WO2019245015A1 - Pharmaceutical composition comprising desloratadine or salt thereof - Google Patents

Pharmaceutical composition comprising desloratadine or salt thereof Download PDF

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Publication number
WO2019245015A1
WO2019245015A1 PCT/JP2019/024644 JP2019024644W WO2019245015A1 WO 2019245015 A1 WO2019245015 A1 WO 2019245015A1 JP 2019024644 W JP2019024644 W JP 2019024644W WO 2019245015 A1 WO2019245015 A1 WO 2019245015A1
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WIPO (PCT)
Prior art keywords
pharmaceutical composition
salt
desloratadine
acid
present
Prior art date
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PCT/JP2019/024644
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French (fr)
Japanese (ja)
Inventor
孝司 稲垣
隆司 森本
悠 梶原
Original Assignee
参天製薬株式会社
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Application filed by 参天製薬株式会社 filed Critical 参天製薬株式会社
Priority to JP2020525815A priority Critical patent/JP7337791B2/en
Publication of WO2019245015A1 publication Critical patent/WO2019245015A1/en

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Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • 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
    • 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
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a pharmaceutical composition containing desloratadine or a salt thereof as an active ingredient, wherein the pharmaceutical composition does not contain benzalkonium chloride. Thing).
  • a preservative 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 preservative effect as compared with other preservatives.
  • benzalkonium chloride has cytotoxic effects, and increasing exposure increases the likelihood of causing corneal epithelial damage. Therefore, it cannot be used especially for patients who have a hypersensitivity reaction to benzalkonium chloride or patients with severe corneal epithelial disorder.
  • desloratadine which is one of the H1 histamine receptor antagonists, is an active ingredient of a therapeutic agent for allergic diseases “Dezalex (registered trademark) 5 mg”, and its effective amount is orally administered once a day. Is known to exert 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 topical preparation such as eye drops and nasal drops, but benzalkonium chloride is added to each of these preparations (Patent Document 1 and Patent Document 1). 2).
  • Patent Document 1 discloses that the higher the concentration of benzalkonium chloride, the more stable the pH and activity of the ophthalmic solution. Therefore, the highest concentration (0.127%) described in the list of excipients is used as a preservative. It is also described that it is preferable to contain.
  • pharmaceutical composition containing desloratadine or a salt thereof for topical administration to which benzalkonium chloride is not added there is no report that desloratadine or its salt itself has an antiseptic effect.
  • Another object of the present invention is to provide a pharmaceutical composition for topical administration containing desloratadine or a salt thereof, which exhibits antiseptic effect even if a preservative is not added, besides benzalkonium chloride.
  • the present inventors have conducted intensive studies and found that a pharmaceutical composition for topical administration containing desloratadine or a salt thereof as an active ingredient does not contain a preservative containing benzalkonium chloride and has a sufficient preservative effect. Have been found, and the present invention has been accomplished. Specifically, the present invention provides the following. (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), comprising desloratadine or a salt thereof at a concentration of 0.001% (w / v) or more.
  • the pharmaceutical composition according to (1) comprising desloratadine or a salt thereof at a concentration of 0.01% to 5% (w / v).
  • the pharmaceutical composition according to (1) to (3) which is an ophthalmic composition, an otolaryngological composition, a composition for inhalation, or a composition for transdermal absorption.
  • the pharmaceutical composition according to (1) to (4) which is an eye drop.
  • the pharmaceutical composition according to (5), wherein the container for eye drops is a multidose container.
  • the pharmaceutical composition according to (7) comprising a buffer, an isotonic agent, and a pH adjuster.
  • the pharmaceutical composition according to (8) further comprising a stabilizer.
  • the pharmaceutical composition according to (13), wherein the administration to the vicinity of the eye is application to eyelid skin.
  • the dosage form is selected from the group consisting of ointments, creams, lotions, gels, liniments, transdermal preparations, patches, sprays and injections, The pharmaceutical composition according to any one of 4) and (7) to (15).
  • a pharmaceutical composition comprising at least one member selected from the group consisting of an agent and not containing benzalkonium chloride.
  • a pharmaceutical composition comprising at least one selected from the group consisting of a preservative and no preservative.
  • 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 without an antiseptic as an additive can be obtained.
  • 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 without an antiseptic as an additive can be obtained. How to maintain preservative efficacy.
  • each of the configurations (1) to (20) can be arbitrarily selected from two or more and combined.
  • the present invention also provides the following. (21) treating and / or preventing an allergic disease, which comprises administering to a patient in need of treatment a therapeutically effective amount of the pharmaceutical composition according to any of (1) to (18). how to. (22) The pharmaceutical composition according to any one of (1) to (18), which is used for treating and / or preventing an allergic disease. (23) Use of the pharmaceutical composition according to any one of (1) to (18) for producing a medicament for treating and / or preventing an allergic disease.
  • a pharmaceutical composition for topical administration containing desloratadine or a salt thereof, which does not contain benzalkonium chloride can be obtained.
  • the present invention can also provide a pharmaceutical composition for topical administration containing desloratadine or a salt thereof, which exhibits antiseptic effect without adding a preservative, in addition to benzalkonium chloride.
  • “desloratadine” is a chemical name of 8-Chloro-11- (piperidin-4-ylidene) -6,11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b] pyridine. And a compound represented by the following formula: It is a compound represented by these.
  • the desloratadine contained in the pharmaceutical composition of the present invention may be a salt, and is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • the salt include a salt with an inorganic acid and a salt with an organic acid.
  • the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
  • acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptoic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, alanine Lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p- Salts with toluene sulfonic acid, lauryl sulfuric acid, naphthalene sulfonic acid, sulfosalicylic acid and the like can be mentioned.
  • the contained desloratadine or a salt thereof can be mentioned.
  • 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.
  • loratadine known as a prodrug form of desloratadine is included in desloratadine or a salt thereof 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). w / v) or more, more preferably 0.06% (w / v) or more, still more preferably 0.08% (w / v) or more, and particularly preferably 0.12% (w / v). / 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 drug, for example, 5% (w / v), preferably 3% (w / v), and more preferably 2% (w / v). It 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 more preferable, 0.06 to 3% (w / v) is still more preferable, 0.08 to 3% (w / v) is still more preferable, and 0.12 to 2% (w / v) is particularly preferable.
  • 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).
  • “% (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. The same applies hereinafter unless otherwise specified.
  • examples of the preservative include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, chlorhexidine or a salt thereof, sorbic acid or a salt thereof, methyl paraoxybenzoate, methyl paraoxybenzoate, propyl paraoxybenzoate and chlorobutanol.
  • 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.
  • does not contain benzalkonium chloride means that the pharmaceutical composition does not substantially contain benzalkonium chloride
  • does not contain a preservative means that the pharmaceutical composition contains the above preservative. Refers to substantially no agent.
  • the term “substantially free of benzalkonium chloride” means that benzalkonium chloride is not contained, or that the amount of benzalkonium chloride that does not exhibit the antiseptic effect required for the pharmaceutical composition
  • the preservative is “substantially free of” 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 product, nor is it intended to exclude all components that also have preservative action that are used for other purposes. .
  • antiseptic effect refers to the action of preventing the growth and growth of microorganisms such as bacteria and fungi
  • "having an antiseptic effect without containing a preservative” means that the pharmaceutical composition has the antiseptic effect. Refers to exhibiting the preservative effect even without containing an agent.
  • the preservative efficacy of the pharmaceutical composition can be confirmed by, for example, conducting a test according to the preservative efficacy test method described in the 17th revised Japanese Pharmacopoeia, and preferably the 17th revised Japanese Pharmacopoeia Refers to the preservative efficacy conforming to the test based on the preservative efficacy test method described above.
  • the pharmaceutical composition of the present invention is, for example, an ophthalmic composition, an otolaryngological composition, a composition for inhalation or a composition for transdermal absorption, and each of which is an ophthalmic formulation, an otological formulation, an inhalant formulation, It can be used as a preparation for skin absorption.
  • the administration route of the pharmaceutical composition of the present invention is not particularly limited as long as it is a local administration route that is pharmaceutically acceptable.
  • Examples of the administration route include topical administration to the eye (for example, ophthalmic administration), nasal (nasal) administration, local administration to the ear (for example, ear administration), inhalation administration, spray administration, transdermal administration, Intradermal administration, injection administration and the like can be mentioned.
  • the dosage form of the pharmaceutical composition of the present invention is not particularly limited as long as it can be used locally as a pharmaceutical.
  • Dosage forms include, for example, eye drops, nasal drops (nasal powders, nasal solutions), ear drops, inhalants (inhalable powders, inhalants, aerosols), ointments, creams, gels Preparations, transdermal preparations, patches (tapes, cataplasms), external solutions (lotions, liniments), external solids (external powders), sprays (pump sprays, external aerosols), injections (Infusion, implantable injection, continuous injection) and the like.
  • Preferred are eye drops, nasal drops, ear drops, inhalants, creams, lotions, patches, ophthalmic transdermal preparations, or ophthalmic injections. These can be produced according to the usual methods in the art.
  • the pharmaceutical composition of the present invention is preferably an ophthalmic composition.
  • its dosage form is preferably an ophthalmic solution, an ointment, an ophthalmic transdermal preparation or an ophthalmic injection, and an ophthalmic solution or an ophthalmic transdermal preparation.
  • Formulations are more preferred, and eye drops are most preferred.
  • the administration route is preferably eye drops, application to the mucous membrane of the eye, application to the vicinity of the eye, or injection into or near the eye, and to the eye or near the eye. Is more preferable, and eye drops are most preferable.
  • near the eye refers to the eyelid and its vicinity, and also includes eyelid skin and skin in the vicinity thereof.
  • the vicinity of the eye is preferably the eyelid skin.
  • application to the vicinity of the eye is preferably application to eyelid skin.
  • the pharmaceutical composition of the present invention may contain a pharmaceutical additive as necessary.
  • a pharmaceutical additive for example, in order to satisfy the requirements as an ophthalmic composition, an otolaryngological composition, a composition for inhalation or a composition for transdermal absorption, a buffer, a tonicity agent, a thickening agent, a surfactant, Stabilizers, antioxidants, pH adjusters and the like can be added.
  • a pharmaceutical additive as necessary.
  • an otolaryngological composition a composition for inhalation or a composition for transdermal absorption
  • a buffer e.g., a tonicity agent
  • a thickening agent e.g., a surfactant, Stabilizers, antioxidants, pH adjusters and the like
  • surfactant e.g., Stabilizers, antioxidants, pH adjusters and the like
  • 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. It may be Japanese.
  • boric acid or a salt thereof examples include boric acid, sodium borate, potassium borate and the like, and these may be hydrates.
  • citric acid or a salt thereof examples include citric acid, sodium citrate, disodium citrate and the like, and these may be hydrates.
  • Acetic acid or a salt thereof includes acetic acid, sodium acetate, potassium acetate and the like, and these may be hydrates.
  • the carbonic acid or a salt thereof include sodium carbonate, sodium hydrogencarbonate and the like, and these may be hydrates.
  • tartaric acid or a salt thereof examples include tartaric acid, sodium tartrate, potassium tartrate and the like, and these may be hydrates.
  • the buffer may be used alone or in combination of two or more components.
  • phosphoric acid or a salt thereof boric acid or a salt thereof is more preferable, phosphoric acid or a salt thereof is more preferable, and sodium dihydrogen phosphate, disodium hydrogen phosphate or a hydrate thereof is particularly preferable. preferable.
  • the content of the buffer can be appropriately adjusted depending on the type of the buffer and the like, but is preferably 0.001 to 10% (w / v), 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 ionic tonicity agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride and the like.
  • examples of the nonionic tonicity agent include glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose and the like.
  • the tonicity agent When a tonicity agent is blended with the pharmaceutical composition of the present invention, the tonicity agent may be used alone or in combination of two or more. Among these tonicity agents, ionic tonicity agents are more preferred, and sodium chloride is particularly preferred.
  • the content of the tonicity agent when the tonicity agent is blended with the pharmaceutical composition of the present invention can be appropriately adjusted depending on the kind of the tonicity agent and the like, but is 0.001 to 10% (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 added to the pharmaceutical composition of the present invention include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, Examples include hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyethylene glycol, sodium hyaluronate and the like.
  • the thickening agent when a thickening agent is blended into the pharmaceutical composition of the present invention, the thickening agent may be used alone or in combination of two or more components.
  • the content of the thickening agent when the thickening agent is added to the pharmaceutical composition of the present invention can be appropriately adjusted depending on the kind of the thickening agent and the like, but is 0.001 to 5% (w / v) is preferable, 0.01 to 3% (w / v) is more preferable, and 0.1 to 2% (w / v) is further preferable.
  • cationic surfactant include an alkylamine salt, an alkylamine polyoxyethylene adduct, a fatty acid triethanolamine monoester salt, an acylaminoethyl diethylamine salt, a fatty acid polyamine condensate, an alkylimidazoline, and 1-acylaminoethyl-2. -Alkylimidazoline, 1-hydroxyethyl-2-alkylimidazoline and the like.
  • benzalkonium chloride has the property of a cationic surfactant, it is not included in this.
  • the anionic surfactant include phospholipids such as lecithin.
  • the nonionic surfactant include polyoxyethylene fatty acid esters such as polyoxyl stearate 40; polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan triolate, polysorbate 65 and the like.
  • 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 oil Oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl castor oil such as polyoxyl 40 castor oil; polyoxyethylene (160) Lioxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, Polyoxyethylene polyoxypropylene glycol such as polyoxyethylene (20) polyoxypropylene (20) glycol; sucrose fatty acid ester such as sucrose stearic acid ester; tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS); Can be
  • one surfactant may be used alone, or two or more components may be used in combination.
  • the content of the surfactant can be appropriately adjusted depending on the type of the surfactant, and is preferably 0.01 to 10% (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 edetic acid or a salt thereof include edetic acid, edetate disodium, edetate tetrasodium, and the like.
  • the stabilizer When a stabilizer is added to the pharmaceutical composition of the present invention, the stabilizer may be used alone, or two or more kinds of components may be used in combination.
  • the content of the stabilizer can be appropriately adjusted depending on the type of the stabilizer, etc., but is preferably 0.001 to 5% (w / v). Preferably, it is 0.01 to 3% (w / v), more preferably 0.1 to 2% (w / v).
  • antioxidants examples include ascorbic acid, tocopherol, dibutylhydroxytoluene, sodium sulfite, 2-mercaptobenzimidazole and the like.
  • the antioxidant may be used singly, or two or more components may be used in combination.
  • the content of the antioxidant can be appropriately adjusted depending on the kind of the antioxidant, but is preferably 0.001 to 5% (w / v). Preferably, it is 0.01 to 3% (w / v), more preferably 0.1 to 2% (w / v).
  • PH Acids or bases can be used as pH adjusters that can be added to the pharmaceutical composition of the present invention.
