JP2022136242A - Pollen rupture inhibitor containing epinastine or salt thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pollen rupture inhibitor containing epinastine or a salt thereof that can be expected to have stronger drug action by suitably inhibiting rupture of exterior walls of pollen.

SOLUTION: A pollen rupture inhibitor contains epinastine or a salt thereof and a lower aliphatic carboxylic acid. There is also provided an eye drop containing epinastine or a salt thereof and a lower aliphatic carboxylic acid.

SELECTED DRAWING: None

COPYRIGHT: (C)2022,JPO&INPIT

Description

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

In recent years, various studies have been made on the treatment of allergic diseases, and the pathogenesis of allergic diseases is being elucidated. For example, according to Non-Patent Document 1 and Non-Patent Document 2, allergic conjunctivitis caused by cedar pollen is caused by scattering pollen particles entering the conjunctival sac, followed by rupture of the pollen outer wall by tear fluid, and the eluted allergens entering the conjunctival tissue. It is thought to occur by migration and binding to antibodies on mast cells. The rupture of the pollen outer wall is likely to occur in tears, and the factors that affect the rupture of the pollen outer wall include physicochemical effects such as pH and temperature, as well as components in the tear (lysozyme, proteins, and various decompositions). Enzymes, etc.) have been suggested to have an effect. It has also been suggested that various types of antiallergic ophthalmic solutions may affect the rupture of pollen outer walls and the elution of allergens in addition to conventional pharmacological actions.

In addition, according to Non-Patent Document 3, additives contained in eye drops may also affect the rupture of pollen outer walls and the elution of allergens. It has been suggested that it may promote the rupture of Therefore, in eye drops for treating allergic conjunctivitis, there was a certain concern about the addition of other ingredients such as phosphoric acid or salts thereof.

Patent Documents 1 and 2 disclose that epinastine or a salt thereof, which is an active ingredient of eye drops for treating allergic conjunctivitis, has an effect of suppressing the rupture of the outer wall of cedar pollen, and that phosphorus promotes the rupture of the outer wall of pollen. It is disclosed that epinastine or its salt has the effect of suppressing the rupture of the outer wall of cedar pollen within a certain range of phosphoric acid concentration even when an acid or its salt is added. However, in Patent Documents 1 and 2, the 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 salt to suppress the rupture of the pollen outer wall. is not listed.

JP 2018-188385 A Retable 2018-203424

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

It is important to clarify how various anti-allergic preparations, such as anti-allergic eye drops and additives contained in eye drops, affect the rupture of pollen outer walls and the elution of allergens. Very useful to consider. Therefore, it is an interesting subject to provide a pollen rupture inhibitor containing epinastine or a salt thereof as an active ingredient, which is expected to have stronger efficacy by strongly suppressing the rupture of the pollen outer wall.

The present inventors have conducted intensive research on formulations containing epinastine or a salt thereof, and have found that by blending epinastine or a salt thereof with lower aliphatic carboxylic acids in eye drops, the pollen outer wall possessed by epinastine or a salt thereof itself can be obtained. It was found that an excellent effect of suppressing the rupture of the pollen outer wall was produced without hindering the effect of suppressing the rupture of the pollen. Furthermore, administration of a pharmaceutical composition (pollen burst inhibitor) containing epinastine or a salt thereof and a lower aliphatic carboxylic acid to the eye has the effect of improving the migration of epinastine to ocular tissues. also found. The present invention has been 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 suppression of pollen bursting 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. agent.
(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) The pollen burst inhibitor according to (1) or (2), wherein 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 its salt is epinastine hydrochloride.
(6) The pollen burst inhibitor according to any one of (1) to (5), for use in eye drop administration.
(7) The agent for suppressing pollen bursting according to any one of (1) to (6), which is used by instilling 1 or 2 drops per eye 2 to 4 times a day.
(8) A method of suppressing bursting of pollen adhering to or near the ocular surface by administering the agent for suppressing pollen bursting according to any one of (1) to (5) to the eye.
(9) A method for suppressing pollen bursting, which comprises bringing the pollen bursting inhibitor according to any one of (1) to (5) into contact with pollen.

