JP2017119669A - Ophthalmic composition for improved foreign matter feeling - Google Patents

Abstract

PROBLEM TO BE SOLVED: 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

  The present invention relates to an ophthalmic composition useful for improving the foreign body sensation of the eye.

  The cornea is a tissue composed of five layers of the corneal epithelium, Bowman's membrane, corneal stroma, Descemet's membrane, and corneal endothelium in order from the outside, and is formed on the outermost surface of the eyeball. Due to anatomical features that are in direct contact with the outside world, various foreign substances such as antigens, microorganisms, and dust are likely to enter. On the other hand, most sensory nerves distributed in the cornea are trigeminal nerves. The perception of the cornea is regarded as one of the most sensitive pain perceptions of 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 loss or detachment of the corneal epithelium exposes and stimulates the nerve endings just below the corneal epithelium, so it feels as strong pain (non-) Patent Document 1).

  For this reason, when the barrier function inherent to the cornea is reduced due to corneal epithelial defect or detachment, when dust, pollen, excessive amounts of protein, cosmetic stains, etc., adhere to the ocular surface, the foreign body feel becomes stronger. I feel it.

Here, pranoprofen is known as a propionic acid-type non-steroidal anti-inflammatory agent having excellent anti-inflammatory action, analgesic action and antipyretic action, and has high safety. It is widely used as a composition and internal medicine.
As the efficacy of the ophthalmic composition containing pranoprofen, there are known improvements in foreign body sensation, smooth eyes, itching, haze, conjunctival hyperemia, and the like.

An ophthalmic composition such as an eye drop usually contains a very large number of components. However, depending on the combination of ingredients, the efficacy of the active ingredient may be reduced, and the current situation is that it cannot be predicted.
About the aqueous composition containing pranoprofen, it is likely to become cloudy or to be decomposed during storage, particularly during storage under light irradiation. Therefore, pranoprofen can be formulated by adding dibutylhydroxytoluene or the like. Attempts have been made to improve the stability of the aqueous compositions.

Kondo Takehisa, Corneal Nervous, Monthly Ophthalmology Practice 72: 30,2001

The present inventor has added butyl group-containing phenol (such as dibutylhydroxytoluene) to an ophthalmic composition containing pranoprofen and / or a pharmaceutically acceptable salt thereof (hereinafter sometimes abbreviated as “a salt thereof”). ) Has been found to decrease the corneal barrier function, and consequently, the foreign matter sensation improving effect of pranoprofen or a salt thereof is reduced.
Then, this invention makes it a subject to provide the ophthalmic composition which contains a planoprofen and / or its salt, and has the outstanding foreign material feeling improvement effect.

In order to solve the above problems, the present inventors have conducted research and developed an ophthalmic composition containing (A) pranoprofen and / or a salt thereof and (B) a butyl group-containing phenol (such as dibutylhydroxytoluene). , (C) a composition that improves the corneal barrier function and thus improves the foreign body sensation by blending at least one selected from the group consisting of tocopherol, pyridoxine, chondroitin sulfate, derivatives thereof, and salts thereof I found it to be a thing.
Surprisingly, the addition of the component (C) not only suppresses the deterioration of the corneal barrier function and the foreign body feeling due to the combination of pranoprofen and a butyl group-containing phenol, but also includes pranoprofen and / or its The effect of improving the corneal barrier function and the foreign body feeling is higher than when the salt is used alone (that is, when the butyl group-containing phenol is not included).
Further unexpectedly, although butyl group-containing phenol is a component that lowers the corneal barrier function and reduces the effect of improving the foreign body sensation of pranoprofen and / or a salt thereof, pranoprofen and / or Alternatively, by adding a butyl group-containing phenol to an ophthalmic composition containing the salt and the component (C), the corneal barrier function is improved, and the effect of improving the feeling of foreign matter is enhanced.

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 material sensation, comprising the following component (A), component (B), and component (C).
(A) Planoprofen and / or a pharmaceutically acceptable salt thereof
(B) Butyl group-containing phenol (dibutylhydroxytoluene, butylhydroxyanisole, etc.)
(C) at least one selected from the group consisting of tocopherol, pyridoxine, chondroitin sulfate, derivatives thereof, and salts thereof Item 3. The ophthalmic composition according to Item 1, wherein the total content of the component (A) is 0.04 to 0.15 w / v% with respect to the total amount of the ophthalmic composition.
Item 3. Item 3. The ophthalmic composition according to Item 1 or 2, comprising two or more of the following (i), (ii), and (iii) of the component (C).
(i) Tocopherol, its derivatives, and / or their salts
(ii) pyridoxine, its derivatives, and / or their salts
(iii) Chondroitin sulfate, a derivative thereof, and / or a salt 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. object.
Item 5. The ophthalmic composition is selected from the group consisting of (A) pranoprofen and / or its salt, (B) butyl group-containing phenol, and (C) tocopherol, pyridoxine, chondroitin sulfate, their derivatives, and their salts. A method for imparting or improving the effect of suppressing (improving or mitigating) a foreign body sensation to an ophthalmic composition, containing at least one selected from
Item 6. The ophthalmic composition is selected from the group consisting of (A) pranoprofen and / or its salt, (B) butyl group-containing phenol, and (C) tocopherol, pyridoxine, chondroitin sulfate, their derivatives, and their salts. A method for imparting or improving a lacrimal eye suppression (improvement or alleviation) effect to an ophthalmic composition, comprising at least one of the above.

By blending a butyl group-containing phenol (such as dibutylhydroxytoluene) with an ophthalmic composition containing pranoprofen and / or a salt thereof, the corneal barrier function is lowered, and the effect of improving foreign body feeling is lowered.
In this regard, the ophthalmic composition of the present invention exhibits an excellent corneal barrier function improving effect and, in turn, an excellent foreign body feeling improving effect, despite containing pranoprofen and / or a salt thereof and a butyl group-containing phenol.
The degree is not only higher than when pranoprofen and / or a salt thereof and a butyl group-containing phenol are included, but also more than pranoprofen or a salt thereof alone (ie, when it does not include a butyl group-containing phenol). Is significantly higher.
In addition, when butyl group-containing phenol is contained together with pranoprofen and / or a salt thereof, it contains butyl group-containing phenol even though it is a component that reduces the effect of improving the corneal barrier function and the feeling of foreign matter. The ophthalmic composition of the present invention exhibits an excellent corneal barrier function improving effect and, consequently, a foreign body feeling improving effect, as compared with an ophthalmic composition containing pranoprofen and / or a salt thereof and the component (C).
Therefore, the ophthalmic composition of the present invention can be suitably used for improving the corneal barrier function and thus improving the feeling of foreign matter in the eye. In addition, when the corneal barrier function is lowered, a tingling sensation of a foreign body is strongly felt among the foreign sensations, so the ophthalmic composition of the present invention is particularly preferably used for the improvement of the tingling sensation and the sensation of the foreign object. it can.

Hereinafter, the present invention will be described in detail.
The ophthalmic composition of the present invention comprises:
(A) pranoprofen and / or a salt thereof,
(B) butyl group-containing phenol, and (C) at least one selected from the group consisting of tocopherol, pyridoxine, chondroitin sulfate, derivatives thereof, and salts thereof,
Is an ophthalmic composition for improving the feeling of foreign matter.

Planoprofen and / or its salt (component (A))
The planoprofen salt may be a pharmaceutically or physiologically acceptable salt, such as an alkali metal salt (sodium salt, potassium salt, etc.), an alkaline earth metal salt (calcium salt, magnesium salt, etc.), Salts with inorganic bases such as ammonium salts, metal salts (aluminum salts, etc.), organic amine salts (methylamine salt, triethylamine salt, diethylamine salt, triethanolamine salt, morpholine salt, piperazine salt, pyrrolidine salt, tripyridine salt, And salts with organic bases such as picoline salts).
Planoprofen and its salts include those in the form of hydrates.
Planoprofen and its salt can be used singly or in combination of two or more.
Of the pranoprofen and its salts, the most preferred is pranoprofen.

