JP2022017344A - Eyedrop-type eyewash composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a composition suitable for eyewashing by instillation, and a dosage regimen thereof.

SOLUTION: The present invention relates to an eyedrop-type eyewash composition with viscosity of 12 mPa s or less, where at least 4 drops thereof are applied each time for each eye.

SELECTED DRAWING: None

COPYRIGHT: (C)2022,JPO&INPIT

Description

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

With the increase in hay fever patients and the spread of contact lenses, problems that occur in the eyes are increasing. In addition, various eye drops have been developed and used for the prevention and treatment thereof. As a method for preventing such troubles that occur in the eyes in advance, the use of eyewashes that effectively remove pollen, dust, proteins, and other stains that have entered the eyes is increasing. As such an eyewash, after putting the eyewash in the eyewash cup, the user's eye peripheral area is pressed against the edge of the cup opening, and the face is turned upward together with the cup to make the eyewash in the cup. Generally, the type of eyewash that comes into contact with the user's eye surface and is blinked several times to wash the eyes (this type of eyewash is also referred to as "cup-type eyewash" below).

This cup-type eyewash requires about 5 mL of eyewash for one eyewash, and is not excellent in portability because it becomes large when used multiple times. In addition, since a large amount of eyewash of about 5 mL is used in one eyewash, there is a problem that tears on the surface of the eye are washed away excessively, causing a feeling of dryness in the eyes. Further, according to the cup-type eye washing method, since the eyewash comes into contact with the skin around the eye, the skin moisturizing component around the eye is washed away and the skin dries (Patent Document 1). There is also a problem that the attached dirt (sweat, pollen, dust, etc.) gets into the eyes that should have been washed and causes eye troubles.

However, research on eyewashing methods that have an effect of removing stains (pollen, dust, protein, etc.) similar to or higher than that of cup-type eyewashes and solve the above-mentioned problems of cup-type eyewashes has been studied. Almost never done.

Japanese Unexamined Patent Publication No. 2002-003404

An object of the present invention is to find a new eye-washing method, that is, a composition suitable for eye-washing by eye drops (hereinafter, also referred to as "eye-drop-type eye-washing") and a dosage thereof.

The present inventors have wondered what kind of composition should be used and what kind of dosage should be used in the case of eye drop type eyewashing to obtain an eyewashing effect similar to or better than that of a cup-type eyewashing drug. Diligently studied. As a result, the present inventors have determined the viscosity of the composition and the number of times (the number of drops) to be instilled at one time per eye (or the total amount of ophthalmic solution to be instilled at one time per eye) when performing eye drop type eye drops. We found that there was a large correlation with the eye-washing effect. More specifically, the composition having a viscosity of 12 mPa · s or less is instilled once per eye with 4 drops or more, preferably 4 drops or more and 6 drops or less, which is similar to a cup-type eyewash. It has been found that an eye-washing effect equivalent to or better than that can be obtained. In addition, since the eyes are washed by eye drops, the contact of the eyewash with the skin and eyelashes around the eye is minimized, and the eyewash contaminated by contacting the skin and eyelashes around the eye is in the eye. We have found that eye troubles caused by entering can be prevented and / or avoided, and the present invention has been completed. Furthermore, the present inventors have also found that a composition in which boric acid or a salt thereof and / or edetonic acid or a salt thereof is further blended in the above composition has an effect of suppressing pollen rupture.

That is, the present invention is as follows.
[1] An eye drop-type eye drop composition having a viscosity of 12 mPa · s or less, which is used so that 4 drops or more are instilled once per eye.
[2] The eye drop-type eye drop medicinal composition according to [1], which is used so that 6 drops or less are instilled once per eye.
[3] A composition for eye drops having a viscosity of 12 mPa · s or less, which is used for eye drops once per eye so that the total amount of ophthalmic solution is 120 μL or more. Composition.
[4] The eye drop-type eye drop medicinal composition according to [3], which is used so that the total amount of eye drops is 300 μL or less once per eye.
[5] Further, any one of [1] to [4] containing at least one selected from the group consisting of an anti-inflammatory / convergence component, an antihistamine component, an inorganic salt, an alkylpolyaminoethylglycine and boric acid or a salt thereof. The eye drop type medicated composition for eye wash according to.
[6] The eye drop-type eye drop medicinal composition according to any one of [1] to [4], which further contains boric acid.
[7] The eye drop-type eye drop medicinal composition according to any one of [1] to [6], which further contains a viscous agent.
[8] The composition for eye drops according to any one of [1] to [7], which further contains an tonicity agent, a stabilizer, a pH adjuster and a solubilizer.
[9] The eye drop-type eye drop 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 eye drop-type eye drop medicinal composition according to any one of [1] to [9], which is used for washing away dirt and foreign substances on the surface of the eye.
[11] The eye drop-type eye drop medicinal composition according to [10], wherein the stain or foreign substance is pollen, ocular secretions or PM2.5.
[12] [1] to [11] are contained in an eyelet 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 instillation type eye wash medicinal composition according to any one of.
[13] The eye drop-type eye drop medicinal composition according to [12], wherein the eye drop container is a liquid-repellable eye drop container.

Further, the present invention also relates to the following.
[14] An eye drop-type eye-washing 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 eye drop-type eye-washing method comprising instilling a composition having a viscosity of 12 mPa · s or less once per eye with a total ophthalmic solution volume of 120 μL or more.
[17] The method according to [16], wherein the total amount of ophthalmic solution is 300 μL or less once per eye.
[18] The composition further comprises at least one selected from the group consisting of anti-inflammatory / convergent components, antihistamine components, inorganic salts, alkylpolyaminoethylglycine and boric acid or salts thereof, [14] to [ 17] The method according to any one of.
[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 viscous agent.
[21] The method according to any one of [14] to [20], wherein the composition further contains an tonicity 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 substances on the surface of the eye.
[24] The method according to [23], wherein the stain or foreign substance is pollen, ocular secretions or PM2.5.
[25] The composition is contained in an ophthalmic 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 a liquid dropable eye drop container.

