Topical pharmaceuticals containing epinastine or its salts.

Abstract

The invention proposes a topical pharmaceutical consisting of epinastine or its salts at concentrations ranging from 0.05 to 1% (by weight) as the active ingredient, capable of maintaining the concentration of the active ingredient for a long period of time even at low concentrations.

Description

Pharmaceutical composition for topical administration containing epinastine or a salt thereof

[0001] The present invention relates to a pharmaceutical composition for topical administration containing epinastine or a salt thereof (hereinafter also referred to as "the pharmaceutical composition of the present invention").

[0002] Currently, pharmaceuticals containing epinastine or its salts include, for example, Alesion, a therapeutic agent for allergic conjunctivitis, which contains epinastine hydrochloride as an active ingredient. （登録商標） LX ophthalmic solution 0.1% is commercially available, and this ophthalmic solution is typically used with a dosage of one drop twice daily (Non-Patent Document 1). While reducing the frequency of instillation of ophthalmic solutions is considered desirable from the perspective of medication adherence, reducing the frequency of instillation may result in an inability to maintain an effective concentration in ocular tissue, potentially reducing medicinal efficacy. Therefore, maintaining an effective concentration in ocular tissue is necessary to achieve medicinal efficacy. One method for maintaining an effective concentration in ocular tissue is to increase the active ingredient concentration, but increasing the active ingredient concentration may increase the risk of side effects. In fact, Non-Patent Document 1 suggests that increasing the concentration of epinastine hydrochloride increases eye irritation, and it is believed that there is an upper limit to the concentration of the active ingredient that can be safely administered in ophthalmic solutions.

[0003] Therefore, in recent years, in an attempt to maintain an effective concentration in ocular tissues, the selection of administration methods other than eye drops has been investigated. For example, Patent Document 1 describes a transdermal preparation for treating ocular diseases (specifically, a patch) having a structure in which a paste layer containing an ocular disease therapeutic agent is provided on a support, and the preparation is applied to the skin surface, including the anterior surface of the eyelid, so that the ocular disease therapeutic agent in the paste layer is administered to local ocular tissues via skin permeation, substantially without passing through the systemic bloodstream. Also, an ophthalmic transdermal preparation for epinastine or a salt thereof has been reported as a preparation other than eye drops (Patent Document 2). Patent Document 2 reports that a patch containing a high concentration of epinastine hydrochloride (10% w / w) exhibits a prolonged antiallergic effect compared to eye drops containing 0.05% (w / v) epinastine hydrochloride.

[0004] WO2004 / 064817WO2007 / 007851

[0005] Alesion (registered trademark) LX eye drops 0.1% Pharmaceutical Interview Form

[0006] Transdermal preparations are broadly classified into patches, topical preparations, aerosol preparations, etc., among which patches are suitable for sustained delivery of the active ingredient to the affected area on the skin surface or to a local affected area through the skin surface because a base containing the active ingredient is adhered to the skin surface for a long period of time. On the other hand, patches may cause dermatitis (rash) due to prolonged contact with the skin, and this concern may be particularly heightened on the eyelid skin, which is thin and sensitive to irritation. Furthermore, Patent Document 1 describes that eye ointments, which are a type of topical preparation, have a better sustained efficacy than eye drops, but it is difficult to accurately adjust the dosage of the active ingredient and can cause vision loss upon application, indicating that they are preparations with a high risk of side effects when used to treat eye diseases. Furthermore, ointments, which are a type of liniment, are composed only of an oily base and are therefore sticky, difficult to remove by washing with water, and difficult to spread on the skin, leaving the feel of use unsatisfactory. Creams, which are also a type of liniment, are smoother than ointments, easy to remove by washing with water, and easy to spread on the skin, providing an excellent feel, but they contain hydrophilic substances and therefore contain various additives such as preservatives and surfactants, raising concerns about skin irritation.

[0007] In view of the above, in developing a transdermal formulation, for example, a formulation for topical administration, it is desirable to reduce the concentration of the active ingredient from the viewpoint of side effects, and to reduce the frequency of administration from the viewpoint of medication adherence. However, to date, no therapeutic agent for allergic conjunctivitis for topical administration that is low in skin irritation and effective with once-daily administration at a low concentration has been known, and none has been marketed as a pharmaceutical.

[0008] Therefore, it is an interesting task to provide a topical therapeutic agent for allergic conjunctivitis that is effective when administered at a low concentration once a day, particularly a new pharmaceutical composition containing epinastine or a salt thereof as an active ingredient.

[0009]

[0006] In the course of intensive research into new pharmaceutical compositions containing epinastine or a salt thereof as an active ingredient, the present inventors have found that when a pharmaceutical composition containing low concentrations of epinastine or a salt thereof is administered to the eyelid skin, the active ingredient retained in the eyelid skin tissue gradually migrates to the ocular tissue, thereby maintaining the concentration of the active ingredient in the ocular tissue for a long period of time and further exhibiting therapeutic effects as a therapeutic agent for allergic conjunctivitis. In addition, they have found that a pharmaceutical composition containing low concentrations of epinastine or a salt thereof causes little skin irritation, minimizing safety concerns even when administered to the eyelid skin, which is thin and sensitive to irritation, and that adjusting the viscosity of the formulation provides an excellent feel when used, leading to the completion of the present invention.

[0010] Specifically, the present invention provides the following: (1) A pharmaceutical composition for topical administration containing epinastine or a salt thereof at a concentration of 0.05 to 1% (w / w) as an active ingredient. (2) The pharmaceutical composition according to (1), which is used for administration to the eyelid skin. (3) The pharmaceutical composition according to (1) or (2), which is used to be administered to a patient once daily. (4) The pharmaceutical composition according to any one of (1) to (3), which is used for treating allergic conjunctivitis. (5) The pharmaceutical composition according to any one of (1) to (4), which has a viscosity of 150 Pa s or less at 20°C. (6) The pharmaceutical composition according to any one of (1) to (5), which is in the form of an ointment, cream, or gel. (7) The pharmaceutical composition according to any one of (1) to (5), which is in the form of a cream. (8) The pharmaceutical composition according to any one of (1) to (7), which is in the form of a water-in-oil emulsion. (9) The pharmaceutical composition according to any one of (1) to (8), which is epinastine or a salt thereof at a concentration of 0.05% (w / w). (10) The pharmaceutical composition according to any one of (1) to (8), which is epinastine or a salt thereof at a concentration of 0.5% (w / w). (11) The pharmaceutical composition according to any one of (1) to (10), wherein epinastine or a salt thereof is epinastine hydrochloride. (12) The pharmaceutical composition according to any one of (1) to (10), wherein epinastine or a salt thereof is epinastine. (13) The pharmaceutical composition according to any one of (1) to (12), which contains one or more oil components selected from the group consisting of hydrocarbons, waxes, fats and oils, aliphatic carboxylic acids or salts thereof, fatty acid esters, and higher alcohols. (14) The pharmaceutical composition according to any one of (1) to (12), which contains a surfactant. (15) The pharmaceutical composition according to (14), wherein the surfactant is a glycerin fatty acid ester. (16) The pharmaceutical composition according to (14) or (15), wherein the surfactant has an HLB of 3.0 to 6.0. (17) The pharmaceutical composition according to any one of (1) to (16), which does not contain parabens. (18) A pharmaceutical composition for topical administration, which contains epinastine or a salt thereof at a concentration of 0.05 to 0.5% (w / w) as an active ingredient, and is a water-in-oil emulsion cream characterized in that it is used to be administered to the eyelid skin once a day.(19) A pharmaceutical composition for topical administration, which is a water-in-oil emulsion cream containing epinastine or a salt thereof at a concentration of 0.5% (w / w) as an active ingredient, and is used to be administered once daily to the eyelid skin. (20) A method for transferring a therapeutically effective amount of epinastine to ocular tissue by administering to the eyelid skin a pharmaceutical composition containing epinastine or a salt thereof at a concentration of 0.05 to 1% (w / w) as an active ingredient. (21) A method for sustained release of a therapeutically effective amount of epinastine from the eyelid skin to ocular tissue by administering to the eyelid skin a pharmaceutical composition containing epinastine or a salt thereof at a concentration of 0.05 to 1% (w / w) as an active ingredient. (22) The method according to (20) or (21), which is used to be administered once daily to a patient. (23) The method according to any one of (20) to (22), wherein the ocular tissue is the conjunctiva.

