formula 2 Formula 3 Sodium hyaluronate 0.1 0.1 0.1 Pranoprofen 0.05 0.1 - Boric acid 1,6 1,6 1,6 Borach 0.65 0.65 0.65 Purified water Enough Enough Enough The degree of conservation of viscosity (%) 36 43 29th

[0042] 2. The inhibitory effect of pranoprofen and edetic acid sodium salt on viscosity reduction.

As can be seen from the following table 2, liquid aqueous preparations of formulas 4 and 5, which are preparations additionally containing sodium salt of edetic acid compared with formulas 1 and 2, respectively, receive and store for 4 weeks at 60 ° C, and compare their degree of conservation of viscosity. As a result, it was found that the combination of pranoprofen with the sodium salt of edetic acid gives an even more noticeable suppression of viscosity reduction.

[0043]

table 2 Formula (% w / v) Formula 1 Formula 4 Formula 2 Formula 5 Sodium hyaluronate 0.1 0.1 0.1 0.1 Pranoprofen 0.05 0.05 0.1 0.1 Disodium edetate hydrate - 0.01 - 0.1 Boric acid 1,6 1,6 1,6 1,6 Borach 0.65 0.65 0.65 0.65 Purified water Enough Enough Enough Enough The degree of conservation of viscosity (%) 36 40 43 46

[0044] 3. Investigation of the intrinsic inhibitory effect of sodium edetate on viscosity reduction.

To evaluate the intrinsic effect of sodium edetate on lowering the viscosity of a liquid aqueous preparation containing sodium hyaluronate, a liquid aqueous preparation of formula 3E is shown in Table 3 (a preparation additionally containing 0.01% w / v disodium edetate hydrate compared to the above preparation formula 3 without pranoprofen) is prepared, stored for 4 weeks at 60 ° C in the same manner as described above, the degree of conservation of viscosity is determined and the results are compared with the result obtained above for formula 3.

[0045]

Table 3 Formula (% w / v) Formula 3 Formula 3E Sodium hyaluronate 0.1 0.1 Pranoprofen - - Disodium edetate hydrate - 0.01 Boric acid 1,6 1,6 Borach 0.65 0.65 Purified water Enough Enough The degree of conservation of viscosity (%) 29th 21

[0046] As can be seen from table 3, when compared with formula 3, which corresponds to a preparation not containing pranoprofen, a preparation of formula 3E, additionally containing 0.01% w / v. disodium edetate hydrate exhibits a reduced degree of viscosity retention, indicating that the sodium salt of edetic acid itself does not affect the inhibition of the decrease in viscosity of a liquid aqueous preparation containing sodium hyaluronate. However, table 2 shows that, compared with the above-mentioned preparations of formulas 1 and 2, containing 0.1% wt./about. pranoprofen, but not containing sodium salt of edetic acid, preparations of formulas 4 and 5, i.e. preparations additionally containing, in comparison with the previous ones, 0.01% w / v. disodium edetate hydrate exhibit a high degree of viscosity retention. It is believed that this is due to some kind of synergistic effect that occurs with the combination of pranoprofen and the sodium salt of edetic acid.

[0047] 4. The inhibitory effect on reducing viscosity at various concentrations of sodium hyaluronate.

According to tables 4-6 below, liquid aqueous preparations are prepared containing sodium hyaluronate at various concentrations, and liquid aqueous preparations additionally containing pranoprofen, as well as disodium hydrate hydrate, respectively, are stored for 4 weeks at 60 ° C and their degrees are compared preservation of viscosity. As a result, as can be seen from Tables 4-6, a noticeable inhibitory effect of pranoprofen on reducing viscosity is observed, as well as an even more noticeable inhibitory effect of the combination of pranoprofen with the sodium salt of hyaluronic acid at each concentration of sodium hyaluronate.

[0048]

Table 4 Formula (% w / v) Formula 6 Formula 7 Formula 8 Sodium hyaluronate 0.02 0.02 0.02 Pranoprofen 0.1 0.1 - Disodium edetate hydrate - 0.01 - Boric acid 1,6 1,6 1,6 Borach 0.65 0.65 0.65 Purified water Enough Enough Enough The degree of conservation of viscosity (%) 49 56 29th

[0049]

Table 5 Formula (% w / v) Formula 9 Formula 10 Formula 11 Sodium hyaluronate 0.05 0.05 0.05 Pranoprofen 0.1 0.1 - Disodium edetate hydrate - 0.01 - Boric acid 1,6 1,6 1,6

Borach 0.65 0.65 0.65 Purified water Enough Enough Enough The degree of conservation of viscosity (%) 43 47 25

[0050]

Table 6 Formula (% w / v) Formula 12 Formula 13 Formula 14 Sodium hyaluronate 0.3 0.3 0.3 Pranoprofen 0.1 0.1 - Disodium edetate hydrate - 0.01 - Boric acid 1,6 1,6 1,6 Borach 0.65 0.65 0.65 Purified water Enough Enough Enough The degree of conservation of viscosity (%) twenty 25 13

[0051] 5. Investigation of the effect of buffer changes on the effect of suppressing viscosity reduction.

The corresponding liquid aqueous preparations are prepared according to formulas 15 and 16 from table 7, according to which preparations are obtained by replacing the buffer used in formulas 1 and 4 with phosphate buffer, and according to formula 17, when a preparation is obtained by removing pranoprofen from formula 16, preparations 4 are stored weeks at 60 ° C and examine their viscosity retention rates. As a result, it was found that the degree of conservation of the viscosity of liquid aqueous preparations according to formulas 15 and 16 is essentially comparable to the degree of liquid aqueous preparations according to formulas 1 and 4, respectively, and that replacing the borate buffer with a phosphate buffer does not significantly affect the effect of suppressing the decrease in viscosity, demonstrated by pranoprofen per se, a combination of pranoprofen and edetic acid sodium salt, or edetic acid sodium salt per se.

