WO2019022225A1 - Aqueous pharmaceutical composition containing alcaftadine or salt thereof - Google Patents

Aqueous pharmaceutical composition containing alcaftadine or salt thereof Download PDF

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Publication number
WO2019022225A1
WO2019022225A1 PCT/JP2018/028216 JP2018028216W WO2019022225A1 WO 2019022225 A1 WO2019022225 A1 WO 2019022225A1 JP 2018028216 W JP2018028216 W JP 2018028216W WO 2019022225 A1 WO2019022225 A1 WO 2019022225A1
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Prior art keywords
pharmaceutical composition
aqueous pharmaceutical
salt
preservative
acid
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PCT/JP2018/028216
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French (fr)
Japanese (ja)
Inventor
隆司 森本
孝司 稲垣
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参天製薬株式会社
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Priority to JP2019532878A priority Critical patent/JP7191022B2/en
Publication of WO2019022225A1 publication Critical patent/WO2019022225A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • 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
    • 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 an aqueous pharmaceutical composition comprising alfaftadine or a salt thereof at a concentration of more than 0.15% (w / v), which is characterized by containing no preservative, hereinafter referred to as Also referred to as “the aqueous pharmaceutical composition of the present invention”.
  • Aqueous pharmaceutical compositions intended for repeated use require a certain level of antiseptic measures to prevent the growth of fungi and the like. Therefore, preservatives are usually incorporated into aqueous pharmaceutical compositions.
  • preservatives are usually incorporated into aqueous pharmaceutical compositions.
  • 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 high preservative efficacy compared to other preservatives.
  • benzalkonium chloride has a cytotoxic effect, and when it is contained in, for example, eye drops, the possibility of causing a corneal epithelial disorder increases as the exposure dose increases. Therefore, it can not be used especially for patients showing hypersensitivity to benzalkonium chloride or patients with severe corneal epithelial disorder.
  • Alcaftadine one of the H1 histamine receptor antagonists, is known to exert its therapeutic effect on the clinical symptoms of eye allergy by administering its effective dose to the eye, and has been marketed as eye drops in the United States .
  • Benzalkonium chloride is added to the eye drops as a preservative (Patent Document 1, Non-patent Document 1). That is, it is recognized that, in an aqueous pharmaceutical composition containing alkaftadine or a salt thereof, it is necessary to secure the preservative efficacy with a preservative such as benzalkonium chloride.
  • aqueous pharmaceutical composition such as an eye drop containing alcaftadine or a salt thereof, to which no preservative is added.
  • the aqueous pharmaceutical composition marketed for example, the eyedrops which the preservative is not added in the eyedrops, is known, they are a unit dose type (single use type), or preservative free Generally, those stored in a container (a container having a special structure for exerting antiseptic effect) are generally known, and there is hardly known an eye drop such that the active ingredient itself exerts antiseptic effect. In addition, it is not known at all that alkaftadine or its salt itself has preservative efficacy.
  • the inventors of the present invention have conducted intensive studies to find an aqueous pharmaceutical composition containing alkaftadine or a salt thereof which exhibits antiseptic efficacy even if no preservative is added.
  • the inventors have found that by setting the concentration of the salt to more than 0.15% (w / v), sufficient preservative efficacy can be obtained without containing a preservative, leading to the present invention.
  • the present invention provides the following. (1) An aqueous pharmaceutical composition containing an alkaftadine or a salt thereof at a concentration of more than 0.15% (w / v) as an active ingredient, which is characterized by containing no preservative.
  • the aqueous pharmaceutical composition according to (1) which contains at least one selected from the group consisting of a buffer, an isotonicity agent, a pH regulator and a stabilizer as an additive.
  • the aqueous pharmaceutical composition according to (1) or (2) which contains a buffer, an isotonicity agent and a pH adjuster as additives.
  • the aqueous pharmaceutical composition according to (3) which further contains a stabilizer.
  • the aqueous pharmaceutical composition according to any one of (1) to (5) which contains alkaftadine or a salt thereof at a concentration of 0.25% to 5% (w / v).
  • the aqueous pharmaceutical composition according to any one of (1) to (6) which is an ophthalmic composition, an otolaryngological composition, a composition for inhalation or a composition for percutaneous absorption.
  • the preservative is selected from the group consisting of benzalkonium chloride, benzalkonium bromide, benzethonium chloride, chlorhexidine or salts thereof, sorbic acid or salts thereof, methyl parahydroxybenzoate, propyl parahydroxybenzoate and chlorobutanol
  • (11) The pharmaceutical composition according to any one of (1) to (7), wherein the administration route is dermal administration or transdermal administration.
  • (12) The pharmaceutical composition according to any one of (1) to (7), wherein the administration route is administration close to the eye.
  • the pharmaceutical composition according to (12), wherein the administration in the vicinity of the eye is an application to eyelid skin.
  • the dosage form is selected from the group consisting of an ointment, cream, lotion, gel, liniment, transdermal preparation, patch, spray and injection, (1) to (1) 7) The pharmaceutical composition according to any one of (11) to (13).
  • An aqueous pharmaceutical composition comprising alkaftadine or a salt thereof at a concentration of more than 0.15% (w / v) as an active ingredient, which comprises, as an additive, a buffer, an isotonicity agent, a pH adjuster and a stabilizer.
  • An aqueous pharmaceutical composition containing alcaftadine or a salt thereof at a concentration of more than 0.15% (w / v) as an active ingredient which comprises, as an additive, a buffer, a tonicity agent, a pH regulator and a stabilizer.
  • An aqueous pharmaceutical composition comprising at least one member selected from the group consisting of agents and having preservative efficacy without containing a preservative.