Further, the present invention also relates to the following.
[27] A composition for use in eye drop type eye washing, which has a viscosity of 12 mPa · s or less, and is characterized in that it is used so that 4 drops or more are instilled once per eye. 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 eye-drop type eye-washing, which has a viscosity of 12 mPa · s or less, and is characterized in that it is used so that 120 μL or more is instilled once per eye with a total ophthalmic solution volume. The composition to be.
[30] The composition for use according to [29], which is used so that the total amount of ophthalmic solution is 300 μL or less once per eye.
[31] Further, any one of [27] to [30] containing at least one selected from the group consisting of an anti-inflammatory / convergence component, an antihistamine component, an inorganic salt, an alkylpolyaminoethylglycine and boric acid or a salt thereof. The composition for use as described in.
[32] The composition for use according to any one of [27] to [30], which further contains boric acid.
[33] The composition for use according to any one of [27] to [32], which further contains a viscous agent.
[34] The composition for use according to any one of [27] to [33], which further contains an tonicity 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 for washing away stains and foreign substances on the surface of the eye.
[37] The composition for use according to [36], wherein the stain or foreign substance is pollen, ocular secretions or PM2.5.
[38] Contained in eye drops formed from at least one selected from polypropylene, low density polyethylene, high density polyethylene, polyethylene terephthalate, polybutylene terephthalate, cycloolefin polymers and cycloolefin copolymers [27]-[37] ] The composition for use according to any one of.
[39] The composition for use according to [38], wherein the eye drop container is a liquid-repellable eye drop container.

Further, the present invention also relates to the following.
[40] The use of a composition having a viscosity of 12 mPa · s or less for the production of an eye drop type eyewash, and the eye drop type eyewash is to be instilled in 4 drops or more once per eye. Use, characterized by being used in.
[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] The use of a composition having a viscosity of 12 mPa · s or less for the production of an eye drop type eyewash, wherein the eye drop type eyewash is instilled once per eye with a total ophthalmic solution volume of 120 μL or more. Use, characterized by being used as such.
[43] The use according to [42], wherein the eye drop type eyewash is used once per eye so that the total amount of eye drops is 300 μL or less.
[44] The composition further comprises at least one selected from the group consisting of anti-inflammatory / convergent components, antihistamine components, inorganic salts, alkylpolyaminoethylglycine and boric acid or salts thereof, [40] to [ 43] The use described in any one of.
[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 viscous agent.
[47] The use according to any one of [40] to [46], wherein the composition further contains an tonicity 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 surface of the eye.
[50] The use according to [49], wherein the stain or foreign substance is pollen, ocular secretions or PM2.5.
[51] The composition is contained in an ophthalmic 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 use according to any one of 40] to [50].
[52] The use according to [51], wherein the eye drop container is a liquid-repellable eye drop container.

Further, the present invention also relates to the following.
[53] An eye drop type eye drop having a viscosity of 12 mPa · s or less, characterized in that it is used so that 4 drops or more are instilled once per eye.
[54] The eye-drop type eye-washing agent according to [53], which is used so that 6 drops or less are instilled once per eye.
[55] An eye drop type eye drop having a viscosity of 12 mPa · s or less, characterized in that it is used once per eye so that the total amount of ophthalmic solution is 120 μL or more.
[56] The eye drop type eye drop according to [55], which is used so that the total amount of eye drops is 300 μL or less once per eye.
[57] Further, any one of [53] to [56] containing at least one selected from the group consisting of an anti-inflammatory / convergence component, an antihistamine component, an inorganic salt, an alkylpolyaminoethylglycine and boric acid or a salt thereof. The eye drop type eye wash according to.
[58] The eye drop type eye wash agent according to any one of [53] to [56], which further contains boric acid.
[59] The eye drop type eye drop according to any one of [53] to [58], which further contains a viscous agent.
[60] The eye drop type eye wash agent according to any one of [53] to [59], which further contains an tonicity agent, a stabilizer, a pH adjuster and a solubilizer.
[61] The eye drop type eye wash agent according to any one of [53] to [60], which has a pH of 6.5 or more and 7.0 or less.
[62] The eye drop type eye drop according to any one of [53] to [61], which is used for washing away dirt and foreign substances on the surface of the eye.
[63] The eye drop type eyewash according to [62], wherein the stain or foreign substance is pollen, ocular secretions or PM2.5.
[64]-[63]-[63]-[63] contained in eye drops formed from at least one selected from polypropylene, low density polyethylene, high density polyethylene, polyethylene terephthalate, polybutylene terephthalate, cycloolefin polymer and cycloolefin copolymer. ] The instillation type eye wash agent according to any one of.
[65] The eye-drop type eye-washing agent according to [64], wherein the eye-drop container is a liquid-repellable eye-drop container.

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

By instilling 4 drops or more, preferably 4 drops or more and 6 drops or less, once per eye of an eye drop-type eyewash composition having a viscosity of 12 mPa · s or less, it is similar to and equivalent to a cup-type eyewash. Or more eye wash effect can be obtained. In addition, the eye drop-type eyewash composition has minimal contact with the skin, eyelashes, etc. around the eye of the eyewash as compared with the cup-type eyewash, and stains (sweat, pollen) adhering to the area around the eye. , Dust, etc.) can be significantly reduced, so eye troubles caused by contaminated eyewash after contact with the skin, eyelashes, etc. around the eyes can enter the eyes. Can be expected to have preventive and / or avoidant effects. Further, when boric acid or a salt thereof and / or edetonic acid or a salt thereof is further added to the eye drop type medicated composition, this composition has an effect of suppressing pollen rupture. Therefore, in this case, it is also expected that the pollen can be washed away before the pollen bursts in the eye and the allergen inside the pollen is released.

FIG. 1 is a graph showing the relationship between the viscosity of eye drops for eye washing and the cleaning effect thereof. FIG. 2 is a graph showing the relationship between the number of eye drops of the eye drop for eye washing once per eye and the cleaning effect thereof. FIG. 3A is a graph showing the pollen rupture suppressing effect of various components. FIG. 3B is a graph showing the pollen rupture suppressing effect of an aqueous solution containing various components. FIG. 4 is a graph showing the results of comparison of intraocular contamination after eye washing between the case of eye drop type eye washing and the case of cup type eye washing.

Hereinafter, the present invention will be described in detail. 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 low, specifically 12 mPa · s or less, and is not particularly limited as long as it 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, further preferably 3 mPa · s or less, and particularly preferably 1 mPa · s or less. The lower limit of the viscosity is not particularly limited as long as it exceeds 0 mPa · s, but 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 limit and the lower limit of the viscosity can be appropriately combined into a range. For example, more than 0 mPa · s and 10 mPa · s or less is preferable, 0.01 mPa · s or more and 5 mPa · s or less is more preferable, 0.1 mPa · s or more and 3 mPa · s or less is further preferable, and 0.3 mPa · s or more and 1 mPa · s. The following are particularly preferred. In the present specification, the low viscosity means, for example, a viscosity of 20 mPa · s or less.

