JPWO2019245015A1 - Pharmaceutical composition containing desloratadine or a salt thereof - Google Patents

Abstract

The present invention provides a pharmaceutical composition for topical administration, which is a pharmaceutical composition containing desloratadine or a salt thereof and does not contain benzalkonium chloride.

Description

The present invention is a pharmaceutical composition containing desloratadine or a salt thereof as an active ingredient, which does not contain benzalkonium chloride (hereinafter, "the pharmaceutical composition of the present invention"). Also called "things").

A pharmaceutical composition containing a solvent such as water, which is intended for repeated use, is required to have a certain level of antiseptic measures in order to prevent the growth of fungi and the like. Therefore, such pharmaceutical compositions are usually formulated with preservatives. For example, in the case of eye drops, benzalkonium chloride is often used as a preservative. Benzalkonium chloride is widely used as a preservative because it is water-soluble, chemically stable, and has a high antiseptic effect compared to other preservatives. However, benzalkonium chloride has a cytotoxic effect, and increased exposure increases the likelihood of causing corneal epithelial damage. Therefore, it cannot be used especially for patients who show a hypersensitive reaction to benzalkonium chloride or patients with severe corneal epithelial disorder.

On the other hand, most of the eye drops on the market that do not contain preservatives are unit dose type (single-use type) or preservative-free containers (special for exerting antiseptic effect). It is generally stored in a container having a similar structure).

By the way, desloratadine, which is one of the H1 histamine receptor antagonists, is an active ingredient of the allergic disease therapeutic agent "Desalex (registered trademark) tablet 5 mg", and the effective amount thereof should be orally administered once a day. It is known that it has a therapeutic effect on the symptoms of pruritus associated with allergic rhinitis, urticaria, and skin diseases (Non-Patent Document 1). In addition, it has been reported that desloratadine can be used as a preparation for topical administration such as eye drops and nasal drops, but benzalkonium chloride is added to both of these preparations (Patent Documents 1 and Patent Documents). 2). In particular, in Patent Document 1, the higher the concentration of benzalkonium chloride, the more stable the pH and activity of the eye drops. Therefore, as a preservative at the highest concentration (0.127%) listed in the list of pharmaceutical additives. It is also stated that it is preferable to include it. On the other hand, there is no known pharmaceutical composition containing desloratadine or a salt thereof for topical administration to which benzalkonium chloride is not added. Furthermore, there are no reports that desloratadine or its salts themselves have antiseptic properties.

International Publication WO98 / 48803 Japanese Unexamined Patent Publication No. 2005-53825

"Desalex (registered trademark) tablet 5 mg" package insert

It is an interesting subject to provide a topical pharmaceutical composition containing desloratadine or a salt thereof, which does not contain benzalkonium chloride. Furthermore, an object of the present invention is to provide a pharmaceutical composition for topical administration containing desloratadine or a salt thereof, which exerts an antiseptic effect even when an antiseptic is not added, not limited to benzalkonium chloride.

As a result of diligent research, the present inventors have found that a pharmaceutical composition for topical administration containing desloratazine or a salt thereof as an active ingredient has sufficient antiseptic efficacy without containing a preservative containing benzalkonium chloride. It has been found to have, and the present invention has been reached. Specifically, the present invention provides:
(1) A pharmaceutical composition for topical administration, which comprises desloratadine or a salt thereof as an active ingredient and does not contain benzalkonium chloride.
(2) The pharmaceutical composition according to (1), which contains desloratadine or a salt thereof at a concentration of 0.001% (w / v) or more.
(3) The pharmaceutical composition according to (1), which contains desloratadine or a salt thereof at a concentration of 0.01% to 5% (w / v).
(4) The pharmaceutical composition according to (1) to (3), which is an ophthalmic composition, an otolaryngological composition, an inhalation composition or a transdermal absorption composition.
(5) The pharmaceutical composition according to (1) to (4), which is an eye drop.
(6) The pharmaceutical composition according to (5), wherein the container for eye drops is a multi-dose type container.
(7) The pharmaceutical composition according to any one of (1) to (6), which contains at least one selected from the group consisting of a buffer, an isotonic agent, a pH adjuster and a stabilizer as an additive. Stuff.
(8) The pharmaceutical composition according to (7), which contains a buffer, an isotonic agent and a pH adjuster.
(9) The pharmaceutical composition according to (8), which further contains a stabilizer.
(10) The pharmaceutical composition according to any one of (1) to (9), which has a pH of 4.0 to 8.5.
(11) The pharmaceutical composition according to any one of (1) to (10), wherein the pH is 6.0 to 8.0.
(12) The pharmaceutical composition according to any one of (1) to (11), which does not contain a preservative.
(13) The pharmaceutical composition according to any one of (1) to (12), wherein the route of administration is administration to the vicinity of the eye.
(14) The pharmaceutical composition according to (13), wherein the administration to the vicinity of the eye is application to the skin of the eyelid.
(15) The pharmaceutical composition according to any one of (1) to (4) and (7) to (12), wherein the route of administration is intradermal or transdermal administration.
(16) The dosage form is selected from the group consisting of ointments, creams, lotions, gels, liniments, transdermal preparations, patches, sprays and injections, (1) to (1). 4) and the pharmaceutical composition according to any one of (7) to (15).
(17) A pharmaceutical composition containing desloratadine or a salt thereof having a concentration of 0.01% (w / v) or more as an active ingredient, and as an additive, a buffer, an isotonic agent, a pH adjuster and a stable agent. A pharmaceutical composition comprising at least one selected from the group consisting of agents and not containing benzalkonium chloride.
(18) A pharmaceutical composition containing desloratadine or a salt thereof having a concentration of 0.01% (w / v) or more as an active ingredient, and as an additive, a buffer, an isotonic agent, a pH adjuster and a stable agent. A pharmaceutical composition comprising at least one selected from the group consisting of agents and containing no preservatives.
(19) By blending desloratadine or a salt thereof at a concentration of 0.01% (w / v) or more, a pharmaceutical composition containing desloratadine or a salt thereof can be obtained without containing a preservative as an additive. A method of imparting antiseptic effect.
(20) By blending desloratadine or a salt thereof at a concentration of 0.01% (w / v) or more, a pharmaceutical composition containing desloratadine or a salt thereof can be obtained without containing a preservative as an additive. How to maintain antiseptic efficacy.
It should be noted that each of the configurations (1) to (20) can be arbitrarily selected and combined in combination of two or more.

