Ophthalmic composition for improved foreign matter feeling

Abstract

To provide an ophthalmic composition that comprises pranoprofen and / or a salt thereof and has an excellent foreign matter feeling improvement effect.SOLUTION: An ophthalmic composition for improved foreign matter feeling comprises the following components: (A) pranoprofen, and / or a pharmaceutically acceptable salt thereof; (B) butyl group-containing phenol; (C) at least one selected from the group consisting of tocopherol, pyridoxine, chondroitin sulfate, a derivative thereof, and a salt thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an ophthalmic composition that is useful for improving foreign body sensation in the eye. [Background technology]

[0002] The cornea is a tissue that is formed on the outermost surface of the eyeball and is composed of five layers, namely, the corneal epithelium, Bowman's membrane, corneal stroma, Descemet's membrane, and corneal endothelium, in that order from the outside world. Due to its anatomical characteristics of direct contact with the outside world, various foreign bodies such as antigens, microorganisms, and sand dust are likely to invade the cornea. On the other hand, most of the sensory nerves distributed in the cornea are trigeminal nerves. The sensation of the cornea is considered to be one of the most sensitive pain sensations in the human body, and the degree of pain is extremely sharp. In other words, the nerve endings end just below the corneal epithelium, and even a slight defect or peeling of the corneal epithelium exposes and stimulates the nerve endings just below the corneal epithelium, which is felt as strong pain (Non-Patent Document 1).

[0003] Therefore, when the cornea's natural barrier function is weakened due to a defect or detachment of the corneal epithelium, the eye becomes more sensitive to foreign body sensations when dust, pollen, excess protein, makeup or other contaminants adhere to the surface of the eye.

[0004] Pranoprofen is known as a propionic acid-based nonsteroidal anti-inflammatory agent that has excellent anti-inflammatory, analgesic, and antipyretic effects, and is widely used in ophthalmic compositions such as eye drops and as oral preparations due to its high safety. The efficacy of ophthalmic compositions containing pranoprofen is known to be the improvement of foreign body sensation, watery eyes, itchiness, blurred vision, and conjunctival congestion.

[0005] Ophthalmic compositions such as eye drops usually contain a large number of different ingredients, but depending on the combination of ingredients, the efficacy of the active ingredient may be reduced, which is difficult to predict. Aqueous compositions containing pranoprofen tend to become cloudy or the pranoprofen tends to decompose during storage, particularly when stored under light exposure, so attempts have been made to improve the stability of pranoprofen-containing aqueous compositions by incorporating dibutylhydroxytoluene or the like. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Takehisa Kondo, Nerves of the Cornea, Monthly Ophthalmology Practice 72:30, 2001 Summary of the Invention [Problem to be solved by the invention]

[0007] The present inventor has discovered a new problem in that the incorporation of a butyl group-containing phenol (such as dibutylhydroxytoluene) into an ophthalmic composition containing pranoprofen and / or a pharma- ceutically acceptable salt thereof (hereinafter sometimes abbreviated as "the salt") reduces the corneal barrier function, thereby reducing the effect of pranoprofen or a salt thereof in improving foreign body sensation. Therefore, an object of the present invention is to provide an ophthalmic composition which contains pranoprofen and / or a salt thereof and has an excellent effect of improving foreign body sensation. [Means for solving the problem]

[0008] In order to solve the above problems, the inventors conducted extensive research and found that by blending an ophthalmic composition containing (A) pranoprofen and / or a salt thereof, and (B) a butyl group-containing phenol (such as dibutylhydroxytoluene), with (C) at least one selected from the group consisting of tocopherol, pyridoxine, chondroitin sulfate, derivatives thereof, and salts thereof, a composition can be obtained that improves the corneal barrier function and thereby improves foreign body sensation. Surprisingly, the incorporation of the above-mentioned (C) component not only inhibits the deterioration of the corneal barrier function and foreign body sensation caused by the combination of pranoprofen and butyl-group-containing phenol, but also improves the corneal barrier function and foreign body sensation more than when pranoprofen and / or its salt are used alone (i.e., when butyl-group-containing phenol is not included). Even more unexpectedly, although butyl group-containing phenols are components that reduce the corneal barrier function and reduce the effect of pranoprofen and / or its salts in improving the foreign body sensation, by incorporating butyl group-containing phenols into an ophthalmic composition containing pranoprofen and / or its salts and the above-mentioned component (C), the corneal barrier function is improved and the effect of improving the foreign body sensation is enhanced.

[0009] The present invention is based on the above findings and provides the following ophthalmic compositions and methods. Item 1. An ophthalmic composition for improving foreign body sensation, comprising the following components (A), (B), and (C): (A) Pranoprofen, and / or a pharma- ceutically acceptable salt thereof. (B) Butyl-containing phenols (dibutylhydroxytoluene, butylhydroxyanisole, etc.) (C) at least one member selected from the group consisting of tocopherol, pyridoxine, chondroitin sulfate, derivatives thereof, and salts thereof Item 2. The ophthalmic composition according to Item 1, wherein the total content of the component (A) is 0.04 to 0.15 w / v % based on the total amount of the ophthalmic composition. Item 3. The ophthalmic composition according to item 1 or 2, which contains two or more of the following (i), (ii), and (iii) as the component (C): (i) Tocopherol, its derivatives, and / or their salts (ii) pyridoxine, its derivatives, and / or their salts (iii) Chondroitin sulfate, its derivatives, and / or salts thereof Item 4. The ophthalmic composition according to any one of Items 1 to 3, further comprising at least one selected from the group consisting of aspartic acid, aminoethylsulfonic acid, chlorpheniramine, glycyrrhizic acid, edetic acid, and salts thereof. Item 5. A method for imparting or improving an effect of suppressing (improving or alleviating) foreign body sensation to an ophthalmic composition, comprising comprising incorporating into the ophthalmic composition (A) pranoprofen and / or a salt thereof, (B) a butyl group-containing phenol, and (C) at least one member selected from the group consisting of tocopherol, pyridoxine, chondroitin sulfate, derivatives thereof, and salts thereof. Item 6. A method for imparting or improving an effect of suppressing (improving or alleviating) watery eyes to an ophthalmic composition, comprising comprising comprising: (A) pranoprofen and / or a salt thereof; (B) a butyl group-containing phenol; and (C) at least one member selected from the group consisting of tocopherol, pyridoxine, chondroitin sulfate, derivatives thereof, and salts thereof. Effect of the Invention

[0010] When a butyl-group-containing phenol (such as dibutylhydroxytoluene) is added to an ophthalmic composition containing pranoprofen and / or a salt thereof, the corneal barrier function is reduced, and the effect of improving foreign body sensation is also reduced. In this regard, the ophthalmic composition of the present invention exhibits an excellent effect of improving the corneal barrier function, and further an excellent effect of improving foreign body sensation, despite containing pranoprofen and / or a salt thereof and a butyl group-containing phenol. The degree of this is not only higher than when pranoprofen and / or a salt thereof is contained in combination with a butyl group-containing phenol, but also significantly higher than when pranoprofen or a salt thereof is contained alone (i.e., when no butyl group-containing phenol is contained). Furthermore, although butyl group-containing phenol is an ingredient that reduces the effect of improving the corneal barrier function and foreign body sensation when contained together with pranoprofen and / or a salt thereof, the ophthalmic composition of the present invention containing butyl group-containing phenol exhibits a superior effect of improving the corneal barrier function and thus the effect of improving foreign body sensation compared to an ophthalmic composition containing pranoprofen and / or a salt thereof and the above-mentioned component (C). Therefore, the ophthalmic composition of the present invention can be suitably used for improving the corneal barrier function and, in turn, for improving foreign body sensation in the eye. In addition, when the corneal barrier function is reduced, foreign body sensations, particularly tingling foreign body sensations, become more pronounced, so the ophthalmic composition of the present invention can be suitably used in particular for improving tingling or prickling foreign body sensations. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The present invention will be described in detail below. The ophthalmic composition of the present invention comprises: (A) pranoprofen and / or a salt thereof, (B) butyl-containing phenols, and (C) at least one selected from the group consisting of tocopherol, pyridoxine, chondroitin sulfate, derivatives thereof, and salts thereof; An ophthalmic composition for improving foreign body sensation comprising:

[0012] Pranoprofen and / or its salts ((A) component) The salt of pranoprofen may be any pharma- ceutically or physiologically acceptable salt, and examples thereof include salts with inorganic bases such as alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (calcium salt, magnesium salt, etc.), ammonium salts, and metal salts (aluminum salt, etc.); and salts with organic bases such as organic amine salts (methylamine salt, triethylamine salt, diethylamine salt, triethanolamine salt, morpholine salt, piperazine salt, pyrrolidine salt, tripyridine salt, picoline salt, etc.). Pranoprofen and its salts also include those in the form of hydrates. Pranoprofen and its salts can be used alone or in combination of two or more. Among pranoprofen and its salts, pranoprofen is most preferred.

