JP7370316B2 - Eye drop type eyewash medicinal composition - Google Patents

Description

The present invention is an eye drop type eye wash medicinal composition having a viscosity of 12 mPa·s or less, which is characterized in that it is used so that 4 or more drops are instilled into each eye once. Regarding.

Eye problems are increasing with the increase in the number of hay fever patients and the spread of contact lenses. In addition, various eye drops have been developed and used for its prevention and treatment. As a way to prevent such eye problems in advance, the use of eye washes that effectively remove pollen, dust, protein, and other stains that have entered the eyes is increasing. For such eyewashes, after putting the eyewash into an eyewash cup, the user presses the area around the eyes of the user against the opening edge of the cup, and turns the user's face upward along with the cup to drain the eyewash inside the cup. Generally, the eyewash is of the type that the user contacts with the eye surface and blinks several times to wash the eyes (this type of eyewash is also referred to hereinafter as a "cup-type eyewash").

This cup-type eyewash requires about 5 mL of eyewash for one eyewash, and the amount is large if used multiple times, so it is not very portable. In addition, since a large amount of eyewash, about 5 mL, is used in one eyewash, there is a problem in that the lachrymal fluid on the ocular surface is washed away excessively, causing a feeling of dryness in the eyes. Furthermore, according to the cup-type eyewash method, the eyewash comes into contact with the skin around the eyes, so the skin moisturizing ingredients around the eyes are washed away and the skin becomes dry (Patent Document 1). There is also the problem that adhering dirt (sweat, pollen, dust, etc.) gets into the eyes even though they have been washed, causing eye problems.

However, there has been no research on eyewash methods that have similar or equal or greater dirt (pollen, dust, protein, etc.) removal effects than cup-type eyewashes, and that solve the aforementioned problems of cup-type eyewashes. Very little done.

Japanese Patent Application Publication No. 2002-003404

An object of the present invention is to find a composition suitable for a new eyewashing technique, that is, a composition suitable for eyewashing using eyedrops (hereinafter also referred to as "eyedrop type eyewash") and its dosage.

The present inventors wondered what kind of composition and dosage should be used when using eyedrop-type eyewashes to obtain an eyewashing effect similar to, equivalent to, or better than that of cup-type eyewashes. researched extensively. As a result, the present inventors found that when using eyedrop-type eyewash, the viscosity of the composition and the number of drops per eye (or the total amount of eyedrops applied per eye) It was found that there is a large correlation between the eyewash effect and the eyewash effect. More specifically, by instilling 4 or more drops, preferably 4 or more and 6 or less drops of a composition having a viscosity of 12 mPa·s or less per eye, the composition is similar to a cup-type eyewash. It has been found that an eye washing effect equivalent to or greater than that can be obtained. In addition, since the eyewash is performed using eye drops, contact of the eyewash with the skin, eyelashes, etc. around the eye is minimized, and the eyewash that is contaminated by contact with the skin, eyelashes, etc. around the eye is prevented from entering the eye. The present invention was completed based on the discovery that eye problems caused by exposure to the skin can be prevented and/or avoided. Furthermore, the present inventors have also found that a composition in which boric acid or a salt thereof and/or edetic acid or a salt thereof is further blended into the above composition has an effect of suppressing pollen bursting.

That is, the present invention is as follows.
[1] An eye drop type eye wash composition having a viscosity of 12 mPa·s or less, which is used so that 4 or more drops are instilled into each eye once.
[2] The eye-drop type eyewash medicinal composition according to [1], which is used so that 6 drops or less are instilled once per eye.
[3] An eye drop type eye wash composition having a viscosity of 12 mPa·s or less, which is used so that the total eye drop volume is 120 μL or more once per eye. Composition.
[4] The eye-drop type eyewash medicinal composition according to [3], which is used so as to be instilled once per eye in a total amount of 300 μL or less of eye drops.
[5] Any one of [1] to [4] further contains at least one selected from the group consisting of anti-inflammatory/astringent components, antihistamine components, inorganic salts, alkyl polyaminoethylglycine, and boric acid or its salts. The eye drop type eyewash medicinal composition described in .
[6] The eyedrop type eyewash medicinal composition according to any one of [1] to [4], further containing boric acid.
[7] The eye drop type eyewash medicinal composition according to any one of [1] to [6], further containing a thickening agent.
[8] The eye drop type eyewash medicinal composition according to any one of [1] to [7], further comprising an isotonic agent, a stabilizer, a pH adjuster, and a solubilizer.
[9] The eyedrop type eyewash medicinal composition according to any one of [1] to [8], which has a pH of 6.5 or more and 7.0 or less.
[10] The eyedrop-type eyewash medicinal composition according to any one of [1] to [9], which is used to wash away dirt and foreign matter from the ocular surface.
[11] The eyedrop type eyewash medicinal composition according to [10], wherein the dirt or foreign matter is pollen, eye secretions, or PM2.5.
[12] Housed in an eye drop container made of at least one selected from polypropylene, low density polyethylene, high density polyethylene, polyethylene terephthalate, polybutylene terephthalate, cycloolefin polymer and cycloolefin copolymer [1] to [11] ] The eyedrop type eyewash medicinal composition according to any one of the above.
[13] The eye-drop type eyewash medicinal composition according to [12], wherein the eye-drop container is an eye-drop container that allows liquid to be splashed.

Furthermore, the present invention also relates to the following.
[14] An eyedrop type eyewash method comprising instilling four or more drops of a composition having a viscosity of 12 mPa·s or less once per eye.
[15] The method according to [14], wherein 6 drops or less are instilled once per eye.
[16] An eyedrop-type eyewash method comprising instilling a composition having a viscosity of 12 mPa·s or less into the eyes once per eye in a total amount of 120 μL or more.
[17] The method according to [16], wherein a total amount of eye drops of 300 μL or less is instilled once per eye.
[18] The composition further contains at least one selected from the group consisting of an anti-inflammatory/astringent component, an antihistamine component, inorganic salts, alkyl polyaminoethylglycine, and boric acid or a salt thereof, [14] to [ 17].
[19] The method according to any one of [14] to [17], wherein the composition further contains boric acid.
[20] The method according to any one of [14] to [19], wherein the composition further contains a thickening agent.
[21] The method according to any one of [14] to [20], wherein the composition further contains an isotonic agent, a stabilizer, a pH adjuster, and a solubilizer.
[22] The method according to any one of [14] to [21], wherein the pH of the composition is 6.5 or more and 7.0 or less.
[23] The method according to any one of [14] to [22] for washing away dirt and foreign matter from the ocular surface.
[24] The method according to [23], wherein the dirt or foreign matter is pollen, eye secretion, or PM2.5.
[25] The composition is housed in an eye drop container formed from at least one selected from polypropylene, low density polyethylene, high density polyethylene, polyethylene terephthalate, polybutylene terephthalate, cycloolefin polymer and cycloolefin copolymer. The method according to any one of [14] to [24].
[26] The method according to [25], wherein the eye drop container is an eye drop container that can be splashed.