  • each structure of said (1) to (18) can select 2 or more arbitrarily, and can combine them.
  • the present invention also provides the following. (19) A method for treating and / or treating allergic diseases, which comprises administering a therapeutically effective amount of the aqueous pharmaceutical composition according to any of (1) to (16) to a patient in need of such treatment. How to prevent.
  • the present invention can provide an aqueous pharmaceutical composition containing alcaftadine or a salt thereof that exhibits preservative efficacy without the addition of a preservative.
  • alkaftadine is a chemical name of 6,11-Dihydro-11- (1-methyl-4-piperidinylidene) -5H-imidazo [2,1-b] [3] benzazepine-3-carboxaldehyde. And a compound of the following formula: It is a compound represented by
  • the alkaftadine contained may be a salt, and is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • the salt include salts with inorganic acids and salts with organic acids.
  • salts with inorganic acids salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like can be mentioned.
  • the contained alpaftadine or a salt thereof may be in the form of a hydrate or a solvate.
  • the content of alkaftadine or a salt thereof may be 0.15% (w / v) or more, preferably 0.25% (w / v) or more, and the upper limit thereof is the effectiveness of the pharmaceutical.
  • the amount used may be, for example, 5% (w / v), preferably 2.5% (w / v), more preferably 1% (w / v), further preferably 0.5. It is% (w / v).
  • the content of alkaftadine or a salt thereof is preferably more than 0.15% (w / v) to 5% (w / v), more preferably 0.25 to 5% (w / v), 0.25 -2.5% (w / v) is more preferred, 0.25-1% (w / v) is even more preferred, 0.25-0.5% (w / v) is particularly preferred.
  • these values are the content of the salt of alcaftadine.
  • % (W / v) means the mass (g) of the subject component (here, alcaftadine or a salt thereof) contained in 100 mL of the aqueous pharmaceutical composition of the present invention.
  • the subject component here, alcaftadine or a salt thereof
  • the preservative is benzalkonium chloride, benzalkonium bromide, benzethonium chloride, chlorhexidine or a salt thereof, sorbic acid or a salt thereof, methyl parahydroxybenzoate, propyl parahydroxybenzoate or chlorobutanol.
  • chlorhexidine or a salt thereof include chlorhexidine, chlorhexidine gluconate, chlorhexidine hydrochloride, chlorhexidine acetate and the like.
  • sorbic acid or a salt thereof sorbic acid, sodium sorbate, potassium sorbate and the like can be mentioned.
  • preservative-free means that the aqueous pharmaceutical composition does not substantially contain the above-mentioned preservative.
  • substantially free of preservatives means that the preservatives are not contained, or that the preservatives are contained in a range that does not exhibit the preservative efficacy required for pharmaceutical compositions. Is intended.
  • having preservative efficacy refers to the action of preventing the growth and growth of microorganisms such as bacteria and fungi, and "having preservative efficacy without containing preservatives” means an aqueous pharmaceutical composition. It has antiseptic efficacy even if it does not contain the above-mentioned preservative.
  • the degree of antiseptic efficacy of the aqueous pharmaceutical composition can be confirmed, for example, by conducting a test according to the preservation efficacy test method described in the 17th revised Japanese Pharmacopoeia, and preferably the 17th revised Japan It refers to preservative efficacy compatible with the test based on the preservation efficacy test method described in the pharmacopoeia.
  • the aqueous pharmaceutical composition of the present invention can be administered orally or parenterally (eg, topically).
  • the parenteral administration route of the aqueous pharmaceutical composition of the present invention includes pharmaceutically acceptable topical administration route, for example, topical administration to the eye (for example, eye drop administration), nasal administration (transnasal) administration, topical application to the ear Administration (for example, ear drop administration), inhalation administration, spray administration, transdermal administration, dermal administration, injection administration and the like.
  • the aqueous pharmaceutical composition of the present invention can be used as an ophthalmic preparation, an otolaryngological preparation, an inhalation preparation, a percutaneous absorption preparation, and the dosage form is particularly limited as long as it can be used as a pharmaceutical. It is not a thing.
  • orally administered agents such as solution, suspension, eye drops, nasal drops, ear drops, inhalant, (inhalable powder, inhalable liquid, inhalable aerosol), ointment, cream , Gel, transdermal preparation, patch (tape, patch), external solution (lotion, liniment), external solid (external powder), spray (pump spray, external aerosol), Locally administered agents such as injections (transfusions, implanted injections, sustained injections) and the like can be mentioned.
  • the eye drop, nasal drop, ear drop, inhalant, cream, lotion, patch, ophthalmic transdermal preparation or ophthalmic injection is preferred, and eye drops or ophthalmic injection is more preferred. More preferably, it is an eye drop.
  • These can be prepared according to the usual methods in the art.
  • the aqueous pharmaceutical composition of the present invention may optionally contain a pharmaceutical additive.
  • a pharmaceutical additive for example, a buffering agent, a tonicity agent, a thickening agent, a surfactant, and the like to satisfy the requirements as an ophthalmic composition, an otolaryngological composition, an inhalable composition, and a transdermal absorption composition.
  • 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 combination as appropriate, and an appropriate amount can be blended.
  • buffers that can be incorporated into the aqueous 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 Its salts, ⁇ -aminocaproic acid, trometamol and the like may be mentioned, and these may be hydrates or solvates.
  • phosphoric acid or salts thereof include phosphoric acid, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, etc. It may be a hydrate.
  • the boric acid or a salt thereof includes boric acid, sodium borate, potassium borate and the like, and may be a hydrate of these.
