JP2023109174A - Hyaluronic Acid-Containing Eye Drops - Google Patents

Abstract

To suppress viscosity reduction of eye drops containing hyaluronic acid or a pharmaceutically acceptable salt thereof, preferably viscosity reduction due to lapse of time.SOLUTION: The problem of viscosity reduction of hyaluronic acid or a pharmaceutically acceptable salt thereof is solved by combining citric acid or a pharmaceutically acceptable salt thereof and propylene glycol, and furthermore boric acid or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

TECHNICAL FIELD The present invention relates to suppression of viscosity reduction in eye drops containing hyaluronic acid.

Hyaluronic acid has the function of retaining a large number of water molecules in the molecule, and has the effect of retaining and stabilizing tears to prevent dryness of the eyes. Therefore, it is used in eye drops for treating corneal epithelial disorders. However, hyaluronic acid is easily decomposed in eye drops, and the viscosity may decrease over time. If the viscosity of hyaluronic acid is lowered, sufficient pharmacological effects cannot be obtained. Therefore, a method for effectively suppressing the viscosity decrease of hyaluronic acid in eye drops is desired.

The hyaluronic acid concentrations of hyaluronic acid-containing eye drops currently used for the treatment of corneal epithelial disorders are 0.1 w/v% and 0.3 w/v%. Sodium Acid Ophthalmic Solution”. The Japanese Pharmacopoeia describes the standard of kinematic viscosity, and when sodium hyaluronate is contained as an eye drop, the kinematic viscosity must be within the range of the described standard.

Known eye drops containing a polyol such as glycerin or propylene glycol and a phosphate buffer (Patent Document 1) and eye drops containing boric acid are known as eye drops that suppress the decrease in the viscosity of hyaluronic acid ( Patent document 2). However, although these eye drops suppress the decrease in viscosity, the viscosity at the time of preparation increases and exceeds the standard range of the Japanese Pharmacopoeia, so they do not meet the standards as pharmaceuticals.

Hitherto, among hyaluronic acid-containing eye drops, eye drops containing boric acid or a pharmaceutically acceptable salt thereof and propylene glycol have not been known, and moreover, citric acid or a pharmaceutically acceptable salt thereof. It is completely unknown that the addition of hyaluronic acid or a salt thereof can suppress the increase in viscosity during preparation of eye drops, and in particular, can extremely effectively suppress the decrease in viscosity of hyaluronic acid or a salt thereof when preparing eye drops having a preferable osmotic pressure ratio. Not done.

JP-A-10-72376 JP-A-11-43446

An object of the present invention is to provide an eye drop containing hyaluronic acid or a pharmaceutically acceptable salt thereof for suppressing a decrease in viscosity.

As a result of intensive research to solve the above problems, the present inventors have found that the viscosity reduction of hyaluronic acid or a pharmaceutically acceptable salt thereof, preferably the viscosity reduction over time, can be reduced by boric acid or a pharmaceutically acceptable salt thereof. It has been found that a combination of possible salts and propylene glycol can be effectively inhibited. Furthermore, the addition of citric acid or a pharmaceutically acceptable salt thereof can suppress the increase in viscosity during preparation, and in particular, can extremely effectively suppress the decrease in viscosity when preparing eye drops having a favorable osmotic pressure ratio. I found out. Based on the above knowledge, the present inventors have further studied and completed the present invention.