[0013] The total content of pranoprofen and / or a salt thereof in the ophthalmic composition is preferably 0.03 w / v% or more, more preferably 0.04 w / v% or more, and even more preferably 0.05 w / v% or more, based on the total amount of the composition. Furthermore, the total content of pranoprofen and / or its salt is preferably 0.5 w / v% or less, more preferably 0.2 w / v% or less, even more preferably 0.1 w / v% or less, even more preferably 0.08 w / v% or less, particularly preferably 0.07 w / v% or less, and most preferably 0.06 w / v% or less, based on the total amount of the composition. If the amount is within the above range, the effects of the present invention, including the effect of improving the corneal barrier function and the effect of improving foreign body sensation, can be sufficiently obtained. The total content of pranoprofen and / or a salt thereof in the ophthalmic composition is, for example, 0.05 w / v % or 0.1 w / v % based on the total amount of the composition.

[0014] Butyl group-containing phenol ((B) component) Butyl-group-containing phenols include, but are not limited to, dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), and the like. Of these, dibutylhydroxytoluene is preferred. The content of the butyl group-containing phenol in the ophthalmic composition is preferably 0.00005 w / v% or more, more preferably 0.0001 w / v% or more, even more preferably 0.0005 w / v% or more, even more preferably 0.001 w / v% or more, and particularly preferably 0.005 w / v% or more, based on the total amount of the composition. Within the above range, the effects of the present invention, including the effect of improving the corneal barrier function and the effect of improving foreign body sensation, can be sufficiently obtained, and the stability of pranoprofen and / or a salt thereof in the ophthalmic composition can be made sufficient for practical use. The content of the butyl group-containing phenol is preferably 1 w / v% or less, more preferably 0.1 w / v% or less, even more preferably 0.05 w / v% or less, even more preferably 0.01 w / v% or less, and particularly preferably 0.005 w / v% or less, based on the total amount of the composition. Within the above ranges, the effects of the present invention, including the effect of improving the corneal barrier function and the effect of improving foreign body sensation, can be sufficiently obtained.

[0015] The content of the butyl group-containing phenol in the ophthalmic composition is preferably 0.001 parts by weight or more, more preferably 0.01 parts by weight or more, even more preferably 0.05 parts by weight or more, and even more preferably 0.09 parts by weight or more, relative to 1 part by weight of pranoprofen and / or a salt thereof. Within the above range, the effects of the present invention, including the effect of improving the corneal barrier function and the effect of improving foreign body sensation, can be sufficiently obtained, and the stability of pranoprofen and / or a salt thereof in the ophthalmic composition can be made sufficient for practical use. The content of the butyl group-containing phenol is preferably 5 parts by weight or less, more preferably 1 part by weight or less, even more preferably 0.5 parts by weight or less, even more preferably 0.15 parts by weight or less, and particularly preferably 0.1 parts by weight or less, relative to 1 part by weight of pranoprofen and / or a salt thereof. Within the above range, the effects of the present invention, including the effect of improving the corneal barrier function and the effect of improving foreign body sensation, can be sufficiently obtained.

[0016] Tocopherols ((C) component) Component (C) of the ophthalmic composition of the present invention may be tocopherol, its derivatives, and / or salts thereof. Examples of tocopherol include α-tocopherol, β-tocopherol, γ-tocopherol, and δ-tocopherol. Examples of tocopherol derivatives include tocopherol acetate, tocopherol nicotinate, and tocopherol succinate. The salt of tocopherol or a derivative thereof may be any pharma- ceutically or physiologically acceptable salt, and examples thereof include salts with inorganic bases such as alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (calcium salt, magnesium salt, etc.), ammonium salts, and metal salts (aluminum salt, etc.); and salts with organic bases such as organic amine salts (methylamine salt, triethylamine salt, diethylamine salt, triethanolamine salt, morpholine salt, piperazine salt, pyrrolidine salt, tripyridine salt, picoline salt, etc.).

[0017] The total content of tocopherol, its derivatives, and / or their salts in the ophthalmic composition is preferably 0.001 w / v% or more, more preferably 0.005 w / v% or more, even more preferably 0.01 w / v% or more, and even more preferably 0.025 w / v% or more, based on the total amount of the composition. Furthermore, the total content of tocopherol, its derivatives, and / or their salts is preferably 1 w / v% or less, more preferably 0.5 w / v% or less, even more preferably 0.1 w / v% or less, and even more preferably 0.05 w / v% or less, based on the total amount of the composition. If the amount is within the above range, the effects of the present invention, including the effect of improving the corneal barrier function and the effect of improving foreign body sensation, can be sufficiently obtained.

[0018] The total content of tocopherol, its derivatives, and / or their salts in the ophthalmic composition is preferably 0.01 part by weight or more per 1 part by weight of the total content of pranoprofen and / or its salts, more preferably 0.1 part by weight or more, even more preferably 0.2 part by weight or more, and even more preferably 0.5 part by weight or more. In addition, the total content of tocopherol, its derivatives, and / or their salts is preferably 10 parts by weight or less, more preferably 5 parts by weight or less, even more preferably 1.5 parts by weight or less, and even more preferably 1 part by weight or less, per 1 part by weight of the total content of pranoprofen and / or its salts. If the amount is within the above range, the effects of the present invention, including the effect of improving the corneal barrier function and the effect of improving foreign body sensation, can be sufficiently obtained.

[0019] The total content of tocopherol, its derivatives, and / or their salts in the ophthalmic composition is preferably 0.01 parts by weight or more, more preferably 0.1 parts by weight or more, even more preferably 0.5 parts by weight or more, even more preferably 1 part by weight or more, and particularly preferably 10 parts by weight or more, per 1 part by weight of the butyl group-containing phenol. In addition, the total content of tocopherol, its derivatives, and / or their salts is preferably 500 parts by weight or less, more preferably 100 parts by weight or less, even more preferably 50 parts by weight or less, and even more preferably 10 parts by weight or less, per part by weight of the butyl group-containing phenol. If the amount is within the above range, the effects of the present invention, including the effect of improving the corneal barrier function and the effect of improving foreign body sensation, can be sufficiently obtained.

[0020] Pyridoxines ((C) component) Component (C) of the ophthalmic composition of the present invention may be pyridoxine and / or a salt thereof. Pyridoxine or a salt thereof may be any pharma- ceutical or physiologically acceptable salt, and examples thereof include hydrochloride salts.

[0021] The total content of pyridoxine, its derivatives, and / or their salts in the ophthalmic composition is preferably 0.001 w / v% or more, more preferably 0.01 w / v% or more, even more preferably 0.05 w / v% or more, and even more preferably 0.1 w / v% or more, based on the total amount of the composition. Furthermore, the total content of pyridoxine, its derivatives, and / or their salts is preferably 5 w / v% or less, more preferably 1 w / v% or less, even more preferably 0.5 w / v% or less, and even more preferably 0.1 w / v% or less, based on the total amount of the composition. If the amount is within the above range, the effects of the present invention, including the effect of improving the corneal barrier function and the effect of improving foreign body sensation, can be sufficiently obtained.

[0022] The total content of pyridoxine, its derivatives, and / or their salts in the ophthalmic composition is preferably 0.01 part by weight or more per 1 part by weight of the total content of pranoprofen and / or its salts, more preferably 0.1 part by weight or more, even more preferably 0.2 part by weight or more, and even more preferably 1 part by weight or more. In addition, the total content of pyridoxine, its derivatives, and / or their salts is preferably 10 parts by weight or less, more preferably 5 parts by weight or less, even more preferably 3 parts by weight or less, and even more preferably 2 parts by weight or less, per 1 part by weight of the total content of pranoprofen and / or its salts. If the amount is within the above range, the effects of the present invention, including the effect of improving the corneal barrier function and the effect of improving foreign body sensation, can be sufficiently obtained.

