JP7628098B2 - A pollen burst inhibitor containing epinastine or its salt - Google Patents

Description

The present invention relates to a pollen burst inhibitor containing epinastine or a salt thereof, more specifically, to a pollen burst inhibitor containing epinastine or a salt thereof and a lower aliphatic carboxylic acid (hereinafter, also referred to as the "pollen burst inhibitor of the present invention").

In recent years, various studies have been conducted on the treatment of allergic diseases, and the mechanism of onset of allergic diseases is gradually being elucidated. For example, according to Non-Patent Documents 1 and 2, it is believed that allergic conjunctivitis caused by cedar pollen occurs when scattered pollen particles enter the conjunctival sac, the outer wall of the pollen is ruptured by tears, and the eluted allergens migrate to the conjunctival tissue and bind to antibodies on mast cells. The rupture of the outer wall of pollen is likely to occur in tears, and it has been suggested that factors that affect the rupture of the outer wall of pollen include physicochemical effects such as pH and temperature, as well as the effects of components in tears (lysozyme, proteins, various decomposition enzymes, etc.). It has also been suggested that various types of anti-allergic eye drops may affect the rupture of the outer wall of pollen and the elution of allergens in addition to the conventional pharmacological effects.

According to Non-Patent Document 3, additives contained in eye drops may also affect the rupture of the pollen outer wall and the elution of allergens; for example, it has been suggested that PBS (phosphate buffered saline) may promote the rupture of the pollen outer wall. For this reason, there have been certain concerns about the addition of other ingredients such as phosphoric acid or its salts to eye drops for treating allergic conjunctivitis.

Patent Document 1 and Patent Document 2 disclose that epinastine or its salts, which are the active ingredients of eye drops for treating allergic conjunctivitis, have the effect of suppressing the rupture of the outer wall of cedar pollen, and that even if phosphoric acid or its salts, which promote the rupture of the pollen outer wall, are added, epinastine or its salts have the effect of suppressing the rupture of the outer wall of cedar pollen within a certain range of phosphoric acid concentrations. However, Patent Document 1 and Patent Document 2 do not disclose that lower aliphatic carboxylic acids do not have the effect of promoting the rupture of the pollen outer wall, and do not interfere with the effect of epinastine or its salts in suppressing the rupture of the pollen outer wall.

JP 2018-188385 A Re-table No. 2018-203424

Allergy and Immunology 2010, Vol. 17, No. 2, 124-129 Allergy and Immunology 2011, Vol. 18, No. 2, 82-87 Allergy and Immunology 2016, Vol. 23, No. 2, 124-130

It is very useful to clarify the effect of various anti-allergy preparations, such as anti-allergy eye drops and additives contained in eye drops, on the rupture of the pollen outer wall and the elution of allergens, considering the effect on the effectiveness of the active ingredients. Therefore, it is an interesting task to provide a pollen burst inhibitor containing epinastine or a salt thereof as an active ingredient, which is expected to have a stronger medicinal effect by strongly suppressing the rupture of the pollen outer wall.

The inventors conducted extensive research into preparations containing epinastine or a salt thereof and found that by combining epinastine or a salt thereof with lower aliphatic carboxylic acids in an eye drop, an excellent effect of inhibiting the rupture of the pollen outer wall can be achieved without interfering with the effect of epinastine or a salt thereof itself in inhibiting the rupture of the pollen outer wall. Furthermore, they also found that administering to the eye a pharmaceutical composition (pollen burst inhibitor) containing epinastine or a salt thereof and lower aliphatic carboxylic acids has the effect of improving the transfer of epinastine to ocular tissue. The present invention was completed based on these findings.

Specifically, the present invention provides the following:
(1) A pollen burst inhibitor containing epinastine or a salt thereof and a lower aliphatic carboxylic acid.
(2) The pollen burst inhibitor according to (1), wherein the lower aliphatic carboxylic acids are one or more selected from the group consisting of citric acid, edetic acid, acetic acid, ε-aminocaproic acid, glutamic acid, and salts thereof.
(3) The pollen burst inhibitor according to (1) or (2), wherein the concentration of epinastine or a salt thereof is 0.01 to 5% (w/v).
(4) A pollen burst inhibitor described in (1) or (2), in which the concentration of epinastine or a salt thereof is 0.05% (w/v) or more.
(5) The pollen burst inhibitor according to any one of (1) to (4), wherein the epinastine or a salt thereof is epinastine hydrochloride.
(6) A pollen burst inhibitor according to any one of (1) to (5) for use in eye drop administration.
(7) The pollen burst inhibitor according to any one of (1) to (6), which is administered by instilling one or two drops per eye, two to four times a day.
(8) A method for inhibiting the bursting of pollen attached to the surface of the eye or in the vicinity thereof by administering to the eye a pollen burst inhibitor according to any one of (1) to (5).
(9) A method for inhibiting pollen bursting, comprising contacting the pollen burst inhibitor according to any one of (1) to (5) with pollen.

