CN115397430A - Aqueous composition containing epinastine or salt thereof - Google Patents
Aqueous composition containing epinastine or salt thereof Download PDFInfo
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- CN115397430A CN115397430A CN202180026833.3A CN202180026833A CN115397430A CN 115397430 A CN115397430 A CN 115397430A CN 202180026833 A CN202180026833 A CN 202180026833A CN 115397430 A CN115397430 A CN 115397430A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
Abstract
The present invention provides an aqueous composition having improved migration to an eye tissue, comprising epinastine or a salt thereof and a quaternary ammonium compound, wherein the content of the quaternary ammonium compound is 0.1 part by weight or less relative to epinastine or a salt thereof per 1 part by weight of the epinastine or a salt thereof.
Description
Technical Field
The present invention relates to an aqueous composition containing epinastine or a salt thereof, and more specifically, to an aqueous composition containing epinastine or a salt thereof and a quaternary ammonium compound (hereinafter, also referred to as "the aqueous composition of the present invention").
Background
In order to prevent the propagation of fungi and the like, an aqueous composition containing a solvent such as water, which is repeatedly used, is required to have a certain or more preservative measure. Therefore, a preservative is generally blended in such a composition. For example, benzalkonium chloride is commonly used for eye drops. The benzalkonium chloride is water soluble, stable in chemical property and high in preservative effect compared with other preservative. However, benzalkonium chloride is cell-damaging, and when the exposure amount is increased, the possibility of causing damage to the corneal epithelium is increased, and therefore it is desirable to make it as unnecessary as possible.
Alesion currently marketed in Japan (registered trademark) Eye drops 0.05% are eye drops containing epinastine hydrochloride as an active ingredient, and benzalkonium chloride is not added as an additive, but boric acid is added instead (non-patent document 1).
Further, it is also known that a sufficient preservative effect can be obtained without substantially containing a preservative or a component having a preservative effect by increasing the concentration of epinastine or a salt thereof in an eye drop to more than 0.075% (w/v) (patent document 1).
As described above, in recent years, eye drops not using benzalkonium chloride have been developed, and there is a tendency to avoid the use of benzalkonium chloride in aqueous compositions.
In addition, from the viewpoint of medication compliance, it is desirable that the number of administrations per day is small. However, if the number of administrations is reduced, the effective concentration in the body tissue cannot be maintained, and the drug efficacy may be reduced. In the case of eye drops, as a method for maintaining an effective concentration in an ocular tissue, a method for increasing a blending concentration of an active ingredient, a method for using an absorption enhancer, a method for improving retention in an ocular tissue by blending a thickener, and the like are known.
For example, patent document 2 describes that the action time after administration is prolonged by adding a β receptor blocker to an aqueous solution containing alginic acid and adjusting the pH to 6 to 8. Patent document 3 describes that the intraocular migration of a drug is improved by including a sugar alcohol in a β receptor blocker.
On the other hand, it has been reported that a topically administrable aqueous solution containing epinastine, which contains a certain amount of benzalkonium chloride added thereto as an antiseptic, can suppress the influx of neutrophils and eosinophils into the conjunctiva of the eyeball and the tissue of the nasal mucosa, thereby reducing or preventing the occurrence of a delayed phase reaction (patent document 4).
There is no report that the migration of epinastine or a salt thereof into an ocular tissue is enhanced by adding a quaternary ammonium compound such as benzalkonium chloride to an aqueous composition containing epinastine or a salt thereof, thereby maintaining an effective concentration in the ocular tissue.
Prior art documents
Patent document
Patent document 1: japanese patent No. 6134853
Patent document 2: japanese Kohyo publication 2002-511430
Patent document 3: international publication No. 2012/026609 handbook
Patent document 4: japanese patent application laid-open No. 2003-514021
Non-patent document
Non-patent document 1: alesion (registered trademark) 0.05% specification of eye drops
Disclosure of Invention
Problems to be solved by the invention
Therefore, in order to provide an excellent drug effect, it is very useful to improve the migration of the active ingredient into tissues, particularly into ocular tissues, and it is an interesting object to provide an aqueous composition containing epinastine or a salt thereof as an active ingredient, which improves the migration into tissues, particularly into ocular tissues.
Means for solving the problems
The present inventors have conducted intensive studies on an aqueous composition containing epinastine or a salt thereof, and as a result, have found that when an aqueous composition containing epinastine or a salt thereof and a quaternary ammonium compound adjusted to a specific content is applied to the eye in the form of eye drops, the migration of epinastine into the eye tissue is improved, and have completed the present invention.
