JP6177019B2 - Eye drops - Google Patents

Description

  The present invention relates to eye drops.

  Many types of eye drops are sold as pharmaceuticals for treating eye diseases. One of the components blended in eye drops is a thickener. The thickener is a component blended in the eye drop for the purpose of extending the residence time of the eye drop on the surface of the eyeball and suppressing drying of the eye.

  However, an eye drop containing a thickener has a known problem that causes blurring of vision called fog vision immediately after eye drop. Therefore, there is a demand for a method for suppressing fog vision during instillation while maintaining the function of the thickener.

On the other hand, terpenoid compounds, imidazoline-based vasoconstrictors, neostigmine or salts thereof are each known as a component of eye drops, but their effects on fog vision are not known at all.
In addition, it is known that the amount of eye drops used at one time is usually 29.5 to 53 μL (Non-patent Document 1), and avoids the occurrence of periocular dermatitis and the like due to a chemical overflowing from the eye. For this purpose, there is known a technique for reducing the amount of one drop of eye drops (Patent Document 1), but the relationship between such a technique and fogging with a thickener is completely known. The current situation is not.

Japanese Patent Laying-Open No. 2005-211884

Hiroaki Ikeda and five others, “Information on Medical Eye Drops Necessary for Proper Use”, Hospital Pharmacy, 1998, 24 (6), p. 595-600

  This invention is made | formed in view of the said situation, Comprising: It aims at providing the eye drop with which the fog vision was suppressed, containing a thickener.

As a result of intensive studies in order to solve the above problems, the present inventors have noticed fog vision with an eye drop that contains a predetermined component and is designed to be instilled with a predetermined amount of one drop. It was found that it can be suppressed.
In addition, the present inventors found a new problem that the drop amount per drop varies when the drop amount of the eye drop containing a thickener is designed to be small, Furthermore, the problem is solved by containing at least one selected from the group consisting of a terpenoid compound, an imidazoline vasoconstrictor, neostigmine, and a salt of the neostigmine, and variation in the amount of the eyedrops per drop is suppressed. I found out.
Further, the present inventors have found a new problem that the eye drop effect is low in the eye drop having a small amount per drop, and the problem is that the eye drop has a thickener and a terpenoid compound. The present invention has been found to solve the problem by containing at least one selected from the group consisting of an imidazoline-based vasoconstrictor, neostigmine, and a salt of the neostigmine, and increase the effectiveness of eye drops.
That is, the present invention provides the following (1) to (9).
(1) The eye drop of the present invention contains (A) a thickener and (B) at least one selected from the group consisting of a terpenoid compound, an imidazoline vasoconstrictor, neostigmine, and a salt of the neostigmine. The ophthalmic solution is characterized in that the amount per drop is 5 to 25 μL.
(2) It is preferable that the eye drop of the present invention is further filled in a container having an internal volume of 4 to 30 mL.
(3) It is preferable that the eye drop of the present invention is further filled in a container having a nozzle having an inner diameter of less than 1.5 mm at the dropping port.
(4) In the eye drop of the present invention, the thickener is at least one selected from the group consisting of carboxyvinyl polymer, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, alginic acid, and sodium hyaluronate. Preferably there is.
(5) In the eye drop of the present invention, the terpenoid compound is at least one selected from the group consisting of dl-menthol, l-menthol, dl-camphor, d-camphor, d-borneol, and geraniol. Is preferred.

(6) The method for suppressing fog vision according to the present invention is selected from the group consisting of (A) a thickener and (B) a terpenoid compound, an imidazoline vasoconstrictor, neostigmine, and a salt of the neostigmine. And at least one kind of ophthalmic solution is designed to be 5 to 25 μL.
(7) The method for suppressing the variation in the amount of one drop of the eye drop of the present invention includes (A) a thickener, (B) a terpenoid compound, an imidazoline vasoconstrictor, neostigmine, and the neostigmine. It is characterized by containing at least one selected from the group consisting of salts, and designed so that the amount of the eye drop per drop is 5 to 25 μL.
(8) The method for improving the eye drop effectiveness of the present invention is selected from the group consisting of (A) a thickener and (B) a terpenoid compound, an imidazoline vasoconstrictor, neostigmine, and a salt of the neostigmine. And at least one kind of ophthalmic solution is designed to be 5 to 25 μL.
(9) The method for producing an eye drop in a container of the present invention is selected from the group consisting of (A) a thickener and (B) a terpenoid compound, an imidazoline vasoconstrictor, neostigmine, and a salt of the neostigmine. The ophthalmic solution containing at least one kind is filled in a container designed so that a drop amount per drop is 5 to 25 μL.

According to the present invention, the eye drop contains (A) a thickener, and (B) a terpenoid compound, an imidazoline vasoconstrictor, neostigmine, and at least one selected from the group consisting of the neostigmine salts. By designing the eye drop so that the drop amount per drop is 5 to 25 μL, it is possible to provide an eye drop that contains a thickener and whose fog is significantly suppressed. The eye drop of the present invention makes it difficult for the field of vision to blur even immediately after the eye drop, leading to improved patient compliance.
In addition, as another effect of the present invention, it is possible to provide an eye drop in which variation in the amount of drops per drop is suppressed. That is, the present inventors have found a new problem that the drop amount is likely to vary in the eye drop which is designed to contain a thickener and the drop amount per drop is small. However, by containing at least one selected from the group consisting of a terpenoid compound, an imidazoline vasoconstrictor, neostigmine, and a salt of the neostigmine, variation in the amount of the ophthalmic solution dropped per drop is suppressed. I found out. With the eye drops of the present invention, an accurate amount of eye drops can be obtained even in small amounts, and a more reliable therapeutic effect can be obtained.
As another effect of the present invention, an eye drop having a high eye drop effect can be provided. That is, in the case of eye drops in which the amount per drop is small, the present inventors have difficulty in perceiving that one drop has entered the eye when actually instilling into the human eye. A new problem of low feeling was found, but the eye drop was selected from the group consisting of (A) a thickener and (B) a terpenoid compound, an imidazoline vasoconstrictor, neostigmine, and a salt of the neostigmine. It has been found that the effectiveness of eye drops is enhanced by containing at least one of the above. With the eye drop of the present invention, it can be surely felt whether one drop has entered the eye, compliance with medication can be improved, and a more reliable therapeutic effect can be obtained.

It is an example of the dripping nozzle with which the container filled with the eye drop of the present invention is attached. It is an example of the dripping nozzle with which the container filled with the eye drop of the present invention is attached.

1. The present invention is selected from the group consisting of a thickener as component (A) and a terpenoid compound, an imidazoline vasoconstrictor, neostigmine, and a salt of the neostigmine as component (B) It is an ophthalmic solution containing at least one kind and designed to have a drop amount of 5 to 25 μL per drop.

In the present specification, the unit of content “%” means “w / v%” and “g / 100 mL”.
It is synonymous with.

In this specification, unless otherwise specified, the abbreviation “POE” represents polyoxyethylene, and the abbreviation “P
“OP” means polyoxypropylene, respectively.