  • the acid include hydrochloric acid, phosphoric acid, citric acid, and acetic acid
  • the base include sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydrogen carbonate.
  • pH adjuster When a pH adjuster is blended with the pharmaceutical composition of the present invention, one type of pH adjuster may be used alone, or two or more types of components may be used in combination.
  • 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.
  • the pH of the pharmaceutical composition may be within a range acceptable as an ophthalmic preparation, for example, preferably 4.0 to 8.5, and preferably 6.0. -8.0 is more preferable, 6.5-7.5 is more preferable, and 6.7-7.3 is particularly preferable. More specifically, the 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.
  • the osmotic pressure ratio of the pharmaceutical composition may be within an acceptable range for an ophthalmic preparation, for example, preferably from 0.5 to 2.0, and more preferably from 0.5 to 2.0. 7 to 1.6 is more preferable, 0.8 to 1.4 is more 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.
  • a solvent such as water.
  • all of the components may be 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 components are dissolved, and most preferably an aqueous solution.
  • the solvent or the dispersion medium is, but not limited to, water, ethanol, or a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, or the like), and is preferably water.
  • the pharmaceutical composition of the present invention is an emulsion, even if it is an oil-in-water emulsion (emulsion composed of an aqueous phase and an oil droplet dispersed in an aqueous phase as a continuous phase), a water-in-oil emulsion (oil)
  • the emulsion may be an emulsion composed of oil and aqueous droplets dispersed as a continuous phase.
  • the average size of the oily or aqueous droplets is from 20 to 3000 nm, preferably from 30 to 1000 nm, more preferably from 50 to 600 nm, and even more preferably from 100 to 300 nm.
  • oils, oils and fats, higher fatty acids, higher alcohols, and the like derived from oils, petroleum, minerals, and synthetic systems.
  • oils, oils and fats, higher fatty acids, higher alcohols, and the like derived from oils, petroleum, minerals, and synthetic systems.
  • aqueous phase examples are not particularly limited as long as they are acceptable as an external preparation for skin or skin cosmetics, and include, for example, polyhydric alcohols, and specifically, glycerin, Examples include concentrated glycerin, diethylene glycol, polyethylene glycol, dipropylene glycol, polypropylene glycol, butylene glycol, polybutylene glycol, sorbitol, xylitol and the like. These may be used alone or in combination of two or more.
  • 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.
  • the above-mentioned oil phase component and aqueous phase component utilize respective physicochemical properties, and ointments, creams, lotions, gels, liniments, transdermal preparations, tapes, It may be used for poultices, external powders, pump sprays, external aerosols and the like.
  • the container containing the pharmaceutical composition is not particularly limited in the size and shape of the container body.
  • the container containing the pharmaceutical composition is preferably an ophthalmic container, and the ophthalmic container is a multi-dose container, a single-use unit-dose container.
  • it may be a PFMD (Preservative Free Multi Dose) container, but a multidose container is particularly preferable because the pharmaceutical composition of the present invention has an antiseptic effect.
  • 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.
  • the multi-dose type container can be used for a certain period after opening, and is easy to carry.
  • the material of the container containing the pharmaceutical composition is not particularly limited as long as it conforms to the shape of the container, and examples thereof include a resin container, an aluminum container, and a glass 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 the like.
  • 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. Further, the pharmaceutical composition of the present invention may contain other pharmaceutically active ingredients other than desloratadine or a salt thereof as long as the effects of the present invention are not impaired. 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, vitamins, vasoconstrictors, mydriatics, miotics, ocular hypotensives, dry eye treatments, local anesthetics, etc. Active ingredients may be mentioned. Other pharmaceutically active ingredients may be incorporated, for example, in an amount of 0.001 to 5% (w / v) based on the total weight of the pharmaceutical composition. These may be used in combination of two or more.
  • the pharmaceutical composition of the present invention is useful as a therapeutic agent for allergic diseases.
  • the “allergic disease” refers to a disease or a symptom thereof caused by an immune reaction to an external antigen.
  • allergic diseases include, but are not limited to, allergic conjunctivitis, allergic rhinitis, atopic dermatitis, urticaria and the like.
  • the treatment of an allergic disease refers to any treatment (for example, cure, amelioration, alleviation, suppression of progress, etc.) of an allergic disease or its symptom, and its prevention. It also includes preventing recurrence of allergic diseases.
  • "patient” means not only humans but also other animals, for example, dogs, cats, horses, and the like.
  • the patient is preferably a mammal, more preferably a human.
  • the “therapeutically effective amount” refers to an amount that produces a therapeutic effect on a disease and its symptoms, or an amount that delays the progression of a disease and its symptoms, as compared to 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 any treatment (eg, cure, amelioration, reduction, suppression of progression, etc.) of allergic conjunctivitis and its symptoms and its prevention.
  • the dosage is not particularly limited as long as it is sufficient to exhibit the desired medicinal effect.
  • the pharmaceutical composition of the present invention is an ophthalmic composition
  • it is administered in one drop at a time, 1 to 6 times a day, preferably 1 to 4 times a day, more preferably 1 to 2 times a day. can do.
  • the pharmaceutical composition of the present invention is an eye drop, it can be used both when wearing a hard contact lens and when wearing a soft contact lens.
  • the soft contact lens include a contact lens containing hydroxyethyl methacrylate as a main component or a silicone hydrogel contact lens.
  • the kind of the soft contact lens to which the present invention is applied is not particularly limited, and may be any of ionic or nonionic, water-containing or non-water-containing.
  • the present invention can be applied to all commercially available soft contact lenses such as a lens used repeatedly, a lens used for one day, a lens used for one week, and a lens used for two weeks.
  • 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 once to three times a day.
  • the pharmaceutical composition of the present invention is a composition for ear drops, one 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. Can be divided into ears.
  • the pharmaceutical composition of the present invention is a composition for inhalation
  • one spray to several sprays at a time 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.
  • the pharmaceutical composition of the present invention is a percutaneous absorption preparation for ophthalmology
  • the method of imparting the preservative effect to the pharmaceutical composition of the present invention includes blending desloratadine or a salt thereof with the pharmaceutical composition.
  • the method for maintaining the preservative effect of the pharmaceutical composition of the present invention comprises blending desloratadine or a salt thereof with the pharmaceutical composition.
  • Example of formulation The representative preparation examples of the present invention are shown below.
  • the amount of each component is the content in 1 mL of the formulation.
  • Test example 1 Preservative efficacy test This test was conducted according to the preservative efficacy test method described in the 17th revised Japanese Pharmacopoeia. 1. Preparation of Test Formulation Desloratadine (0.24 g), sodium dihydrogen phosphate (0.5 g) and sodium chloride (0.5 g) are dissolved in water, and a pH adjuster and water are added to make a total volume of 100 mL. The preparation of Example 1 was prepared by performing filtration sterilization.
  • Example 1 2.4mg desloratadine in 1mL Sodium dihydrogen phosphate 5mg Sodium chloride 5mg Dilute hydrochloric acid qs Sodium hydroxide qs Purified water qs pH 7.0
  • Example 2 The preparations 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 was an active ingredient of "Zyzar (registered trademark) tablet 5 mg"
  • the bepotastine besylate used in Comparative Example 2 was an active ingredient of "Talion (registered trademark) tablet 5 mg”. It is. All of these are marketed as therapeutic agents for allergic diseases.
  • Example 2 1.2mg desloratadine in 1mL Sodium dihydrogen phosphate 5mg Sodium chloride 5mg Dilute hydrochloric acid qs Sodium hydroxide qs Purified water qs pH 7.0
  • Example 3 0.6mg desloratadine in 1mL Sodium dihydrogen phosphate 5mg Sodium chloride 5mg Dilute hydrochloric acid qs Sodium hydroxide qs Purified water qs pH 7.0
  • Example 4 0.3mg of desloratadine in 1mL Sodium dihydrogen phosphate 5mg Sodium chloride 5mg Dilute hydrochloric acid qs Sodium hydroxide qs Purified water qs pH 7.0
  • Bacteria Escherichia coli, Escherichia Coli ATCC 8739 (also called E. coli) Pseudomonas aeruginosa ATCC 9027 (also called P. aeruginosa) Staphylococcus aureus ATCC 6538 (also called S. aureus) Yeasts and molds: Candida albicans ATCC 10231 (also called C. albicans) Aspergillus brasiliensis ATCC16404 (also called A. brasiliensis)
  • the inoculated bacterial solution was inoculated to the test sample so that the concentration of the bacterial solution in the test sample composed of each preparation was 10 5 to 10 6 cells / mL (all five bacterial species). Specifically, an inoculated bacterial solution was prepared so as to have a concentration of 10 7 to 10 8 cfu / mL, and the inoculated bacterial solution was prepared so as to have a concentration of 10 5 to 10 6 cfu / mL. A test sample comprising the preparations 1 and 2 was inoculated with each inoculum and mixed uniformly to obtain a sample. These samples were stored at 20 to 25 ° C.
  • each sample was collected with a micropipette, and the viable cell count was measured.
  • sampling was performed by opening the lid of the sample solution and closing the lid.
  • Test results and discussion Table 1 shows the test results.
  • the test results in Table 1 are shown as common logarithmic values of the ratio (B / A) of the number of bacteria (B) at the time of inoculation to the number of bacteria (A) when the number of viable bacteria was measured. In the case of "1", it indicates that the viable cell count at the time of the test was reduced to 10% of the inoculated cell count.
  • the bacterial species E. coli, P. aeruginosa, S. aureus
  • the bacterial species must be 1.0 or more after 7 days from seeding and 3.0 or more after 14 days or 28 days.
  • fungal species C. albicans, A. brasiliensis
  • desloratadine, levocetirizine, and bepotastine are all active ingredients that exhibit an allergic disease-treating action
  • the pharmaceutical composition of the present invention containing desloratadine or a salt thereof has a sufficient antiseptic effect without containing any preservatives, not only benzalkonium chloride.
  • Example 5 0.1mg desloratadine in 1mL Sodium dihydrogen phosphate 5mg 7mg sodium chloride Dilute hydrochloric acid qs Sodium hydroxide qs Purified water qs pH 6.5
  • Example 6 0.3mg of desloratadine in 1mL Sodium dihydrogen phosphate 5mg 7mg sodium chloride Dilute hydrochloric acid qs Sodium hydroxide qs Purified water qs pH 6.5
  • Example 7 1mg desloratadine in 1mL Sodium dihydrogen phosphate 5mg 7mg sodium chloride Dilute hydrochloric acid qs Sodium hydroxide qs Purified water qs pH 6.5
  • test method preparation of sensitizing solution
  • a physiological saline solution containing an OVA (chicken-derived ovalbumin) solution (Sigma) and an aluminum hydroxide gel was prepared and used as a sensitizing solution.
  • concentrations of OVA and aluminum hydroxide gel in the sensitized solution were 20 ⁇ g / mL and 20 mg / mL, respectively.
  • VA active sensitization allergic conjunctivitis model and confirmation of allergic reaction Active sensitization was performed by using a guinea pig under general anesthesia by inhalation of isoflurane and injecting a sensitizing solution under the binocular conjunctiva of the guinea pig. 14 days after the sensitization, conjunctivitis was induced by instilling 10 ⁇ L of a 0.05% OVA solution prepared by diluting with a physiological saline solution into both eyes of a guinea pig. Thirty minutes after the induction, scores of the conjunctival inflammation in both eyes of the guinea pig were evaluated according to the following criteria.
  • One group was composed of 12 mice and 12 eyes, and the groups were divided into 4 groups so that the average score was not biased among the groups.
  • Test results and discussion Table 2 shows the test results.
  • the average value of the scores is 12 eyes (6 animals) each.
  • the results of the test examples show that, even without adding benzalkonium chloride and other preservatives, the pharmaceutical composition containing desloratadine or a salt thereof exhibits an antiseptic effect and a therapeutic effect for allergic conjunctivitis.
  • a pharmaceutical composition for topical administration containing desloratadine or a salt thereof that does not contain benzalkonium chloride can be obtained.
  • a pharmaceutical composition for topical administration containing desloratadine or a salt thereof, which exhibits an antiseptic effect without adding a preservative, not limited to benzalkonium chloride can also be obtained.
  • the present invention provides a pharmaceutical composition containing desloratadine or a salt thereof, which does not contain benzalkonium chloride, for topical administration. Further, the present invention provides a pharmaceutical composition for topical administration containing desloratadine or a salt thereof, which exhibits an antiseptic effect without adding an antiseptic.

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Abstract

Provided is a pharmaceutical composition for topical administration that comprises desloratadine or a salt thereof and is characterized by containing no benzalkonium chloride.

Description

デスロラタジン又はその塩を含有する医薬組成物Pharmaceutical composition containing desloratadine or a salt thereof
　本発明は、有効成分としてデスロラタジン又はその塩を含有する医薬組成物であって、塩化ベンザルコニウムを含有しないことを特徴とする、局所投与用医薬組成物（以下、「本発明の医薬組成物」ともいう）に関する。 The present invention relates to a pharmaceutical composition containing desloratadine or a salt thereof as an active ingredient, wherein the pharmaceutical composition does not contain benzalkonium chloride. Thing).
　繰り返しの使用を想定した、水等の溶媒を含む医薬組成物は、菌類等の繁殖を防止するため、一定以上の防腐対策が要求される。そのため、そのような医薬組成物には通常、防腐剤が配合されている。例えば、点眼剤であれば、多くの場合、防腐剤として塩化ベンザルコニウムが使用される。塩化ベンザルコニウムは水溶性であり、化学的に安定で、他の防腐剤と比較しても防腐効力が高いために防腐剤として汎用されている。しかし、塩化ベンザルコニウムには細胞障害作用があり、曝露量が増えると角膜上皮障害を引き起こす可能性が増大する。そのため、特に塩化ベンザルコニウムに過敏な反応を示す患者や重度の角膜上皮障害を有する患者には使用することができない。 医 薬 Pharmaceutical compositions containing solvents such as water, which are supposed to be used repeatedly, require a certain level of preservative measures to prevent the propagation of fungi and the like. Therefore, such pharmaceutical compositions usually contain a preservative. 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 preservative effect as compared with other preservatives. However, benzalkonium chloride has cytotoxic effects, and increasing exposure increases the likelihood of causing corneal epithelial damage. Therefore, it cannot be used especially for patients who have a hypersensitivity reaction to benzalkonium chloride or patients with severe corneal epithelial disorder.
　一方で、防腐剤が添加されていない点眼剤で、上市されているほとんどの点眼剤は、ユニットドーズ型（１回使い切りタイプ）のもの、または防腐剤フリー容器（防腐効力を発揮するための特別な構造を有する容器）に保存されているものが一般的である。 On the other hand, most of the eye drops without preservatives on the market are unit dose type (single use type) or preservative-free containers (special for preservative effect). Stored in a container having a simple structure).