Furthermore, the present invention also relates to the following.
[27] A composition for use in eyedrop type eyewash, which has a viscosity of 12 mPa·s or less and is used in such a manner that 4 or more drops are instilled into each eye once. thing.
[28] The composition for use according to [27], which is used so that 6 drops or less are instilled once per eye.
[29] A composition for use in eyedrop-type eyewash, characterized by having a viscosity of 12 mPa·s or less, and used so that the total amount of eye drops is 120 μL or more once per eye. composition.
[30] The composition for use according to [29], which is used so as to be instilled into the eye in a total amount of 300 μL or less once per eye.
[31] Any one of [27] to [30] further contains at least one selected from the group consisting of anti-inflammatory/astringent components, antihistamine components, inorganic salts, alkyl polyaminoethylglycine, and boric acid or its salts. Compositions for use as described in.
[32] The composition for use according to any one of [27] to [30], further containing boric acid.
[33] The composition for use according to any one of [27] to [32], further containing a thickening agent.
[34] The composition for use according to any one of [27] to [33], further comprising an isotonic agent, a stabilizer, a pH adjuster, and a solubilizer.
[35] The composition for use according to any one of [27] to [34], which has a pH of 6.5 or more and 7.0 or less.
[36] The composition for use according to any one of [27] to [35], which is used to wash away dirt and foreign matter from the ocular surface.
[37] The composition for use according to [36], wherein the dirt or foreign matter is pollen, eye secretion, or PM2.5.
[38] Housed in an eye drop container formed from at least one selected from polypropylene, low density polyethylene, high density polyethylene, polyethylene terephthalate, polybutylene terephthalate, cycloolefin polymer and cycloolefin copolymer [27] to [37] ] A composition for use according to any one of the above.
[39] The composition for use according to [38], wherein the eye drop container is a splashable eye drop container.

Furthermore, the present invention also relates to the following.
[40] Use of a composition having a viscosity of 12 mPa·s or less for the production of an eyedrop type eyewash, wherein the eyedrop type eyewash is such that 4 or more drops are instilled once per eye. A use characterized by being used for.
[41] The use according to [40], wherein the eye drop type eyewash is used so that 6 drops or less are instilled once per eye.
[42] Use of a composition having a viscosity of 12 mPa·s or less for the production of an eye drop type eye wash, wherein the eye drop type eye wash is instilled once per eye with a total eye drop volume of 120 μL or more. A use characterized in that it is used in such a way.
[43] The use according to [42], wherein the eye drop type eyewash is used so that a total amount of eye drops of 300 μL or less is applied once per eye.
[44] The composition further contains at least one selected from the group consisting of an anti-inflammatory/astringent component, an antihistamine component, inorganic salts, alkyl polyaminoethylglycine, and boric acid or a salt thereof, [40] to [ 43].
[45] The use according to any one of [40] to [43], wherein the composition further contains boric acid.
[46] The use according to any one of [40] to [45], wherein the composition further contains a thickening agent.
[47] The use according to any one of [40] to [46], wherein the composition further contains an isotonic agent, a stabilizer, a pH adjuster, and a solubilizer.
[48] The use according to any one of [40] to [47], wherein the composition has a pH of 6.5 or more and 7.0 or less.
[49] The use according to any one of [40] to [48], wherein the eye drop type eyewash is used to wash away dirt and foreign substances on the ocular surface.
[50] The use according to [49], wherein the dirt or foreign matter is pollen, eye secretion, or PM2.5.
[51] The composition is housed in an eye drop container formed from at least one selected from polypropylene, low density polyethylene, high density polyethylene, polyethylene terephthalate, polybutylene terephthalate, cycloolefin polymers and cycloolefin copolymers, [ 40] to [50].
[52] The use according to [51], wherein the eye drop container is an eye drop container that allows liquid to be splashed.

Furthermore, the present invention also relates to the following.
[53] An eyedrop-type eyewash having a viscosity of 12 mPa·s or less, which is used so that 4 or more drops are instilled into each eye once.
[54] The eyedrop type eyewash according to [53], which is used so that 6 drops or less are instilled once per eye.
[55] An eyedrop-type eyewash having a viscosity of 12 mPa·s or less, which is used so that a total amount of eyedrops of 120 μL or more is instilled once per eye.
[56] The eye drop type eyewash according to [55], which is used so that a total amount of eye drops of 300 μL or less is applied once per eye.
[57] Any one of [53] to [56] further contains at least one selected from the group consisting of an anti-inflammatory/astringent component, an antihistamine component, inorganic salts, alkyl polyaminoethylglycine, and boric acid or a salt thereof. The eye drop type eyewash described in .
[58] The eye drop type eyewash according to any one of [53] to [56], further containing boric acid.
[59] The eye drop type eyewash according to any one of [53] to [58], further containing a thickening agent.
[60] The eye drop type eyewash according to any one of [53] to [59], further containing an isotonic agent, a stabilizer, a pH adjuster, and a solubilizer.
[61] The eyedrop type eyewash according to any one of [53] to [60], which has a pH of 6.5 or more and 7.0 or less.
[62] The eyedrop type eyewash according to any one of [53] to [61], which is used to wash away dirt and foreign substances from the ocular surface.
[63] The eyedrop type eyewash according to [62], wherein the dirt or foreign matter is pollen, eye secretions, or PM2.5.
[64] Housed in an eye drop container formed from at least one selected from polypropylene, low density polyethylene, high density polyethylene, polyethylene terephthalate, polybutylene terephthalate, cycloolefin polymer and cycloolefin copolymer [53] to [63] ] The eye drop type eyewash according to any one of the above.
[65] The eye drop type eyewash according to [64], wherein the eye drop container is a dropper container that allows liquid to be splashed.

Note that the above [1] to [65] can be arbitrarily selected and combined or applied mutatis mutandis.

By instilling 4 or more drops, preferably 4 to 6 drops, of an eyedrop-type eyewash medicinal composition having a viscosity of 12 mPa・s or less once per eye, it is close to or equivalent to a cup-type eyewash. Or even more eye-washing effect can be obtained. In addition, compared to cup-type eyewashes, the eyedrop-type eyewash medicinal composition minimizes contact of the eyewash with the skin, eyelashes, etc. around the eyes, and removes dirt (sweat, pollen, etc.) attached to the eyelashes. , dust, etc.) can significantly reduce the risk of contamination of the eyes with contaminated eyewash, which can prevent eye problems caused by contaminated eyewash entering the eyes after coming into contact with the skin, eyelashes, etc. around the eyes. Prevention and/or avoidance effects can be expected. Furthermore, when boric acid or a salt thereof and/or edetate acid or a salt thereof is further blended into the eyedrop type eyewash medicinal composition, this composition has an effect of suppressing pollen bursting. Therefore, in this case, it is also expected that the pollen can be washed away before it bursts in the eye and the allergens inside the pollen are released.

FIG. 1 is a graph showing the relationship between the viscosity of an eyewash eye drop and its cleaning effect. FIG. 2 is a graph showing the relationship between the number of drops of eyewash eye drops per eye and its cleaning effect. FIG. 3A is a graph showing the pollen burst suppressing effects of various components. FIG. 3B is a graph showing the effect of suppressing pollen bursting of an aqueous solution containing various components. FIG. 4 is a graph showing the results of comparing intraocular contamination after eyewashing between eyedrop type eyewashing and cup type eyewashing.

The present invention will be explained in detail below. In the present invention, "% (w/v)" means the mass (g) of the target component contained in 100 mL of the composition of the present invention (hereinafter, the same applies unless otherwise specified).

The viscosity of the composition of the present invention is not particularly limited as long as it has a low viscosity, specifically 12 mPa·s or less, and is acceptable as an eye drop. More specifically, the upper limit of the viscosity is preferably 10 mPa·s or less, more preferably 5 mPa·s or less, even more preferably 3 mPa·s or less, and particularly preferably 1 mPa·s or less. Further, the lower limit of the viscosity is not particularly limited as long as it exceeds 0 mPa·s, but it is preferably 0.01 mPa·s or more, more preferably 0.1 mPa·s or more, and particularly preferably 0.3 mPa·s or more. Further, the upper and lower limits of the viscosity described above can be appropriately combined to form a range. For example, more than 0 mPa・s and less than 10 mPa・s is preferable, more than 0.01 mPa・s and less than 5 mPa・s is more preferable, more than 0.1 mPa・s and less than 3 mPa・s is more preferable, and more than 0.3 mPa・s and less than 1 mPa・s The following are particularly preferred. Note that in this specification, low viscosity refers to, for example, a viscosity of 20 mPa·s or less.