(1) Thickener [(A) component]
The eye drop of the present invention contains (A) a thickener (hereinafter sometimes simply referred to as “component (A)”).
The thickener used as the component (A) is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such thickeners include vinyl-based thickeners [eg, polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone (K25, K30, K90, etc.), carboxyvinyl polymer, etc.], cellulose-based Thickeners [for example, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose (2208, 2906, 2910, etc.), carboxymethylcellulose, carboxyethylcellulose, nitrocellulose or salts thereof], polyethylene glycol (Macrogol 300 , Macrogol 400, Macrogol 1500, Macrogol 4000, etc.) or mucopolysaccharide [eg chondroitin sulfate, alginic acid, hyaluronic acid or salts thereof Etc.] and the like. These thickeners may be used alone or in any combination of two or more. The salt of the thickener includes, for example, a salt with an inorganic base, preferably an alkali metal salt or an alkaline earth metal salt, more preferably a sodium salt, potassium salt, calcium salt or magnesium salt. In particular, a sodium salt is preferable.

Among these, from the viewpoint of further enhancing the effect of suppressing fog vision, the effect of suppressing variation in dripping amount, and the effect of improving the effectiveness of eye drops, the component (A) is preferably a vinyl thickener, a cellulose thickener, polyethylene glycol or It is a mucopolysaccharide. More preferably, the vinyl thickener is polyvinyl alcohol, polyvinylpyrrolidone or carboxyvinyl polymer, and the cellulose thickener is methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose or a salt thereof. The polyethylene glycol is Macrogol 300 and Macrogol 400, and the mucopolysaccharide is chondroitin sulfate or a salt thereof, alginic acid or a salt thereof, hyaluronic acid or a salt thereof. More preferred are carboxyvinyl polymer, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, alginic acid, sodium hyaluronate, and particularly preferred are polyvinylpyrrolidone (K25, K90), carboxyvinyl polymer, hydroxyethylcellulose, hydroxypropylmethylcellulose. (2208, 2906, 2910), and most preferred are polyvinylpyrrolidone K25, carboxyvinyl polymer, hydroxyethylcellulose, and hydroxypropylmethylcellulose 2906.
Further, among these thickeners, those having a viscosity at 25 ° C. of the following values when dissolved in purified water so as to be 1.0 w / v% are preferable. In addition, the measurement of a viscosity follows the method as described in an Example.
Polyvinylpyrrolidone: preferably 0.1 to 5.0 mPa · s, more preferably 0.3 to 3.5 mPa · s, particularly preferably 0.5 to 2.0 mPa · s.
Carboxyvinyl polymer: preferably 1 to 30000 mPa · s, more preferably 200 to 5000 mPa · s, particularly preferably 400 to 3000 mPa · s.
Hydroxyethyl cellulose: preferably 1 to 5000 mPa · s, more preferably 5 to 1000 mPa · s, and particularly preferably 15 to 600 mPa · s.
Hydroxypropyl methylcellulose: preferably 1 to 3000 mPa · s, more preferably 50 to 800 mPa · s, particularly preferably 100 to 400 mPa · s.

In the eye drop of the present invention, the content of the component (A) is not particularly limited, and is appropriately set according to the type of the component (A), the use of the eye drop, and the like. As the content of the component (A), for example, the content of the component (A) is preferably 0.01 to 10 w / v% based on the total amount of the eye drop of the present invention. More preferably, it is 01-5 w / v%, It is especially preferable that it is 0.05-3 w / v%, It is most preferable that it is 0.1-1 w / v%.
When the content of the component (A) is within the above range, an eye drop excellent in the effect of improving the retention on the surface of the eyeball and suppressing the drying of the eye can be obtained.
Moreover, when content of (A) component exists in the said range, the fog reduction inhibitory effect of this invention, the dispersion | variation suppression effect of dripping amount, and the favorable eyedrop effective feeling improvement effect are acquired.

(2) Terpenoid compound, imidazoline vasoconstrictor, neostigmine or a salt thereof [(B) component]
The eye drop of the present invention is at least one selected from the group consisting of (B) a terpenoid compound, an imidazoline vasoconstrictor, neostigmine, and a salt of the neostigmine (hereinafter simply referred to as “component (B)”) There is also.).

The terpenoid compound used as the component (B) is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such terpenoid compounds include menthol, camphor, borneol, geraniol, cineole, citronellol, menthone, carvone, anethole, eugenol, limonene, linalool, linalyl acetate, and derivatives thereof. These compounds may be d-form, l-form or dl-form. In the present invention, an essential oil containing the above compound may be used as the terpenoid compound. Examples of such essential oils include eucalyptus oil, bergamot oil, peppermint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, and rose oil. These terpenoid compounds may be used alone or in any combination of two or more.
Among these, from the viewpoint of further enhancing the fog vision suppressing action, the drop amount variation suppressing action, and the ophthalmic efficacy improving action of the present invention, dl-menthol, l-menthol, dl-camphor, d-camphor, There may be mentioned at least one selected from the group consisting of d-borneol and geraniol, and preferable essential oils containing these include cool mint oil, peppermint oil, mint oil, camphor oil and the like. More preferably, dl-menthol, l-menthol, dl-camphor, d-camphor, d-borneol and geraniol are mentioned, more preferably l-menthol, d-camphor and dl-camphor, particularly preferably l- Mentor is mentioned.

The imidazoline-based vasoconstrictor used as the component (B) is a known compound, and may be synthesized by a known method or obtained as a commercial product.
The imidazoline vasoconstrictor is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of the imidazoline-based vasoconstrictor include tetrahydrozoline, naphazoline, oxymetazoline, xylometazoline, tramazoline, thimazoline, methizolin, and salts thereof. Examples of the salt form of the compound include inorganic acid salts such as hydrochloride and nitrate. Further, the above compound and its salt may be in the form of a hydrate.
Among these, from the viewpoint of further enhancing the effect of suppressing the variation in dripping amount, preferably tetrahydrozoline, naphazoline, oxymetazoline, or a salt thereof, more preferably tetrahydrozoline hydrochloride, naphazoline hydrochloride, or naphazoline nitrate. .

Neostigmine used as the component (B) is a compound also referred to as N-(-3-dimethylcarbamoyloxyphenyl) -N, N, N-trimethylammonium. Neostigmine and a salt thereof are known compounds, and may be synthesized by a known method or obtained as a commercial product.
The salt of neostigmine is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. Specifically, methylsulfate (methylsulphate neostigmine), bromide salt (Neostigmine bromide) and the like are exemplified. Among these salts, methyl sulfate is preferable. The compound and the salt thereof may be in the form of a hydrate.
Among these, from the viewpoint of further enhancing the effect of suppressing the variation in the amount of dripping, neostigmine salt is preferable, and neostigmine methyl sulfate is more preferable.