That is, the present invention relates to the following [1] to [8].
[1] (a) 0.1% (w/v) or 0.3% (w/v) of hyaluronic acid or a pharmaceutically acceptable salt thereof relative to the total eye drop;
(b) chlorhexidine or a pharmaceutically acceptable salt thereof;
(c) propylene glycol,
(d) citric acid or a pharmaceutically acceptable salt thereof; and (e) boric acid or a pharmaceutically acceptable salt thereof.
[2] The ophthalmic solution according to [1] above, wherein the citric acid or a pharmaceutically acceptable salt thereof is sodium citrate or a hydrate thereof.
[3] The ophthalmic solution of [1] or [2] above, containing 0.1% (w/v) hyaluronic acid or a pharmaceutically acceptable salt thereof.
[4] Any one of the above [1] to [3], which contains 0.3 to 0.9% (w/v) citric acid or a pharmaceutically acceptable salt thereof based on the entire eye drop. The eye drops described in .
[5] The ophthalmic solution according to any one of [1] to [4], containing 0.05 to 0.5% (w/v) propylene glycol with respect to the entire ophthalmic solution.
[6] The ophthalmic solution according to any one of [1] to [5], which has an osmotic pressure ratio of 0.8 to 1.2.
[7] The ophthalmic solution according to any one of [1] to [6], which has a pH of 6.5 to 7.5.
[8] citric acid or a pharmaceutically acceptable salt thereof and propylene glycol, and boric acid or a pharmaceutically acceptable salt thereof, in an eye drop containing hyaluronic acid or a salt thereof, A method for inhibiting viscosity reduction of a pharmaceutically acceptable salt.
[9] A pharmaceutical, wherein the ophthalmic solution according to any one of [1] to [7] is stored in a storage container that has been sterilized with an electron beam or gas.
[10] The drug according to [9] above, wherein the gas is hydrogen peroxide gas or ethylene oxide gas.
[11] The drug according to [9] or [10], wherein the storage container is polyolefin or PET.

INDUSTRIAL APPLICABILITY According to the present invention, an eye drop containing hyaluronic acid or a pharmaceutically acceptable salt thereof can suppress a decrease in viscosity of hyaluronic acid or a pharmaceutically acceptable salt thereof. Furthermore, in a hyaluronic acid-containing eye drop containing boric acid or a pharmaceutically acceptable salt thereof and propylene glycol, the addition of citric acid or a pharmaceutically acceptable salt thereof can extremely effectively suppress the decrease in viscosity. .

[Hyaluronic acid or a pharmaceutically acceptable salt thereof]
The hyaluronic acid in the present invention may be any hyaluronic acid that can be used as eye drops. Hyaluronic acid or a pharmaceutically acceptable salt thereof can be used alone or in combination of two or more. Examples of such pharmaceutically acceptable salts of hyaluronic acid preferably include sodium, potassium, magnesium, calcium and the like, more preferably sodium hyaluronate, but are not limited thereto.

The weight average molecular weight of hyaluronic acid or a pharmaceutically acceptable salt thereof is preferably about 300,000 to 4,000,000, more preferably about 500,000 to 1,200,000, but is not limited thereto.
In the ophthalmic solution of the present invention, the amount of hyaluronic acid or a pharmaceutically acceptable salt thereof is 0.1 w/v% or 0.3 w/v% of the total ophthalmic solution. Preferably, it is 0.1 w/v%, and another preferable example is 0.3 w/v%.

Eye drops containing hyaluronic acid or a pharmaceutically acceptable salt thereof of the present invention are usually used for treatment of corneal epithelial disorders, etc., but are not limited thereto. "Treatment" means alleviating or curing and alleviating a condition or disease and/or its attendant symptoms.
In addition, "corneal epithelial injury" is clinically classified finely according to the defect site, pathological findings, etc. The barrier of the corneal epithelium is damaged due to various external factors, such as temporary scars on the corneal surface due to various factors, such as dry eyes such as Sjögren's syndrome, Stevens-Johnson syndrome, and dry eye, and exposure to light such as ultraviolet rays and X-rays. Includes, but is not limited to, ocular discomfort resulting from impaired function. Examples of discomfort symptoms include, but are not limited to, eye discomfort, dry eyes, itchy eyes, and the like.

[Citric acid or a pharmaceutically acceptable salt thereof]
In the present invention, citric acid or a pharmaceutically acceptable salt thereof is used to adjust the viscosity when preparing eye drops.
In the eye drops of the present invention, citric acid or a pharmaceutically acceptable salt thereof is preferably about 0.01 to 3.5 w/v% of the entire eye drops. , more preferably about 0.2 to 1.0 w/v %, and more preferably about 0.6 w/v % with respect to the entire ophthalmic solution, but are not limited thereto. In addition, when citric acid or a pharmaceutically acceptable salt thereof is a hydrate, the hydration number is preferably 0 to 2, more preferably a dihydrate, but limited to these not. In the present invention, citric acid is preferably citric acid hydrate or anhydrous citric acid, but is not limited to these. In the present invention, the pharmaceutically acceptable salt of citric acid is preferably sodium citrate hydrate, sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate etc., preferably sodium citrate monohydrate, sodium citrate dihydrate, sodium citrate, but not limited thereto.

