JP6304474B2 - 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. As a method of use, a method of using 1 to 3 drops once a day is generally used.
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 avoiding the occurrence of periocular dermatitis or the like due to a chemical overflowing from the eye. For this purpose, a technique is known in which the amount of one drop of eyedrop is reduced by attaching an adapter to the nozzle of an eye drop container or increasing the water repellency of the nozzle (Patent Documents 1 and 2). However, the current situation is that the relationship between such a technique and the components actually blended into the ophthalmic solution has not been sufficiently studied.

  On the other hand, thickeners, terpenoid compounds, and boric acid buffers are each known as a component of eye drops, but their behavior in eye drops with a small amount of one drop is not well known.

Japanese Patent Laying-Open No. 2005-211884 JP 2011-105339 A

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

  The present inventors have found a new problem that when the amount of one drop is made small in an eye drop containing either a thickener or a terpenoid compound, the drop amount varies. An object of the present invention is to provide an eye drop in which variation in the drop amount is suppressed even when the drop amount is reduced in an eye drop containing a thickener or a terpenoid compound.

In order to solve the above-mentioned problems, the present inventors have conducted intensive research. As a result, the present invention can solve the problems by using eye drops that contain a predetermined component and can be instilled with a predetermined amount of one drop. I found it. That is, the present invention provides the following (1) to (7).
(1) The eye drop of the present invention is an eye drop containing (A) a thickener or a terpenoid compound and (B) a boric acid buffer, and the drop amount per drop is 5 to 25 μL. It is characterized by that.
(2) The eye drop of the present invention is preferably filled in a container having an internal volume of 4 to 30 mL.
(3) The eye drop of the present invention is preferably 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 variation in the amount of one drop of the eye drop of the present invention comprises (A) a thickener or a terpenoid compound and (B) a borate buffer, and It is designed so that the dropping amount per drop is 5 to 25 μL.
(7) The method for producing an eye drop in a container according to the present invention comprises (A) a thickener or a terpenoid compound, and (B) an eye drop containing a borate buffer. It is characterized by filling a container designed to be 25 μL.

  According to the present invention, even when the amount of one drop of eye drops is made small, variation in the amount of drops can be suppressed.

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. Eye drops and eye drops in containers The present invention contains a thickener or terpenoid compound as component (A) and a borate buffer as component (B), and the amount per drop is 5 to 25 μL. It is characterized by being an eye drop designed as described above.

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, terpenoid compound [component (A)]
The eye drop of the present invention contains (A) a thickener or a terpenoid compound (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. Examples of the salt of the thickener include a salt with an inorganic base, preferably an alkali metal salt or an alkaline earth metal salt, and more preferably a sodium salt, potassium salt, calcium salt or magnesium salt. In particular, a sodium salt is preferable.

Among these, vinyl-based thickeners, cellulose-based thickeners, polyethylene glycols, or mucopolysaccharides are preferred from the viewpoint of further enhancing the effect of suppressing the variation in dripping amount. 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, polyvinylalcohol, alginic acid, sodium hyaluronate, particularly preferred 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.

The terpenoid compound used as the component (A) 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 effect of suppressing the variation in the amount of dripping, at least one selected from the group consisting of dl-menthol, l-menthol, dl-camphor, d-camphor, d-borneol and geraniol is preferable. Examples of the essential oil containing these include cool mint oil, peppermint oil, mint oil, camphor oil and the like. More preferred examples include dl-menthol, l-menthol, dl-camphor, d-camphor, d-borneol geraniol, particularly preferably l-menthol, d-camphor, dl-camphor, most preferably l-menthol. Is mentioned.

  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, the preparation form, the usage method, and the like. As content of (A) component, it is preferable that the total content of (A) component is 0.0001-10 w / v% on the basis of the total amount of the eye drop of the present invention, for example, 0.0005 It is more preferably 5 w / v%, particularly preferably 0.001 to 3 w / v%, and most preferably 0.001 to 1 w / v%.

  When the component (A) is a thickener, the content of the thickener is preferably 0.01 to 10 w / v% in terms of the total amount based on the total amount of the eye drop of the present invention. It is more preferably ˜5 w / v%, particularly preferably 0.1 to 3%, and most preferably 0.1 to 1%.

  When the component (A) is a terpenoid compound, the total content of the terpenoid compound is preferably 0.0001 to 0.2 w / v% based on the total amount of the eye drop of the present invention, and 0.0005 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 dripping amount variation suppressing effect.

(2) Borate buffer [component (B)]
The eye drop of the present invention contains (B) a borate buffer (hereinafter sometimes simply referred to as “component (B)”).