[0023] The total content of pyridoxine, its derivatives, and / or their salts in the ophthalmic composition is preferably 0.01 parts by weight or more, more preferably 0.1 parts by weight or more, even more preferably 1 part by weight or more, and even more preferably 10 parts by weight or more, per 1 part by weight of the butyl group-containing phenol. In addition, the total content of pyridoxine, its derivatives, and / or their salts is preferably 500 parts by weight or less, more preferably 100 parts by weight or less, even more preferably 50 parts by weight or less, and even more preferably 20 parts by weight or less, per 1 part by weight of the butyl group-containing phenol. If the amount is within the above range, the effects of the present invention, including the effect of improving the corneal barrier function and the effect of improving foreign body sensation, can be sufficiently obtained.

[0024] Chondroitin sulfate ((C) component) Component (C) of the ophthalmic composition of the present invention may be chondroitin sulfate, a derivative thereof, and / or a salt thereof. Chondroitin sulfate is a sugar chain in which D-glucuronic acid and N-acetylglucosamine are repeated, with sulfate bonded to all or some of the hydroxyl groups via ester bonds. The positions and number of sulfate bonds vary, and some N-acetylglucosamines are replaced by iduronic acid. The chondroitin sulfate used in the present invention may have any structure. Examples include chondroitin 4-sulfate (chondroitin sulfate A), chondroitin 6-sulfate (chondroitin sulfate C), and chondroitin sulfate E in which the 4- and 6-positions of N-acetylglucosamine are sulfated. Chondroitin sulfate may also be extracted from animals. The salt of chondroitin sulfate may be any pharma- ceutically or physiologically acceptable salt, and examples thereof include salts with inorganic bases such as alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (calcium salt, magnesium salt, etc.), ammonium salts, and metal salts (aluminum salt, etc.), and salts with organic bases such as organic amine salts (methylamine salt, triethylamine salt, diethylamine salt, triethanolamine salt, morpholine salt, piperazine salt, pyrrolidine salt, tripyridine salt, picoline salt, etc.). Preferred are alkali metal salts, and more preferred is sodium chondroitin sulfate, and among these, sodium chondroitin sulfate listed in the Japanese Pharmacopoeia Non-Prescribed Pharmaceutical Standards 2002 can be mentioned.

[0025] The total content of chondroitin sulfate, its derivatives, and / or their salts in the ophthalmic composition is preferably 0.001 w / v% or more, more preferably 0.01 w / v% or more, even more preferably 0.05 w / v% or more, even more preferably 0.1 w / v% or more, and even more preferably 0.5 w / v% or more, based on the total amount of the composition. In addition, the total content of chondroitin sulfate, its derivatives, and / or their salts is preferably 5 w / v% or less, more preferably 1 w / v% or less, even more preferably 0.7 w / v% or less, and even more preferably 0.5 w / v% or less, based on the total amount of the composition. If the amount is within the above range, the effects of the present invention, including the effect of improving the corneal barrier function and the effect of improving foreign body sensation, can be sufficiently obtained.

[0026] The total content of chondroitin sulfate, its derivatives, and / or their salts in the ophthalmic composition is preferably 0.1 parts by weight or more per 1 part by weight of the total content of pranoprofen and / or its salts, more preferably 1 part by weight or more, even more preferably 2 parts by weight or more, and even more preferably 9 parts by weight or more. In addition, the total content of chondroitin sulfate, its derivatives, and / or their salts is preferably 100 parts by weight or less, more preferably 50 parts by weight or less, even more preferably 20 parts by weight or less, and even more preferably 10 parts by weight or less, per 1 part by weight of the total content of pranoprofen and / or its salts. If the amount is within the above range, the effects of the present invention, including the effect of improving the corneal barrier function and the effect of improving foreign body sensation, can be sufficiently obtained.

[0027] The total content of chondroitin sulfate, its derivatives, and / or their salts in the ophthalmic composition is preferably 1 part by weight or more, more preferably 5 parts by weight or more, even more preferably 10 parts by weight or more, and even more preferably 60 parts by weight or more, per 1 part by weight of the butyl group-containing phenol. In addition, the total content of chondroitin sulfate, its derivatives, and / or their salts is preferably 5,000 parts by weight or less, more preferably 1,000 parts by weight or less, even more preferably 500 parts by weight or less, and even more preferably 100 parts by weight or less, per 1 part by weight of butyl group-containing phenol. If the amount is within the above range, the effects of the present invention, including the effect of improving the corneal barrier function and the effect of improving foreign body sensation, can be sufficiently obtained.

[0028] Total content of (C) component The total content of the (C) component in the ophthalmic composition is preferably 0.0001 w / v% or more, more preferably 0.001 w / v% or more, even more preferably 0.05 w / v% or more, and even more preferably 0.25 w / v% or more, based on the total amount of the composition. Furthermore, the total content of the (C) component is preferably 5 w / v% or less, more preferably 2 w / v% or less, even more preferably 1 w / v% or less, and even more preferably 0.7 w / v% or less, based on the total amount of the composition. If the amount is within the above range, the effects of the present invention, including the effect of improving the corneal barrier function and the effect of improving foreign body sensation, can be sufficiently obtained.

[0029] The total content of component (C) in the ophthalmic composition is preferably 0.01 part by weight or more per 1 part by weight of the total content of pranoprofen and / or its salt, more preferably 0.1 part by weight or more, even more preferably 0.2 part by weight or more, and even more preferably 1 part by weight or more. In addition, the total content of component (C) is preferably 500 parts by weight or less, more preferably 50 parts by weight or less, even more preferably 20 parts by weight or less, and even more preferably 15 parts by weight or less, per part by weight of the total content of pranoprofen and / or a salt thereof. If the amount is within the above range, the effects of the present invention, including the effect of improving the corneal barrier function and the effect of improving foreign body sensation, can be sufficiently obtained.

[0030] The total content of the (C) component in the ophthalmic composition is preferably 0.01 part by weight or more, more preferably 0.1 part by weight or more, even more preferably 0.5 part by weight or more, and even more preferably 1 part by weight or more, per 1 part by weight of the butyl group-containing phenol. The total content of the component (C) is preferably 1000 parts by weight or less, more preferably 500 parts by weight or less, even more preferably 200 parts by weight or less, and even more preferably 150 parts by weight or less, per part by weight of the butyl group-containing phenol. If the amount is within the above range, the effects of the present invention, including the effect of improving the corneal barrier function and the effect of improving foreign body sensation, can be sufficiently obtained.

[0031] The component (C) can use one type alone, or two or more types in combination. When two or more types are used in combination, two or three of the three series of components (i) to (iii) of component (C) ((i) tocopherol, its derivatives, and salts thereof, (ii) pyridoxine, its derivatives, and salts thereof, and (iii) chondroitin sulfate, its derivatives, and salts thereof) can be used. It is also possible to use two or more compounds encompassed within one series of components.

[0032] Formulation The properties of the ophthalmic composition are not particularly limited, and may be any of liquid, fluid, gel, and semi-solid, for example. Also included are those that are liquid, fluid, gel, or semi-solid when prepared just before use. The semi-solid state refers to a state that has plasticity that can be deformed by applying force, such as an ointment.

[0033] In addition, the ophthalmic composition may be an aqueous composition (mainly containing an aqueous or hydrophilic base or carrier) or an oil-based composition (mainly containing an oil-based or hydrophobic base or carrier). In the case of an aqueous composition, the content of water is preferably 50% by weight or more, more preferably 75% by weight or more, and even more preferably 90% by weight or more, based on the total amount of the formulation. It may also be 95% by weight or more, or 98% by weight or more. The base or carrier may consist of only water. In the case of an oil-based composition, the water content is preferably less than 50% by weight, more preferably 30% by weight or less, and even more preferably 20% by weight or less, based on the total weight of the formulation. The ophthalmic composition of the present invention is preferably an aqueous composition.