Two or more of the configurations (1) to (9) can be arbitrarily selected and combined.

Furthermore, the present invention also provides the following.
(10) Eye drops containing epinastine or a salt thereof and lower aliphatic carboxylic acids.
(11) A method of improving the transmissibility of epinastine or a salt thereof into ocular tissues by adding a lower aliphatic carboxylic acid to an eye drop containing epinastine or a salt thereof.
(12) A method of treating an allergic disease, which comprises administering a therapeutically effective amount of the pollen burst inhibitor according to any one of (1) to (7) to a patient in need of treatment. .
(13) The pollen burst inhibitor according to any one of (1) to (7), which is used for treating allergic diseases.
(14) Use of the pollen burst inhibitor according to any one of (1) to (7) for manufacturing a medicament for treating allergic diseases.

ADVANTAGE OF THE INVENTION By mix|blending epinastine or its salt, and lower aliphatic carboxylic acids, this invention can obtain the pollen rupture inhibitor which brings about the effect which suppresses the rupture of the pollen outer wall excellent. Also, an eye drop that improves the migration of epinastine to ocular tissues and provides excellent efficacy by administering to the eye a pollen burst inhibitor containing epinastine or a salt thereof and a lower aliphatic carboxylic acid. Obtainable.

The present invention will be 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 expression:

It is a compound represented by

Epinastine contained in the pollen bursting inhibitor of the present invention may be a racemate or an optical isomer.

Epinastine contained in the pollen bursting inhibitor of the present invention may be a salt, and there is no particular limitation as long as it is a pharmaceutically acceptable salt. Salts include, for example, salts with inorganic acids, salts with organic acids, and the like.
Salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
Salts with organic acids include 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, and 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- Salts with toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, sulfosalicylic acid and the like can be mentioned.
As the salt of epinastine, monohydrochloride (epinastine hydrochloride) is particularly preferred.

Epinastine or a salt thereof contained in the pollen bursting inhibitor of the present invention may be in the form of a hydrate or a solvate.

In the pollen bursting 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, and 0.09% ( w/v) or more is more preferable, and 0.1% (w/v) or more is even more preferable, and the upper limit thereof may be a concentration acceptable as 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), and more preferably 0.05 to 0.2% (w/v). v) is more preferred, and 0.05-0.1% (w/v) is particularly preferred. For example, its content is 0.09% (w/v) or 0.1% (w/v).

In the present invention, "% (w/v)" means the mass (g) of the target component contained in 100 mL of the pollen burst inhibitor (eye drops) of the present invention. When the salt of epinastine is contained in the present invention, the value is the content of the salt of epinastine. In the present invention, when epinastine or a salt thereof is formulated 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 shall apply hereinafter unless otherwise specified.

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

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

When the lower aliphatic carboxylic acid contained in the pollen bursting inhibitor of the present invention is in the form of a salt, it is not particularly limited as long as it is a pharmaceutically acceptable salt. Examples of salts include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as magnesium and calcium salts, and the like. In addition, when the lower aliphatic carboxylic acid to be contained has, for example, an amino group as a substituent, salts thereof include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid. and the like.

In the pollen bursting inhibitor of the present invention, the lower aliphatic carboxylic acids contained are, for example, 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 (epsilon-aminocaproic acid), glycine, alanine, leucine, isoleucine, valine, serine, aspartic acid, Examples thereof include glutamic acid and salts thereof, and hydrates and solvates thereof may also be used. Preferred are citric acid, edetic acid, acetic acid, ε-aminocaproic acid, glutamic acid or salts thereof or hydrates thereof, more preferably citric acid or salts thereof, ε-aminocaproic acid or salts thereof, glutamic acid or A salt thereof, more preferably citric acid or a salt thereof. Examples of citric acid or salts thereof include citric acid, monosodium citrate, disodium citrate, trisodium citrate (sodium citrate), monopotassium citrate, dipotassium citrate, tripotassium citrate, and magnesium citrate. , calcium citrate. Examples of edetic acid or salts thereof include edetic acid, monosodium edetate, disodium edetate (sodium edetate), trisodium edetate, tetrasodium edetate, monopotassium edetate, dipotassium edetate, and trisodium edetate. Potassium, tetrapotassium edetate, calcium sodium edetate, magnesium sodium edetate. Acetic acid or salts thereof include, for example, acetic acid, sodium acetate, and potassium acetate. Examples of ε-aminocaproic acid or salts thereof include ε-aminocaproic acid, ε-aminocaproic acid sodium, ε-aminocaproic acid potassium, ε-aminocaproic acid hydrochloride, ε-aminocaproic acid hydrobromide, ε-aminocaproic acid iodine Hydrochloride, ε-aminocaproic acid nitrate, ε-aminocaproic acid sulfate, ε-aminocaproic acid phosphate. Examples of glutamic acid or salts thereof 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 , glutamic acid phosphate.