In addition, it was found that the degree of preservation of the viscosity of the liquid aqueous preparation corresponding to formula 17, which is a preparation containing sodium salt of edetic acid, but not containing pranoprofen, is only 25%. On the other hand, the corresponding value for formula 3 (borate buffer; the same concentration of sodium hyaluronate), which is a preparation that does not contain a viscosity reduction inhibiting ingredient, is 29%. Comparison of these results shows that edetic acid, used alone, does not have an overwhelming effect on viscosity reduction.

[0052]

Table 7 Formula (% w / v) Formula 15 Formula 16 Formula 17 Sodium hyaluronate 0.1 0.1 0.1 Pranoprofen 0.05 0.05 - Disodium edetate hydrate - 0.01 0.01 Disodium Hydrogen Phosphate Dodecahydrate 0.32 0.32 0.32 Sodium dihydrogen phosphate dihydrate 0.02 0.02 0.02 Purified water Enough Enough Enough The degree of conservation of viscosity (%) 39 43 25

[0053] 6. Evaluation of the inhibitory effect of pranoprofen on lowering the viscosity of liquid aqueous preparations containing hyaluronic acid at low concentrations.

According to the following table 8, prepare liquid aqueous preparations containing sodium hyaluronate (weight average molecular weight 3220000, Hyaluronsan HA-QSE, manufactured by Kewpie Corp.) at lower concentrations than in the above preparations. The pH of each liquid aqueous preparation was adjusted to 7.5. Similarly, as in the previous examples, liquid aqueous preparations (15 ml each) were distributed in 15 ml polyethylene terephthalate (PET) containers, the containers were corked and stored for 4 weeks at 60 ° C. The viscosity (kinematic viscosity) of each liquid aqueous preparation is determined before and after storage in the same way as in previous experiments, their degrees of conservation of viscosity are calculated and the results are compared.

[0054]

Table 8 Formula
(% w / v) Formula 18 Formula 19 Formula 20 Formula 21 Formula 22 Formula 23 Sodium hyaluronate 0.001 0.001 0.002 0.002 0.005 0.005 Pranoprofen 0.05 - 0.05 - 0.05 - Boric acid 1,6 1,6 1,6 1,6 1,6 1,6 Borach 0.65 0.65 0.65 0.65 0.65 0.65 Purified water Enough Enough Enough Enough Enough Enough The degree of conservation of viscosity (%) fifty 42 53 44 34 16

[0055] Table 8 shows the results of determining the degree of conservation of viscosity in liquid aqueous preparations containing sodium hyaluronate at concentrations of 0.001, 0.002 and 0.005% wt./about. with or without pranoprofen. It can be seen from the results that in any of the concentration groups of sodium hyaluronate, the pranoprofen-containing liquid aqueous preparation shows a significantly higher degree of viscosity conservation than its analogue, which does not contain pranoprofen.

[0056] As described hereinabove, it has been found that a decrease in the viscosity of liquid aqueous preparations containing sodium hyaluronates is noticeably suppressed by the addition of pranoprofen, regardless of the molecular weight of the hyaluronic acid. In addition, it has also been found that the additional addition of the edetic acid sodium salt results in a more pronounced suppression. In addition, it is confirmed that a noticeable inhibitory effect on reducing the viscosity of a liquid aqueous preparation is achieved by adding pranoprofen in combination with sodium salt of edetic acid at various concentrations of sodium hyaluronate, and that the type of buffer used does not affect the suppressing effect.

INDUSTRIAL APPLICABILITY

[0057] The present invention is useful as a novel means of suppressing a decrease in the viscosity of a liquid aqueous preparation containing hyaluronic acid or a pharmaceutically acceptable salt thereof over time.

Claims (7)

1. A method of suppressing a decrease in viscosity of a liquid aqueous preparation containing hyaluronic acid or a pharmaceutically acceptable salt thereof, comprising adding pranoprofen or a pharmaceutically acceptable salt to the liquid aqueous preparation, wherein the concentration of hyaluronic acid or its pharmaceutically acceptable salt is 0.001-1.0% by weight. /about. and where the addition of pranoprofen or a pharmaceutically acceptable salt thereof is produced in such a way that the concentration of pranoprofen or its pharmaceutically acceptable salt in a liquid aqueous preparation is 0.001-1.0% w / v. 2. The method of claim 1, wherein the pharmaceutically acceptable salt of hyaluronic acid is sodium hyaluronate. 3. The method according to p. 1 or 2, comprising the additional addition of edetic acid or its pharmaceutically acceptable salt. 4. The method according to p. 3, where the pharmaceutically acceptable salt of edetic acid is a sodium salt of edetic acid. 5. The method according to p. 1, where the addition of pranoprofen or its pharmaceutically acceptable salt is produced in such a way that its ratio in combination is 0.05-25 wt. shares per 1 wt. the proportion of hyaluronic acid or its pharmaceutically acceptable salt. 6. The method according to p. 1, where the liquid aqueous preparation is an eye drop. 7. A viscosity reduction suppressant for a liquid aqueous preparation, wherein the agent contains pranoprofen or a pharmaceutically acceptable salt thereof, and where the liquid aqueous preparation is a liquid aqueous preparation containing hyaluronic acid or a pharmaceutically acceptable salt thereof, wherein the concentration of hyaluronic acid or a pharmaceutically acceptable salt thereof is 0.001-1.0% wt./about. and where the concentration of pranoprofen or a pharmaceutically acceptable salt thereof in a liquid aqueous preparation is 0.001-1.0% w / v.