In the eye drop of the present invention, the content of the component (B) is not particularly limited, and the type of the component (B), the type and content of the component (A) to be used together, the use of the eye drop, the preparation form, and the method of use It sets suitably according to etc. As content of (B) component, it is preferable that content of (B) component is 0.0001-0.5 w / v% in total amount on the basis of the total amount of eyedrops of this invention, for example. 0.0005 to 0.1 w / v% is more preferable, and 0.001 to 0.08 w / v% is particularly preferable. When the component (A) is contained in the eye drop, there is a problem that fogging occurs immediately after the eye drop, but when the content of the component (B) is within the above range, the above component (A) has The fog can be effectively suppressed without impairing the effect. In addition, in the eye drop containing a small amount per drop while containing the component (A), the content of the component (B) When it exists in the range, the dispersion | variation in dripping amount can be suppressed effectively, without impairing the effect which the said (A) component has. Furthermore, in the case of an eye drop with a small amount of dripping, the eye drop effect is remarkably improved when the content of the component (B) is within the above range, in contrast to the new problem that the eye drop effect is low.
In the eye drop of the present invention, the content ratio of the component (B) is not particularly limited, and the type of the component (B), the type and content of the component (A) to be used together, the use of the eye drop, the formulation form, It is set as appropriate according to the method of use. As the content ratio of the component (B) to the component (A), for example, the total content of the component (B) is 1 part by mass of the total content of the component (A) contained in the eye drop of the present invention. It is preferably 0.00003 to 10 parts by mass, more preferably 0.0001 to 2 parts by mass, still more preferably 0.0005 to 1 part by mass, and 0.001 to 0.8 parts by mass. It is particularly preferred that The ophthalmic solution contains the component (A), which causes a problem that fogging occurs immediately after the instillation. However, the content ratio of the component (B) is within the above range, and the amount per droplet is small. When used in such a manner, it is possible to effectively suppress fog vision without impairing the above-described effects of the component (A). In addition, in the ophthalmic solution that contains the component (A) and is used so that the drop amount per drop is small, the problem of the component (B) When the content ratio is within the above range, variation in the amount of dripping can be effectively suppressed without impairing the above-described effect of the component (A). Furthermore, in the ophthalmic solution used so that the amount of dripping is small, when the content ratio of the component (B) is within the above range, the eye drop effective feeling is remarkable for the new problem that the eye drop effective feeling is low. To improve.

As the content of the terpenoid compound, for example, based on the total amount of the eye drop of the present invention, the content of the terpenoid compound is preferably 0.0001 to 0.2 w / v% in total, 0.0005 to More preferably, it is 0.1 w / v%, and it is further more preferable that it is 0.001-0.08 w / v%. In addition, when using the essential oil containing a terpenoid compound, it can set so that the terpenoid compound in the essential oil contained in an eye drop may satisfy | fill the said content. The content of the terpenoid compound is suitable from the viewpoint of improving the fog vision suppressing effect, the dripping amount variation suppressing effect, and the eye drop effective feeling.
Moreover, as a content ratio of the terpenoid compound with respect to (A) component, for example, the total content of the terpenoid compound is 0.1 parts per 1 part by mass of the total content of the (A) component contained in the eye drop of the present invention. It is preferably 0.0003 to 4 parts by mass, more preferably 0.0001 to 2 parts by mass, still more preferably 0.0005 to 1 part by mass, and 0.001 to 0.8 parts by mass. It is particularly preferred. The content ratio of the terpenoid compound is suitable from the viewpoint of improving the fog vision suppressing effect, the dripping amount variation suppressing effect, and the eye drop effective feeling.

The content of the imidazoline-based vasoconstrictor is, for example, based on the total amount of the eye drop of the present invention, and the total content of the imidazoline-based vasoconstrictor is 0.0001 to 0.5 w / v%. Preferably, it is 0.0005 to 0.1 w / v%, more preferably 0.001 to 0.05 w / v%. The content of the imidazoline-based vasoconstrictor is suitable from the viewpoint of improving the dripping amount variation suppressing action.
The content ratio of the imidazoline vasoconstrictor to the component (A) is, for example, the total amount of imidazoline vasoconstrictor with respect to 1 part by mass of the total content of the component (A) contained in the eye drop of the present invention. The content is preferably 0.00003 to 10 parts by mass, more preferably 0.0001 to 2 parts by mass, further preferably 0.0005 to 1 part by mass, and 0.001 to 0 Particularly preferred is 5 parts by mass. The content ratio of the imidazoline-based vasoconstrictor is suitable from the viewpoint of improving the dripping amount variation suppressing effect.

The content of neostigmine and / or a salt thereof is, for example, 0.0001 to 0.05 w / v% in terms of the total content of neostigmine and / or a salt thereof based on the total amount of the eye drops of the present invention. It is preferably 0.0005 to 0.01 w / v%, and more preferably 0.001 to 0.005 w / v%. The content of the neostigmine and / or salt thereof is suitable from the viewpoint of improving the dripping amount variation suppressing effect.
Moreover, as a content ratio of neostigmine and / or its salt with respect to (A) component, for example, with respect to 1 mass part of total content of (A) component contained in the eye drop of this invention, neostigmine and / or its salt The total content is preferably 0.00003 to 1 part by mass, more preferably 0.0001 to 0.2 part by mass, and still more preferably 0.0005 to 0.1 part by mass. 0.001-0.05 parts by mass is particularly preferable. The content ratio of the neostigmine and / or salt thereof is suitable from the viewpoint of improving the dripping amount variation suppressing effect.

The eye drop of the present invention can further contain epsilon-aminocaproic acid or a salt thereof.
The epsilon-aminocaproic acid or a salt thereof used in the eye drop according to the present invention is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of epsilon-aminocaproic acid or a salt thereof used in the eye drop of the present invention include sodium salt and potassium salt. Epsilon-aminocaproic acid or a salt thereof can be used alone or in combination of two or more. Epsilon-aminocaproic acid is preferred.
The content of epsilon-aminocaproic acid or a salt thereof is preferably 0.1 to 10 w / v%, more preferably 0.25 to 7.5 w / v%, and more preferably 0.5 to 7.5% with respect to the whole ophthalmic composition. 5.0 w / v% is particularly preferable.

(3) Other ingredients [arbitrary ingredients]
In addition to the component (A) and the component (B), the eye drop of the present invention can further contain an active ingredient (pharmacologically active ingredient, physiologically active ingredient, etc.) widely used in eye drops. The kind of such component is not particularly limited, and examples thereof include an anti-inflammatory component or an astringent component, an antiallergic component, a vitamin, an amino acid, an antibacterial component or a bactericidal component. Examples of the pharmacologically active component and physiologically active component suitable in the present invention include the following components.

  Anti-inflammatory component or astringent component: zinc sulfate, zinc lactate, allantoin, lysozyme chloride, pranoprofen, sodium azulenesulfonate, dipotassium glycyrrhizinate, sodium bromfenac, berberine chloride, berberine sulfate and the like.

  Antihistamine component or antiallergic agent component: acitazanolast, diphenhydramine hydrochloride, chlorpheniramine maleate, tranilast, sodium cromoglycate, pemirolast potassium and the like.

  Vitamins: retinol acetate, retinol palmitate, pyridoxine hydrochloride, flavin adenine dinucleotide sodium, pyridoxine hydrochloride, cyanocobalamin, panthenol, calcium pantothenate, sodium pantothenate, tocopherol acetate, etc.

  Amino acids: aminoethylsulfonic acid (taurine), potassium aspartate, magnesium aspartate, magnesium aspartate / potassium mixture, and the like. These may be d-form, l-form or dl-form.

  Antibacterial component or bactericidal component: alkylpolyaminoethylglycine, sulfamethoxazole, sulfisoxazole, sulfamethoxazole sodium, sulfisomidine sodium and the like.

  In addition, the eye drop of the present invention is appropriately selected from various components and additives according to a conventional method according to its use and form as long as the effects of the invention are not impaired, and one or more of them are used in combination. Can be contained. As those components or additives, for example, carriers (aqueous solvent, aqueous or oily base, etc.) commonly used in the preparation of solutions, surfactants, preservatives, bactericides or antibacterial agents, pH adjusters, Various additives such as an isotonizing agent, a chelating agent, a buffering agent, and a stabilizing agent are included.

  Carrier: water, aqueous solvent such as water-containing ethanol.