Furthermore, the present invention also provides:
(21) Treatment and / or prevention of allergic diseases, which comprises administering to a patient in need of treatment a therapeutically effective amount of the pharmaceutical composition according to any one of (1) to (18). how to.
(22) The pharmaceutical composition according to any one of (1) to (18), which is used for the treatment and / or prevention of allergic diseases.
(23) Use of the pharmaceutical composition according to any one of (1) to (18) for producing a drug for treating and / or preventing an allergic disease.

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to obtain a pharmaceutical composition for topical administration containing desloratadine or a salt thereof, which does not contain benzalkonium chloride. Further, the present invention is not limited to benzalkonium chloride, and it is also possible to obtain a pharmaceutical composition for topical administration containing desloratadine or a salt thereof, which exerts an antiseptic effect without adding an antiseptic.

Hereinafter, the present invention will be described in detail.

で表される化合物である。In the present invention, the term "desloratadine" refers to the chemical name 8-Chloro-11- (piperidin-4-ylidine) -6,11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b] pyridine. It is a compound represented by, and the following formula:

It is a compound represented by.

In the pharmaceutical composition of the present invention, the desloratadine contained 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, a salt with an organic acid, and the like.
Examples of the salt with the inorganic acid 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, glucoheptoic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, and alanine. , Lactic acid, horse uric acid, 1,2-ethanedisulfonic acid, isetioic acid, lactobionic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p- Examples thereof include salts with toluene sulfonic acid, lauryl sulphate, naphthalene sulfonic acid, sulfosalicylic acid and the like.
In the present invention, the contained desloratadine or a salt thereof may take the form of a hydrate or a solvate.

In the present invention, the contained desloratadine or a salt thereof also includes a pharmaceutically acceptable prodrug. A pharmaceutically acceptable prodrug is a compound having a group that can be converted to an amino group or the like by solvolysis or under physiological conditions. For example, loratadine known as a prodrug form of desloratadine is included in desloratadine or a salt thereof in the present invention.

In the present invention, the content of desloratadine or a salt thereof is 0.001% (w / v) or more, preferably 0.01% (w / v) or more, and more preferably 0.03% (w / v) or more. It is w / v) or more, more preferably 0.06% (w / v) or more, even more preferably 0.08% (w / v) or more, and particularly preferably 0.12% (w). / V) or more, and may be 0.24% (w / v) or more. The upper limit may be an amount used as an active ingredient of a pharmaceutical product, for example, 5% (w / v), preferably 3% (w / v), and more preferably 2% (w / v). Is. The content of desloratadine or a salt thereof is 0.001 to 5% (w / v), preferably 0.01 to 5% (w / v), and 0.03 to 5% (w / v). Is even more preferable, 0.06 to 3% (w / v) is even more preferable, 0.08 to 3% (w / v) is even more preferable, and 0.12 to 2% (w / v) is particularly preferable. More specifically, the content is preferably 0.001% (w / v), 0.01% (w / v), 0.03% (w / v), 0.06% (w / v). v), 0.08% (w / v), 0.1% (w / v), 0.12% (w / v), 0.24% (w / v), 0.5% (w / v) v), 1% (w / v), 1.5% (w / v), 2% (w / v), 3% (w / v) or 5% (w / v).
When a salt of desloratadine is contained in the present invention, these values are the content of the salt of desloratadine. “% (W / v)” means the mass (g) of the target component (here, desloratadine or a salt thereof) contained in 100 mL of the pharmaceutical composition of the present invention. Hereinafter, the same shall apply unless otherwise specified.

In the present invention, examples of the preservative include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, chlorhexidine or a salt thereof, sorbic acid or a salt thereof, methyl paraoxybenzoate, propyl paraoxybenzoate or chlorobutanol and the like. However, it is not limited to these.
Chlorhexidine or a salt thereof is chlorhexidine, chlorhexidine gluconate, chlorhexidine hydrochloride or chlorhexidine acetate.
Sorbic acid or a salt thereof is sorbic acid, sodium sorbate or potassium sorbate.

In the present invention, "does not contain benzalkonium chloride" means that the pharmaceutical composition does not substantially contain benzalkonium chloride, and "does not contain preservatives" means that the pharmaceutical composition contains the above-mentioned preservatives. Refers to the fact that it contains virtually no agent. As used herein, "substantially free of benzalkonium chloride" means that benzalkonium chloride is not contained, or that benzalkonium chloride does not exhibit the antiseptic effect required for a pharmaceutical composition. "Substantially free of preservatives" means that it does not contain a component widely known as a preservative, or that a component widely known as a preservative is a pharmaceutical composition. It is intended to be contained in an amount that does not exhibit the antiseptic effect required for the above, and is not intended to eliminate all components that are used for other purposes and also have an antiseptic effect. ..