Note that any two or more of the configurations (1) to (9) above may be combined.

In addition, the present invention also provides the following:
(10) An eye drop containing epinastine or a salt thereof and a lower aliphatic carboxylic acid.
(11) A method for improving the transferability of epinastine or a salt thereof into ocular tissues by blending a lower aliphatic carboxylic acid with an eye drop containing epinastine or a salt thereof.
(12) A method for treating an allergic disease, comprising administering to a patient in need of treatment a therapeutically effective amount of the pollen burst inhibitor according to any one of (1) to (7).
(13) A pollen burst inhibitor according to any one of (1) to (7), for use in the treatment of an allergic disease.
(14) Use of the pollen burst inhibitor according to any one of (1) to (7) for producing a medicine for treating an allergic disease.

The present invention makes it possible to obtain a pollen burst inhibitor that has an excellent effect of inhibiting the bursting of the outer wall of pollen by blending epinastine or a salt thereof with a lower aliphatic carboxylic acid. In addition, by administering a pollen burst inhibitor containing epinastine or a salt thereof and a lower aliphatic carboxylic acid to the eye, it is possible to obtain an eye drop that improves the transfer of epinastine to ocular tissues and provides excellent medicinal effects.

The present invention is described in detail below.

で表される化合物である。 In the present invention, “epinastine” is a compound represented by the chemical name (±)-3-amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine and the following formula:

It is a compound represented by the formula:

The epinastine contained in the pollen burst inhibitor of the present invention may be a racemate or an optical isomer.

In the pollen burst inhibitor of the present invention, epinastine may be in the form of a salt, and there is no particular limitation as long as it is a medicamentously acceptable salt. Examples of salts include salts with inorganic acids and salts with organic acids.
Examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
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, glucoheptic 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, and sulfosalicylic acid.
As a salt of epinastine, the monohydrochloride salt (epinastine hydrochloride) is particularly preferred.

In the pollen burst inhibitor of the present invention, epinastine or a salt thereof may be in the form of a hydrate or solvate.

In the pollen burst inhibitor of the present invention, the content of epinastine or a salt thereof is preferably 0.01% (w/v) or more, more preferably 0.05% (w/v) or more, even more preferably 0.09% (w/v) or more, and even more preferably 0.1% (w/v) or more, with the upper limit being any concentration acceptable for an ophthalmic preparation, for example 5% (w/v). The content of epinastine or a salt thereof is preferably 0.01 to 5% (w/v), more preferably 0.05 to 1% (w/v), even more preferably 0.05 to 0.2% (w/v), and particularly preferably 0.05 to 0.1% (w/v). For example, the content is 0.09% (w/v) or 0.1% (w/v).

In the present invention, "% (w/v)" refers to the mass (g) of the target ingredient contained in 100 mL of the pollen burst inhibitor (eye drops) of the present invention. When a salt of epinastine is contained in the present invention, the value is the content of the salt of epinastine. In addition, when epinastine or a salt thereof is formulated in the present invention in the form of a hydrate or solvate, the value is the content of the hydrate or solvate of epinastine or a salt thereof. The same applies hereinafter unless otherwise specified.

In the present invention, the term "lower aliphatic carboxylic acids" refers to carboxylic acids having 15 or less carbon atoms and one or more carboxyl groups, or salts thereof, or hydrates or solvates thereof.
The number of carboxyl groups in the lower aliphatic carboxylic acids is not particularly limited, but is preferably 1 to 4, and more preferably 1 to 3. The number of carbon atoms in the lower aliphatic carboxylic acids may be 15 or less, and is preferably 2 to 12, and more preferably 4 to 10.

The carbon chains in the lower aliphatic carboxylic acids may be straight or branched, saturated or unsaturated.
The lower aliphatic carboxylic acids may have a substituent other than the carboxyl group, and the number and type of the substituent are not particularly limited. Examples of the substituent include an amino group and a hydroxyl group.