　ところで、Ｈ１ヒスタミン受容体拮抗薬の一つであるデスロラタジンは、アレルギー性疾患治療剤「デザレックス（登録商標）錠５ｍｇ」の有効成分であり、その有効量を１日１回経口投与することにより、アレルギー性鼻炎、じんましん、皮膚疾患に伴うそう痒の症状の治療効果を奏することが知られている（非特許文献１）。また、デスロラタジンは、点眼剤および点鼻剤といった局所投与用製剤として使用できることは報告されているが、それらの製剤にはいずれも塩化ベンザルコニウムが添加されている（特許文献１および特許文献２）。特に、特許文献１には、塩化ベンザルコニウムの濃度が高いほど点眼剤のｐＨや活性が安定するため、医薬品添加物一覧表に記載されている最高濃度（０．１２７％）で保存剤として含有させるのが好ましいとも記載されている。一方で、デスロラタジン又はその塩を含有する医薬組成物であって、塩化ベンザルコニウムが添加されていない局所投与用医薬組成物は一切知られていない。さらに、デスロラタジン又はその塩自身が防腐効力を有するとの報告もない。 By the way, desloratadine, which is one of the H1 histamine receptor antagonists, is an active ingredient of a therapeutic agent for allergic diseases “Dezalex (registered trademark) 5 mg”, and its effective amount is orally administered once a day. Is known to exert 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 topical preparation such as eye drops and nasal drops, but benzalkonium chloride is added to each of these preparations (Patent Document 1 and Patent Document 1). 2). In particular, Patent Document 1 discloses that the higher the concentration of benzalkonium chloride, the more stable the pH and activity of the ophthalmic solution. Therefore, the highest concentration (0.127%) described in the list of excipients is used as a preservative. It is also described that it is preferable to contain. 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 is no report that desloratadine or its salt itself has an antiseptic effect.
国際公開ＷＯ９８／４８８０３号公報International Publication WO98 / 48803 特開第２００５－５３８２５号公報JP-A-2005-53825
　塩化ベンザルコニウムを含有しない、デスロラタジン又はその塩を含有する局所投与用医薬組成物を提供することは興味深い課題である。さらに、本発明は、塩化ベンザルコニウムに限らず防腐剤が添加されていなくても防腐効力を奏する、デスロラタジン又はその塩を含有する局所投与用医薬組成物を提供することを目的とする。 It is an interesting task to provide a pharmaceutical composition for topical administration containing desloratadine or a salt thereof that does not contain benzalkonium chloride. Furthermore, another object of the present invention is to provide a pharmaceutical composition for topical administration containing desloratadine or a salt thereof, which exhibits antiseptic effect even if a preservative is not added, besides benzalkonium chloride.
　本発明者らは、鋭意研究を行ったところ、有効成分としてデスロラタジン又はその塩を含有する局所投与用医薬組成物が塩化ベンザルコニウムを含む防腐剤を含有することなく、十分な防腐効力を有することを見出し、本発明に至った。具体的に、本発明は以下を提供する。
（１）有効成分としてデスロラタジン又はその塩を含有する医薬組成物であって、塩化ベンザルコニウムを含有しないことを特徴とする、局所投与用医薬組成物。
（２）０．００１％（ｗ／ｖ）以上の濃度のデスロラタジン又はその塩を含有する、（１）に記載の医薬組成物。
（３）０．０１％～５％（ｗ／ｖ）の濃度のデスロラタジン又はその塩を含有する、（１）に記載の医薬組成物。
（４）眼科用組成物、耳鼻科用組成物、吸入用組成物又は経皮吸収用組成物である、（１）～（３）に記載の医薬組成物。
（５）点眼剤である、（１）～（４）に記載の医薬組成物。
（６）点眼剤用容器がマルチドーズ型容器である、（５）に記載の医薬組成物。
（７）添加剤として緩衝剤、等張化剤、ｐＨ調節剤及び安定化剤からなる群より選択される少なくとも１種を含有する、（１）～（６）のいずれかに記載の医薬組成物。
（８）緩衝剤、等張化剤及びｐＨ調節剤を含有する、（７）に記載の医薬組成物。
（９）さらに安定化剤を含有する、（８）に記載の医薬組成物。
（１０）ｐＨが、４．０～８．５である、（１）～（９）のいずれかに記載の医薬組成物。
（１１）ｐＨが、６．０～８．０である、（１）～（１０）のいずれかに記載の医薬組成物。
（１２）防腐剤を含有しない、（１）～（１１）のいずれかに記載の医薬組成物。
（１３）投与経路が、眼の近傍への投与である、（１）～（１２）のいずれかに記載の医薬組成物。
（１４）眼の近傍への投与が、眼瞼皮膚への塗布である、（１３）に記載の医薬組成物。
（１５）投与経路が、皮膚上投与又は経皮投与である、（１）～（４）および（７）～（１２）のいずれかに記載の医薬組成物。
（１６）投与剤形が、軟膏剤、クリーム剤、ローション剤、ゲル剤、リニメント剤、経皮吸収型製剤、貼付剤、スプレー剤および注射剤よりなる群から選択される、（１）～（４）および（７）～（１５）のいずれかに記載の医薬組成物。
（１７）有効成分として０．０１％（ｗ／ｖ）以上の濃度のデスロラタジン又はその塩を含有する医薬組成物であって、添加剤として緩衝剤、等張化剤、ｐＨ調節剤及び安定化剤からなる群より選択される少なくとも１種を含有し、かつ塩化ベンザルコニウムを含有しないことを特徴とする、医薬組成物。
（１８）有効成分として０．０１％（ｗ／ｖ）以上の濃度のデスロラタジン又はその塩を含有する医薬組成物であって、添加剤として緩衝剤、等張化剤、ｐＨ調節剤及び安定化剤からなる群より選択される少なくとも１種を含有し、かつ防腐剤を含有しないことを特徴とする、医薬組成物。
（１９）デスロラタジン又はその塩を０．０１％（ｗ／ｖ）以上の濃度で配合することで、添加剤として防腐剤を含有せずに、デスロラタジン又はその塩を含有する医薬組成物に防腐効力を付与する方法。
（２０）デスロラタジン又はその塩を０．０１％（ｗ／ｖ）以上の濃度で配合することで、添加剤として防腐剤を含有せずに、デスロラタジン又はその塩を含有する医薬組成物に防腐効力を維持する方法。
　なお、前記（１）から（２０）の各構成は、任意に２以上を選択して組み合わせることができる。 The present inventors have conducted intensive studies and found that a pharmaceutical composition for topical administration containing desloratadine or a salt thereof as an active ingredient does not contain a preservative containing benzalkonium chloride and has a sufficient preservative effect. Have been found, and the present invention has been accomplished. Specifically, the present invention provides the following.
(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), comprising desloratadine or a salt thereof at a concentration of 0.001% (w / v) or more.
(3) The pharmaceutical composition according to (1), comprising 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, a composition for inhalation, or a composition for transdermal absorption.
(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 multidose 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. object.
(8) The pharmaceutical composition according to (7), comprising a buffer, an isotonic agent, and a pH adjuster.
(9) The pharmaceutical composition according to (8), further comprising 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), which has a pH of 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 of (1) to (12), wherein the administration route 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 eyelid skin.
(15) The pharmaceutical composition according to any one of (1) to (4) and (7) to (12), wherein the administration route is dermal 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, The pharmaceutical composition according to any one of 4) and (7) to (15).
(17) A pharmaceutical composition containing desloratadine or a salt thereof at a concentration of 0.01% (w / v) or more as an active ingredient, and a buffer, an isotonicity agent, a pH regulator, and a stabilizer as additives. A pharmaceutical composition comprising at least one member selected from the group consisting of an agent and not containing benzalkonium chloride.
(18) A pharmaceutical composition containing desloratadine or a salt thereof at a concentration of 0.01% (w / v) or more as an active ingredient, wherein a buffer, an isotonicity agent, a pH regulator, and a stabilizer are used as additives. A pharmaceutical composition comprising at least one selected from the group consisting of a preservative and no preservative.
(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 without an antiseptic as an additive can be obtained. 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 without an antiseptic as an additive can be obtained. How to maintain preservative efficacy.
In addition, each of the configurations (1) to (20) can be arbitrarily selected from two or more and combined.
　さらに、本発明は以下も提供する。
（２１）治療が必要な患者に、治療上の有効量の（１）～（１８）のいずれかに記載の医薬組成物を投与することを特徴とする、アレルギー性疾患を治療および／または予防する方法。
（２２）アレルギー性疾患の治療および／または予防に使用する、（１）～（１８）のいずれかに記載の医薬組成物。
（２３）アレルギー性疾患を治療および／または予防するための医薬を製造するための、（１）～（１８）のいずれかに記載の医薬組成物の使用。 Further, the present invention also provides the following.
(21) treating and / or preventing an allergic disease, which comprises administering to a patient in need of treatment a therapeutically effective amount of the pharmaceutical composition according to any of (1) to (18). how to.
(22) The pharmaceutical composition according to any one of (1) to (18), which is used for treating and / or preventing an allergic disease.
(23) Use of the pharmaceutical composition according to any one of (1) to (18) for producing a medicament for treating and / or preventing an allergic disease.
　本発明は、塩化ベンザルコニウムを含有しない、デスロラタジン又はその塩を含有する局所投与用医薬組成物を得ることができる。また、本発明は、塩化ベンザルコニウムに限らず防腐剤を添加しなくても防腐効力を奏する、デスロラタジン又はその塩を含有する局所投与用医薬組成物を得ることもできる。 According to the present invention, a pharmaceutical composition for topical administration containing desloratadine or a salt thereof, which does not contain benzalkonium chloride, can be obtained. In addition, the present invention can also provide a pharmaceutical composition for topical administration containing desloratadine or a salt thereof, which exhibits antiseptic effect without adding a preservative, in addition to benzalkonium chloride.
　以下に、本発明について詳細に説明する。 Hereinafter, the present invention will be described in detail.
　本発明において、「デスロラタジン」とは、化学名８－Ｃｈｌｏｒｏ－１１－（ｐｉｐｅｒｉｄｉｎ－４－ｙｌｉｄｅｎｅ）－６，１１－ｄｉｈｙｄｒｏ－５Ｈ－ｂｅｎｚｏ［５，６］ｃｙｃｌｏｈｅｐｔａ［１，２－ｂ］ｐｙｒｉｄｉｎｅで表される化合物であり、また下記式：
Figure JPOXMLDOC01-appb-C000001
 で表される化合物である。 In the present invention, “desloratadine” is a chemical name of 8-Chloro-11- (piperidin-4-ylidene) -6,11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b] pyridine. And a compound represented by the following formula:
Figure JPOXMLDOC01-appb-C000001
 It is a compound represented by these.
　本発明の医薬組成物において、含有されるデスロラタジンは塩であってもよく、医薬として許容される塩であれば特に制限されるものではない。塩としては、例えば無機酸との塩、有機酸との塩等が挙げられる。
　無機酸との塩としては、塩酸、臭化水素酸、ヨウ化水素酸、硝酸、硫酸、リン酸等との塩が挙げられる。
　有機酸との塩としては、酢酸、シュウ酸、フマル酸、マレイン酸、コハク酸、リンゴ酸、クエン酸、酒石酸、アジピン酸、グルコン酸、グルコヘプト酸、グルクロン酸、テレフタル酸、メタンスルホン酸、アラニン、乳酸、馬尿酸、１，２－エタンジスルホン酸、イセチオン酸、ラクトビオン酸、オレイン酸、没食子酸、パモ酸、ポリガラクツロン酸、ステアリン酸、タンニン酸、トリフルオロメタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、ラウリル硫酸、ナフタレンスルホン酸、スルホサリチル酸等との塩が挙げられる。
　本発明において、含有されるデスロラタジン又はその塩は、水和物又は溶媒和物の形態をとってもよい。 The desloratadine contained in the pharmaceutical 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.
As salts with organic acids, acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptoic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, alanine Lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p- Salts with toluene sulfonic acid, lauryl sulfuric acid, naphthalene sulfonic acid, sulfosalicylic acid and the like can be mentioned.
In the present invention, the contained desloratadine or a salt thereof may be in the form of a hydrate or a solvate.
　本発明において、含有されるデスロラタジン又はその塩は、製薬学的に許容されるプロドラッグも包含する。製薬学的に許容されるプロドラッグとは、可溶媒分解によりまたは生理学的条件下により、アミノ基などに変換されうる基を有する化合物である。例えば、デスロラタジンのプロドラッグ体として知られるロラタジンは、本発明におけるデスロラタジン又はその塩に包含される。 に お い て 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.
　本発明において、デスロラタジン又はその塩の含有量は、０．００１％（ｗ／ｖ）以上であり、好ましくは０．０１％（ｗ／ｖ）以上であり、より好ましくは０．０３％（ｗ／ｖ）以上であり、さらに好ましくは０．０６％（ｗ／ｖ）以上であり、さらにより好ましくは０．０８％（ｗ／ｖ）以上であり、特に好ましくは０．１２％（ｗ／ｖ）以上であり、０．２４％（ｗ／ｖ）以上であってもよい。その上限は、医薬品の有効成分として用いられる量であればよく、例えば５％（ｗ／ｖ）であり、好ましくは３％（ｗ／ｖ）であり、より好ましくは２％（ｗ／ｖ）である。デスロラタジン又はその塩の含有量としては、０．００１～５％（ｗ／ｖ）であり、０．０１～５％（ｗ／ｖ）が好ましく、０．０３～５％（ｗ／ｖ）がより好ましく、０．０６～３％（ｗ／ｖ）がさらに好ましく、０．０８～３％（ｗ／ｖ）がさらにより好ましく、０．１２～２％（ｗ／ｖ）が特に好ましい。より具体的には、その含有量は、好ましくは０．００１％（ｗ／ｖ）、０．０１％（ｗ／ｖ）、０．０３％（ｗ／ｖ）、０．０６％（ｗ／ｖ）、０．０８％（ｗ／ｖ）、０．１％（ｗ／ｖ）、０．１２％（ｗ／ｖ）、０．２４％（ｗ／ｖ）、０．５％（ｗ／ｖ）、１％（ｗ／ｖ）、１．５％（ｗ／ｖ）、２％（ｗ／ｖ）、３％（ｗ／ｖ）又は５％（ｗ／ｖ）である。
　なお、本発明においてデスロラタジンの塩が含有される場合、これらの値はデスロラタジンの塩の含有量である。「％（ｗ／ｖ）」は、本発明の医薬組成物１００ｍＬ中に含まれる対象成分（ここでは、デスロラタジン又はその塩）の質量（ｇ）を意味する。以下、特に断りがない限り同様とする。 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). w / v) or more, more preferably 0.06% (w / v) or more, still more preferably 0.08% (w / v) or more, and particularly preferably 0.12% (w / v). / 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 drug, for example, 5% (w / v), preferably 3% (w / v), and more preferably 2% (w / v). It 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 more preferable, 0.06 to 3% (w / v) is still more preferable, 0.08 to 3% (w / v) is still 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 desloratadine salt is contained in the present invention, these values are the content of desloratadine salt. “% (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. The same applies hereinafter unless otherwise specified.