In the present invention, "antiseptic effect" refers to an action of preventing the growth and proliferation of microorganisms such as bacteria and fungi, and "having an antiseptic effect without containing an antiseptic" means the above-mentioned antiseptic in a pharmaceutical composition. It means that it exerts an antiseptic effect even if it does not contain an agent. The degree of antiseptic efficacy of the pharmaceutical composition can be confirmed, for example, by conducting a test in accordance with the preservation efficacy test method described in the 17th revised Japanese Pharmacopoeia, preferably the 17th revised Japanese Pharmacopoeia. Refers to the antiseptic effect that conforms to the test based on the storage efficacy test method described in the above.

The pharmaceutical composition of the present invention is, for example, an ophthalmic composition, an otolaryngological composition, an inhalation composition or a transdermal absorption composition, which are an ophthalmic preparation, an otolaryngology preparation, an inhalation preparation, and a transdermal preparation, respectively. It can be used as a skin-absorbing preparation.

The administration route of the pharmaceutical composition of the present invention is not particularly limited as long as it is a locally acceptable route of administration as a pharmaceutical product. The routes of administration include, for example, local administration to the eye (for example, eye drop administration), nasal (nasal) administration, local administration to the ear (for example, ear drop administration), inhalation administration, spray administration, and transdermal administration. Examples include intradermal administration and injection administration.

The dosage form of the pharmaceutical composition of the present invention is not particularly limited as long as it can be locally used as a pharmaceutical product. Dosage forms include, for example, eye drops, nasal drops (nasal drops, nasal drops), ear drops, inhalants (inhalation powders, inhalants, inhaled aerosols), ointments, creams, gels. Agents, transdermal absorbent formulations, patches (tapes, poultices), external liquids (lotions, liniments), external solids (external powders), sprays (pump sprays, external aerosols), injections (Infusion, implantable injection, continuous injection) and the like. Preferably, it is an eye drop, a nasal drop, an ear drop, an inhalant, a cream, a lotion, a patch, a transdermal preparation for ophthalmology, or an injection for ophthalmology. These can be manufactured according to the usual methods in the art.

The pharmaceutical composition of the present invention is preferably an ophthalmic composition. When the pharmaceutical composition of the present invention is an ophthalmic composition, the dosage form is preferably an eye drop, an ophthalmic ointment, a percutaneous absorption type preparation for ophthalmology or an ophthalmic injection, and the eye drop or the percutaneous absorption for ophthalmology. Type preparations are more preferable, eye drops are most preferable, and the administration route thereof is preferably eye drops, application to the ophthalmic mucosa, application near the eye or injection into the eye or near the eye, and to the eye drop or the vicinity of the eye. Is more preferable, and eye drops are most preferable. In the present invention, the “neighborhood of the eye” refers to the eyelid and its vicinity, and also includes the eyelid skin and the skin in the vicinity thereof. The vicinity of the eye is preferably the eyelid skin. For example, the application to the vicinity of the eye is preferably an application to the eyelid skin.

The pharmaceutical composition of the present invention may contain a pharmaceutical additive, if necessary. For example, buffering agents, tonicity agents, thickening agents, surfactants, to meet the requirements of ophthalmic compositions, otolaryngology compositions, inhalation compositions or transdermal absorption compositions. Stabilizers, antioxidants, pH regulators and the like can be added. These may be used alone or in combination of two or more as appropriate, and an appropriate amount may be blended.

Examples of buffers that can be incorporated into the pharmaceutical composition of the present invention include phosphoric acid or a salt thereof, boric acid or a salt thereof, citric acid or a salt thereof, acetic acid or a salt thereof, carbonic acid or a salt thereof, tartrate acid or a salt thereof. Examples include salts, ε-aminocaproic acid, tromethamole and the like. These may be in the form of hydrates or solvates.
Examples of phosphoric acid or a salt thereof include phosphoric acid, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate and the like, and these are water. It may be Japanese.
Examples of boric acid or a salt thereof include boric acid, sodium borate, potassium borate and the like, and these may be hydrates.
Examples of citric acid or a salt thereof include citric acid, sodium citrate, disodium citrate and the like, and these may be hydrates.
Examples of acetic acid or a salt thereof include acetic acid, sodium acetate, potassium acetate and the like, and these may be hydrates.
Examples of carbonic acid or a salt thereof include sodium carbonate, sodium hydrogencarbonate and the like, and these may be hydrates.
Examples of tartaric acid or a salt thereof include tartaric acid, sodium tartrate, potassium tartrate and the like, and these may be hydrates.

When a buffer is added to the pharmaceutical composition of the present invention, the buffer may be used alone or in combination of two or more components. Among these buffers, phosphoric acid or a salt thereof, boric acid or a salt thereof is more preferable, phosphoric acid or a salt thereof is further preferable, and sodium dihydrogen phosphate, disodium hydrogen phosphate or a hydrate thereof is particularly preferable. preferable.

The content of the buffer when the buffer is added to the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the buffer and the like, but is preferably 0.001 to 10% (w / v), and is 0. 0.01 to 5% (w / v) is more preferable, 0.1 to 3% (w / v) is further preferable, and 0.2 to 1.5% (w / v) is most preferable.