[0034] The dosage form of the ophthalmic composition of the present invention is not particularly limited, and examples thereof include eye drops (also called eye drops or eye drops. Eye drops include eye drops that can be applied while wearing contact lenses), eye washes, eye ointments (water-soluble eye ointments, oil-soluble eye ointments), contact lens wetting solutions, intraocular injections (e.g., intravitreal injections), contact lens solutions (cleaning solutions, storage solutions, disinfectants, multipurpose solutions, packaged solutions), preservatives for excised eye tissues such as corneas for transplantation, irrigation solutions for surgery, etc. Eye drops, eye washes, and eye ointments also include those used when wearing contact lenses. It should be noted that the term "contact lenses" includes hard contact lenses and soft contact lenses (including both ionic and non-ionic, and both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses). Preferred dosage forms of the ophthalmic composition of the present invention include eye drops, eye wash, eye ointment (water-soluble eye ointment, oil-soluble eye ointment), contact lens wearing solution, contact lens solution (cleaning solution, storage solution, disinfectant, multi-purpose solution, packaging solution), etc., more preferred are eye drops, eye wash, contact lens wearing solution, contact lens solution (cleaning solution, storage solution, disinfectant, multi-purpose solution), etc., even more preferred are eye drops and eye wash, and particularly preferred are eye drops. However, the ophthalmic composition of the present invention may exclude ophthalmic compositions (particularly, eye drops, eye washes, or eye ointments) that are applied when wearing or placing contact lenses (hard contact lenses, soft contact lenses, especially silicone hydrogel contact lenses).

[0035] The ophthalmic composition of the present invention may be in the form of a single-use unit dose or a multi-dose that can be used repeatedly, but is preferably stored and used in the form of a multi-dose because of its excellent preservative effectiveness.

[0036] The ophthalmic composition of the present invention can be prepared by mixing the above-mentioned components (A), (B), and (C) with a pharma- ceutically acceptable base or carrier, and, if necessary, with pharma- ceutically acceptable additives for the ophthalmic composition and other active ingredients, in a conventional manner, for example, as described in the 16th Edition of the Japanese Pharmacopoeia.

[0037] Base or carrier Examples of the base or carrier include water, polar solvents such as ethanol, oily bases, etc. The base or carrier may be used alone or in combination of two or more.

[0038] Additive Examples of additives include nonionic surfactants, preservatives, buffers, pH adjusters, isotonicity agents, thickeners or viscosifiers, stabilizers, oils, sugars, polymeric compounds, polyhydric alcohols, inorganic salts, refreshing agents, and antioxidants. The additives may be used alone or in combination of two or more. Furthermore, each additive may be used alone or in combination of two or more.

[0039] Specific examples of the additives are given below.

[0040] <Nonionic surfactant> The ophthalmic composition of the present invention preferably contains a nonionic surfactant. Nonionic surfactants include POE sorbitan fatty acid esters such as POE(20) sorbitan monolaurate (polysorbate 20), POE(20) sorbitan monopalmitate (polysorbate 40), POE(20) sorbitan monostearate (polysorbate 60), POE(20) sorbitan tristearate (polysorbate 65), and POE(20) sorbitan monooleate (polysorbate 80); poloxamer 407, poloxamer 235, poloxamer 188, poloxamer 403, poloxamer 501, poloxamer 502, poloxamer 503, poloxamer 504, poloxamer 505, poloxamer 506, poloxamer 507, poloxamer 508, poloxamer 509, poloxamer 510, poloxamer 511, poloxamer 512, poloxamer 513, poloxamer 514, poloxamer 515, poloxamer 516, poloxamer 517, poloxamer 518, poloxamer 519, poloxamer 520, poloxamer 521, poloxamer 522, poloxamer 523, poloxamer 524, poloxamer 525, poloxamer 526, poloxamer 527, poloxamer 528, poloxamer 529, poloxamer 530, poloxamer 531, poloxamer 532, poloxamer 533, poloxamer 53 POE·POP glycols such as Poloxamer 237 and Poloxamer 124;POE hydrogenated castor oils such as POE hydrogenated castor oil 40, POE hydrogenated castor oil 50, POE hydrogenated castor oil 60 and POE hydrogenated castor oil 80;POE castor oils such as POE castor oil 3, POE castor oil 4, POE castor oil 6, POE castor oil 7, POE castor oil 10, POE castor oil 13.5, POE castor oil 17, POE castor oil 20, POE castor oil 25, POE castor oil 30, POE castor oil 35 and POE castor oil 50;Polyethylene monostearate Recall (2 E.O.), polyethylene glycol monostearate (4 E.O.), polyethylene glycol monostearate (9 E.O.), polyethylene glycol monostearate (10 E.O.), polyethylene glycol monostearate (23 E.O.), polyethylene glycol monostearate (25 E.O.), polyethylene glycol monostearate (32 E.O.), polyethylene glycol monostearate (40 E.O., Polyoxyl 40 stearate), polyethylene glycol monostearate Examples of the polyethylene glycol monostearate include polyethylene glycol monostearate (45 E.O.), polyethylene glycol monostearate (55 E.O.), polyethylene glycol monostearate (75 E.O.), and polyethylene glycol monostearate (140 E.O.); POE alkyl ethers such as POE(9) lauryl ether; POE-POP alkyl ethers such as POE(20)POP(4) cetyl ether; and POE alkyl phenyl ethers such as POE(10) nonylphenyl ether. In the above-listed compounds, POE stands for polyoxyethylene, POP stands for polyoxypropylene, and the numbers in parentheses stand for the number of moles added.

[0041] Among these, POE sorbitan fatty acid esters; POE·POP glycols; POE hydrogenated castor oil; POE castor oil, and polyethylene glycol monostearate are preferred, with polysorbate 80, poloxamer 407, POE hydrogenated castor oil 40, POE hydrogenated castor oil 60, POE castor oil 3, POE castor oil 10, POE castor oil 35, and polyoxyl 40 stearate being more preferred, with polysorbate 80 and POE hydrogenated castor oil 60 being even more preferred, and polysorbate 80 being particularly preferred.

[0042] When a nonionic surfactant is blended in the ophthalmic composition of the present invention, an example of the blending amount of the nonionic surfactant is 0.001 w / v% or more, preferably 0.005 w / v% or more, preferably 0.01 w / v% or more, preferably 0.05 w / v% or more, based on the total amount of the ophthalmic composition. Also, the total amount of the nonionic surfactant is 5 w / v% or less, preferably 1 w / v% or less, preferably 0.5 w / v% or less, preferably 0.3 w / v% or less, based on the total amount of the ophthalmic composition.

[0043] <Preservative> Examples of preservatives include polydonium chloride, alkyl polyaminoethyl glycines (e.g., alkyl diaminoethyl glycine hydrochloride, etc.), sodium benzoate, ethanol, quaternary ammonium salts (e.g., benzalkonium chloride, benzethonium chloride, etc.), chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, paraoxybenzoic acid esters (e.g., methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, etc.), oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (e.g., polyhexanide hydrochloride, etc.), and Glokill (manufactured by Rhodia). Among these, alkyl polyaminoethyl glycines (e.g., alkyl diaminoethyl glycine hydrochloride), sodium benzoate, ethanol, quaternary ammonium salts, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, paraoxybenzoic acid esters, and biguanide compounds are preferred, with quaternary ammonium salts, chlorhexidine gluconate, chlorobutanol, and biguanide compounds being more preferred, and benzalkonium chloride and polyhexanide hydrochloride being even more preferred.

[0044] When a preservative is blended in the ophthalmic composition of the present invention, an example of the blending amount of the preservative is 0.000001 w / v% or more, preferably 0.00001 w / v% or more, preferably 0.00005 w / v% or more, preferably 0.001 w / v% or more, preferably 0.005 w / v% or more, in terms of the total amount of the preservative, relative to the total amount of the ophthalmic composition. Also, the total amount of the preservative is 1 w / v% or less, preferably 0.1 w / v% or less, preferably 0.05 w / v% or less, preferably 0.02 w / v% or less, preferably 0.01 w / v% or less, in terms of the total amount of the preservative, relative to the total amount of the ophthalmic composition.

[0045] <Buffer> The ophthalmic composition of the present invention preferably comprises a buffering agent. Examples of the buffer include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, acetate buffer and the like. The components of the borate buffer include boric acid, borate salts (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.), etc. The borate salts may be hydrates. Examples of components of phosphate buffers include phosphoric acid and phosphates (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, calcium dihydrogen phosphate, etc.). The phosphates may be hydrates. Examples of components of the carbonate buffer include carbonic acid, carbonates (potassium carbonate, sodium carbonate, calcium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, magnesium carbonate, etc.) The carbonates may be hydrates. Components of the citrate buffer include citric acid, citrate salts (sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, etc.), etc. The citrate salts may be hydrates. The components of the acetate buffer include acetic acid, acetate salts (ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.), etc. The acetate salts may be hydrates. Among them, boric acid buffers and phosphate buffers are preferred, and boric acid buffers are more preferred. As the boric acid buffer, a combination of boric acid and its salts is preferred, a combination of boric acid and an alkali metal salt and / or an alkaline earth metal salt of boric acid is more preferred, a combination of boric acid and an alkali metal salt of boric acid is even more preferred, and a combination of boric acid and borax is even more preferred.