[0011] The present invention further provides the following: (24) A method for treating allergic conjunctivitis, comprising administering a therapeutically effective amount of the pharmaceutical composition according to any one of (1) to (19) to a patient in need of such treatment. (25) Use of the pharmaceutical composition according to any one of (1) to (19) for producing a medicament for treating allergic conjunctivitis.

[0012] It should be noted that any two or more of the above configurations (1) to (25) can be selected and combined.

[0013] According to the present invention, it is possible to provide a pharmaceutical composition for topical administration containing epinastine or a salt thereof as an active ingredient, which has sufficient therapeutic effect even at a low concentration and with a reduced frequency of administration.

[0014] The present invention allows epinastine to be used at a low concentration, ensuring sufficient safety as a pharmaceutical. Furthermore, the present invention has low skin irritation, minimizing safety concerns even when administered to irritation-sensitive tissues (e.g., eyelid skin).

[0015] The present invention can improve the feel of a pharmaceutical composition when used by adjusting the viscosity of the pharmaceutical composition, for example, by adjusting the viscosity at 20° C. to 150 Pa·s or less.

[0016] The present invention will be described in detail below.

[0017] In the present invention, "epinastine" refers to a compound represented by the chemical name (±)-3-Amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine, and also has the following formula: It is a compound represented by the formula:

[0018] In the pharmaceutical composition of the present invention, the epinastine contained therein may be a racemate or an optical isomer.

[0019] In the pharmaceutical composition of the present invention, epinastine may be contained in the form of a salt, and there are no particular limitations on the salt as long as it is a pharmaceutically acceptable salt. Examples of salts include salts with inorganic acids and salts with organic acids.

[0020] Examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.

[0021] Examples of salts with organic acids include salts with acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptoic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, alanine, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, sulfosalicylic acid, and the like.

[0022] As a salt of epinastine, the monohydrochloride salt (epinastine hydrochloride) is particularly preferred.

[0023] In the pharmaceutical composition of the present invention, epinastine or a salt thereof may be in the form of a hydrate or solvate.

[0024] When preparing the pharmaceutical composition of the present invention, the form of epinastine in the pharmaceutical composition may be a salt of epinastine, but in order to more efficiently improve transdermal absorption, it is more preferable that epinastine is in free form.In the manufacturing process of the pharmaceutical composition of the present invention, the pharmaceutical composition may be prepared using free form epinastine, or a salt of epinastine (e.g., epinastine hydrochloride) and an appropriate amount of base (e.g., sodium hydroxide) may be used to desalt during the process, thereby producing free form epinastine in the pharmaceutical composition.

[0025] In the pharmaceutical composition of the present invention, epinastine or a salt thereof may be present in an amount sufficient to achieve the desired therapeutic effect as a pharmaceutical; however, if the content is too low, it is difficult to achieve the desired efficacy. Furthermore, if the content is too high, for example, when administered to the skin, a large amount of components will remain in the skin tissue at the administration site, increasing the risk of unexpected side effects, and in the event of side effects, it is difficult to remove the components remaining in the skin tissue. The lower limit of the epinastine or a salt thereof content is, for example, 0.01% (w / w), preferably 0.03% (w / w), and more preferably 0.05% (w / w). The upper limit is, for example, 3% (w / w), preferably 2% (w / w), and more preferably 1% (w / w) or less than 1% (w / w). Furthermore, in the pharmaceutical composition of the present invention, the content of epinastine or a salt thereof is preferably 0.03 to 2% (w / w), more preferably 0.05 to 1% (w / w) or 0.05 to less than 1% (w / w), even more preferably 0.05 to 0.5% (w / w), and particularly preferably 0.1 to 0.5% (w / w). Furthermore, the content of epinastine or a salt thereof is preferably 0.05% (w / w), 0.1% (w / w), 0.2% (w / w), 0.25% (w / w), 0.3% (w / w), 0.4% (w / w), 0.5% (w / w), 0.6% (w / w), 0.7% (w / w), 0.75% (w / w), 0.8% (w / w), 0.9% (w / w), or 1% (w / w), with 0.5% (w / w) being particularly preferred.

[0026] In the present invention, "% (w / w)" means the mass (g) of the target ingredient contained in 100 g of the pharmaceutical composition of the present invention. When a salt of epinastine is contained in the present invention, the value is the content of the epinastine salt. Furthermore, when epinastine or a salt thereof is formulated in the form of a hydrate or solvate in the present invention, the value is the content of the hydrate or solvate of epinastine or a salt thereof. The same applies hereinafter unless otherwise specified.

[0027] The pharmaceutical composition of the present invention is preferably used for transdermal administration by application (topical administration), but may also be used for parenteral (for example, topical) administration such as transdermal administration other than topical administration.

[0028] The pharmaceutical composition of the present invention can be prepared as an external preparation or as an external preparation for transdermal administration. The pharmaceutical composition of the present invention is preferably prepared as an external preparation for topical administration. Furthermore, the pharmaceutical composition of the present invention is preferably an ophthalmic external preparation, more preferably an ophthalmic transdermal absorption preparation, and even more preferably an ophthalmic topical administration preparation.

[0029] The dosage form of the pharmaceutical composition of the present invention is not particularly limited as long as it is usable as a pharmaceutical, and examples thereof include ointments, creams, gels, external liquid preparations (lotions, liniments), external solid preparations (external powders), etc. The pharmaceutical composition of the present invention is preferably an ointment, cream, gel, or external liquid preparation, more preferably an ointment, cream, or gel, and particularly preferably a cream.

[0030] These can be prepared according to methods conventional in the art.

[0031] The pharmaceutical composition of the present invention is preferably administered near the eye. "Near the eye" refers to the eyelids, such as the upper eyelid and lower eyelid, and their vicinity, or the area around the orbit, including the eyelid skin and the skin in the vicinity, or the skin around the orbit. Administration near the eye includes, for example, application to the eyelid skin and its vicinity of the upper eyelid, lower eyelid, or both, or application to the skin around the orbit. Note that the eyelid margin may be included in the vicinity of the eye, but because blinking can cause a portion of the pharmaceutical composition administered to the eyelid margin to come into contact with the sensitive ocular surface, increasing the likelihood of eye irritation, it is more preferable not to administer the composition to the eyelid margin, and even more preferable not to administer the composition intraocularly.

[0032] When administering the pharmaceutical composition of the present invention near the eye, the eyelid skin is a very thin and soft tissue, and strong pressure on the eyelid skin may cause pain in the underlying eyeball or affect vision. Therefore, when administering the pharmaceutical composition of the present invention, it is preferable to spread the composition smoothly and evenly on the eyelid skin rather than applying it by spreading it on the eyelid skin while applying strong pressure. Furthermore, when the pharmaceutical solution is a liquid such as water, it can be easily applied to the eyelid skin without pressure, but there is a risk that the pharmaceutical solution may drip into the eyes or mouth, causing irritation or discomfort. Therefore, it is preferable that the pharmaceutical composition of the present invention has a viscosity that does not drip when administered to the eyelid skin.

[0033] In the pharmaceutical composition of the present invention, the viscosity at 20°C is, for example, 300 Pa·s (Pascal·second) or less, preferably 200 Pa·s or less, more preferably 150 Pa·s or less, even more preferably 100 Pa·s or less, and particularly preferably 80 Pa·s or less. Alternatively, the viscosity is, for example, 0.001 Pa·s or more, preferably 0.01 Pa·s or more, more preferably 0.1 Pa·s or more, even more preferably 1 Pa·s or more, and particularly preferably 10 Pa·s or more. Alternatively, the viscosity is, for example, 0.001 to 300 Pa·s, preferably 0.01 to 200 Pa·s, more preferably 0.1 to 150 Pa·s, even more preferably 1 to 100 Pa·s, and particularly preferably 10 to 80 Pa·s. More preferably, the viscosity is, for example, 5 to 150 Pa s, 5 to 100 Pa s, 10 to 150 Pa s, or 10 to 100 Pa s. The viscosity of the pharmaceutical composition of the present invention can be measured, for example, by the viscosity measurement method described in the General Test Methods of the 17th Edition of the Japanese Pharmacopoeia.

[0034] Pharmaceutical additives may be used in the pharmaceutical composition of the present invention as needed, for example, pH adjusters, buffers, isotonicity agents, thickeners, stabilizers, antioxidants, preservatives, surfactants, cooling agents, oil components, etc. These may be used alone or in appropriate combinations of two or more, and may be blended in appropriate amounts.