[Propylene glycol]
In the eye drops of the present invention, boric acid or a pharmaceutically acceptable salt thereof and propylene glycol are preferably added over time (preferably under severe conditions of about 50 to 70 degrees) to adjust the viscosity of the eye drops. about 1 to 2 weeks, more preferably about 2 weeks under severe conditions of about 60 degrees, but not limited thereto).
In the eye drops of the present invention, propylene glycol is preferably 0.05 to 0.5 w/v% with respect to the whole eye drops, and about 0.2 to 0.4 w/v% with respect to the whole eye drops. It is more preferably contained by v %, more preferably about 0.3 w/v % with respect to the entire eye drop, but is not limited thereto.
In addition, in the present invention, polyhydric alcohols other than propylene glycol (eg, polyethylene glycol, glycerin, xylitol, diethylene glycol, mannitol, sorbitol, polyvinyl alcohol, etc.) may be further included.

[boric acid or a pharmaceutically acceptable salt thereof]
Uses of boric acid or a pharmaceutically acceptable salt thereof in the ophthalmic solution of the present invention include stabilizers, buffers, tonicity agents, pH adjusters, preservatives, preservatives, and the like. Not limited.
In the ophthalmic solution of the present invention, boric acid or a pharmaceutically acceptable salt thereof is preferably about 0.01 to 1.0 w/v% of the entire ophthalmic solution. , about 0.02 to 0.3 w/v%, but not limited thereto. Further, when boric acid or a pharmaceutically acceptable salt thereof is a hydrate, the hydration number is preferably 0 to 10, and more preferably a decahydrate, but limited to these not. In the present invention, the pharmaceutically acceptable salt of boric acid preferably includes borax (Na ₂ B ₄ O _{7.10H 2} O (also called sodium borate), ammonium borate, etc. Borax (sodium borate) is more preferred, but is not limited thereto.

[Chlorhexidine or a pharmaceutically acceptable salt thereof]
In the present invention, chlorhexidine or a pharmaceutically acceptable salt thereof is used as a preservative so that eye drops have a certain preservative effect. Chlorhexidine or a pharmaceutically acceptable salt thereof can be used alone or in combination of two or more. Examples of such salts include gluconate, hydrochloride, acetate and the like, with gluconate being preferred, but not limited thereto.
The amount of chlorhexidine or a pharmaceutically acceptable salt thereof is preferably 0.0001 to 0.01 w/v% of the total formulation. More preferably, it is 0.0005 w/v% to 0.01 w/v%. More preferably 0.0005 w/v% to less than 0.01 w/v%, still more preferably 0.001 w/v% to less than 0.01 w/v%, particularly preferably 0.0009 to 0.002 w/v%. When the amount of chlorhexidine or a pharmaceutically acceptable salt thereof is within the above range, the eye drops are useful because they have a certain preservative effect.

[Buffer]
In the present invention, a boric acid-based buffer solution, preferably boric acid or a pharmaceutically acceptable salt thereof, is preferably used. Boric acid or a pharmaceutically acceptable salt thereof may be used as an eye drop. In the present invention, as boric acid, one or more of boric acid salts such as potassium tetraborate, potassium metaborate, and ammonium borate may be used, but the boric acid is not limited to these. Also, boric acid may be a hydrate.

In the present invention, it is preferable to use boric acid and a pharmaceutically acceptable salt of boric acid in combination as a buffer solution. When the amount of boric acid or a pharmaceutically acceptable salt thereof is within the above range, it is possible to more effectively suppress the decrease in viscosity of hyaluronic acid or a pharmaceutically acceptable salt thereof. , The feeling of use is good because it is low irritation. In addition, since boric acid or a pharmaceutically acceptable salt thereof itself also has an antiseptic effect, for example, by reducing the amount of preservatives such as chlorhexidine or a pharmaceutically acceptable salt thereof, cell It is preferable because it has the advantage of reducing toxicity.
In the present invention, a phosphate buffer may be further included, but preferably not included. Examples of such a phosphate-based buffer include sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium acetate, and the like, including hydrates, but are not limited thereto. Also, in the present invention, it is preferred that epsilon-aminocaproic acid is not contained.