In the pollen bursting inhibitor of the present invention, the lower aliphatic carboxylic acids also act as pharmaceutical additives such as buffers, stabilizers, preservatives, and pH adjusters. Therefore, lower aliphatic carboxylic acids can also be used as additives for pharmaceuticals. If the lower aliphatic carboxylic acid is, for example, citric acid or a salt thereof, it acts as a buffering agent or a pH adjuster, and if it is edetic acid or a salt thereof, it acts as a stabilizer, an antioxidant, a chelating agent, or the like. acetic acid or a salt thereof has an action such as a buffering agent and a pH adjuster; ε-aminocaproic acid or a salt thereof has an action such as a buffering agent; and glutamic acid or a salt thereof. It acts as a buffering agent.
Moreover, in the pollen burst inhibitor of the present invention, the lower aliphatic carboxylic acids may be used singly or in combination of two or more.

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

The pollen rupture inhibitor of the present invention can suppress the rupture of pollen present on the surface of the eye and mucous membranes, and can effectively suppress allergic symptoms caused by pollen. The pollen burst inhibitor of the present invention can be used for treating allergic diseases.
In addition, the agent for suppressing pollen bursting of the present invention can improve the transferability of epinastine to ocular tissues and efficiently bring about the efficacy of epinastine.

In the present invention, the term "allergic disease" refers to a disease or its symptom caused by an immune reaction against an external antigen. An antigen from outside is, for example, pollen. Examples of allergic diseases include, but are not limited to, allergic conjunctivitis. In the present invention, the treatment of allergic diseases refers to any treatment (eg, cure, amelioration, alleviation, inhibition of progression, etc.) and prevention of allergic diseases or their symptoms. It also includes prevention of recurrence of allergic disease.

In the present invention, "ocular tissue" includes, for example, the conjunctiva, cornea, tears, aqueous humor, anterior chamber, and the like. When the agent for inhibiting pollen bursting of the present invention is administered to the eye, it is possible to suppress the bursting of pollen adhering to the ocular surface such as the cornea and conjunctiva, eyelashes in the vicinity thereof, eyelid margins, and the like. Furthermore, it is possible to 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, "patient" means not only humans but also other animals such as dogs, cats, and horses. Patients are preferably mammals, more preferably humans. In the present invention, the term “therapeutically effective amount” refers to an amount that provides a therapeutic effect on allergic diseases and their symptoms, an amount that delays the progress of allergic diseases and their symptoms, etc., compared to untreated subjects. Point.

The pollen bursting inhibitor of the present invention may optionally contain pharmaceutical additives such as buffers, thickeners, surfactants, tonicity agents, stabilizers, preservatives, etc. , antioxidants, pH adjusters and the like can be added. Each of these may be used alone, or two or more of them may be used in appropriate combination, and can be blended in an appropriate amount.

The buffering agent when blending the pollen bursting inhibitor of the present invention with a buffering agent can be appropriately blended with a buffering agent that can be used as an additive for pharmaceuticals. Examples thereof include carbonic acid or salts thereof, organic amines, and the like, and hydrates and solvates thereof may also be used.

Examples of phosphoric acid or salts thereof include phosphoric acid, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate. It may be a Japanese product.