Specifically, the present invention provides the following.
(1) An aqueous composition comprising epinastine or a salt thereof and a quaternary ammonium compound, wherein the content ratio of the quaternary ammonium compound to epinastine or a salt thereof is 0.1 part by weight or less based on 1 part by weight of the epinastine or a salt thereof.
(2) The aqueous composition according to (1), wherein the epinastine or the salt thereof is epinastine hydrochloride.
(3) The aqueous composition as described in (1) or (2), wherein the concentration of epinastine or a salt thereof is 0.01 to 5% (w/v).
(4) The aqueous composition as described in (1) or (2), wherein the concentration of epinastine or a salt thereof is 0.05% (w/v) or more.
(5) The aqueous composition according to any one of (1) to (4), wherein the concentration of epinastine or a salt thereof is 0.1% (w/v).
(6) The aqueous composition according to any one of (1) to (5), wherein the quaternary ammonium compound is at least 1 selected from the group consisting of benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride and porcellonium chloride.
(7) The aqueous composition according to any one of (1) to (6), wherein the quaternary ammonium compound is benzalkonium chloride.
(8) The aqueous composition as described in any one of (1) to (7), wherein the content ratio of the quaternary ammonium compound to epinastine or a salt thereof is 0.05 parts by weight or less with respect to 1 part by weight of the epinastine or a salt thereof.
(9) The aqueous composition according to any one of (1) to (8), which is for ophthalmic use.
(10) The aqueous composition according to any one of (1) to (9), which is an eye drop.
(11) A method for improving the migration of epinastine or a salt thereof into an ocular tissue, which comprises adding a quaternary ammonium compound to an aqueous composition containing epinastine or a salt thereof as an active ingredient.
(12) The method according to (11), wherein the quaternary ammonium compound is at least 1 selected from the group consisting of benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride and polonium chloride.
(13) The method according to (11) or (12), wherein the quaternary ammonium compound is benzalkonium chloride.
(14) An eye drop comprising benzalkonium chloride and epinastine hydrochloride at a concentration of 0.1% (w/v), wherein the content of benzalkonium chloride relative to epinastine hydrochloride is 0.0001 parts by weight or more and less than 0.1 part by weight relative to 1 part by weight of the epinastine hydrochloride content.
The respective configurations (1) to (14) can be combined by arbitrarily selecting 2 or more.
In addition, the present invention provides the following aspects.
(15) A method for treating an allergic disease, which comprises administering a therapeutically effective amount of the aqueous composition according to any one of (1) to (10) to a patient in need of treatment.
(16) The aqueous composition according to any one of (1) to (10), which is used for the treatment of allergic diseases.
(17) Use of an aqueous composition according to any one of (1) to (10) for the manufacture of a medicament for the treatment of an allergic disease.
ADVANTAGEOUS EFFECTS OF INVENTION
Disclosed is an aqueous composition which is capable of providing an excellent drug effect by adding a quaternary ammonium compound to an aqueous composition containing epinastine or a salt thereof, thereby improving the migration of epinastine or a salt thereof into an ocular tissue.
Detailed Description
The present invention will be described in detail below.
In the present invention, "epinastine" refers to a compound represented by the chemical name (. + -.) -3-Amino-9,13b-dihydro-1H-dibenz [ c, f ] imidizo [1,5-a ] azepine, and further refers to a compound represented by the following formula,
[ chemical formula 1]
Epinastine contained in the aqueous composition of the present invention may be racemic body or optical isomer.
The epinastine contained in the aqueous composition of the present invention may be a salt, and is not particularly limited as long as it is a pharmaceutically acceptable salt. Examples of the salt include a salt with an inorganic acid and a salt with an organic acid.
Examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
Examples of the salt with an organic acid include salts with acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptonic 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 (pamoic acid), polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, dimethyl sulfate, naphthalenesulfonic acid, and sulfosalicylic acid.
As the salt of epinastine, monohydrochloride (epinastine hydrochloride) is particularly preferable.
In the aqueous composition of the present invention, epinastine or a salt thereof may be contained in the form of a hydrate or a solvate.
In the aqueous composition of the present invention, the epinastine or its salt is contained in an amount of preferably 0.01% (w/v) or more, more preferably 0.05% (w/v) or more, and still more preferably 0.1% (w/v) or more, and the upper limit thereof may be, for example, 5% (w/v) as long as it is a concentration allowable for ophthalmic preparations. The content of epinastine or a salt thereof is preferably 0.01 to 5% (w/v), more preferably 0.05 to 1% (w/v), still more preferably 0.05 to 0.2% (w/v), and particularly preferably 0.05 to 0.1% (w/v). For example, the content thereof is 0.1% (w/v).