The eye drops of the present invention preferably further contain a sodium salt and/or a potassium salt. More preferably sodium and potassium salts are used.
Sodium salts include sodium chloride, disodium monohydrogen phosphate, monosodium dihydrogen phosphate, sodium sulfate, sodium hydrogen carbonate, sodium carbonate, sodium citrate, sodium hydroxide and the like. Preferred are sodium chloride, sodium monohydrogen phosphate and sodium dihydrogen phosphate, and more preferred is sodium chloride.
Potassium salts include potassium chloride, dipotassium monohydrogen phosphate, monopotassium dihydrogen phosphate, potassium acetate and the like. Potassium chloride, dipotassium monohydrogen phosphate, and monopotassium dihydrogen phosphate are preferred, and potassium chloride is more preferred. Sodium salt and/or potassium salt can be used alone or in combination of two or more.
In the present invention, when a sodium salt and/or a potassium salt are included, there is a preferred advantage that it is convenient for isotonicity (osmotic pressure) adjustment.

Hyaluronic acid or a pharmaceutically acceptable salt thereof, propylene glycol, citric acid or a pharmaceutically acceptable salt thereof, chlorhexidine or a pharmaceutically acceptable salt thereof, boric acid or a pharmaceutically acceptable salt thereof, used in the present invention Acceptable salts, sodium salts, potassium salts and the like can be easily obtained and used, for example, as commercially available products.

The ophthalmic solution of the present invention further contains dilute hydrochloric acid, sulfuric acid, polyphosphoric acid, propionic acid, oxalic acid, gluconic acid, malic acid, succinic acid, fumaric acid, lactic acid, tartaric acid, sodium hydroxide, and potassium hydroxide as a pH adjuster. , magnesium hydroxide, calcium hydroxide, monoethanolamine, triethanolamine, diisopropanolamine, and the like.

In addition to the above components, the eye drops of the present invention contain a base such as water, other active ingredients, and other known additives (stabilizers, tonicity agents, tonicity agents, tonicity agents, etc.), as long as they do not impair the effects of the present invention. Dissolution aids, antioxidants, solvents, solubilizers, suspending agents, flavoring agents/flavors, cooling agents, coloring agents, surfactants, thickening agents) and the like can be added. These optional components can be added in normal amounts within a range that does not impair the effects of the present invention.
The water used as a base for the production of eye drops is not particularly limited as long as it can be used for ophthalmic agents, and for example, purified water can be used. There are no particular restrictions on the mixing order and mixing method of each component, and each component may be dissolved in water by a known preparation method.

The eye drops of the present invention may contain preservatives other than chlorhexidine or a pharmaceutically acceptable salt thereof as long as the effects of the present invention are exhibited. In addition, since edetic acid (EDTA) and its pharmaceutically acceptable salts are irritating to the eyes, the ophthalmic solution of the present invention should be substantially free of EDTA or its pharmaceutically acceptable salts. is preferred.

[Suppression of Viscosity (Kinematic Viscosity) Reduction]
In the present invention, the viscosity (kinematic viscosity) of eye drops containing hyaluronic acid or a pharmaceutically acceptable salt thereof can be measured by the method described in Japanese Pharmacopoeia (18th revision) 2.53 Viscosity measurement method. Alternatively, it may be measured by a method known in the art.
The viscosity of the eye drops of the present invention is, for example, 3.0 to 4.0 mm ² /s ((a): hyaluronic acid or a pharmaceutically acceptable or 17 to 30 mm ² /s ((b): when the amount of hyaluronic acid or a pharmaceutically acceptable salt thereof is 0.1 w/v% with respect to the entire eye drop) In the case of 0.3 w/v% with respect to the whole)), it is preferably within this range. As for (a), it is more preferably in the range of 3.2 to 4.0 mm ² /s, and more preferably in the range of 3.5 to 4.0 mm ² /s. not. Regarding (b), it is more preferably in the range of 22 to 30 mm ² /s, more preferably in the range of 25 to 29 mm ² /s, but is not limited thereto.
In addition, in the present invention, the suppression of viscosity reduction is preferably, for example, under severe test conditions of about 50 to 70 degrees, after 1 to 2 weeks, the viscosity of the original ophthalmic solution is reduced by 5 to 5. A decrease of about 30% is suppressed, more preferably a decrease of about 10 to 25% of the original viscosity of the ophthalmic solution is suppressed after 1 to 2 weeks, more preferably Under severe test conditions of about 60°C, after about two weeks, the reduction in viscosity is suppressed by about 20% relative to the original viscosity of the ophthalmic solution, but the present invention is not limited to this.