Examples of boric acid or salts thereof include boric acid, sodium borate (borax), potassium borate and the like, and hydrates thereof may also be used.

Examples of carbonic acid or salts thereof include carbonic acid, sodium carbonate, sodium hydrogencarbonate and the like, and hydrates thereof may also be used.

Examples of organic amines include trometamol and the like, and hydrates thereof may also be used.

When a buffer is added to the pollen bursting inhibitor of the present invention, the content of the buffer can be appropriately adjusted depending on the type of buffer, but is preferably 0.001 to 10% (w / v). 0.01 to 5% (w/v) is more preferred, 0.1 to 5% (w/v) is even more preferred, and 0.1 to 1% (w/v) is particularly preferred.
When a buffering agent is added to the pollen bursting inhibitor of the present invention, the buffering agent may be used singly or in combination of two or more.

When a thickening agent is added to the pollen bursting inhibitor of the present invention, a thickening agent that can be used as an additive for pharmaceuticals can be appropriately added. Methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol , carboxyvinyl polymer, polyethylene glycol, sodium hyaluronate, and the like.

The content of the thickening agent when blending the pollen bursting inhibitor of the present invention with a thickening agent can be appropriately adjusted depending on the type of thickening agent, etc., but 0.001 to 5% (w /v), more preferably 0.01 to 3% (w/v), even more preferably 0.1 to 2% (w/v).
When a thickening agent is added to the pollen bursting inhibitor of the present invention, the thickening agent may be used alone or in combination of two or more.

The surfactant when blending a surfactant with the pollen bursting inhibitor of the present invention can be appropriately blended with a surfactant that can be used as an additive for pharmaceuticals, for example, a cationic surfactant surfactants, anionic surfactants, nonionic surfactants, and the like.

Cationic surfactants include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyldiethylamine salts, fatty acid polyamine condensates, alkylimidazolines, 1-acylaminoethyl-2 -alkylimidazoline, 1-hydroxyethyl-2-alkylimidazoline, and the like.

Examples of anionic surfactants include phospholipids such as lecithin.

Examples of nonionic surfactants include polyoxyethylene fatty acid esters such as polyoxyl stearate 40; Polyoxyethylene sorbitan fatty acid ester; polyoxyethylene hydrogenated castor oil such as polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60; polyoxyl 5 castor oil, polyoxyl castor oil such as polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 castor oil; polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxy Polypropylenes such as propylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene (20) polyoxypropylene (20) glycol, oxyethylene polyoxypropylene glycol; sucrose fatty acid esters such as sucrose stearate; tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS);

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

The tonicity agent when blending the tonicity agent with the pollen bursting inhibitor of the present invention can be appropriately blended with an isotonicity agent that can be used as an additive for pharmaceuticals. agents, nonionic isotonizing agents, and the like.

Ionic tonicity agents include sodium chloride, potassium chloride, calcium chloride, magnesium chloride and the like.

Nonionic tonicity agents include glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose, xylitol and the like.

As the tonicity agent when blending the agent for suppressing pollen bursting of the present invention with an tonicity agent, an ionic tonicity agent is preferred, and sodium chloride is particularly preferred.

The content of the tonicity agent when blending the tonicity agent with the pollen bursting inhibitor of the present invention can be appropriately adjusted depending on the type of the tonicity agent, etc., but 0.001 to 10% (w /v) is preferred, 0.01 to 5% (w/v) is more preferred, 0.1 to 3% (w/v) is even more preferred, and 0.2 to 1% (w/v) is particularly preferred. .
When a tonicity agent is added to the pollen bursting inhibitor of the present invention, the tonicity agent may be used alone or in combination of two or more.

When a stabilizer is added to the pollen bursting inhibitor of the present invention, a stabilizer that can be used as an additive for pharmaceuticals can be appropriately added. For example, cyclodextrin, sodium thiosulfate, etc. mentioned.

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

Preservatives that can be used as additives for pharmaceuticals can be appropriately added when the antiseptic agent is added to the pollen bursting inhibitor of the present invention. For example, benzalkonium chloride, benzalkonium bromide, benzethonium chloride, chlorhexidine gluconate, chlorhexidine hydrochloride, methyl parahydroxybenzoate, propyl parahydroxybenzoate, sodium chlorite, chlorobutanol and the like.