Further, the viscosity of the composition of the present invention can be measured by, for example, the viscosity measuring method described in the 17th revised Japanese Pharmacopoeia. Specific measurement methods include a capillary viscometer method, a rotational viscometer method, and the like, and a rotational viscometer method is preferable. More specifically, a cone plate type viscometer can be used to measure the viscosity of each pharmaceutical product at a shear rate of 100s ^-1 and a measurement temperature of 25.0 ° C. Further, there is no limitation on the timing of measuring the viscosity of the composition of the present invention, but preferably immediately after the preparation of the composition of the present invention, immediately before the use of the composition of the present invention, or the expiration date of the composition of the present invention. It may be measured during (effective period), and more preferably immediately after the preparation of the composition of the present invention or immediately before the use of the composition of the present invention.

The number of times the composition of the present invention is used is not particularly limited as long as the number of times of instillation (eye washing) 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. However, since the present invention is excellent in portability, it can be used immediately when it is noticed that a foreign substance has entered the eye. can.

In the composition of the present invention, it is preferable to instill 3 drops or more as the lower limit once per eye, and more preferably 4 drops or more. The upper limit is not particularly limited, but from the viewpoint of patient convenience, eyewashing effect, problems due to an increase in the amount of eyewash, it is preferable to instill 8 drops or less per eye, and 6 drops or less. It is more preferable to instill. Further, the upper limit and the lower limit can be appropriately combined to form a range. For example, it is preferable to instill 3 drops or more and 8 drops or less once per eye, more preferably 4 drops or more and 8 drops or less, and particularly preferably 4 or more and 6 drops or less.

Further, considering that the amount of one drop by normal instillation is 30 to 50 μL, the lower limit of the total amount of ophthalmic solution for one instillation per eye is preferably 90 μL or more, more preferably 120 μL or more. .. The upper limit thereof is not particularly limited, but is preferably 400 μL or less, and more preferably 300 μL or less, once per eye from the viewpoint of patient convenience, eyewashing effect, problems due to an increase in the amount of eyewashing drug, and the like. Further, the upper limit and the lower limit can be appropriately combined to form a range. Specifically, for example, the range of the total amount of ophthalmic solution 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, "instilling n or more drops once per eye" means instilling n or more drops continuously in one use per eye. The composition of the present invention is not particularly limited in blinking after instillation, but specifically, it may be blinked for each drop instillation, or it may be blinked after instillation of a plurality of drops. It does not have to be. From the viewpoint of the eye-washing effect, it is preferable to blink every 1 or 2 drops, and it is more preferable to blink every 1 drop. The number of blinks is not particularly limited, but it is preferably 1 to 3 blinks for each drop or after a plurality of drops, and more preferably 1 to 2 blinks.

The composition of the present invention can contain the following components in an appropriate amount as long as it does not interfere with the effects of the present invention, and can be contained without particular limitation as long as it is pharmaceutically acceptable. In addition, it is desirable that the following ingredients are contained as pharmacologically active ingredients (physiologically active ingredients or active ingredients). Specifically, epsilon-aminocaproic acid, allantin, berberines (berberine chloride, berberine sulfate), sodium azulene sulfonate, dipotassium glycyrrhizinate, zinc (zinc sulfate, zinc lactate), lysoteam chloride, etc. Anti-inflammatory and astringent components, antihistamines such as diphenhydramine hydrochloride, chlorpheniramine maleate, flavinadenine dinucleotide sodium, cyanocobalamine, retinols (retinol acetate, retinol partimate), pyridoxin hydrochloride, pantothenic acids (pantenol, calcium pantothenate, Sodium pantothenate), vitamins such as tocopherol acetate, asparagates (potassium L-aspartate, magnesium L-aspartate, magnesium potassium L-aspartate (equal mixture)), aminoethylsulfonic acid (taurine), Amino acids such as chondroitin sodium sulfate, inorganic substances such as potassium chloride, calcium chloride, sodium chloride, sodium hydrogencarbonate, sodium carbonate, dry sodium carbonate, magnesium sulfate, sodium hydrogenphosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, etc. Examples thereof include boric acid such as salts, alkylpolyaminoethylglycine, boric acid and hosand, and salts thereof, and it is more preferable to contain boric acid such as boric acid and hosand or a salt thereof.

The above-mentioned components may be used alone or in combination of two or more, and when these components are contained as pharmacologically active ingredients, the content thereof is pharmacologically active. Depending on the type of ingredient, the type and content of other compounded ingredients, the use of the composition, the form of the formulation, the method of use, etc. It can be appropriately set based on (2) Ophthalmic drug manufacturing and marketing approval criteria described in "Guide 2017".

For example, according to the above-mentioned over-the-counter drug manufacturing and marketing approval standard, 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 contains up to 3 types, and further contains up to 1 type of pharmacologically active ingredients of Group B, and the pharmacology of Group C and Group D. It is preferable to contain up to 3 types of each active ingredient. When the pharmacologically active ingredient of Group B is contained, it is preferable to contain only one type, further containing up to three types of pharmacologically active ingredients of Group A, and up to three types of pharmacologically active ingredients of Group C and Group D, respectively. .. Further, when the pharmacologically active ingredient of the E or F group is contained, it is preferable to contain only one of them. When there are subgroups in each group, it is preferable to contain only one species from the same subgroup.

In the composition of the present invention, when boric acid such as boric acid or borax or a salt thereof is contained as a pharmacologically active ingredient (physiologically active ingredient or active ingredient), the content (concentration) thereof is acceptable as a medicine. If so, there is no particular limitation. For example, 0.01 to 5% (w / v) is preferable, 0.1 to 3% (w / v) is more preferable, and 0.5 to 1.2% (w / v) is particularly preferable.