The borate buffer used as the component (B) is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Specific examples of such a boric acid buffer include boric acid or a salt thereof. Examples of the salt of boric acid include a combination of an inorganic acid salt of boric acid, preferably an alkali metal salt and / or alkaline earth metal salt of boric acid, and more preferably an alkali metal salt of boric acid. Specific examples of the borate include sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, and borax, and borax is particularly preferable.
These boric acids or salts thereof may be used alone or in any combination of two or more. A combination of boric acid and an alkali metal salt of boric acid is preferable, and a combination of boric acid and borax 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, 0.01 to 10 w / v% of total content of (B) component is preferable on the basis of the total amount of the eye drop of this invention, for example, 0.05 to 5 w / v% is more preferable, and 0.1 to 2 w / v% is more preferable. The content of the component (B) is suitable from the viewpoint of improving the dripping amount variation suppressing effect.
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 0.01 to 10000 parts by mass, more preferably 0.05 to 5000 parts by mass, and still more preferably 0.1 to 2000 parts by mass. In eye drops that contain one of the component (A) or the component (B) and are designed to have a small drop amount per drop, a new problem is that the drop amount is likely to vary. On the other hand, when the content ratio of the component (B) is within the above range, the variation in the drop amount can be effectively suppressed without impairing the above-described effect of the component (A).

When the component (A) is a thickener, for example, the total content of the component (B) is 0.01 to 1 part by mass of the total content of the component (A) contained in the eye drop of the present invention. The amount is preferably 500 parts by weight, more preferably 0.05 to 50 parts by weight, and particularly preferably 0.1 to 20 parts by weight.
When the component (A) is a terpenoid compound, for example, the total content of the component (B) is 0.5 to 10,000 with respect to 1 part by mass of the total content of the component (A) contained in the eye drop of the present invention. It is preferable that it is a mass part, It is more preferable that it is 0.625-5000 mass part, It is especially preferable that it is 1.25-2000 weight part.

(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 type of such components is not particularly limited, and examples thereof include anti-inflammatory components or astringent components, anti-allergic components, vitamins, amino acids, antibacterial components or bactericidal components, local anesthetic components, glaucoma treatment components The cataract treatment component can be exemplified. Examples of the pharmacologically active component and physiologically active component suitable in the present invention include the following components.

Decongestant: Tetrahydrozoline, naphazoline, epinephrine, ephedrine, methylephedrine, etc.
Eye muscle modulator component: For example, cholinesterase inhibitor having an active center similar to acetylcholine, specifically, neostigmine methyl sulfate, tropicamide, atropine sulfate helenien, and the like.
Anti-inflammatory component or astringent component: zinc sulfate, zinc lactate, allantoin, epsilon-aminocaproic acid, lysozyme chloride, pranoprofen, sodium azulenesulfonate, dipotassium glycyrrhizinate, bromfenac sodium, berberine chloride, berberine sulfate, etc. .

  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 and potassium aspartate mixture, epsilon-aminocaproic acid 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)) Castor oil), polyethylene glycol monostearate (specifically polyoxyl 40 stearate), nonionic surfactants; glycine-type amphoteric surfactants such as alkyldiaminoethylglycine; alkyl quaternary ammonium salts (specific Cation interfaces such as benzalkonium chloride and benzethonium chloride) Activators 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.

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 of the present invention is not particularly limited as long as it is within a pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable range. 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 of 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 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. It is designed so that the amount of the eye drop per drop is 5 to 25 μL, which is within the capacity of the conjunctival sac, so that the overflow eye drops adhere to the eyes and the user feels uncomfortable. There is no fear of generating.
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 15 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 0.0 to 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, it is particularly preferable from the viewpoint of suppressing variation in the amount of dripping even when instillation is performed using an instillation nozzle having a small diameter. 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.

In order to drop a small amount of the eye drop of the present invention, it is preferable to set the dropping port to the following value.
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. Can do.
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.
The constituent material of the nozzle is preferably made of plastic, 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, polybutylene terephthalate 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 drop in container It is preferable that the eye drop of the present invention is 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 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 containing the container of the present invention is within the above range, the effect of suppressing variation in the amount of dripping can be more remarkably exhibited.
The measurement of the displacement of the container at the time of dripping is performed according to the method as described in an Example.

(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.

2.1 Droplet Variation Control Method As described above, the eye drop of the present invention contains (A) a thickener or a terpenoid compound, and (B) a borate buffer, By designing the drop amount to be 5 to 25 μL, variations in the drop amount can be suppressed.
Therefore, the present invention, from yet another point of view, contains a thickener or a terpenoid compound as the component (A) and a borate buffer as the component (B) in the eye drop, and per drop of the eye drop There is also provided a method of designing the ophthalmic solution so that the drop amount of the solution is 5 to 25 μL, and suppressing variations in the drop amount.
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 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.