In the pollen burst inhibitor of the present invention, when the lower aliphatic carboxylic acids contained therein are in the form of a salt, there are no particular limitations as long as the salt is medicamentously acceptable. Examples of salts include alkali metal salts such as sodium salts and potassium salts, and alkaline earth metal salts such as magnesium and calcium. In addition, when the lower aliphatic carboxylic acids contained therein have, for example, an amino group as a substituent, examples of the salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid.

In the pollen burst inhibitor of the present invention, examples of the lower aliphatic carboxylic acids contained include acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, lactic acid, malic acid, citric acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, fumaric acid, maleic acid, pyruvic acid, tartaric acid, sorbic acid, edetic acid, ε-aminocaproic acid (ε-aminocaproic acid), glycine, alanine, leucine, isoleucine, valine, serine, aspartic acid, glutamic acid, or salts thereof, and may be hydrates or solvates thereof. Preferred are citric acid, edetic acid, acetic acid, ε-aminocaproic acid, glutamic acid, or salts thereof, or hydrates thereof, more preferably citric acid or a salt thereof, ε-aminocaproic acid or a salt thereof, glutamic acid or a salt thereof, and even more preferably citric acid or a salt thereof. Examples of citric acid or its salts include citric acid, monosodium citrate, disodium citrate, trisodium citrate (sodium citrate), monopotassium citrate, dipotassium citrate, tripotassium citrate, magnesium citrate, and calcium citrate. Examples of edetic acid or its salts include edetic acid, monosodium edetate, disodium edetate (sodium edetate), trisodium edetate, tetrasodium edetate, monopotassium edetate, dipotassium edetate, tripotassium edetate, tetrapotassium edetate, calcium sodium edetate, and magnesium sodium edetate. Examples of acetic acid or its salts include acetic acid, sodium acetate, and potassium acetate. Examples of ε-aminocaproic acid or its salts include ε-aminocaproic acid, sodium ε-aminocaproate, potassium ε-aminocaproate, ε-aminocaproic acid hydrochloride, ε-aminocaproic acid hydrobromide, ε-aminocaproic acid hydroiodide, ε-aminocaproic acid nitrate, ε-aminocaproic acid sulfate, and ε-aminocaproic acid phosphate. Examples of glutamic acid or its salts include glutamic acid, monosodium glutamate, disodium glutamate, monopotassium glutamate, dipotassium glutamate, glutamic acid hydrochloride, glutamic acid hydrobromide, glutamic acid hydroiodide, glutamic acid nitrate, glutamic acid sulfate, and glutamic acid phosphate.

In the pollen burst inhibitor of the present invention, the lower aliphatic carboxylic acids also act as pharmaceutical additives, such as buffers, stabilizers, preservatives, pH regulators, etc. Therefore, the lower aliphatic carboxylic acids can also be used as pharmaceutical additives. For example, if the lower aliphatic carboxylic acids are citric acid or a salt thereof, they act as a buffer, pH regulator, etc., if they are edetic acid or a salt thereof, they act as a stabilizer, antioxidant, chelating agent, etc., if they are acetic acid or a salt thereof, they act as a buffer, pH regulator, etc., if they are ε-aminocaproic acid or a salt thereof, they act as a buffer, etc., and if they are glutamic acid or a salt thereof, they act as a buffer, etc.
In the pollen burst inhibitor of the present invention, the lower aliphatic carboxylic acids may be used alone or in combination of two or more kinds.

In the pollen burst inhibitor of the present invention, the content of the lower aliphatic carboxylic acids can be adjusted appropriately depending on the type, but for example, 0.01 to 5% (w/v) is preferable, 0.1 to 4% (w/v) is more preferable, and 0.5 to 3.5% (w/v) is even more preferable. For example, when the lower aliphatic carboxylic acids are citric acid or a salt thereof, the content is preferably 0.01 to 5% (w/v), more preferably 0.5 to 3.5% (w/v), and even more preferably 1 to 3.5% (w/v). For example, the content is 1.6% (w/v) or 3.2% (w/v). For example, when the lower aliphatic carboxylic acids are ε-aminocaproic acid or a salt thereof, the content is preferably 0.01 to 5% (w/v), more preferably 0.1 to 3.5% (w/v), and even more preferably 0.5 to 2% (w/v). For example, the content is 0.5% (w/v) or 2% (w/v). For example, when the lower aliphatic carboxylic acid is glutamic acid or a salt thereof, the content is preferably 0.01 to 5% (w/v), more preferably 0.1 to 3.5% (w/v), and even more preferably 0.5 to 2% (w/v). For example, the content is 0.6% (w/v) or 2% (w/v).