　本発明において、防腐剤とは、塩化ベンザルコニウム、臭化ベンザルコニウム、塩化ベンゼトニウム、クロルヘキシジン又はその塩、ソルビン酸又はその塩、パラオキシ安息香酸メチル、パラオキシ安息香酸プロピル又はクロロブタノール等が挙げられるが、これらに限定されるものではない。
　クロルヘキシジン又はその塩は、クロルヘキシジン、クロルヘキシジングルコン酸塩、クロルヘキシジン塩酸塩又はクロルヘキシジン酢酸塩である。
　ソルビン酸又はその塩は、ソルビン酸、ソルビン酸ナトリウム又はソルビン酸カリウムである。 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, methyl paraoxybenzoate, propyl paraoxybenzoate and chlorobutanol. However, the present invention 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.
　本発明において、「塩化ベンザルコニウムを含有しない」とは、医薬組成物に塩化ベンザルコニウムを実質的に含有しないことを指し、「防腐剤を含有しない」とは、医薬組成物に上記防腐剤を実質的に含有しないことを指す。なお、ここで用いる、塩化ベンザルコニウムを「実質的に含有しない」とは、塩化ベンザルコニウムを含まないこと、又は塩化ベンザルコニウムが医薬組成物に求められる防腐効力を発揮しない量の範囲で含有することを意図するものであり、防腐剤を「実質的に含有しない」とは、防腐剤として広く知られた成分を含まないこと、又は防腐剤として広く知られた成分が医薬組成物に求められる防腐効力を発揮しない量の範囲で含有することを意図するものであり、また、別の用途で用いる成分で、防腐作用も併せ持つような成分をすべて排除することを意図するものでもない。 In the present invention, "does not contain benzalkonium chloride" means that the pharmaceutical composition does not substantially contain benzalkonium chloride, and "does not contain a preservative" means that the pharmaceutical composition contains the above preservative. Refers to substantially no agent. In addition, as used herein, the term "substantially free of benzalkonium chloride" means that benzalkonium chloride is not contained, or that the amount of benzalkonium chloride that does not exhibit the antiseptic effect required for the pharmaceutical composition It is intended that the preservative is "substantially free of" 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 product, nor is it intended to exclude all components that also have preservative action that are used for other purposes. .
　本発明において、「防腐効力」とは、細菌、真菌等の微生物の発育、増殖を防止する作用を指し、「防腐剤を含有することなく防腐効力を有する」とは、医薬組成物に上記防腐剤を含有していなくても防腐効力を発揮することを指す。なお、医薬組成物の防腐効力は、例えば第１７改正日本薬局方に記載の保存効力試験法に準じた試験を行うことにより、その程度を確認することができ、好ましくは、第１７改正日本薬局方に記載の保存効力試験法に基づく試験に適合する防腐効力を指す。 In the present invention, "antiseptic effect" refers to the action of preventing the growth and growth of microorganisms such as bacteria and fungi, and "having an antiseptic effect without containing a preservative" means that the pharmaceutical composition has the antiseptic effect. Refers to exhibiting the preservative effect even without containing an agent. The preservative efficacy of the pharmaceutical composition can be confirmed by, for example, conducting a test according to the preservative efficacy test method described in the 17th revised Japanese Pharmacopoeia, and preferably the 17th revised Japanese Pharmacopoeia Refers to the preservative efficacy conforming to the test based on the preservative efficacy test method described above.
　本発明の医薬組成物は、例えば、眼科用組成物、耳鼻科用組成物、吸入用組成物又は経皮吸収用組成物であり、それぞれ眼科用製剤、耳鼻科用製剤、吸入用製剤、経皮吸収用製剤として用いることができる。 The pharmaceutical composition of the present invention is, for example, an ophthalmic composition, an otolaryngological composition, a composition for inhalation or a composition for transdermal absorption, and each of which is an ophthalmic formulation, an otological formulation, an inhalant formulation, It can be used as a preparation for skin absorption.
　本発明の医薬組成物の投与経路は、医薬品として許容される局所投与経路であれば特に制限されるものではない。投与経路としては、例えば、眼への局所投与（例えば、点眼投与）、点鼻（経鼻）投与、耳への局所投与（例えば、点耳投与）、吸入投与、噴霧投与、経皮投与、皮膚上投与、注射投与等が挙げられる。 投 与 The administration route of the pharmaceutical composition of the present invention is not particularly limited as long as it is a local administration route that is pharmaceutically acceptable. Examples of the administration route include topical administration to the eye (for example, ophthalmic administration), nasal (nasal) administration, local administration to the ear (for example, ear administration), inhalation administration, spray administration, transdermal administration, Intradermal administration, injection administration and the like can be mentioned.
　本発明の医薬組成物の剤形は、医薬品として局所的に使用可能なものであれば特に制限されるものではない。剤形としては、例えば、点眼剤、点鼻剤（点鼻粉末剤、点鼻液剤）、点耳剤、吸入剤（吸入粉末剤、吸入液剤、吸入エアゾール剤）、軟膏剤、クリーム剤、ゲル剤、経皮吸収型製剤、貼付剤（テープ剤、パップ剤）、外用液剤（ローション剤、リニメント剤）、外用固形剤（外用散剤）、スプレー剤（ポンプスプレー剤、外用エアゾール剤）、注射剤（輸液剤、埋め込み注射剤、持続性注射剤）等が挙げられる。好ましくは点眼剤、点鼻剤、点耳剤、吸入剤、クリーム剤、ローション剤、貼付剤、眼科用経皮吸収型製剤又は眼科用注射剤である。これらは当該技術分野における通常の方法に従って製造することができる。 剤 The dosage form of the pharmaceutical composition of the present invention is not particularly limited as long as it can be used locally as a pharmaceutical. Dosage forms include, for example, eye drops, nasal drops (nasal powders, nasal solutions), ear drops, inhalants (inhalable powders, inhalants, aerosols), ointments, creams, gels Preparations, transdermal preparations, patches (tapes, cataplasms), external solutions (lotions, liniments), external solids (external powders), sprays (pump sprays, external aerosols), injections (Infusion, implantable injection, continuous injection) and the like. Preferred are eye drops, nasal drops, ear drops, inhalants, creams, lotions, patches, ophthalmic transdermal preparations, or ophthalmic injections. These can be produced according to the usual methods in the art.
　本発明の医薬組成物は、好ましくは眼科用組成物である。本発明の医薬組成物が眼科用組成物である場合、その剤形は、点眼剤、眼軟膏剤、眼科用経皮吸収型製剤又は眼科用注射剤が好ましく、点眼剤又は眼科用経皮吸収型製剤がより好ましく、点眼剤が最も好ましく、その投与経路は、点眼、眼粘膜への塗布、眼の近傍への塗布又は眼内もしくは眼の近傍への注射が好ましく、点眼又は眼の近傍への塗布がより好ましく、点眼が最も好ましい。本発明において、「眼の近傍」とは、眼瞼及びその近傍を指し、眼瞼皮膚及びその近傍の皮膚も含まれる。眼の近傍は、好ましくは眼瞼皮膚である。例えば、眼の近傍への塗布とは、好ましくは眼瞼皮膚への塗布である。 医 薬 The pharmaceutical composition of the present invention is preferably an ophthalmic composition. When the pharmaceutical composition of the present invention is an ophthalmic composition, its dosage form is preferably an ophthalmic solution, an ointment, an ophthalmic transdermal preparation or an ophthalmic injection, and an ophthalmic solution or an ophthalmic transdermal preparation. Formulations are more preferred, and eye drops are most preferred. The administration route is preferably eye drops, application to the mucous membrane of the eye, application to the vicinity of the eye, or injection into or near the eye, and to the eye or near the eye. Is more preferable, and eye drops are most preferable. In the present invention, “near the eye” refers to the eyelid and its vicinity, and also includes eyelid skin and skin in the vicinity thereof. The vicinity of the eye is preferably the eyelid skin. For example, application to the vicinity of the eye is preferably application to eyelid skin.
　本発明の医薬組成物は、必要に応じて医薬品の添加剤を含んでいてもよい。例えば、眼科用組成物、耳鼻科用組成物、吸入用組成物又は経皮吸収用組成物としての要件を満たすために、緩衝剤、等張化剤、粘稠化剤、界面活性化剤、安定化剤、抗酸化剤、ｐＨ調節剤等を加えることができる。これらは、それぞれ単独で用いてもよく、また、２種以上を適宜組み合わせて用いてもよく、適量を配合することができる。 医 薬 The pharmaceutical composition of the present invention may contain a pharmaceutical additive as necessary. For example, in order to satisfy the requirements as an ophthalmic composition, an otolaryngological composition, a composition for inhalation or a composition for transdermal absorption, a buffer, a tonicity agent, a thickening agent, a surfactant, Stabilizers, antioxidants, pH adjusters and the like can be added. Each of these may be used alone, or two or more of them may be used in appropriate combination, and may be used in an appropriate amount.
　本発明の医薬組成物に配合することができる緩衝剤の例としては、リン酸又はその塩、ホウ酸又はその塩、クエン酸又はその塩、酢酸又はその塩、炭酸又はその塩、酒石酸又はその塩、ε－アミノカプロン酸、トロメタモール等が挙げられる。これらは、水和物又は溶媒和物の形態であってもよい。
　リン酸又はその塩としては、リン酸、リン酸ナトリウム、リン酸二水素ナトリウム、リン酸水素二ナトリウム、リン酸カリウム、リン酸二水素カリウム、リン酸水素二カリウム等が挙げられ、これらは水和物であってもよい。
　ホウ酸又はその塩としては、ホウ酸、ホウ酸ナトリウム、ホウ酸カリウム等が挙げられ、これらは水和物であってもよい。
　クエン酸又はその塩としては、クエン酸、クエン酸ナトリウム、クエン酸二ナトリウム等が挙げられ、これらは水和物であってもよい。
　酢酸又はその塩としては、酢酸、酢酸ナトリウム、酢酸カリウム等が挙げられ、これらは水和物であってもよい。
　炭酸又はその塩としては、炭酸ナトリウム、炭酸水素ナトリウム等が挙げられ、これらは水和物であってもよい。
　酒石酸又はその塩としては、酒石酸、酒石酸ナトリウム、酒石酸カリウム等が挙げられ、これらは水和物であってもよい。 Examples of buffers that can be incorporated in 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, tartaric acid or a salt thereof Salts, ε-aminocaproic acid, trometamol 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. 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.
Acetic acid or a salt thereof includes acetic acid, sodium acetate, potassium acetate and the like, and these may be hydrates.
Examples of the 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.
　本発明の医薬組成物に緩衝剤を配合する場合、緩衝剤は、１種単独で用いてもよく、また、２種以上の成分を組み合わせて用いてもよい。これらの緩衝剤の中でも、リン酸又はその塩、ホウ酸又はその塩がより好ましく、リン酸又はその塩がさらに好ましく、リン酸二水素ナトリウム、リン酸水素二ナトリウムまたはこれらの水和物が特に好ましい。 場合 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 more preferable, and sodium dihydrogen phosphate, disodium hydrogen phosphate or a hydrate thereof is particularly preferable. preferable.
　本発明の医薬組成物に緩衝剤を配合する場合の緩衝剤の含有量は、緩衝剤の種類などにより適宜調整することができるが、０．００１～１０％（ｗ／ｖ）が好ましく、０．０１～５％（ｗ／ｖ）がより好ましく、０．１～３％（ｗ／ｖ）がさらに好ましく、０．２～１．５％（ｗ／ｖ）が最も好ましい。 When a buffer is added to the pharmaceutical composition of the present invention, the content of the buffer can be appropriately adjusted depending on the type of the buffer and the like, but is preferably 0.001 to 10% (w / v), 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.
　本発明の医薬組成物に配合することができる等張化剤の例としては、イオン性等張化剤、非イオン性等張化剤等が挙げられる。
　イオン性等張化剤としては、塩化ナトリウム、塩化カリウム、塩化カルシウム、塩化マグネシウム等が挙げられる。
　非イオン性等張化剤としては、グリセリン、プロピレングリコール、ポリエチレングリコール、ソルビトール、マンニトール、トレハロース、マルトース、スクロース等が挙げられる。 Examples of tonicity agents that can be incorporated into the pharmaceutical composition of the present invention include ionic tonicity agents, nonionic tonicity agents, and the like.
Examples of the ionic tonicity agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride and the like.
Examples of the nonionic tonicity agent include glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose and the like.
　本発明の医薬組成物に等張化剤を配合する場合、等張化剤は、１種単独で用いてもよく、また、２種以上の成分を組み合わせて用いてもよい。これらの等張化剤の中でも、イオン性等張化剤がより好ましく、塩化ナトリウムが特に好ましい。 When a tonicity agent is blended with the pharmaceutical composition of the present invention, the tonicity agent may be used alone or in combination of two or more. Among these tonicity agents, ionic tonicity agents are more preferred, and sodium chloride is particularly preferred.
　本発明の医薬組成物に等張化剤を配合する場合の等張化剤の含有量は、等張化剤の種類などにより適宜調整することができるが、０．００１～１０％（ｗ／ｖ）が好ましく、０．０１～５％（ｗ／ｖ）がより好ましく、０．１～２％（ｗ／ｖ）がさらに好ましく、０．２～１％（ｗ／ｖ）が最も好ましい。 The content of the tonicity agent when the tonicity agent is blended with the pharmaceutical composition of the present invention can be appropriately adjusted depending on the kind of the tonicity agent and the like, but is 0.001 to 10% (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.
　本発明の医薬組成物に配合することができる粘稠化剤の例としては、メチルセルロース、エチルセルロース、ヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシエチルメチルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースナトリウム、ヒドロキシプロピルメチルセルロースアセテートサクシネート、ヒドロキシプロピルメチルセルロースフタレート、カルボキシメチルエチルセルロース、酢酸フタル酸セルロース、ポリビニルピロリドン、ポリビニルアルコール、カルボキシビニルポリマー、ポリエチレングリコール、ヒアルロン酸ナトリウム等が挙げられる。 Examples of the thickening agent that can be added to the pharmaceutical composition of the present invention include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, Examples include hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, cellulose acetate phthalate, polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyethylene glycol, sodium hyaluronate and the like.
　本発明の医薬組成物に粘稠化剤を配合する場合、粘稠化剤は、１種単独で用いてもよく、また、２種以上の成分を組み合わせて用いてもよい。 配合 When a thickening agent is blended into the pharmaceutical composition of the present invention, the thickening agent may be used alone or in combination of two or more components.