[0035] When a pH adjuster is added to the pharmaceutical composition of the present invention, a pH adjuster that can be used as an additive for pharmaceuticals can be appropriately added. Examples of pH adjusters include acids and bases. Examples of acids include hydrochloric acid, phosphoric acid, acetic acid, citric acid, and salts thereof, and examples of bases include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, and the like. These may also be hydrates or solvates. Note that bases may be added for the purpose of desalting epinastine salts to produce free epinastine.

[0036] The pH of the pharmaceutical composition of the present invention may be within a pharmaceutically acceptable range, for example, 4.0 to 8.5 or 4.0 to 8.0, preferably 6.0 to 8.0, and more preferably 6.5 to 7.5. A particularly preferred pH is 6.7 to 7.3. For example, the pH may be 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, or 7.3.

[0037] When a buffer is added to the pharmaceutical composition of the present invention, any buffer usable as an additive for pharmaceuticals can be appropriately added. Examples of the buffer include phosphoric acid or a salt thereof, boric acid, borax, trometamol, organic acids or salts thereof, and hydrates or solvates thereof.

[0038] Examples of phosphoric acid or a salt thereof include phosphoric acid, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate.

[0039] Examples of organic acids include citric acid, acetic acid, ε-aminocaproic acid, gluconic acid, fumaric acid, lactic acid, ascorbic acid, succinic acid, maleic acid, malic acid, and amino acids, and examples of salts thereof include sodium salts and potassium salts.

[0040] When a buffer is incorporated into the pharmaceutical composition of the present invention, the content of the buffer can be adjusted appropriately depending on the type of buffer, and is, for example, 0.01 to 5% (w / w), preferably 0.05 to 3% (w / w), more preferably 0.1 to 2% (w / w), and even more preferably 0.1 to 1% (w / w), although this does not apply when the buffer also has an effect other than that of a buffer. Furthermore, when a buffer is incorporated into the pharmaceutical composition of the present invention, one type of buffer may be used, or two or more types of buffers may be used together.

[0041] The phosphoric acid or a salt thereof and the organic acid or a salt thereof incorporated in the pharmaceutical composition of the present invention may act as a pH adjuster and a buffering agent.

[0042] When an isotonicity adjusting agent is added to the pharmaceutical composition of the present invention, the isotonicity adjusting agent can be any isotonicity adjusting agent that can be used as an additive for pharmaceuticals. Examples of the isotonicity adjusting agent include ionic isotonicity adjusting agents and nonionic isotonicity adjusting agents. Ionic isotonicity adjusting agents are preferred.

[0043] Examples of ionic tonicity agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and the like, and may be hydrates or solvates of these.

[0044] Examples of non-ionic tonicity agents include glycerin (concentrated glycerin), propylene glycol, 1,3-butylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose, and xylitol, and these may also be hydrates or solvates.

[0045] When an isotonicity agent is incorporated into the pharmaceutical composition of the present invention, the content of the isotonicity agent can be adjusted appropriately depending on the type of isotonicity agent, and is, for example, 0.01 to 5% (w / w), preferably 0.05 to 3% (w / w), more preferably 0.1 to 2% (w / w), and even more preferably 0.1 to 1% (w / w), although this does not apply when the isotonicity agent also has an effect other than that of an isotonicity agent. Furthermore, when an isotonicity agent is incorporated into the pharmaceutical composition of the present invention, one or more isotonicity agents may be used together.

[0046] When a thickener is incorporated into the pharmaceutical composition of the present invention, the thickener can be any thickener that can be used as an additive for pharmaceuticals. Examples of thickeners include cellulose-based polymers, polyvinylpyrrolidone, carboxyvinyl polymers, mucopolysaccharides, or polyhydric alcohols, and may also include salts, hydrates, or solvates thereof. Examples of cellulose-based polymers include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, and cellulose acetate phthalate. Examples of carboxyvinyl polymers include carbopol. Examples of polyhydric alcohols include polyvinyl alcohol and polyethylene glycol. Examples of mucopolysaccharides include hyaluronic acid, sodium hyaluronate, and chondroitin sulfate. Cellulose-based polymers are preferred.

[0047] When a thickener is incorporated into the pharmaceutical composition of the present invention, the content of the thickener can be adjusted appropriately depending on the type of thickener, for example, 0.01 to 20% (w / w), preferably 0.1 to 10% (w / w), and more preferably 1 to 10% (w / w), although this does not apply if the thickener also has an effect other than that of a thickener. Furthermore, if the pharmaceutical composition of the present invention is in the form of a gel, the thickener may be contained in an amount of, for example, 20% (w / w) or more. Furthermore, when a thickener is incorporated into the pharmaceutical composition of the present invention, one or more thickeners may be used together.

[0048] When a stabilizer is added to the pharmaceutical composition of the present invention, a stabilizer that can be used as an additive for pharmaceuticals can be appropriately added. Examples of stabilizers include edetic acid or a salt thereof, cyclodextrin, etc., and hydrates or solvates thereof. Edetic acid or a salt thereof is preferred.

[0049] Examples of edetic acid or salts thereof include edetic acid, disodium edetate (sodium edetate), tetrasodium edetate, and the like.

[0050] When a stabilizer is incorporated into the aqueous pharmaceutical composition of the present invention, the content of the stabilizer can be adjusted appropriately depending on the type of stabilizer, and is, for example, 0.01 to 5% (w / w), preferably 0.01 to 3% (w / w), and more preferably 0.01 to 1% (w / w), although this does not apply when the stabilizer also has an effect other than as a stabilizing agent. Furthermore, when a stabilizer is incorporated into the pharmaceutical composition of the present invention, one type of stabilizer may be used, or two or more types of stabilizers may be used together.

[0051] When an antioxidant is incorporated into the pharmaceutical composition of the present invention, an antioxidant that can be used as an additive for pharmaceuticals can be appropriately incorporated. Examples of antioxidants include ascorbic acid, sodium ascorbate, tocopherol, tocopherol acetate, citric acid, sodium citrate, potassium citrate, dibutylhydroxytoluene, propyl gallate, cysteine, N-acetylcysteine, methionine, sodium bisulfite, sodium sulfite, sodium thiosulfate, benzotriazole, and 2-mercaptobenzimidazole, and may also be hydrates or solvates thereof. Furthermore, when the antioxidant contained has a chiral center, it may be a racemate or an optical isomer. Preferred are dibutylhydroxytoluene and 2-mercaptobenzimidazole.

[0052] When an antioxidant is incorporated into the aqueous pharmaceutical composition of the present invention, the content of the antioxidant can be adjusted appropriately depending on the type of antioxidant, and is, for example, 0.01 to 2% (w / w), preferably 0.01 to 1% (w / w), and more preferably 0.01 to 0.5% (w / w), although this does not apply when the antioxidant also has an effect other than that of an antioxidant. Furthermore, when an antioxidant is incorporated into the pharmaceutical composition of the present invention, one type of antioxidant may be used, or two or more types of antioxidants may be used together.

[0053] When a preservative is added to the pharmaceutical composition of the present invention, the preservative can be any preservative that can be used as an additive in pharmaceuticals, and examples thereof include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, chlorhexidine gluconate, chlorhexidine hydrochloride, parabens, sodium chlorite, phenoxyethanol, thymol, sorbic acid, chlorobutanol, etc. Examples of parabens include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, etc.

[0054] When a preservative is incorporated into the pharmaceutical composition of the present invention, the content of the preservative can be appropriately adjusted depending on the type of preservative, for example, 0.001 to 1% (w / w), although this is not limited thereto if the preservative also has an effect other than that of a preservative. Furthermore, when a preservative is incorporated into the pharmaceutical composition of the present invention, one type of preservative or two or more types of preservatives may be used together.

[0055] If the pharmaceutical composition of the present invention can exhibit the preservative effectiveness required for pharmaceuticals without containing a preservative, it is preferable to not include a preservative, for example, it is preferable to not include a paraben. The preservative effectiveness required for pharmaceuticals is determined by the criteria for each formulation classification, for example, in the Japanese Pharmacopoeia, 17th Edition, and each formulation is recognized as having preservative effectiveness if it meets these criteria. Furthermore, since epinastine or a salt thereof exhibits preservative effectiveness depending on the concentration at which it is incorporated, the pharmaceutical composition of the present invention can exhibit the desired preservative effectiveness without incorporating parabens, depending on the type of formulation. The desired preservative effectiveness refers, for example, to compliance with the preservative effectiveness test method described in the Japanese Pharmacopoeia, 17th Edition. Furthermore, the absence of a preservative can reduce irritation when the pharmaceutical composition of the present invention is applied to the skin.