The pollen burst inhibitor of the present invention can inhibit the bursting of pollen present on the surface of the eye or on the mucous membrane, and can effectively suppress allergic symptoms caused by pollen. The pollen burst inhibitor of the present invention can be used for the treatment of allergic diseases.
Furthermore, the pollen burst inhibitor of the present invention can improve the transferability of epinastine to eye tissues and efficiently bring about the medicinal effects of epinastine.

In the present invention, "allergic disease" refers to a disease or its symptoms caused by an immune response to an external antigen. An example of an external antigen is pollen. An example of an allergic disease is allergic conjunctivitis, but is not limited to this. In the present invention, treatment of an allergic disease refers to any treatment (e.g., cure, improvement, relief, inhibition of progression, etc.) and prevention of an allergic disease or its symptoms. It also includes prevention of recurrence of an allergic disease.

In the present invention, "ocular tissue" includes, for example, the conjunctiva, cornea, tears, aqueous humor, anterior chamber, etc. When the pollen burst inhibitor of the present invention is administered to the eye, it can inhibit the bursting of pollen adhering to the ocular surface such as the cornea and conjunctiva, and to the eyelashes, eyelid margins, etc. in the vicinity thereof. Furthermore, it can increase (or improve) the amount of epinastine or a salt thereof transferred to ocular tissues, and it is particularly preferable to increase the amount transferred to the conjunctiva.

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, and more preferably a human. In the present invention, the term "therapeutically effective amount" refers to an amount that provides a therapeutic effect for an allergic disease and its symptoms, or an amount that provides a delay in the progression of an allergic disease and its symptoms, compared to an untreated subject.

The pollen burst inhibitor of the present invention can contain pharmaceutical additives as needed, such as buffers, thickeners, surfactants, isotonicity agents, stabilizers, preservatives, antioxidants, pH regulators, etc. These can be used alone or in appropriate combinations of two or more, and can be blended in appropriate amounts.

When a buffering agent is added to the pollen burst inhibitor of the present invention, the buffering agent can be any buffering agent that can be used as an additive in pharmaceuticals, such as phosphoric acid or a salt thereof, boric acid or a salt thereof, carbonic acid or a salt thereof, or an organic amine, and may be a hydrate or solvate thereof.

Examples of phosphoric acid or salts thereof include phosphoric acid, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, etc., and may be hydrates of these.

Examples of boric acid or its salts include boric acid, sodium borate (borax), potassium borate, etc., and may also be hydrates of these.

Carbonic acid or its salts include carbonic acid, sodium carbonate, sodium hydrogen carbonate, etc., and may also be hydrates of these.

Organic amines include trometamol, etc., and may be hydrates thereof.

When a buffering agent is blended with the pollen burst inhibitor of the present invention, the content of the buffering agent can be adjusted appropriately depending on the type of buffering agent, etc., but is preferably 0.001 to 10% (w/v), more preferably 0.01 to 5% (w/v), even more preferably 0.1 to 5% (w/v), and particularly preferably 0.1 to 1% (w/v).
When a buffer is added to the pollen burst inhibitor of the present invention, one or more kinds of buffers may be used together.

When a thickening agent is added to the pollen burst inhibitor of the present invention, the thickening agent can be any thickening agent that can be used as an additive in pharmaceuticals, such as methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyethylene glycol, sodium hyaluronate, etc.

When a thickener is blended with the pollen burst inhibitor of the present invention, the content of the thickener can be appropriately adjusted depending on the type of thickener, etc., but is preferably 0.001 to 5% (w/v), more preferably 0.01 to 3% (w/v), and even more preferably 0.1 to 2% (w/v).
When a thickening agent is added to the pollen bursting inhibitor of the present invention, one or more types of thickening agents may be used together.

When a surfactant is added to the pollen burst inhibitor of the present invention, the surfactant may be any surfactant that can be used as an additive in pharmaceuticals, such as a cationic surfactant, an anionic surfactant, or a nonionic surfactant.

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, 1-hydroxyethyl-2-alkylimidazolines, etc.

Anionic surfactants include phospholipids such as lecithin.