Examples of the isotonic agent that can be blended in the pharmaceutical composition of the present invention include an ionic isotonic agent, a nonionic isotonic agent, and the like.
Examples of the ionic isotonic agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride and the like.
Examples of the nonionic isotonic agent include glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose and the like.

When the isotonic agent is blended in the pharmaceutical composition of the present invention, the isotonic agent may be used alone or in combination of two or more kinds of components. Among these isotonic agents, an ionic isotonic agent is more preferable, and sodium chloride is particularly preferable.

The content of the isotonic agent when the isotonic agent is blended in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the isotonic agent and the like, but is 0.001 to 10% (w / w /). v) is preferable, 0.01 to 5% (w / v) is more preferable, 0.1 to 2% (w / v) is further preferable, and 0.2 to 1% (w / v) is most preferable.

Examples of the thickening agent that can be incorporated into the pharmaceutical composition of the present invention include methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, and the like. Examples thereof include hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, carboxymethylethyl cellulose, cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyethylene glycol, sodium hyaluronate and the like.

When the thickening agent is blended in the pharmaceutical composition of the present invention, the thickening agent may be used alone or in combination of two or more kinds of components.

The content of the thickening agent when the thickening agent is blended in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the thickening agent and the like, but is 0.001 to 5% (w / w /). v) is preferable, 0.01 to 3% (w / v) is more preferable, and 0.1 to 2% (w / v) is further preferable.

Examples of the surfactant that can be blended in the pharmaceutical composition of the present invention include a cationic surfactant, an anionic surfactant, a nonionic surfactant and the like.
Cationic surfactants include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyl diethylamine salts, fatty acid polyamine condensates, alkylimidazolin, 1-acylaminoethyl-2. -Alkyl imidazoline, 1-hydroxyl ethyl-2-alkyl imidazoline and the like can be mentioned. However, although benzalkonium chloride has the property of a cationic surfactant, it is not included in this.
Examples of the anionic surfactant include lipid phosphates such as lecithin.
Examples of the nonionic surfactant include polyoxyethylene fatty acid esters such as polyoxyl 40 stearate; polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan triolate, and polysorbate 65. Polyoxyethylene sorbitan fatty acid ester; polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, etc. Polyoxyethylene hydrogenated castor oil; polyoxyl 5 castor Polyoxyl castor oil such as oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 castor oil; polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxy Poly such as propylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene (20) polyoxypropylene (20) glycol, etc. Oxyethylene polyoxypropylene glycol; sucrose fatty acid ester such as sucrose stearic acid ester; tocopherol polyethylene glycol 1000 succinic acid ester (vitamin E TPGS) and the like.

When a surfactant is blended in the pharmaceutical composition of the present invention, the surfactant may be used alone or in combination of two or more components.

The content of the surfactant when the surfactant is blended in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the surfactant and the like, but is 0.01 to 10% (w / w /). v) is preferable, 0.05 to 5% (w / v) is more preferable, 0.05 to 3% (w / v) is further preferable, and 0.05 to 1% (w / v) is particularly preferable.

Examples of the stabilizer that can be blended in the pharmaceutical composition of the present invention include edetic acid or a salt thereof.
Examples of edetic acid or a salt thereof include edetic acid, disodium edetate, tetrasodium edetate and the like.

When the stabilizer is blended in the pharmaceutical composition of the present invention, the stabilizer may be used alone or in combination of two or more components.

The content of the stabilizer when the stabilizer is blended in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the stabilizer and the like, but is 0.001 to 5% (w / v). Preferably, 0.01 to 3% (w / v) is more preferable, and 0.1 to 2% (w / v) is even more preferable.

Examples of antioxidants that can be incorporated into the pharmaceutical composition of the present invention include ascorbic acid, tocopherol, dibutylhydroxytoluene, sodium sulfite, 2-mercaptobenzimidazole and the like.

When an antioxidant is added to the pharmaceutical composition of the present invention, the antioxidant may be used alone or in combination of two or more components.

The content of the antioxidant when the antioxidant is blended in the pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the antioxidant and the like, but is 0.001 to 5% (w / v). Preferably, 0.01 to 3% (w / v) is more preferable, and 0.1 to 2% (w / v) is even more preferable.

Acids or bases are examples of pH regulators that can be incorporated into the pharmaceutical composition of the present invention. Examples of the acid include hydrochloric acid, phosphoric acid, citric acid, acetic acid and the like, and examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like.

When the pH adjusting agent is blended in the pharmaceutical composition of the present invention, the pH adjusting agent may be used alone or in combination of two or more kinds of components.

The pH of the pharmaceutical composition of the present invention is preferably in the range of 4.0 to 8.5, more preferably 6.0 to 8.0. When the pharmaceutical composition of the present invention is an ophthalmic composition, the pH of the pharmaceutical composition may be within an acceptable range for an ophthalmic preparation, for example, 4.0 to 8.5 is preferable, and 6.0. ~ 8.0 is more preferable, 6.5 to 7.5 is even more preferable, and 6.7 to 7.3 is particularly preferable. More specifically, its pH is preferably 6.7, 6.8, 6.9, 7.0, 7.1, 7.2 or 7.3.

The osmotic pressure ratio of the pharmaceutical composition of the present invention is preferably in the range of 0.5 to 2.0. When the pharmaceutical composition of the present invention is an ophthalmic composition, the osmotic pressure ratio of the pharmaceutical composition may be within an acceptable range for an ophthalmic preparation, for example, 0.5 to 2.0 is preferable, and 0. 7 to 1.6 is more preferable, 0.8 to 1.4 is further preferable, and 0.9 to 1.2 is particularly preferable.