Further, the viscosity of the composition of the present invention can be measured, for example, by the viscosity measurement method described in the 17th edition of the Japanese Pharmacopoeia. Specific measurement methods include a capillary viscometer method, a rotational viscometer method, and the like, with the rotational viscometer method being preferred. More specifically, the viscosity of each formulation can be measured using a cone-plate viscometer at a shear rate of 100 s ^-1 and a measurement temperature of 25.0°C. Furthermore, there is no limit to the timing of measuring the viscosity of the composition of the present invention, but preferably immediately after preparation of the composition of the present invention, immediately before use of the composition of the present invention, or at the expiration date of the composition of the present invention. (effective period), and more preferably, immediately after preparing the composition of the present invention or immediately before using the composition of the present invention.

The number of times the composition of the present invention can be used is not particularly limited as long as the number of eye drops (eyewashes) is sufficient to achieve the desired effect. For example, 1 to 6 times/day is preferable, and 3 to 6 times/day is more preferable, but since the present invention is highly portable, it can be used immediately when the user realizes that a foreign object has entered the eye. can.

The composition of the present invention is preferably instilled in a lower limit of 3 or more drops, more preferably 4 or more drops, once per eye. The upper limit is not particularly limited, but from the viewpoint of patient convenience, eye wash effect, and problems caused by increased amount of eye wash, it is preferable to instill 8 drops or less per eye once, and 6 drops or less. It is more preferable to apply it to the eye. Furthermore, the above upper and lower limits can be appropriately combined to form a range. For example, it is preferable to instill 3 to 8 drops per eye, more preferably 4 to 8 drops, particularly preferably 4 to 6 drops.

In addition, considering that the amount of one drop of normal eye drops is 30 to 50 μL, the lower limit of the total amount of eye drops per eye is preferably 90 μL or more, and more preferably 120 μL or more. . Further, the upper limit is not particularly limited, but from the viewpoint of patient convenience, eyewash effect, problems caused by increased amount of eyewash, etc., it is preferably 400 μL or less, more preferably 300 μL or less per eye. Furthermore, the above upper and lower limits can be appropriately combined to form a range. Specifically, for example, the range of the total amount of eye drops per eye is preferably 90 μL or more and 400 μL or less, and more preferably 120 μL or more and 300 μL or less.

In the use of the composition of the present invention, "n or more drops are instilled once per eye" means that n or more drops are continuously instilled per eye in one use. There is no particular restriction on how to blink after instilling the composition of the present invention, but specifically, you may blink after instilling one drop, you may blink after instilling multiple drops, or you may blink after instilling multiple drops. You don't have to. In addition, from the viewpoint of eyewashing effect, it is preferable to blink every time one or two drops are instilled, and it is more preferable to blink every time one drop is instilled. The number of blinks is not particularly limited, but it is preferable to blink 1 to 3 times, more preferably 1 to 2 times after instilling one drop or after instilling multiple drops.

The composition of the present invention may contain appropriate amounts of the following components as long as they do not impede the effects of the present invention, and may contain any pharmaceutically acceptable components without particular limitation. Further, the following components are preferably contained as pharmacologically active ingredients (physiologically active ingredients or active ingredients). Specifically, epsilon-aminocaproic acid, allantoin, berberines (berberine chloride, berberine sulfate), sodium azulene sulfonate, dipotassium glycyrrhizinate, zincs (zinc sulfate, zinc lactate), lysozyme chloride, etc. anti-inflammatory and astringent ingredients, antihistamines such as diphenhydramine hydrochloride and chlorpheniramine maleate, sodium flavin adenine dinucleotide, cyanocobalamin, retinols (retinol acetate, retinol palmitate), pyridoxine hydrochloride, pantothenic acids (panthenol, calcium pantothenate, (sodium pantothenate), vitamins such as tocopherol acetate, aspartates (potassium L-aspartate, magnesium L-aspartate, magnesium and potassium L-aspartate (mixture of equal amounts)), aminoethylsulfonic acid (taurine), Amino acids such as sodium chondroitin sulfate, inorganic substances such as potassium chloride, calcium chloride, sodium chloride, sodium hydrogen carbonate, sodium carbonate, dry sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, etc. Examples include salts, alkyl polyaminoethylglycine, boric acid, boric acid such as borax, or a salt thereof, and it is more preferable to contain boric acid or a salt thereof such as boric acid or borax.

The above ingredients may be used alone or in any combination of two or more, and when these ingredients are contained as pharmacologically active ingredients, the content is determined by the pharmacologically active ingredients. Depending on the type of ingredient, the type and content of other compounded ingredients, the purpose of the composition, the formulation form, the method of use, etc., They can be set as appropriate based on (2) Ophthalmic drug manufacturing and sales approval standards described in the 2017 Guidance.

For example, according to the above-mentioned OTC drug manufacturing and sales approval standards, the composition of the present invention can contain the above-mentioned pharmacologically active ingredient at the maximum concentration (% (w/v)) shown in Table 1.

For example, when the composition of the present invention contains the pharmacologically active ingredients of group A shown in Table 1, it may contain up to three pharmacologically active ingredients, and furthermore, up to one pharmacologically active ingredient of group B, and the pharmacologically active ingredients of group C and D. Preferably, each composition contains up to three active ingredients. In addition, when containing a pharmacologically active ingredient of group B, it is preferable to contain only one type, and further contain up to three types of pharmacologically active ingredients of group A, and up to three types each of group C and D group. . Furthermore, when containing a pharmacologically active ingredient of group E or F, it is preferable to contain only one type. In addition, when a subgroup exists in each group, it is preferable to contain only one type from the same subgroup.

When the composition of the present invention contains boric acid or a salt thereof such as boric acid or borax as a pharmacologically active ingredient (physiologically active ingredient or active ingredient), the content (concentration) thereof should be within a pharmaceutically acceptable range. If so, there are no particular restrictions. For example, it is preferably 0.01 to 5% (w/v), more preferably 0.1 to 3% (w/v), and particularly preferably 0.5 to 1.2% (w/v).

In addition to the above-mentioned ingredients, the composition of the present invention may also contain appropriate amounts of the following pharmaceutically acceptable pharmacologically active ingredients (physiologically active ingredients or active ingredients), as long as they do not impede the effects of the present invention. Specifically, decongestant components (vasoconstrictor components) such as epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, and dl-methylephedrine hydrochloride, neostigmine methyl sulfate, tropicamide, helenien, and sulfuric acid. Eye muscle regulating ingredients such as atropine (focus regulating ingredients), zinc sulfate hydrate, pranoprofen, salicylic acid, tranexamic acid, anti-inflammatory and astringent ingredients such as licorice, cromoglylic acid or its salt (sodium cromoglycate), amlexanox, ibudilast , suplatast, pemirolast or its salts (pemilolast potassium, pemirolast sodium), tranilast, olopatadine or its salts (olopatadine hydrochloride), levocabastine or its salts (levocabastine hydrochloride), acitazanolast, ketotifen or its salts (fumaric acid) antihistamines or antiallergic agents such as epinastine or its salt (epinastine hydrochloride), vitamin B ₁₂ (hydroxocobalamin, methylcobalamin, and adenosylcobalamin), vitamin B ₆ (pyridoxine, pyridoxal, pyridoxamine), vitamin E (acetic acid- d-α tocopherol), vitamin B ₁ (thiamine, thiamine hydrochloride), niacin (nicotinic acid and nicotinamide), biotin, folic acid and other vitamins, aspartic acid, glycine, alanine, γ-aminobutyric acid, glutamic acid, arginine , amino acids such as lysine, sulfa drugs such as sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, sulfisoxazole sodium, polyvinyl alcohol, polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose , thickening components such as glucose, bactericidal agents such as acrinol, cetylpyridinium, benzalkonium chloride, benzethonium chloride, chlorhexidine, polyhexamethylene biguanide, alkyldiaminoethylglycine hydrochloride, corneal protection such as sodium hyaluronate, and treatment of corneal disorders. Ingredients etc. The composition of the present invention may not contain sodium hyaluronate at a concentration of 0.075% (w/v) as a pharmacologically active ingredient, and may contain substantially or no sodium hyaluronate. Good too. Further, polyhexamethylene biguanide may not be contained substantially or at all.