When a preservative is added to the pollen bursting inhibitor of the present invention, the content of the preservative can be appropriately adjusted depending on the type of preservative, etc., but the amount that does not adversely affect safety is good. , 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, an antioxidant that can be used as an additive for pharmaceuticals can be appropriately added. For example, ascorbic acid, tocopherol, dibutylhydroxytoluene , sodium sulfite and the like.

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

When a pH adjuster is added to the pollen bursting inhibitor of the present invention, the pH adjuster can be appropriately blended with a pH adjuster that can be used as an additive for pharmaceuticals. Examples include hydrochloric acid, phosphoric acid and the like, and examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like.

The pH of the pollen bursting inhibitor of the present invention may be within a range acceptable for pharmaceuticals, for example, within the range of 4.0 to 8.5 or 4.0 to 8.0, 6.0 to 8 .0 is preferred, and 6.5 to 7.5 are more preferred. A particularly preferred pH is between 6.7 and 7.3, but even more preferred is 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3.

The osmotic pressure ratio of the pollen bursting inhibitor of the present invention may be within the range acceptable for pharmaceuticals, for example, 0.5 to 2.0, preferably 0.7 to 1.6, 0.8 to 1 0.4 is more preferred, and 0.9 to 1.2 is even more preferred.

The pollen burst inhibitor of the present invention is suitable for parenteral (eg, topical) administration. Parenteral administration routes of the pollen burst inhibitor of the present invention include pharmaceutically acceptable local administration routes, such as topical administration to the eye (e.g., eye drop administration), nasal (nasal) administration, and topical administration to the ear. Administration (eg, ear drop administration), inhalation administration, spray administration, transdermal administration, epicutaneous administration, injection administration, and the like can be mentioned. Topical administration to the eye is preferred.

The pollen burst inhibitor of the present invention can be used as an ophthalmic formulation, an otolaryngological formulation, an inhalation formulation, or a percutaneous absorption formulation, and its dosage form is particularly limited as long as it can be used as a pharmaceutical. not something. Dosage forms include, for example, oral administration agents such as liquid agents and suspensions, eye drops, nasal drops, ear drops, inhalants, (inhalable powders, inhalable solutions, and inhalable aerosols), ointments, and creams. , gels, transdermal preparations, patches (tapes, poultices), external liquids (lotions, liniments), external solids (external powders), sprays (pump sprays, external aerosols), Locally administered agents such as injections (infusions, implanted injections, long-acting injections) can be mentioned. Eye drops are preferred. These can be produced according to the usual methods in the technical field.

The pollen bursting inhibitor of the present invention may have all its components dissolved or partially suspended, or may be in the form of an emulsion or a semi-solid. The pollen bursting inhibitor of the present invention is more preferably in the form of a solution in which all constituent components are dissolved, and most preferably in the form of an aqueous solution.

When the pollen bursting inhibitor of the present invention is an emulsion, even if it is an oil-in-water emulsion (an aqueous phase as a continuous phase, an emulsion composed of an aqueous phase and dispersed oily droplets), a water-in-oil emulsion ( It may be an emulsion composed of aqueous droplets dispersed with oil, with an oil phase as a continuous phase.

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. In addition, unless otherwise specified, the pollen burst inhibitor of the present invention may contain pharmaceutical active ingredients other than epinastine or a salt thereof, such as active ingredients used in other eye drops, or may contain epinastine or a salt thereof. It may be the only active ingredient.

When the pollen burst inhibitor of the present invention is administered to the eye as an eye drop, the dosage and administration is not particularly limited as long as it is sufficient to exhibit the desired efficacy. can be instilled 1 to 6 times a day, 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 type container, a single-use unit dose type container, or a PFMD (Preservative Free Multi Dose) container. The material of the container is not particularly limited, and it may be a commonly used container for eye drops. Preferably, it is a container made of resin, such as polyethylene (PE), polypropylene (PP), polyethylene terephthalate ( PET), polybutylene terephthalate (PBT), polypropylene-polyethylene copolymer, polyvinyl chloride, acrylic, polystyrene, polycyclic olefin copolymer, and other containers can be used. In addition, if the material of the resin container is, for example, polyethylene, polyethylene is classified according to its density. can be used.