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, based on the total amount of the composition. 05 w / v% or more is more preferable.
Further, the total content of pranoprofen and / or a salt thereof is preferably 0.5 w / v% or less, more preferably 0.2 w / v% or less, and more preferably 0.1 w / v based on the total amount of the composition. % Or less is more preferred, 0.08 w / v% or less is even more preferred, 0.07 w / v% or less is particularly preferred, and 0.06 w / v% or less is most preferred.
If it is the said range, the effect of this invention including the cornea barrier function improvement effect and the foreign material feeling improvement effect will fully be acquired.
The total content of pranoprofen and / or a salt thereof in the ophthalmic composition includes, for example, 0.05 w / v% and 0.1 w / v% with respect to the total amount of the composition.

Butyl group-containing phenol (component (B))
Examples of the butyl group-containing phenol include, but are not limited to, dibutylhydroxytoluene (BHT) and butylhydroxyanisole (BHA).
Of these, dibutylhydroxytoluene is preferable.
The content of butyl group-containing phenol in the ophthalmic composition is preferably 0.00005 w / v% or more, more preferably 0.0001 w / v% or more, and 0.0005 w / v% or more based on the total amount of the composition. Is more preferable, 0.001 w / v% or more is even more preferable, and 0.005 w / v% or more is particularly preferable. Within the above range, the effects of the present invention including the corneal barrier function improving effect and the foreign body feeling improving effect are sufficiently obtained, and the stability of pranoprofen and / or a salt thereof in the ophthalmic composition is practically sufficient. Can be made.
The content of the butyl group-containing phenol is preferably 1 w / v% or less, more preferably 0.1 w / v% or less, still more preferably 0.05 w / v% or less, based on the total amount of the composition. 0.01 w / v% or less is even more preferable, and 0.005 w / v% or less is particularly preferable. If it is the said range, the effect of this invention including the cornea barrier function improvement effect and the foreign material feeling improvement effect will fully be acquired.

The content of the butyl group-containing phenol in the ophthalmic composition is preferably 0.001 part by weight or more, more preferably 0.01 part by weight or more, based on 1 part by weight of pranoprofen and / or a salt thereof. 0.05 parts by weight or more is even more preferred, and 0.09 parts by weight or more is even more preferred. Within the above range, the effects of the present invention including the corneal barrier function improving effect and the foreign body feeling improving effect are sufficiently obtained, and the stability of pranoprofen and / or a salt thereof in the ophthalmic composition is practically sufficient. Can be made.
Further, the content of the butyl group-containing phenol is preferably 5 parts by weight or less, more preferably 1 part by weight or less, and further preferably 0.5 parts by weight or less with respect to 1 part by weight of pranoprofen and / or a salt thereof. Preferably, 0.15 parts by weight or less is even more preferable, and 0.1 parts by weight or less is particularly preferable. If it is the said range, the effect of this invention including the cornea barrier function improvement effect and the foreign material feeling improvement effect will fully be acquired.

Tocopherols (component (C))
Component (C) of the ophthalmic composition of the present invention may be tocopherol, a derivative thereof, and / or a salt thereof.
Examples of tocopherol include α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol and the like.
Examples of the tocopherol derivative include tocopherol acetate, tocopherol nicotinate, tocopherol succinate and the like.
The salt of tocopherol or a derivative thereof may be a pharmaceutically or physiologically acceptable salt. For example, an alkali metal salt (sodium salt, potassium salt, etc.), an alkaline earth metal salt (calcium salt, magnesium salt, etc.) Salts with inorganic bases such as ammonium salts and metal salts (aluminum salts, etc.), organic amine salts (methylamine salts, triethylamine salts, diethylamine salts, triethanolamine salts, morpholine salts, piperazine salts, pyrrolidine salts, tripyridine salts And salts with organic bases such as picoline salts).

The total content of tocopherol, derivatives thereof and / or salts thereof in the ophthalmic composition is preferably 0.001 w / v% or more, more preferably 0.005 w / v% or more, based on the total amount of the composition. 0.01 w / v% or more is even more preferable, and 0.025 w / v% or more is even more preferable.
Further, the total content of tocopherol, its derivatives, and / or salts thereof is preferably 1 w / v% or less, more preferably 0.5 w / v% or less, and more preferably 0.1 w / v based on the total amount of the composition. v% or less is even more preferable, and 0.05 w / v% or less is even more preferable.
If it is the said range, the effect of this invention including the cornea barrier function improvement effect and the foreign material feeling improvement effect will fully be acquired.

The total content of tocopherol, its derivatives, and / or salts thereof in the ophthalmic composition is preferably 0.01 parts by weight or more with respect to 1 part by weight of the total content of pranoprofen and / or its salts. 0.1 parts by weight or more is more preferable, 0.2 parts by weight or more is even more preferable, and 0.5 parts by weight or more is even more preferable.
Further, the total content of tocopherol, its derivatives, and / or salts thereof is preferably 10 parts by weight or less, preferably 5 parts by weight or less with respect to 1 part by weight of the total content of pranoprofen and / or its salts. Is more preferred, 1.5 parts by weight or less is even more preferred, and 1 part by weight or less is even more preferred.
If it is the said range, the effect of this invention including the cornea barrier function improvement effect and the foreign material feeling improvement effect will fully be acquired.

The total content of tocopherols, derivatives thereof and / or salts thereof in the ophthalmic composition is preferably 0.01 parts by weight or more, and 0.1 parts by weight or more with respect to 1 part by weight of the butyl group-containing phenol. More preferably, 0.5 parts by weight or more is even more preferable, 1 part by weight or more is even more preferable, and 10 parts by weight or more is particularly preferable.
Further, the total content of tocopherol, its derivatives, and / or salts thereof is preferably 500 parts by weight or less, more preferably 100 parts by weight or less, and more preferably 50 parts by weight or less with respect to 1 part by weight of the butyl group-containing phenol. Is more preferable, and 10 parts by weight or less is even more preferable.
If it is the said range, the effect of this invention including the cornea barrier function improvement effect and the foreign material feeling improvement effect will fully be acquired.

Pyridoxine (component (C))
The component (C) of the ophthalmic composition of the present invention may be pyridoxine and / or a salt thereof.
The pyridoxine or a salt thereof may be a pharmaceutically or physiologically acceptable salt, and examples thereof include hydrochloride.

The total content of pyridoxine, derivatives thereof and / or salts thereof in the ophthalmic composition is preferably 0.001 w / v% or more, more preferably 0.01 w / v% or more, based on the total amount of the composition. 0.05 w / v% or more is even more preferable, and 0.1 w / v% or more is even more preferable.
Further, the total content of pyridoxine, derivatives thereof and / or salts thereof is preferably 5 w / v% or less, more preferably 1 w / v% or less, and more preferably 0.5 w / v% based on the total amount of the composition. The following is still more preferable, and 0.1 w / v% or less is even more preferable.
If it is the said range, the effect of this invention including the cornea barrier function improvement effect and the foreign material feeling improvement effect will fully be acquired.

The total content of pyridoxine, derivatives thereof and / or salts thereof in the ophthalmic composition is preferably 0.01 parts by weight or more with respect to 1 part by weight of the total content of pranoprofen and / or salts thereof. 0.1 parts by weight or more is more preferable, 0.2 parts by weight or more is even more preferable, and 1 part by weight or more is even more preferable.
Further, the total content of pyridoxine, derivatives thereof and / or salts thereof is preferably 10 parts by weight or less, preferably 5 parts by weight or less with respect to 1 part by weight of the total content of pranoprofen and / or salts thereof. Is more preferably 3 parts by weight or less, still more preferably 2 parts by weight or less.
If it is the said range, the effect of this invention including the cornea barrier function improvement effect and the foreign material feeling improvement effect will fully be acquired.