　本発明の医薬組成物に粘稠化剤を配合する場合の粘稠化剤の含有量は、粘稠化剤の種類などにより適宜調整することができるが、０．００１～５％（ｗ／ｖ）が好ましく、０．０１～３％（ｗ／ｖ）がより好ましく、０．１～２％（ｗ／ｖ）がさらに好ましい。 The content of the thickening agent when the thickening agent is added to the pharmaceutical composition of the present invention can be appropriately adjusted depending on the kind of the thickening agent and the like, but is 0.001 to 5% (w / v) is preferable, 0.01 to 3% (w / v) is more preferable, and 0.1 to 2% (w / v) is further preferable.
　本発明の医薬組成物に配合することができる界面活性化剤の例としては、カチオン性界面活性化剤、アニオン性界面活性化剤、非イオン性界面活性化剤等が挙げられる。
　カチオン性界面活性化剤としては、アルキルアミン塩、アルキルアミンポリオキシエチレン付加物、脂肪酸トリエタノールアミンモノエステル塩、アシルアミノエチルジエチルアミン塩、脂肪酸ポリアミン縮合物、アルキルイミダゾリン、１－アシルアミノエチル－２－アルキルイミダゾリン、１－ヒドロキシルエチル－２－アルキルイミダゾリン等が挙げられる。ただし、塩化ベンザルコニウムはカチオン性界面活性化剤の性質を有しているが、これには含まれない。
　アニオン性界面活性化剤としては、レシチン等のリン酸脂質等が挙げられる。
　非イオン性界面活性化剤としては、ステアリン酸ポリオキシル４０等のポリオキシエチレン脂肪酸エステル；ポリソルベート８０、ポリソルベート６０、ポリソルベート４０、ポリオキシエチレンソルビタンモノラウレート、ポリオキシエチレンソルビタントリオレート、ポリソルベート６５等のポリオキシエチレンソルビタン脂肪酸エステル；ポリオキシエチレン硬化ヒマシ油１０、ポリオキシエチレン硬化ヒマシ油４０、ポリオキシエチレン硬化ヒマシ油５０、ポリオキシエチレン硬化ヒマシ油６０等のポリオキシエチレン硬化ヒマシ油；ポリオキシル５ヒマシ油、ポリオキシル９ヒマシ油、ポリオキシル１５ヒマシ油、ポリオキシル３５ヒマシ油、ポリオキシル４０ヒマシ油等のポリオキシルヒマシ油；ポリオキシエチレン（１６０）ポリオキシプロピレン（３０）グリコール、ポリオキシエチレン（４２）ポリオキシプロピレン（６７）グリコール、ポリオキシエチレン（５４）ポリオキシプロピレン（３９）グリコール、ポリオキシエチレン（１９６）ポリオキシプロピレン（６７）グリコール、ポリオキシエチレン（２０）ポリオキシプロピレン（２０）グリコール等のポリオキシエチレンポリオキシプロピレングリコール；ショ糖ステアリン酸エステル等のショ糖脂肪酸エステル；トコフェロールポリエチレングリコール１０００コハク酸エステル（ビタミンＥ　ＴＰＧＳ）等が挙げられる。 Examples of surfactants that can be incorporated in the pharmaceutical composition of the present invention include cationic surfactants, anionic surfactants, and nonionic surfactants.
Examples of the cationic surfactant include an alkylamine salt, an alkylamine polyoxyethylene adduct, a fatty acid triethanolamine monoester salt, an acylaminoethyl diethylamine salt, a fatty acid polyamine condensate, an alkylimidazoline, and 1-acylaminoethyl-2. -Alkylimidazoline, 1-hydroxyethyl-2-alkylimidazoline and the like. However, although benzalkonium chloride has the property of a cationic surfactant, it is not included in this.
Examples of the anionic surfactant include phospholipids such as lecithin.
Examples of the nonionic surfactant include polyoxyethylene fatty acid esters such as polyoxyl stearate 40; polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan triolate, polysorbate 65 and the like. 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 oil Oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl castor oil such as polyoxyl 40 castor oil; polyoxyethylene (160) Lioxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, Polyoxyethylene polyoxypropylene glycol such as polyoxyethylene (20) polyoxypropylene (20) glycol; sucrose fatty acid ester such as sucrose stearic acid ester; tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS); Can be
　本発明の医薬組成物に界面活性化剤を配合する場合、界面活性化剤は、１種単独で用いてもよく、また、２種以上の成分を組み合わせて用いてもよい。 配合 When a surfactant is blended with the pharmaceutical composition of the present invention, one surfactant may be used alone, or two or more components may be used in combination.
　本発明の医薬組成物に界面活性化剤を配合する場合の界面活性化剤の含有量は、界面活性化剤の種類などにより適宜調整することができるが、０．０１～１０％（ｗ／ｖ）が好ましく、０．０５～５％（ｗ／ｖ）がより好ましく、０．０５～３％（ｗ／ｖ）がさらに好ましく、０．０５～１％（ｗ／ｖ）が特に好ましい。 When the surfactant is added to the pharmaceutical composition of the present invention, the content of the surfactant can be appropriately adjusted depending on the type of the surfactant, and is preferably 0.01 to 10% (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.
　本発明の医薬組成物に配合することができる安定化剤の例としては、エデト酸又はその塩等が挙げられる。
　エデト酸又はその塩としては、エデト酸、エデト酸二ナトリウム、エデト酸四ナトリウム等が挙げられる。 Examples of stabilizers that can be added to the pharmaceutical composition of the present invention include edetic acid or a salt thereof.
Examples of the edetic acid or a salt thereof include edetic acid, edetate disodium, edetate tetrasodium, and the like.
　本発明の医薬組成物に安定化剤を配合する場合、安定化剤は、１種単独で用いてもよく、また、２種以上の成分を組み合わせて用いてもよい。 場合 When a stabilizer is added to the pharmaceutical composition of the present invention, the stabilizer may be used alone, or two or more kinds of components may be used in combination.
　本発明の医薬組成物に安定化剤を配合する場合の安定化剤の含有量は、安定化剤の種類などにより適宜調整することができるが、０．００１～５％（ｗ／ｖ）が好ましく、０．０１～３％（ｗ／ｖ）がより好ましく、０．１～２％（ｗ／ｖ）がさらに好ましい。 When the stabilizer is added to the pharmaceutical composition of the present invention, the content of the stabilizer can be appropriately adjusted depending on the type of the stabilizer, etc., but is preferably 0.001 to 5% (w / v). Preferably, it is 0.01 to 3% (w / v), more preferably 0.1 to 2% (w / v).
　本発明の医薬組成物に配合することができる抗酸化剤の例としては、アスコルビン酸、トコフェロール、ジブチルヒドロキシトルエン、亜硫酸ナトリウム、２－メルカプトベンズイミダゾール等が挙げられる。 抗 Examples of antioxidants that can be added to the pharmaceutical composition of the present invention include ascorbic acid, tocopherol, dibutylhydroxytoluene, sodium sulfite, 2-mercaptobenzimidazole and the like.
　本発明の医薬組成物に抗酸化剤を配合する場合、抗酸化剤は、１種単独で用いてもよく、また、２種以上の成分を組み合わせて用いてもよい。 場合 When an antioxidant is added to the pharmaceutical composition of the present invention, the antioxidant may be used singly, or two or more components may be used in combination.
　本発明の医薬組成物に抗酸化剤を配合する場合の抗酸化剤の含有量は、抗酸化剤の種類などにより適宜調整することができるが、０．００１～５％（ｗ／ｖ）が好ましく、０．０１～３％（ｗ／ｖ）がより好ましく、０．１～２％（ｗ／ｖ）がさらに好ましい。 When the antioxidant is added to the pharmaceutical composition of the present invention, the content of the antioxidant can be appropriately adjusted depending on the kind of the antioxidant, but is preferably 0.001 to 5% (w / v). Preferably, it is 0.01 to 3% (w / v), more preferably 0.1 to 2% (w / v).
　本発明の医薬組成物に配合することができるｐＨ調節剤としては、酸又は塩基がある。酸の例としては、塩酸、リン酸、クエン酸、酢酸等が挙げられ、塩基の例としては、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸水素ナトリウム等が挙げられる。 ＰＨ Acids or bases can be used as pH adjusters that can be added to the pharmaceutical composition of the present invention. Examples of the acid include hydrochloric acid, phosphoric acid, citric acid, and acetic acid, and examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydrogen carbonate.
　本発明の医薬組成物にｐＨ調節剤を配合する場合、ｐＨ調節剤は、１種単独で用いてもよく、また、２種以上の成分を組み合わせて用いてもよい。 When a pH adjuster is blended with the pharmaceutical composition of the present invention, one type of pH adjuster may be used alone, or two or more types of components may be used in combination.
　本発明の医薬組成物のｐＨは、４．０～８．５の範囲内が好ましく、６．０～８．０がより好ましい。本発明の医薬組成物が眼科用組成物である場合、医薬組成物のｐＨは、眼科用製剤として許容される範囲内にあればよく、例えば４．０～８．５が好ましく、６．０～８．０がより好ましく、６．５～７．５がさらに好ましく、６．７～７．３が特に好ましい。より具体的には、そのｐＨは、好ましくは６．７、６．８、６．９、７．０、７．１、７．２又は７．３である。 ＰＨ 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 a range acceptable as an ophthalmic preparation, for example, preferably 4.0 to 8.5, and preferably 6.0. -8.0 is more preferable, 6.5-7.5 is more preferable, and 6.7-7.3 is particularly preferable. More specifically, the pH is preferably 6.7, 6.8, 6.9, 7.0, 7.1, 7.2 or 7.3.
　本発明の医薬組成物の浸透圧比は、０．５～２．０の範囲内が好ましい。本発明の医薬組成物が眼科用組成物である場合、医薬組成物の浸透圧比は、眼科用製剤として許容される範囲内にあればよく、例えば０．５～２．０が好ましく、０．７～１．６がより好ましく、０．８～１．４がさらに好ましく、０．９～１．２が特に好ましい。 浸透 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, preferably from 0.5 to 2.0, and more preferably from 0.5 to 2.0. 7 to 1.6 is more preferable, 0.8 to 1.4 is more preferable, and 0.9 to 1.2 is particularly preferable.
　本発明の医薬組成物は、水等の溶媒を含む医薬組成物が好ましい。本発明の医薬組成物は、構成成分が全て溶解または一部懸濁していてもよく、またエマルション、半固体状の形態であってもよい。本発明の医薬組成物は、構成成分が全て溶解している溶液状態であることがより好ましく、水溶液であることが最も好ましい。溶媒又は分散媒は、限定されるものではないが、水、エタノール、ポリオール（例えば、グリセロール、プロピレングリコール、液体ポリエチレングリコール等）であり、好ましくは水である。 医 薬 The pharmaceutical composition of the present invention is preferably a pharmaceutical composition containing a solvent such as water. In the pharmaceutical composition of the present invention, all of the components may be 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 components are dissolved, and most preferably an aqueous solution. The solvent or the dispersion medium is, but not limited to, water, ethanol, or a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, or the like), and is preferably water.
　本発明の医薬組成物がエマルションである場合は、水中油型エマルション（水相を連続相として、水相と分散した油性液滴から構成されるエマルション）であっても油中水型エマルション（油相を連続相として、油と分散した水性液滴から構成されるエマルション）であってもよい。油性液滴または水性液滴の平均サイズは、２０～３０００ｎｍであり、好ましくは３０～１０００ｎｍであり、より好ましくは５０～６００ｎｍであり、さらに好ましくは１００～３００ｎｍである。 When the pharmaceutical composition of the present invention is an emulsion, even if it is an oil-in-water emulsion (emulsion composed of an aqueous phase and an oil droplet dispersed in an aqueous phase as a continuous phase), a water-in-oil emulsion (oil) The emulsion may be an emulsion composed of oil and aqueous droplets dispersed as a continuous phase. The average size of the oily or aqueous droplets is from 20 to 3000 nm, preferably from 30 to 1000 nm, more preferably from 50 to 600 nm, and even more preferably from 100 to 300 nm.
　本発明の医薬組成物がエマルションである場合、用いられる油相の例としては、皮膚外用剤または皮膚化粧料として許容されるものであれば特に制限されるものではなく、例えば、動物系、植物系、石油系、鉱物系及び合成系由来の油分、油脂、高級脂肪酸、高級アルコール等が挙げられ、具体的にはワセリン、白色ワセリン、パラフィン、流動パラフィン、軽質流動パラフィン、スクワラン、スクワレン、セレシン、ミツロウ、サラシミツロウ、オリーブ油、ゴマ油、ヒマシ油、シリコン油、中鎖脂肪酸トリグリセリド、ラウリン酸又はそのエステル、ミリスチン酸又はそのエステル、パルミチン酸又はそのエステル、ステアリン酸又はそのエステル、ラウリルアルコール、ミリスチルアルコール、パルミチルアルコール、ステアリルアルコール、オクチルドデカノール等が挙げられる。これらは、１種単独で用いてもよく、また、２種以上の成分を組み合わせて用いてもよい。
　また、用いられる水相の例としては、皮膚外用剤または皮膚化粧料として許容されるものであれば特に制限されるものではなく、例えば、多価アルコール等が挙げられ、具体的にはグリセリン、濃グリセリン、ジエチレングリコール、ポリエチレングリコール、ジプロピレングリコール、ポリプロピレングリコール、ブチレングリコール、ポリブチレングリコール、ソルビトール、キシリトール等が挙げられる。これらは、１種単独で用いてもよく、また、２種以上の成分を組み合わせて用いてもよい。
　エマルション中の油相の量は、例えば水中油型エマルションであれば、組成物全量に対して０．１～５０％（ｗ／ｖ）であり、好ましくは５～３０％（ｗ／ｖ）である。 When the pharmaceutical composition of the present invention is an emulsion, examples of the oil phase to be used are not particularly limited as long as it is acceptable as a skin external preparation or a skin cosmetic. Oils, oils and fats, higher fatty acids, higher alcohols, and the like derived from oils, petroleum, minerals, and synthetic systems.Specifically, petrolatum, white petrolatum, paraffin, liquid paraffin, light liquid paraffin, squalane, squalene, ceresin, Beeswax, beeswax, olive oil, sesame oil, castor oil, silicone 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, Palmityl alcohol, stearyl alcohol Lumpur, octyl dodecanol and the like. These may be used alone or in combination of two or more.
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 include, for example, polyhydric alcohols, and specifically, glycerin, Examples include concentrated glycerin, diethylene glycol, polyethylene glycol, dipropylene glycol, polypropylene glycol, butylene glycol, polybutylene glycol, sorbitol, xylitol and the like. These may be used alone or in combination of two or more.
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.