The pharmaceutical composition of the present invention is preferably a pharmaceutical composition containing a solvent such as water. The pharmaceutical composition of the present invention may have all the constituents dissolved or partially suspended, or may be in the form of an emulsion or a semi-solid. The pharmaceutical composition of the present invention is more preferably in a solution state in which all the constituent components are dissolved, and most preferably in an aqueous solution. The solvent or dispersion medium is, but is not limited to, water, ethanol, polyol (eg, glycerol, propylene glycol, liquid polyethylene glycol, etc.), preferably water.

When the pharmaceutical composition of the present invention is an emulsion, even an oil-in-water emulsion (an emulsion composed of oily droplets dispersed in an aqueous phase with the aqueous phase as a continuous phase) is an aqueous emulsion in oil (oil). It may be an emulsion composed of aqueous droplets dispersed with oil, with the phase as a continuous phase). The average size of the oily or aqueous droplets is 20 to 3000 nm, preferably 30 to 1000 nm, more preferably 50 to 600 nm, and even more preferably 100 to 300 nm.

When the pharmaceutical composition of the present invention is an emulsion, examples of the oil phase used are not particularly limited as long as they are acceptable as an external preparation for skin or paraffin wax, and are, for example, animal-based or plant. Examples include oils, fats and oils, higher fatty acids, higher alcohols derived from petrolatum, petrolatum, minerals and synthetics, and specific examples thereof include petrolatum, white petrolatum, paraffin, liquid paraffin, light liquid paraffin, squalane, squalane, and ceresin. Petrolatum, paraffin wax, olive oil, sesame oil, capsicum oil, silicon oil, medium-chain fatty acid triglyceride, lauric acid or its ester, myristic acid or its ester, palmitic acid or its ester, stearic acid or its ester, lauryl alcohol, myristyl alcohol, Examples thereof include palmityl alcohol, esteryl alcohol, and octyldodecanol. These may be used individually by 1 type, or may be used in combination of 2 or more types of components.
Further, examples of the aqueous phase used are not particularly limited as long as they are acceptable as an external preparation for skin or skin cosmetics, and examples thereof include polyhydric alcohols, and specifically, glycerin and the like. Examples thereof include concentrated glycerin, diethylene glycol, polyethylene glycol, dipropylene glycol, polypropylene glycol, butylene glycol, polybutylene glycol, sorbitol, xylitol and the like. These may be used individually by 1 type, or may be used in combination of 2 or more types of components.
The amount of the oil phase in the emulsion is, for example, 0.1 to 50% (w / v), preferably 5 to 30% (w / v), based on the total amount of the composition in the case of an oil-in-water emulsion. is there.

In the present invention, the above-mentioned oil phase component and aqueous phase component utilize their respective physicochemical properties to provide an ointment, a cream, a lotion, a gel, a liniment, a percutaneous absorption type preparation, a tape preparation, and the like. It may be used as a poultice, an external powder, a pump spray, an external aerosol, and the like.

In the present invention, the container for accommodating the pharmaceutical composition is not particularly limited in the size and shape of the container body. When the pharmaceutical composition of the present invention is an ophthalmic composition, the container for accommodating the pharmaceutical composition is preferably an eye drop container, and the eye drop container is a multi-dose container or a single-use unit dose container. Alternatively, it may be any PFMD (Preservative Free Multi Dose) container, but since the pharmaceutical composition of the present invention has an antiseptic effect, a multi-dose type container is particularly preferable. The multi-dose type container is a container in which a cap or the like can be freely opened and closed for the purpose of being used a plurality of times, and can be used for a certain period of time after opening and is easy to carry.

In the present invention, the material of the container for accommodating the pharmaceutical composition is not particularly limited as long as it conforms to the form of the container, and examples thereof include a resin container, an aluminum container, and a glass container. In particular, when the container containing the pharmaceutical composition of the present invention is an eye drop container, a resin container is preferable. The material of the resin container is, for example, polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET), polybutylene terephthalate, polypropylene-polyethylene copolymer, polyvinyl chloride, acrylic resin, polystyrene, cyclic olefin polymer, cyclic olefin copolymer. And so on. Further, polyethylene is classified according to its density, and examples thereof include low density polyethylene (LDPE), medium density polyethylene (MDPE), and high density polyethylene (HDPE).

The pharmaceutical composition of the present invention may contain desloratadine or a salt thereof as the only active ingredient. In addition, the pharmaceutical composition of the present invention may contain a pharmaceutical active ingredient other than desloratadine or a salt thereof as long as it does not interfere with the effects of the present invention. In particular, when the pharmaceutical composition of the present invention is an ophthalmic composition, it may contain other pharmaceutically active ingredients used in eye drops other than desloratadine or a salt thereof. Other pharmaceutically active ingredients include, for example, anti-inflammatory agents, antibacterial agents, antiviral agents, vitamin agents, vasoconstrictors, mydriatic agents, miotic agents, intraocular pressure-lowering agents, dry eye therapeutic agents, local anesthetics, etc. The active ingredient is mentioned. Other pharmaceutically active ingredients may be added in an amount of, for example, 0.001 to 5% (w / v) with respect to the total weight of the pharmaceutical composition. Moreover, these may be used in combination of 2 or more types.