The pharmacologically active ingredients (physiologically active ingredients or active ingredients) that can be used in the composition of the present invention may be used alone or in any combination of two or more types. Further, the content of the pharmacologically active ingredient can be appropriately set depending on the type of the pharmacologically active ingredient, the type and content of other ingredients, the use of the composition, the formulation form, the usage method, etc.

The composition of the present invention may further contain a thickening agent, an isotonizing agent, a stabilizer, a pH adjusting agent, and/or a solubilizing agent.

The thickening agent that can be used in the composition of the present invention is not particularly limited as long as it is pharmaceutically acceptable. For example, polyvinylpyrrolidones such as polyvinylpyrrolidone K25, polyvinylpyrrolidone K30, polyvinylpyrrolidone K90, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose 2208, hydroxypropylmethylcellulose 2906, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxyethylcellulose, Cellulose derivatives such as nitrocellulose or their salts, polyethylene glycols such as macrogol 300, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000, dextrans such as dextran 40 and dextran 70, sodium hyaluronate (purified (sodium hyaluronate, etc.), hyaluronic acid derivatives such as cross-linked hyaluronic acid, alginic acid, alginic acid derivatives such as sodium alginate, polyvinyl alcohol, carboxyvinyl polymer, sodium chondroitin sulfate, gum arabic, gellan gum, tragacanth, etc., polyvinylpyrrolidone K25, Polyvinylpyrrolidones such as polyvinylpyrrolidone K30 and polyvinylpyrrolidone K90, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose 2208, hydroxypropylmethylcellulose 2906, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxyethylcellulose, nitrocellulose or salts thereof Cellulose derivatives such as, hyaluronic acid derivatives such as crosslinked hyaluronic acid, alginic acid, alginic acid derivatives such as sodium alginate are preferred, and polyvinylpyrrolidone K30 is more preferred. Note that the composition of the present invention may not contain substantially or no sodium hyaluronate (purified sodium hyaluronate, etc.).

The thickening agents that can be used in the composition of the present invention may be used alone or in any combination of two or more. Further, the content of the thickening agent can be appropriately set depending on the type of the thickening agent, the type and content of other ingredients, the use of the composition, the formulation form, the usage method, etc.

When using a thickening agent in the composition of the present invention, the total content (concentration) of the thickening agent is, for example, preferably 0 to 1.0% (w/v), and 0.01 to 0.5%. (w/v) is more preferable, and 0.1 to 0.3% (w/v) is particularly preferable.

The tonicity agent that can be used in the composition of the present invention is not particularly limited as long as it is pharmaceutically acceptable. For example, potassium salts such as potassium chloride and potassium acetate, calcium salts such as calcium chloride, sodium salts such as sodium chloride, sodium bicarbonate, sodium carbonate, dry sodium carbonate, sodium acetate, sodium bisulfite, sodium sulfite, and sodium thiosulfate. , inorganic salts such as magnesium salts such as magnesium sulfate and magnesium chloride, polyhydric alcohols such as glycerin, propylene glycol, polyethylene glycol, mannitol, sorbitol, xylitol, and trometamol, potassium chloride, calcium chloride, calcium chloride, and chloride. Sodium, sodium bicarbonate, sodium carbonate, dry sodium carbonate or magnesium sulfate are preferred, and potassium chloride and sodium chloride are more preferred.

The tonicity agents that can be used in the composition of the present invention may be used alone or in any combination of two or more. Further, the content of the tonicity agent can be appropriately set depending on the type of the tonicity agent, the type and content of other ingredients, the use of the composition, the formulation form, the usage method, etc.

When using an isotonizing agent in the composition of the present invention, the total content (concentration) of the tonicity agent is, for example, preferably 0.05 to 5% (w/v), and 0.1 to 1. 8% (w/v) is more preferred, and 0.3 to 0.9% (w/v) is particularly preferred.

The stabilizer that can be used in the composition of the present invention is not particularly limited as long as it is pharmaceutically acceptable. For example, trometamol, sodium formaldehyde sulfoxylate (Rongalit), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, glyceryl monostearate, dibutylhydroxytoluene, edetic acid, sodium edetate, sodium edetate hydrate. , polyoxyethylene polyoxypropylene glycol, etc., dibutylhydroxytoluene, edetic acid, sodium edetate or sodium edetate hydrate are preferred, and sodium edetate hydrate is more preferred.

The stabilizers that can be used in the composition of the present invention may be used alone or in any combination of two or more. Further, the content of the stabilizer can be appropriately set depending on the type of stabilizer, the type and content of other ingredients, the use of the composition, the formulation form, the usage method, etc.

When using a stabilizer in the composition of the present invention, the total content (concentration) of the stabilizer is, for example, preferably 0.0001 to 1% (w/v), and 0.001 to 0.5% (w/v). /v) is more preferable, and 0.005 to 0.1% (w/v) is particularly preferable.

The pH adjusting agent that can be used in the composition of the present invention is not particularly limited as long as it is pharmaceutically acceptable. Examples include dilute hydrochloric acid, acetic acid, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, etc., with dilute hydrochloric acid and sodium hydroxide being preferred.

The pH adjusters that can be used in the composition of the present invention may be used alone or in any combination of two or more. Furthermore, the content of the pH adjuster can be appropriately set depending on the type of pH adjuster, the type and content of other ingredients, the use of the composition, the formulation form, the usage method, etc.

When using a pH adjuster in the composition of the present invention, the total content (concentration) of the pH adjuster is, for example, preferably 0 to 5% (w/v), and 0.005 to 1% (w/v). ) is more preferred, and 0.01 to 0.5% (w/v) is particularly preferred.

The pH of the composition of the present invention is not particularly limited as long as it is pharmaceutically acceptable, but its upper limit is preferably 7.5 or less, more preferably 7.2 or less, and particularly preferably 7.0 or less. . Moreover, the lower limit is preferably 5.0 or more, more preferably 6.0 or more, and particularly preferably 6.5 or more. Further, the upper and lower limits of pH can be appropriately combined to form a range. Specifically, for example, it is preferably 5.0 or more and 7.5 or less, more preferably 6.0 or more and 7.2 or less, and particularly preferably 6.5 or more and 7.0 or less.

Note that pH can be measured, for example, according to the pH measurement method described in the 17th edition of the Japanese Pharmacopoeia.

The solubilizer (solvent and/or dispersion medium) that can be used in the composition of the present invention is not particularly limited as long as it is pharmaceutically acceptable. Examples include water-based dissolving agents such as water (distilled water, regular water, purified water, sterile purified water, water for injection, distilled water for injection, etc.), aqueous ethanol, etc. Purified water, water for injection, distilled water for injection, etc.) are preferred.

The solubilizers that can be used in the composition of the present invention may be used alone or in any combination of two or more. Further, the content of the solubilizing agent can be appropriately set depending on the type of the solubilizing agent, the type and content of other ingredients, the use of the composition, the formulation form, the usage method, etc.

In the composition of the present invention, for example, when the solubilizing agent is water, it is preferably 90% (w/v) or more, more preferably 95% (w/v) or more, and 97% (w/v) or more based on the total amount of the composition. w/v) or more is particularly preferred.

The composition of the present invention may contain an appropriate amount of additives other than the above-mentioned additives (thickening agent, tonicity agent, stabilizer, pH adjuster, solubilizing agent), as long as they do not impede the effects of the present invention. can. Additives other than the above-mentioned additives are not particularly limited as long as they are pharmaceutically acceptable, and for example, surfactants (solubilizers), buffers, preservatives, cooling agents, etc. can be used.