[0046] When a buffer is added to the ophthalmic composition of the present invention, the amount of the buffer varies depending on the type of the buffer and the types and amounts of other ingredients, and cannot be uniformly specified, but examples of the buffer amount include a total amount of 0.001 w / v% or more, particularly 0.01 w / v% or more, particularly 0.05 w / v% or more, particularly 0.1 w / v% or more, based on the total amount of the ophthalmic composition. Also, the buffer amount is 10 w / v% or less, particularly 5 w / v% or less, particularly 3 w / v% or less, particularly 2 w / v% or less, based on the total amount of the ophthalmic composition.

[0047] <pH adjuster> Examples of pH adjusters include hydrochloric acid, sulfuric acid, polyphosphoric acid, organic acids (propionic acid, oxalic acid, gluconic acid, fumaric acid, lactic acid, tartaric acid, malic acid, succinic acid, etc.), sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, and diisopropanolamine.

[0048] <Isotonic agent> Examples of isotonicity agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, potassium acetate, sodium acetate, magnesium sulfate, glycerin, and propylene glycol.

[0049] <Thickening agent or viscosifying agent> The ophthalmic composition of the present invention can contain a thickening agent or a viscosifying agent other than chondroitin sulfate, a derivative thereof, or a salt thereof, as long as the effect of the present invention is not impaired. Examples of thickening agents or viscosifying agents include guar gum, hydroxypropyl guar gum, cellulose-based polymer compounds (e.g., methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, etc.), gum arabic, karaya gum, xanthan gum, agar, alginic acid, α-cyclodextrin, dextrin, dextran, mucopolysaccharides (e.g., heparinoids, heparin, heparin sulfate, heparan sulfate, heparinoid, hyaluronic acid, hyaluronate (sodium salt, etc.), etc.), starch, chitin and derivatives thereof, chitosan and derivatives thereof, carrageenan, sorbitol, polyvinyl chloride, polyvinyl alcohol ... Examples of the polyacrylic acid include vinyl polymer compounds (polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl methacrylate, carboxyvinyl polymer, etc.), alkali metal salts of polyacrylic acid (sodium salt, potassium salt, etc.), amine salts of polyacrylic acid (monoethanolamine salt, diethanolamine salt, triethanolamine salt, etc.), casein, gelatin, collagen, pectin, elastin, ceramide, liquid paraffin, glycerin, polyethylene glycol, macrogol, polyethyleneimine alginate (sodium salt, etc.), alginate esters (propylene glycol ester, etc.), powdered tragacanth, and triisopropanolamine.

[0050] <Stabilizer> Stabilizers include trometamol, sodium formaldehyde sulfoxylate (Rongalit), monoethanolamine, aluminum monostearate, and glyceryl monostearate.

[0051] <Oil component> Examples of oils include animal oils such as squalane and refined lanolin, mineral oils such as liquid paraffin and white petrolatum, and vegetable oils such as castor oil and sesame oil.

[0052] <Sugars> Examples of sugars include monosaccharides and disaccharides, specifically glucose, maltose, trehalose, sucrose, cyclodextrin, xylitol, sorbitol, and mannitol.

[0053] <Polyhydric alcohols> Examples of the polyhydric alcohol include polyethylene glycol, glycerin, propylene glycol, xylitol, diethylene glycol, mannitol, sorbitol, and polyvinyl alcohol.

[0054] <Inorganic salts> Inorganic salts include, but are not limited to, potassium chloride, sodium chloride, calcium chloride, magnesium chloride, sodium bicarbonate, sodium carbonate (including dry sodium carbonate), potassium bicarbonate, potassium carbonate, magnesium sulfate, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium bisulfite, sodium sulfite, potassium acetate, sodium acetate, sodium thiosulfate, and the like. Among these, potassium chloride, sodium chloride, calcium chloride, sodium hydrogen carbonate, sodium carbonate (including dry sodium carbonate), magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, and potassium dihydrogen phosphate are preferred, potassium chloride, sodium chloride, calcium chloride, sodium hydrogen phosphate, and sodium dihydrogen phosphate are more preferred, and potassium chloride and sodium chloride are even more preferred.

[0055] <Cooling agent> Examples of the cooling agent include terpenoids such as menthol, anethole, eugenol, camphor, geraniol, cineol, borneol, limonene, and rhubarb. These may be in the d-, l-, or dl-form. These may be in the d-, l-, or dl-form. In addition, examples of the cooling agent include essential oils such as peppermint oil, cool mint oil, spearmint oil, peppermint oil, fennel oil, cinnamon oil, bergamot oil, eucalyptus oil, and rose oil.

[0056] <Antioxidant> The ophthalmic composition of the present invention may contain an antioxidant other than the butyl group-containing phenol, provided that the effect of the present invention is not impaired. Lipid-soluble antioxidants include nordihydroguaiaretic acid (NDGA); ascorbyl palmitate, ascorbyl stearate, aminopropyl ascorbyl phosphate, tocopherol ascorbyl phosphate, ascorbyl triphosphate, and ascorbyl phosphate palmitate; gallic acid esters, such as ethyl gallate, propyl gallate, octyl gallate, and dodecyl gallate; propyl gallate; 3-Butyl-4-hydroxyquinolin-2-one; carotenoids such as lutein and astaxanthin; polyphenols such as anthocyanins, catechins, tannins, and curcumin; retinol, retinol esters (retinol acetate, retinol propionate, retinol butyrate, retinol octylate, retinol laurate, retinol stearate, retinol myristate, retinol oleate, retinol linolenate, retinol linoleate, and retinol palmitate), retinal, and retinal esters Vitamin A derivatives such as vitamin A (retinal acetate, retinal propionate, retinal palmitate, etc.), retinoic acid, retinoic acid esters (methyl retinoate, ethyl retinoate, retinol retinoate, tocopherol retinoate, etc.), retinol dehydrogenase, retinal dehydrogenase, retinoic acid dehydrogenase, provitamin A (α-carotene, β-carotene, γ-carotene, δ-carotene, lycopene, zeaxanthin, β-cryptoxanthin, echinenone, etc.), vitamin A; CoQ10, etc. Examples of water-soluble antioxidants include ascorbic acid, ascorbic acid derivatives (such as disodium ascorbic acid 2-sulfate, sodium ascorbate, magnesium ascorbyl 2-phosphate, and sodium ascorbyl 2-phosphate), sodium hydrogen sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, and edetic acid or salts thereof (such as disodium edetate and tetrasodium edetate).

[0057] The ophthalmic composition of the present invention preferably contains edetic acid or a salt thereof. When the ophthalmic composition of the present application contains edetic acid and / or a salt thereof, the total content of edetic acid and / or a salt thereof in the ophthalmic composition can be preferably 0.0001 w / v% or more, more preferably 0.001 w / v% or more, and even more preferably 0.01 w / v% or more, based on the total amount of the composition. Also, for example, it can be 0.5 w / v% or less, 0.1 w / v% or less, or 0.05 w / v% or less.

[0058] Other pharmacologically active ingredients or physiologically active ingredients The ophthalmic composition of the present invention may contain, in addition to the above-mentioned components (A), (B), and (C), components having pharmacological activity or physiological activity. The pharmacologically active ingredient or physiologically active ingredient can be used alone or in combination of two or more. Examples of such pharmacologically active ingredients and physiologically active ingredients include active ingredients in various medicines listed in the 2012 edition of the General Drug Manufacturing and Sales Approval Standards (supervised by the Japan Society of Regulatory Science). Examples include congestion relief ingredients, ocular muscle regulating ingredients, anti-inflammatory ingredients, astringent ingredients, antihistamine ingredients or antiallergic ingredients, vitamins, amino acids, antibacterial agents or germicides, local anesthetic ingredients, and analgesics. Specific examples of these drugs are given below.

[0059] <Decongestant component (vasoconstrictor)> The ophthalmic composition of the present invention preferably contains a congestion relief component, whereby the effects of the present invention are more pronounced. Examples of congestion relief components include α-adrenergic agonists, specifically imidazoline congestion relief components such as oxymetazoline, tetrahydrozoline, naphazoline, or salts thereof such as hydrochlorides and nitrates, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, epinephrine bitartrate, etc. These may be in the d-, l- or dl-form. Among the vasoconstrictor components, imidazoline-based vasoconstrictor components are preferred, and tetrahydrozoline or a salt thereof is more preferred.