  Surfactant: POE-POP block copolymer (specifically, poloxamer 407, etc.), POE-POP block copolymer adduct of ethylenediamine (specifically, poloxamine, etc.), POE sorbitan (specifically, polysorbate 80, etc.) ), POE hydrogenated castor oil (specifically, POE (60) hydrogenated castor oil, POE (40) hydrogenated castor oil, etc.), POE castor oil (specifically, POE (10) castor oil, POE (35)) Nonionic surfactants such as castor oil, polyethylene glycol monostearate (specifically polyoxyl 40 stearate); glycine-type amphoteric surfactants such as alkyldiaminoethylglycine; alkyl quaternary ammonium salts (specific Cation fields such as benzalkonium chloride and benzethonium chloride) Surfactant etc. The numbers in parentheses indicate the number of added moles.

  Preservatives, bactericides or antibacterial agents: polydronium 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, biguanide compounds (specifically, polyhexamethylene biguanide or its hydrochloride, etc.).

  pH adjusting agent: hydrochloric acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, diisopropanolamine, sulfuric acid, phosphoric acid, diethanolamine and the like.

  Isotonizing agents: potassium chloride, sodium chloride, glycerin, propylene glycol and the like.

  Chelating agent: sodium edetate, citric acid, or hydrates thereof.

  Buffer: citrate buffer, acetate buffer, carbonate buffer, borate buffer, phosphate buffer, Tris-HCl buffer, etc. Specifically, citric acid, sodium citrate, acetic acid, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, boric acid, borax, phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, phosphoric acid Such as potassium dihydrogen.

Stabilizer: Dibutylhydroxytoluene, trometamol, sodium bisulfite, sodium sulfite and the like.
Vegetable oil: Sesame oil, castor oil, etc.

(4) Physical properties of eye drops
The pH of the eye drop according to the present invention is not particularly limited as long as it is within a range that is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. As pH of eyedrops, it is preferable that it is 4.0-9.5, for example, it is more preferable that it is 5.0-9.0, and it is still more preferable that it is 5.5-8.5.
Further, the osmotic pressure of the eye drop according to the present invention is not particularly limited as long as it is within the range allowed by the living body. The osmotic pressure ratio of the eye drop is, for example, preferably 0.5 to 5.0, more preferably 0.6 to 3.0, and still more preferably 0.7 to 2.0. 0.9 to 1.55 is particularly preferable. The osmotic pressure can be adjusted by a method known in the art using an inorganic salt, a polyhydric alcohol, a sugar alcohol, a sugar, or the like. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to 286 mOsm (0.9 w / v% sodium chloride aqueous solution) based on the 16th revised Japanese Pharmacopoeia. Measure with reference to (freezing point depression method). In addition, about the standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution), after drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500-650 degreeC for 40-50 minutes, it is in a desiccator (silica gel). It is allowed to cool, and 0.900 g is accurately weighed and dissolved in purified water to prepare exactly 100 mL, or a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution) can be used. .
The viscosity of the eye drop of the present invention containing the components described above is preferably 1.1 to 9000 mPa · s.
In the present invention, the viscosity is measured in accordance with the viscosity measuring method described in the 16th revised Japanese Pharmacopoeia general test method. When the viscosity at 25 ° C. is 100 mPa · s or more, (2) single cylindrical rotation When the viscosity at 25 ° C. is less than 100 mPa · s, (3) a cone-plate rotational viscometer (cone plate viscometer) is used. In the present invention, selection of conditions such as the rotor and rotation speed is based on the instruction manual of the apparatus, and the viscosity at 25 ° C. is measured.

(5) One drop volume of eye drops The eye drop of the present invention is designed so that the drop volume per drop is 5 to 25 μL. By designing the drop amount per drop of the eye drop containing the component (A) and the component (B) to be 5 to 25 μL, the fog vision suppressing action, the drop amount variation suppressing action of the present invention, An even more remarkable effect of improving the effectiveness of eye drops is obtained.
In addition, the eye drop of the present invention is preferably designed so that the drop amount per drop is 7 to 20 μL, and more preferably 9 to 16 μL.

(6) Eye Drop Container, etc. The eye drop of the present invention is preferably filled in a container having an internal volume of 4 to 30 mL, more preferably 5 to 20 mL. It is particularly preferable that the container is filled with 10 mL.
When the internal volume of the container filled with the eye drop of the present invention is within the above range, even if the amount of one drop is small, it is easy to instill and the effect of the present invention can be exhibited more remarkably. Further, as will be described later, even when instillation is performed using a small-diameter eye drop nozzle, it is particularly preferable from the viewpoint of suppressing variation in the amount of dripping and making the user feel the eye drop effective. As such an eye drop, a multi-dose type eye drop, that is, an eye drop that is used several times or more after the product is once opened is preferable.

As an example of the dropping nozzle attached to the container filled with the eye drop of the present invention, those having the shape shown in FIGS. As a dropping nozzle attached to a container filled with the eye drop of the present invention, the inner diameter D1 at the dropping port is preferably less than 1.5 mm, more preferably 0.01 to 1.0 mm, It is particularly preferably 0.05 to 0.8 mm, further particularly preferably 0.1 to 0.5 mm, and most preferably 0.1 to 0.4 mm. The dropping port refers to an outlet portion where droplets are formed when the eye drop is filled in the container and the nozzle is attached and then in an open state.
Further, the outer diameter of the dropping nozzle attached to the container filled with the eye drop of the present invention is appropriately set according to the shape, material, purpose, etc. of the nozzle, and cannot be generally defined, for example, 8 mm The following is preferable, more preferably 0.1 to 5 mm, particularly preferably 0.3 to 3 mm, still more preferably 0.5 to 2 mm, and more preferably 0.5 to 1.5 mm. Most preferred. The outer diameter of the dropping nozzle in the present invention indicates the outer diameter of the pouring tube body near the dropping port, and the tip (dropping port) of the nozzle may be rounded.

The said range in the nozzle aperture of the container filled with the eyedrops of this invention is suitable in order to make the dripping amount per drop into 5-25 microliters.
By adopting such a nozzle shape, it becomes easy to set the drop amount per one drop of the eye drop to 5 to 25 μL. For example, the eye drop is efficiently used so that the drop amount per drop is 15 μL. Therefore, the effect of the present invention including the above-described effect of suppressing fog can be remarkably exhibited.
The nozzle may have either a structure formed separately from the container body or a structure in which the nozzle and the container body are integrally formed (for example, a one-time-use type eye drop).

The container filled with the eye drop of the present invention is preferably made of plastic. The constituent material of the plastic container is not particularly limited. For example, any one of polyesters such as polyethylene terephthalate, polybutylene terephthalate, and polyethylene naphthalate, polyarylate, polycarbonate, polyethylene, polypropylene, polyimide, and elastomer, A copolymer or a mixture of two or more of these may be mentioned. In particular, polyethylene terephthalate, polyarylate, polyethylene naphthalate, a copolymer thereof, or a mixture of two or more of these is preferable from the viewpoint of easily exerting the effect of the present invention by adjusting the extrusion and the like. Particularly, a container made of polyethylene terephthalate. Is preferred.
In the present invention, for example, a container made of polyethylene terephthalate is not particularly limited as long as polyethylene terephthalate is contained in the constituent material of the container, but the polyethylene terephthalate is based on the total weight of the constituent material of the container. Is preferably 50 w / w% or more.
The eye drop of the present invention may be filled in a transparent container (a container having transparency that does not interfere with the observation of foreign matter) containing such a material as a main material, or in a light-shielded container. May be. The light shielding may be performed, for example, by adding a colorant to the transparent container material described above, or may be shielded by covering the container with a shrink film or an outer box.
Moreover, about the constituent material of a nozzle, the thing similar to the constituent material of the said plastic container is illustrated, for example. From the viewpoint of further improving the liquid drop of the eye drop of the present invention and suppressing variation in the dripping amount, a nozzle including polyethylene, polypropylene, or elastomer as a constituent material is preferable. Examples of the type of polyethylene include high-density polyethylene and low-density polyethylene, and among them, a nozzle including low-density polyethylene as a constituent material is preferable.