In the present invention, "% (w/v)" means the mass (g) of the target component contained in 100mL of the aqueous composition of the present invention. In the present invention, when the epinastine salt is contained, the value is the content of the epinastine salt. In the present invention, when epinastine or a salt thereof is blended in the form of a hydrate or a solvate, the value is the content of the hydrate or the solvate of epinastine or the salt thereof. Hereinafter, unless otherwise specified, the same shall be understood.
In the present invention, the "quaternary ammonium compound" refers to a salt of a quaternary ammonium cation with other anions, and is also referred to as a quaternary ammonium salt.
Examples of the quaternary ammonium compound contained in the aqueous composition of the present invention include benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride, porelium chloride, cetylpyridinium chloride, benzalkonium bromide, benzethonium bromide, methylbenzethonium bromide, cetrimide and the like, and benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride and porium chloride are preferable, and benzalkonium chloride is more preferable.
In the aqueous composition of the present invention, the quaternary ammonium compound also has an effect as an additive for pharmaceuticals, for example, an antiseptic, a surfactant, a stabilizer, an isotonic agent, a buffer, and the like. Therefore, the quaternary ammonium compound can also be used as an additive for pharmaceuticals.
In the aqueous composition of the present invention, 1 or 2 or more kinds of quaternary ammonium compounds can be used together.
The content of the quaternary ammonium compound in the aqueous composition of the present invention can be appropriately adjusted depending on the kind, and is, for example, 0.0001 to 1% (w/v), preferably 0.0001 to 0.1% (w/v), more preferably 0.0001 to 0.01% (w/v), and still more preferably 0.0001 to 0.005% (w/v). For example, in the case where the quaternary ammonium compound is benzalkonium chloride, the upper limit of the content thereof is preferably 0.01% (w/v) or less than 0.01% (w/v), and more preferably 0.005% (w/v), because the possibility of causing damage to the corneal epithelium increases as the exposure amount increases. The lower limit of the content is preferably 0.0001% (w/v) or more, more preferably 0.001% (w/v) or more, and still more preferably 0.003% (w/v) or more. More specifically, the content is preferably 0.0001 to 0.01% (w/v), more preferably 0.001 to 0.005% (w/v), still more preferably 0.001 to 0.003% (w/v), or 0.003 to 0.005% (w/v).
The content ratio of the quaternary ammonium compound in the aqueous composition of the present invention can be appropriately adjusted depending on the kind, and for example, the upper limit of the content ratio is 0.1 part by weight or less than 0.1 part by weight, preferably 0.05 part by weight or less, relative to 1 part by weight of the content of epinastine or a salt thereof. The lower limit of the content ratio is 0.0001 parts by weight or more, preferably 0.001 parts by weight or more, more preferably 0.003 parts by weight or more, 0.005 parts by weight or more, or 0.01 parts by weight or more, relative to 1 part by weight of the epinastine or salt thereof. More specifically, the content ratio is 0.0001 to 0.1 part by weight, preferably 0.001 to 0.1 part by weight, more preferably 0.003 to 0.1 part by weight, still more preferably 0.005 to 0.05 part by weight, and particularly preferably 0.01 to 0.05 part by weight. For example, in the case where the quaternary ammonium compound is benzalkonium chloride, the possibility of causing damage to the corneal epithelium increases as the exposure amount increases, and therefore the content ratio thereof is 0.1 part by weight or less than 0.1 part by weight, preferably 0.05 part by weight or less or 0.03 part by weight, relative to 1 part by weight of the content of epinastine or a salt thereof. More specifically, the content ratio is 0.0001 to 0.1 part by weight, preferably 0.001 to 0.1 part by weight, more preferably 0.003 to 0.1 part by weight, further preferably 0.005 to 0.05 part by weight, particularly preferably 0.01 to 0.05 part by weight, and particularly preferably 0.03 to 0.05 part by weight.
An aqueous composition containing epinastine or a salt thereof at a concentration of a certain level or more can obtain a sufficient preservative effect without substantially containing a preservative or a component having a preservative effect. In the aqueous composition of the present invention, for example, when the quaternary ammonium compound is benzalkonium chloride which is generally used as a preservative, the content of benzalkonium chloride may be insufficient for exerting the effect as a preservative, or may be contained in an amount for exerting the effect of the present invention. On the other hand, the content of benzalkonium chloride may be an amount that exerts an effect as a preservative as long as the effects of the present invention are exerted.