[0060] To explain the imidazoline vasoconstrictor in detail, the salt of the imidazoline vasoconstrictor may be any pharma- ceutically or physiologically acceptable salt, and examples of such salts include organic acid salts such as maleates and fumarates, inorganic acid salts such as hydrochlorides and sulfates, and metal salts. Among the salts, inorganic acid salts are preferred, hydrochlorides or nitrates are more preferred, and hydrochlorides (e.g., tetrahydrozoline hydrochloride) are particularly preferred.

[0061] When the ophthalmic composition of the present invention contains an imidazoline vasoconstrictor, the total content of the imidazoline vasoconstrictor in the ophthalmic composition can be preferably 0.0001 w / v% or more, more preferably 0.0005 w / v% or more, and even more preferably 0.001 w / v% or more, based on the total amount of the composition. Also, for example, it can be 0.5 w / v% or less, 0.1 w / v% or less, or 0.05 w / v% or less.

[0062] When the ophthalmic composition of the present application contains tetrahydrozoline and / or a salt thereof, the total content of tetrahydrozoline and / or a salt thereof in the ophthalmic composition can be preferably 0.001 w / v% or more, more preferably 0.01 w / v% or more, and even more preferably 0.025 w / v% or more, based on the total amount of the composition. Also, for example, it can be 0.5 w / v% or less, 0.1 w / v% or less, or 0.05 w / v% or less. The total content of tetrahydrozoline and / or a salt thereof is particularly preferably 0.05 w / v %.

[0063] <Ocular muscle regulator component> Examples of the ocular muscle regulating drug component include cholinesterase inhibitors having an active center similar to that of acetylcholine, specifically neostigmine methylsulfate, tropicamide, helenien, and atropine sulfate.

[0064] <Anti-inflammatory drug component> The ophthalmic composition of the present invention may contain an anti-inflammatory drug component other than pranoprofen or a salt thereof, provided that the effect of the present invention is not impaired. Examples of such anti-inflammatory or astringent ingredients include zinc sulfate, zinc lactate, allantoin, indomethacin, lysozyme chloride, silver nitrate, sodium azulene sulfonate, glycyrrhizinic acid or its salts (dipotassium glycyrrhizinate, diammonium glycyrrhizinate, etc.), diclofenac sodium, bromfenac sodium, berberine chloride, and berberine sulfate. In the case where glycyrrhizinic acid and / or a salt thereof is contained, the total content of glycyrrhizinic acid and / or a salt thereof in the ophthalmic composition of the present application is preferably 0.001 w / v% or more, more preferably 0.01 w / v% or more, and even more preferably 0.05 w / v% or more, based on the total amount of the composition. It can also be, for example, 1 w / v% or less, 0.5 w / v% or less, or 0.25 w / v% or less.

[0065] The ophthalmic composition of the present invention may contain no anti-inflammatory drug components other than pranoprofen or a salt thereof, which may improve the effect of the present invention.

[0066] <Antihistamine drug component or anti-allergy drug component> Examples of antihistamines (histamine receptor antagonists) include diphenhydramine or a salt thereof such as its hydrochloride, chlorpheniramine or a salt thereof such as its maleate, and levocabastine or a salt thereof such as its hydrochloride. In addition, examples of antiallergic drug components that exhibit an antiallergic effect by inhibiting the release of chemical mediators include cromoglycic acid or salts such as its sodium salt, tranilast, ibudilast, ashitazanolast, tazanolast, suplatast or salts such as its tosylate salt, and pemirolast or salts such as its potassium salt. In addition, examples of antihistamine drug components that antagonize histamine receptors and exhibit antiallergic effects by inhibiting the release of chemical mediators include olopatadine, ketotifen fumarate, amlexanox, and oxatomide. However, the ophthalmic composition of the present invention preferably does not contain an antiallergic drug component that exerts an antiallergic effect by inhibiting the release of chemical mediators (particularly, tranilast, pemirolast, or a salt thereof such as a potassium salt) and / or an antihistamine drug component that inhibits the release of chemical mediators (particularly, olopatadine or a salt thereof such as a hydrochloride), because the addition of these ingredients to the composition of the present invention may cause an unpleasant irritating sensation.

[0067] The ophthalmic composition of the present invention preferably contains an antihistamine other than an antihistamine having an action of inhibiting the release of chemical mediators, whereby the effect of the present invention is more pronounced. Among them, to explain chlorpheniramine and / or its salts in detail, the salt of chlorpheniramine may be any pharma- ceutically or physiologically acceptable salt, and examples thereof include organic acid salts such as maleate and fumarate, inorganic acid salts such as hydrochloride and sulfate, metal salts, etc. Among the salts, organic acid salts are preferred, and maleate is particularly preferred. Chlorpheniramine and its salts may be in the form of a hydrate, and may be in any of the d-, l- or dl-forms. Chlorpheniramine and its salts can be used alone or in combination of two or more. Among chlorpheniramine and / or its salts, chlorpheniramine maleate is most preferred.

[0068] When the ophthalmic composition of the present application contains chlorpheniramine and / or a salt thereof, the total content of chlorpheniramine and / or a salt thereof in the ophthalmic composition can be, based on the total amount of the composition, preferably 0.02 w / v% or more, more preferably 0.025 w / v% or more, and even more preferably 0.03 w / v% or more. Also, based on the total amount of the composition, the total content can be, for example, 1 w / v% or less, 0.1 w / v% or less, 0.05 w / v% or less, or 0.04 w / v% or less. The total content of chlorpheniramine and / or a salt thereof is particularly preferably 0.03 w / v %.

[0069] <Vitamins> The ophthalmic composition of the present invention may contain vitamins other than tocopherol, pyridoxine, derivatives thereof, or salts thereof, as long as the effects of the present invention are not impaired. Such vitamins include, for example, retinol acetate, retinol palmitate, sodium flavin adenine dinucleotide, pyridoxal phosphate, cyanocobalamin, panthenol, calcium pantothenate, sodium pantothenate, and ubiquinone derivatives.

[0070] <Amino acids> The ophthalmic composition of the present invention preferably contains amino acids other than chondroitin sulfate, its derivatives, or salts thereof, whereby the effects of the present invention are more pronounced. Examples of amino acids include aminoethylsulfonic acid (taurine), aspartic acid or its salts (sodium aspartate, potassium aspartate, magnesium aspartate, a mixture of magnesium and potassium aspartate, etc.), glutamic acid or its salts (sodium glutamate, magnesium glutamate, etc.), creatinine, epsilon-aminocaproic acid, glycine, alanine, arginine, lysine, γ-aminobutyric acid, γ-aminovaleric acid, etc. These may be in the d-, l- or dl-form. Among these, aminoethylsulfonic acid, aspartic acid or a salt thereof (potassium aspartate, magnesium aspartate, a mixture of magnesium and potassium aspartate, etc.), and epsilon-aminocaproic acid are preferred, and aminoethylsulfonic acid, aspartic acid or a salt thereof (potassium aspartate, magnesium aspartate, a mixture of magnesium and potassium aspartate, etc.) are more preferred.

[0071] When an amino acid is blended in the ophthalmic composition of the present invention, an example of the blending amount is, for example, 0.01 w / v% or more, preferably 0.05 w / v% or more, preferably 0.1 w / v% or more, preferably 0.3 w / v% or more, based on the total amount of the ophthalmic composition. Also, the total amount of the amino acid is 10 w / v% or less, preferably 5 w / v% or less, preferably 1 w / v% or less, based on the total amount of the ophthalmic composition.

[0072] <Antibacterial drug component or bactericidal drug component> Examples of the antibacterial or bactericidal component include sulfa drugs such as sulfamethoxazole, sulfisoxazole, sulfamethoxazole sodium, sulfisoxazole diethanolamine, sulfisoxazole monoethanolamine, sulfisomazole sodium, and sulfisomidine sodium, chloramphenicol, ofloxacin, norfloxacin, levofloxacin, lomefloxacin hydrochloride, and acyclovir. However, the ophthalmic compositions of the present invention may be free of sulfa drugs. <Local anesthetic drug component> Examples of local anesthetic ingredients include procaine hydrochloride and lidocaine hydrochloride. <Anesthetic agent> Analgesics include procaine hydrochloride.