[0056] When a surfactant is added to the pharmaceutical composition of the present invention, any surfactant that can be used as an additive for pharmaceuticals can be appropriately added. Examples of surfactants include cationic surfactants, anionic surfactants, and nonionic surfactants.

[0057] Examples of cationic surfactants include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyl diethylamine salts, fatty acid polyamine condensates, alkylimidazolines, 1-acylaminoethyl-2-alkylimidazolines, and 1-hydroxylethyl-2-alkylimidazolines.

[0058] Examples of anionic surfactants include sodium alkylbenzenesulfonate, sodium dodecyl sulfate, and phospholipids such as lecithin.

[0059] Examples of nonionic surfactants include polyoxyethylene fatty acid esters, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyl castor oil, polyoxyethylene polyoxypropylene glycol, polyoxyethylene polyoxypropylene cetyl ether, polyoxyethylene alkyl ethers, glycerin fatty acid esters, and sucrose fatty acid esters. Examples of polyoxyethylene fatty acid esters include polyoxyl 40 stearate, polyoxyl 45 stearate, polyoxyl 55 stearate, polyethylene glycol myristate, polyethylene glycol monooleate, polyethylene glycol monostearate, polyethylene glycol monoisostearate, and polyethylene glycol monolaurate. Examples of sorbitan fatty acid esters include sorbitan caprylate, sorbitan laurate, sorbitan stearate, sorbitan isostearate, sorbitan tristearate, sorbitan behenate, sorbitan tribehenate, sorbitan oleate, and sorbitan trioleate. Examples of polyoxyethylene sorbitan fatty acid esters include polysorbate 80, polysorbate 60, polysorbate 40, polysorbate 20, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, and polysorbate 65. Examples of polyoxyethylene hydrogenated castor oils include polyoxyethylene hydrogenated castor oil 5, polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 20, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, and polyoxyethylene hydrogenated castor oil 100. Examples of polyoxyl castor oils include polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, and polyoxyl 40 castor oil. Examples of polyoxyethylene polyoxypropylene glycols include polyoxyethylene (3) polyoxypropylene (17) glycol, polyoxyethylene (20) polyoxypropylene (20),Examples of polyoxyethylene polyoxypropylene cetyl ethers include polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (120) polyoxypropylene (40) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, and polyoxyethylene (196) polyoxypropylene (67) glycol. Examples of polyoxyethylene polyoxypropylene cetyl ethers include polyoxyethylene (20) polyoxypropylene (4) cetyl ether and polyoxyethylene (20) polyoxypropylene (8) cetyl ether. Examples of polyoxyethylene alkyl ethers include polyoxyethylene cetyl ether, polyoxyethylene lauryl ether, polyoxyethylene behenyl ether, and polyoxyethylene arachyl ether. Examples of glycerin fatty acid esters include glyceryl monocaprylate, glyceryl dicaprylate, glyceryl tricaprylate, polyglyceryl monocaprylate, polyglyceryl dicaprylate, polyglyceryl tricaprylate, glyceryl monocaprate, glyceryl dicaprate, glyceryl tricaprate, polyglyceryl monocaprate, polyglyceryl dicaprate, polyglyceryl tricaprate, glyceryl monolaurate, glyceryl dilaurate, glyceryl trilaurate, polyglyceryl monolaurate, polyglyceryl dilaurate, polyglyceryl trilaurate, glyceryl monomyristate, Glyceryl dimyristate, glyceryl trimyristate, polyglyceryl monomyristate, polyglyceryl dimyristate, polyglyceryl trimyristate, glyceryl monopalmitate, glyceryl dipalmitate, glyceryl tripalmitate, polyglyceryl monopalmitate, polyglyceryl dipalmitate, polyglyceryl tripalmitate, glyceryl monostearate, glyceryl distearate, glyceryl tristearate, polyglyceryl monostearate, polyglyceryl distearate, polyglyceryl tristearate, glyceryl monoisostearate, glyceryl diisostearate,Glyceryl triisostearate, Polyglyceryl monoisostearate, Polyglyceryl diisostearate, Polyglyceryl triisostearate, Glyceryl monobehenate, Glyceryl dibehenate, Glyceryl tribehenate, Polyglyceryl monobehenate, Polyglyceryl dibehenate, Polyglyceryl tribehenate, Glyceryl monooleate, Glyceryl dioleate, Glyceryl trioleate, Polyglyceryl monooleate, Polyglyceryl dioleate, Polyglyceryl trioleate, Glyceryl monolinoleate, Glyceryl dilinoleate, Glyceryl trilinoleate, Polyglyceryl monolinoleate, Polyglyceryl dilinoleate, Polyglyceryl trilinoleate, Glyceryl monolinolenate, Di Examples of the polyglyceryl ester include glyceryl linolenate, glyceryl trilinolenate, polyglyceryl monolinolenate, polyglyceryl dilinolenate, polyglyceryl trilinolenate, glyceryl monoricinoleate, glyceryl diricinoleate, glyceryl triricinoleate, polyglyceryl monoricinoleate, polyglyceryl diricinoleate, polyglyceryl triricinoleate, condensed polyglyceryl ricinoleate (also referred to as polyglyceryl polyricinoleate, condensed polyglyceryl ricinoleate, or polyglyceryl polyricinoleate), glyceryl monoarachidonate, glyceryl diarachidonate, glyceryl triarachidonate, polyglyceryl monoarachidonate, polyglyceryl diarachidonate, and polyglyceryl triarachidonate. Examples of sucrose fatty acid esters include sucrose stearate, sucrose palmitate, and sucrose oleate. Nonionic surfactants are more preferred, and glycerin fatty acid esters are even more preferred. For example, condensed polyglyceryl ricinoleate is used.

[0060] When a surfactant is incorporated into the pharmaceutical composition of the present invention, the content of the surfactant can be adjusted appropriately depending on the type of surfactant, for example, 0.1 to 20% (w / w), preferably 0.5 to 10% (w / w), and more preferably 1 to 5% (w / w). However, this does not apply if the surfactant also has an activity other than that of a surfactant. Furthermore, when a surfactant is incorporated into the pharmaceutical composition of the present invention, one or more surfactants may be used together, or a mixture of two or more surfactants may be used. Surfactants are characterized by the balance between the hydrophilic and lipophilic portions of their molecules and have a hydrophilic-lipophilic balance (HLB) number. The HLB number increases with increasing hydrophilicity, and the HLB number may vary depending on the manufacturer, even if the ingredient name is the same. When a surfactant is incorporated into the pharmaceutical composition of the present invention, the HLB of the surfactant is not particularly limited as long as it can be prepared as a formulation for topical administration, and is, for example, 1 to 20, preferably 1.0 to 10.0, more preferably 2.0 to 8.0, and even more preferably 3.0 to 6.0. Nonionic surfactants with an HLB of 1.0 to 10.0 are preferred, nonionic surfactants with an HLB of 2.0 to 8.0 are more preferred, and nonionic surfactants with an HLB of 3.0 to 6.0 are even more preferred. Glycerin fatty acid esters with an HLB of 1.0 to 10.0 are preferred, glycerin fatty acid esters with an HLB of 2.0 to 8.0 are more preferred, and glycerin fatty acid esters with an HLB of 3.0 to 6.0 are even more preferred.Examples of glycerin fatty acid esters having an HLB of 3.0 to 6.0 include glyceryl monostearate, diglyceryl monostearate (polyglyceryl-2 stearate), tetraglyceryl monostearate (polyglyceryl-4 stearate), glyceryl monoisostearate, diglyceryl monoisostearate (polyglyceryl-2 isostearate), decaglyceryl pentastearate (polyglyceryl-10 pentastearate), decaglyceryl pentaisostearate (polyglyceryl-10 pentaisostearate), glyceryl myristate, polyglyceryl ricinoleate, condensed polyglyceryl ricinoleate, diglyceryl monooleate (polyglyceryl-2 oleate), tetraglyceryl monooleate (polyglyceryl-4 oleate), decaglyceryl pentaoleate (polyglyceryl-10 pentaoleate), and the like.