The surfactant (solubilizer) that can be used in the composition of the present invention is not particularly limited as long as it is pharmaceutically acceptable. For example, nonionic surfactants, amphoteric surfactants, anionic surfactants, cationic surfactants, etc. are preferred, and nonionic surfactants are more preferred.

Examples of nonionic surfactants include POE monolaurate (20) sorbitan (polysorbate 20), POE monopalmitate (20) sorbitan (polysorbate 40), POE monostearate (20) sorbitan (polysorbate 60), POE sorbitan fatty acid esters such as POE stearate (20) sorbitan (polysorbate 65), POE monooleate (20) sorbitan (polysorbate 80), POE (40) hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 40) and POE ( 60) POE hydrogenated castor oil such as hydrogenated castor oil (polyoxyethylene hydrogenated castor oil 60), POE (10) castor oil (polyoxyethylene castor oil 10), POE (35) castor oil (polyoxyethylene castor oil 35) POE castor oil, POE alkyl ether such as POE (9) lauryl ether, POE-POP alkyl ether such as POE (20) POP (4) cetyl ether, POE (54) POP (39) glycol, POE (120) Polyoxyethylene polyoxy such as POP (40) glycol, POE (160) POP (30) glycol, POE (196) POP (67) glycol (poloxamer 407, Pluronic F127), POE (200) POP (70) glycol, etc. Examples include propylene block copolymers, polyethylene glycol monostearate such as polyoxyl stearate 40, monolaurate POE (20) sorbitan (polysorbate 20), monopalmitate POE (20) sorbitan (polysorbate 40), monostearate POE ( 20) POE sorbitan fatty acid esters such as sorbitan (polysorbate 60), tristearate POE (20) sorbitan (polysorbate 65), monooleate POE (20) sorbitan (polysorbate 80) are preferred, and POE monooleate (POE (20) sorbitan) (Polysorbate 80) is more preferred.

Examples of the amphoteric surfactant include N-[2-[[2-(alkylamino)ethyl]amino]ethyl]glycine and salts thereof.

Examples of the anionic surfactant include alkylbenzene sulfonates, alkyl sulfates, polyoxyethylene alkyl sulfates, α-sulfo fatty acid ester salts, α-olefin sulfonic acids, and the like.

Examples of the cationic surfactant include benzalkonium chloride, benzethonium chloride, and chlorhexidine gluconate.

These surfactants may be used alone or in any combination of two or more. Further, the content of the surfactant can be appropriately set depending on the type of surfactant, the type and content of other ingredients, the use of the composition, the formulation form, the usage method, etc.

When using a surfactant in the composition of the present invention, for example, the total content (concentration) of the surfactant is preferably 0.01 to 5% (w/v), and 0.01 to 1% (w/v). /v) is more preferable, and 0.05 to 0.5% (w/v) is even more preferable.

Buffers that can be used in the composition of the present invention are not particularly limited as long as they are pharmaceutically acceptable. For example, boric acid, sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, boric acid or its salts such as borax, phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, dihydrogen phosphate Phosphoric acid or its salts such as potassium, trisodium phosphate, tripotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, carbonic acid, sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, carbonic acid Carbonic acid or its salts such as potassium hydrogen and magnesium carbonate, citric acid, sodium citrate, potassium citrate, calcium citrate, citric acid or its salts such as sodium dihydrogen citrate, disodium citrate, acetic acid, ammonium acetate, Acetic acid or its salts such as potassium acetate, calcium acetate, sodium acetate, aspartic acid or its salts such as aspartic acid, sodium aspartate, magnesium aspartate, potassium aspartate, ethylenediamine diacetic acid (EDDA), ethylenediamine triacetic acid, ethylenediamine tetraacetic acid Ethylenediamine acetic acid such as acetic acid (edetate, EDTA), ethylenediaminetetraacetic acid disodium hydrate (edetate sodium hydrate), N-(2-hydroxyethyl)ethylenediaminetriacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA), etc. boric acid or its salts such as boric acid, sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, phosphoric acid, phosphoric acid, etc. Phosphoric acid or its salts such as disodium oxyhydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, and ε-aminocaproic acid Preferred are amino acids such as boric acid, borax, or ε-aminocaproic acid.

The buffering agents that can be used in the composition of the present invention may be used alone or in any combination of two or more. Furthermore, the content of the buffering agent can be appropriately set depending on the type of buffering agent, the type and content of other ingredients, the use of the composition, the form of preparation, the usage method, etc.

When using a buffer in the composition of the present invention, for example, the total content (concentration) of the buffer is preferably 0.001 to 5% (w/v), and 0.005 to 3% (w/v). ) is more preferred, and 0.01 to 2% (w/v) is particularly preferred.

The preservative that can be used in the composition of the present invention is not particularly limited as long as it is pharmaceutically acceptable. For example, biguanide compounds such as polyhexamethylene biguanide and polyhexanide hydrochloride, zinc chloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate , Sodium dehydroacetate, Methyl paraoxybenzoate, Ethyl paraoxybenzoate, Propyl paraoxybenzoate, Butyl paraoxybenzoate, Oxyquinoline sulfate, Phenethyl alcohol, Benzyl alcohol, Glokill (trade name manufactured by Rhodia), Boric acid, Borax, Examples include chlorous acid, benzalkonium chloride, chlorhexidine gluconate, sorbic acid, phenethyl alcohol, boric acid, borax, and chlorous acid, and benzalkonium chloride, chlorhexidine gluconate, phenethyl alcohol, boric acid, Borax and chlorous acid are more preferred. Note that the composition of the present invention may contain substantially or no polyhexamethylene biguanide.

The preservatives that can be used in the composition of the present invention may be used alone or in any combination of two or more. Further, the content of the preservative can be appropriately set depending on the type of preservative, the type and content of other ingredients, the use of the composition, the formulation form, the usage method, etc.

When using a preservative in the composition of the present invention, for example, the total content (concentration) of the preservative is preferably 0.0001 to 1% (w/v), and 0.0005 to 0.5% (w/v). /v) is more preferred, and 0.001 to 0.2% (w/v) is even more preferred, but preservatives, especially benzalkonium or its salts, or methyl paraoxybenzoate, ethyl paraoxybenzoate, paraoxybenzoic acid Particularly preferred are compositions that contain substantially or no parabens, such as propyl, butyl paraoxybenzoate, or salts thereof.

The cooling agent that can be used in the composition of the present invention is not particularly limited as long as it is pharmaceutically acceptable. For example, essential oils containing terpenoids such as eucalyptus oil, bergamot oil, peppermint oil, fennel oil, rose oil, cinnamon oil, spearmint oil, camphor oil, cool mint, peppermint oil, menthol, menthone, camphor, borneol, geraniol, nerol. , cineole, citronellol, carvone, anethole, eugenol, limonene, linalool, and linalyl acetate. Menthol, camphor, borneol, and geraniol are preferred, and menthol and borneol are more preferred. Further, the terpenoid may be any of the d-form, l-form, and dl-form, such as l-menthol, d-menthol, dl-menthol, dl-camphor, d-camphor, dl-borneol, d-borneol, etc. l-menthol, dl-camphor, d-camphor and d-borneol are preferred.

The refreshing agents that can be used in the composition of the present invention may be used alone or in any combination of two or more. Further, the content of the refreshing agent can be appropriately set depending on the type of the refreshing agent, the type and content of other ingredients, the use of the composition, the formulation form, the usage method, etc.

When using a refreshing agent in the composition of the present invention, for example, the total content (concentration) of the refreshing agent is preferably 0.001 to 0.5% (w/v), and 0.001 to 0.5% (w/v). 1% (w/v) is more preferred, and 0.005 to 0.05% (w/v) is particularly preferred.