The composition of the present invention may also contain an appropriate amount of a pharmacologically active ingredient (physiologically active ingredient or active ingredient) acceptable as the following pharmaceuticals, in addition to the above-mentioned ingredients, as long as the effects of the present invention are not impaired. Specifically, decongestation components (vasoconstrictor components) such as epinephrine, epinephrine hydrochloride, efedrin hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, phenyleffrin hydrochloride, dl-methylephedrine hydrochloride, methylsulfate neostigmine, tropicamide, helenien, sulfate. Eye muscle regulating component such as atropin (focus regulating component), zinc sulfate hydrate, planoprofen, salicylic acid, tranexamic acid, anti-inflammatory / converging component such as licorice, cromoglycic acid or its salt (sodium cromoglycate), anlexanox, ibudilast , Splatast, pemirolast or its salt (pemirolast potassium, pemirolast sodium), tranilast, olopatazine or its salt (olopatazine hydrochloride), levocabastine or its salt (levocabastine hydrochloride), asitazanolast, ketotiphen or its salt (fumaric acid) Antihistamine or antiallergic agent such as ketotiphen), epinastine or a salt thereof (epinastin hydrochloride), vitamin B ₁₂ (hydroxocobalamine, methylcovaramine and adenosylcobalamine), vitamin _B6 (pyridoxine, pyridoxal, pyridoxamine), vitamin E (acetic acid- d-α tocopherol), vitamin B ₁ (thiamine, thiamine hydrochloride), niacin (nicotinic acid and nicotinic acid amide), biotin, vitamins such as folic acid, aspartic acid, glycine, alanine, γ-aminobutyric acid, glutamic acid, arginine , Amino acids such as lysine, sulfa agents such as sulfamethoxazole, sodium sulfametoxazole, sulfisoxazole, sodium sulfisoxazole, polyvinyl alcohol, polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose , Vitrifying components such as glucose, aclinol, cetylpyridinium, benzalkonium chloride, benzethonium chloride, chlorhexidine, polyhexamethylenebiguanide, bactericides such as alkyldiaminoethylglycine hydrochloride, corneal protection such as sodium hyaluronate, treatment of corneal disorders Ingredients and the like can be mentioned. The composition of the present invention does not have to contain sodium hyaluronate at a concentration of 0.075% (w / v) as a pharmacologically active ingredient, and does not contain sodium hyaluronate substantially or at all. May be good. Also, it may be substantially or completely free of polyhexamethylene biguanide.

As the pharmacologically active ingredient (physiologically active ingredient or active ingredient) that can be used in the composition of the present invention, only one kind may be used alone, or two or more kinds may be used in any combination. Further, the content of the pharmacologically active ingredient can be appropriately set according to the type of the pharmacologically active ingredient, the type and content of other compounding ingredients, the use of the composition, the pharmaceutical form, the method of use and the like.

The composition of the present invention may further contain a thickener, an tonicity agent, a stabilizer, a pH adjuster and / or a solubilizer.

The viscous 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 salts thereof, macrogol 300, macrogol 400, macrogol 1500, macrogol 4000, macrogol 6000 and other polyethylene glycols, dextran 40, dextran 70 and other dextrans, sodium hyaluronate (purified). (Sodium hyaluronate, etc.), hyaluronic acid derivatives such as crosslinked hyaluronic acid, alginic acid, alginic acid derivatives such as sodium alginate, polyvinyl alcohol, carboxyvinyl polymer, sodium chondroitin sulfate, gum arabic, gellan gum, traganth, etc., and polyvinylpyrrolidone K25, Polyvinylpyrrolidones such as polyvinylpyrrolidone K30, polyvinylpyrrolidone K90, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose 2208, hydroxypropylmethylcellulose 2906, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxyethylcellulose, nitrocellulose or salts thereof. Such as cellulose derivatives, cross-linked hyaluronic acid and other hyaluronic acid derivatives, and alginic acid, sodium alginate and other alginic acid derivatives are preferable, and polyvinylpyrrolidone K30 is more preferable. The composition of the present invention may be substantially or completely free of sodium hyaluronate (purified sodium hyaluronate, etc.).

As the thickener that can be used in the composition of the present invention, only one kind may be used alone, or two or more kinds may be used in any combination. Further, the content of the viscous agent can be appropriately set according to the type of the viscous agent, the type and content of other compounding ingredients, the use of the composition, the pharmaceutical form, the method of use and the like.

When a viscous agent is used in the composition of the present invention, the total content (concentration) of the viscous agent is preferably, for example, 0 to 1.0% (w / v), preferably 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 chloride, sodium hydrogencarbonate, sodium carbonate, dry sodium carbonate, sodium acetate, sodium hydrogensulfate, sodium sulfite, sodium thiosulfate and the like. , 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, tromethamole and the like, and examples thereof include potassium chloride, calcium chloride, calcium chloride and chloride. Sodium, sodium hydrogencarbonate, sodium carbonate, dry sodium carbonate or magnesium sulfate are preferable, and potassium chloride and sodium chloride are more preferable.

As the tonicity agent that can be used in the composition of the present invention, only one kind may be used alone, or two or more kinds may be used in any combination. Further, the content of the tonicity agent can be appropriately set according to the type of the tonicity agent, the type and content of other compounding components, the use of the composition, the pharmaceutical form, the method of use and the like.

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

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, tromethamol, sodium formaldehyde sulfoxylate (longalit), tocopherol, sodium pyrosulfate, monoethanolamine, aluminum monostearate, glycerin monostearate, dibutylhydroxytoluene, edetic acid, sodium edetate, sodium edetate hydrate. , Polyoxyethylene polyoxypropylene glycol and the like, preferably dibutylhydroxytoluene, edetic acid, sodium edetate or sodium edetate hydrate, and more preferably sodium edetate hydrate.

As the stabilizer that can be used in the composition of the present invention, only one kind may be used alone, or two or more kinds may be used in any combination. Further, the content of the stabilizer can be appropriately set according to the type of the stabilizer, the type and content of other compounding components, the use of the composition, the form of the formulation, the method of use and the like.

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

The pH adjuster that can be used in the composition of the present invention is not particularly limited as long as it is pharmaceutically acceptable. For example, dilute hydrochloric acid, acetic acid, sodium hydroxide, sodium hydrogencarbonate, sodium carbonate and the like can be mentioned, and dilute hydrochloric acid and sodium hydroxide are preferable.

As the pH adjuster that can be used in the composition of the present invention, only one kind may be used alone, or two or more kinds may be used in any combination. Further, the content of the pH adjusting agent can be appropriately set according to the type of the pH adjusting agent, the type and content of other compounding ingredients, the use of the composition, the pharmaceutical form, the method of use and the like.

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

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

The pH can be measured, for example, according to the pH measuring method described in the 17th revised 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 thereof include aqueous solubilizers such as water (distilled water, normal water, purified water, sterile purified water, injection water, distilled water for injection, etc.) and hydrous ethanol, and water (distilled water, normal water, purified water, sterilization, etc.). Purified water, water for injection, distilled water for injection, etc.) are preferable.

As the dissolving agent that can be used in the composition of the present invention, only one kind may be used alone, or two or more kinds may be used in any combination. Further, the content of the solubilizer can be appropriately set according to the type of the solubilizer, the type and content of other compounding components, the use of the composition, the form of the formulation, the method of use and the like.

In the composition of the present invention, for example, when the solubilizer is water, 90% (w / v) or more is preferable, 95% (w / v) or more is more preferable, and 97% (w / v) or more is preferable with respect to the total amount of the composition. w / v) or higher is particularly preferable.