  • Citric acid or a salt thereof includes citric acid, sodium citrate, disodium citrate and the like, and may be a hydrate of these.
  • Acetic acid or a salt thereof includes acetic acid, sodium acetate, potassium acetate and the like, and may be a hydrate of these.
  • Carbonic acid or a salt thereof includes carbonic acid, sodium carbonate, sodium hydrogencarbonate and the like, and may be a hydrate of these.
  • tartaric acid or a salt thereof tartaric acid, sodium tartrate, potassium tartrate and the like can be mentioned, and their hydrates may be used.
  • the buffer is more preferably phosphoric acid or a salt thereof, boric acid or a salt thereof, further preferably phosphoric acid or a salt thereof, sodium dihydrogenphosphate, phosphorus Particular preference is given to disodium hydrogen oxide or hydrates thereof. Also, two or more buffers may be used together.
  • the content of the buffer in the case of incorporating the buffer into the aqueous pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of buffer etc., but preferably 0.001 to 10% (w / v), 0.01 to 5% (w / v) is more preferable, 0.1 to 3% (w / v) is more preferable, and 0.2 to 1.5% (w / v) is most preferable.
  • tonicity agents examples include ionic tonicity agents, non-ionic tonicity agents, and the like.
  • examples of the ionic tonicity agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride and the like.
  • the nonionic tonicity agent glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose and the like can be mentioned.
  • the tonicity agent is more preferably an ionic tonicity agent, particularly preferably sodium chloride.
  • tonicity agents may be used together.
  • the content of the tonicity agent in the case of incorporating the tonicity agent into the aqueous pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of tonicity agent etc., but it is 0.001 to 10% (w / V) is preferred, 0.01 to 5% (w / v) is more preferred, 0.1 to 2% (w / v) is more preferred, 0.2 to 1% (w / v) is most preferred .
  • thickening agents which can be incorporated into the aqueous pharmaceutical composition of the present invention include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium And hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, carboxymethyl ethyl cellulose, cellulose acetate phthalate, polyvinyl pyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyethylene glycol, sodium hyaluronate and the like.
  • the content of the thickening agent in the case of incorporating the thickening agent into the aqueous pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the thickening agent, etc., but 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 more preferable.
  • surfactants which can be incorporated into the aqueous pharmaceutical composition of the present invention include cationic surfactants, anionic surfactants, nonionic surfactants and the like.
  • cationic surfactants include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyl diethylamine salts, fatty acid polyamine condensates, alkyl imidazolines, 1-acylaminoethyl-2 And -alkyl imidazoline, 1-hydroxy ethyl 2-alkyl imidazoline and the like.
  • benzalkonium chloride has the property of a cationic surfactant, but it is not included.
  • anionic surfactants include phosphate lipids such as lecithin.
  • nonionic surfactants include polyoxyethylene fatty acid esters such as polyoxyl stearate and the like; polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, polysorbate 65 and the like Polyoxyethylene sorbitan fatty acid ester; polyoxyethylene hydrogenated castor oil such as polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60; polyoxyl 5 castor oil Polyoxyl castor oil such as polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 castor oil, etc .; polyoxyethylene (160) Lyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol,
  • the content of the surfactant in the case of incorporating the surfactant into the aqueous pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the surfactant, etc., but it is 0.01 to 10% (w / V) is preferable, 0.05 to 5% (w / v) is more preferable, 0.05 to 2% (w / v) is further preferable, and 0.05 to 0.2% (w / v) is Particularly preferred.
  • Examples of stabilizers that can be incorporated into the aqueous pharmaceutical composition of the present invention include edetic acid or salts thereof.
  • Examples of edetic acid or salts thereof include edetic acid, disodium edetate, tetrasodium edetate and the like.
  • the content of the stabilizer in the case of incorporating the stabilizer into the aqueous pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the stabilizer etc., but 0.001 to 5% (w / v) Is preferred, 0.01 to 3% (w / v) is more preferred, and 0.1 to 2% (w / v) is even more preferred.
  • antioxidants examples include ascorbic acid, tocopherol, dibutylhydroxytoluene, sodium sulfite and the like.
  • the content of the antioxidant in the case of incorporating the antioxidant into the aqueous pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the antioxidant etc., but it is 0.001 to 5% (w / v) Is preferred, 0.01 to 3% (w / v) is more preferred, and 0.1 to 2% (w / v) is even more preferred.
  • the pH adjuster which can be incorporated into the aqueous pharmaceutical composition of the present invention is an acid or a base.
  • the acid include hydrochloric acid, phosphoric acid, citric acid, acetic acid and the like
  • the base include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate and the like.
  • the pH of the aqueous 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 aqueous pharmaceutical composition may be within the range acceptable for the ophthalmic preparation, preferably 4.0 to 8.5, 0 to 8.0 is more preferable, 6.5 to 7.5 is more preferable, and 6.7 to 7.3 is particularly preferable. Also, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3 are even more preferred.
  • the osmotic pressure ratio of the aqueous pharmaceutical composition of the present invention is preferably in the range of 0.5 to 2.0.
  • the osmotic pressure ratio of the aqueous pharmaceutical composition may be within the range acceptable for the ophthalmic preparation, for example, 0.5 to 2.0. 0.7 to 1.6 is preferable, 0.8 to 1.4 is more preferable, and 0.9 to 1.2 is more preferable.
  • the aqueous pharmaceutical composition refers to a pharmaceutical composition containing water.
  • the content of water contained in the aqueous pharmaceutical composition of the present invention is not particularly limited as long as it can be used as a pharmaceutical composition, but 10% (w / v) based on the total weight of the aqueous pharmaceutical composition. Or more is preferable, 30% (w / v) or more is more preferable, and 50% (w / v) or more is more preferable. In particular, it is preferably 70% (w / v) or more, more preferably 90% (w / v) or more, and still more preferably 95% (w / v) or more.