In the present invention, the ocular tissue includes, for example, conjunctiva, cornea, lacrimal fluid, aqueous humor, anterior chamber, and the like. When the aqueous composition of the present invention is administered to the eye, the amount of epinastine or a salt thereof migrating to the ocular tissue can be increased (or also referred to as increased).
In the present invention, the "aqueous composition" refers to a composition containing water. The content of water contained in the aqueous composition of the present invention is not particularly limited, but is preferably 10% (w/v) or more, more preferably 30% (w/v) or more, and still more preferably 50% (w/v) or more, based on the total weight of the aqueous composition. In particular, it is preferably 70% (w/v) or more, more preferably 90% (w/v) or more, and still more preferably 95% (w/v) or more.
In the present invention, "patient" is not limited to humans, but also refers to other animals such as dogs, cats, horses, and the like. The patient is preferably a mammal, more preferably a human. In the present invention, the "therapeutically effective amount" refers to an amount that brings about a therapeutic effect of a disease and its symptoms, or an amount that brings about a delay in the progress of a disease and its symptoms, or the like, as compared to an untreated subject.
The aqueous composition of the present invention may contain pharmaceutical additives as needed, for example, buffers, thickeners, surfactants, isotonic agents, stabilizers, preservatives, antioxidants, pH adjusters, and the like. These can be used alone, or 2 or more kinds can be used in combination as appropriate, and an appropriate amount can be blended.
When a buffer is added to the aqueous composition of the present invention, a buffer that can be used as an additive for a pharmaceutical can be appropriately added, and examples thereof include phosphoric acid or a salt thereof, boric acid or a salt thereof, carbonic acid or a salt thereof, citric acid or a salt thereof, acetic acid or a salt thereof, tartaric acid or a salt thereof, epsilon-aminocaproic acid or a salt thereof, glutamic acid or a salt thereof, organic amines, and the like, and hydrates or solvates thereof may be used.
Examples of the phosphoric acid or a salt thereof include phosphoric acid, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate (hereinafter, also referred to as sodium hydrogen phosphate), potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and the like, and hydrates thereof may be used.
Examples of boric acid or a salt thereof include boric acid, sodium borate (borax), potassium borate, and the like, and hydrates thereof may be used.
Examples of the carbonic acid or a salt thereof include carbonic acid, sodium carbonate, sodium hydrogencarbonate, and the like, and hydrates thereof are also possible.
Examples of citric acid or a salt thereof include citric acid, monosodium citrate, disodium citrate, trisodium citrate, and the like, and hydrates of these acids may also be used.
Examples of acetic acid or a salt thereof include acetic acid and sodium acetate, and hydrates thereof are also possible.
Examples of tartaric acid or a salt thereof include tartaric acid, monosodium tartrate, disodium tartrate, and the like, and hydrates thereof are also possible.
Examples of the epsilon-aminocaproic acid or a salt thereof include epsilon-aminocaproic acid, epsilon-sodium aminocaproate, epsilon-aminocaproic acid hydrochloride, and hydrates thereof.
Examples of glutamic acid or a salt thereof include glutamic acid, monosodium glutamate, disodium glutamate, and glutamic acid hydrochloride, and hydrates thereof are also acceptable.
Examples of the organic amine include tromethamine and the like, and hydrates of these are also possible.
The content of the buffer in the case of blending the buffer in the aqueous composition of the present invention can be appropriately adjusted depending on the kind of the buffer, and is preferably 0.001 to 10% (w/v), more preferably 0.01 to 5% (w/v), still more preferably 0.1 to 5% (w/v), and particularly preferably 0.1 to 2% (w/v).
When a buffer is added to the aqueous composition of the present invention, 1 or 2 or more kinds of buffers may be used together.
When a thickener is added to the aqueous composition of the present invention, a thickener that can be used as an additive for a pharmaceutical can be appropriately added, and examples thereof include methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, carboxymethyl ethyl cellulose, cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyethylene glycol, sodium hyaluronate, and the like.
The content of the thickener in the case of blending the thickener in the aqueous composition of the present invention can be appropriately adjusted depending on the kind of the thickener, and is preferably 0.001 to 5% (w/v), more preferably 0.01 to 3% (w/v), and still more preferably 0.1 to 2% (w/v).
When a thickener is added to the aqueous composition of the present invention, 1 or 2 or more thickeners may be used together.