[0073] pH The pH of the ophthalmic composition of the present invention is preferably 3 or more, more preferably 4 or more, even more preferably 5 or more, and even more preferably 6 or more. Also, it is preferably 10 or less, more preferably 9 or less, even more preferably 8.5 or less, and even more preferably 8 or less. If it is within the above range, eye irritation is suppressed and the above-mentioned effects of the present invention can be obtained.

[0074] Osmotic pressure The osmotic pressure ratio of the ophthalmic composition of the present invention is preferably 0.4 or more, more preferably 0.6 or more, and even more preferably 0.8 or more. It is also preferably 5 or less, more preferably 3 or less, and even more preferably 2 or less. If it is within the above range, eye irritation is suppressed and the above-mentioned effects of the present invention can be obtained. The osmotic pressure ratio is the ratio of the osmotic pressure of the sample to the osmotic pressure of 286 mOsm (0.9 w / v% sodium chloride aqueous solution) based on the 16th revised Japanese Pharmacopoeia. The osmotic pressure is measured according to the osmotic pressure measurement method (freezing point depression method) described in the 16th revised Japanese Pharmacopoeia. The standard solution for measuring the osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution) is prepared by drying sodium chloride (Japanese Pharmacopoeia standard reagent) at 500-650°C for 40-50 minutes, cooling it in a desiccator (silica gel), accurately weighing 0.900 g of it, dissolving it in purified water to make exactly 100 mL, or by using a commercially available standard solution for measuring the osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution).

[0075] Container The container refers to a packaging body having a surface that comes into contact with the formulation, such as the container body portion that contains the liquid, the portion including the container's extraction port (nozzle, inner plug), the suction tube, and the cap. The material constituting the container for housing the ophthalmic composition of the present invention can be selected from a wide range of materials. For example, there may be mentioned a container in which at least a part or all of the surface that comes into contact with the ophthalmic composition is made of at least one material selected from the group consisting of plastic (e.g., polyolefin, acrylic resin, terephthalic acid ester, 2,6-naphthalenedicarboxylic acid ester, polycarbonate, polymethylpentene, fluororesin, polyvinyl chloride, polyamide, ABS resin, AS resin, polyacetal, modified polyphenylene ether, polyarylate, polysulfone, polyimide, cellulose acetate, hydrocarbons which may be substituted with halogen atoms, etc.), metal (e.g., aluminum), and glass.

[0076] Polyolefins include polyethylene (including high density polyethylene, low density polyethylene, very low density polyethylene, linear low density polyethylene, ultra high molecular weight polyethylene, etc.), polypropylene (including isotactic polypropylene, syndiotactic polypropylene, atactic polypropylene, etc.), and ethylene-propylene copolymers.

[0077] Examples of the acrylic acid resin include acrylic acid esters such as methyl acrylate, and methacrylic acid esters such as methyl methacrylate, cyclohexyl methacrylate, and t-butylcyclohexyl methacrylate.

[0078] Examples of the terephthalic acid ester include polyethylene terephthalate, polytrimethylene terephthalate, and polybutylene terephthalate.

[0079] Examples of 2,6-naphthalenedicarboxylic acid esters include polyethylene naphthalate and polybutylene naphthalate.

[0080] Examples of fluororesin include fluorine-substituted polyethylene (polytetrafluoroethylene, polychlorotrifluoroethylene, etc.), polyvinylidene fluoride, polyvinyl fluoride, perfluoroalkoxy fluororesin, tetrafluoroethylene-hexafluoropropylene copolymer, ethylene-tetrafluoroethylene copolymer, and ethylene-chlorotrifluoroethylene copolymer.

[0081] The polyamide includes nylon.

[0082] The polyacetal may be one consisting only of oxymethylene units, or one partially containing oxyethylene units.

[0083] The modified polyphenylene ether may, for example, be polystyrene-modified polyphenylene ether.

[0084] The polyarylate may be, for example, amorphous polyarylate.

[0085] The polyimide may be an aromatic polyimide, for example, a polymer of pyromellitic dianhydride and 4,4'-diaminodiphenyl ether.

[0086] Examples of the cellulose acetate include cellulose diacetate and cellulose triacetate. The container for housing the ophthalmic composition of the present invention is preferably made of polyolefin or terephthalic acid ester, more preferably terephthalic acid ester, further preferably polyethylene terephthalate or polybutylene terephthalate, and even more preferably polyethylene terephthalate. The container for storing the ophthalmic composition of the present invention may be made of a blended polymer with a polymer other than the above polymer. When the container material for storing the ophthalmic composition of the present invention is a blended polymer with the above polymer, the mixing ratio of the above polymer to the polymer other than the above polymer is not particularly limited as long as the effects of the present invention are achieved, but the total weight of the above polymers is preferably 30 w / w% or more, more preferably 50 w / w% or more, even more preferably 65 w / w% or more, and particularly preferably 80 w / w% or more, based on the total weight of the entire constituent materials.

[0087] At least a portion of the surface of the container that comes into contact with the ophthalmic composition of the present application may be made of the above material. For example, a layer or film made of the above material may be formed on the inner surface of the container, or the container itself may be molded from the above material. Furthermore, the constituent parts of the container (the container body, the part including the container's extraction port (nozzle, inner plug), suction tube, cap, etc.) may be made of the above materials, or the entire container may be made of the above materials. In particular, it is preferable that the container body is made of the above materials, and it is more preferable that the entire container body is made of the above materials (a state in which some of the layers constituting the container body are not made of the above materials).

[0088] Target disease The ophthalmic composition of the present invention has an excellent effect of improving the corneal barrier function, and is therefore useful for alleviating, improving, suppressing, or treating foreign body sensation (such as a tingling sensation or a rolling sensation). Therefore, the ophthalmic composition of the present invention can be suitably used for improving the corneal barrier function, and for alleviating, improving, suppressing, or treating foreign body sensation (such as a tingling sensation or a rolling sensation). The ophthalmic composition of the present invention can be suitably used for improving, suppressing, or treating watery eyes (epiphora), which is a symptom that occurs when the tear drainage pathway from the lacrimal puncta to the lacrimal canaliculus, lacrimal sac, and nasolacrimal duct becomes blocked by eye discharge or the like, or when excessive tears are produced due to irritation.

[0089] In the present invention, "alleviation" includes alleviation of symptoms and inhibition of progression of symptoms, and "improvement", "inhibition", and "treatment" include alleviation of symptoms, inhibition of progression of symptoms, cure, or complete recovery.

[0090] Method of use When the ophthalmic composition of the present invention is a preparation to be applied to the eyes, such as eye drops, eye washes, or eye ointments, the method of use varies depending on the symptoms to be treated, and may be, for example, once or more, twice or more, three or more, four or more, five or more, or six or more times a day. It may also be 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, or 4 or less times a day. It is particularly preferred to administer the composition four times a day.

[0091] When the ophthalmic composition of the present invention is in the form of eye drops, the eye drops containing each component at the above-mentioned concentrations may be administered in an amount of, for example, 1 to 3 drops, preferably 1 to 2 drops, each time. It is also possible to administer only one drop. When the ophthalmic composition of the present invention is an eyewash, the eye may be washed with, for example, 1 to 30 mL, preferably 1 to 20 mL, and more preferably 4 to 6 mL of the eyewash containing each component at the above concentrations each time. When the ophthalmic composition of the present invention is an eye ointment, the eye ointment containing each component at the above-mentioned concentrations may be applied to the eye in an amount of, for example, 0.001 to 5 g per application.

[0092] When the ophthalmic composition of the present invention is a contact lens wetting solution, when putting on or taking off the contact lenses, for example, 1 to 3 drops, preferably 1 to 2 drops, may be dropped onto one and / or both sides of the contact lenses each time to wet them before wearing, and it is preferable to wet both sides of the contact lenses before wearing.

[0093] Others The present invention encompasses a method for imparting or enhancing an effect of suppressing (improving or alleviating) foreign body sensation to an ophthalmic composition, which comprises incorporating into the ophthalmic composition (A) pranoprofen and / or a salt thereof, (B) a butyl group-containing phenol, and (C) at least one member selected from the group consisting of tocopherol, pyridoxine, chondroitin sulfate, derivatives thereof, and salts thereof.