  • the aqueous pharmaceutical composition of the present invention may have all the components dissolved or partially suspended, and may be in the form of an emulsion or semisolid.
  • the aqueous pharmaceutical composition of the present invention is more preferably in the form of a solution in which all the components are dissolved, and most preferably in the form of an aqueous solution.
  • the solvent or dispersion medium is, but not limited to, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol etc.), preferably water.
  • the aqueous pharmaceutical composition of the present invention is an emulsion
  • it is a water-in-oil emulsion (even an oil-in-water emulsion (emulsion comprising an aqueous phase as a continuous phase and an aqueous phase and dispersed oily droplets)).
  • the oil phase may be an emulsion composed of an oil and dispersed aqueous droplets as the continuous phase.
  • the average size of the oily droplets or aqueous droplets is 20 to 3000 nm, preferably 30 to 1000 nm, more preferably 50 to 600 nm, and still more preferably 100 to 300 nm.
  • the oil phase of the oil phase thereof include medium- or long-chain triglycerides such as triglycerides, monoglycerides and diglycerides, vegetable oils such as castor oil and sesame oil, or paraffin hydrocarbons Etc. mineral oil etc. are mentioned.
  • the amount of the oil phase in the emulsion is, for example, 0.1 to 50% (w / v), preferably 1 to 30% (w / v) in the case of an oil-in-water emulsion.
  • aqueous pharmaceutical composition of the present invention When the aqueous pharmaceutical composition of the present invention is an emulsion, it takes advantage of its physicochemical properties to produce ointments, creams, lotions, gels, liniments, transdermal preparations, tapes, patches, It may be used for external powder, pump spray, external aerosol and the like.
  • the container for containing the aqueous pharmaceutical composition is not particularly limited to the size and shape of the container body.
  • the container for containing the aqueous pharmaceutical composition is preferably an eye drop container, and the eye drop container is a multi-dose container, a single dose unit dose container
  • PFMD Preservative Free Multi Dose
  • a multi-dose container is particularly preferable because the aqueous pharmaceutical composition of the present invention has preservative efficacy.
  • a multi-dose type container is a container in which opening and closing of a cap and the like can be freely performed for the purpose of multiple use, can be used for a certain period after opening, and is easy to carry.
  • a multidose aqueous pharmaceutical composition refers to an aqueous pharmaceutical composition contained in a multidose container.
  • the material of the container for containing the aqueous pharmaceutical composition is not particularly limited as long as it conforms to the form of the container, and resin containers, aluminum containers, glass containers, etc. may be mentioned.
  • 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 Etc.
  • polyethylene is classified according to its density and includes low density polyethylene (LDPE), medium density polyethylene (MDPE), high density polyethylene (HDPE) and the like.
  • the aqueous pharmaceutical composition of the present invention may contain a pharmaceutically active ingredient other than alcaftadine or a salt thereof, unless otherwise specified.
  • a pharmaceutically active ingredient other than alcaftadine or a salt thereof, unless otherwise specified.
  • the aqueous pharmaceutical composition of the present invention when it is an ophthalmic composition, it may contain a pharmaceutically active ingredient to be used for eye drops other than alkaftadine or a salt thereof.
  • other pharmaceutically active ingredients other than alcaftadine or a salt thereof for example, anti-inflammatory agent, antibacterial agent, antiviral agent, vitamin agent, vasoconstrictor, mydriatic agent, miotic agent, intraocular pressure reducing agent, dry eye treatment Agents, local anesthetics and the like.
  • Other pharmaceutically active ingredients may be formulated, for example, in an amount of 0.001 to 5% (w / v) based on the total weight of the aqueous pharmaceutical composition. Moreover, you
  • the aqueous pharmaceutical composition of the present invention is useful as a therapeutic agent for allergic diseases.
  • Treatment of allergic disease includes any treatment (eg, amelioration, reduction, suppression of progression, etc.) of the allergic condition and its prevention.
  • the aqueous pharmaceutical composition of the present invention is more preferably used as a therapeutic agent for ophthalmic allergic diseases, and particularly useful as a therapeutic agent for allergic conjunctivitis.
  • Treatment of allergic conjunctivitis includes all treatments (eg, amelioration, reduction, suppression of progression, etc.) of allergic conjunctivitis and its symptoms and the prevention thereof.
  • patient means not only human but also other animals such as dogs, cats, horses and the like.
  • the patient is preferably a mammal, more preferably a human.
  • 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, etc., as compared to an untreated subject.
  • the aqueous pharmaceutical composition of the present invention When the aqueous pharmaceutical composition of the present invention is administered, it is not particularly limited to the dosage regimen as long as it is sufficient to produce the desired medicinal effect.
  • the aqueous pharmaceutical composition of the present invention is an ophthalmic composition, it is divided into one drop once a day, 1 to 6 times a day, preferably 1 to 4 times a day, more preferably 1 to 2 times a day It can be instilled and can be used even when wearing a contact lens.
  • the contact lens may be a hard contact lens or a soft contact lens.
  • a soft contact lens a contact lens which has hydroxyethyl methacrylate as a main component, a silicone hydrogel contact lens, etc. are mentioned, for example.
  • the type of the soft contact lens to which the present invention is applied is not particularly limited, and may be any of ionic, nonionic, water-containing or non-water-containing.
  • it is applicable to all commercially available soft contact lenses such as daily disposable lenses, one week disposable lenses, and two week disposable lenses.