(7) Physical properties of eye drops contained in a container The eye drops of the present invention are preferably contained in a container suitable for dropping a predetermined amount of one drop. The squeeze force of the ophthalmic solution in a container is preferably 0.5 to 12N, more preferably 1 to 10N, and particularly preferably 1.5 to 8N. The squeeze force indicates a force that pushes a container necessary for dropping one drop of eye drops. When the squeeze force of the eye drop in a container of the present invention is within the above range, the effect of suppressing variation in the amount of dripping and the effect of improving the eye drop effectiveness can be more remarkably exhibited.
The squeeze force is measured according to the method described in the examples.
Further, the displacement of the container when the eye drop in the container of the present invention is dropped is preferably 0.01 to 2.0 mm, more preferably 0.05 to 1.0 mm, and 0.05 to 0. 0.5 mm is particularly preferable, and 0.07 to 0.3 mm is most preferable.
The displacement of the container when the eye drop in the container is dropped is the displacement of the container necessary for dropping one drop of the eye drop. When the displacement of the container at the time of dropping of the eye drop in the container of the present invention is within the above range, the effect of suppressing variation in the amount of dripping and the effect of improving the eye drop effectiveness can be more remarkably exhibited.
The measurement of the displacement of the container at the time of dripping is performed according to the method described in the Examples.

(8) Use of eye drops In addition to general eye drops, the eye drops according to the present invention include antibacterial eye drops, artificial tears, and eye drops that can be applied while wearing contact lenses.
The eye drops that can be instilled while wearing the contact lens can be applied to all contact lenses including hard contact lenses and soft contact lenses. Soft contact lenses include both ionic and non-ionic, and include silicone hydrogel contact lenses (hereinafter abbreviated as SHCL) and non-silicone hydrogel contact lenses (silicone hydrogel lenses). Including both soft contact lenses).

(9) Eye drop method The drop method of the eye drop of the present invention is not particularly limited, and it can be instilled from any angle depending on the eye drop container, the shape of the nozzle, the purpose of use, and the like. It is preferable that the dropping port is dropped directly below from the viewpoint of achieving the effect of suppressing variation in the dropping amount of the present invention more remarkably.

2. As described above, the eye drop of the present invention comprises (A) a thickener, and (B) a terpenoid compound, an imidazoline vasoconstrictor, neostigmine, and a salt of the neostigmine. As a result of containing at least one selected from the above and being designed so that the drop amount per drop is 5 to 25 μL, fogging can be suppressed.
Accordingly, the present invention, from yet another point of view, comprises a group comprising an eye drop as a thickener as component (A), a terpenoid compound, an imidazoline vasoconstrictor, neostigmine, and a salt of the neostigmine as component (B). A method for imparting an antifogging action to the eye drop, wherein the eye drop is designed so as to contain at least one selected from the above, and the drop amount per drop of the eye drop is 5 to 25 μL Also provide.
In the above method, as long as the component (A) and the component (B) coexist, they may be added simultaneously or separately, and the order thereof is not particularly limited. Component (A) to be used, type of component (B), their content (or blending amount), their content ratio, drop amount per drop, other types of component to be blended, content (or blending amount) ), The preparation form of the eye drop, the type of container, the type of nozzle, the combination thereof, the method of implementation, and the like are the same as those in “1.
In addition, in this specification, it can be determined by the method as described in the below-mentioned Example whether the inhibitory effect of the fog vision is provided to the eye drop.

3.1 Droplet Variation Control Method As described above, the eye drop of the present invention comprises (A) a thickener, (B) a terpenoid compound, an imidazoline vasoconstrictor, neostigmine, and the neostigmine. By containing at least one selected from the group consisting of salts and designed to have a drop volume of 5 to 25 μL per drop, variations in the drop volume can be suppressed.
Accordingly, the present invention, from yet another point of view, comprises a group comprising an eye drop as a thickener as component (A), a terpenoid compound, an imidazoline vasoconstrictor, neostigmine, and a salt of the neostigmine as component (B). There is also provided a method for suppressing variation in the amount of one drop, which contains at least one selected from the above, and designs the eye drop so that the amount of the eye drop per drop is 5 to 25 μL. .
In the above method, as long as the component (A) and the component (B) coexist, they may be added simultaneously or separately, and the order thereof is not particularly limited. Component (A) to be used, type of component (B), their content (or blending amount), their content ratio, drop amount per drop, other types of component to be blended, content (or blending amount) ), The preparation form of the eye drop, the type of container, the type of nozzle, the combination thereof, the method of implementation, and the like are the same as those in “1.
In addition, in this specification, it can be determined by the method as described in the below-mentioned Example whether the dispersion | variation in the amount of 1 drop of eyedrops is suppressed.

4). Method for Improving Eye Drop Effectiveness As described above, the eye drop of the present invention comprises (A) a thickener, and (B) a terpenoid compound, an imidazoline vasoconstrictor, neostigmine, and a salt of the neostigmine. The eye drop effectiveness can be improved by designing the eye drop so that it contains at least one selected from the group and the drop amount per drop is 5 to 25 μL.
Accordingly, the present invention, from yet another point of view, comprises a group comprising an eye drop as a thickener as component (A), a terpenoid compound, an imidazoline vasoconstrictor, neostigmine, and a salt of the neostigmine as component (B). There is also provided a method for improving the effectiveness of eye drops, wherein the eye drops are designed so as to contain at least one selected from the above, and the amount of the eye drops per drop is 5 to 25 μL.
In the above method, as long as the component (A) and the component (B) coexist, they may be added simultaneously or separately, and the order thereof is not particularly limited. Component (A) to be used, type of component (B), their content (or blending amount), their content ratio, drop amount per drop, other types of component to be blended, content (or blending amount) ), The preparation form of the eye drop, the type of container, the type of nozzle, the combination thereof, the method of implementation, and the like are the same as those in “1. Eye drop”.
In the present specification, whether or not the eye drop effectiveness is improved can be determined by a method described in Examples described later.

Hereinafter, the present invention will be described in detail with reference to Examples and Test Examples, but the present invention is not limited to these Examples and the like.
Moreover, the average dripping amount (μL) was calculated by calculating the average dripping amount (mg) in each eye drop in each container and setting the specific gravity as 1. As a method for measuring the average drop amount (mg), the drop port of the ophthalmic nozzle in the container was dropped almost vertically downward, the drop weight was measured for each drop, and this operation was repeated 20 times. Calculated from the values.
The unit of composition in each table is w / v%.

(1) Preparation of sample Each eye drop having the composition shown in Tables 1 to 6 below was prepared by the following method. That is, under stirring, a thickener such as carboxyvinyl polymer was added and dispersed in purified water, and then components other than the pH adjuster (sodium hydroxide or hydrochloric acid) were added and dissolved by stirring. Furthermore, after adjusting pH using sodium hydroxide or hydrochloric acid, an appropriate amount of purified water was added to prepare a predetermined concentration.
Viscosity is measured for each of the prepared eye drops, and squeeze force measurement, container displacement measurement at the time of dripping, and suppression of fog vision during eye drops are performed for eye drops in containers filled with eye drops in a predetermined container. Tests, drop amount variation tests, and eye drop effect tests were performed.