The ophthalmic solution of the present invention preferably has an osmotic pressure ratio of 0.8 to 1.2. More preferably about 0.9 to 1.1, still more preferably about 1. The osmotic pressure can be measured by the method described in the Japanese Pharmacopoeia (18th revision) general test method osmolality measurement method (osmolality measurement method), or by a method known in the art. good too.
Further, the eye drops of the present invention preferably have a pH of about 6-8. More preferably, it is between 6.5 and 7.5, and even more preferably between about 7.3 and 7.4.
Adjustment of the osmotic pressure ratio and pH can be carried out by methods known in the art using the above-mentioned pH adjusters, tonicity agents, salts and the like.

The eye drops of the present invention are usually packaged in multi-dose eye drop containers suitable for repeated use over a long period of time. The internal volume of the container is usually about 5 mL to 20 mL. The shape, material, and the like of the container are not particularly limited, and a storage container usually used for eye drops can be used. The container need not be light-tight, but may be a light-tight container. The container does not have to be sterile, but is preferably sterile. The container sterilization method is preferably electron beam (EB) sterilization, ethylene oxide gas (EOG) sterilization, hydrogen peroxide (H ₂ O ₂ ) gas sterilization, gamma ray sterilization, etc. More preferably, electron beam ( EB) sterilization, ethylene oxide gas (EOG) sterilization, hydrogen peroxide ( _H2O2 ) _gas sterilization, but not limited to these.
As the material of the storage container, preferably polyolefins such as PP (polypropylene) and PE (polyethylene), PET (polyethylene terephthalate), etc., and more preferably polyolefins, and PE or PP are preferable, but these is not limited to PE may be LDPE (low density polyethylene) or HDPE (high density polyethylene).
The storage container of the present invention includes the main body (bottle), the inner stopper (nozzle) and the lid (cap). Preferably, but not limited to, the body. PE or PP is more preferable as the material for the inner plug or the lid, but the material is not limited to these.

The eye drops of the present invention are usually prepared by dissolving the above-mentioned ingredients and other necessary ingredients in a predetermined amount of water, and filling the resulting solution into an eye drop container. After dissolving each component in water, it is preferable to appropriately adjust the pH and osmotic pressure of the obtained solution by a known method. Generally, after adjusting the osmotic pressure and pH of a solution containing the above-mentioned ingredients and other necessary ingredients, the eye drops of the present invention are filtered and sterilized in a sterile environment, and aseptically filled into washed and sterilized eye drop containers. can be manufactured. The eye drop container is preferably of multi-dose type, but is not limited to this. The term "multi-dose eye drops" means an eye drop contained in a multi-dose eye drop container. It means a storage container that can restore the sealed state to the extent that it can be carried even after opening so that the same container can be used repeatedly for several months (preferably several days to one month).
In this specification, the term "pharmaceutical" may refer to a product in which an eye drop is stored in a storage container.

Preferred subjects for administration of the eye drops of the present invention are individuals (animals) who have or are likely to develop the corneal epithelial injury. Preferably, it is an individual having the corneal epithelial injury. Preferred individuals are mammals such as humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs and monkeys, with humans being particularly preferred.

The dose and administration frequency of the eye drops of the present invention can be appropriately selected according to the symptoms of the subject to be administered. Usually, about 1 to 3 drops are instilled into the eyes for adults about 1 to 6 times a day.