  • the aqueous pharmaceutical composition of the present invention is a composition for nasal use, it is possible for one drop to several drops, or one spray to several sprays, 1 to 6 times a day, preferably 1 to a day. It can be instilled four times, more preferably once to three times a day, and when the aqueous pharmaceutical composition of the present invention is a composition for eardrops, one drop to several drops per day, one day It can be divided into 1 to 6 times, preferably 1 to 4 times a day, more preferably 1 to 3 times a day, and when the aqueous pharmaceutical composition of the present invention is an inhalable composition, It can be inhaled by dividing into one spray to several sprays, 1 to 6 times a day, preferably 1 to 4 times a day, more preferably 1 to 3 times a day.
  • the pharmaceutical composition of the present invention is an ophthalmic transdermal absorption type preparation, 1 mg to 1 g of once administered 1 to 4 times a day, preferably twice a day, more
  • the method for imparting preservative efficacy to the aqueous pharmaceutical composition of the present invention comprises incorporating alkaftadine or a salt thereof into the aqueous pharmaceutical composition.
  • the method of maintaining the preservative efficacy of the aqueous pharmaceutical composition of the present invention comprises incorporating alkaftadine or a salt thereof into the aqueous pharmaceutical composition.
  • Formulation example 1 Alcaftadine 2.5 mg Sodium dihydrogen phosphate 5 mg Sodium chloride 5 mg Diluted hydrochloric acid, appropriate amount Sodium hydroxide, appropriate amount Purified water, appropriate amount
  • Formulation example 2 Alcaftadine 5 mg Sodium dihydrogen phosphate 5 mg Sodium chloride 5 mg Diluted hydrochloric acid, appropriate amount Sodium hydroxide, appropriate amount Purified water, appropriate amount
  • Formulation example 3 Alcaftadine 2.5 mg Sodium dihydrogen phosphate 5 mg Disodium edetate 0.1 mg Sodium chloride 5 mg Diluted hydrochloric acid, appropriate amount Sodium hydroxide, appropriate amount Purified water, appropriate amount
  • Formulation example 4 Alcaftadine 5 mg 1 mg boric acid Sodium chloride 5 mg Diluted hydrochloric acid, appropriate amount Sodium hydroxide, appropriate amount Purified water, appropriate amount
  • Formulation example 5 Alcaftadine 2.5 mg Polysorbate 80 1 mg Polyethylene glycol 1 mg Glycerin Appropriate amount Diluted hydrochloric acid Suitable amount Sodium hydroxide Appropriate amount Purified water Appropriate amount
  • Antiseptic efficacy test This test was conducted according to the preservation efficacy test method described in the 17th revised Japanese Pharmacopoeia. 1. Preparation of test preparation Alkaftadine (0.15 g), sodium dihydrogen phosphate (0.3 g) and sodium chloride (0.3 g) are dissolved in water and sterilized by filtration, pH adjuster and water are added to obtain the total amount. The formulation of Example 1 was prepared by adjusting to 60 g.
  • Example 1 Alcaftadine 2.5mg in 1g Sodium dihydrogen phosphate 5 mg Sodium chloride 5 mg Diluted hydrochloric acid, appropriate amount Sodium hydroxide, appropriate amount Purified water, appropriate amount pH 7.0
  • Example 2 and Comparative Examples 1 to 4 were prepared in the same manner as the preparation method of Example 1.
  • levocetirizine hydrochloride used in Comparative Example 3 is an active ingredient of "Zysal (registered trademark) tablet 5 mg”
  • Bepotastine besilate used in Comparative Example 4 is 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 Alcaftadine 5mg in 1g Sodium dihydrogen phosphate 5 mg Sodium chloride 5 mg Diluted hydrochloric acid, appropriate amount Sodium hydroxide, appropriate amount Purified water, appropriate amount pH 7.0
  • Comparative example 2 Alcaftadine 1.5mg in 1g Sodium dihydrogen phosphate 5 mg Sodium chloride 5 mg Diluted hydrochloric acid, appropriate amount Sodium hydroxide, appropriate amount Purified water, appropriate amount pH 7.0
  • Comparative example 4 1 g of bepotastine besilate 21.1 mg (Equivalent to 15 mg of free body of Bepotastine) Sodium dihydrogen phosphate 5 mg Sodium chloride 5 mg Diluted hydrochloric acid, appropriate amount Sodium hydroxide, appropriate amount Purified water, appropriate amount pH 7.0
  • Bacteria Escherichia coli, Escherichia Coli ATCC 8739 (also referred to as E. coli) Pseudomonas aeruginosa ATCC 9027 (also referred to as P. aeruginosa) Staphylococcus aureus, Staphylococcus aureus ATCC 6538 (also referred to as S. aureus) Yeast and mold: Candida albicans ATCC 10231 (also referred to as C. albicans) Aspergillus niger, Aspergillus brasiliensis ATCC 16404 (also referred to as A. brasiliensis)
  • the inoculum was inoculated to the test sample such that the concentration of the culture solution in the test sample consisting of each preparation was 10 5 to 10 6 cells / mL (5 types of bacteria). Specifically, the inoculum is prepared to be 10 7 to 10 8 cfu / mL, and this inoculum is adjusted to 10 5 to 10 6 cfu / mL according to Examples 1 to 2 and Comparative Example. Test samples consisting of 1 to 4 formulations were inoculated with each inoculum, mixed uniformly, and used as samples. These samples were stored at 20-25 ° C. in the dark, and 1 mL was collected from each sample with a micropipette at each sampling point (7, 14, or 28 days), and the viable cell count was measured. At each sampling point, the lid of the sample solution was removed, sampling was performed, and the lid was closed.