When a surfactant is blended in the aqueous composition of the present invention, a surfactant that can be used as an additive for a pharmaceutical can be appropriately blended, and examples thereof include a cationic surfactant, an anionic surfactant, and a nonionic surfactant.
Examples of the cationic surfactant include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyldiethylamine salts, fatty acid polyamine condensates, alkylimidazolines, 1-acylaminoethyl-2-alkylimidazolines, and 1-hydroxyethyl-2-alkylimidazolines. Quaternary ammonium cations such as benzalkonium chloride have properties of cationic surfactants, but these are not included in the cationic surfactants of the present invention.
Examples of the anionic surfactant include phospholipids such as lecithin.
Examples of the nonionic surfactant include polyoxyethylene fatty acid esters such as polyoxyethylene 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 10 hydrogenated castor oil, polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 50 hydrogenated castor oil, and polyoxyethylene 60 hydrogenated castor oil; polyoxyethylene castor oils such as polyoxyethylene 5 castor oil, polyoxyethylene 9 castor oil, polyoxyethylene 15 castor oil, polyoxyethylene 35 castor oil, and polyoxyethylene 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; tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS), and the like.
The content of the surfactant in the case of blending the surfactant in the aqueous composition of the present invention can be appropriately adjusted depending on the kind of the surfactant, and is preferably 0.01 to 1% (w/v), more preferably 0.05 to 0.5% (w/v), and still more preferably 0.05 to 0.2% (w/v).
When a surfactant is added to the aqueous composition of the present invention, 1 or 2 or more surfactants may be used together.
When an isotonic agent is added to the aqueous composition of the present invention, an isotonic agent that can be used as an additive for a pharmaceutical product can be appropriately added, and examples thereof include an ionic isotonic agent and a nonionic isotonic agent.
Examples of the ionic isotonic agent include sodium chloride, potassium chloride, calcium chloride, and magnesium chloride.
Examples of the nonionic isotonic agent include glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose, xylitol, and the like.
The content of the isotonic agent in the case of blending the isotonic agent in the aqueous composition of the present invention can be appropriately adjusted depending on the kind of the isotonic agent, and is preferably 0.001 to 10% (w/v), more preferably 0.01 to 5% (w/v), still more preferably 0.1 to 3% (w/v), and particularly preferably 0.2 to 1% (w/v).
When an isotonic agent is added to the aqueous composition of the present invention, 1 or 2 or more kinds of the isotonic agent can be used together.
When a stabilizer is blended in the aqueous composition of the present invention, a stabilizer that can be used as an additive for pharmaceutical products can be properly blended, and examples thereof include ethylenediaminetetraacetic acid or a salt thereof, cyclodextrin, sodium thiosulfate, and the like.
Examples of ethylenediaminetetraacetic acid or a salt thereof include ethylenediaminetetraacetic acid, monosodium ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetate (hereinafter, also referred to as sodium ethylenediaminetetraacetate), trisodium ethylenediaminetetraacetate, tetrasodium ethylenediaminetetraacetate, and the like, and hydrates thereof may also be used.
The content of the stabilizer in the case of blending the stabilizer in the aqueous composition of the present invention can be appropriately adjusted depending on the kind of the stabilizer, and is preferably 0.001 to 5% (w/v), more preferably 0.01 to 3% (w/v), and still more preferably 0.01 to 1% (w/v).
When a stabilizer is added to the aqueous composition of the present invention, 1 or 2 or more stabilizers may be used together.
When a preservative is added to the aqueous composition of the present invention, a preservative that can be used as an additive for pharmaceutical products can be appropriately added, and examples thereof include chlorhexidine gluconate, chlorhexidine hydrochloride, methyl paraben, propyl paraben, sodium chlorite, chlorobutanol, and the like.
The content of the preservative in the case of blending the preservative in the aqueous composition of the present invention may be adjusted as appropriate depending on the kind of the preservative and the like, and may be an amount of such a degree that does not adversely affect safety, and is, for example, preferably 0.0001 to 0.1% (w/v), more preferably 0.001 to 0.05% (w/v).
When a preservative is added to the aqueous composition of the present invention, 1 or 2 or more preservatives can be used together.
When an antioxidant is added to the aqueous composition of the present invention, an antioxidant that can be used as an additive for pharmaceutical products can be appropriately added, and examples thereof include ascorbic acid, tocopherol, dibutylhydroxytoluene, sodium sulfite, and the like.