The pharmaceutical composition of the present invention is useful as a therapeutic agent for allergic diseases. In the present invention, the "allergic disease" refers to a disease or a symptom thereof caused by an immune reaction to an external antigen. Examples of allergic diseases include, but are not limited to, allergic conjunctivitis, allergic rhinitis, atopic dermatitis, urticaria and the like. In the present invention, the treatment of an allergic disease refers to any treatment (for example, cure, improvement, alleviation, suppression of progression, etc.) of the allergic disease or its symptoms and prevention thereof. It also includes preventing the recurrence of allergic diseases.
In the present invention, the term "patient" means not only humans but also other animals such as dogs, cats and horses. 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 on a disease and its symptoms, or an amount that causes a delay in the progression of the disease and its symptoms, as compared with an untreated subject.

The pharmaceutical composition of the present invention is more preferably used as a therapeutic agent for allergic diseases for ophthalmology, and is particularly useful as a therapeutic agent for allergic conjunctivitis. Treatment of allergic conjunctivitis includes all treatments of allergic conjunctivitis and its symptoms (eg, cure, improvement, alleviation, suppression of progression, etc.) and prevention thereof.

When the pharmaceutical composition of the present invention is administered, the dosage is not particularly limited as long as it is sufficient to achieve the desired medicinal effect. When the pharmaceutical composition of the present invention is an ophthalmic composition, it is administered 1 drop at a time, 1 to 6 times a day, preferably 1 to 4 times a day, and more preferably 1 to 2 times a day. can do. Furthermore, when the pharmaceutical composition of the present invention is an eye drop, it can be used both when wearing hard contact lenses and when wearing soft contact lenses.
Examples of soft contact lenses include contact lenses containing hydroxyethyl methacrylate as a main component, silicone hydrogel contact lenses, and the like. The type of soft contact lens to which the present invention is applied is not particularly limited, and may be either ionic or nonionic, water-containing or non-water-containing. For example, it can be applied to all commercially available soft contact lenses such as lenses that are used repeatedly, lenses that are disposable for one day, lenses that are disposable for one week, and lenses that are disposable for two weeks.

When the pharmaceutical composition of the present invention is a composition for nasal drops, one drop to several drops at a time, or one spray to several sprays at a time, 1 to 6 times a day, preferably 1 to 4 times a day, More preferably, the nose can be instilled in 1 to 3 divided doses a day.

When the pharmaceutical composition of the present invention is a composition for ear drops, 1 to several drops at a time, 1 to 6 times a day, preferably 1 to 4 times a day, more preferably 1 to 3 times a day. It can be divided into two and can be instilled.

When the pharmaceutical composition of the present invention is an inhalation composition, one spray to several sprays at a time, preferably 1 to 6 times a day, preferably 1 to 4 times a day, more preferably 1 to 3 times a day. Can be inhaled separately.

When the pharmaceutical composition of the present invention is a transdermal preparation for ophthalmology, 1 mg to 1 g at a time is applied to the eyelid skin 1 to 4 times a day, preferably twice a day, more preferably once a day. can do.

The method for imparting an antiseptic effect to the pharmaceutical composition of the present invention comprises blending desloratadine or a salt thereof with the pharmaceutical composition.

A method for maintaining the antiseptic effect of the pharmaceutical composition of the present invention comprises blending desloratadine or a salt thereof with the pharmaceutical composition.

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

[Formulation example]
A typical example of the formulation of the present invention is shown below. In the following formulation example, the blending amount of each component is the content in 1 mL of the formulation.

Pharmaceutical example 1
Desloratadine 0.5 mg
Sodium dihydrogen phosphate 10 mg
Sodium chloride 10 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount

Pharmaceutical example 2
Desloratadine 5 mg
Sodium dihydrogen phosphate 5 mg
Sodium chloride 5 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount

Pharmaceutical example 3
Desloratadine 2.5 mg
Sodium dihydrogen phosphate 5 mg
Disodium edetate 0.1 mg
Sodium chloride 5 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount

Pharmaceutical example 4
Desloratadine 5 mg
Boric acid 1 mg
Sodium chloride 5 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount

Pharmaceutical example 5
Desloratadine 2.5 mg
Polysorbate 80 1 mg
Polyethylene glycol 1 mg
Glycerin Appropriate amount Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount

Pharmaceutical example 6
Desloratadine 10 mg
Glycerin 100 mg
Vaseline 30 mg
Paraffin 30 mg
Polyoxyethylene hydrogenated castor oil 30 mg
Sodium edetate 1 mg
Sodium chloride 5 mg
Appropriate amount of purified water

[Test example]
(1) Antiseptic efficacy test This test was conducted in accordance with the preservation efficacy test method described in the 17th revised Japanese Pharmacopoeia.
1. 1. Preparation of test product Dissolve desloratazine (0.24 g), sodium dihydrogen phosphate (0.5 g), and sodium chloride (0.5 g) in water, and add a pH adjuster and water to make the total volume 100 mL. The preparation of Example 1 was prepared by performing filtration sterilization.

Example 1
Desloratadine 2.4 mg in 1 mL
Sodium dihydrogen phosphate 5 mg
Sodium chloride 5 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0

The formulations of Examples 2 to 4 and Comparative Examples 1 and 2 were prepared in the same manner as the preparation method of Example 1. The levocetirizine hydrochloride used in Comparative Example 1 is the active ingredient of "Zyzar (registered trademark) tablet 5 mg", and the bepotastine besilate used in Comparative Example 2 is the active ingredient of "Talion (registered trademark) tablet 5 mg". Is. All of these are marketed as therapeutic agents for allergic diseases.