The total content of pyridoxine, its derivatives, and / or salts thereof in the ophthalmic composition is preferably 0.01 parts by weight or more, and 0.1 parts by weight or more with respect to 1 part by weight of the butyl group-containing phenol. More preferably, 1 part by weight or more is even more preferable, and 10 parts by weight or more is even more preferable.
Further, the total content of pyridoxine, derivatives thereof and / or salts thereof is preferably 500 parts by weight or less, more preferably 100 parts by weight or less, and more preferably 50 parts by weight or less with respect to 1 part by weight of the butyl group-containing phenol. Is more preferable, and 20 parts by weight or less is even more preferable.
If it is the said range, the effect of this invention including the cornea barrier function improvement effect and the foreign material feeling improvement effect will fully be acquired.

Chondroitin sulfate (component (C))
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 compound in which sulfuric acid is ester-bonded to all or part of the hydroxyl groups of sugar chains in which D-glucuronic acid and N-acetylglucosamine repeat. The binding position and number of sulfuric acid are various, and there are some in which all or part of N-acetylglucosamine is replaced with iduronic acid.
The chondroitin sulfate used in the present invention may have any structure. Examples thereof include chondroitin sulfate sulfate (chondroitin sulfate A), chondroitin hexasulfate (chondroitin sulfate C), chondroitin sulfate E in which the 4th and 6th positions of N-acetylglucosamine are sulfated. In addition, chondroitin sulfate may be extracted from animals.
The salt of chondroitin sulfate may be any salt that is pharmaceutically or physiologically acceptable. For example, alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (calcium salt, magnesium salt, etc.), ammonium Salts, salts with inorganic bases such as metal salts (aluminum salts, etc.), organic amine salts (methylamine salt, triethylamine salt, diethylamine salt, triethanolamine salt, morpholine salt, piperazine salt, pyrrolidine salt, tripyridine salt, picoline salt And a salt with an organic base such as a salt).
Alkali metal salts are preferable, and sodium chondroitin sulfate is more preferable. Among them, sodium chondroitin sulfate described in Japanese Pharmacopoeia Standard 2002 is mentioned.

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 based on the total amount of the composition. Preferably, 0.05 w / v% or more is more preferable, 0.1 w / v% or more is even more preferable, and 0.5 w / v% or more is even more preferable.
Further, the total content of chondroitin sulfate, a derivative thereof, and / or a salt thereof is preferably 5 w / v% or less, more preferably 1 w / v% or less, more preferably 0.7 w / v based on the total amount of the composition. % Or less is even more preferable, and 0.5 w / v% or less is even more preferable.
If it is the said range, the effect of this invention including the cornea barrier function improvement effect and the foreign material feeling improvement effect will fully be acquired.

The total content of chondroitin sulfate, its derivatives, and / or their salts in the ophthalmic composition is 0.1 parts by weight or more with respect to 1 part by weight of the total content of pranoprofen and / or its salts. Preferably, 1 part by weight or more is more preferable, 2 parts by weight or more is even more preferable, and 9 parts by weight or more is even more preferable.
The total content of chondroitin sulfate, its derivatives, and / or salts thereof is preferably 100 parts by weight or less, and 50 parts by weight with respect to 1 part by weight of the total content of pranoprofen and / or its salts. The following is more preferable, 20 parts by weight or less is even more preferable, and 10 parts by weight or less is even more preferable.
If it is the said range, the effect of this invention including the cornea barrier function improvement effect and the foreign material feeling improvement effect will fully be acquired.

The total content of chondroitin sulfate, its derivatives, and / or salts thereof in the ophthalmic composition is preferably 1 part by weight or more, more preferably 5 parts by weight or more, with respect to 1 part by weight of the butyl group-containing phenol. 10 parts by weight or more is even more preferred, and 60 parts by weight or more is even more preferred.
Further, the total content of chondroitin sulfate, a derivative thereof, and / or a salt thereof is preferably 5000 parts by weight or less, more preferably 1000 parts by weight or less, more preferably 500 parts by weight with respect to 1 part by weight of the butyl group-containing phenol. The following is even more preferable, and 100 parts by weight or less is even more preferable.
If it is the said range, the effect of this invention including the cornea barrier function improvement effect and the foreign material feeling improvement effect will fully be acquired.

Total content of component (C) The total content of component (C) in the ophthalmic composition is preferably 0.0001 w / v% or more, more preferably 0.001 w / v% or more based on the total amount of the composition. Preferably, 0.05 w / v% or more is even more preferable, and 0.25 w / v% or more is even more preferable.
Further, the total content of the component (C) is preferably 5 w / v% or less, more preferably 2 w / v% or less, still more preferably 1 w / v% or less, and 0.7 w with respect to the total amount of the composition. Even more preferable is / v% or less.
If it is the said range, the effect of this invention including the cornea barrier function improvement effect and the foreign material feeling improvement effect will fully be acquired.

The total content of component (C) in the ophthalmic composition is preferably 0.01 parts by weight or more, and 0.1 parts by weight or more with respect to 1 part by weight of the total content of pranoprofen and / or a salt thereof. Is more preferable, 0.2 parts by weight or more is even more preferable, and 1 part by weight or more is even more preferable.
The total content of component (C) is preferably 500 parts by weight or less, more preferably 50 parts by weight or less, and more preferably 20 parts by weight with respect to 1 part by weight of the total content of pranoprofen and / or its salt. The following is even more preferable, and 15 parts by weight or less is even more preferable.
If it is the said range, the effect of this invention including the cornea barrier function improvement effect and the foreign material feeling improvement effect will fully be acquired.

The total content of component (C) in the ophthalmic composition is preferably 0.01 parts by weight or more, more preferably 0.1 parts by weight or more, and 0.5 parts by weight with respect to 1 part by weight of the butyl group-containing phenol. Part or more is even more preferable, and 1 part by weight or more is even more preferable.
Further, the total content of the component (C) is preferably 1000 parts by weight or less, more preferably 500 parts by weight or less, still more preferably 200 parts by weight or less, and 150 parts by weight with respect to 1 part by weight of the butyl group-containing phenol. Even more preferred is part or less.
If it is the said range, the effect of this invention including the cornea barrier function improvement effect and the foreign material feeling improvement effect will fully be acquired.

(C) component can be used individually by 1 type or in combination of 2 or more types.
When two or more kinds are used in combination, the three series of components (C) (i) to (iii) ((i) tocopherol, its derivatives, and salts thereof, (ii) pyridoxine, its derivatives, and them And (iii) chondroitin sulfate, derivatives thereof, and salts thereof) can be used.
Two or more compounds included in one series of components can also be used.

The property of the pharmaceutical ophthalmic composition is not particularly limited, and may be any property such as liquid, fluid, gel, or semi-solid. Moreover, the liquid form, the fluid form, the gel form, or the semi-solid form by preparation at the time of use is also included. The semi-solid state refers to a property having plasticity that can be deformed by applying force, such as an ointment.

The ophthalmic composition may be an aqueous composition (mainly containing an aqueous or hydrophilic base or carrier), and an oily composition (an oil or hydrophobic base or carrier). Included).
The content of water in the case of the aqueous composition is preferably 50% by weight or more, more preferably 75% by weight or more, and still more preferably 90% by weight or more based on the total amount of the preparation. Moreover, 95 weight% or more or 98 weight% or more may be sufficient. In addition, the base or carrier may be composed only of water.
The water content in the case of an oily composition 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 amount of the preparation.
The ophthalmic composition of the present invention is preferably an aqueous composition.