Nonionic surfactants include polyoxyethylene fatty acid esters such as polyoxyl 40 stearate; polyoxyethylene sorbitan fatty acid esters such as polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, and polysorbate 65; polyoxyethylene hydrogenated castor oils such as polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, and polyoxyethylene hydrogenated castor oil 60; polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, and polyoxyl Examples of suitable polyoxyl castor oils include polyoxyl 35 castor oil and polyoxyl 40 castor oil; polyoxyethylene polyoxypropylene glycols such as polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, and polyoxyethylene (20) polyoxypropylene (20) glycol; sucrose fatty acid esters such as sucrose stearate; and tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS).

When a surfactant is blended with the pollen burst inhibitor of the present invention, the content of the surfactant can be adjusted appropriately depending on the type of surfactant, etc., but is preferably 0.01 to 1% (w/v), more preferably 0.05 to 0.5% (w/v), and even more preferably 0.05 to 0.2% (w/v).
When a surfactant is added to the pollen burst inhibitor of the present invention, one or more surfactants may be used in combination.

When an isotonicity agent is added to the pollen burst inhibitor of the present invention, the isotonicity agent can be an appropriate one that can be used as an additive in pharmaceuticals, such as an ionic isotonicity agent or a non-ionic isotonicity agent.

Ionic tonicity agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride, etc.

Non-ionic tonicity agents include glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose, xylitol, etc.

When an isotonicity agent is added to the pollen burst inhibitor of the present invention, the isotonicity agent is preferably an ionic isotonicity agent, and sodium chloride is particularly preferred.

When an isotonicity agent is blended with the pollen burst inhibitor of the present invention, the content of the isotonicity agent can be adjusted appropriately depending on the type of isotonicity agent, etc., but is preferably 0.001 to 10% (w/v), more preferably 0.01 to 5% (w/v), even more preferably 0.1 to 3% (w/v), and particularly preferably 0.2 to 1% (w/v).
When an isotonicity agent is added to the pollen bursting inhibitor of the present invention, one or more isotonicity agents may be used together.

When a stabilizer is added to the pollen burst inhibitor of the present invention, the stabilizer can be any stabilizer that can be used as an additive in pharmaceuticals, such as cyclodextrin, sodium thiosulfate, etc.

When a stabilizer is blended with the pollen burst inhibitor of the present invention, the content of the stabilizer can be adjusted appropriately depending on the type of stabilizer, etc., but is preferably 0.001 to 5% (w/v), more preferably 0.01 to 3% (w/v), and even more preferably 0.05 to 1% (w/v).
When a stabilizer is added to the pollen bursting inhibitor of the present invention, one or more stabilizers may be used in combination.

When a preservative is added to the pollen burst inhibitor of the present invention, the preservative may be any preservative that can be used as an additive in pharmaceuticals, such as benzalkonium chloride, benzalkonium bromide, benzethonium chloride, chlorhexidine gluconate, chlorhexidine hydrochloride, methyl parahydroxybenzoate, propyl parahydroxybenzoate, sodium chlorite, or chlorobutanol.

When a preservative is added to the pollen burst inhibitor of the present invention, the amount of the preservative can be adjusted as appropriate depending on the type of preservative, but it is best to use an amount that does not adversely affect safety, for example, 0.0001 to 0.1% (w/v) is preferred, and 0.001 to 0.05% (w/v) is more preferred.

When an antioxidant is added to the pollen burst inhibitor of the present invention, the antioxidant can be an antioxidant that can be used as an additive in pharmaceuticals, such as ascorbic acid, tocopherol, dibutylhydroxytoluene, sodium sulfite, etc.

When an antioxidant is blended with the pollen burst inhibitor of the present invention, the content of the antioxidant can be adjusted appropriately depending on the type of antioxidant, etc., but is preferably 0.001 to 5% (w/v), more preferably 0.01 to 3% (w/v), and even more preferably 0.1 to 2% (w/v).
When an antioxidant is added to the pollen burst inhibitor of the present invention, one or more antioxidants may be used in combination.

When a pH regulator is added to the pollen burst inhibitor of the present invention, the pH regulator can be any pH regulator that can be used as an additive in pharmaceuticals, and may be, for example, an acid or a base. Examples of acids include hydrochloric acid and phosphoric acid, and examples of bases include sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate.

The pH of the pollen burst inhibitor of the present invention may be within a range acceptable for pharmaceutical use, for example, within the range of 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, with 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, and 7.3 being even more preferred.