  • Test Results and Discussion The test results are shown in Table 1.
  • the test results in Table 1 show the common logarithm value of the ratio (B / A) of the number of bacteria (B) at inoculation to the number of bacteria (A) when the number of viable bacteria is measured, for example, the value In the case of 1 ", it indicates that the number of viable bacteria at the time of examination decreased to 10% of the number of inoculated bacteria.
  • the pass / fail judgment of the test for bacterial species (E. coli, P. aeruginosa, S. aureus), 1.0 or more 7 days after sowing, and 3.0 or more after 14 or 28 days, And for fungal species (C. albicans, A. brasiliensis), the values after 14 days or 28 days after sowing were not reduced compared with 7 days after sowing, and it was considered as satisfying when satisfying both.
  • aqueous pharmaceutical composition of the present invention containing alcaftadine or a salt thereof at a concentration of more than 0.15% (w / v) can be used repeatedly by opening and closing the container without containing a preservative. It was suggested that there is.
  • the present invention provides an aqueous pharmaceutical composition containing alkaftadine or a salt thereof at a concentration of more than 0.15% (w / v), which is characterized by containing no preservative. .

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Abstract

The present invention provides an aqueous pharmaceutical composition which contains alcaftadine or a salt thereof at a concentration of more than 0.15% (w/v), and which is characterized by not containing an antiseptic agent.

Description

アルカフタジン又はその塩を含有する水性医薬組成物Aqueous pharmaceutical composition containing alcaftadine or a salt thereof
　本発明は、０．１５％（ｗ／ｖ）超の濃度のアルカフタジン又はその塩を含有する水性医薬組成物であって、防腐剤を含有しないことを特徴とする、水性医薬組成物（以下、「本発明の水性医薬組成物」ともいう）に関する。 The present invention relates to an aqueous pharmaceutical composition comprising alfaftadine or a salt thereof at a concentration of more than 0.15% (w / v), which is characterized by containing no preservative, hereinafter referred to as Also referred to as “the aqueous pharmaceutical composition of the present invention”.
　繰り返しの使用を想定する水性医薬組成物は、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、水性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、防腐剤としてベンザルコニウム塩化物が使用される。ベンザルコニウム塩化物は水溶性であり、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、ベンザルコニウム塩化物には細胞障害作用があり、例えば点眼剤に含有される場合、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、特にベンザルコニウム塩化物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。 Aqueous pharmaceutical compositions intended for repeated use require a certain level of antiseptic measures to prevent the growth of fungi and the like. Therefore, preservatives are usually incorporated into aqueous pharmaceutical compositions. 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 high preservative efficacy compared to other preservatives. However, benzalkonium chloride has a cytotoxic effect, and when it is contained in, for example, eye drops, the possibility of causing a corneal epithelial disorder increases as the exposure dose increases. Therefore, it can not be used especially for patients showing hypersensitivity to benzalkonium chloride or patients with severe corneal epithelial disorder.
　Ｈ１ヒスタミン受容体拮抗薬の一つであるアルカフタジンは、その有効量を眼に投与することにより眼アレルギーの臨床症状の治療効果を奏することが知られており、米国において点眼剤として上市されている。その点眼剤には防腐剤としてベンザルコニウム塩化物が添加されている（特許文献１、非特許文献１）。つまり、アルカフタジン又はその塩を含有する水性医薬組成物では、ベンザルコニウム塩化物等の防腐剤で、防腐効力を担保する必要があると認識されている。一方で、防腐剤が添加されていない、アルカフタジン又はその塩を含有する点眼剤等の水性医薬組成物は一切知られていない。 Alcaftadine, one of the H1 histamine receptor antagonists, is known to exert its therapeutic effect on the clinical symptoms of eye allergy by administering its effective dose to the eye, and has been marketed as eye drops in the United States . Benzalkonium chloride is added to the eye drops as a preservative (Patent Document 1, Non-patent Document 1). That is, it is recognized that, in an aqueous pharmaceutical composition containing alkaftadine or a salt thereof, it is necessary to secure the preservative efficacy with a preservative such as benzalkonium chloride. On the other hand, there is no known aqueous pharmaceutical composition such as an eye drop containing alcaftadine or a salt thereof, to which no preservative is added.
　なお、上市されている水性医薬組成物、例えば点眼剤において、防腐剤が添加されていない点眼剤は知られているが、それら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り、有効成分自身が防腐効力を発揮するような点眼剤はほとんど知られていない。また、アルカフタジン又はその塩自身が防腐効力を有することは一切知られていない。 In addition, although the aqueous pharmaceutical composition marketed, for example, the eyedrops which the preservative is not added in the eyedrops, is known, they are a unit dose type (single use type), or preservative free Generally, those stored in a container (a container having a special structure for exerting antiseptic effect) are generally known, and there is hardly known an eye drop such that the active ingredient itself exerts antiseptic effect. In addition, it is not known at all that alkaftadine or its salt itself has preservative efficacy.
特表第２００９－５３３３３３号公報Japanese Patent Publication No. 2009-533333
　したがって、防腐剤が添加されていなくても防腐効力を奏する、アルカフタジン又はその塩を含有する水性医薬組成物を提供することは興味深い課題である。 Therefore, it is an interesting subject to provide an aqueous pharmaceutical composition containing alkaftadine or a salt thereof that exerts preservative efficacy even without the addition of a preservative.