The dosage form of the ophthalmic composition of the present invention is not particularly limited. For example, eye drops (also referred to as eye drops or eye drops. Eye drops include eye drops that can be applied while wearing contact lenses), eye wash , Eye ointment (water-soluble eye ointment, oil-soluble eye ointment), contact lens mounting solution, intraocular injection (eg, intravitreal injection), contact lens solution (cleaning solution, preservation solution, disinfectant solution, multi-purpose solution, Package solutions), preservatives for isolated ocular tissues such as the cornea for transplantation, and perfusate during surgery. Eye drops, eye washes and eye ointments include those used when wearing contact lenses.
The “contact lens” includes hard contact lenses and soft contact lenses (including both ionic and non-ionic, including both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses).
The dosage form of the ophthalmic composition of the present invention is preferably eye drops, eye wash, eye ointment (water-soluble eye ointment, oil-soluble eye ointment), contact lens mounting solution, contact lens solution (cleaning solution, preservative solution, disinfectant) Liquid, multipurpose solution, package solution), and more preferably, eye drops, eye wash, contact lens mounting liquid, contact lens liquid (cleaning liquid, storage liquid, disinfectant liquid, multipurpose solution), etc. Even more preferred are eye drops and eye washes, and particularly preferred are eye drops.
However, the ophthalmic composition of the present invention is an ophthalmic composition (particularly an eye drop, an eye wash, or an eye ointment) that is applied when a contact lens (hard contact lens, soft contact lens, especially a silicone hydrogel contact lens) is worn or worn. ).

  The ophthalmic composition of the present invention may be a single-use unit dose or a multi-dose that can be repeatedly used. However, since it has excellent storage efficacy, it is preferably contained and used in a multi-dose form.

  The ophthalmic composition of the present invention comprises the above components (A), (B), and (C) as a pharmaceutically acceptable base or carrier, and if necessary, a pharmaceutically acceptable ophthalmic composition. For example, it can be prepared by a conventional method described in the 16th revised Japanese Pharmacopoeia Manual by mixing with other additives and other active ingredients.

Examples of the base or carrier base or carrier include water; polar solvents such as ethanol; oily bases and the like. A base or a support | carrier can be used individually by 1 type or in combination of 2 or more types.

The additives additives, for example, nonionic surfactants, preservatives, buffering agents, pH adjusting agents, isotonic agents, thickening or thickening agents, stabilizing agents, oils, sugars, high molecular compound , Polyhydric alcohols, inorganic salts, cooling agents, antioxidants and the like.
An additive can be used individually by 1 type or in combination of 2 or more types. Moreover, about each additive, 1 type can be used individually or in combination of 2 or more types.

  Specific examples of the additive are exemplified below.

<Nonionic surfactant>
The ophthalmic composition of the present invention preferably contains a nonionic surfactant.
Nonionic surfactants include monolauric acid POE (20) sorbitan (polysorbate 20), monopalmitic acid POE (20) sorbitan (polysorbate 40), monostearic acid POE (20) sorbitan (polysorbate 60), and tristearic acid POE. (20) POE sorbitan fatty acid esters such as sorbitan (polysorbate 65) and monooleic acid POE (20) sorbitan (polysorbate 80); POP glycols: POE hydrogenated castor oil 40, POE hydrogenated castor oil 50, POE hydrogenated castor oil 60, POE hydrogenated castor oil 80, etc .; POE castor oil 3, POE castor oil 4, POE castor oil 6, POE castor oil 6, POE Castor oil 7, POE castor oil 1 POE castor oil such as 0, 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, POE castor oil 50; polyethylene glycol monostearate ( 2E.O.), polyethylene glycol monostearate (4E.O.), polyethylene glycol monostearate (9E.O.), polyethylene glycol monostearate (10E.O.), polyethylene glycol monostearate (23E.O.). O.), polyethylene glycol monostearate (25E.O.), polyethylene glycol monostearate (32E.O.), polyethylene glycol monostearate (40E.O., polyoxyl 40 stearate), polyethylene monostearate Polyglycol monostearate such as Recall (45E.O.), Polyethylene glycol monostearate (55E.O.), Polyethylene glycol monostearate (75E.O.), Polyethylene glycol monostearate (140E.O.) POE alkyl ethers such as POE (9) lauryl ether; POE-POP alkyl ethers such as POE (20) POP (4) cetyl ether; POE alkyl phenyl ethers such as POE (10) nonyl phenyl ether It is done. In the compounds exemplified above, POE is polyoxyethylene, POP is polyoxypropylene, and the numbers in parentheses indicate the number of moles added.

  Among them, POE sorbitan fatty acid esters; POE / POP glycols; POE hydrogenated castor oil; POE castor oil and polyethylene glycol monostearate are preferable, 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 are more preferable, polysorbate 80, POE hydrogenated castor oil 60 are more preferable, and polysorbate 80 is particularly preferable.

  When a nonionic surfactant is blended in the ophthalmic composition of the present invention, as an example of the blending amount, the total amount of the nonionic surfactant is 0.001 w / v% or more with respect to the total amount of the ophthalmic composition, Of these, 0.005 w / v% or more, especially 0.01 w / v% or more, and especially 0.05 w / v% or more. The total amount of the nonionic surfactant is 5 w / v% or less, especially 1 w / v% or less, especially 0.5 w / v% or less, especially 0.3 w / v% or less, based on the total amount of the ophthalmic composition. Is mentioned.

<Preservative>
Preservatives include polydronium chloride, alkylpolyaminoethylglycines (eg, alkyldiaminoethylglycine hydrochloride), sodium benzoate, ethanol, quaternary ammonium salts (eg, benzalkonium chloride, benzethonium chloride, etc.), gluconic acid Chlorhexidine, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, paraoxybenzoate (eg, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate), oxyquinoline sulfate, phenethyl Alcohol, benzyl alcohol, biguanide compounds (for example, polyhexanide hydrochloride, etc.), glow kill (manufactured by Rhodia) and the like can be mentioned.
Among them, alkylpolyaminoethylglycines (for example, alkyldiaminoethylglycine hydrochloride), sodium benzoate, ethanol, quaternary ammonium salt, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, paraoxybenzoate, biguanide compound Are preferred, quaternary ammonium salts, chlorhexidine gluconate, chlorobutanol, and biguanide compounds are more preferred, and benzalkonium chloride and polyhexanide hydrochloride are more preferred.

  When an antiseptic is blended in the ophthalmic composition of the present invention, as an example of the blending amount, the total amount of the preservative is 0.000001 w / v% or more, particularly 0.00001 w / v, based on the total amount of the ophthalmic composition. % Or more, especially 0.00005 w / v% or more, especially 0.001 w / v% or more, especially 0.005 w / v% or more. Further, the total amount of the preservative is 1 w / v% or less, particularly 0.1 w / v% or less, especially 0.05 w / v% or less, especially 0.02 w / v% or less, based on the total amount of the ophthalmic composition. Especially, 0.01 w / v% or less is mentioned.

<Buffer agent>
The ophthalmic composition of the present invention preferably contains a buffer.
Examples of the buffer include borate buffer, phosphate buffer, carbonate buffer, citrate buffer, and acetate buffer.
Examples of the components of the boric acid buffer include boric acid and borates (sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.). The borate may be a hydrate.
Phosphate buffer components include phosphoric acid, phosphate (disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, trisodium phosphate, dipotassium phosphate, calcium monohydrogen phosphate, And calcium dihydrogen phosphate). The phosphate may be a hydrate.
Examples of the component of the carbonate buffer include carbonic acid and carbonate (such as potassium carbonate, sodium carbonate, calcium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, magnesium carbonate). The carbonate may be a hydrate.
Examples of the citrate buffer component include citric acid and citrate (such as sodium citrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, and disodium citrate). The citrate salt may be a hydrate.
Examples of the component of the acetate buffer include acetic acid and acetate (such as ammonium acetate, potassium acetate, calcium acetate, and sodium acetate). The acetate salt may be a hydrate.
Among these, a borate buffer and a phosphate buffer are preferable, and a borate buffer is more preferable. The boric acid buffer is preferably a combination of boric acid and its salt, more preferably a combination of boric acid and an alkali metal salt of boric acid and / or an alkaline earth metal salt, and an alkali metal of boric acid and boric acid. A combination with a salt is further preferred, and a combination of boric acid and borax is even more preferred.