When the composition of the present invention contains boric acid or a salt thereof, and/or edetic acid or a salt thereof, and optionally polyvinylpyrrolidone among the above components, it is preferable because the effect of suppressing pollen bursting is exerted.

The osmotic pressure of the composition of the present invention is not particularly limited as long as it is pharmaceutically acceptable. For example, the osmotic pressure ratio is preferably 0.2 to 2, more preferably 0.7 to 1.5, particularly preferably 1.0 to 1.2.

The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (osmotic pressure of 0.9% (w/v) sodium chloride aqueous solution) based on the 17th edition of the Japanese Pharmacopoeia, and the osmotic pressure is as described in the Japanese Pharmacopoeia. The standard solution for osmotic pressure ratio measurement (0.9% (w/v) sodium chloride aqueous solution) can be measured by referring to the osmotic pressure measurement method (freezing point depression method). ) at 500 to 650°C for 40 to 50 minutes, then let it cool in a desiccator (silica gel), accurately weigh 0.900 g of it, dissolve it in purified water, and prepare exactly 100 mL, or use a commercially available osmotic pressure ratio. A standard measurement solution (0.9% (w/v) aqueous sodium chloride solution) can be used.

The composition of the present invention can be provided in any container (main body, inner stopper, cap). Moreover, the container containing this composition is not particularly limited as long as it is pharmaceutically acceptable. For example, glass containers and polypropylene, low density polyethylene, high density polyethylene, polyethylene terephthalate, polybutylene terephthalate, cycloolefin polymer, cycloolefin copolymer, polyarylate, polyethylene naphthalate, polycarbonate, polytetrafluoroethylene, polyimide, polymethylpentene. , copolymers of monomers constituting these materials, and plastic containers made by combining two or more of these materials, including polypropylene, low-density polyethylene, high-density polyethylene, polyethylene terephthalate, polybutylene terephthalate, and cycloolefin polymers. and cycloolefin copolymers, copolymers of monomers constituting these, and plastic containers made of a combination of two or more of these materials are preferred. Note that the combination here may be a mixture of different materials, or a layered structure of different materials. Further, the container may be a multi-dose container that can be used repeatedly, a unit-dose container that can be used once, or a multi-dose container that can be used repeatedly. is preferred. Note that the containers containing these compositions of the present invention are, for example, common eye drop containers, but as mentioned above, such eye drop containers are usually designed so that the volume of one drop is 30 to 50 μL. has been done.

The composition of the present invention is used, for example, to wash away dirt and foreign matter from the ocular surface. In the present invention, "washing away dirt and foreign matter" means washing away dirt and foreign matter on the ocular surface from inside the eye to outside the eye.

In the present invention, "dirt or foreign matter" is not particularly limited as long as it is a substance that causes discomfort to the eyes. Examples include pollen from cedar, cypress, grass, etc., dust such as house dust, eye secretions such as protein, skin secretions such as sweat, PM2.5, cosmetics such as eye shadow, mascara, foundation, etc. , cedar, cypress, grass, etc., and PM2.5 are preferred.

The composition of the present invention can be used, for example, as a composition for contact lenses, and can be applied to any commercially available contact lens, including hard contact lenses and/or soft contact lenses, and can be applied to any contact lens that is on the market, such as when the contact lens is worn ( It can also be used with contact lenses attached to the ocular surface. Note that soft contact lenses include, for example, both ionic and nonionic lenses, and include both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses. It also encompasses all soft contact lenses classified as Groups I-IV.

The composition of the present invention may be labeled as "can also be used when wearing contact lenses (hard contact lenses/soft contact lenses)" or "for use when wearing contact lenses (hard contact lenses/soft contact lenses)". It is also possible to create a similar display. In addition, the display can be direct or indirect, and examples of direct display include descriptions on the product itself, packaging, containers, labels, tags, etc., and indirect display Examples include advertisements, promotions, and explanations to doctors through transaction documents, instruction manuals, attached documents, catalogs, websites, stores, exhibitions, billboards, bulletin boards, newspapers, magazines, television, radio, e-mail, etc. These activities include:

Furthermore, the above detailed description of the composition of the present invention, etc. also applies to the following embodiments of the present invention.

One aspect of the present invention is an eyedrop-type eyewash method that includes instilling four or more drops of a composition having a viscosity of 12 mPa·s or less once per eye.

One aspect of the present invention is a composition for use in an eye drop type eyewash, which has a viscosity of 12 mPa·s or less, and is used so that 4 or more drops are instilled once per eye. This is a characteristic composition.

One aspect of the present invention is the use of a composition having a viscosity of 12 mPa·s or less for the manufacture of an eyedrop type eyewash, wherein the eyedrop type eyewash is applied once per eye with 4 or more drops. A use characterized in that it is used as an eye drop.

One aspect of the present invention is an eye drop type eye wash having a viscosity of 12 mPa·s or less, which is used so that 4 or more drops are applied once per eye. be.

<Formulation example>
Formulation examples of the present invention are shown in Table 2 below, but these are for better understanding of the present invention and are not intended to limit the scope of the present invention in any way. In addition, in the following formulation examples, the blending amount of each component is the content in 100 mL of the formulation, and their viscosity is 12 mPa·s or less.

Note that a desired composition having a viscosity of 12 mPa·s or less can be obtained by appropriately adjusting the types, amounts, and viscosity of the pharmacologically active ingredients and additives in Formulation Examples 1 to 6.

<Example>
Below, as an example, 1. Correlation test between viscosity of eye drops and cleaning effect, 2. Correlation test between number of eye drops per eye and cleaning effect, 3. Pollen burst suppression effect test, 4. A test to confirm intraocular contamination of eye drops and cup-type eye washes is shown. However, these test examples are for better understanding of the present invention, and do not limit the scope of the present invention in any way.

(Test example 1)
1. Correlation test between viscosity of eyewash eye drops and cleaning effect The following test was conducted to investigate the relationship between the viscosity of eyewash eye drops (eyedrop type eyewash) and its cleaning effect in the case of eyedrop type eyewash.

1) Preparation of eye drops for eye washing (test solution) First, 8700 mL of water was heated to 50°C, boric acid 100.0 g, polyvinylpyrrolidone K30 50.0 g, edetate sodium hydrate 1.0 g, sodium chloride. 40.0 g of potassium chloride, stirred, cooled to room temperature, and adjusted to pH 6.7 with dilute hydrochloric acid/sodium hydroxide. Eye drops for eye washing 1 were prepared. At this time, the viscosity of the low viscosity eyewash eye drops 1 was 0.84 mPa·s. Next, 3.0 g of hydroxymethyl cellulose (HEC) was added and dispersed in 150 mL of low viscosity eye drops for eye washing, and the mixture was stirred and dissolved by heating to 70°C. Prepared with Then, by thoroughly stirring 6 mL of this viscosity-adjusting eye drop and 34 mL of low-viscosity eye-wash eye drop 1, a low-viscosity eye-wash eye drop 2 with a viscosity of 11.56 mPa·s is obtained with 12 mL of viscosity-adjusting eye drop. Combine 28 mL of low-viscosity eye-wash eye drops 1 and stir well to obtain high-viscosity eye-wash eye drops 1 with a viscosity of 56.4 mPa・s, and combine 20 mL of viscosity-adjusting eye drops and 20 mL of low-viscosity eye-wash eye drops 1. High viscosity eyewash eye drops 2 having a viscosity of 194.2 mPa·s were prepared by stirring thoroughly. The viscosity was measured immediately before the test using a cone-plate viscometer at a shear rate of 100 s ⁻¹ and a measurement temperature of 25.0° C. based on the 17th edition of the Japanese Pharmacopoeia mentioned above. The viscosity of each eyewash eyedrop is shown in Table 3.