The composition of the present invention may contain an appropriate amount of additives other than the above-mentioned additives (viscosity agent, tonicity agent, stabilizer, pH adjuster, solubilizer) as long as the effects of the present invention are not impaired. can. The additive other than the additive is not particularly limited as long as it is pharmaceutically acceptable, and for example, a surfactant (solubilizing agent), a buffering agent, a preservative, a cooling agent and the like 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 and the like are preferable, and nonionic surfactants are more preferable.

Examples of the nonionic surfactant include monolaurate POE (20) sorbitan (polysorbate 20), monopalmitate POE (20) sorbitan (polysorbate 40), monostearate POE (20) sorbitan (polysorbate 60), and birds. POE sorbitan fatty acid esters such as POE stearate (20) sorbitan (polysorbate 65), POE monooleic acid (20) sorbitan (polysorbate 80), POE (40) hardened castor oil (polyoxyethylene cured castor oil 40) and POE ( 60) POE cured castor oil such as cured castor oil (polyoxyethylene cured castor oil 60), POE (10) castor oil (polyoxyethylene castor oil 10), POE (35) castor oil (polyoxyethylene castor oil 35) POE castor oil such as 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 (poroxummer 407, sorbonic F127), POE (200) POP (70) glycol, etc. Examples thereof include propylene block copolymer, polyethylene glycol monostearate such as polyoxyl 40 stearate, POE monolaurate (20) sorbitan (polysorbate 20), POE monopalmitate (20) sorbitan (polysorbate 40), POE monostearate (polysorbate 40). 20) POE sorbitan fatty acid esters such as sorbitan (polysorbate 60), POE tristearate (20) sorbitan (polysorbate 65), monooleic acid POE (20) sorbitan (polysorbate 80) are preferable, and monooleic acid POE (20) sorbitan. (Polysorbate 80) is more preferable.

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

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

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

Only one of these surfactants may be used alone, or two or more thereof may be used in any combination. Further, the content of the surfactant can be appropriately set according to the type of the surfactant, the type and content of other compounding components, the use of the composition, the pharmaceutical form, the method of use and the like.

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

The buffering 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, borate or salts thereof such as borate, sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borosand, phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, dihydrogen phosphate. Phosphorus or salts thereof such as potassium, trisodium phosphate, tripotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, carbonic acid, sodium hydrogencarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, carbonic acid. Carbonate or a salt thereof such as potassium hydrogen hydrogen and magnesium carbonate, citrate or a salt thereof such as citrate, sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, acetic acid, ammonium acetate, Acetic acid such as potassium acetate, calcium acetate, sodium acetate or a salt thereof, aspartic acid such as aspartic acid, sodium aspartate, magnesium aspartate, potassium aspartate or a salt thereof, ethylenediamine diacetic acid (EDDA), ethylenediamine triacetic acid, ethylenediamine tetra. Ethylenediamine acetic acid such as acetic acid (edetic acid, EDTA), ethylenediamine tetraacetate disodium hydrate (sodium edetate hydrate), N- (2-hydroxyethyl) ethylenediamine triacetic acid (HEDTA), diethylenetriaminepentaacetic acid (DTPA) Classes or salts thereof, amino acids such as ε-aminocaproic acid, etc. include boric acid, sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, boric acid such as borosand, and salts thereof, phosphoric acid, phosphorus. Phosphorus or salts thereof such as disodium hydrogen acid, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, tripotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate and ε-aminocaproic acid. Such amino acids are preferable, boric acid, boar sand, or ε-aminocaproic acid is more preferable.

As the buffering agent that can be used in the composition of the present invention, only one kind may be used alone, or two or more kinds may be used in any combination. Further, the content of the buffering agent can be appropriately set according to the type of the buffering agent, the type and content of other compounding components, the use of the composition, the pharmaceutical form, the method of use and the like.

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

The preservatives that can be used in the composition of the present invention are not particularly limited as long as they are pharmaceutically acceptable. For example, biguanide compounds such as polyhexamethylene biguanide and polyhexanide hydrochloride, zinc chloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalconium 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, glowkill (trade name manufactured by Rhodia), boric acid, borosand, Examples thereof include benzalconium chloride, chlorhexidine gluconate, sorbic acid, phenethyl alcohol, boric acid, borosand and chloric acid, and benzalconium chloride, chlorhexidine gluconate, phenethyl alcohol and boric acid. Benzoic acid and chloric acid are more preferable. The composition of the present invention may be substantially or completely free of polyhexamethylene biguanide.

As the preservative that can be used in the composition of the present invention, only one kind may be used alone, or two or more kinds may be used in any combination. Further, the content of the preservative can be appropriately set according to the type of the preservative, the type and content of other compounding components, the use of the composition, the pharmaceutical form, the method of use and the like.

When a preservative is used in the composition of the present invention, for example, the total content (concentration) of the preservative is preferably 0.0001 to 1% (w / v), preferably 0.0005 to 0.5% (w). / V) is more preferred, and 0.001 to 0.2% (w / v) is even more preferred, but preservatives, especially benzalconium or salts thereof, or methyl paraoxybenzoate, ethyl paraoxybenzoate, paraoxybenzoic acid. Compositions that are substantially or completely free of parabens such as propyl, butyl paraoxybenzoate or salts thereof are particularly preferred.

The refreshing 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, uikyo oil, rose oil, keihi oil, sparemint oil, tanning oil, cool mint, peppermint oil, menthol, menthol, camphor, borneol, geraniol, nerol. , Cineol, citronellol, carboxylic, anetol, eugenol, limonene, linalol, linaryl acetate and the like, and menthol, camphor, borneol and geraniol are preferable, and menthol and borneol are more preferable. Further, the terpenoid may be d-form, l-form or dl-form, and for example, l-menthol, d-menthol, dl-menthol, dl-camphor, d-camphor, dl-borneol, d-borneol and the like. , L-menthol, dl-camphor, d-camphor and d-borneol are preferred.

As the refreshing agent that can be used in the composition of the present invention, only one kind may be used alone, or two or more kinds may be used in any combination. Further, the content of the refreshing agent can be appropriately set according to the type of the cooling agent, the type and content of other compounding components, the use of the composition, the pharmaceutical form, the method of use and the like.

When a refreshing agent is used in the composition of the present invention, for example, the total content (concentration) of the cooling agent is preferably 0.001 to 0.5% (w / v), and 0.001 to 0. 1% (w / v) is more preferable, and 0.005 to 0.05% (w / v) is particularly preferable.