Formulation examples and test examples are shown below, but these are for better understanding of the present invention and do not limit the scope of the present invention.

Formulation Examples Representative formulation examples of the present invention are shown below. In addition, in the following formulation examples, the amount of each component is the content in 1 mL of the formulation.

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

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

Formulation example 3
Epinastine hydrochloride 0.5 mg
Sodium citrate 8mg
Sodium edetate 1 mg
1 mg of boric acid
5 mg of sodium chloride
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0

Formulation example 4
Epinastine hydrochloride 0.5 mg
4 mg sodium citrate
Sodium edetate 1 mg
Boric acid 0.5 mg
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 0.5 mg
Sodium edetate 1 mg
Boric acid 0.5 mg
Sodium dihydrogen phosphate 12mg
8 mg of sodium chloride
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 0.5 mg
ε-aminocaproic acid 5mg
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 0.5 mg
Sodium 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 1 mg
8 mg of sodium chloride
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0

Test example 1. Pollen bursting test (1) Preparation of test preparation Epinastine hydrochloride, sodium citrate, sodium chloride are dissolved in water so that the concentration is as shown in Table 1 below, and a pH adjuster (dilute hydrochloric acid and / or sodium hydroxide) and water was added to make the total volume 10 mL, and the formulation of Example 1 was prepared by performing filter sterilization.
In addition, preparations of Examples 2 to 4 and Comparative Example 1 in Table 1 below were prepared in the same manner as the preparation method of the preparation of Example 1. In addition, "M" in Table 1 represents the molarity by volume (substance amount (mol) of the target component contained in 1 L of the preparation).

(2) Test method Approximately 3 µL of cedar pollen particles were sampled and seeded in a 96-well microplate. Then, 50 μL of the test preparation was dropped into each well, and immediately after that, the total pollen count was measured under an optical microscope using a hemacytometer. Furthermore, the number of pollen that burst 5 minutes and 10 minutes after dropping was similarly counted under a microscope over time. This was done twice for each formulation tested.

The pollen burst rate was calculated from the following formula, and the average pollen burst rate for each test formulation was calculated.
Pollen rupture rate (%) = (number of pollen burst 5 minutes or 10 minutes after dropping) / (total number of pollen immediately after dropping test preparation) × 100

(3) Test results and discussion Table 1 shows the test results.

As shown in Table 2, for Comparative Example 1 containing a phosphate, Examples 1 and 2 containing lower aliphatic carboxylic acids (citrate), Example 3 (ε-aminocaproic acid) and Example 4 (glutamate) was shown to suppress the rupture of pollen outer walls more.

2. Intraocular Kinetic Test (1) Preparation of Test Formulation Formulations of Examples 5, 6 and Comparative Example 2 in Table 3 below were prepared in the same manner as the preparation method of the formulation of Example 1. In order to equalize the osmotic pressure of all test preparations, the content of sodium chloride was appropriately adjusted.

(2) Test method 5 μL of each test preparation was administered to rats once (n=6), and the eyeballs were removed after slaughter 1 hour after the administration of the eye drops. The epinastine concentration in the conjunctiva was measured and the average value was calculated.

(3) Test results and discussion Table 4 shows the test results.

As shown in Table 4, in Example 5 containing sodium citrate hydrate and Example 6 containing ε-aminocaproic acid, compared with Comparative Example 2 containing no lower aliphatic carboxylic acids, conjunctival tissue It was confirmed that the concentration of epinastine in the Therefore, in the pollen bursting inhibitor of the present invention, it was shown that the translocation of epinastine to the conjunctival tissue is improved.

The present invention provides a pollen burst inhibitor containing epinastine or a salt thereof and lower aliphatic carboxylic acids.

Claims (1)

The invention described in the specification.