　本発明において、上記の油相成分及び水相成分は、それぞれの物理化学的性質を利用して、軟膏剤、クリーム剤、ローション剤、ゲル剤、リニメント剤、経皮吸収型製剤、テープ剤、パップ剤、外用散剤、ポンプスプレー剤、外用エアゾール剤等に用いられてもよい。 In the present invention, the above-mentioned oil phase component and aqueous phase component utilize respective physicochemical properties, and ointments, creams, lotions, gels, liniments, transdermal preparations, tapes, It may be used for poultices, external powders, pump sprays, external aerosols and the like.
　本発明において、医薬組成物を収容する容器は、容器本体の大きさや形状に特に制限されるものではない。本発明の医薬組成物が眼科用組成物である場合、医薬組成物を収容する容器は、点眼剤用容器が好ましく、その点眼剤用容器はマルチドーズ型容器、１回使い切りのユニットドーズ型容器又はＰＦＭＤ（Ｐｒｅｓｅｒｖａｔｉｖｅ　Ｆｒｅｅ　Ｍｕｌｔｉ　Ｄｏｓｅ）容器のいずれであってもよいが、本発明の医薬組成物は防腐効力を有することから、マルチドーズ型容器が特に好ましい。マルチドーズ型容器とは、複数回使用することを目的にキャップ等の開閉を自由に行えるようにした容器であり、開封後一定期間に渡って使用することができ、持ち運びも容易である。 容器 In the present invention, the container containing 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 containing the pharmaceutical composition is preferably an ophthalmic container, and the ophthalmic container is a multi-dose container, a single-use unit-dose container. Alternatively, it may be a PFMD (Preservative Free Multi Dose) container, but a multidose container is particularly preferable because the pharmaceutical composition of the present invention has an antiseptic effect. 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. The multi-dose type container can be used for a certain period after opening, and is easy to carry.
　本発明において、医薬組成物を収容する容器の素材は、容器の形態に沿ったものであれば特に制限されるものではなく、樹脂製容器、アルミ製容器、ガラス製容器等が挙げられるが、特に、本発明の医薬組成物を収容する容器が点眼容器である場合は、樹脂製容器が好ましい。樹脂製容器の材質は、例えば、ポリエチレン（ＰＥ）、ポリプロピレン（ＰＰ）、ポリエチレンテレフタレート（ＰＥＴ）、ポリブチレンテレフタレート、ポリプロピレン－ポリエチレンコポリマー、ポリ塩化ビニル、アクリル樹脂、ポリスチレン、環状オレフィンポリマー、環状オレフィンコポリマー等が挙げられる。さらにポリエチレンは、その密度によって分類され、低密度ポリエチレン（ＬＤＰＥ）、中密度ポリエチレン（ＭＤＰＥ）、高密度ポリエチレン（ＨＤＰＥ）等が挙げられる。 In the present invention, the material of the container containing the pharmaceutical composition is not particularly limited as long as it conforms to the shape 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 ophthalmic 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 the like. 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).
　本発明の医薬組成物は、デスロラタジン又はその塩を唯一の有効成分として含有してもよい。また、本発明の医薬組成物は、本発明の効果を妨げない範囲であれば、デスロラタジン又はその塩以外の他の医薬活性成分を含んでいてもよい。特に、本発明の医薬組成物が眼科用組成物である場合は、デスロラタジン又はその塩以外の点眼剤に用いられる他の医薬活性成分を含んでいてもよい。他の医薬活性成分として、例えば、抗炎症剤、抗菌剤、抗ウイルス剤、ビタミン剤、血管収縮剤、散瞳剤、縮瞳剤、眼圧降下剤、ドライアイ治療剤、局所麻酔剤等の有効成分が挙げられる。他の医薬活性成分は、医薬組成物の総重量に対して、例えば０．００１～５％（ｗ／ｖ）の量で配合してもよい。また、これらは２種以上組み合わせて用いてもよい。 医 薬 The pharmaceutical composition of the present invention may contain desloratadine or a salt thereof as the only active ingredient. Further, the pharmaceutical composition of the present invention may contain other pharmaceutically active ingredients other than desloratadine or a salt thereof as long as the effects of the present invention are not impaired. 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, vitamins, vasoconstrictors, mydriatics, miotics, ocular hypotensives, dry eye treatments, local anesthetics, etc. Active ingredients may be mentioned. Other pharmaceutically active ingredients may be incorporated, for example, in an amount of 0.001 to 5% (w / v) based on the total weight of the pharmaceutical composition. These may be used in combination of two or more.
　本発明の医薬組成物は、アレルギー性疾患の治療剤として有用である。本発明において、「アレルギー性疾患」とは、外部からの抗原に対する免疫反応によって引き起こされる疾患またはその症状を指す。アレルギー性疾患の例として、アレルギー性結膜炎、アレルギー性鼻炎、アトピー性皮膚炎、じんましん等が挙げられるが、それらに限定されるものではない。本発明において、アレルギー性疾患の治療とは、アレルギー性疾患又はその症状のあらゆる治療（例えば、治癒、改善、軽減、進行の抑制等）及びその予防を指す。また、アレルギー性疾患の再発の阻止も含まれる。
　本発明において、「患者」とは、ヒトのみに限らずその他の動物、例えば、イヌ、ネコ、ウマなども意味する。患者は、好ましくは哺乳動物であり、より好ましくはヒトである。本発明において、「治療上の有効量」とは、未治療対象と比べて、疾患およびその症状の治療効果をもたらす量、または疾患およびその症状の進行の遅延をもたらす量などを指す。 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, amelioration, alleviation, suppression of progress, etc.) of an allergic disease or its symptom, and its prevention. It also includes preventing recurrence of allergic diseases.
In the present invention, "patient" means not only humans but also other animals, for example, 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 produces a therapeutic effect on a disease and its symptoms, or an amount that delays the progression of a disease and its symptoms, as compared to an untreated subject.
　本発明の医薬組成物は、眼科用のアレルギー性疾患の治療剤として用いることがより好ましく、特にアレルギー性結膜炎の治療剤として有用である。アレルギー性結膜炎の治療には、アレルギー性結膜炎及びその症状のあらゆる治療（例えば、治癒、改善、軽減、進行の抑制等）及びその予防が含まれる。 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 any treatment (eg, cure, amelioration, reduction, suppression of progression, etc.) of allergic conjunctivitis and its symptoms and its prevention.
　本発明の医薬組成物を投与する場合、所望の薬効を奏するのに十分であれば用法用量は特に制限されるものではない。本発明の医薬組成物が眼科用組成物である場合は、１回１滴、１日１～６回、好ましくは１日１～４回、より好ましくは１日１～２回に分けて投与することができる。さらに、本発明の医薬組成物が点眼剤である場合には、ハードコンタクトレンズ装用時においても、ソフトコンタクトレンズ装用時においても使用することができる。
　ソフトコンタクトレンズとしては、例えば、ヒドロキシエチルメタクリレートを主成分とするコンタクトレンズ又はシリコーンハイドロゲルコンタクトレンズ等が挙げられる。なお、本発明の適用対象となるソフトコンタクトレンズの種類については、特に限定されるものではなく、イオン性または非イオン性、含水性または非含水性のいずれであってもよい。例えば、繰り返し使用されるレンズの他、１日使い捨て用レンズ、１週間使い捨て用レンズ、２週間使い捨て用レンズなどの市販されるすべてのソフトコンタクトレンズに適用可能である。 When administering the pharmaceutical composition of the present invention, the dosage is not particularly limited as long as it is sufficient to exhibit the desired medicinal effect. When the pharmaceutical composition of the present invention is an ophthalmic composition, it is administered in one drop at a time, 1 to 6 times a day, preferably 1 to 4 times a day, 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 a hard contact lens and when wearing a soft contact lens.
Examples of the soft contact lens include a contact lens containing hydroxyethyl methacrylate as a main component or a silicone hydrogel contact lens. The kind of the soft contact lens to which the present invention is applied is not particularly limited, and may be any of ionic or nonionic, water-containing or non-water-containing. For example, the present invention can be applied to all commercially available soft contact lenses such as a lens used repeatedly, a lens used for one day, a lens used for one week, and a lens used for two weeks.
　本発明の医薬組成物が点鼻用組成物である場合は、１回１滴～数滴、又は１回１噴霧～数噴霧、１日１～６回、好ましくは１日１～４回、より好ましくは１日１～３回に分けて点鼻することができる。 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 once to three times a day.
　本発明の医薬組成物が点耳用組成物である場合は、１回１滴～数滴、１日１～６回、好ましくは１日１～４回、より好ましくは１日１～３回に分けて点耳することができる。 When the pharmaceutical composition of the present invention is a composition for ear drops, one 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. Can be divided into ears.
本発明の医薬組成物が吸入用組成物である場合は、１回１噴霧～数噴霧、１日１～６回、好ましくは１日１～４回、より好ましくは１日１～３回に分けて吸入することができる。 When the pharmaceutical composition of the present invention is a composition for inhalation, one spray to several sprays at a time, 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.
　本発明の医薬組成物が眼科用経皮吸収型製剤である場合は、１回１ｍｇ～１ｇを１日１～４回、好ましくは１日２回、より好ましくは１日１回眼瞼皮膚に塗布することができる。 When the pharmaceutical composition of the present invention is a percutaneous absorption preparation for ophthalmology, apply 1 mg to 1 g at a time to the eyelid skin 1 to 4 times a day, preferably twice a day, more preferably once a day. can do.
　本発明の医薬組成物に防腐効力を付与する方法は、医薬組成物にデスロラタジン又はその塩を配合することを含む。 方法 The method of imparting the preservative effect to the pharmaceutical composition of the present invention includes blending desloratadine or a salt thereof with the pharmaceutical composition.
　本発明の医薬組成物の防腐効力を維持する方法は、医薬組成物にデスロラタジン又はその塩を配合することを含む。 方法 The method for maintaining the preservative effect of the pharmaceutical composition of the present invention comprises blending desloratadine or a salt thereof with the pharmaceutical composition.
　以下に、製剤例および試験例を示すが、これらは本発明をより良く理解するためのものであり、本発明の範囲を限定するものではない。 製 剤 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.
［製剤例］
　以下に本発明の代表的な製剤例を示す。なお、下記製剤例において各成分の配合量は製剤１ｍＬ中の含量である。 [Example of formulation]
The representative preparation examples of the present invention are shown below. In the following formulation examples, the amount of each component is the content in 1 mL of the formulation.
製剤例１
　デスロラタジン　　　　　　　０．５ｍｇ
　リン酸二水素ナトリウム　　　　１０ｍｇ
　塩化ナトリウム　　　　　　　　１０ｍｇ
　希塩酸　　　　　　　　　　　　　　適量
　水酸化ナトリウム　　　　　　　　　適量
　精製水　　　　　　　　　　　　　　適量 Formulation Example 1
Desloratadine 0.5mg
Sodium dihydrogen phosphate 10mg
Sodium chloride 10mg
Dilute hydrochloric acid qs Sodium hydroxide qs Purified water qs
製剤例２
　デスロラタジン　　　　　　　　　５ｍｇ
　リン酸二水素ナトリウム　　　　　５ｍｇ
　塩化ナトリウム　　　　　　　　　５ｍｇ
　希塩酸　　　　　　　　　　　　　　適量
　水酸化ナトリウム　　　　　　　　　適量
　精製水　　　　　　　　　　　　　　適量 Formulation Example 2
Desloratadine 5mg
Sodium dihydrogen phosphate 5mg
Sodium chloride 5mg
Dilute hydrochloric acid qs Sodium hydroxide qs Purified water qs
製剤例３
　デスロラタジン　　　　　　　２．５ｍｇ
　リン酸二水素ナトリウム　　　　　５ｍｇ
　エデト酸二ナトリウム　　　　０．１ｍｇ
　塩化ナトリウム　　　　　　　　　５ｍｇ
　希塩酸　　　　　　　　　　　　　　適量
　水酸化ナトリウム　　　　　　　　　適量
　精製水　　　　　　　　　　　　　　適量 Formulation Example 3
Desloratadine 2.5mg
Sodium dihydrogen phosphate 5mg
Edetate disodium 0.1mg
Sodium chloride 5mg
Dilute hydrochloric acid qs Sodium hydroxide qs Purified water qs
製剤例４
　デスロラタジン　　　　　　　　　５ｍｇ
　ホウ酸　　　　　　　　　　　　　１ｍｇ
　塩化ナトリウム　　　　　　　　　５ｍｇ
　希塩酸　　　　　　　　　　　　　　適量
　水酸化ナトリウム　　　　　　　　　適量
　精製水　　　　　　　　　　　　　　適量 Formulation Example 4
Desloratadine 5mg
Boric acid 1mg
Sodium chloride 5mg
Dilute hydrochloric acid qs Sodium hydroxide qs Purified water qs
製剤例５
　デスロラタジン　　　　　　　２．５ｍｇ
　ポリソルベート８０　　　　　　　１ｍｇ
　ポリエチレングリコール　　　　　１ｍｇ
　グリセリン　　　　　　　　　　　　適量
　希塩酸　　　　　　　　　　　　　　適量
　水酸化ナトリウム　　　　　　　　　適量
　精製水　　　　　　　　　　　　　　適量 Formulation Example 5
Desloratadine 2.5mg
Polysorbate 80 1mg
Polyethylene glycol 1mg
Glycerin qs Dilute hydrochloric acid qs Sodium hydroxide qs Purified water qs
製剤例６
　デスロラタジン　　　　　　　　　　１０ｍｇ
　グリセリン　　　　　　　　　　　１００ｍｇ
　ワセリン　　　　　　　　　　　　　３０ｍｇ
　パラフィン　　　　　　　　　　　　３０ｍｇ
　ポリオキシエチレン硬化ヒマシ油　　３０ｍｇ
　エデト酸ナトリウム　　　　　　　　　１ｍｇ
　塩化ナトリウム　　　　　　　　　　　５ｍｇ
　精製水　　　　　　　　　　　　　　　　適量 Formulation Example 6
Desloratadine 10mg
Glycerin 100mg
Vaseline 30mg
Paraffin 30mg
Polyoxyethylene hydrogenated castor oil 30mg
Sodium edetate 1mg
Sodium chloride 5mg
Purified water qs
［試験例］
（１）防腐効力試験
　本試験は、第１７改正日本薬局方に記載の保存効力試験法に準じて実施した。
１．被験製剤の調製
　デスロラタジン（０．２４ｇ）、リン酸二水素ナトリウム（０．５ｇ）、塩化ナトリウム（０．５ｇ）を水に溶解して、ｐＨ調節剤と水を加えて全量を１００ｍＬとし、濾過滅菌を行うことにより、実施例１の製剤を調製した。 [Test example]
(1) Preservative efficacy test This test was conducted according to the preservative efficacy test method described in the 17th revised Japanese Pharmacopoeia.