[0094] The present invention also encompasses a method for imparting or enhancing an effect of suppressing (improving or alleviating) foreign body sensation to an ophthalmic composition comprising (A) pranoprofen and / or a salt thereof, and (B) a butyl group-containing phenol, by adding (C) at least one member selected from the group consisting of tocopherol, pyridoxine, chondroitin sulfate, derivatives thereof, and salts thereof to the ophthalmic composition.

[0095] The present invention also encompasses a method for imparting or enhancing a foreign body sensation suppressing (improving or alleviating) effect to an ophthalmic composition, which comprises adding (B) a butyl group-containing phenol to an ophthalmic composition containing (A) pranoprofen and / or a salt thereof, and (C) at least one member selected from the group consisting of tocopherol, pyridoxine, chondroitin sulfate, derivatives thereof, and salts thereof.

[0096] The present invention also encompasses a method for imparting or enhancing an effect of inhibiting (improving or alleviating) watery eyes to an ophthalmic composition, comprising comprising: (A) pranoprofen and / or a salt thereof; (B) a butyl group-containing phenol; and (C) at least one member selected from the group consisting of tocopherol, pyridoxine, chondroitin sulfate, derivatives thereof, and salts thereof.

[0097] The present invention also encompasses a method for imparting or enhancing an effect of inhibiting (improving or alleviating) watery eyes to an ophthalmic composition comprising (A) pranoprofen and / or a salt thereof, and (B) a butyl group-containing phenol, by adding (C) at least one member selected from the group consisting of tocopherol, pyridoxine, chondroitin sulfate, derivatives thereof, and salts thereof.

[0098] The present invention also encompasses a method for imparting or enhancing an effect of inhibiting (improving or alleviating) watery eyes to an ophthalmic composition comprising (A) pranoprofen and / or a salt thereof, and (C) at least one member selected from the group consisting of tocopherol, pyridoxine, chondroitin sulfate, derivatives thereof, and salts thereof, by adding (B) a butyl group-containing phenol to the ophthalmic composition.

[0099] In each method of the present invention, the type and concentration of each component, dosage form, pH, osmotic pressure, container, etc. are as explained for the ophthalmic composition of the present invention. EXAMPLES

[0100] The unit of the amounts of ingredients in each table in the following examples is w / v %. Test Example 1 (Effect of improving barrier function) Culture media containing each drug with the compositions shown in Tables 1 to 3 were used to evaluate the effects of these culture media on the corneal barrier function. That is, human corneal epithelial cell line HCE-T (RIKEN Bioresource Center, No. RCB2280) was cultured in a Transwell (registered trademark, 24-well, Corning) insert at 1.0 × 10 5 Cells were seeded at 200 μL per well (n=3). 600 μL of each drug-containing culture solution was placed in the reservoir well so that the final concentration of each drug in the culture solution was the concentration shown in Tables 1 to 3, and cultured for 30 minutes under conditions of 37°C and 5% CO2. At the same time, Comparative Example 1-1 was prepared, which is the same as Comparative Example 1-2 except that it does not contain dibutylhydroxytoluene, and tested in the same manner. After the culture, the transcorneal epithelial electrical resistance (TER) was measured using MILLICELL (registered trademark)-ERS (manufactured by Millipore Corporation), and the increase rate of TER compared to Comparative Example 1-1 was calculated based on the following formula (1). A higher increase rate of TER means that the barrier between corneal epithelial cells is stronger and the barrier function is enhanced.

[0101] Formula (1): TER increase rate (%) compared to Comparative Example 1-1 = [(TER value of each comparative example or example - TER value of comparative example 1-1) / (TER value of Comparative Example 1-1)] × 100

[0102] [Table 1]

[0103] [Table 2]

[0104] [Table 3]

[0105] When dibutylhydroxytoluene was added to pranoprofen, the TER increase rate was lower compared to the case of pranoprofen alone (Comparative Example 1-1). It can be seen that the addition of dibutylhydroxytoluene weakened the corneal barrier, making the patient more sensitive to the foreign body sensation. By further adding tocopherol acetate, pyridoxine hydrochloride, or sodium chondroitin sulfate, the TER increase rate became positive. This shows that the addition of tocopherol acetate, pyridoxine hydrochloride, or sodium chondroitin sulfate not only inhibited the decrease in corneal barrier function caused by dibutylhydroxytoluene, but also improved the corneal barrier function, making it difficult to feel a foreign body sensation.

[0106] Furthermore, the TER increase rate increased when pranoprofen was combined with tocopherol acetate, pyridoxine hydrochloride, or sodium chondroitin sulfate. In other words, the corneal barrier function improved, making it difficult to feel a foreign body sensation. By further blending dibutylhydroxytoluene into this product, the TER increase rate was further improved. It can be seen that the blending of dibutylhydroxytoluene further improved the corneal barrier function, making it even less likely for the patient to feel a foreign body sensation.

[0107] Test Example 2 (Human eye drop test 1) Each ophthalmic composition (eye drops) was prepared according to the formulations shown in Table 4, and 13 mL was filled into a polyethylene terephthalate eye drop container (container body) with a capacity of 14.2 mL. After filling, a polyethylene nozzle was attached to the eye drop container. Three adult subjects who were aware of "foreign body sensation" and "tingling sensation (stinging sensation)" were given one drop of each eye drop in each of their left and right eyes, and the post-instillation sensation regarding the symptoms shown in Table 4 was evaluated using a VAS (Visual Analog Scale).

[0108] The VAS evaluation was carried out as follows: On a subjective symptom survey sheet with a 100mm line drawn, the subject marked the level of the item they felt, with 0mm representing no improvement at all in foreign body sensation and 100mm representing a strong improvement. This length (mm) was taken as the VAS value. In other words, the higher the VAS value, the higher the subjective score for the improvement of each symptom. Using this VAS value, the VAS improvement rate (%) of each test example relative to the comparative example serving as a reference was calculated using the following formula (2). Here, the reference comparative example is Comparative Example 2-1. Formula (2): VAS improvement rate (%) = {(VAS value of test example - VAS value of reference comparative example) / VAS value of reference comparative example} x 100

[0109] [Table 4] The results in Table 4 show that when pranoprofen, dibutylhydroxytoluene, and tocopherol acetate or sodium chondroitin sulfate were used in combination, the effects of foreign body sensation and tingling sensation were significantly improved.

[0110] Test Example 3 (Human eye drop test 2) According to the formulations shown in Table 5, each ophthalmic composition (eye drop) was prepared, and the actual sensation after instillation was evaluated in terms of "foreign body sensation" and "tingling sensation (prickly sensation)" in the same manner as in Test Example 2, except that Comparative Example 3-1 was used as the reference comparative example.

[0111] [Table 5]

[0112] The results in Table 5 show that when pranoprofen, dibutylhydroxytoluene, tocopherol acetate, pyridoxine hydrochloride, and sodium chondroitin sulfate were used in combination with tetrahydrozoline hydrochloride, dipotassium glycyrrhizinate, chlorpheniramine maleate, potassium aspartate, aminoethylsulfonic acid, and sodium edetate, the effects on foreign body sensation and tingling sensation were significantly improved.

[0113] Formulation example Formulation examples of eye drops that are representative of the ophthalmic composition of the present invention are shown in Tables 6 to 9. All units in the tables are w / v %. The eye drops formulated in Formulation Examples 1 to 40 were filled in polyethylene terephthalate containers (container body). The eye drops of Formulation Examples 1 to 40 were filled in polyethylene terephthalate containers (container body) and equipped with polyethylene nozzles, which were designated Formulation Examples 1' to 40'. The eye drops of Formulation Examples 1 to 40 were filled in polyethylene terephthalate containers (container body) and equipped with polybutylene terephthalate nozzles, which were designated Formulation Examples 1'' to 40''.

[0114] [Table 6]

[0115] [Table 7]

[0116] [Table 8]

[0117] TIFF2025023354000009.tif114155

[0118] [Table 9] [Industrial Applicability]

[0119] The ophthalmic composition of the present invention is a very practical ophthalmic composition because it effectively improves the corneal barrier function and, in turn, can effectively prevent, alleviate, improve, suppress, or treat foreign body sensation (such as a tingling sensation or a rolling sensation).

Claims

[Claim 1] An ophthalmic composition for improving foreign body sensation, comprising the following components (A), (B), and (C): (A) Pranoprofen, and / or a pharma- ceutically acceptable salt thereof. (B) Butyl-containing phenol (C) at least one selected from the group consisting of tocopherol, pyridoxine, chondroitin sulfate, derivatives thereof, and salts thereof;

Images