　本発明者らは、防腐剤が添加されていなくても防腐効力を奏する、アルカフタジン又はその塩を含有する水性医薬組成物を見出すために鋭意研究を行なったところ、水性医薬組成物中のアルカフタジン又はその塩の濃度を０．１５％（ｗ／ｖ）超とすることにより、防腐剤を含有することなく、十分な防腐効力が得られることを見出し、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０．１５％（ｗ／ｖ）超の濃度のアルカフタジン又はその塩を含有する水性医薬組成物であって、防腐剤を含有しないことを特徴とする、水性医薬組成物。
（２）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）に記載の水性医薬組成物。
（３）添加剤として緩衝剤、等張化剤及びｐＨ調節剤を含有する、（１）または（２）に記載の水性医薬組成物。
（４）さらに安定化剤を含有する、（３）に記載の水性医薬組成物。
（５）５％（ｗ／ｖ）以下の濃度のアルカフタジン又はその塩を含有する、（１）～（４）のいずれかに記載の水性医薬組成物。
（６）０．２５％～５％（ｗ／ｖ）の濃度のアルカフタジン又はその塩を含有する、（１）～（５）のいずれかに記載の水性医薬組成物。
（７）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）～（６）のいずれかに記載の水性医薬組成物。
（８）点眼剤である、（１）～（７）のいずれかに記載の水性医薬組成物。
（９）マルチドーズ型水性医薬組成物である、（１）～（８）のいずれかに記載の水性医薬組成物。
（１０）防腐剤が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及びクロロブタノールからなる群より選択される、（１）～（９）のいずれかに記載の水性医薬組成物。
（１１）投与経路が、皮膚上投与又は経皮投与である、（１）～（７）のいずれかに記載の医薬組成物。
（１２）投与経路が、眼の近傍への投与である、（１）～（７）のいずれかに記載の医薬組成物。
（１３）眼の近傍への投与が、眼瞼皮膚への塗布である、（１２）に記載の医薬組成物。
（１４）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、スプレー剤及び注射剤からなる群より選択される、（１）～（７）および（１１）～（１３）のいずれかに記載の医薬組成物。
（１５）有効成分として０．１５％（ｗ／ｖ）超の濃度のアルカフタジン又はその塩を含有する水性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、防腐剤を含有しない、水性医薬組成物。
（１６）有効成分として０．１５％（ｗ／ｖ）超の濃度のアルカフタジン又はその塩を含有する水性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、防腐剤を含有することなく防腐効力を有する、水性医薬組成物。
（１７）アルカフタジン又はその塩を０．１５％（ｗ／ｖ）超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、アルカフタジン又はその塩を含有する水性医薬組成物に防腐効力を付与する方法。
（１８）アルカフタジン又はその塩を０．１５％（ｗ／ｖ）超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、アルカフタジン又はその塩を含有する水性医薬組成物に防腐効力を維持する方法。
　なお、前記（１）から（１８）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。
　さらに、本発明は以下も提供する。
（１９）治療が必要な患者に、治療上の有効量の（１）～（１６）のいずれかに記載の水性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。
（２０）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）～（１６）のいずれかに記載の水性医薬組成物。
（２１）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）～（１６）のいずれかに記載の水性医薬組成物の使用。 The inventors of the present invention have conducted intensive studies to find an aqueous pharmaceutical composition containing alkaftadine or a salt thereof which exhibits antiseptic efficacy even if no preservative is added. The inventors have found that by setting the concentration of the salt to more than 0.15% (w / v), sufficient preservative efficacy can be obtained without containing a preservative, leading to the present invention. Specifically, the present invention provides the following.
(1) An aqueous pharmaceutical composition containing an alkaftadine or a salt thereof at a concentration of more than 0.15% (w / v) as an active ingredient, which is characterized by containing no preservative.
(2) The aqueous pharmaceutical composition according to (1), which contains at least one selected from the group consisting of a buffer, an isotonicity agent, a pH regulator and a stabilizer as an additive.
(3) The aqueous pharmaceutical composition according to (1) or (2), which contains a buffer, an isotonicity agent and a pH adjuster as additives.
(4) The aqueous pharmaceutical composition according to (3), which further contains a stabilizer.
(5) The aqueous pharmaceutical composition according to any one of (1) to (4), which contains alcaftadine or a salt thereof at a concentration of 5% (w / v) or less.
(6) The aqueous pharmaceutical composition according to any one of (1) to (5), which contains alkaftadine or a salt thereof at a concentration of 0.25% to 5% (w / v).
(7) The aqueous pharmaceutical composition according to any one of (1) to (6), which is an ophthalmic composition, an otolaryngological composition, a composition for inhalation or a composition for percutaneous absorption.
(8) The aqueous pharmaceutical composition according to any one of (1) to (7), which is an eye drop.
(9) The aqueous pharmaceutical composition according to any one of (1) to (8), which is a multidose aqueous pharmaceutical composition.
(10) The preservative is selected from the group consisting of benzalkonium chloride, benzalkonium bromide, benzethonium chloride, chlorhexidine or salts thereof, sorbic acid or salts thereof, methyl parahydroxybenzoate, propyl parahydroxybenzoate and chlorobutanol The aqueous pharmaceutical composition according to any one of (1) to (9).
(11) The pharmaceutical composition according to any one of (1) to (7), wherein the administration route is dermal administration or transdermal administration.
(12) The pharmaceutical composition according to any one of (1) to (7), wherein the administration route is administration close to the eye.
(13) The pharmaceutical composition according to (12), wherein the administration in the vicinity of the eye is an application to eyelid skin.
(14) The dosage form is selected from the group consisting of an ointment, cream, lotion, gel, liniment, transdermal preparation, patch, spray and injection, (1) to (1) 7) The pharmaceutical composition according to any one of (11) to (13).