[0061] When a cooling agent is added to the pharmaceutical composition of the present invention, any cooling agent that can be used as an additive for pharmaceuticals can be appropriately added. Examples of cooling agents include terpenoids and essential oils containing terpenoids.

[0062] Examples of terpenoids include menthol, camphor, borneol, geraniol, nerol, cineole, citronellol, carvone, anethole, eugenol, limonene, linalool, and linalyl acetate, and they may be in the d-, l-, or dl-form.

[0063] Examples of essential oils containing terpenoids include eucalyptus oil, bergamot oil, peppermint oil, fennel oil, rose oil, cinnamon oil, spearmint oil, camphor oil, cool mint, and peppermint oil.

[0064] When a cooling agent is incorporated into the pharmaceutical composition of the present invention, the content of the cooling agent can be appropriately adjusted depending on the type of cooling agent, and is, for example, 0.001 to 1% (w / w). When a cooling agent is incorporated into the pharmaceutical composition of the present invention, one type of cooling agent or two or more types of cooling agents may be used together.

[0065] When an oil component is incorporated into the pharmaceutical composition of the present invention, the content of the oil component may be any oil component that can be used as an additive for pharmaceuticals. Examples of oil components include hydrocarbons, waxes, fats and oils, aliphatic carboxylic acids or salts thereof, fatty acid esters, medium-chain fatty acid triglycerides (MCTs), and higher alcohols.

[0066] Examples of hydrocarbons include petrolatum, white petrolatum, liquid paraffin (light liquid paraffin, heavy liquid paraffin), solid paraffin (paraffin), squalene, squalane, ceresin, microcrystalline wax, etc., and mixtures of these may also be used, such as a mixture of paraffin and microcrystalline wax.

[0067] Examples of waxes include beeswax, white beeswax, and lanolin.

[0068] Examples of fats and oils include olive oil, castor oil, sesame oil, and soybean oil.

[0069] Examples of aliphatic carboxylic acids include short-chain fatty acids such as butyric acid, valeric acid, and caproic acid, medium-chain fatty acids such as caprylic acid and capric acid, long-chain fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, linoleic acid, linolenic acid, ricinoleic acid (ricinoleic acid), and arachidonic acid, and aliphatic dicarboxylic acids such as succinic acid, glutaric acid, adipic acid, and sebacic acid, including branched aliphatic carboxylic acids. Examples of salts of aliphatic carboxylic acids include sodium salts of these.

[0070] In the present invention, the term "fatty acid ester" refers to a compound in which an alcohol is ester-bonded to a carboxyl group of an aliphatic carboxylic acid. Examples of the alcohol that may be ester-bonded to the carboxyl group of the aliphatic carboxylic acid include monohydric alcohols such as methanol, ethanol, n-propanol, n-butanol, n-pentanol, n-hexanol, n-heptanol, n-octanol, isopropanol, isobutanol, sec-butanol, and isopentanol, polyhydric alcohols such as ethylene glycol, diethylene glycol, propylene glycol, butylene glycol, and glycerin, and multimers (polymers) of polyhydric alcohols such as dipolyethylene glycol, polyethylene glycol, dipropylene glycol, polypropylene glycol, diglycerin, triglycerin, and polyglycerin. Examples include polyethylene glycol laurate, isopropyl myristate, octyl myristate, glycol palmitate, polyethylene glycol stearate, isopropyl oleate, propylene glycol linoleate, ethyl linolenate, ethylene glycol ricinoleate (ricinoleic acid), diisopropyl adipate, etc. When the aliphatic ester has two or more ester bonds, the alcohols constituting the ester bonds may be the same or different.

[0071] Examples of higher alcohols include lauryl alcohol, myristyl alcohol, palmityl alcohol (cetyl alcohol), stearyl alcohol, behenyl alcohol, oleyl alcohol, linolyl alcohol, linolenyl alcohol, and octyldodecanol.

[0072] When the oil component incorporated in the pharmaceutical composition of the present invention acts as a surfactant, the oil component may be read as a surfactant.

[0073] When the oil component incorporated in the pharmaceutical composition of the present invention acts as a solubilizer (solubilizer), the oil component may be interpreted as a solubilizer.

[0074] When an oil component is incorporated into the pharmaceutical composition of the present invention, the content of the oil component can be adjusted appropriately depending on the type of oil component, and is, for example, 0.1 to 50% (w / w), preferably 1 to 40% (w / w), and more preferably 10 to 30% (w / w). However, if the pharmaceutical composition of the present invention is in the form of an ointment, the content may be, for example, 50% (w / w) or more. Furthermore, when an oil component is incorporated into the pharmaceutical composition of the present invention, one type of oil component or two or more types of oil components may be used together.

[0075] The pharmaceutical composition of the present invention may further contain a solvent and / or dispersion medium. In the pharmaceutical composition of the present invention containing a solvent and / or dispersion medium, all of the components may be dissolved or partially suspended, or the composition may be in the form of an emulsion or semi-solid. Examples of the solvent and / or dispersion medium include, but are not limited to, water, ethanol, polyol (e.g., glycerin (glycerol), propylene glycol, 1,3-butylene glycol, liquid polyethylene glycol, macrogol, etc.), etc.

[0076] When a solvent and / or dispersion medium is blended into the pharmaceutical composition of the present invention, the content of the solvent and / or dispersion medium can be appropriately adjusted depending on the type of the solvent and / or dispersion medium, but is preferably 10% (w / w) or more, and more preferably 30% (w / w) or more, based on the total weight of the pharmaceutical composition. Furthermore, when a solvent and / or dispersion medium is blended into the pharmaceutical composition of the present invention, one type of solvent and / or dispersion medium may be used, or two or more types of solvents and / or dispersion media may be used together.

[0077] When the pharmaceutical composition of the present invention is used as an emulsion, the pharmaceutical composition of the present invention may be an oil-in-water emulsion (an emulsion consisting of oily droplets dispersed in an aqueous phase with an aqueous phase as the continuous phase) or a water-in-oil emulsion (an emulsion consisting of aqueous droplets dispersed in an oil with an oil phase as the continuous phase). The pharmaceutical composition of the present invention is preferably a water-in-oil emulsion.

[0078] The average size of the oily or aqueous droplets is, for example, 20 to 3000 nm, preferably 50 to 2000 nm, more preferably 100 to 1000 nm, and even more preferably 200 to 800 nm.

[0079] The pharmaceutical composition of the present invention can be produced according to conventional methods commonly used in the art. For example, it can be produced by mixing, in addition to the active ingredient, additives such as stabilizers, antioxidants, preservatives, surfactants, oil components, and solvents and / or dispersion media such as water. If necessary, it can also be produced as a sterile preparation according to conventional sterilization methods commonly used in the art. The sterilization method is not particularly limited as long as it is a method that can be used during the manufacturing process, and examples include autoclaving, filtration sterilization, dry heat sterilization, electron beam (EB) sterilization, gamma ray sterilization, ethylene oxide gas (EOG) sterilization, and hydrogen peroxide gas sterilization.

[0080] Unless otherwise specified, the pharmaceutical composition of the present invention may contain a pharmaceutically active ingredient other than epinastine or a salt thereof. Examples of other pharmaceutically active ingredients include anti-inflammatory agents, antibacterial agents, antiviral agents, vitamins, vasoconstrictors, mydriatics, miotics, intraocular pressure-lowering agents, dry eye treatment agents, and local anesthetics. In addition, the pharmaceutical composition of the present invention may contain epinastine or a salt thereof as the only active ingredient.

[0081] The pharmaceutical composition of the present invention is particularly useful as a therapeutic agent for allergic conjunctivitis. In the present invention, "treatment of allergic conjunctivitis" includes any treatment of allergic conjunctivitis and its symptoms (e.g., improvement, alleviation, inhibition of progression, etc.) and prevention thereof.

[0082] In the present invention, "ocular tissue" includes, for example, the conjunctiva, cornea, tears, aqueous humor, anterior chamber, etc. In particular, for the treatment of allergic conjunctivitis, it is preferable that epinastine or a salt thereof is transferred into the conjunctiva.

[0083] In the present invention, the term "patient" refers not only to humans but also to other animals, such as dogs, cats, and horses. The patient is preferably a mammal, more preferably a human. In the present invention, the term "therapeutically effective amount" refers to an amount that produces a therapeutic effect on a disease and its symptoms, or an amount that delays the progression of a disease and its symptoms, compared to an untreated subject.