  When blending a buffering agent in the ophthalmic composition of the present invention, the blending amount of the buffering agent varies depending on the type of buffering agent, the type and amount of other blending components, and cannot be defined uniformly, for example, The total amount of the buffering agent is 0.001 w / v% or more, especially 0.01 w / v% or more, especially 0.05 w / v% or more, especially 0.1 w / v% or more with respect to the total amount of the ophthalmic composition. Is mentioned. Further, the total amount of the buffering agent is 10 w / v% or less, particularly 5 w / v% or less, especially 3 w / v% or less, especially 2 w / v% or less with respect to the total amount of the ophthalmic composition.

<PH regulator>
Examples of pH regulators 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, hydroxide Examples include calcium, magnesium hydroxide, triethanolamine, monoethanolamine, and diisopropanolamine.

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

<Thickener or thickener>
The ophthalmic composition of the present invention can contain a thickener or thickener other than chondroitin sulfate, a derivative thereof, or a salt thereof within a range not impairing the effects of the present invention.
Examples of thickeners or thickeners include guar gum, hydroxypropyl guar gum, cellulosic polymer compounds (for example, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, etc.), gum arabic, karaya gum, xanthan gum, agar , Alginic acid, α-cyclodextrin, dextrin, dextran, mucopolysaccharide (eg, heparin analog, heparin, heparin sulfate, heparan sulfate, heparinoid, hyaluronic acid, hyaluronate (sodium salt, etc.)), starch, chitin and Derivatives thereof, chitosan and derivatives thereof, carrageenan, sorbitol, polyvinyl polymer compounds (polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride) Polymethacrylate, carboxyvinyl polymer, etc.), alkali metal salt of polyacrylic acid (sodium salt, potassium salt, etc.), amine salt of polyacrylic acid (monoethanolamine salt, diethanolamine salt, triethanolamine salt, etc.), casein , Gelatin, collagen, pectin, elastin, ceramide, liquid paraffin, glycerin, polyethylene glycol, macrogol, polyethyleneimine alginate (such as sodium salt), alginate (such as propylene glycol ester), tragacanth powder, and triisopropanolamine Can be mentioned.

<Stabilizer>
Examples of the stabilizer include trometamol, sodium formaldehyde sulfoxylate (Longalite), monoethanolamine, aluminum monostearate, and glyceryl monostearate.

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

<Sugar>
Examples of the saccharide include monosaccharides and disaccharides, specifically glucose, maltose, trehalose, sucrose, cyclodextrin, xylitol, sorbitol, mannitol and the like.

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

<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, hydrogen phosphate Examples include sodium, potassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium hydrogen sulfite, sodium sulfite, potassium acetate, sodium acetate, sodium thiosulfate, etc. It is done.
Among them, potassium chloride, sodium chloride, calcium chloride, sodium hydrogen carbonate, sodium carbonate (including dry sodium carbonate), magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate are preferable, potassium chloride, Sodium chloride, calcium chloride, sodium hydrogen phosphate, and sodium dihydrogen phosphate are more preferable, and potassium chloride and sodium chloride are still more preferable.

<Cooling agent>
Examples of the refreshing agent include terpenoids such as menthol, anethole, eugenol, camphor, geraniol, cineol, borneol, limonene, and agate. These may be any of d-form, l-form or dl-form. These may be either d-form, l-form or dl-form, and also 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. .

<Antioxidant>
The ophthalmic composition of the present invention can contain an antioxidant other than the butyl group-containing phenol as long as the effects of the present invention are not impaired.
Examples of fat-soluble antioxidants include nordihydroguaiaretic acid (NDGA); ascorbyl palmitate, ascorbyl stearate, aminopropyl ascorbate phosphate, tocopherol ascorbate phosphate, triphosphate phosphate, ascorbate phosphate Ascorbic acid esters such as palmitate; gallic acid esters such as ethyl gallate, propyl gallate, octyl gallate, dodecyl gallate; propyl gallate; 3-butyl-4-hydroxyquinolin-2-one; lutein, astaxanthin Carotenoids; polyphenols such as anthocyanins, catechins, tannins, curcumins; retinol, retinol esters (retinol acetate, retinol propionate, retinol butyrate, retinol octylate, latin Retinol rillate, retinol stearate, retinol myristate, retinol oleate, retinol linolenate, retinol linoleate, retinol palmitate), retinal, retinal esters (retinal acetate, retinal propionate, retinal palmitate, etc.), retinoic acid Retinoic acid esters (methyl retinoic acid, ethyl retinoic acid, retinol retinoic acid, tocopherol retinoic acid, etc.), retinol dehydro form, retinal dehydro form, retinoic acid dehydro form, provitamin A (α-carotene, β-carotene, γ- Carotene, δ-carotene, lycopene, zeaxanthin, β-cryptoxanthin, echinone, etc.), vitamin A such as vitamin A; CoQ10 and the like.
Water-soluble antioxidants include ascorbic acid and ascorbic acid derivatives (ascorbic acid-2-sodium sulfate, sodium ascorbate, ascorbic acid-2-magnesium phosphate, ascorbic acid-2-sodium phosphate, etc.) Sodium bisulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, edetic acid or a salt thereof (eg, disodium edetate, tetrasodium edetate) and the like.

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 is preferably 0.0001 w / v with respect to the total amount of the composition. % Or more, more preferably 0.001 w / v% or more, and even more preferably 0.01 w / v% or more. For example, it can be 0.5 w / v% or less, can be 0.1 w / v% or less, and can be 0.05 w / v% or less.

Other Pharmacologically Active Components or Physiologically Active Components In addition to the components (A), (B), and (C) described above, the ophthalmic composition of the present invention contains components having pharmacological activity or physiological activity. be able to.
A pharmacologically active ingredient or a physiologically active ingredient can be used individually by 1 type or in combination of 2 or more types.
Examples of such pharmacologically active ingredients and physiologically active ingredients include active ingredients in various pharmaceuticals described in the General Occupational Drug Manufacturing and Sales Approval Standards 2012 edition (supervised by the Japanese Society for Regulatory Science). For example, decongestant component, ocular muscle modulator component, anti-inflammatory component, astringent component, antihistamine component or antiallergic component, vitamins, amino acids, antibacterial or bactericidal agent, local anesthetic component, analgesic Agents and the like. Specific examples of these drugs are illustrated below.

<Decongestant component (vasoconstrictor)>
The ophthalmic composition of the present invention preferably contains a decongestant component, whereby the effects of the present invention are more remarkably exhibited.
Examples of the decongestant component include α-adrenergic agonists, specifically, imidazoline-type decongestant components such as oxymetazoline, tetrahydrozoline, naphazoline, or salts thereof such as hydrochloride, nitrate, epinephrine, epinephrine hydrochloride. , Ephedrine hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, epinephrine hydrogen tartrate, and the like. These may be d-form, l-form or dl-form.
Among the vasoconstriction components, imidazoline-based vasoconstriction components are preferable, and tetrahydrozoline or a salt thereof is more preferable.