EXAMPLES The present invention will be described in more detail below with reference to Examples, but these are not intended to limit the present invention in any way.

[Experimental Example 1] Confirmation of Effect of Citrate and Propylene Glycol (Production of Eye Drops of Example 1) After adding and dissolving 0.1 g of sodium hyaluronate to 80 g of purified water, 0.3 g of boric acid and boron were dissolved. 0.025 g of sand, 0.33 g of sodium chloride, 0.15 g of potassium chloride, 0.6 g of sodium citrate hydrate, 0.3 g of propylene glycol and 5 μL of chlorhexidine gluconate solution (20% solution) were added and dissolved. rice field. Purified water was added thereto, and appropriate amounts of hydrochloric acid and sodium hydroxide were added to adjust the pH to 6.5 to make the total volume 100 mL, thereby obtaining the eye drops of Example 1.

(Production of eye drops of Examples 2 to 6 and eye drops of Comparative Examples 1 to 9) /v%), the eye drops of Examples 2 to 6 and the eye drops of Comparative Examples 1 to 9 were prepared in the same manner as for eye drop 1 above, except for the blending amount and pH of each component described in .

According to the method described in the Japanese Pharmacopoeia (18th revision) general test methods, viscosity measurement method, method 1, capillary viscometer method, perform a kinematic viscosity measurement test by measuring kinematic viscosity at a measurement temperature of 30 ° C, and instill each eye. The kinematic viscosity of the liquid (starting kinematic viscosity) was measured. Furthermore, under the same severe test conditions of about 60 degrees, the kinematic viscosity was measured after 2 weeks had passed, and the viscosity retention rate was calculated. A Ubbelohde viscometer manufactured by Sogo Rikagaku Glass Co., Ltd. (TOP) was used for viscosity measurement. Similar methods and calculations were used in Experimental Examples 2-3.

The numerical unit for the components in Tables 1 to 4 below is w/v %, and the numerical unit for kinematic viscosity is mm ² /s.

(Results and Consideration of Experimental Example 1) Compared with Comparative Examples 1 to 3 in Table 1, in Comparative Examples 4 to 6 in Table 1, boric acid and borax were used instead of phosphate, and the initial movement Both viscosity and kinematic viscosity retention are improved. Here, when only propylene glycol is added to the eye drops of Comparative Examples 4 to 6 (Table 1) and Comparative Examples 7 to 9 (Table 2), respectively, the initial kinematic viscosity and the kinematic viscosity retention rate are further improved ( Data not shown (see also Reference Examples 2 and 4 in Experimental Example 3 below). However, it is necessary to adjust the osmotic pressure ratio of the ophthalmic solution when making it into a product. The osmotic pressure ratio of pharmaceutical eye drop products is preferably 1, because corneal damage may occur in the case of hypertonicity or hypotonicity. The inventor of the present application found that this problem can be solved by adding citric acid or a salt thereof to the eye drops of Comparative Examples 4 to 6 (Table 1) and Comparative Examples 7 to 9 (Table 2). rice field. That is, in the eye drops having the compositions described in Examples 1 to 3 (Table 1) and Examples 4 to 6 (Table 2), Comparative Examples 4 to 6 (Table 1) and Comparative Examples 7 to 9 (Table 2) It is considered to be superior to eye drops in that the initial kinematic viscosity does not increase too much.

[Experimental Example 2] Confirmation of the effect when the osmotic pressure ratio is adjusted to 1 (manufacturing of eye drops of Example 7) After adding 0.1 g of sodium hyaluronate to 80 g of purified water and dissolving, 0.3 g of boric acid was added. , 0.025 g of borax, 0.15 g of potassium chloride, 0.966 g of sodium citrate hydrate, 0.811 g of propylene glycol and 5 μL of chlorhexidine gluconate solution (20% solution) were added and dissolved. Purified water was added thereto, and appropriate amounts of hydrochloric acid and sodium hydroxide were added to adjust the pH to 7.3 to make the total volume 100 mL, thereby obtaining an eye drop of Example 7.