[0084] The pharmaceutical composition of the present invention is preferably administered once a day, but the dosage is not particularly limited as long as it is sufficient to achieve the desired medicinal effect.

[0085] When the pharmaceutical composition of the present invention is used as an ointment, cream, or gel, the dosage is not particularly limited as long as it is sufficient to achieve the desired efficacy, and will vary depending on the content of the active ingredient and the patient. For example, in the case of a cream, for example, for an adult, an appropriate amount per administration, specifically about 1 mg to about 5 g, preferably about 5 mg to about 1 g, more preferably about 10 mg to about 500 mg, and particularly preferably about 20 mg to about 100 mg, can be applied to the skin. For example, the dosage is 30 mg. As an example of administration, when the pharmaceutical composition of the present invention is used as an ophthalmic topical administration formulation, the patient themselves takes an appropriate amount of the pharmaceutical composition, for example, about 20 to about 40 mg, on their finger, distributes it so that half is applied to the upper eyelid skin and half is applied to the lower eyelid skin of one eye, and then applies it in the same way to the other eye. In actual use, the patient may use the pharmaceutical composition by eyeballing it without weighing it, using the above-mentioned dosage per eye as a guide. Although it depends on the size and shape of the container in which the pharmaceutical composition of the present invention is stored, as a guideline for the dosage, the amount of drug placed on an adult's index finger from the tip to the first joint is defined as 1 FTU (1 fingertip unit), and for example, 0.5 FTU or 1 FTU may be taken out and used.

[0086] When applied to the skin, the application time is preferably 0.5 to 24 hours, more preferably 2 to 12 hours, and even more preferably 4 to 8 hours. After the application time has elapsed, even if the pharmaceutical composition on the skin is removed, a sufficient amount of the active ingredient remains in the skin tissue, and this is expected to be released gradually, thereby maintaining the medicinal effect. As an example of usage, by applying the pharmaceutical composition of the present invention to the eyelid skin before going to bed and removing it after waking up, the effect of treating and preventing allergic conjunctivitis can be expected to be sustained even without daytime administration.

[0087] When the pharmaceutical composition of the present invention is used as an ointment, cream, or gel, there is no particular limitation on the container in which it is housed, and it may be housed in any of a tube, bottle, can, or the like. The material of the container is also no particular limitation, and it may be a resin container made of polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polypropylene-polyethylene copolymer, polyvinyl chloride, acrylic, polystyrene, polycyclic olefin copolymer, or the like; a metal container made of aluminum or the like; or a laminated container made by bonding together multiple materials such as resin, paper, and aluminum foil. Furthermore, if the resin container is made of polyethylene, for example, polyethylene is classified by its density, and containers made of low-density polyethylene (LDPE), linear low-density polyethylene (LLDPE), medium-density polyethylene (MDPE), high-density polyethylene (HDPE), or the like may be used.

[0088] The pharmaceutical composition of the present invention can be used when wearing both hard and soft contact lenses.

[0089] The following formulation examples and examples are provided to aid in better understanding of the present invention and are not intended to limit the scope of the present invention.

[0090] In the following examples, the following condensed polyglyceryl ricinoleate, polyoxyethylene arachyl ether-stearyl alcohol mixture, glycerol monostearate, polyglyceryl monooleate, polyethylene glycol monostearate, polyoxyethylene hydrogenated castor oil 60, and polysorbate 80 were used, but the present invention is not limited to these. Condensed polyglyceryl ricinoleate: NIKKOL Hexaglyn PR-15; Polyoxyethylene arachidyl ether / stearyl alcohol mixture: NIKKOL WAX230; Glycerol monostearate: Glycerol monostearate manufactured by Fujifilm Wako Chemical Co., Ltd.; Polyglyceryl monooleate: NIKKOL DGMO-CV; Polyethylene glycol monostearate: NIKKOL MYS-2V; Polyoxyethylene hydrogenated castor oil 60: NIKKOL HCO-60; Polysorbate 80: NIKKOL TO-10MV

[0091] Representative formulation examples of the present invention are shown below. In the formulation examples below, the blending amount of each component is the content in 100 g of the formulation. Furthermore, "% (w / w)" means the content (g) of each component in 100 g of the formulation.

[0092] Formulation Example 1 Epinastine 1.0 g Squalane 5.0 g Light liquid paraffin 5.0 g Ceresin 3.0 g White petrolatum 10.0 g White beeswax 1.0 g Glycerin fatty acid ester 5.0 g Dibutylhydroxytoluene 0.1 g Sodium edetate hydrate 0.5 g Concentrated glycerin 15.0 g Purified water appropriate amount

[0093] Formulation Example 2 Epinastine hydrochloride 0.75 g Cetyl alcohol 0.5 g White petrolatum 8.0 g Isopropyl myristate 4.0 g Polysorbate 80 0.5 g Dibutylhydroxytoluene 0.2 g 2-mercaptobenzimidazole 0.05 g Propylene glycol 5.0 g Sodium hydroxide appropriate amount Purified water appropriate amount

[0094] Formulation Example 3 Epinastine hydrochloride 0.5 g Cetyl alcohol 2.0 g Squalane 10.0 g Glycerin fatty acid ester 4.0 g Polyoxyethylene hydrogenated castor oil 0.5 g 2-mercaptobenzimidazole 0.3 g Octyldodecanol 5.0 g Sodium edetate hydrate 0.5 g Sodium hydroxide appropriate amount Purified water appropriate amount

[0095] Furthermore, Formulation Examples 4 to 19 are shown in Tables 1 and 2.

[0096]

[0097] Example 1. Efficacy Evaluation Test Using an Allergic Conjunctivitis Model (1) To evaluate the antiallergic effect on allergic conjunctivitis, an allergic conjunctivitis model was created using guinea pigs, and the therapeutic effect of the pharmaceutical composition of the present invention was examined. (1) Preparation of Test Formulations Using a commonly used method, test formulations 1 to 3 in the form of water-in-oil emulsions were prepared by mixing the active ingredient epinastine hydrochloride with white petrolatum, light liquid paraffin, squalane, a mixture of paraffin and microcrystalline wax, white beeswax, an oil component of glycerin fatty acid ester, sodium edetate hydrate, 2-mercaptobenzimidazole, sodium hydroxide, sodium chloride, concentrated glycerin, and purified water. The amounts of epinastine hydrochloride, the active ingredient in test preparations 1 to 3, were adjusted to 0.005% (w / w), 0.05% (w / w), and 0.5% (w / w), respectively, and the amount of sodium hydroxide added was adjusted appropriately according to the amount of epinastine hydrochloride, with the remaining additives being added in the same amounts in each preparation. Test preparation 4, which is in the form of a water-in-oil emulsion containing no epinastine hydrochloride or sodium hydroxide, was prepared using the same method as test preparations 1 to 3, except for the addition of epinastine hydrochloride and sodium hydroxide. Furthermore, "Allegion," which is marketed in Japan, was also used. （登録商標） LX eye drops 0.1% was used as test preparation 5.

[0098] (2) Preparation of Conjunctivitis Model and Evaluation Test Method Guinea pigs (male, Hartley strain) were randomly divided into emulsion test formulation administration groups (test formulations 1 to 4 administration groups) and eye drop test formulation administration group (test formulation 5 administration group) (multiple animals per group). In the emulsion test formulation administration group (test formulations 1 to 4 administration group), guinea pigs were given general anesthesia by intramuscular administration of a mixed anesthetic solution of ketalar and celactal, and the hair around the right eyelid was shaved with clippers and an electric razor. A histamine solution was instilled into the right eye of the guinea pigs in each test formulation administration group to induce conjunctivitis, and an allergic conjunctivitis model was prepared. In the emulsion test formulation groups (test formulations 1-4), guinea pigs were given general anesthesia, and then 15 μL of the test formulation was applied to the upper and lower eyelids of the right eye 24 hours before instillation of the histamine solution, and an Elizabethan collar was placed. Meanwhile, in the eye drop test formulation group (test formulation 5), 10 μL of the test formulation was instilled into the right eye of the guinea pigs 8 hours before instillation of the histamine solution. Prior to instillation of the histamine solution, Evans blue solution was administered intravenously to the ear vein of each test formulation group under isoflurane inhalation anesthesia. After instillation of the histamine solution, the guinea pigs were euthanized under isoflurane inhalation anesthesia, and the right eyeball and eyelid tissue were excised. The weight of each excised tissue was measured, and the excised tissue was immersed in a pigment extractant (acetone solution containing sodium sulfate) to extract the pigment. The pigment extract solution in which the excised tissue was immersed was centrifuged, and the supernatant was used as a sample, and its absorbance at 620 nm was measured using a spectrophotometer. The mean and standard error of the amount of pigment leakage per weight of conjunctival tissue (μg / g) for each test preparation administration group were calculated using a commonly used method.