  The imidazoline-based vasoconstrictor component will be described in detail. The salt of the imidazoline-based vasoconstrictor component may be a pharmaceutically or physiologically acceptable salt, for example, an organic acid salt such as maleate or fumarate; hydrochloric acid Inorganic acid salts such as salts and sulfates; and salts such as metal salts. Among the salts, inorganic acid salts are preferable, hydrochlorides or nitrates are more preferable, and hydrochlorides (tetrahydrozoline hydrochloride and the like) are particularly preferable.

  When the ophthalmic composition of the present invention contains an imidazoline vasoconstrictor component, the total content of the imidazoline vasoconstrictor component in the ophthalmic composition is preferably 0.0001 w / v% or more with respect to the total amount of the composition, More preferably, it may be 0.0005 w / v% or more, and still more preferably 0.001 w / v% or more. For example, it can be 0.5 w / v% or less, can be 0.1 w / v% or less, and can be 0.05 w / v% or less.

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 is preferably 0.001 w / v% or more based on the total amount of the composition. More preferably, it can be 0.01 w / v% or more, and still more preferably 0.025 w / v% or more. For example, it can be 0.5 w / v% or less, can be 0.1 w / v% or less, and can be 0.05 w / v% or less.
The total content of tetrahydrozoline and / or its salt is particularly preferably 0.05 w / v%.

<Eye muscle regulator component>
Examples of the eye muscle modulator component include cholinesterase inhibitors having an active center similar to acetylcholine, specifically, neostigmine methyl sulfate, tropicamide, helenien, and atropine sulfate.

<Anti-inflammatory component>
The ophthalmic composition of the present invention can contain an anti-inflammatory drug component other than pranoprofen or a salt thereof as long as the effects of the present invention are not impaired.
Examples of such an anti-inflammatory component or astringent component include zinc sulfate, zinc lactate, allantoin, indomethacin, lysozyme chloride, silver nitrate, sodium azulenesulfonate, glycyrrhizic acid or a salt thereof (dipotassium glycyrrhizinate, diammonium glycyrrhizinate) Etc.), diclofenac sodium, bromfenac sodium, berberine chloride, and berberine sulfate.
The case where glycyrrhizic acid and / or a salt thereof is included will be described in detail. When the ophthalmic composition of the present application includes glycyrrhizic acid and / or a salt thereof, the total content of glycyrrhizic acid and / or a salt thereof in the ophthalmic composition is: Preferably it is 0.001 w / v% or more with respect to the whole quantity of a composition, More preferably, it is 0.01 w / v% or more, More preferably, it can be 0.05 w / v% or more. For example, it can be 1 w / v% or less, can be 0.5 w / v% or less, and can also be 0.25 w / v% or less.

  The ophthalmic composition of the present invention may also contain no anti-inflammatory component other than pranoprofen or a salt thereof. Thereby, the effect of the present invention may be improved.

<Antihistamine component or antiallergic component>
Examples of the antihistamine (histamine receptor antagonist) include salts such as diphenhydramine or its hydrochloride, salts such as chlorpheniramine or its maleate, salts such as levocabastine or its hydrochloride, and the like.
In addition, as an antiallergic agent component that exhibits antiallergic action by inhibiting the release of chemical mediators, salts such as cromoglycic acid or its sodium salt, tranilast, ibudilast, acitazanolast, tazanolast, suplatast or a tosylate thereof, Examples thereof include salts such as pemirolast or a potassium salt thereof.
Examples of the antihistamine component that antagonizes the histamine receptor and exerts an antiallergic action by suppressing the release of chemical mediators include olopatadine, ketotifen fumarate, amlexanox, and oxatomide.
However, the ophthalmic composition of the present invention is an antiallergic drug component that exhibits an antiallergic action by suppressing the release of chemical mediators (particularly, salts such as tranilast, pemirolast or potassium salts thereof), and / or the release inhibitory action of chemical mediators. It is preferable not to contain an antihistamine component (in particular, a salt such as olopatadine or its hydrochloride) having This is because an unpleasant irritation may occur when these components are added to the composition of the present invention.

The ophthalmic composition of the present invention preferably contains an antihistamine other than an antihistamine having a chemical mediator release inhibitory effect, whereby the effects of the present invention are more remarkably exhibited.
In particular, chlorpheniramine and / or a salt thereof will be described in detail. The salt of chlorpheniramine may be a pharmaceutically or physiologically acceptable salt, for example, an organic acid such as maleate or fumarate. Salt; inorganic acid salt such as hydrochloride and sulfate; salt such as metal salt. Among the salts, organic acid salts are preferable, and maleic acid salts are particularly preferable.
Chlorpheniramine and a salt thereof may be in the form of a hydrate, and may be any of d-form, l-form, and dl-form.
Chlorpheniramine and its salt can be used individually by 1 type or in combination of 2 or more types.
Of chlorpheniramine and / or a salt thereof, most preferred is chlorpheniramine maleate.

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 is preferably 0.02 w relative to the total amount of the composition. / V% or more, more preferably 0.025 w / v% or more, still more preferably 0.03 w / v% or more. Further, for example, it can be 1 w / v% or less, can be 0.1 w / v% or less, can be 0.05 w / v% or less, and can be 0 0.04 w / v% or less.
The total content of chlorpheniramine and / or a salt thereof is particularly preferably 0.03 w / v%.

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

<Amino acids>
The ophthalmic composition of the present invention preferably contains amino acids other than chondroitin sulfate, a derivative thereof, or a salt thereof, whereby the effects of the present invention are more remarkably exhibited.
Examples of amino acids include aminoethylsulfonic acid (taurine), aspartic acid or a salt thereof (sodium aspartate, potassium aspartate, magnesium aspartate, magnesium aspartate / potassium mixture, etc.), glutamic acid or a salt thereof (sodium glutamate, Magnesium glutamate, etc.), creatinine, epsilon-aminocaproic acid, glycine, alanine, arginine, lysine, γ-aminobutyric acid, γ-aminovaleric acid and the like. These may be d-form, l-form or dl-form.
Of these, aminoethylsulfonic acid, aspartic acid or a salt thereof (potassium aspartate, magnesium aspartate, magnesium aspartate / potassium mixture, etc.) or epsilon-aminocaproic acid is preferable. Aminoethylsulfonic acid, aspartic acid or a salt thereof (aspartic acid) Potassium, magnesium aspartate, magnesium aspartate / potassium mixture, etc.) are more preferred.

  When an amino acid is blended with the ophthalmic composition of the present invention, as an example of the blending amount, for example, with respect to the total amount of the ophthalmic composition, the total amount of amino acids is 0.01 w / v% or more, especially 0.05 w / v%. Above all, 0.1 w / v% or more, especially 0.3 w / v% or more can be mentioned. In addition, the total amount of amino acids is 10 w / v% or less, particularly 5 w / v% or less, especially 1 w / v% or less, based on the total amount of the ophthalmic composition.

<Antimicrobial component or bactericidal component>
Examples of the antibacterial component or bactericidal component include sulfamethoxazole, sulfisoxazole, sulfamethoxazole sodium, sulfisoxazole diethanolamine, sulfisoxazole monoethanolamine, and sulfisoisomer. Examples include sulfa drugs such as sol sodium and sulfisomidine sodium, chloramphenicol, ofloxacin, norfloxacin, levofloxacin, lomefloxacin hydrochloride, and acyclovir.
However, the ophthalmic composition of the present invention can be free of sulfa drugs.
<Local anesthetic component>
Examples of the local anesthetic component include procaine hydrochloride and lidocaine hydrochloride.
<Painkiller>
Examples of soothing agents include procaine hydrochloride.

pH
The pH of the ophthalmic composition of the present invention is preferably 3 or more, more preferably 4 or more, still more preferably 5 or more, and even more preferably 6 or more. Moreover, 10 or less is preferable, 9 or less is more preferable, 8.5 or less is further more preferable, and 8 or less is still more preferable. If it is the said range, irritation | stimulation to eyes will be suppressed and the said effect of this invention will be acquired.