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 1-2 was prepared by the following method. That is, under stirring, a thickener such as hydroxyethylcellulose 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, measurement of container displacement at the time of dropping, and dispersion amount variation test for eye drops in containers filled with eye drops in a predetermined container. Went.

(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-1 w / v% aqueous solution of the following thickeners-carboxyvinyl polymer, hydroxypropyl methylcellulose 2906:
Measuring device_TV-10M, rotation speed_12 rpm, rotor No. _M2, Viscosity after 1 minute of measurement time Viscosity at 25 ° C. is less than 100 mPa · s is described in the 16th revised Japanese Pharmacopoeia General Test Method Viscosity Measurement Method 2 Method Viscometer “(3) Cone -The viscosity at 25 ° C was measured under the following conditions in accordance with the test method of "flat plate viscometer (cone plate viscometer)".

Measuring device, rotation speed, rotor No. And set time-Example 2-1, 1 w / v% aqueous solution of hydroxyethyl cellulose:
Measuring device_RC-550, rotation speed_20 rpm, rotor_standard cone rotor (1 ° 34 ′ × R24), set time_viscosity after 3 minutes / other than Example 2-1.
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 polyvinylpyrrolidone K25:
Measuring device_RC-550, rotation speed_100rpm, rotor_standard cone rotor (1 ° 34 'x 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 dropping one drop 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 The thickener used was one having a viscosity at 25 ° C. of the following value when dissolved in purified water so as to be 1.0 w / v% (measurement conditions are (2) physical property measurement method (2-1) According to the method described in the viscosity measurement).
Carboxyvinyl polymer: 1911 mPa · s
Hydroxyethyl cellulose: 18.6 mPa · s
Hydroxypropyl methylcellulose 2906: 258.5 mPa · s
Polyvinylpyrrolidone K25: 1.2 mPa · s

[Test 1] Evaluation of variation in dripping amount 1
Each formulation example (eye drops) was prepared by a conventional method according to the composition shown in Table 1, 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, (i) a nozzle suitable for dropping 5 to 15 μL (the inner diameter of the dropping port is 0.3 mm, the outer diameter is 0.9 mm, and sometimes referred to as nozzle (i) below the nozzle), and (ii) 2) Nozzles suitable for dropping 30 to 50 μL (inner diameter 2 mm, outer diameter 6 mm, hereinafter sometimes referred to as nozzle (ii)) 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 (I). The results are also shown in Table 1.

* The squeeze force of Example 1-1 was 2.0 N, and the displacement of the container at the time of dripping was 0.08 mm.

As shown in Table 1, when prescription example 1-A containing hydroxyethyl cellulose (hereinafter sometimes referred to as HEC) as a thickener is filled in an eye dropper container and then dropped with a nozzle (ii) (reference) In comparison with Example 1-1), it was confirmed that when the nozzle (i) was mounted, the variation in the dripping amount was remarkably increased (Comparative Example 1-1). On the other hand, a formulation example (Comparative Example 1-2, Comparative Example 1-3) containing a phosphate buffer and a borate buffer respectively, and a formulation example (Comparative Example) containing both hydroxyethyl cellulose and a phosphate buffer Also in Example 1-4), when the nozzle (i) was mounted, it was confirmed that the dripping amount was almost constant and varied.
On the other hand, surprisingly, in the case where both hydroxyethyl cellulose and borate buffer were contained (Example 1-1), the variation count was remarkably improved and dropped to almost the same level as in Reference Example 1-1. It was confirmed that variation in the amount could be suppressed.
In addition, when two healthy subjects instilled Example 1-1 into both eyes, one drop per eye, there was no irritation and the feeling was very good.

[Test 2] Drip amount variation evaluation 2
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. The prescription example was changed to the one shown in Table 2, and a variation evaluation test was performed in the same manner as in Test 1 except that all the nozzles (i) were used as polyethylene nozzles, and according to the above formula (I) The variation of the dripping amount (coefficient of variation CV:%) was calculated. Furthermore, using the following formula (II), the variation improvement rate (%) for the corresponding comparative example was determined. The results are shown in Table 2.
The corresponding comparative examples are Comparative Example 2-1, Comparative Example 2-2, and Comparative Example 2 for Example 2-1, Example 2-2, Example 2-3, and Example 2-4, respectively. -3, Comparative Example 2-4.