Example 2
Desloratadine 1.2 mg in 1 mL
Sodium dihydrogen phosphate 5 mg
Sodium chloride 5 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0

Example 3
Desloratadine 0.6 mg in 1 mL
Sodium dihydrogen phosphate 5 mg
Sodium chloride 5 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0

Example 4
Desloratadine 0.3 mg in 1 mL
Sodium dihydrogen phosphate 5 mg
Sodium chloride 5 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0

Comparative Example 1
Levocetirizine hydrochloride 2.85 mg in 1 mL
(Equivalent to 2.4 mg of levocetirizine free)
Sodium dihydrogen phosphate 5 mg
Sodium chloride 5 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0

Comparative Example 2
Bepotastine besilate 21.1 mg in 1 mL
(Equivalent to 15 mg of free bepotastine)
Sodium dihydrogen phosphate 5 mg
Sodium chloride 5 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 7.0

2. Test method The following strains were used as inoculum.
Bacteria:
Escherichia coli ATCC 8739 (also called E. coli)
Pseudomonas aeruginosa ATCC 9027 (also called P. aeruginosa)
Staphylococcus aureus ATCC 6538 (also known as S. aureus)
Yeast and molds:
Candida albicans ATCC 10231 (also known as C. albicans)
Aspergillus brasiliensis ATCC16404 (also called A. brasiliensis)

As bacterial solution concentration in a test sample consisting of the formulation is 10 ⁵ to 10 ⁶ cells / mL (5 strains both), were inoculated with inoculum in the test sample. Specifically, the ^{inoculated bacterial solution was prepared so as to be 10 7} to 10 ⁸ cfu / mL, and Examples 1 to 4 and Comparative Examples were prepared so that the inoculated bacterial solution was 10 ⁵ to 10 ^{6 cfu / mL.} Each inoculated bacterial solution was inoculated into a test sample composed of 1 to 2 preparations and mixed uniformly to prepare a sample. These samples were stored at 20-25 ° C. under shading, and at each sampling point (7 days, 14 days, or 28 days), 0.5 mL was collected from each sample with a micropipette, and the viable cell count was measured. At each sampling point, the sample solution was sampled by opening the lid and closing the lid.

3. 3. Test Results and Discussion Table 1 shows the test results. The test results in Table 1 are shown as a common logarithmic value of the ratio (B / A) of the number of bacteria (B) at the time of inoculation to the number of bacteria (A) when the viable cell count was measured. In the case of "1", it indicates that the viable cell count at the time of inspection was reduced to 10% of the inoculated bacterial count.

Regarding the pass / fail judgment of the test, for bacterial species (E.coli, P.aeruginosa, S.aureus), it should be 1.0 or more 7 days after sowing and 3.0 or more 14 or 28 days after sowing. And for fungal species (C. albicans, A. brasiliensis), the values were not decreased 14 or 28 days after sowing as compared with 7 days after sowing.

As shown in Table 1, the formulations of Examples 1 to 4 containing desloratadine or a salt thereof showed sufficient antiseptic activity against any of the bacteria even though they did not contain a preservative. The antiseptic effect was exhibited even at a very low concentration (0.03%) of desloratadine or a salt thereof. On the other hand, the formulations of Comparative Example 1 and Comparative Example 2 did not have sufficient antiseptic effect, and in particular, Comparative Example 2 had a high concentration (converted to 1.5% of the amount of the active ingredient), but had an antiseptic effect. It was shown not to have. Although desloratadine, levocetirizine and bepotastine are all active ingredients that exert a therapeutic effect on allergic diseases, it has been shown that only desloratadine has a specific antiseptic effect on the compound itself.
This suggests that the pharmaceutical composition of the present invention containing desloratadine or a salt thereof has sufficient antiseptic activity even if it does not contain not only benzalkonium chloride but also any preservative.

(2) Drug Efficacy Evaluation Test Using Allergic Conjunctivitis Model In this test, the conjunctivitis symptom score was determined in the guinea pig active sensitization allergic conjunctivitis model, and the therapeutic effect of the preparation of the present invention was examined.

1. 1. Preparation of test product The preparations of Examples 5 to 7 and the base of Comparative Example 3 were prepared by the same method as the preparation method of Example 1.

Example 5
Desloratadine 0.1 mg in 1 mL
Sodium dihydrogen phosphate 5 mg
Sodium chloride 7 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 6.5

Example 6
Desloratadine 0.3 mg in 1 mL
Sodium dihydrogen phosphate 5 mg
Sodium chloride 7 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 6.5

Example 7
Desloratadine 1 mg in 1 mL
Sodium dihydrogen phosphate 5 mg
Sodium chloride 7 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 6.5

Comparative Example 3
Sodium dihydrogen phosphate 5 mg in 1 mL
Sodium chloride 7 mg
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount pH 6.5

2. Test method (preparation of sensitizing solution)
A physiological saline solution containing an OVA (chicken-derived egg white albumin) solution (Sigma) and an aluminum hydroxide gel was prepared and used as a sensitizing solution. The concentrations of OVA and aluminum hydroxide gel in the sensitizing solution were 20 μg / mL and 20 mg / mL, respectively.