1. Preparation of Test Formulation Desloratadine (0.24 g), sodium dihydrogen phosphate (0.5 g) and sodium chloride (0.5 g) are dissolved in water, and a pH adjuster and water are added to make a total volume of 100 mL. The preparation of Example 1 was prepared by performing filtration sterilization.
実施例１
１ｍＬ中
　デスロラタジン　　　　　　　　　　２．４ｍｇ
　リン酸二水素ナトリウム　　　　　　　　５ｍｇ
　塩化ナトリウム　　　　　　　　　　　　５ｍｇ
　希塩酸　　　　　　　　　　　　　　　　　適量
　水酸化ナトリウム　　　　　　　　　　　　適量
　精製水　　　　　　　　　　　　　　　　　適量
　ｐＨ　　　　　　　　　　　　　　　　　７．０ Example 1
2.4mg desloratadine in 1mL
Sodium dihydrogen phosphate 5mg
Sodium chloride 5mg
Dilute hydrochloric acid qs Sodium hydroxide qs Purified water qs pH 7.0
　実施例１の調製方法と同様の方法にて、実施例２～４および比較例１～２の製剤を調製した。なお、比較例１で用いたレボセチリジン塩酸塩は「ザイザル（登録商標）錠５ｍｇ」の有効成分、比較例２で用いたベポタスチンベシル酸塩は「タリオン（登録商標）錠５ｍｇ」の有効成分である。これらはいずれもアレルギー性疾患治療剤として上市されている。 製 剤 The preparations 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 was an active ingredient of "Zyzar (registered trademark) tablet 5 mg", and the bepotastine besylate used in Comparative Example 2 was an active ingredient of "Talion (registered trademark) tablet 5 mg". It is. All of these are marketed as therapeutic agents for allergic diseases.
実施例２
１ｍＬ中
　デスロラタジン　　　　　　　　　　１．２ｍｇ
　リン酸二水素ナトリウム　　　　　　　　５ｍｇ
　塩化ナトリウム　　　　　　　　　　　　５ｍｇ
　希塩酸　　　　　　　　　　　　　　　　　適量
　水酸化ナトリウム　　　　　　　　　　　　適量
　精製水　　　　　　　　　　　　　　　　　適量
　ｐＨ　　　　　　　　　　　　　　　　　７．０ Example 2
1.2mg desloratadine in 1mL
Sodium dihydrogen phosphate 5mg
Sodium chloride 5mg
Dilute hydrochloric acid qs Sodium hydroxide qs Purified water qs pH 7.0
実施例３
１ｍＬ中
　デスロラタジン　　　　　　　　　　０．６ｍｇ
　リン酸二水素ナトリウム　　　　　　　　５ｍｇ
　塩化ナトリウム　　　　　　　　　　　　５ｍｇ
　希塩酸　　　　　　　　　　　　　　　　　適量
　水酸化ナトリウム　　　　　　　　　　　　適量
　精製水　　　　　　　　　　　　　　　　　適量
　ｐＨ　　　　　　　　　　　　　　　　　７．０ Example 3
0.6mg desloratadine in 1mL
Sodium dihydrogen phosphate 5mg
Sodium chloride 5mg
Dilute hydrochloric acid qs Sodium hydroxide qs Purified water qs pH 7.0
実施例４
１ｍＬ中
　デスロラタジン　　　　　　　　　　０．３ｍｇ
　リン酸二水素ナトリウム　　　　　　　　５ｍｇ
　塩化ナトリウム　　　　　　　　　　　　５ｍｇ
　希塩酸　　　　　　　　　　　　　　　　　適量
　水酸化ナトリウム　　　　　　　　　　　　適量
　精製水　　　　　　　　　　　　　　　　　適量
　ｐＨ　　　　　　　　　　　　　　　　　７．０ Example 4
0.3mg of desloratadine in 1mL
Sodium dihydrogen phosphate 5mg
Sodium chloride 5mg
Dilute hydrochloric acid qs Sodium hydroxide qs Purified water qs pH 7.0
比較例１
１ｍＬ中
　レボセチリジン塩酸塩　　　　　　２．８５ｍｇ
　　（レボセチリジンのフリー体　２．４ｍｇ相当）
　リン酸二水素ナトリウム　　　　　　　　５ｍｇ
　塩化ナトリウム　　　　　　　　　　　　５ｍｇ
　希塩酸　　　　　　　　　　　　　　　　　適量
　水酸化ナトリウム　　　　　　　　　　　　適量
　精製水　　　　　　　　　　　　　　　　　適量
　ｐＨ　　　　　　　　　　　　　　　　　７．０ Comparative Example 1
2.85 mg of levocetirizine hydrochloride in 1 mL
(2.4mg of free form of levocetirizine)
Sodium dihydrogen phosphate 5mg
Sodium chloride 5mg
Dilute hydrochloric acid qs Sodium hydroxide qs Purified water qs pH 7.0
比較例２
１ｍＬ中
　ベポタスチンベシル酸塩　　　　　２１．１ｍｇ
　　（ベポタスチンのフリー体　１５ｍｇ相当）
　リン酸二水素ナトリウム　　　　　　　　５ｍｇ
　塩化ナトリウム　　　　　　　　　　　　５ｍｇ
　希塩酸　　　　　　　　　　　　　　　　　適量
　水酸化ナトリウム　　　　　　　　　　　　適量
　精製水　　　　　　　　　　　　　　　　　適量
　ｐＨ　　　　　　　　　　　　　　　　　７．０ Comparative Example 2
Bepotastine besilate 21.1mg in 1mL
(15mg free form of Bepotastine)
Sodium dihydrogen phosphate 5mg
Sodium chloride 5mg
Dilute hydrochloric acid qs Sodium hydroxide qs Purified water qs pH 7.0
２．試験方法
　接種菌として以下の菌株を使用した。
　　細菌：
　　　大腸菌，Escherichia Coli ATCC 8739（E.coliともいう）
　　　緑膿菌，Pseudomonas aeruginosa ATCC 9027（P.aeruginosaともいう）
　　　黄色ブドウ球菌，Staphylococcus aureus ATCC 6538（S.aureusともいう）
　　酵母菌およびカビ類：
　　　カンジダ，Candida albicans ATCC 10231（C.albicansともいう）
　　　クロコウジカビ，Aspergillus brasiliensis ATCC16404（A.brasiliensisともいう） 2. Test method The following strains were used as inoculum.
Bacteria:
Escherichia coli, Escherichia Coli ATCC 8739 (also called E. coli)
Pseudomonas aeruginosa ATCC 9027 (also called P. aeruginosa)
Staphylococcus aureus ATCC 6538 (also called S. aureus)
Yeasts and molds:
Candida albicans ATCC 10231 (also called C. albicans)
Aspergillus brasiliensis ATCC16404 (also called A. brasiliensis)
　各製剤からなる試験試料中の菌液濃度が１０５～１０６個／ｍＬ（５菌種共）となるように、接種菌液を試験試料に接種した。具体的には、１０７～１０８ｃｆｕ／ｍＬとなるように接種菌液を調製し、この接種菌液を１０５～１０６ｃｆｕ／ｍＬとなるように、実施例１～４及び比較例１～２の製剤からなる試験試料に各接種菌液を接種し、均一に混合し試料とした。これらの試料を遮光下２０～２５℃に保存し、各サンプリングポイント（７日後、１４日後、又は２８日後）において、各試料からマイクロピペットで０．５ｍＬを採取し、生菌数を測定した。各サンプリングポイントでは、試料溶液の蓋を空けてサンプリングを実施し、蓋を閉める操作を行った。 The inoculated bacterial solution was inoculated to the test sample so that the concentration of the bacterial solution in the test sample composed of each preparation was 10 5 to 10 6 cells / mL (all five bacterial species). Specifically, an inoculated bacterial solution was prepared so as to have a concentration of 10 7 to 10 8 cfu / mL, and the inoculated bacterial solution was prepared so as to have a concentration of 10 5 to 10 6 cfu / mL. A test sample comprising the preparations 1 and 2 was inoculated with each inoculum and mixed uniformly to obtain a sample. These samples were stored at 20 to 25 ° C. under light shielding, and at each sampling point (after 7, 14, or 28 days), 0.5 mL of each sample was collected with a micropipette, and the viable cell count was measured. At each sampling point, sampling was performed by opening the lid of the sample solution and closing the lid.
３．試験結果及び考察
　試験結果を表１に示す。表１の試験結果は、生菌数を測定したときの菌数（Ａ）に対する接種時の菌数（Ｂ）の比（Ｂ／Ａ）の常用対数値で示しており、例えば、値が「１」の場合には、検査時の生菌数が接種菌数の１０％に減少したことを示している。 3. Test results and discussion Table 1 shows the test results. The test results in Table 1 are shown as common logarithmic values of the ratio (B / A) of the number of bacteria (B) at the time of inoculation to the number of bacteria (A) when the number of viable bacteria was measured. In the case of "1", it indicates that the viable cell count at the time of the test was reduced to 10% of the inoculated cell count.
　試験の合否判定について、細菌種（E.coli、P.aeruginosa、S.aureus）に対しては、播種７日後に１．０以上、かつ１４日後または２８日後に３．０以上であること、および真菌種（C.albicans、A.brasiliensis）に対しては、播種７日後と比較して播種１４日後または２８日後の数値が減少していないこと、をいずれも満たす時に適合とした。
Figure JPOXMLDOC01-appb-T000002
 Regarding the pass / fail judgment of the test, the bacterial species (E. coli, P. aeruginosa, S. aureus) must be 1.0 or more after 7 days from seeding and 3.0 or more after 14 days or 28 days. For fungal species (C. albicans, A. brasiliensis), it was determined that the condition was satisfied when the values were not decreased after 14 or 28 days after sowing compared to 7 days after sowing.
Figure JPOXMLDOC01-appb-T000002
　表１に示されるように、デスロラタジン又はその塩を含有する実施例１～４の製剤は、防腐剤を含有しないにもかかわらず、いずれの菌に対しても十分な防腐効力を示し、その防腐効力はデスロラタジン又はその塩がごく低濃度（０．０３％）であっても発揮された。それに対して、比較例１及び比較例２の製剤は、十分な防腐効力を有さず、特に比較例２は高濃度（有効成分量１．５％換算）であるにも関わらず、防腐効力を有さないことが示された。デスロラタジン、レボセチリジン及びベポタスチンはいずれもアレルギー性疾患治療作用を発揮する有効成分であるにも関わらず、デスロラタジンのみが化合物自体に防腐効力を特異的に有することが示された。
　これにより、デスロラタジン又はその塩を含有する本発明の医薬組成物は、塩化ベンザルコニウムのみならず、あらゆる防腐剤を含有しなくても十分な防腐効力を有することが示唆された。 As shown in Table 1, the preparations of Examples 1 to 4 containing desloratadine or a salt thereof showed a sufficient antiseptic effect against any bacteria despite containing no preservative. The preservative effect was exhibited even at very low concentrations (0.03%) of desloratadine or its salt. In contrast, the preparations of Comparative Example 1 and Comparative Example 2 did not have sufficient preservative efficacy. In particular, Comparative Example 2 had a high concentration (in terms of the active ingredient amount of 1.5%), but the preservative efficacy was high. It was shown not to have. Although desloratadine, levocetirizine, and bepotastine are all active ingredients that exhibit an allergic disease-treating action, it was shown that only desloratadine specifically has a preservative effect on the compound itself.
This suggests that the pharmaceutical composition of the present invention containing desloratadine or a salt thereof has a sufficient antiseptic effect without containing any preservatives, not only benzalkonium chloride.
（２）アレルギー性結膜炎モデルを用いた薬効評価試験　本試験では、モルモット能動感作アレルギー性結膜炎モデルにおいて、結膜炎症状スコアを判定し、本発明の製剤の治療効果を検討した。 (2) Efficacy evaluation test using allergic conjunctivitis model In this test, a conjunctivitis symptom score was determined in a guinea pig active sensitization allergic conjunctivitis model, and the therapeutic effect of the preparation of the present invention was examined.
１．被験製剤の調製
　実施例１の調製方法と同様の方法にて、実施例５～７の製剤および比較例３の基剤を調製した。 1. Preparation of Test Preparation The preparations of Examples 5 to 7 and the base of Comparative Example 3 were prepared in the same manner as in the preparation method of Example 1.
実施例５
１ｍＬ中
　デスロラタジン　　　　　　　　　　０．１ｍｇ
　リン酸二水素ナトリウム　　　　　　　　５ｍｇ
　塩化ナトリウム　　　　　　　　　　　　７ｍｇ
　希塩酸　　　　　　　　　　　　　　　　　適量
　水酸化ナトリウム　　　　　　　　　　　　適量
　精製水　　　　　　　　　　　　　　　　　適量
　ｐＨ　　　　　　　　　　　　　　　　　６．５ Example 5
0.1mg desloratadine in 1mL
Sodium dihydrogen phosphate 5mg
7mg sodium chloride
Dilute hydrochloric acid qs Sodium hydroxide qs Purified water qs pH 6.5
実施例６
１ｍＬ中
　デスロラタジン　　　　　　　　　　０．３ｍｇ
　リン酸二水素ナトリウム　　　　　　　　５ｍｇ
　塩化ナトリウム　　　　　　　　　　　　７ｍｇ
　希塩酸　　　　　　　　　　　　　　　　　適量
　水酸化ナトリウム　　　　　　　　　　　　適量
　精製水　　　　　　　　　　　　　　　　　適量
　ｐＨ　　　　　　　　　　　　　　　　　６．５ Example 6
0.3mg of desloratadine in 1mL
Sodium dihydrogen phosphate 5mg
7mg sodium chloride
Dilute hydrochloric acid qs Sodium hydroxide qs Purified water qs pH 6.5
実施例７
１ｍＬ中
　デスロラタジン　　　　　　　　　　　　１ｍｇ
　リン酸二水素ナトリウム　　　　　　　　５ｍｇ
　塩化ナトリウム　　　　　　　　　　　　７ｍｇ
　希塩酸　　　　　　　　　　　　　　　　　適量
　水酸化ナトリウム　　　　　　　　　　　　適量
　精製水　　　　　　　　　　　　　　　　　適量
　ｐＨ　　　　　　　　　　　　　　　　　６．５ Example 7
1mg desloratadine in 1mL
Sodium dihydrogen phosphate 5mg
7mg sodium chloride
Dilute hydrochloric acid qs Sodium hydroxide qs Purified water qs pH 6.5
比較例３
１ｍＬ中
　リン酸二水素ナトリウム　　　　　　　　５ｍｇ
　塩化ナトリウム　　　　　　　　　　　　７ｍｇ
　希塩酸　　　　　　　　　　　　　　　　　適量
　水酸化ナトリウム　　　　　　　　　　　　適量
　精製水　　　　　　　　　　　　　　　　　適量
　ｐＨ　　　　　　　　　　　　　　　　　６．５ Comparative Example 3
Sodium dihydrogen phosphate 5mg in 1mL
7mg sodium chloride
Dilute hydrochloric acid qs Sodium hydroxide qs Purified water qs pH 6.5
２．試験方法
（感作液の調製）
　ＯＶＡ（鶏由来卵白アルブミン）溶液（Ｓｉｇｍａ社）及び水酸化アルミニウムゲルを含有する生理食塩液を調製して、感作液とした。なお、前記感作液中のＯＶＡ及び水酸化アルミニウムゲルの濃度は、それぞれ、２０μｇ／ｍＬ及び２０ｍｇ／ｍＬとした。 2. Test method (preparation of sensitizing solution)
A physiological saline solution containing an OVA (chicken-derived ovalbumin) 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 sensitized solution were 20 μg / mL and 20 mg / mL, respectively.