The osmotic pressure ratio of the pollen burst inhibitor of the present invention may be within a range acceptable for pharmaceutical use, for example, 0.5 to 2.0, preferably 0.7 to 1.6, more preferably 0.8 to 1.4, and even more preferably 0.9 to 1.2.

The pollen burst inhibitor of the present invention is suitable for parenteral (e.g., topical) administration. Parenteral administration routes for the pollen burst inhibitor of the present invention include medicamentously acceptable local administration routes, such as local administration to the eye (e.g., eye drop administration), nasal (transnasal) administration, local administration to the ear (e.g., ear drop administration), inhalation administration, spray administration, transdermal administration, epicutaneous administration, injection administration, etc. Preferred is local administration to the eye.

The pollen burst inhibitor of the present invention can be used as an ophthalmic preparation, an otolaryngological preparation, an inhalation preparation, or a transdermal preparation, and the dosage form is not particularly limited as long as it can be used as a pharmaceutical. Dosage forms include, for example, oral preparations such as liquids and suspensions, eye drops, nasal drops, ear drops, inhalants (inhalation powders, inhalation liquids, inhalation aerosols), ointments, creams, gels, transdermal preparations, patches (tapes, poultices), external liquids (lotions, liniments), external solids (external powders), sprays (pump sprays, external aerosols), and injections (infusions, implant injections, sustained release injections). Eye drops are preferred. These can be manufactured according to conventional methods in the art.

The pollen burst inhibitor of the present invention may have all of its components dissolved or partially suspended, or may be in the form of an emulsion or semi-solid. It is more preferable that the pollen burst inhibitor of the present invention is in a solution state in which all of its components are dissolved, and it is most preferable that it is an aqueous solution.

When the pollen burst inhibitor of the present invention is an emulsion, it may be an oil-in-water emulsion (an emulsion in which the aqueous phase is the continuous phase and is composed of oily droplets dispersed in the aqueous phase) or a water-in-oil emulsion (an emulsion in which the oil phase is the continuous phase and is composed of aqueous droplets dispersed in the oil).

When the pollen burst inhibitor of the present invention is used as an ophthalmic preparation, it is particularly useful as a therapeutic agent for allergic conjunctivitis. Furthermore, unless otherwise specified, the pollen burst inhibitor of the present invention may contain a pharmaceutical active ingredient other than epinastine or a salt thereof, for example, an active ingredient used in other eye drops, or epinastine or a salt thereof may be the only active ingredient.

When the pollen burst inhibitor of the present invention is administered to the eye as eye drops, there are no particular limitations on the dosage and administration as long as it is sufficient to achieve the desired medicinal effect, but it can be administered as one drop at a time, 1 to 10 times a day, preferably 1 to 6 times a day, and more preferably 2 to 4 times a day. It can also be used when wearing contact lenses.

When the pollen burst inhibitor of the present invention is used as an eye drop, it may be contained in any of a multi-dose container, a single-use unit dose container, or a PFMD (Preservative Free Multi Dose) container. There is no particular restriction on the material of the container, and it may be any commonly used eye drop container, but it is preferably a resin container, such as a container made of polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polypropylene-polyethylene copolymer, polyvinyl chloride, acrylic, polystyrene, polycyclic olefin copolymer, etc. Also, if the material of the resin container is, for example, polyethylene, polyethylene is classified according to its density, and a container made of low density polyethylene (LDPE), medium density polyethylene (MDPE), high density polyethylene (HDPE), etc. can be used.

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

Formulation Examples Representative formulation examples of the present invention are shown below. Note that the blending amount of each ingredient in the following formulation examples is the content per 1 mL of the formulation.

Formulation Example 1
Epinastine hydrochloride 1mg
Sodium citrate 8mg
Sodium chloride 5mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0

Formulation Example 2
Epinastine hydrochloride 0.5mg
Sodium citrate 8mg
Sodium chloride 5mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0

Formulation Example 3
Epinastine hydrochloride 0.5mg
Sodium citrate 8mg
Sodium edetate 1mg
Boric acid 1mg
Sodium chloride 5mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0

Formulation Example 4
Epinastine hydrochloride 0.5mg
Sodium citrate 4mg
Sodium edetate 1mg
Boric acid 0.5mg
Sodium dihydrogen phosphate 5mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0

Formulation Example 5
Epinastine hydrochloride 0.5mg
Sodium edetate 1mg
Boric acid 0.5mg
Sodium dihydrogen phosphate 12mg
Sodium chloride 8mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0