The content of the antioxidant in the case of blending the antioxidant in the aqueous composition of the present invention can be suitably adjusted depending on the kind of the antioxidant, and is preferably 0.001 to 5% (w/v), more preferably 0.01 to 3% (w/v), and still more preferably 0.1 to 2% (w/v).
When an antioxidant is added to the aqueous composition of the present invention, 1 or 2 or more antioxidants may be used together.
When a pH adjuster is added to the aqueous composition of the present invention, a pH adjuster that can be used as an additive to a pharmaceutical can be appropriately added, and examples of the pH adjuster include an acid or an alkali, examples of the acid include hydrochloric acid and phosphoric acid, and examples of the alkali include sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydrogen carbonate.
The pH of the aqueous composition of the present invention may be in a range allowable as a pharmaceutical, for example, in a 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. The pH is particularly preferably 6.7 to 7.3, and is still more preferably 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, and 7.3.
The osmotic pressure ratio of the aqueous composition of the present invention may be in a range allowable as a pharmaceutical, and is, for example, 0.5 to 2.0, preferably 0.7 to 1.6, more preferably 0.8 to 1.4, and further preferably 0.9 to 1.2.
The aqueous composition of the present invention is particularly preferably used as a medicament, suitable for parenteral (e.g., topical) administration. Examples of parenteral administration routes of the aqueous composition of the present invention include topical administration routes allowable as a pharmaceutical, for example, topical administration to the eye (e.g., eye drop administration), nasal (nasal) administration, topical administration to the ear (e.g., ear drop administration), inhalation administration, spray administration, transdermal administration, administration on the skin, injection administration, and the like. Topical administration to the eye is preferred. The aqueous composition of the present invention can also be administered orally.
The aqueous composition of the present invention can be used as an ophthalmic preparation, an otorhinological preparation, an inhalation preparation, or a transdermal preparation, and the dosage form thereof is not particularly limited as long as it can be used as a pharmaceutical. Examples of the dosage form include oral preparations such as liquid and suspension, eye drops, nasal drops, ear drops, inhalants, (inhalation powder, inhalation liquid, inhalation aerosol), ointments, creams, gels, transdermally absorbable preparations, patches (patches, cataplasms), external liquid preparations (lotions, liniments), solid external preparations (powders for external use), sprays (pump sprays, aerosol sprays), and injections (infusion solutions, buried injections, and sustained injections). Preferred are eye drops, transdermal preparations for ophthalmic use, and ophthalmic injections, and more preferred are eye drops. These can be manufactured according to methods common in the art.
The aqueous composition of the present invention may be in the form of an emulsion or a semisolid, as long as the constituent components are completely dissolved or partially suspended. The aqueous composition of the present invention is more preferably in the form of a solution in which all the components are dissolved, and most preferably an aqueous solution. For example, eye drops (eye drops) are particularly preferable for ophthalmic use.
When the aqueous composition of the present invention is an emulsion, it may be an oil-in-water emulsion (an emulsion composed of an aqueous phase and dispersed oily droplets with the aqueous phase as the continuous phase) or a water-in-oil emulsion (an emulsion composed of an oil and dispersed aqueous droplets with the oil phase as the continuous phase).
When the aqueous composition of the present invention is used as an ophthalmic preparation, the aqueous composition is particularly useful as a therapeutic agent for allergic conjunctivitis. The aqueous composition of the present invention may contain a pharmaceutically active ingredient other than epinastine or a salt thereof, for example, an active ingredient used in other eye drops, unless otherwise specified.
When the aqueous composition of the present invention is administered to the eye as an eye drop, the amount to be used is not particularly limited as long as the desired drug effect is sufficiently achieved, and the eye drop can be administered 1 time 1 drop, 1 day 1 to 10 times, preferably 1 day 1 to 6 times, more preferably 1 day 2 to 4 times, further preferably 1 day 2 times, 1 day 4 times, and particularly preferably 1 day 2 times.
When the aqueous composition of the present invention is used as an eye drop, it may be contained in any of a Multi-Dose container, a disposable single-Dose container, and a PFMD (pressurized Free Multi Dose) container. The material of the container is not particularly limited, and any container is acceptable as long as it is a container for eye drops that is generally used, and preferably a resin container, for example, a container made of Polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET), polybutylene terephthalate (PBT), polypropylene-polyethylene copolymer, polyvinyl chloride, acrylic acid, polystyrene, and polycycloolefin copolymer can be used. In the case where the material of the resin container is polyethylene, for example, containers made of Low Density Polyethylene (LDPE), medium Density Polyethylene (MDPE), high Density Polyethylene (HDPE), or the like can be used as the polyethylene classified according to its density.