(2) Physical property measurement method (2-1) Viscosity measurement The viscosity of each eye drop was measured by the following method.
Those having a viscosity at 25 ° C. of 100 mPa · s or more are described in “16th revised Japanese Pharmacopoeia General Test Method Viscosity Measurement Method 2 Method Rotary Viscometer Method (2) Single Cylindrical Rotational Viscometer (Brook Based on the test method of “field type viscometer”, the viscosity at 25 ° C. was measured under the following conditions.

Measuring device, rotation speed, rotor No. Setting time / formulation examples 2-A, 2-B, 2-C, 4-A, 4-B, 4-C, 4-D, 1 w / v aqueous solution of the following thickeners-carboxyvinyl polymer, hydroxy Ethylcellulose (Test 1, Test 5), hydroxypropyl methylcellulose 2906:
Measuring device_TV-10M, rotation speed_12 rpm, rotor No. _M2, viscosity after 1 minute of measurement and formulation examples 2-D, 2-E, 2-F:
Measuring device_TV-10M, rotation speed_3 rpm, rotor No. _M2, viscosity after 1 minute of measurement time

Those with a viscosity at 25 ° C. of less than 100 mPa · s are described in the 16th revised Japanese Pharmacopoeia General Test Method Viscosity Measurement Method Second Method Rotary Viscometer Method “(3) Cone-Plate Rotational Viscometer (Cone Plate The viscosity at 25 ° C. was measured under the following conditions in accordance with the test method “type viscometer”.

Measuring device, rotation speed, rotor No. And set time / prescription examples 3-D, 3-E, 3-F:
Measuring apparatus_RC-550, rotation speed_50 rpm, rotor_standard cone rotor (1 ° 34 ′ × R24), set time_viscosity after 1 minute. 1 w / v% aqueous solution of hydroxyethyl cellulose (test 3):
Measuring device_RC-550, rotation speed_20 rpm, rotor_standard cone rotor (1 ° 34 ′ × R24), set time_viscosity after 3 minutes, 1 w / v% aqueous solution of polyvinylpyrrolidone K25:
Measuring apparatus_RC-550, rotation speed_100 rpm, rotor_standard cone rotor (1 ° 34 ′ × R24), set time_viscosity after 3 minutes / prescription examples 5-A, 5-B:
Measuring apparatus_TV-20, rotation speed_100 rpm, rotor_standard cone rotor (1 ° 34 ′ × R24), set time_viscosity after 3 minutes / prescription examples 1, 5-C, 5-D:
Measuring device_TV-20, rotation speed_10rpm, rotor_standard cone rotor (1 ° 34 '× R24), set time_viscosity after 3 minutes

(2-2) Squeeze force measurement The squeeze force of each eye drop in each container was measured by the following method.
Two drops of the eye drop in a container to be tested were dropped with the dropping port directed directly below in an unused state after filling. Next, the ophthalmic solution in a container was fixed by pressing with a finger on a vertical wall surface with the dripping port directed directly below. Next, squeeze when one drop is dropped by applying pressure to the side of the container with a 5 mm diameter flat jig attached to the tip of a digital push-pull gauge (CPU GAUGE 9520A, manufactured by Aiko Engineering Co., Ltd.) The force (N) was measured. The measurement was carried out 10 times (for 10 drops), and the average was obtained.

(2-3) Measurement of container displacement at the time of dropping The container displacement at the time of dropping each container-containing eye drop was measured by the following method.
The relationship between displacement and squeeze force of the eye drop in a container to be tested was determined using an autograph (product name: AUTO GRAPH AGS-X 5kN TRAPEZIUM (manufactured by SHIMADZU)) in an unused state after filling. Thereafter, the displacement value of the container corresponding to the squeeze force determined in advance according to the method (2-2) was determined. The autograph measurement conditions are as follows.
・ Cross head speed: 100mm / min
・ Jig: Φ5mm

(3) Reagent A thickener having a viscosity at 25 ° C. of the following value when dissolved in purified water so as to be 1.0 w / v% was used. (Measurement conditions were based on the method described in (2) Physical property measurement method (2-1) Viscosity measurement)
Carboxyvinyl polymer: 1911 mPa · s
Hydroxyethyl cellulose (Test 1, Test 5): 481.0 mPa · s
Hydroxyethyl cellulose (Test 3): 18.6 mPa · s
Hydroxypropyl methylcellulose 2906: 258.5 mPa · s
Polyvinylpyrrolidone K25: 1.2 mPa · s

[Test 1] Mist vision suppression test at the time of instillation A formulation example (eye drops) having the composition shown in Table 1 was prepared, and 6 mL and 13 mL of polyethylene terephthalate eye drop containers having an internal volume of 7.7 mL and 14.2 mL were respectively filled. These containers were equipped with polyethylene nozzles. As a nozzle made of polyethylene, a container having an internal volume of 7.7 mL is (i) a nozzle suitable for dropping 5 to 15 μL (inner diameter 0.3 mm, outer diameter 0.9 mm, hereinafter referred to as nozzle (i). And (ii) a nozzle suitable for dripping 30 to 50 μL (inner diameter 2 mm, outer diameter 5.5 mm, hereinafter referred to as nozzle (ii)). Used). Using this ophthalmic solution in a container, a fog vision suppression test was performed.
For three subjects, visual acuity was first measured before instillation. Next, the eye drop in the container equipped with the nozzle (i) is Example 1, the eye drop in the container equipped with the nozzle (ii) is Comparative Example 1, and the Comparative Example 1 is applied to both eyes once (one drop). The visual acuity after instillation was measured after 10 seconds. After sufficiently resting the eyes, the pre-eyesight was first measured in the same procedure, and then the eyesight after instillation from 10 seconds after Example 1 was instilled three times (three drops) continuously. Was measured.
Based on the visual acuity before and after instillation, the visual acuity reduction rate (%) was calculated using the following formula (I).
The visual acuity was measured using a “multi-contrast visual acuity table” (manufactured by Kowa Co., Ltd.). The subject stood at a position 3 meters away from the device, and looked at the Landolt ring in Chart 1 of the visual acuity chart with both eyes, and examined how large it could be read. If both the Landolt rings of the same size arranged side by side could be read, the reading was regarded as correct reading, and this value was defined as the visual acuity at that time.
Moreover, the average dripping amount (μL) in each eye drop in each container was determined in advance.

Table 1 also shows the visual acuity reduction rate (%).
When Example 1 was instilled three times, the visual acuity reduction rate was remarkably suppressed as compared with the case where Comparative Example 1 was instilled once. That is, when the drop amount of one drop is small, it is confirmed that although the total drop amount is almost the same, the visual acuity is hardly reduced and the fog vision after instillation is remarkably improved. It was.
In addition, the squeeze force of Example 1 was 2.5 N, and the displacement of the container at the time of dripping was 0.12 mm.