(Production of Eye Drops of Comparative Example 10) Eye drops of Comparative Example 10 were produced in the same manner as for the eye drops of Example 7 above, except for the blending amounts and pH of each component shown in Table 3 below.

(Results and Discussion of Experimental Example 2) In the eye drops of Comparative Example 10 containing only propylene glycol, the kinematic viscosity was 4.24 when the osmotic pressure ratio was set to 1.0 by adjusting the amounts of sodium chloride and potassium chloride. When the amount ^of hyaluronic acid or a pharmaceutically acceptable salt thereof is 0.1 w/v% of the total ophthalmic solution, the Japanese Pharmacopoeia (18th Amendment), but the ophthalmic solution of Example 7 containing propylene glycol and citrate had a kinematic viscosity of 3.0 to 4 when the osmotic pressure ratio was adjusted to 1.0. 0 mm ² /s, which was preferable.

[Experimental Example 3] Confirmation of effect when edetate is used instead of citrate (manufacture of eye drops of Example 8) After adding and dissolving 0.1 g of sodium hyaluronate to 80 g of purified water, 0.3 g of boric acid, 0.025 g of borax, 0.33 g of sodium chloride, 0.15 g of potassium chloride, 0.6 g of sodium citrate hydrate, 0.3 g of propylene glycol and chlorhexidine gluconate solution (20% solution) ) was added and dissolved. Purified water was added thereto, and appropriate amounts of hydrochloric acid and sodium hydroxide were added to adjust the pH to 6.5 to make the total volume 100 mL, thereby obtaining an eye drop of Example 8.

(Production of eye drops of Example 9, eye drops of Reference Examples 1-4, and eye drops of Comparative Examples 11-12)
The eye drops of Example 9, the eye drops of Reference Examples 1 to 4, and the eye drops of Comparative Examples 11 and 12 were prepared in the same manner as for eye drop 8, except for the amount and pH of each component shown in Table 4 below. manufactured.

(Results and Discussion of Experimental Example 3) The eye drops of Examples 8 and 9 containing propylene glycol and citric acid or a salt thereof were compared with the eye drops of Reference Examples 1 and 2 and Reference Examples 3 and 4, respectively. As a result, the initial kinematic viscosity did not rise too much, which was preferable. In addition, the eye drops of Examples 8 and 9 containing propylene glycol and citric acid or a salt thereof were found to be less effective in the initial movement than the eye drops containing propylene glycol and edetic acid of Comparative Examples 11 and 12, respectively. It was preferable because the viscosity did not increase too much. The eye drops of Examples 8 and 9 were also excellent in kinematic viscosity retention.

[Experimental Example 4] Examination of the effects of the material of the storage container and the sterilization method (manufacture of the eye drops of Example 10) 0.1 g of sodium hyaluronate was added to 80 g of purified water and dissolved, and then 0.3 g of boric acid was added. , 0.025 g of borax, 0.33 g of sodium chloride, 0.15 g of potassium chloride, 0.6 g of sodium citrate hydrate, 0.3 g of propylene glycol and 5 μL of chlorhexidine gluconate solution (20% solution) were added. Dissolved. Purified water was added thereto, and appropriate amounts of hydrochloric acid and sodium hydroxide were added to adjust the pH to 7.0 to make the total volume 100 mL, thereby obtaining an eye drop of Example 10.
Then, the obtained eyedrops were filled into a storage container made of the material (PP) shown in Table 5 and sterilized by the method (EOG) shown in Table 5 to obtain a pharmaceutical product.

(Production of eye drops of Examples 11 to 15 and eye drops of Comparative Examples 12 to 17)
Eye drops of Examples 11 to 15 and comparative eye drops were prepared in the same manner as for the eye drops of Example 10 above, except for the blending amount of each component, pH, container material, and sterilization method shown in Tables 5 and 6 below. The eye drops of Examples 12 to 17 were produced, and the resulting eye drops were filled in storage containers to obtain pharmaceuticals.