Among the above components, when the composition of the present invention contains boric acid or a salt thereof and / or edetonic acid or a salt thereof, and in some cases polyvinylpyrrolidone, it is preferable because it exhibits an effect of suppressing pollen rupture.

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, and 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 revised Japanese Pharmacy, and the osmotic pressure is described in the Japanese Pharmacy. It can be measured with reference to the osmotic pressure measurement method (freezing point drop method), and for the standard solution for osmotic pressure ratio measurement (0.9% (w / v) sodium chloride aqueous solution), sodium chloride (Japanese Pharmacopoeia standard reagent). ) Is dried at 500 to 650 ° C. for 40 to 50 minutes, then allowed to cool in a chloride (silica chloride), weigh accurately 0.900 g thereof, dissolve in purified water and prepare exactly 100 mL, or a commercially available osmotic pressure ratio. A standard solution for measurement (0.9% (w / v) sodium chloride aqueous solution) can be used.

The composition of the present invention can be provided by being contained in any container (main body, inner plug, cap). Further, the container for accommodating 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 the monomers constituting these, plastic containers containing two or more kinds of these materials, etc. include polypropylene, low density polyethylene, high density polyethylene, polyethylene terephthalate, polybutylene terephthalate, cycloolefin polymer. And a cycloolefin copolymer, a copolymer of the monomers constituting these, and a plastic container in which two or more kinds containing these materials are combined are preferable. Here, the combination may be a mixture of different materials, or a combination of different materials may be used as a layered structure. Further, the container may be a multi-dose container that can be used repeatedly or a single-use unit-dose container, and is a multi-dose container that can be sprayed and can be used repeatedly. Is preferable. The container for accommodating these compositions of the present invention is, for example, a general eye drop container, but as described above, such an eye drop container is usually designed so that the amount 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 substances on the surface of the eye. In the present invention, "washing away dirt and foreign matter" means washing away dirt and foreign matter on the surface of the eye from the inside of the eye to the outside of the eye.

In the present invention, the term "dirt or foreign substance" is not particularly limited as long as it is a substance that causes discomfort to the eyes. Examples thereof include pollen of cedar, cypress, gramineous plants, dust such as house dust, ocular secretions such as protein, skin secretions such as sweat, and cosmetics such as PM2.5, eye shadow, mascara, and foundation. , Sugi, cypress, gramineous plants and the like pollen and PM2.5 are preferable.

The composition of the present invention can be used, for example, as a composition for contact lenses, can be applied to any commercially available contact lens, including hard contact lenses and / or soft contact lenses, and is in a state of wearing contact lenses ( It can also be used with contact lenses attached to the surface of the eye). Here, the soft contact lens includes, for example, both ionic and nonionic, and includes both a silicone hydrogel contact lens and a non-silicone hydrogel contact lens. It also includes all soft contact lenses classified as groups I-IV.

The composition of the present invention may be labeled as "can be used when wearing contact lenses (hard contact lenses / soft contact lenses)", "for wearing contact lenses (hard contact lenses / soft contact lenses)", and the like. It can be displayed, and it can be displayed similar to them. In addition, the display can be made directly or indirectly, and examples of the direct display include the description on the packaging of the product itself, the package, the container, the label, the tag, etc., and the indirect display is given. Examples of such as transaction documents, instruction manuals, package inserts, catalogs, websites, stores, exhibitions, signboards, bulletin boards, newspapers, magazines, televisions, radios, e-mails, etc. Activities such as.

Further, the detailed description of the composition and the like of the present invention also applies to the following aspects of the present invention.

One aspect of the present invention is an eye drop-type eye-washing method comprising 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 eye drop type eye washing, which has a viscosity of 12 mPa · s or less and is used so that 4 drops or more are instilled once per eye. It 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 production of an eye drop type eyewash, wherein the eye drop type eyewash is 4 drops or more once per eye. It is a use characterized by being used so as to be instilled.

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

<Formulation example>
Examples of the pharmaceutical products of the present invention are shown in Table 2 below, but these are for better understanding of the present invention and do not limit the scope of the present invention at all. In the following pharmaceutical example, the blending amount of each component is the content in 100 mL of the pharmaceutical product, and their viscosities are 12 mPa · s or less.

The desired composition having a viscosity of 12 mPa · s or less can be obtained by appropriately adjusting the types, blending amounts and viscosities of the pharmacologically active ingredients and additives in the above-mentioned preparation examples 1 to 6.

<Example>
Below, as an example, 1. Correlation test between the viscosity of eye drops for eye washing and the cleaning effect, 2.1 Correlation test between the number of eye drops per eye and the cleaning effect, 3. Pollen rupture suppression effect test, 4. The intraocular contamination confirmation test of the eye drop type eyewash and the cup type eyewash is shown. However, these test examples are for better understanding of the present invention and do not limit the scope of the present invention at all.

(Test Example 1)
1. 1. Correlation test between the viscosity of eye drops for eye washing and the cleaning effect The following tests were conducted to investigate the relationship between the viscosity of eye drops for eye washing (eye drops) and the cleaning effect in the case of eye drops.

1) Preparation of eye wash eye drops (test solution) First, heat 8700 mL of water to 50 ° C., boric acid 100.0 g, polyvinylpyrrolidone K30 50.0 g, sodium edetate hydrate 1.0 g, sodium chloride. Add 40.0 g and 10.0 g of potassium chloride, stir, cool to room temperature, add dilute hydrochloric acid / sodium hydroxide to adjust the pH to 6.7, and add water to make the total volume 10000 mL, resulting in low viscosity. Ophthalmic solution 1 for eye washing was prepared. At this time, the viscosity of the low-viscosity eye-washing eye drops 1 was 0.84 mPa · s. Next, 3.0 g of hydroxymethyl cellulose (HEC) is added and dispersed in 150 mL of low-viscosity eye-washing ophthalmic solution 1 for viscosity-adjusting high-viscosity ophthalmic solution used for viscosity adjustment, and the mixture is heated to 70 ° C. to stir and dissolve. Prepared in. Then, by thoroughly stirring 6 mL of this viscosity-adjusting ophthalmic solution and 134 mL of the low-viscosity eye-washing ophthalmic solution, the low-viscosity eye-washing ophthalmic solution 2 having a viscosity of 11.56 mPa · s was combined with 12 mL of the viscosity-adjusting ophthalmic solution. Low-viscosity eye wash 1 28 mL is mixed well to mix high-viscosity eye wash 1 with a viscosity of 56.4 mPa · s, and 20 mL of viscosity-adjusting eye drops and 20 mL of low-viscosity eye wash 1 are combined. High-viscosity eye-washing ophthalmic solutions 2 having a viscosity of 194.2 mPa · s were prepared by stirring well. The viscosity was measured using a cone plate type viscometer at a shear rate of 100s ^-1 and a measurement temperature of 25.0 ° C. immediately before the test was carried out, based on the above-mentioned 17th revised Japanese Pharmacopoeia. Table 3 shows the viscosities of each eye drop for eye washing.