2) Test method Male Japanese white rabbits were used for the cleaning effect test. The experimental subjects were one animal with both eyes. The animal was given general anesthesia and ocular surface anesthesia, and a solution in which spherical fluorescent beads with an average diameter of approximately 40 μm were uniformly suspended (3% suspension, 1% suspension of spherical fluorescent beads manufactured by Spherotech Inc. was concentrated) 50 μL of the solution was instilled into each eye. Thereafter, the eye surface was washed with the eye drop type eyewash by administering the above-mentioned eyewash eyedrops to the eyes using a pipetman in an amount of 4 drops per eye (4 times of 46 μL). After washing, fluorescent beads remaining on the ocular surface were collected using a pipetman. The volume of the liquid containing the recovered fluorescent beads was measured using a pipetman (x μL). A portion of the collected solution was placed on a Fuchs-Rosenthal type hemocytometer, and the bead density was measured using an optical microscope (y beads/μL) according to the instructions for using the hemocytometer. The number of fluorescent beads (number) collected was calculated from the volume of the collected liquid (x μL) and the bead density (y beads/μL) using the formula (x×y), and was defined as the number of beads remaining after eyewash (b). In addition, the collection operation was performed without administering the eyewash eye drops to the eyes, and the number of fluorescent beads collected was calculated in the same manner. This was defined as the number of remaining beads (a) without washing. The bead survival rate after eyewashing with each eyewash eyedrop was calculated according to the following formula 1. Here, a low bead residual rate means a high cleaning effect. Note that the bead survival rate without washing was 100%.
[Formula 1]
Bead residual rate (%) = {Number of beads remaining after eyewash (b)/Number of beads remaining without washing (a)} x 100

3) Test results and discussion The test results are shown in Table 4 and Figure 1. Here, FIG. 1 is a graph in which the viscosity of the eyewash eye drops (mPa·s) is plotted on the horizontal axis, and the bead residual rate (%) is plotted on the vertical axis.

As shown in Table 4 and Figure 1, the cleaning effect (expressed as bead residual rate) of low-viscosity eye-wash eye drops 1 (0.84 mPa・s) and low-viscosity eye-wash eye drops 2 (11.56 mPa・s) was , 15% or less, which was excellent. Among them, the cleaning effect of low viscosity eye drops 1 (0.84 mPa·s) was extremely excellent with a bead residual rate of 3.0%. In addition, the bead residual rate of high-viscosity eye-wash eye drops 1 (56.4 mPa s) increased from the bead residual rate (14.7%) of low-viscosity eye-wash ophthalmic solution 2 (11.56 mPa s), It was 39.6%. From the above, it was shown that when the viscosity of eye drops for eye washing exceeds about 12 mPa·s, the cleaning effect decreases rapidly.

(Test example 2)
2. Correlation test between the number of eye drops per eye and cleaning effect The following test was conducted, and the number of drops of eye drops (eye drop type eye wash) per eye when using eye drop type eye wash. The relationship between this and its cleaning effect was investigated.

1) Preparation of eyewash eyedrops (test solution) An eyewash eyedrop with the same composition as low viscosity eyewash eyedrops 1 in Test Example 1 (viscosity 0.84 mPa·s) was used.

2) Test method The experimental subjects were four eyes, both eyes of two male Japanese white rabbits. Test Example 1 except that eye-drop-type eyewash was performed by administering 2, 4, 6, and 8 drops of the eyewash solution to each eye (46 μL 2, 4, 6, and 8 times, respectively) using a pipetman. A test was conducted in the same manner, and the bead survival rate after eye washing was calculated based on the number of eye drops. In addition, as a reference example, instead of using an eyewash type eyewash, a cup-type eyewash can be used, in which 5 mL of eyewash eye drops are brought into contact with the animal's ocular surface using the eyewash cup that comes with a commercially available cup-type eyewash (manufactured by Rohto Pharmaceutical Co., Ltd.). The test was conducted in the same manner except that the eyes were washed, and the bead survival rate was calculated.

3) Test results and discussion The test results are shown in Table 5 and Figure 2. Here, FIG. 2 is a graph showing the relationship between the dose of each eyewash eyedrop (the number of drops per eye, a cup-type eyewash as a reference example) and the bead residual rate (%). Note that the bead survival rate without washing was 100%.

As shown in Table 5 and FIG. 2, when 4 or more drops of eye drops were applied to each eye at a time, the bead residual rate was 2% or less, showing an excellent cleaning effect. In addition, the cleaning effect of the eyedrop type eyewash using 4 or more drops per eye was superior to the cup type eyewash using the existing eyewash cup. From the above, it has been shown that washing the eyes with 4 or more drops of eye drops per eye at a time has a sufficient effect of removing foreign substances from the ocular surface.

(Test example 3)
3. Pollen burst suppression effect test 3-1. Effect of various ingredients on suppressing pollen bursting The following tests were conducted to examine the effects of various ingredients on suppressing pollen bursting.

1) Preparation of test solution 12.5 g of disodium hydrogen phosphate hydrate was added to 900 mL of water, stirred and dissolved, and water was added to make the total volume 1000 mL, which was designated as 1.25 times solution 1. 40 mL of 1.25x solution 1 was taken, diluted hydrochloric acid/sodium hydroxide was added to adjust the pH to 7.0, and water was added to bring the total volume to 50 mL, which was designated as test solution 1. 0.05 g of potassium chloride was added to 40 mL of 1.25 times solution 1 and stirred and dissolved. Dilute hydrochloric acid/sodium hydroxide was added to this solution to adjust the pH to 7.0, and water was added to bring the total volume to 50 mL, which was used as test solution 2. 0.2 g of sodium chloride was added to 40 mL of 1.25 times solution 1 and stirred and dissolved. Dilute hydrochloric acid/sodium hydroxide was added to this solution to adjust the pH to 7.0, and water was added to bring the total volume to 50 mL, which was used as test solution 3. 0.5 g of boric acid was added to 40 mL of 1.25 times solution 1 and stirred and dissolved. Dilute hydrochloric acid/sodium hydroxide was added to this solution to adjust the pH to 7.0, and water was added to bring the total volume to 50 mL, which was designated as test solution 4. 0.05 g of sodium edetate hydrate was added to 40 mL of 1.25 times solution 1, and stirred and dissolved. Dilute hydrochloric acid/sodium hydroxide was added to this solution to adjust the pH to 7.0, and water was added to bring the total volume to 50 mL, which was designated as test solution 5. 0.25 g of polyvinylpyrrolidone K30 was added to 40 mL of 1.25 times solution 1 and stirred and dissolved. Dilute hydrochloric acid/sodium hydroxide was added to this solution to adjust the pH to 7.0, and water was added to bring the total volume to 50 mL, which was designated as test solution 6. The compositions of the aqueous solutions of Test Solutions 1 to 6 are shown in Table 6. Here, disodium hydrogen phosphate hydrate was included as a pH buffer. Further, test liquids 1 to 6 had a viscosity of 12 mPa·s or less.

2) Test method 50 μL of each test solution was dropped onto approximately 3 μL of cedar pollen particles. After 5 minutes, ruptured and unruptured vacuoles were counted under an optical microscope. The pollen bursting rate was calculated according to the following formula 2.
[Formula 2]
Pollen rupture rate (%) = {number of ruptured vacuoles / (number of ruptured vacuoles + number of unruptured vacuoles)} × 100

3) Test results and discussion The test results are shown in Figure 3A. Here, FIG. 3A is a graph showing the pollen bursting rate of each test solution. Here, the aqueous solution containing boric acid or sodium edetate hydrate had a pollen bursting rate of 15% or less, and exhibited an excellent pollen bursting suppressing effect. On the other hand, an aqueous solution containing potassium chloride, sodium chloride, or polyvinylpyrrolidone K30 showed an effect of promoting pollen bursting.

3-2. Effect of various compositions on suppressing pollen bursting The following tests were conducted to examine the effects of suppressing pollen bursting of various compositions.