Osmotic pressure ratio of ophthalmic compositions of the osmotic pressure present invention is preferably 0.4 or more, more preferably 0.6 or more, even more preferably 0.8 or more. Moreover, 5 or less is preferable, 3 or less is more preferable, and 2 or less is still more preferable. If it is the said range, irritation | stimulation to eyes will be suppressed and the said effect of this invention will be acquired.
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 revision Japanese Pharmacopoeia. The standard solution for measuring the osmotic pressure ratio (0.9 w / v% sodium chloride aqueous solution) was dried in sodium chloride (Japanese Pharmacopoeia standard reagent) at 500 to 650 ° C. for 40 to 50 minutes and then released in a desiccator (silica gel). Cool and accurately measure 0.900 g and dissolve in purified water to make exactly 100 mL, or use a commercially available standard solution for osmotic pressure ratio measurement (0.9 w / v% sodium chloride aqueous solution).

A container container refers to a package body having a surface that comes into contact with a preparation, such as a container main body part that contains a liquid, a part including an extraction port of the container (nozzle, inner plug), a suction tube, and a cap.
The material which comprises the container which accommodates the ophthalmic composition of this invention can be selected from a wide range.
For example, at least part or all of the contact surface with the ophthalmic composition is made of plastic (for example, polyolefin, acrylic acid resin, terephthalic acid ester, 2,6-naphthalenedicarboxylic acid ester, polycarbonate, polymethylpentene, fluororesin, Vinyl chloride, polyamide, ABS resin, AS resin, polyacetal, modified polyphenylene ether, polyarylate, polysulfone, polyimide, cellulose acetate, hydrocarbons optionally substituted with halogen atoms), metal (such as aluminum), and glass Examples thereof include a container composed of at least one material selected from the group.

  Polyolefins include polyethylene (including high density polyethylene, low density polyethylene, ultra low density polyethylene, linear low density polyethylene, ultra high molecular weight polyethylene, etc.), polypropylene (isotactic polypropylene, syndiotactic polypropylene, atactic polypropylene). And ethylene-propylene copolymer.

  Examples of the acrylic resin include an acrylic ester such as methyl acrylate, a methacrylic ester such as methyl methacrylate, cyclohexyl methacrylate, and t-butylcyclohexyl methacrylate.

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

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

  Fluorine resins include fluorine-substituted polyethylene (polytetrafluoroethylene, polychlorotrifluoroethylene, etc.), polyvinylidene fluoride, polyvinyl fluoride, perfluoroalkoxy fluororesin, tetrafluoroethylene / hexafluoropropylene copolymer, ethylene / tetra Examples thereof include a fluorinated ethylene copolymer and an ethylene / chlorotrifluoroethylene copolymer.

  Examples of the polyamide include nylon.

  Examples of the polyacetal include those composed only of oxymethylene units and those partially containing oxyethylene units.

  Examples of the modified polyphenylene ether include polystyrene-modified polyphenylene ether.

  Examples of polyarylate include amorphous polyarylate.

  Examples of the polyimide include aromatic polyimides such as those obtained by polymerizing pyromellitic dianhydride and 4,4'-diaminodiphenyl ether.

Examples of cellulose acetate include cellulose diacetate and cellulose triacetate.
As a container for storing the ophthalmic composition of the present invention, polyolefin and terephthalic acid ester are preferable, terephthalic acid ester is more preferable, polyethylene terephthalate and polybutylene terephthalate are further preferable, and polyethylene terephthalate is still more preferable.
As a container for storing the ophthalmic composition of the present invention, the container material may be a blend polymer with a polymer other than the above-mentioned polymer. When the container material of the container containing the ophthalmic composition of the present invention is a polymer blended with the polymer, the mixing ratio of the polymer and a polymer other than the polymer is not particularly limited as long as the effect of the present invention is achieved, The total weight of the polymer is preferably 30 w / w% or more, more preferably 50 w / w% or more, and even more preferably 65 w / w% or more based on the total amount of the constituent materials. It is especially preferable that it is 80 w / w% or more.

The container should just be comprised with the said material at least one part of the surface which contacts the ophthalmic composition of this application.
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.
In addition, the parts constituting the container (the container body part, the part including the extraction port of the container (nozzle, inner plug), suction tube, cap, etc.) may be made of the above materials, and the whole part of the container may be made of the above materials. It may be comprised. In particular, it is preferable that the container main body portion is made of the above material, and that all of the container main body portion is made of the above material (some layers constituting the container main body are made of the above material. Is not preferred).

Target Diseases 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 a foreign body sensation (such as a tingling sensation, a feeling of tingling).
Therefore, the ophthalmic composition of the present invention can be suitably used for improving the corneal barrier function, relieving, improving, suppressing, or treating the feeling of foreign matter (such as a tingling sensation, a feeling of tingling).
In addition, the ophthalmic composition of the present invention can be suitably used for improvement, suppression, or treatment of watery eyes (tears). Naked eyes are a symptom that occurs when the drainage path of tears from the punctum to the lacrimal canal, lacrimal sac, and nasolacrimal duct becomes obstructed by the eyes or the like, or excessive tears are made by stimulation.

  In the present invention, "relief" includes symptom relief, symptom progression inhibition, and "improvement", "suppression", and "treatment" include symptom relief, symptom progression inhibition, cure or completeness. To do.

Method of Use When the ophthalmic composition of the present invention is a preparation to be applied to the eye, such as eye drops, eye wash, eye ointment, etc., the usage varies depending on the intended symptoms, but for example, once or more twice a day As mentioned above, it can be 3 times or more, 4 times or more, 5 times or more, or 6 times or more. Also, it can be 9 times or less, 8 times or less, 7 times or less, 6 times or less, 5 times or less, or 4 times or less per day. It is particularly preferred to administer 4 times a day.

When the ophthalmic composition of the present invention is an eye drop, the eye drop containing each component at the above concentration may be instilled, for example, 1 to 3 drops, preferably 1 to 2 drops. One drop can also be used.
When the ophthalmic composition of the present invention is an eye wash, the eye wash containing each component at the above concentration may be washed using, for example, 1 to 30 mL, preferably 1 to 20 mL, more preferably 4 What is necessary is just to wash eyes using ~ 6mL.
When the ophthalmic composition of the present invention is an eye ointment, an eye ointment containing each component at the above concentration may be applied to, for example, 0.001 to 5 g of eyes per time.

  When the ophthalmic composition of the present invention is a contact lens mounting solution, at the time of wearing or removing the contact lens, for example, 1 to 3 drops, preferably 1 to 2 drops per side, Alternatively, it may be worn after being dropped on both sides and wetted, and is preferably worn after wetting both sides of the contact lens.

Others The present invention provides an ophthalmic composition comprising (A) pranoprofen and / or a salt thereof, (B) a butyl group-containing phenol, and (C) tocopherol, pyridoxine, chondroitin sulfate, a derivative thereof, and a salt thereof. And a method of imparting or improving the effect of suppressing (improving or alleviating) a foreign body sensation to an ophthalmic composition, comprising at least one selected from the group consisting of:

  The present invention also relates to an ophthalmic composition comprising (A) pranoprofen and / or a salt thereof and (B) a butyl group-containing phenol, (C) tocopherol, pyridoxine, chondroitin sulfate, derivatives thereof, and their It includes at least one method selected from the group consisting of salts, and a method for imparting or improving the foreign body feeling suppression (improvement or alleviation) effect to the ophthalmic composition.

  The present invention also provides an ophthalmology comprising (A) pranoprofen and / or a salt thereof, and (C) at least one selected from the group consisting of tocopherol, pyridoxine, chondroitin sulfate, derivatives thereof, and salts thereof. The composition includes (B) a butyl group-containing phenol, and includes a method for imparting or improving foreign substance feeling suppression (improvement or relaxation) to the ophthalmic composition.