[0099] (3) Test results and discussion The test results are shown in Table 3.

[0100] Compared with Test Preparation 4, which does not contain the active ingredient epinastine or a salt thereof, Test Preparations 1 to 3, when applied to the eyelid skin, all showed reduced pigment leakage, demonstrating that Test Preparations 1 to 3 have a therapeutic effect on allergic conjunctivitis. Furthermore, Test Preparation 5 showed comparable or greater therapeutic effects 8 hours after instillation and Test Preparations 2 and 3 showed comparable or greater therapeutic effects 24 hours after topical administration. In other words, the therapeutic effects of Test Preparations 2 and 3 were demonstrated to last longer than those of Test Preparation 5. Therefore, considering that Test Preparation 5, which is actually used as a therapeutic agent for allergic conjunctivitis, is instilled twice daily, it was suggested that the pharmaceutical composition of the present invention is sufficiently effective as a therapeutic agent for allergic conjunctivitis when applied topically once daily.

[0101] 2. Efficacy evaluation test using an allergic conjunctivitis model (2) The therapeutic effect of the pharmaceutical composition of the present invention was examined in the same manner as in "1. Efficacy evaluation test using an allergic conjunctivitis model (1)" above. (1) Preparation of test preparations Test preparations 6 to 13 were prepared by mixing the active ingredient epinastine hydrochloride with each additive component and purified water using a conventional method to achieve the concentrations shown in Table 4 below. Test preparations 6, 7, 10, and 11 were in the form of water-in-oil emulsions, and test preparations 8, 9, 12, and 13 were in the form of oil-in-water emulsions.

[0102] (2) Preparation of Conjunctivitis Model and Evaluation Test Method An allergic conjunctivitis model was prepared (multiple animals for each test preparation) according to the same method as in "1. Efficacy evaluation test using allergic conjunctivitis model (1)" above, and the mean and standard error of the amount of dye leakage per weight of conjunctival tissue (μg / g) for test preparations 6 to 13 were calculated.

[0103] (3) Test results and discussion The test results are shown in Table 5.

[0104] When compared with the amount of pigment leakage (μg / g) for test preparation 4 (a preparation not containing epinastine or a salt thereof as an active ingredient), test preparations 6 to 13 applied to the eyelid skin all showed a reduced amount of pigment leakage, despite the different additive ingredients. This suggests that the pharmaceutical composition of the present invention is sufficiently effective as a therapeutic agent for allergic conjunctivitis when applied topically once a day.

[0105] 3. Skin Irritation Evaluation Test Using rabbits, the presence or absence of skin irritation when a composition containing epinastine or a salt thereof as an active ingredient was administered to the eyelid skin was examined. (1) Preparation of Test Formulations Test formulations used were Test Formulations 3 and 4, and Test Formulation 14, a water-in-oil emulsion prepared in the same manner as in "1. Efficacy Evaluation Test Using an Allergic Conjunctivitis Model (1)" above. Test Formulations 3 and 4 were prepared again in the same manner as in "1. Efficacy Evaluation Test Using an Allergic Conjunctivitis Model (1)" above. Test Formulation 14 was prepared by adjusting the amount of epinastine hydrochloride to 1% (w / w), adjusting the amount of sodium hydroxide added appropriately based on the amount of epinastine hydrochloride, and adding the remaining additives in the same amounts as Test Formulations 3 and 4.

[0106] (2) Evaluation Test Method: After appropriate acclimation, rabbits (male, Kbl:JW) were given general anesthesia by intramuscular administration of a mixed anesthetic solution of ketalar and celactal. The upper eyelids of the rabbits were shaved approximately 5 mm from the eyelid margin using clippers, an electric shaver, or an eyebrow shaver. Furthermore, eyelashes and any hair that might come into contact with the administration site were removed. The rabbits were fitted with Elizabethan collars and assigned to an untreated group and treatment groups containing test formulations 3, 4, and 14. For each treatment group, 30 μL of each test formulation was applied to the upper eyelid using a Microman. The rabbits were periodically observed, and skin reactions at the application site of the test substance were evaluated according to the Draize skin reaction assessment criteria approximately 3, 6, and 24 hours after administration.

[0107] The criteria for skin reaction according to the Draize method are scored based on the following symptoms: <Erythema and crust formation (erythema score)> 0: No erythema 1: Very mild erythema (barely noticeable) 2: Obvious erythema 3: Moderate to strong erythema 4: Deep crimson erythema with slight crust formation (damage is deep) <Edema formation (edema score)> 0: No edema 1: Very mild edema (barely noticeable) 2: Obvious edema (clearly distinguishable from surrounding area) 3: Moderate edema (raised by about 1 mm) 4: Severe edema (raised by 1 mm or more, spreading to surrounding area)

[0108] (3) Test Results and Discussion In the untreated group (n = 2) and the group administered Test Formulation 4 (n = 4), the erythema score and edema score were 0 at each time point (3, 6, and 24 hours after administration), and no clear findings indicating skin irritation were observed. Therefore, it was demonstrated that the safety concerns regarding the water-in-oil emulsion formulation base used in this study were extremely low. In the group administered Test Formulation 3 (n = 5), the edema score was 0 at each time point (3, 6, and 24 hours after administration), and the erythema score was 0 at 3 and 6 hours after administration, but an erythema score of 1 was observed in one eyelid 24 hours after administration. In the group administered Test Formulation 14 (n = 5), the edema score was 0 at each time point (3, 6, and 24 hours after administration), but an erythema score of 1 was observed in all five eyelids 3, 6, and 24 hours after administration.

[0109] Therefore, it was shown that when a composition containing epinastine or a salt thereof as an active ingredient is administered to the eyelid skin, the higher the concentration of epinastine or a salt thereof, the more likely it is to cause skin irritation, and from the viewpoint of safety, a concentration of epinastine or a salt thereof of less than 1% (w / w) is preferable, and a concentration of epinastine or a salt thereof of 0.5% (w / w) is particularly preferable. Furthermore, since the skin irritation observed with test preparations 3 and 14 was mild, it is considered that there is little concern about the safety of both preparations in clinical practice.

[0110] 4. Efficacy Evaluation Test in Humans To evaluate the antiallergic effect on allergic conjunctivitis in humans, a clinical trial was conducted to examine the therapeutic effect of the pharmaceutical composition of the present invention. (1) Preparation of Test Formulations Using a conventional method, cream formulations 1 and 2 were prepared by mixing the active ingredient epinastine hydrochloride with white petrolatum, light liquid paraffin, squalane, a mixture of paraffin and microcrystalline wax, white beeswax, an oil component of glycerin fatty acid ester, sodium edetate hydrate, 2-mercaptobenzimidazole, sodium hydroxide, sodium chloride, concentrated glycerin, and purified water. The amounts of epinastine hydrochloride, the active ingredient in cream formulations 1 and 2, were adjusted to 0.05% (w / w) and 0.5% (w / w), respectively. The amount of sodium hydroxide added was adjusted appropriately based on the amount of epinastine hydrochloride. The remaining additives were added in equal amounts in each formulation. In addition, a placebo cream formulation 3 containing no epinastine hydrochloride or sodium hydroxide was prepared in the same manner as cream formulations 1 and 2, except that epinastine hydrochloride and sodium hydroxide were added.

[0111] (2) Test method Healthy adult volunteers (8 people per cohort) with an allergic reaction due to cedar pollen allergen challenge were tested. After determining the optimal antigen concentration for each subject, they were randomly assigned to receive either the left or right eyelid cream formulation (Cohort 1: Cream formulation 1, Cohort 2: Cream formulation 2) or placebo cream formulation 3. Under a double-blind method, cream formulation 1 or 2 was applied to one eyelid (upper and lower eyelid) and placebo cream formulation 3 was applied to the other eyelid (upper and lower eyelid). Allergen challenge was performed 25 hours after application (corresponding to the administration interval when administered once daily).