* The squeeze force (N) in each container eye drop was as follows.
Example 2-1 4.6
Example 2-2 2.3
Example 2-3 2.2
Example 2-4 2.5
* Displacement (mm) of the container at the time of dropping in each container-containing eye drop was as follows.
Example 2-1 0.20
Example 2-2 0.10
Example 2-3 0.10
Example 2-4 0.12

In the case where carboxyvinyl polymer and hydroxypropylmethylcellulose 2906 are used as thickeners, the boric acid buffering agent compared to the comparative examples (Comparative Example 2-1 and Comparative Example 2-2) both containing a phosphate buffering agent. It was found that the examples (Example 2-1 and Example 2-2) containing the phenotype significantly improved the dispersion at the time of dropping.
Furthermore, even when 1-menthol and d-camphor were contained, a borate buffer was added to the comparative examples (Comparative Examples 2-3 and 2-4) both containing a phosphate buffer. In the examples (Example 2-3 and Example 2-4), it was confirmed that the dispersion at the time of dropping was remarkably improved.
Moreover, when 2 healthy persons instilled Example 2-2 drop by drop into one eye to one eye, there was no irritation | stimulation and it was a very favorable usability | use_condition.

[Test 3] Evaluation of variation in dripping amount 3
Each formulation example (eye drops) was prepared according to the composition shown in Table 3, 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. The prescription example was changed to the one described in Table 3, and a variation evaluation test was performed in the same manner as in Test 1 except that all the nozzles (i) were used as polyethylene nozzles, and according to the above formula (I) The variation of the dripping amount (coefficient of variation CV:%) was calculated. Furthermore, using the formula (II), the variation improvement rate (%) for the corresponding comparative example was obtained. The results are also shown in Table 3.
The corresponding comparative examples are Comparative Example 3-1 for Example 3-1, Comparative Example 3-2 for Example 3-2, and Comparative Example 3-3 for Example 3-3.

* The squeeze force (N) in each container eye drop was as follows.
Example 3-1 2.1
Example 3-2 1.8
Example 3-3 7.0
* Displacement (mm) of the container at the time of dropping in each container-containing eye drop was as follows.
Example 3-1 0.09
Example 3-2 0.07
Example 3-3 0.31

  When a thickener such as polyvinylpyrrolidone K25 or a terpenoid compound such as l-menthol, dl-camphor and bergamot oil and a borate buffer are contained (Example 3-1 and Example 3-2) In Example 3-3), it was surprisingly confirmed that the variation in the dripping amount was improved.

[Formulation example]
Formulation formulation examples (eye drops) shown in Tables 4 and 5, and Tables 6 and 7 were prepared. did.
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 in a container having an internal 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 method for improving the variation in the drop amount of the eye drop of the present invention can suppress the variation in the drop amount when the eye drop containing a thickener or a terpenoid compound is instilled with a small drop amount. Therefore, the eye drop of the present invention is highly practical and has a good feeling of use.

Claims (10)

An eye drop containing (A) a thickener or a terpenoid compound and (B) a borate buffer, wherein the thickener is selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. An ophthalmic solution characterized in that it is at least one, and the terpenoid compound is at least one selected from the group consisting of menthol, camphor, and bergamot oil, and the drop amount per drop is 5 to 25 μL . (Excluding eye drops containing diclofenac sodium 0.1 w / v%, boric acid, borax, chlorobutanol, povidone, and polysorbate 80)   The eye drop according to claim 1 filled in a container having an internal volume of 4 to 30 mL.   The eye drop according to claim 1 or 2, filled in a container having a nozzle having an inner diameter of less than 1.5 mm at the dropping port. The ophthalmic solution according to any one of claims 1 to 3 , wherein the content of the component (A) is 0.0001 to 10 w / v%. The eye drop according to any one of claims 1 to 4 , wherein the content of the component (B) is 0.01 to 10 w / v%. The eye drop according to any one of claims 1 to 5 , wherein the total content of the component (B) is 0.01 to 10000 parts by mass with respect to 1 part by mass of the total content of the component (A). . The eye drop according to any one of claims 1 to 6 , comprising a thickener and a terpenoid compound as the component (A). The ophthalmic solution according to any one of claims 1 to 7 , further comprising a surfactant. The eye drop contains (A) a thickener or a terpenoid compound and (B) a boric acid buffer, and the thickener is at least one selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. It is a seed, and the terpenoid compound is at least one selected from the group consisting of menthol, camphor, and bergamot oil, and is designed so that the drop amount per drop of the eye drop is 5 to 25 μL. A method for suppressing variation in the amount of one drop of eye drops. (Except when the eye drop contains diclofenac sodium 0.1 w / v%, boric acid, borax, chlorobutanol, povidone, and polysorbate 80) (A) a thickener or terpenoid compound, and (B) a borate buffer, wherein the thickener is at least one selected from the group consisting of hydroxyethylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone The terpenoid compound is filled with an eye drop that is at least one selected from the group consisting of menthol, camphor, and bergamot oil in a container designed so that the drop amount per drop is 5 to 25 μL. A method for producing an eye drop in a container. (Except when the eye drop contains diclofenac sodium 0.1 w / v%, boric acid, borax, chlorobutanol, povidone, and polysorbate 80)

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