[Test 2] Evaluation of variation in dripping amount 1
Each formulation example (eye drops) was prepared according to the composition shown in Table 2, and 6 mL of a polyethylene terephthalate eye drop container having an internal volume of 7.7 mL was filled, and a polyethylene nozzle was attached to the container.
As the polyethylene nozzle, nozzles (i) and (iii) nozzles suitable for dropping 30 to 50 μL (inner diameter 2 mm, outer diameter 6 mm, sometimes referred to as nozzle (iii) below) were used. . The ophthalmic solution in a container was dropped with the nozzle drop opening facing substantially vertically downward, and the drop weight was measured for each drop. From the average drop amount (AVG: mg) and standard deviation (SD: mg) determined by repeating this operation 20 times, the drop amount variation (variation coefficient CV:%) was calculated by the following formula (II). The results are also shown in Table 2.

* The squeeze force (N) of the eye drop in a container was as follows.
Example 2-2-1 5.6
Example 2-2-2 5.4
* Displacement (mm) of the container at the time of dropping the ophthalmic solution in the container was as follows.
Example 2-2-1 0.24
Example 2-2-2 0.24

From the results of Table 2, in Formulation Examples 2-A to 2-C containing a carboxyvinyl polymer (hereinafter also referred to as CVP) as a thickener, Reference Example 2-1 equipped with a nozzle (iii) In Comparative Example 2-1 equipped with the nozzle (i), it was confirmed that the variation in the dripping amount significantly increased. On the other hand, when 1-menthol and d-camphor were further added to Comparative Example 2-1, it was surprisingly confirmed that variation in the dripping amount was remarkably suppressed (Example 2). -1-1, 2-1-2).
In addition, in the case of Formulation Examples 2-D to 2-F in which ε-aminocaproic acid was further added in addition to CVP, the same tendency as in the case where ε-aminocaproic acid was not blended was confirmed (Comparative Example 2). -2, Reference Example 2-2, Example 2-2-1, Example 2-2-2).

[Test 3] Evaluation of variation in dripping amount 2
Each formulation example (eye drops) was prepared according to the composition shown in Tables 3 and 4, and 6 mL of a polyethylene terephthalate eye drop container having an internal volume of 7.7 mL was filled, and a polyethylene nozzle was attached to the container.
As the polyethylene nozzle, nozzle (i) and nozzle (iii) were used.
The ophthalmic solution in a container was dropped with the nozzle drop opening facing substantially vertically downward, and the drop weight was measured for each drop. From the average drop amount (AVG: mg) and standard deviation (SD: mg) obtained by repeating this operation 20 times, the drop amount variation (variation coefficient CV:%) was calculated by the above formula (II).
Furthermore, variation (%) of the dripping amount with respect to the corresponding comparative example was calculated using the following formula (III). The calculation results are shown in Tables 3 and 4 together.

  The corresponding comparative examples are, for example, for Example 3-1-1, Example 3-1-2, Reference Example 3-1-1, Reference Example 3-1-2, and Reference Example 3-1-3. Are Comparative Example 3-1, Example 3-2-1, and Example 3-2-2, Comparative Example 3-2, Example 3-3, Reference Example 3-3-1, and Reference Example 3- 3-2 is Comparative Example 3-3.

* The squeeze force (N) in each container eye drop was as follows.
Example 3-1-1 1.6
Example 3-1-2 2.0
Example 3-2-1 2.1
Example 3-2-2 1.9
* Displacement (mm) of the container at the time of dropping in each container-containing eye drop was as follows.
Example 3-1-1 0.06
Example 3-1-2 0.14
Example 3-2-1 0.10
Example 3-2-2 0.07
* Viscosity (mPa · s) in each formulation example was as follows.
Formulation Example 3D 3.14
Formulation Example 3E 3.19
Formulation Example 3F 3.26

  In addition, the squeeze force of Example 3-3 was 1.5 N, and the displacement of the container at the time of dripping was 0.08 mm.

From the results shown in Table 3, in Reference Examples 3-A to 3-C containing hydroxypropylmethylcellulose (hereinafter sometimes referred to as HPMC) as a thickener, Reference Example 3 equipped with a nozzle (iii) Compared to 1, in Comparative Example 3-1, in which the nozzle (i) was mounted, it was confirmed that the variation in the dripping amount significantly increased. In addition, when the nozzle (iii) is mounted, even if 1-menthol or d-camphor is further added to the formulation example containing HPMC (Reference Example 3-1-1), variation in the amount of dripping is suppressed. Rather, it tended to increase (Reference Example 3-1-2, Reference Example 3-1-3)
On the other hand, when the nozzle (i) is installed, when the l-menthol or d-camphor is further added to the comparative example 3-1, the variation in the dripping amount is significantly suppressed. Was confirmed (Example 3-1-1, Example 3-1-2).
Further, from the results in Table 3, when hydroxyethyl cellulose (hereinafter sometimes referred to as HEC) is further included as a thickener, HEC is also included when the nozzle (i) is mounted. In comparison with Comparative Example 3-2, when 1-menthol or d-camphor was further added, it was confirmed that variation in the dripping amount was remarkably suppressed (Example 3-2-1). Example 3-2-2).
Furthermore, from the results of Table 4, even when polyvinyl pyrrolidone K25 (hereinafter sometimes referred to as PVP) is contained as a thickener, similarly, Reference Example 3-3-1 equipped with nozzle (iii) In Comparative Example 3-3 equipped with the nozzle (i), the variation in the dripping amount increased. When the nozzle (iii) is mounted, even if d-camphor is further added to Reference Example 3-3-1 containing PVP, the variation in the dripping amount is not suppressed, but rather increases. When the nozzle (i) was mounted, it was confirmed that when d-camphor was further added to Comparative Example 3-3 containing PVP, variation in the amount of dripping was suppressed (Example 3-3). ).

[Test 4] Variation evaluation of dripping amount 3
Each formulation example (eye drops) was prepared according to the composition shown in Table 5, filled with 6 mL of a polyethylene terephthalate eye drop container having an internal volume of 7.7 mL, and a polyethylene nozzle was attached to the container. The nozzle (i) was used as the polyethylene nozzle.
The ophthalmic solution in a container was dropped with the nozzle drop opening facing substantially vertically downward, and the drop weight was measured for each drop. From the average drop amount (AVG: mg) and the standard deviation (SD: mg) obtained by repeating this operation 20 times, the drop amount variation (variation coefficient CV:%) is calculated by the above formula (II). The variation (%) of the dripping amount with respect to the corresponding comparative example 4 was calculated using the above (III). The calculation results are also shown in Table 5.

  From the results of Table 5, when the nozzle (i) was mounted, compared to Comparative Example 4 containing CVP, when tetrahydrozoline hydrochloride, naphazoline hydrochloride, neostigmine methylsulfate was further added, It was confirmed that variation in the amount of dripping was suppressed (Example 4-1, Example 4-2, Example 4-3).

[Test 5] Efficacy test at the time of instillation Each formulation example (eye drops) was prepared according to the composition shown in Table 6, and 6 mL and 13 mL were filled in an eye drop container made of polyethylene terephthalate having an internal volume of 7.7 mL and 14.2 mL, respectively. A polyethylene nozzle was attached to the container. As the polyethylene nozzle, nozzle (i) was used for a container having an internal volume of 7.7 mL, and nozzle (ii) was used for a container having an internal volume of 14.2 mL. This eye drop in a container was instilled once (one drop) by the subject himself, and the eye drop effective feeling at the time of eye drop was measured. The effect of eye drops indicates a feeling that allows the user to be aware that the dropped eye drops have entered the eye when he / she drops.
Specifically, a VAS (Visual Analog Scale) method is used in which 10 subjects are blindly instilled with a predetermined amount of the test solution, 10 when the instillation can be clearly recognized, and 0 when the instillation cannot be recognized at all. An eye drop effectiveness score was obtained. The results are also shown in Table 6.
Moreover, the average dripping amount (μL) in each eye drop in each container was obtained in advance.