(Preparation of ОVA active sensitization allergic conjunctivitis model and confirmation of allergic reaction)
Active sensitization was performed by injecting a sensitizing solution under the binocular conjunctiva of the guinea pig using a guinea pig under general anesthesia by inhaling isoflurane.
After 14 days of sensitization, conjunctivitis was induced by instilling 10 μL of a 0.05% OVA solution prepared by diluting with physiological saline into both eyes of a guinea pig. Thirty minutes after the induction, the conjunctivitis symptoms of both eyes of the guinea pig were scored according to the following criteria. One group consisted of 6 animals and 12 eyes, and the groups were divided into 4 groups so that the average score was not biased among the groups.
<Criteria>
0: No findings 1: Edema or hyperemia is observed in a part of the bulbar conjunctiva (not found on the eyelids).
2: Edema and hyperemia are observed throughout the bulbar conjunctiva, but the edema does not affect the cornea (not considered on the eyelids).
3: A condition in which edema and hyperemia are observed throughout the bulbar conjunctiva. In addition, if edema covers a part of the corneal ring or the eyelid margin is slightly lifted from the eyeball.
4: A condition in which edema and hyperemia are observed throughout the bulbar conjunctiva. In addition, if the edema covers part of the corneal ring and either the upper or lower eyelid margin is clearly floating from the eyeball, or if the edema covers more than half of the cornea, the eyelid margin is the eyeball. If it floats slightly from.
5: A condition in which edema and hyperemia are observed throughout the bulbar conjunctiva. In addition, if the edema covers more than half of the cornea and either the upper or lower eyelid margin is clearly floating from the eyeball, or if the edema is on the cornea and both the upper and lower eyelid margins are clearly visible from the eyeball. If floating.

(Medicinal efficacy evaluation)
Seven days after the confirmation of the allergic reaction, 10 μL of each test product and base was instilled into both eyes of the guinea pig 15 minutes and 5 minutes before the induction of conjunctivitis in order to evaluate the drug efficacy. Furthermore, conjunctivitis was caused by instilling 10 μL of a 0.1% OVA solution prepared by diluting with physiological saline into both eyes of the guinea pig.
Thirty minutes after the induction, the conjunctivitis symptoms of both eyes of the guinea pig were scored according to the above criteria. Furthermore, using general-purpose data processing software, the average value and standard error of the conjunctivitis symptom score in each group were calculated.

3. 3. Test results and discussion Table 2 shows the test results. The average score is 12 eyes (6 animals) each.

As shown in Table 2, the preparations of Examples 5 to 7 containing desloratadine or a salt thereof have been shown to have a therapeutic effect on allergic conjunctivitis.

From the results of Test Examples, it was shown that a pharmaceutical composition containing desloratadine or a salt thereof exerts an antiseptic effect and a therapeutic effect on allergic conjunctivitis without adding benzalkonium chloride and other preservatives. It was. Therefore, a pharmaceutical composition for topical administration containing desloratadine or a salt thereof, which does not contain benzalkonium chloride, can be obtained. In addition, not only benzalkonium chloride but also a pharmaceutical composition for topical administration containing desloratadine or a salt thereof, which exerts an antiseptic effect without adding an antiseptic, can be obtained.

The present invention provides a pharmaceutical composition for topical administration, which is a pharmaceutical composition containing desloratadine or a salt thereof and does not contain benzalkonium chloride. Furthermore, the present invention provides a pharmaceutical composition for topical administration containing desloratadine or a salt thereof, which exerts an antiseptic effect without adding an antiseptic.

Claims (16)

A pharmaceutical composition containing desloratadine or a salt thereof as an active ingredient, which does not contain benzalkonium chloride, and is a pharmaceutical composition for topical administration. The pharmaceutical composition according to claim 1, which contains desloratadine or a salt thereof at a concentration of 0.001% (w / v) or more. The pharmaceutical composition according to claim 1, which contains desloratadine or a salt thereof at a concentration of 0.01% to 5% (w / v). The pharmaceutical composition according to any one of claims 1 to 3, which is an ophthalmic composition, an otolaryngological composition, an inhalation composition or a transdermal absorption composition. The pharmaceutical composition according to any one of claims 1 to 4, which is an eye drop. The pharmaceutical composition according to claim 5, wherein the container for eye drops is a multi-dose type container. The pharmaceutical composition according to any one of claims 1 to 6, which contains at least one selected from the group consisting of a buffer, an isotonic agent, a pH adjuster and a stabilizer as an additive. The pharmaceutical composition according to claim 7, which contains a buffer, an isotonic agent, and a pH adjuster. The pharmaceutical composition according to claim 8, further comprising a stabilizer. The pharmaceutical composition according to any one of claims 1 to 9, wherein the pH is 4.0 to 8.5. The pharmaceutical composition according to any one of claims 1 to 10, wherein the pH is 6.0 to 8.0. The pharmaceutical composition according to any one of claims 1 to 11, which does not contain a preservative. A pharmaceutical composition containing desloratadine or a salt thereof having a concentration of 0.01% (w / v) or more as an active ingredient, and is composed of a buffer, an isotonic agent, a pH adjuster and a stabilizer as additives. A pharmaceutical composition comprising at least one selected from the above group and not containing benzalkonium chloride. A pharmaceutical composition containing desloratadine or a salt thereof at a concentration of 0.01% (w / v) or more as an active ingredient, from a buffer, an isotonic agent, a pH adjuster and a stabilizer as additives. A pharmaceutical composition comprising at least one selected from the above group and containing no preservative. By blending desloratadine or a salt thereof at a concentration of 0.01% (w / v) or more, the pharmaceutical composition containing desloratadine or a salt thereof has an antiseptic effect without containing a preservative as an additive. How to grant. By blending desloratadine or a salt thereof at a concentration of 0.01% (w / v) or more, the antiseptic effect of a pharmaceutical composition containing desloratadine or a salt thereof can be obtained without containing a preservative as an additive. How to maintain.