（ОＶＡ能動感作アレルギー性結膜炎モデルの作製及びアレルギー反応の確認）
　イソフルラン吸入による全身麻酔下のモルモットを用いて、そのモルモットの両眼球結膜下に感作液を注射することにより、能動感作を行った。
　感作１４日以降に、生理食塩液で希釈して調製した０．０５％ＯＶＡ溶液１０μＬをモルモットの両眼に点眼することで結膜炎を惹起した。惹起３０分後に、モルモットの両眼の結膜炎症状について下記の基準に従ってスコア判定を行った。１群を６匹１２眼とし、群間で平均スコアに偏りがないように４群に群分けを行った。
＜判定基準＞
０：所見なし
１：眼球結膜の一部に浮腫又は充血が認められる状態（眼瞼には所見なし）。
２：眼球結膜全体に浮腫及び充血が認められるが、浮腫が角膜にかかっていない状態（眼瞼には所見なし）。
３：眼球結膜全体に浮腫及び充血が認められる状態。加えて、浮腫が角膜輪部の一部を覆っている状態、又は、眼瞼縁が眼球からわずかに浮いている状態のいずれか一方が認められる場合。
４：眼球結膜全体に浮腫及び充血が認められる状態。加えて、浮腫が角膜輪部の一部を覆っており、上下いずれかの眼瞼縁が眼球から明らかに浮いている場合、又は、浮腫が角膜の半分以上を覆っているが、眼瞼縁は眼球からわずかに浮いている場合。
５：眼球結膜全体に浮腫及び充血が認められる状態。加えて、浮腫が角膜の半分以上を覆っており、上下いずれかの眼瞼縁が眼球から明らかに浮いている場合、又は、浮腫が角膜にかかっており、上下両方の眼瞼縁が眼球から明らかに浮いている場合。 (Construction of VA active sensitization allergic conjunctivitis model and confirmation of allergic reaction)
Active sensitization was performed by using a guinea pig under general anesthesia by inhalation of isoflurane and injecting a sensitizing solution under the binocular conjunctiva of the guinea pig.
14 days after the sensitization, conjunctivitis was induced by instilling 10 μL of a 0.05% OVA solution prepared by diluting with a physiological saline solution into both eyes of a guinea pig. Thirty minutes after the induction, scores of the conjunctival inflammation in both eyes of the guinea pig were evaluated according to the following criteria. One group was composed of 12 mice and 12 eyes, and the groups were divided into 4 groups so that the average score was not biased among the groups.
<Judgment criteria>
0: No finding 1: A state in which edema or hyperemia is observed in a part of the bulbar conjunctiva (no finding in the eyelid).
2: Edema and hyperemia are observed throughout the bulbar conjunctiva, but edema is not applied to the cornea (no eyelids are found).
3: A state in which edema and hyperemia are observed in the entire bulbar conjunctiva. In addition, when either edema covers a part of the limbus or a state where the eyelid margin is slightly floating from the eyeball is observed.
4: A state in which edema and hyperemia are observed throughout the conjunctiva of the eye. In addition, if the edema covers part of the limbus, and either the upper or lower lid margin is clearly floating from the eyeball, or the edema covers more than half of the cornea, but the lid margin is If slightly floating from.
5: A state in which edema and congestion are observed throughout the bulbar conjunctiva. In addition, if the edema covers more than half of the cornea and either the upper or lower lid margin is clearly floating from the eyeball, or if the edema is on the cornea and both upper and lower lid margins are clearly visible from the eyeball If floating.
（薬効評価）
　アレルギー反応の確認から７日後に、薬効評価を行うため、結膜炎惹起の１５分前及び５分前に各被験製剤および基剤をモルモットの両眼にそれぞれ１０μＬずつ点眼投与を行った。さらに、生理食塩液で希釈して調製した０．１％ＯＶＡ溶液をモルモットの両眼に１０μＬずつ点眼することで結膜炎を惹起した。
　惹起３０分後に、モルモットの両眼の結膜炎症状について上記の判定基準に従ってスコア判定を行った。さらに、汎用的なデータ処理ソフトを用いて、各群における結膜炎症状スコアの平均値及び標準誤差を算出した。 (Efficacy evaluation)
Seven days after the confirmation of the allergic reaction, in order to evaluate the efficacy, 10 μL of each of the test preparations and the base was administered to both eyes of guinea pigs 15 minutes before and 5 minutes before the induction of conjunctivitis. Furthermore, conjunctivitis was induced by instilling 10 μL of a 0.1% OVA solution prepared by diluting with a physiological saline solution into both eyes of a guinea pig.
Thirty minutes after the induction, a score was determined for the conjunctivitis symptoms in both eyes of the guinea pig according to the above criteria. Furthermore, the average value and standard error of the conjunctivitis symptom score in each group were calculated using general-purpose data processing software.
３．試験結果及び考察
　試験結果を表２に示す。スコアの平均値は、各１２眼（６匹）である。
Figure JPOXMLDOC01-appb-T000003
 3. Test results and discussion Table 2 shows the test results. The average value of the scores is 12 eyes (6 animals) each.
Figure JPOXMLDOC01-appb-T000003
　表２に示されるように、デスロラタジン又はその塩を含有する実施例５～７の製剤は、アレルギー性結膜炎の治療作用を有することが示された。 As shown in Table 2, the preparations of Examples 5 to 7 containing desloratadine or a salt thereof were shown to have a therapeutic effect on allergic conjunctivitis.
　試験例の結果より、塩化ベンザルコニウムおよびその他の防腐剤を添加しなくても、デスロラタジン又はその塩を含有する医薬組成物が、防腐効力及びアレルギー性結膜炎の治療効果を奏することが示された。そのため、塩化ベンザルコニウムを含有しない、デスロラタジン又はその塩を含有する局所投与用医薬組成物を得ることができる。また、塩化ベンザルコニウムに限らず防腐剤を添加しなくても防腐効力を奏する、デスロラタジン又はその塩を含有する局所投与用医薬組成物を得ることもできる。 The results of the test examples show that, even without adding benzalkonium chloride and other preservatives, the pharmaceutical composition containing desloratadine or a salt thereof exhibits an antiseptic effect and a therapeutic effect for allergic conjunctivitis. Was. Therefore, a pharmaceutical composition for topical administration containing desloratadine or a salt thereof that does not contain benzalkonium chloride can be obtained. In addition, a pharmaceutical composition for topical administration containing desloratadine or a salt thereof, which exhibits an antiseptic effect without adding a preservative, not limited to benzalkonium chloride, can also be obtained.
　本発明は、デスロラタジン又はその塩を含有する医薬組成物であって、塩化ベンザルコニウムを含有しないことを特徴とする、局所投与用医薬組成物を提供する。さらに、本発明は、防腐剤を添加しなくても防腐効力を奏する、デスロラタジン又はその塩を含有する局所投与用医薬組成物を提供する。 (4) The present invention provides a pharmaceutical composition containing desloratadine or a salt thereof, which does not contain benzalkonium chloride, for topical administration. Further, the present invention provides a pharmaceutical composition for topical administration containing desloratadine or a salt thereof, which exhibits an antiseptic effect without adding an antiseptic.

Claims (16)

  1. 　有効成分としてデスロラタジン又はその塩を含有する医薬組成物であって、塩化ベンザルコニウムを含有しないことを特徴とする、局所投与用医薬組成物。 (4) A pharmaceutical composition for topical administration, which comprises desloratadine or a salt thereof as an active ingredient, and does not contain benzalkonium chloride.
  2. 　０．００１％（ｗ／ｖ）以上の濃度のデスロラタジン又はその塩を含有する、請求項１に記載の医薬組成物。 The pharmaceutical composition according to claim 1, which comprises desloratadine or a salt thereof at a concentration of 0.001% (w / v) or more.
  3. 　０．０１％～５％（ｗ／ｖ）の濃度のデスロラタジン又はその塩を含有する、請求項１に記載の医薬組成物。 The pharmaceutical composition according to claim 1, which comprises desloratadine or a salt thereof at a concentration of 0.01% to 5% (w / v).
  4. 　眼科用組成物、耳鼻科用組成物、吸入用組成物又は経皮吸収組成物である、請求項１～３のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 3, which is an ophthalmic composition, an otolaryngological composition, a composition for inhalation, or a transdermal absorption composition.
  5. 　点眼剤である、請求項１～４のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 4, which is an ophthalmic solution.
  6. 　点眼剤用容器がマルチドーズ型容器である、請求項５に記載の医薬組成物。 The pharmaceutical composition according to claim 5, wherein the ophthalmic container is a multidose container.
  7. 　添加剤として緩衝剤、等張化剤、ｐＨ調節剤及び安定化剤からなる群より選択される少なくとも１種を含有する、請求項１～６のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 6, further comprising at least one selected from the group consisting of a buffer, an isotonic agent, a pH adjuster, and a stabilizer as an additive.
  8. 　緩衝剤、等張化剤及びｐＨ調節剤を含有する、請求項７に記載の医薬組成物。 8. The pharmaceutical composition according to claim 7, comprising a buffer, an isotonic agent, and a pH adjuster.
  9. 　さらに安定化剤を含有する、請求項８に記載の医薬組成物。 医 薬 The pharmaceutical composition according to claim 8, further comprising a stabilizer.
  10. 　ｐＨが、４．０～８．５である、請求項１～９のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 9, wherein the pH is 4.0 to 8.5.
  11. 　ｐＨが、６．０～８．０である、請求項１～１０のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 10, wherein the pH is 6.0 to 8.0.
  12. 　防腐剤を含有しない、請求項１～１１のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 11, which does not contain a preservative.
  13. 　有効成分として０．０１％（ｗ／ｖ）以上の濃度のデスロラタジン又はその塩を含有する医薬組成物であって、添加剤として緩衝剤、等張化剤、ｐＨ調節剤及び安定化剤からなる群より選択される少なくとも１種を含有し、かつ塩化ベンザルコニウムを含有しないことを特徴とする、医薬組成物。 A pharmaceutical composition containing desloratadine or a salt thereof at a concentration of 0.01% (w / v) or more as an active ingredient, comprising a buffer, an isotonic agent, a pH adjuster, and a stabilizer as additives. A pharmaceutical composition comprising at least one member selected from the group consisting of: and no benzalkonium chloride.
  14. 　有効成分として０．０１％（ｗ／ｖ）以上の濃度のデスロラタジン又はその塩を含有する医薬組成物であって、添加剤として緩衝剤、等張化剤、ｐＨ調節剤及び安定化剤からなる群より選択される少なくとも１種を含有し、かつ防腐剤を含有しないことを特徴とする、医薬組成物。 A pharmaceutical composition containing desloratadine or a salt thereof at a concentration of 0.01% (w / v) or more as an active ingredient, comprising a buffer, an isotonic agent, a pH adjuster, and a stabilizer as additives. A pharmaceutical composition comprising at least one selected from the group consisting of: and no preservative.
  15. 　デスロラタジン又はその塩を０．０１％（ｗ／ｖ）以上の濃度で配合することで、添加剤として防腐剤を含有せずに、デスロラタジン又はその塩を含有する医薬組成物に防腐効力を付与する方法。 By blending desloratadine or a salt thereof at a concentration of 0.01% (w / v) or more, a preservative effect can be imparted to a pharmaceutical composition containing desloratadine or a salt thereof without containing a preservative as an additive. How to grant.
  16. 　デスロラタジン又はその塩を０．０１％（ｗ／ｖ）以上の濃度で配合することで、添加剤として防腐剤を含有せずに、デスロラタジン又はその塩を含有する医薬組成物の防腐効力を維持する方法。 By blending desloratadine or a salt thereof at a concentration of 0.01% (w / v) or more, the preservative effect of a pharmaceutical composition containing desloratadine or a salt thereof without containing a preservative as an additive can be obtained. How to maintain.
PCT/JP2019/024644 2018-06-22 2019-06-21 Pharmaceutical composition comprising desloratadine or salt thereof WO2019245015A1 (en)

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JP2005053825A (en) * 2003-08-04 2005-03-03 Nidek Co Ltd Composition for instillation or rhinenchysis
JP2007106777A (en) * 1999-10-08 2007-04-26 Schering Plough Corp Topical nasal treatment
WO2010021607A2 (en) * 2008-08-22 2010-02-25 Mahmut Bilgic Pharmaceutical formulation
CN101766617A (en) * 2010-01-12 2010-07-07 北京华禧联合科技发展有限公司 Compound composition of intal and Statins
JP2010523695A (en) * 2007-04-11 2010-07-15 アルコン リサーチ， リミテッド Use of inhibitors of TNFα and antihistamines to treat allergic rhinitis and allergic conjunctivitis
KR20100112293A (en) * 2009-04-09 2010-10-19 마상규 Ophthalmic compositions comprising desloratadine
CN101991574A (en) * 2009-08-27 2011-03-30 杭州赛利药物研究所有限公司 Desloratadine external preparation and preparation method thereof

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007106777A (en) * 1999-10-08 2007-04-26 Schering Plough Corp Topical nasal treatment
US20020183344A1 (en) * 2001-04-24 2002-12-05 Schleimer Robert P. Inhibition of cytokine generation
JP2005053825A (en) * 2003-08-04 2005-03-03 Nidek Co Ltd Composition for instillation or rhinenchysis
JP2010523695A (en) * 2007-04-11 2010-07-15 アルコン リサーチ， リミテッド Use of inhibitors of TNFα and antihistamines to treat allergic rhinitis and allergic conjunctivitis
WO2010021607A2 (en) * 2008-08-22 2010-02-25 Mahmut Bilgic Pharmaceutical formulation
KR20100112293A (en) * 2009-04-09 2010-10-19 마상규 Ophthalmic compositions comprising desloratadine
CN101991574A (en) * 2009-08-27 2011-03-30 杭州赛利药物研究所有限公司 Desloratadine external preparation and preparation method thereof
CN101766617A (en) * 2010-01-12 2010-07-07 北京华禧联合科技发展有限公司 Compound composition of intal and Statins

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