* The squeeze force (N) in each container eye drop was as follows.
Example 5-1 2.9
Example 5-2 2.5
* Displacement (mm) of the container at the time of dropping in each container-containing eye drop was as follows.
Example 5-1 0.12
Example 5-2 0.12

Table 6 also shows the eye drop effectiveness score.
When Reference Example 5-1 and 5-2, in which prescription examples 5-A and 5-B are filled and nozzle (ii) is mounted, are instilled in all subjects regardless of the presence or absence of menthol. Became 10. On the other hand, in the case of Comparative Example 5-1, in which the nozzle (i) was mounted, the effectiveness score was low, and even when menthol was added, the effectiveness was hardly felt (Comparative Example 5-2). Surprisingly, by using a thickener and menthol in combination (Example 5-1 and Example 5-2), a marked improvement in eye drop effect was recognized.

[Test 6] Evaluation of variation in dripping amount 4
Each formulation example (eye drops) was prepared according to the composition shown in Table 7, filled with 6 mL of a polyethylene terephthalate eye drop container having an internal volume of 7.7 mL, and a polyethylene nozzle was attached to the container. The nozzle (i) was used as the polyethylene nozzle.
The ophthalmic solution in a container was dropped with the nozzle drop opening facing substantially vertically downward, and the drop weight was measured for each drop. From the average drop amount (AVG: mg) and the standard deviation (SD: mg) obtained by repeating this operation 20 times, the drop amount variation (variation coefficient CV:%) is calculated by the above formula (II). The variation (%) of the dripping amount with respect to the corresponding comparative example was calculated using the above (III). The calculation results are also shown in Table 7. Corresponding comparative examples are Comparative Example 6-1 and Comparative Example 6-2 for Example 6-1 and Example 6-2, respectively.

* The squeeze force (N) in each container eye drop was as follows.
Example 6-1 2.2
Example 6-2 1.7
* Displacement (mm) of the container at the time of dropping in each container-containing eye drop was as follows.
Example 5-1 0.09
Example 5-2 0.07

  From the results of Table 7, when the nozzle (i) was mounted, it was dripped when a terpenoid was further added as compared with Comparative Example 6-1 and Comparative Example 6-2 containing a thickener. It was confirmed that the variation in the amount was suppressed (Example 6-1 and Example 6-2).

[Formulation example]
Preparation formulation examples (eye drops) shown in Table 8 and Table 9 (Prescription Formulation Examples 1 to 7) and Table 10 and Table 11 (Prescription Formulation Examples 8 to 13) are prepared, filled into a predetermined container, and then a predetermined nozzle. A formulation example (eye drop in a container) was used.
Formulation Examples 1 to 13: After filling Formulation Formulation Examples 1 to 13 in a container with an internal volume of 6 mL, a nozzle having an inner diameter of 0.1 mm and an outer diameter of 0.4 mm attached to the dripping port (dropping) (Amount: 9μL)
Formulation Examples 14 to 26: After filling Formulation Formulation Examples 1 to 13 in a container with an internal volume of 8 mL, a nozzle having an inner diameter of 0.3 mm and an outer diameter of 1.0 mm attached to the dropping port (dropping) (Amount: 15 μL)
Formulation Examples 27 to 39: After filling Formulation Formulation Examples 1 to 13 into a container with an inner volume of 10 mL, a nozzle having an inner diameter of 0.5 mm and an outer diameter of 1.2 mm attached to the dropping port (dropping) (Amount: 18 μL)

  The eye drop of the present invention suppresses fog vision while maintaining the function of the thickener, and suppresses variation in the drop amount when instilling with a small amount of one drop. Can be improved. Therefore, the eye drop of the present invention leads to an improvement in medication compliance and a reliable therapeutic effect, is highly practical, and has a good feeling of use.

Claims (15)

(A) a thickener, and (B) an eye drop containing at least one selected from the group consisting of a terpenoid compound, an imidazoline vasoconstrictor, neostigmine, and a salt of the neostigmine, dropping weight 5~25μL der of is, the (a) thickener, hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, alginic acid, and at least one selected from the group consisting of sodium hyaluronate eye drops, wherein the Rukoto Oh.   Furthermore, the eye drop of Claim 1 with which the container whose internal volume is 4-30 mL was filled.   The eye drop according to claim 1 or 2, further filled in a container having a nozzle having an inner diameter of less than 1.5 mm at the dropping port. The thickener, hydroxycarboxylic methylcellulose, eye drops according to claim 1 at least one of hydroxyethyl cell row scan, and selected from the group consisting of polyvinylpyrrolidone.   Measured by the following measurement method at 25 ° C. when at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, and polyvinylpyrrolidone is dissolved in purified water so as to be 1.0 w / v%. The eye drop according to claim 4, wherein the obtained viscosity shows the following value.
  Hydroxyethyl cellulose: 1 to 5000 mPa · s,
  Hydroxypropyl methylcellulose: 1 to 3000 mPa · s
  Polyvinyl pyrrolidone: 0.1 to 5 mPa · s
[Measuring method]
16th revised Japanese Pharmacopoeia General test method Viscosity measurement method Measurement in accordance with the test method of “(2) Single cylindrical rotational viscometer (Brookfield viscometer)” described in the second method rotational viscometer method Method.   The eye drop according to any one of claims 1 to 5, wherein a blending amount of the component (A) is 0.01 to 10 w / v%. The terpenoid compound is, dl-menthol, l-menthol, dl-camphor, d-camphor, d-borneol, and any one of claims 1 to 6 at least one selected from the group consisting of geraniol The eye drops described.   The ophthalmic solution according to any one of claims 1 to 7, wherein a blending amount of the component (B) is 0.0001 to 0.5 w / v%.   The eye drop according to any one of claims 1 to 8, wherein the total content of the component (B) is 0.00003 to 10 parts by weight with respect to 1 part by weight of the total content of the component (A). .   Furthermore, the eye drop as described in any one of Claims 1-9 containing at least 1 sort (s) selected from the group which consists of surfactant, an isotonic agent, a chelating agent, and a buffering agent.   The ophthalmic solution according to any one of claims 1 to 10, wherein the eye drop is contained in a container having a squeeze force of 0.5 to 12N required for dropping one drop.   The ophthalmic solution according to any one of claims 1 to 11, wherein the ophthalmic solution is accommodated in a container having a displacement of 0.01 to 2.0 mm when dropping one drop.   The eye drop contains (A) a thickener and (B) at least one selected from the group consisting of a terpenoid compound, an imidazoline-based vasoconstrictor, neostigmine, and a salt of the neostigmine, and the eye drop A method for suppressing fogging, which is designed so that a drop amount per drop is 5 to 25 μL.   The eye drop contains (A) a thickener and (B) at least one selected from the group consisting of a terpenoid compound, an imidazoline-based vasoconstrictor, neostigmine, and a salt of the neostigmine, and the eye drop A method for suppressing variation in the amount of one drop of eye drops, wherein the drop amount per drop is designed to be 5 to 25 μL.   The eye drop contains (A) a thickener and (B) at least one selected from the group consisting of a terpenoid compound, an imidazoline-based vasoconstrictor, neostigmine, and a salt of the neostigmine, and the eye drop An eye drop effective feeling improving method, wherein the drop amount per drop is designed to be 5 to 25 μL.

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