2) Test method Male Japanese white rabbits were used for the cleaning effect test. The subjects of the experiment are one binocular and two eyes. The animals were subjected to general anesthesia and ocular surface anesthesia, and a solution in which spherical fluorescent beads having an average diameter of about 40 μm were uniformly suspended (3% suspension, 1% suspension of spherical fluorescent beads manufactured by Spherotech Inc. was concentrated. 50 μL of each eye was instilled. Then, the above-mentioned eye-washing ophthalmic solution was instilled in 4 drops (46 μL 4 times) per eye with Pipetman, and the ocular surface was washed by eye-drop type eye-washing. After washing, the fluorescent beads remaining on the ocular surface were collected by Pipetman. The volume of the liquid containing the recovered fluorescent beads was measured by Pipetman (xμL). A part of the collected liquid was placed on a Fuchs-Rosenthal type hemocytometer, and the bead density was measured with an optical microscope according to the usage of the hemocytometer (y pieces / μL). The number of recovered fluorescent beads (pieces) was calculated from the volume of the recovered liquid (xμL) and the bead density (y pieces / μL) by the formula (xxy), and used as the number of beads remaining after eye washing (b). In addition, the collection operation was performed without instilling eye drops for eye washing, 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 residual rate of beads after washing with each eye drop was calculated according to the following formula 1. Here, a low bead residual rate means a high cleaning effect. The residual ratio of beads without washing was 100%.
[Equation 1]
Bead residual rate (%) = {Number of residual beads after eye washing (b) / Number of residual beads without washing (a)} x 100

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

As shown in Table 4 and FIG. 1, the cleaning effect (shown as the residual ratio of beads) in the low-viscosity eye-washing eye drops 1 (0.84 mPa · s) and the low-viscosity eye-washing eye drops 2 (11.56 mPa · s) is , 15% or less, which was excellent. Above all, the cleaning effect of the low-viscosity eye-washing eye drops 1 (0.84 mPa · s) was extremely excellent with a bead residual rate of 3.0%. Further, the bead residual rate of the high-viscosity eye drop eye drops 1 (56.4 mPa · s) increased from the bead residual rate (14.7%) of the low-viscosity eye drop eye drops 2 (11.56 mPa · s). It was 39.6%. From the above, it was shown that the cleaning effect of the eye-washing eye drops sharply decreases when the viscosity exceeds about 12 mPa · s.

(Test Example 2)
2.1 Correlation test between the number of eye drops per eye and the cleaning effect The number of eye drops (eye drops) for eye washing once per eye when the following tests are performed and eye drops are performed. And its relationship with the cleaning effect were investigated.

1) Preparation of eye drop for eye wash (test solution) An eye drop for eye wash (viscosity 0.84 mPa · s) having the same composition as the low-viscosity eye drop for eye wash 1 in Test Example 1 was used.

2) Test method The subjects of the experiment were two male Japanese white rabbits with two eyes and four eyes. Except for the fact that eye-washing eye drops were administered by using Pipetman in 2, 4, 6 or 8 drops per eye (46 μL each 2, 4, 6 or 8 times), the same as Test Example 1 The same test was conducted, and the residual rate of beads after eye washing was calculated according to the number of eye drops. In addition, as a reference example, instead of the eye-drop type eye-wash, a cup-type eye-washing solution is used to bring 5 mL of eye-washing eye drops into contact with the animal's eye surface using an eye-washing cup attached to a commercially available cup-type eyewash (manufactured by Rohto Pharmaceutical Co., Ltd.). The test was carried out in the same manner except that the eyes were washed, and the residual rate of beads was calculated.

3) Test results and discussion The test results are shown in Table 5 and FIG. Here, FIG. 2 is a graph showing the relationship between the dose of each eye drop for eye wash (the number of eye drops per eye, cup-type eye drops as a reference example) and the residual rate of beads (%). The residual ratio of beads without washing was 100%.

As shown in Table 5 and FIG. 2, when the eye-washing ophthalmic solution was instilled with 4 drops or more per eye at a time, the residual rate of beads was 2% or less, showing an excellent detergency effect. In addition, the cleaning effect of the eye drop type eye wash with 4 drops or more per eye was superior to the cup type eye wash using the existing eye wash cup. From the above, it was shown that a sufficient effect of removing foreign substances on the surface of the eye can be obtained by instilling eye drops with 4 drops or more once per eye.

(Test Example 3)
3. 3. Pollen rupture suppression effect test 3-1. Pollen rupture inhibitory effect of various components The following tests were conducted to investigate the pollen rupture inhibitory effect of various components.

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 a total volume of 1000 mL, which was 1.25 times solution 1. 1.25 times solution 1 40 mL was taken, dilute hydrochloric acid / sodium hydroxide was added to adjust the pH to 7.0, and water was added to make a total volume of 50 mL, which was used as test solution 1. 0.05 g of potassium chloride was added to 40 mL of a 1.25-fold solution, and the mixture was 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 make a total volume of 50 mL, which was used as test solution 2. 0.2 g of sodium chloride was added to 40 mL of a 1.25-fold solution, and the mixture was 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 make a total volume of 50 mL, which was used as test solution 3. 0.5 g of boric acid was added to 40 mL of a 1.25-fold solution, and the mixture was 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 make a total volume of 50 mL, which was used as test solution 4. 0.05 g of sodium edetate hydrate was added to 140 mL of a 1.25-fold solution, and the mixture was 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 make the total volume 50 mL, which was used as the test solution 5. 0.25 g of polyvinylpyrrolidone K30 was added to 40 mL of a 1.25-fold solution, and the mixture was 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 make a total volume of 50 mL, which was used as test solution 6. The composition of the aqueous solutions of the test solutions 1 to 6 is shown in Table 6. Here, disodium hydrogen phosphate hydrate was contained as a pH buffer. The viscosities of the test solutions 1 to 6 were 12 mPa · s or less.