Examples
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.
Preparation examples
Representative formulation examples of the present invention are shown below. In the following formulation examples, the amount of each component added was 1mL of the formulation content.
Formulation example 1
Preparation example 2
Preparation example 3
Preparation example 4
Preparation example 5
Test examples
1. Intraocular pharmacokinetic testing
(1) Preparation of test formulations
The formulation of example 1 (pH 7.0) was prepared by dissolving epinastine hydrochloride, benzalkonium chloride, sodium dihydrogen phosphate, and sodium hydrogen phosphate hydrate in water to a concentration of table 1 below, adding a pH adjuster (dilute hydrochloric acid and/or sodium hydroxide) and water to a total amount of 10mL, and filter-sterilizing.
In addition, the formulations of example 2 and comparative example 1 in table 1 below were prepared by the same method as the preparation method of the formulation of example 1.
TABLE 1
(2) Test method
50 μ L of each test preparation was applied to the eyes of rabbits in a form of eye drops at 15-minute intervals for 3 times in total, and the dead eyes were removed at time points after 0.25 hour, 0.5 hour, 1 hour, 2 hours, and 4 hours from the last eye drop. Epinastine concentrations in the cornea and in the aqueous humor were measured at each time point, and AUC (area under blood concentration-time curve) was calculated. Note that AUC was determined by using Phoenix WinNonlin (registered trademark) Sparse sampling (Sparse sampling) analysis of V8.1.
(3) Test results and discussion
The test results are shown in table 2. In the table, "Mean" represents an average value, "SE" represents a standard error, "N" represents the number of samples, and these are calculated by a common statistical process.
TABLE 2
As shown in table 2, it was confirmed that the migration amount of epinastine in the cornea and the aqueous humor increased in examples 1 and 2 containing benzalkonium chloride as a quaternary ammonium compound compared to comparative example 1 containing no benzalkonium chloride. Thus, it was shown that the aqueous composition of the present invention significantly improves the migration to the eye tissue.
Industrial applicability
The present invention provides an aqueous composition containing epinastine or a salt thereof and a quaternary ammonium compound, wherein the content ratio of the quaternary ammonium compound to epinastine or a salt thereof is 0.1 part by weight or less with respect to 1 part by weight of the content of epinastine or a salt thereof.
Claims (14)
1. An aqueous composition comprising epinastine or a salt thereof and a quaternary ammonium compound, wherein the content of the quaternary ammonium compound is 0.1 part by weight or less relative to epinastine or a salt thereof per 1 part by weight of the epinastine or a salt thereof.
2. The aqueous composition as claimed in claim 1, wherein epinastine or the salt thereof is epinastine hydrochloride.
3. The aqueous composition as claimed in claim 1 or 2, wherein the concentration of epinastine or a salt thereof is 0.01 to 5% (w/v).
4. The aqueous composition according to claim 1 or 2, wherein the concentration of epinastine or a salt thereof is 0.05% (w/v) or more.
5. The aqueous composition of any one of claims 1 to 4, wherein the concentration of epinastine or a salt thereof is 0.1% (w/v).
6. The aqueous composition according to any one of claims 1 to 5, wherein the quaternary ammonium compound is at least 1 selected from the group consisting of benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride and porilium chloride.
7. The aqueous composition of any one of claims 1-6, wherein the quaternary ammonium compound is benzalkonium chloride.
8. The aqueous composition as claimed in any one of claims 1 to 7, wherein the content ratio of the quaternary ammonium compound to epinastine or a salt thereof is 0.05 parts by weight or less with respect to 1 part by weight of the content of epinastine or a salt thereof.
9. Aqueous composition according to any one of claims 1 to 8, which is for ophthalmic use.
10. The aqueous composition according to any one of claims 1 to 9, which is an eye drop.
11. A method for improving the migration of epinastine or a salt thereof into an ocular tissue, which comprises adding a quaternary ammonium compound to an aqueous composition containing epinastine or a salt thereof as an active ingredient.
12. The method according to claim 11, wherein the quaternary ammonium compound is at least one selected from the group consisting of benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride and porilium chloride.