1) Preparation of test solution 160 mL of water was heated to 45°C, and 2.5 g of boric acid, 1.0 g of sodium chloride, and 0.25 g of potassium chloride were added and stirred. After cooling the liquid to room temperature, water was added to make the total volume 200 mL, which was designated as 1.25 times liquid 2. 40 mL of 1.25x solution 2 was taken, diluted hydrochloric acid/sodium hydroxide was added to adjust the pH to 7.2, and water was added to bring the total volume to 50 mL, which was designated as test solution 7. 40 mL of 1.25 times solution 2 was heated to 45°C, 0.40 g of boric acid was added, and the mixture was stirred. After cooling the liquid to room temperature, dilute hydrochloric acid/sodium hydroxide was added to adjust the pH to 7.2, and water was added to bring the total volume to 50 mL, which was designated as test liquid 8. 40 mL of 1.25 times solution 2 was heated to 45°C, 0.025 g of sodium edetate hydrate was added, and the mixture was stirred. After cooling the liquid to room temperature, dilute hydrochloric acid/sodium hydroxide was added to adjust the pH to 7.2, and water was added to bring the total volume to 50 mL, which was designated as test liquid 9. 40 mL of 1.25 times solution 2 was heated to 45°C, 0.05 g of sodium edetate hydrate was added, and the mixture was stirred. After cooling the liquid to room temperature, dilute hydrochloric acid/sodium hydroxide was added to adjust the pH to 7.2, and water was added to bring the total volume to 50 mL, which was designated as test liquid 10. 12.0 g of boric acid, 4.8 g of sodium chloride, 1.2 g of potassium chloride, 0.12 g of sodium edetate hydrate, and 6.0 g of polyvinylpyrrolidone K30 were added to 800 mL of water and stirred. Water was added to the solution to make a total volume of 960 mL, which was designated as 1.25 times solution 3. 320 mL of 1.25x solution 3 was taken, diluted hydrochloric acid/sodium hydroxide was added to adjust the pH to 7.0, and water was added to make the total volume 400 mL, which was used as test solution 11. 320 mL of 1.25x solution 3 was taken, diluted hydrochloric acid/sodium hydroxide was added to adjust the pH to 6.5, and water was added to make the total volume 400 mL, which was used as test solution 12. Table 7 shows the compositions of the aqueous solutions of Test Solutions 7 to 12. Note that test solutions 7 to 12 had a viscosity of 12 mPa·s or less.

2) Test method The test was conducted according to the method described in "3-1. Pollen burst suppression effect of various components 2) Test method".

3) Test results and discussion The test results are shown in Figure 3B. Here, FIG. 3B is a graph showing the pollen bursting rate of each test solution. Here, test solutions 7 to 12 had a pollen bursting rate of 20% or less, and exhibited an excellent pollen bursting suppressing effect. In addition, the pollen bursting rate was found to be enhanced depending on the concentration of boric acid, and in the presence of boric acid, the pollen bursting inhibiting effect was enhanced depending on the concentration of sodium edetate hydrate. , it was shown that in those compositions, the effect of suppressing pollen bursting was enhanced by lowering the pH. Furthermore, from these results, in the presence of boric acid and sodium edetate hydrate, polyvinylpyrrolidone K30, which is thought to have the effect of promoting pollen bursting, has the effect of suppressing pollen bursting of boric acid and sodium edetate hydrate. It was suggested that it complements or enhances the

(Test example 4)
4. Comparison test of intraocular contamination between eyedrop type eyewash and cup type eyewash The following test was conducted to compare intraocular contamination after eyewash between eyedrop type eyewash and cup type eyewash.

1) Preparation of eyewash eyedrops (test solution) An eyewash eyedrop with the same composition as low viscosity eyewash eyedrops 1 in Test Example 1 (viscosity 0.84 mPa·s) was used.

2) Test method Two eyes of a male Japanese white rabbit were used in the test. The animals were given general anesthesia, the hair around the eyes was shaved, and the skin around the eyes was thoroughly washed with physiological saline. After administering ocular surface anesthesia and washing the ocular surface with eye drops, the residual fluid in the conjunctival sac was collected and used as a background sample. After wiping off moisture from the skin around the eyes, 2 μL of a 5% fluorescein solution was applied as a contaminant to four locations on the skin 5 mm apart from the eyelid margin. Then, the eye drops were administered in an amount of 4 drops per eye (4 times of 46 μL) using a pipetman to perform an eye-drop type eye wash. After the eyewash operation was performed, the residual fluid in the conjunctival sac was collected and used as a sample after washing. Fluorescein concentrations in background samples and post-wash samples were quantified using a fluorescence plate reader. The contaminant concentration in the conjunctival sac was calculated according to Equation 3 below. Note that values below the lower limit of quantification were calculated as 0.
[Formula 3]
Contaminant concentration (mg/mL) = Fluorescein concentration of washed sample (mg/mL) - Fluorescein concentration of background sample (mg/mL)

In addition, the procedure was repeated in the same manner, except that instead of using the eyedrop type eyewash, the same commercially available cup type eyewash cup as in Test Example 2 was used, and the cup type eyewash was performed by contacting 5 mL of the eyewash eyedrops with the eye surface. Tests were performed to calculate contaminant concentrations within the conjunctival sac.

3) Test results and discussion The test results are shown in Figure 4. Here, FIG. 4 is a graph showing the average concentration of contaminants in the conjunctival sac after washing in the case of eyedrop-type eyewash and the case of cup-type eyewash.

As shown in FIG. 4, the concentration of contaminants in the conjunctival sac when the eyedrops were used was about 1/40 of that when the cup was used. Therefore, compared to cup-type eyewashes, eyedrop-type eyewashes are more effective in preventing and/or avoiding eye problems caused by contaminated eyewashes coming into contact with the peripheral area of the eyes during eyewashing and entering the eyes. It was shown that high

Claims (10)

Having a viscosity of 0.1 mPa・s or more and 10 mPa・s or less, 0.5 to 1.2% (w/v) boric acid or its salt , 0.001 to 0.5% (w/v) An eye drop type eyewash medicinal composition containing edetic acid or a salt thereof , and 0.01 to 1.0% (w/v) polyvinylpyrrolidone K30 , and having a pH of 6.5 or more and 7.0 or less. , an eyedrop-type eyewash medicinal composition that is used by instilling 4 to 6 drops per eye once and is characterized by suppressing pollen rupture (however, it does not contain olopatadine or its salt) . The eye drop type eyewash composition according to claim 1, which is used so that a total amount of eye drops of 120 μL or more is applied once per eye. The eye drop type eyewash composition according to claim 2, which is used so that a total amount of eye drops of 300 μL or less is applied once per eye. The eye drop type eyewash medicinal composition according to any one of claims 1 to 3, further comprising at least one selected from the group consisting of anti-inflammatory/astringent ingredients, antihistamine ingredients, inorganic salts, and alkyl polyaminoethylglycine. thing. The eyedrop type eyewash medicinal composition according to any one of claims 1 to 4, which contains boric acid. The eyedrop type eyewash medicinal composition according to any one of claims 1 to 5, further comprising a thickening agent. The eye drop type eyewash medicinal composition according to any one of claims 1 to 6, further comprising an isotonic agent, a stabilizer, a pH adjuster, and a solubilizer. The eye-drop type eyewash medicinal composition according to any one of claims 1 to 7 , which is used to wash away dirt and foreign substances from the ocular surface. The eye drop type eyewash medicinal composition according to claim 8 , wherein the dirt or foreign matter is pollen, eye secretion, or PM2.5. Any one of claims 1 to 9 housed in an eyedropper made of at least one selected from polypropylene, low density polyethylene, high density polyethylene, polyethylene terephthalate, polybutylene terephthalate, cycloolefin polymer and cycloolefin copolymer. The eye drop type eyewash medicinal composition described in 2.

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