2) Test method 50 μL of each test solution was added dropwise to about 3 μL of Sugi pollen particles. Vacuoles that ruptured and unruptured after 5 minutes were measured under a light microscope. The pollen rupture rate was calculated according to Equation 2 below.
[Equation 2]
Pollen rupture rate (%) = {number of ruptured vacuoles / (number of ruptured vacuoles + number of unruptured vacuoles)} x 100

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

3-2. Pollen rupture inhibitory effect of various compositions The following tests were conducted to investigate the pollen rupture inhibitory effect of various compositions.

1) Preparation of test solution 160 mL of water was heated to 45 ° C., 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 a total volume of 200 mL, and the liquid was made 1.25 times liquid 2. 40 mL of 1.25 times solution 2 was taken, dilute hydrochloric acid / sodium hydroxide was added to adjust the pH to 7.2, and water was added to make the total volume 50 mL, which was used as test solution 7. 1.25 times solution 2 40 mL was heated to 45 ° C., 0.40 g of boric acid was added, and the mixture was stirred. After cooling the solution to room temperature, dilute hydrochloric acid / sodium hydroxide was added to adjust the pH to 7.2, and water was added to make the total volume 50 mL, which was used as the test solution 8. 1.25 times solution 2 40 mL was heated to 45 ° C., 0.025 g of sodium edetate hydrate was added, and the mixture was stirred. After cooling the solution to room temperature, dilute hydrochloric acid / sodium hydroxide was added to adjust the pH to 7.2, and water was added to make the total volume 50 mL, which was used as the test solution 9. 1.25 times solution 2 40 mL was heated to 45 ° C., 0.05 g of sodium edetate hydrate was added, and the mixture was stirred. After cooling the solution to room temperature, dilute hydrochloric acid / sodium hydroxide was added to adjust the pH to 7.2, and water was added to make the total volume 50 mL, which was used as the test solution 10. To 800 mL of water, 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 and stirred. Water was added to the liquid to make a total volume of 960 mL, and the liquid was 1.25 times liquid 3. 320 mL of 1.25 times solution 3 was taken, dilute 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 1.25 times solution 3 was taken, dilute 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 the test solution 12. The composition of the aqueous solution of the test solutions 7 to 12 is shown in Table 7. The viscosities of the test liquids 7 to 12 were 12 mPa · s or less.

2) Test method The test was carried out by the method described in "3-1. Pollen rupture inhibitory effect of various components 2) Test method".

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

(Test Example 4)
4. Intraocular contamination comparison test between eye drop type eye wash and cup type eye wash The following tests were conducted to compare the intraocular contamination after eye wash between the case of eye drop type eye wash and the case of cup type eye wash.

1) Preparation of eye drop for eye wash (test solution) An eye drop for eye wash (viscosity 0.84 mPa · s) having the same composition as the low-viscosity eye drop for eye wash 1 in Test Example 1 was used.

2) Test method Two eyes of a male Japanese white rabbit were used for the test. The animals were given general anesthesia, the hair around the eyes was shaved, and then the skin around the eyes was thoroughly rinsed with saline. After anesthesia was applied to the surface of the eye and the surface of the eye was washed with eye drops for eye washing, the residual fluid in the conjunctival sac was collected and used as a background sample. After wiping off the water on the skin around the eye, 2 μL of 5% fluorescein solution as a contaminant was applied to 4 places on the skin 5 mm away from the eyelid margin. Then, the eye drops for eye washing were administered by instilling 4 drops (46 μL 4 times) per eye with Pipetman to perform eye drop type eye washing. After performing the eye washing operation, the residual liquid in the conjunctival sac was collected and used as a sample after washing. The fluorescein concentration in the background sample and the washed sample was quantified with a fluorescent plate reader. The concentration of contaminants in the conjunctival sac was calculated according to Equation 3 below. The value below the lower limit of quantification was calculated as 0.
[Equation 3]
Contaminant concentration (mg / mL) = fluorescein concentration of the sample after washing (mg / mL) -fluorescein concentration of the background sample (mg / mL)

In addition, instead of the eye drop type eye wash, a cup of the same commercially available cup type eyewash as in Test Example 2 was used, and 5 mL of eye wash eye drops was brought into contact with the eye surface to perform a cup type eye wash. A test was performed to calculate the concentration of contaminants in the conjunctival sac.

3) Test results and discussion The test results are shown in Fig. 4. Here, FIG. 4 is a graph showing the average value of the concentrations of contaminants in the conjunctival sac after washing in the case of eye drop type eye washing and the case of cup type eye washing.

As shown in FIG. 4, the concentration of contaminants in the conjunctival sac when the eye drops were washed was about 1/40 of that when the cup-type eyes were washed. Therefore, compared to the cup-type eyewash, the eye-drop type eyewash has the effect of preventing and / or avoiding eye troubles caused by the contaminated eyewash that comes into contact with the peripheral part of the eye during the eyewash and enters the eye. It was shown to be high.

Claims (13)

An eye drop type eye drop composition having a viscosity of 12 mPa · s or less, which is used so that 4 drops or more are instilled once per eye. The eye drop-type eye drop medicinal composition according to claim 1, wherein the composition is used so that 6 drops or less are instilled once per eye. An eye drop type eye drop composition having a viscosity of 12 mPa · s or less, which is used so as to be instilled at a total ophthalmic solution volume of 120 μL or more once per eye. The eye drop-type eye drop medicinal composition according to claim 3, wherein the composition is used so that the total amount of eye drops is 300 μL or less once per eye. The invention according to any one of claims 1 to 4, further comprising at least one selected from the group consisting of an anti-inflammatory / convergence component, an antihistamine component, an inorganic salt, an alkylpolyaminoethylglycine and boric acid or a salt thereof. Eye drop type medicated composition for eye wash. The eye drop-type eye-washing medicinal composition according to any one of claims 1 to 4, further comprising boric acid. The eye drop-type eye drop medicinal composition according to any one of claims 1 to 6, further comprising a viscous agent. The eye drop-type eye drop medicinal composition according to any one of claims 1 to 7, further comprising an tonicity agent, a stabilizer, a pH adjuster and a solubilizer. The eye drop-type eye drop medicinal composition according to any one of claims 1 to 8, wherein the pH is 6.5 or more and 7.0 or less. The eye drop-type eye drop medicinal composition according to any one of claims 1 to 9, which is used for washing away stains and foreign substances on the surface of the eye. The eye drop-type eye-washing medicinal composition according to claim 10, wherein the stain or foreign substance is pollen, ocular secretions or PM2.5. Any one of claims 1 to 11 contained 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 instillation type eye wash medicinal composition according to the section. The eye drop-type eye drop medicinal composition according to claim 12, wherein the eye drop container is a liquid-repellable eye drop container.

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