[0112] (3) Evaluation method for allergic symptoms caused by antigen induction Eye itching and conjunctival hyperemia (bulbar conjunctival hyperemia and palpebral conjunctival hyperemia) were evaluated by assigning scores using criteria based on the severity of the symptoms. The score for eye itching is 5 levels from 0 to 4, and the score for conjunctival hyperemia is 7 levels from 0 to 6 (total score of bulbar conjunctival hyperemia 0 to 3 and palpebral conjunctival hyperemia 0 to 3).

[0113] (4) Test Results and Discussion The average ocular itching scores at three time points (3, 5, and 10 minutes) after antigen challenge and the average conjunctival hyperemia scores at three time points (5, 10, and 20 minutes) after antigen challenge are shown in Table 6. The average values ​​and standard deviations in the table were calculated by general statistical processing.

[0114] As shown in Table 6, Cream Preparations 1 and 2 showed differences compared to Cream Preparation 3 (placebo) in the ocular itching score and conjunctival hyperemia score when administered once daily. In particular, Cream Preparation 2 containing 0.5% (w / w) epinastine hydrochloride showed significantly large differences in both scores. Therefore, it was demonstrated that the pharmaceutical composition of the present invention is effective as a therapeutic agent for allergic conjunctivitis in humans. Furthermore, in this test, no side effects were observed when any of the test preparations were applied to the eyelids, and they were well tolerated as pharmaceuticals.

[0115] Allergic conjunctivitis is an inflammation of the conjunctiva, the mucous membrane covering the inside of the eyelid and the white of the eye, caused by allergens such as pollen. Current treatments for allergic conjunctivitis involve the direct administration of eye drops to the surface of the eye. The eyelid skin, which is connected to the facial skin and covers the eyeball from above and below, is a key component of the treatment. As shown in the above test results, a cream containing a low concentration of epinastine or its salts administered once daily to the eyelid skin was effective in treating allergic conjunctivitis. Furthermore, it was surprising that safety concerns were minimized even when administered to the thin and sensitive eyelid skin.

[0116] 5. Evaluation of Formulation Properties Focusing on the feel of the formulation when used as an ophthalmic topical administration formulation, the formulation properties of the pharmaceutical composition of the present invention were evaluated. (1) Preparation of Test Formulations Test formulations 6 to 13 from "2. Efficacy evaluation test using an allergic conjunctivitis model (2)" above were used as test formulations. Furthermore, test formulations 15 to 20 in the form of water-in-oil emulsions and test formulations 21 to 29 in the form of oil-in-water emulsions were prepared by mixing the active ingredient epinastine hydrochloride with each additive component and purified water using a conventional method to achieve the concentrations shown in Tables 7 to 9 below.

[0117]

[0118]

[0119] (2) Evaluation Test Method: Because eyelid skin is a very thin and soft tissue, and strong pressure on the eyelid skin may cause pain in the underlying eyeball and affect vision, four subjects were asked to evaluate the sensation of use when each test formulation was applied to artificial skin, assuming administration of the pharmaceutical composition of the present invention to the eyelid skin. Furthermore, the viscosity of each test formulation was measured. Each subject used their index finger to dispense an appropriate amount (roughly the size of a grain of rice) of each test formulation from an ointment acupuncture point and spread it horizontally across an area of ​​approximately 2 cm x 2 cm on the artificial skin. Regarding the sensation of use during application, pressure strength and ease of spreadability were scored on a three-point scale, as shown below, and the sum of the scores was used as the evaluation score for each test formulation. A maximum of 16 points was possible (maximum of 4 points per subject x 4 subjects). Test formulations 27 to 29 were assigned a maximum of 8 points (maximum of 4 points per subject x evaluation by 2 subjects). <Pressure strength> 2 points: Can be applied without pressure 1 point: Can be applied with slight pressure 0 point: Can be applied with strong pressure / Cannot be applied even with strong pressure <Ease of spreading of formulation> 2 points: Can be applied easily and evenly 1 point: Can be applied evenly 0 point: Cannot be applied evenly

[0120] The artificial skin used in the test was commercially available Spacerail L988, a base material that is felt to have the softness closest to that of eyelid skin. The viscosity of each test formulation was measured at a temperature of 20°C ± 0.1°C using a cone-plate rotational viscometer in accordance with the viscosity measurement method described in the General Test Methods of the Seventeenth Edition of the Japanese Pharmacopoeia.

[0121] (3) Test Results and Discussion The test results are shown in Table 10 (sorted in order of viscosity).

[0122] As shown in Table 10, it was suggested that a low viscosity of the test formulation provided a good feel when applied to artificial skin, while a high viscosity of the test formulation tended to provide a poor feel when applied to artificial skin. The eyelid skin is very thin and soft compared to the skin of other parts of the body, making it difficult to apply, and because the eyeball is located directly below the eyelid skin tissue, strong pressure cannot be applied. Therefore, when the pharmaceutical composition of the present invention is used as a formulation for ophthalmic topical administration, a low viscosity of the formulation is preferred as a formulation characteristic that does not irritate the eyeball and can be easily and uniformly applied to the eyelid skin; for example, a formulation having a viscosity of 150 Pa s or less is considered more preferable.

[0123] The present invention provides a pharmaceutical composition for topical administration containing epinastine or a salt thereof as an active ingredient, which has sufficient therapeutic effect even at low concentrations and with reduced frequency of administration, minimizes safety concerns, and is easy to use.

Claims

1. A pharmaceutical composition for topical administration, containing epinastine or a salt thereof at a concentration of 0.05 to 1% (w / w) as an active ingredient.

2. The pharmaceutical composition according to claim 1, which is for administration to the eyelid skin.

3. A pharmaceutical composition according to claim 1 or 2, characterized in that it is administered to a patient once a day.

4. A pharmaceutical composition according to any one of claims 1 to 3 for treating allergic conjunctivitis.

5. The pharmaceutical composition according to any one of claims 1 to 4, having a viscosity of 150 Pa·s or less at 20°C.

6. The pharmaceutical composition according to any one of claims 1 to 5, which is in the form of an ointment, cream or gel.

7. The pharmaceutical composition according to any one of claims 1 to 5, which is a cream.

8. The pharmaceutical composition according to any one of claims 1 to 7, which is a water-in-oil emulsion.

9. A pharmaceutical composition according to any one of claims 1 to 8, which is epinastine or a salt thereof at a concentration of 0.05% (w / w).

10. A pharmaceutical composition according to any one of claims 1 to 8, which is epinastine or a salt thereof at a concentration of 0.5% (w / w).

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the epinastine or a salt thereof is epinastine hydrochloride.

12. The pharmaceutical composition according to any one of claims 1 to 10, wherein the epinastine or a salt thereof is epinastine.

13. The pharmaceutical composition according to any one of claims 1 to 12, which contains one or more oil components selected from the group consisting of hydrocarbons, waxes, oils and fats, aliphatic carboxylic acids or salts thereof, fatty acid esters, and higher alcohols.

14. The pharmaceutical composition according to any one of claims 1 to 12, further comprising a surfactant.

15. The pharmaceutical composition of claim 14, wherein the surfactant is a glycerol fatty acid ester.

16. The pharmaceutical composition of claim 14 or 15, wherein the surfactant has an HLB of 3.0 to 6.

0.

17. The pharmaceutical composition according to any one of claims 1 to 16, which does not contain parabens.

18. A pharmaceutical composition for topical administration containing epinastine or a salt thereof at a concentration of 0.05 to 0.5% (w / w) as an active ingredient, the pharmaceutical composition being a water-in-oil emulsion cream that is administered to the eyelid skin once a day.

19. A pharmaceutical composition for topical administration containing epinastine or a salt thereof at a concentration of 0.5% (w / w) as an active ingredient, the pharmaceutical composition being a cream of a water-in-oil emulsion, characterized in that it is used to be administered once a day to the eyelid skin.

20. A method for delivering a therapeutically effective amount of epinastine to ocular tissue by administering to the eyelid skin a pharmaceutical composition containing epinastine or a salt thereof at a concentration of 0.05 to 1% (w / w) as an active ingredient.

21. A method for sustained release of a therapeutically effective amount of epinastine from the eyelid skin into ocular tissue by administering to the eyelid skin a pharmaceutical composition containing epinastine or a salt thereof at a concentration of 0.05 to 1% (w / w) as an active ingredient.

22. The method according to claim 20 or 21, characterized in that it is used to be administered to a patient once a day.

23. The method of any one of claims 20 to 22, wherein the ocular tissue is the conjunctiva.