Formulation Example 6
Epinastine hydrochloride 1mg
Sodium edetate hydrate 0.5mg
ε-aminocaproic acid 5 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0

Formulation Example 7
Epinastine hydrochloride 1mg
Sodium edetate hydrate 0.5mg
Monosodium glutamate 5mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0

Formulation Example 8
Epinastine hydrochloride 1mg
Sodium edetate hydrate 1mg
Sodium chloride 8mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0

Test Example 1. Pollen Burst Test (1) Preparation of Test Formulation Epinastine hydrochloride, sodium citrate, and sodium chloride were dissolved in water to the concentrations shown in Table 1 below, and a pH adjuster (dilute hydrochloric acid and/or sodium hydroxide) and water were added to make the total volume 10 mL, and the mixture was sterilized by filtration to prepare the formulation of Example 1.
Furthermore, the formulations of Examples 2 to 4 and Comparative Example 1 in Table 1 below were prepared in the same manner as the preparation of the formulation of Example 1. Note that "M" in Table 1 represents the volume molar concentration (the amount of substance (mol) of the target component contained in 1 L of the formulation).

(2) Test method Approximately 3 μL of cedar pollen particles were collected and seeded on a 96-well microplate. Then, 50 μL of the test preparation was dropped into each well, and the total number of pollen grains was counted immediately after dropping under an optical microscope using a hemocytometer. Furthermore, the number of pollen grains that burst 5 minutes and 10 minutes after dropping was also counted under a microscope over time. This was carried out twice for each test preparation.

The pollen burst rate was calculated using the following formula, and the average pollen burst rate for each test preparation was further calculated.
Pollen burst rate (%) = (number of pollen that burst within 5 or 10 minutes after dropping) / (total number of pollen immediately after dropping the test preparation) x 100

(3) Test Results and Observations The test results are shown in Table 1.

As shown in Table 2, compared to Comparative Example 1, which contained phosphate, Examples 1 and 2 (citrate), Example 3 (ε-aminocaproic acid), and Example 4 (glutamate), which contained lower aliphatic carboxylic acids, were shown to better suppress the rupture of the pollen outer wall.

2. Intraocular kinetics test (1) Preparation of test preparations The preparations of Examples 5, 6 and Comparative Example 2 in Table 3 below were prepared in the same manner as the preparation of Example 1. The content of sodium chloride was appropriately adjusted to equalize the osmotic pressure of each test preparation.

(2) Test Method 5 μL of each test preparation was instilled into the eyes of rats (n=6), and the rats were sacrificed and their eyeballs were removed 1 hour after the instillation. The epinastine concentration in the conjunctiva was measured and the average value was calculated.

(3) Test results and considerations The test results are shown in Table 4.

As shown in Table 4, it was confirmed that Example 5, which contains sodium citrate hydrate, and Example 6, which contains ε-aminocaproic acid, have an increased epinastine concentration in the conjunctival tissue compared to Comparative Example 2, which does not contain lower aliphatic carboxylic acids. This shows that the pollen burst inhibitor of the present invention improves the transfer of epinastine to the conjunctival tissue.

The present invention provides a pollen burst inhibitor that contains epinastine or a salt thereof and a lower aliphatic carboxylic acid.

Claims (6)

An eye drop preparation for treating an allergic disease, comprising epinastine or a salt thereof and a lower aliphatic carboxylic acid, wherein the concentration of epinastine or a salt thereof is 0.09% (w/v) or 0.1% (w/v), the lower aliphatic carboxylic acid is one or more selected from the group consisting of citric acid, acetic acid, ε-aminocaproic acid, glutamic acid, salts thereof, and hydrates thereof, and the eye drop preparation does not contain pranoprofen. 2. The ophthalmic preparation according to claim 1 , wherein the concentration of the lower aliphatic carboxylic acid is 0.1 to 4% (w/v). The ophthalmic preparation according to claim 1 or 2 , wherein the allergic disease is allergic conjunctivitis. The ophthalmic preparation according to any one of claims 1 to 3 , wherein the epinastine or a salt thereof is epinastine hydrochloride. The eye drop preparation according to any one of claims 1 to 4 , which has an effect of inhibiting the bursting of pollen attached to the eye surface or in the vicinity thereof. The ophthalmic preparation according to any one of claims 1 to 4 , which has the effect of improving the transfer of epinastine to ocular tissues.