  The present invention also provides an ophthalmic composition comprising (A) pranoprofen and / or a salt thereof, (B) a butyl group-containing phenol, and (C) tocopherol, pyridoxine, chondroitin sulfate, a derivative thereof, and a salt thereof. And a method for imparting or improving a smooth eye suppression (improvement or alleviation) action to an ophthalmic composition, comprising at least one selected from the group consisting of:

  The present invention also relates to an ophthalmic composition comprising (A) pranoprofen and / or a salt thereof and (B) a butyl group-containing phenol, (C) tocopherol, pyridoxine, chondroitin sulfate, derivatives thereof, and their It includes at least one method selected from the group consisting of salts, and includes a method for imparting or improving the smooth eye suppression (improvement or alleviation) effect to the ophthalmic composition.

  The present invention also provides an ophthalmology comprising (A) pranoprofen and / or a salt thereof, and (C) at least one selected from the group consisting of tocopherol, pyridoxine, chondroitin sulfate, derivatives thereof, and salts thereof. The composition includes (B) a butyl group-containing phenol, and includes a method for imparting or improving the smooth eye suppression (improvement or alleviation) action to the ophthalmic composition.

  In each method of the present invention, the type, concentration, dosage form, pH, osmotic pressure, container and the like of each component are as described for the ophthalmic composition of the present invention.

Hereinafter, the units of the component amounts in each table described in the examples are all w / v%.
Test Example 1 (Barrier function improvement effect)
The influence which these culture solutions have on a corneal barrier function was evaluated using the culture solution which has each medicine with the composition of Tables 1-3.
That is, human corneal epithelial cell line HCE-T (RIKEN BioResource Center, No. RCB2280) was inserted into a Transwell (registered trademark, 24 well, Corning) insert at 1.0 × 10 ⁵ cells / well (200 μL). (N = 3). 600 μL of each drug-containing culture solution in which the final concentration of each drug in the culture solution is the concentration shown in Tables 1 to 3 is placed in the well on the reservoir side, and cultured at 37 ° C. under 5% CO ₂ for 30 minutes. did. At the same time, Comparative Example 1-1, which is the same as Comparative Example 1-2 except that it does not contain dibutylhydroxytoluene, was prepared and tested in the same manner.
After culturing, the transcorneal epithelial electrical resistance value (TER) was measured using MILLICELL (registered trademark) -ERS (manufactured by Millipore), and the increase in TER relative to Comparative Example 1-1 based on the following formula (1) The rate was calculated. The higher the TER increase rate, the stronger the barrier between corneal epithelial cells, which means that the barrier function is enhanced.

Formula (1):
TER increase rate (%) relative 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

When dibutylhydroxytoluene was blended with pranoprofen, the rate of increase in TER relative to Comparative Example 1-1 was lower than that of pranoprofen alone. It can be seen that the addition of dibutylhydroxytoluene lowers the corneal barrier and makes the foreign body feel more sensitive.
Further, by adding tocopherol acetate, pyridoxine hydrochloride, or sodium chondroitin sulfate, the TER increase rate was positive. From this, the combination of tocopherol acetate, pyridoxine hydrochloride, or sodium chondroitin sulfate not only suppressed the decrease in corneal barrier function due to dibutylhydroxytoluene, but rather improved the corneal barrier function and made it difficult to feel foreign objects. You can see that

Moreover, the rate of increase in TER was increased by blending tocopherol acetate, pyridoxine hydrochloride, or sodium chondroitin sulfate with pranoprofen. That is, the corneal barrier ability was improved, and it was difficult to feel a foreign body feeling.
The TER increase rate was further improved by further adding dibutylhydroxytoluene here. It can be seen that the addition of dibutylhydroxytoluene further improved the corneal barrier ability and made it more difficult to feel foreign matter.

Test example 2 (human eye drop test 1)
Each ophthalmic composition (eye drops) was prepared according to the formulation described in Table 4, and 13 mL was filled in an eye drop container (container body portion) made of polyethylene terephthalate having an internal volume of 14.2 mL. After filling, a polyethylene nozzle was attached to the eye drop container. Three adult subjects who are aware of “foreign sensation” and “tingling sensation (tingling sensation)” each eye drop is instilled into each of the left and right eyes, and the post-instillation feeling regarding symptoms described in Table 4 is VAS. (Visual analog scale).

Evaluation by VAS was performed as follows. On the subjective symptom survey sheet in which a 100 mm line is drawn, 0 mm is used when no improvement effect on the foreign body sensation is felt, and 100 mm is marked when the feeling is strong, and the level of the item felt by the subject is marked. This length (mm) was taken as the VAS value. That is, the higher the VAS value, the higher the awareness score of the improvement effect of each symptom.
Using this VAS value, the VAS improvement rate (%) of each test example relative to the reference comparative example was determined 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 example) / VAS value of reference example} × 100

表４の結果から、プラノプロフェンと、ジブチルヒドロキシトルエンと、酢酸トコフェロール又はコンドロイチン硫酸ナトリウムとを組み合わせて使用した場合には、異物感、チクチクする感じの効果が顕著に改善したことが分かる。

From the results of Table 4, it can be seen that the effects of foreign body sensation and tingling sensation were significantly improved when pranoprofen, dibutylhydroxytoluene and tocopherol acetate or sodium chondroitin sulfate were used in combination.

Test Example 3 (human eye drop test 2)
According to the prescription in Table 5, each ophthalmic composition (eye drops) was prepared, and “Comparative sensation” “Prickling” was performed in the same manner as in Test Example 2 except that Comparative Example 3-1 was used as a reference. The feeling of execution after instillation was evaluated for “feeling to tingle (tingling sensation)”.

  From the results in Table 5, pranoprofen, dibutylhydroxytoluene, tocopherol acetate, pyridoxine hydrochloride, and sodium chondroitin sulfate, tetrahydrozoline hydrochloride, dipotassium glycyrrhizinate, chlorpheniramine maleate, potassium aspartate, aminoethylsulfonic acid, When sodium edetate is used in combination, it can be seen that the effect on the foreign body sensation and tingling sensation is remarkably improved.

Formulation Examples Tables 6 to 9 illustrate formulation examples of eye drops representing the ophthalmic composition of the present invention. All units in the table are w / v%.
The eye drops prescribed in Preparation Examples 1 to 40 were filled in a polyethylene terephthalate container (container main body part). In addition, preparation examples 1 ′ to 40 ′ were prepared by filling the eye drops of Preparation Examples 1 to 40 into a polyethylene terephthalate container (container body portion) and equipped with a polyethylene nozzle. In addition, preparation examples 1 ″ to 40 ″ were prepared by filling the eye drops of Preparation Examples 1 to 40 into a polyethylene terephthalate container (container main body part) and equipped with a polybutylene terephthalate nozzle.

  Since the ophthalmic composition of the present invention can effectively improve the corneal barrier function, and can effectively prevent, alleviate, improve, suppress, or treat a foreign body sensation (a tingling sensation, a feeling of tingling, etc.). It is a practical ophthalmic composition.

Claims (4)

An ophthalmic composition for improving foreign material sensation, comprising the following component (A), component (B), and component (C).
(A) Planoprofen 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, derivatives thereof, and salts thereof   The ophthalmic composition according to claim 1, wherein the total content of the component (A) is 0.04 to 0.15 w / v% with respect to the total amount of the ophthalmic composition. The ophthalmic composition according to claim 1 or 2, comprising two or more of the following (i), (ii), and (iii) of 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 their salts   Furthermore, at least 1 sort (s) selected from the group which consists of aspartic acid, aminoethylsulfonic acid, tetrahydrozoline, chlorpheniramine, glycyrrhizic acid, edetic acid, and those salts is contained in any one of Claims 1-3 Ophthalmic composition.