(Results and Discussion of Experimental Example 4) Regarding the eye drops containing propylene glycol and citric acid or a salt thereof of the present invention, for which favorable results were obtained in Experimental Examples 1 to 3, the material and sterilization of the storage container were further examined. It was confirmed whether the same effect could be obtained even when the method was changed.
The obtained results were as follows.
(1) When using a storage container made of PP (polypropylene) and sterilized by EOG (ethylene oxide gas):
Compared to the pharmaceutical of Comparative Example 12, which is the same condition except that it does not contain propylene glycol and citric acid or a salt thereof, the pharmaceutical of Example 10 of the present invention does not have an excessively high initial kinematic viscosity, It was also excellent in viscosity retention (Table 5).
(2) If the material is PP and a non-sterilized storage container is used:
Compared to the drug of Comparative Example 13, which is the same condition except that it does not contain propylene glycol and citric acid or a salt thereof, the drug of Example 11 of the present invention does not have an excessively high initial kinematic viscosity, and the dynamic viscosity is not too high. It was also excellent in viscosity retention (Table 5).
(3) When using a storage container made of PET (polyethylene terephthalate) and EB (electron beam) sterilized:
Compared to the drug of Comparative Example 14, which is the same condition except that it does not contain citrate, the drug of Example 12 of the present invention does not have an excessively high initial kinematic viscosity, and is also excellent in kinematic viscosity retention. (Table 5).
(4) When using a PP sterilized storage container:
Compared to the pharmaceutical of Comparative Example 15, which is the same condition except that it does not contain citrate, the pharmaceutical of Example 13 of the present invention does not have an excessively high initial kinematic viscosity, and is also excellent in kinematic viscosity retention. (Table 6).
(5) If the material is LDPE (low density polyethylene) and a non-sterile storage container is used:
Compared to the pharmaceutical of Comparative Example 16, which is the same condition except that it does not contain propylene glycol and citric acid or a salt thereof, the pharmaceutical of Example 14 of the present invention does not have an excessively high initial kinematic viscosity, and the dynamic viscosity is not too high. It was also excellent in viscosity retention (Table 6).
(6) When using a storage container made of LDPE and sterilized with H ₂ O ₂ (hydrogen peroxide) gas:
Compared to the drug of Comparative Example 17, which is the same condition except that it does not contain propylene glycol and citric acid or a salt thereof, the drug of Example 15 of the present invention does not have an excessively high initial kinematic viscosity, It was also excellent in viscosity retention (Table 6).
From the results of (1) to (6) above, the pharmaceuticals filled with the hyaluronic acid-containing eye drops containing propylene glycol and citric acid or a salt thereof of the present invention are excellent even when various containers and sterilization methods are used. It has been shown to be useful due to its kinematic viscosity.

INDUSTRIAL APPLICABILITY The present invention is useful in the field of ophthalmology, particularly in the field of eye drops.

Claims (8)

(a) 0.1% (w/v) or 0.3% (w/v) of hyaluronic acid or a pharmaceutically acceptable salt thereof based on the total eye drop;
(b) chlorhexidine or a pharmaceutically acceptable salt thereof;
(c) propylene glycol,
(d) citric acid or a pharmaceutically acceptable salt thereof; and (e) boric acid or a pharmaceutically acceptable salt thereof. The ophthalmic solution according to claim 1, wherein the citric acid or its pharmaceutically acceptable salt is sodium citrate or its hydrate. 2. The ophthalmic solution according to claim 1, containing 0.1% (w/v) hyaluronic acid or a pharmaceutically acceptable salt thereof. The ophthalmic solution according to claim 1, which contains 0.3 to 0.9% (w/v) of citric acid or a pharmaceutically acceptable salt thereof based on the total ophthalmic solution. 5. The eye drop according to any one of claims 1 to 4, which contains 0.05 to 0.5% (w/v) of propylene glycol relative to the whole eye drop. The ophthalmic solution according to any one of claims 1 to 4, which has an osmotic pressure ratio of 0.8 to 1.2. The ophthalmic solution according to any one of claims 1 to 4, which has a pH of 6.5 to 7.5. Citric acid or a pharmaceutically acceptable salt thereof and propylene glycol, and further boric acid or a pharmaceutically acceptable salt thereof, in eye drops containing hyaluronic acid or a pharmaceutically acceptable salt thereof. A method for reducing the viscosity reduction of acceptable salts.