13. The method of claim 11 or 12, wherein the quaternary ammonium compound is benzalkonium chloride.
14. An eye drop comprising benzalkonium chloride and epinastine hydrochloride at a concentration of 0.1% (w/v), wherein the content of benzalkonium chloride relative to epinastine hydrochloride is 0.0001 parts by weight or more and less than 0.1 part by weight relative to 1 part by weight of the epinastine hydrochloride content.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| JP2020-073507 | 2020-04-16 | ||
| JP2020073507A JP6963651B2 (en) | 2020-04-16 | 2020-04-16 | Aqueous composition containing epinastine or a salt thereof |
| PCT/JP2021/015601 WO2021210646A1 (en) | 2020-04-16 | 2021-04-15 | Aqueous composition containing epinastine or salt thereof |
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| CN202180026833.3A Pending CN115397430A (en) | 2020-04-16 | 2021-04-15 | Aqueous composition containing epinastine or salt thereof |
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| JP (2) | JP6963651B2 (en) |
| KR (1) | KR20230004582A (en) |
| CN (1) | CN115397430A (en) |
| WO (1) | WO2021210646A1 (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030050303A1 (en) * | 1999-11-12 | 2003-03-13 | Boehringer Ingelheim Pharma Gmbh | Solutions containing epinastin |
| US7378082B1 (en) * | 2007-11-05 | 2008-05-27 | Inspire Pharmaceuticals, Inc. | Method for treating allergic rhinitis without adverse effects |
| US20080194544A1 (en) * | 2007-02-08 | 2008-08-14 | Ramesh Krishnamoorthy | Aqueous formulations of epinastine for treating allergic rhinitis |
| EP3037094A1 (en) * | 2014-12-23 | 2016-06-29 | Poifa Warszawa SA | Ophthalmic pharmaceutical composition |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5910328A (en) | 1982-07-09 | 1984-01-19 | Hiroo Tominaga | Method for purifying waste gas using hydrogen sulfate |
| DE19542281C2 (en) * | 1995-11-14 | 1997-12-04 | Boehringer Ingelheim Kg | Use of Epinastin for the treatment of migraines |
| FR2777189B1 (en) | 1998-04-09 | 2001-04-06 | Chauvin Lab Sa | OPHTHALMIC COMPOSITION COMPRISING A BETA-BLOCKER |
| WO2008098122A2 (en) * | 2007-02-08 | 2008-08-14 | Inspire Pharmaceuticals, Inc. | Method for treating allergic rhinitis without adverse effects |
| WO2012026609A1 (en) | 2010-08-27 | 2012-03-01 | わかもと製薬株式会社 | Aqueous composition for ophthalmic administration |
| JP7355539B2 (en) * | 2018-07-20 | 2023-10-03 | ロート製薬株式会社 | Ophthalmic composition |
| JP2019108320A (en) * | 2018-10-31 | 2019-07-04 | 参天製薬株式会社 | Ophthalmologic composition which suppresses deterioration of soft contact lens |
-
2020
- 2020-04-16 JP JP2020073507A patent/JP6963651B2/en active Active
-
2021
- 2021-04-15 CN CN202180026833.3A patent/CN115397430A/en active Pending
- 2021-04-15 WO PCT/JP2021/015601 patent/WO2021210646A1/en active Application Filing
- 2021-04-15 KR KR1020227039244A patent/KR20230004582A/en unknown
- 2021-10-15 JP JP2021169635A patent/JP2022001606A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030050303A1 (en) * | 1999-11-12 | 2003-03-13 | Boehringer Ingelheim Pharma Gmbh | Solutions containing epinastin |
| US20080194544A1 (en) * | 2007-02-08 | 2008-08-14 | Ramesh Krishnamoorthy | Aqueous formulations of epinastine for treating allergic rhinitis |
| US7378082B1 (en) * | 2007-11-05 | 2008-05-27 | Inspire Pharmaceuticals, Inc. | Method for treating allergic rhinitis without adverse effects |
| EP3037094A1 (en) * | 2014-12-23 | 2016-06-29 | Poifa Warszawa SA | Ophthalmic pharmaceutical composition |
Non-Patent Citations (1)
| Title |
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| A. PAULY 等: "Multiple endpoint analysis of BAC-preserved and unpreserved antiallergic eye drops on a 3D-reconstituted corneal epithelial model", 《MOLECULAR VISION》, vol. 17, pages 745 - 755, XP055868062 * |
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| Publication number | Publication date |
|---|---|
| JP2021169431A (en) | 2021-10-28 |
| JP2022001606A (en) | 2022-01-06 |
| WO2021210646A1 (en) | 2021-10-21 |
| JP6963651B2 (en) | 2021-11-10 |
| KR20230004582A (en) | 2023-01-06 |
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