(15) An aqueous pharmaceutical composition comprising alkaftadine or a salt thereof at a concentration of more than 0.15% (w / v) as an active ingredient, which comprises, as an additive, a buffer, an isotonicity agent, a pH adjuster and a stabilizer. Aqueous pharmaceutical composition containing at least 1 sort (s) selected from the group which consists of agents, and containing no preservative.
(16) An aqueous pharmaceutical composition containing alcaftadine or a salt thereof at a concentration of more than 0.15% (w / v) as an active ingredient, which comprises, as an additive, a buffer, a tonicity agent, a pH regulator and a stabilizer. An aqueous pharmaceutical composition comprising at least one member selected from the group consisting of agents and having preservative efficacy without containing a preservative.
(17) By blending alkaftadine or a salt thereof at a concentration of more than 0.15% (w / v), it is preserved in an aqueous pharmaceutical composition containing alkaftadine or a salt thereof without containing a preservative as an additive. How to give effect.
(18) By blending alkaftadine or a salt thereof at a concentration of more than 0.15% (w / v), it is preserved in an aqueous pharmaceutical composition containing alkaftadine or a salt thereof without containing a preservative as an additive. How to maintain efficacy.
In addition, each structure of said (1) to (18) can select 2 or more arbitrarily, and can combine them.
Furthermore, the present invention also provides the following.
(19) A method for treating and / or treating allergic diseases, which comprises administering a therapeutically effective amount of the aqueous pharmaceutical composition according to any of (1) to (16) to a patient in need of such treatment. How to prevent.
(20) The aqueous pharmaceutical composition according to any one of (1) to (16), which is used for the treatment and / or prevention of allergic diseases.
(21) Use of the aqueous pharmaceutical composition according to any one of (1) to (16) for the manufacture of a medicament for treating and / or preventing allergic diseases.
　本発明は、防腐剤を添加しなくても防腐効力を奏する、アルカフタジン又はその塩を含有する水性医薬組成物を得ることができる。 The present invention can provide an aqueous pharmaceutical composition containing alcaftadine or a salt thereof that exhibits preservative efficacy without the addition of a preservative.
　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、「アルカフタジン」とは、化学名６，１１－Ｄｉｈｙｄｒｏ－１１－（１－ｍｅｔｈｙｌ－４－ｐｉｐｅｒｉｄｉｎｙｌｉｄｅｎｅ）－５Ｈ－ｉｍｉｄａｚｏ［２，１－ｂ］［３］ｂｅｎｚａｚｅｐｉｎｅ－３－ｃａｒｂｏｘａｌｄｅｈｙｄｅ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, “alkaftadine” is a chemical name of 6,11-Dihydro-11- (1-methyl-4-piperidinylidene) -5H-imidazo [2,1-b] [3] benzazepine-3-carboxaldehyde. And a compound of the following formula:
Figure JPOXMLDOC01-appb-C000001
 It is a compound represented by
　本発明の水性医薬組成物において、含有されるアルカフ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、硫酸ラウリル、硫酸メチル、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。 In the aqueous pharmaceutical composition of the present invention, the alkaftadine contained may be a salt, and is not particularly limited as long as it is a pharmaceutically acceptable salt. Examples of the salt include salts with inorganic acids and salts with organic acids.
As salts with inorganic acids, salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like can be mentioned.
As salts with organic acids, acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, citric acid, tartaric acid, tartaric acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, alanine , Lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p- Examples thereof include salts with toluene sulfonic acid, lauryl sulfate, methyl sulfate, naphthalene sulfonic acid, sulfosalicylic acid and the like.
　本発明において、含有されるアルカフ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。 In the present invention, the contained alpaftadine or a salt thereof may be in the form of a hydrate or a solvate.
　本発明において、アルカフタジン又はその塩の含有量は、０．１５％（ｗ／ｖ）超であればよく、好ましくは０．２５％（ｗ／ｖ）以上であり、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２．５％（ｗ／ｖ）、より好ましくは１％（ｗ／ｖ）、さらに好ましくは０．５％（ｗ／ｖ）である。アルカフタジン又はその塩の含有量としては、０．１５％（ｗ／ｖ）超乃至５％（ｗ／ｖ）以下が好ましく、０．２５～５％（ｗ／ｖ）がより好ましく、０．２５～２．５％（ｗ／ｖ）がさらに好ましく、０．２５～１％（ｗ／ｖ）がさらにより好ましく、０．２５～０．５％（ｗ／ｖ）が特に好ましい。
　なお、本発明においてアルカフタジンの塩が含有される場合、これらの値はアルカフタジンの塩の含有量である。「％（ｗ／ｖ）」は、本発明の水性医薬組成物１００ｍＬ中に含まれる対象成分（ここでは、アルカフタジン又はその塩）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 alkaftadine or a salt thereof may be 0.15% (w / v) or more, preferably 0.25% (w / v) or more, and the upper limit thereof is the effectiveness of the pharmaceutical. The amount used may be, for example, 5% (w / v), preferably 2.5% (w / v), more preferably 1% (w / v), further preferably 0.5. It is% (w / v). The content of alkaftadine or a salt thereof is preferably more than 0.15% (w / v) to 5% (w / v), more preferably 0.25 to 5% (w / v), 0.25 -2.5% (w / v) is more preferred, 0.25-1% (w / v) is even more preferred, 0.25-0.5% (w / v) is particularly preferred.
In the present invention, when a salt of alkaftadine is contained, these values are the content of the salt of alcaftadine. “% (W / v)” means the mass (g) of the subject component (here, alcaftadine or a salt thereof) contained in 100 mL of the aqueous pharmaceutical composition of the present invention. Hereinafter, the same applies unless otherwise noted.
　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である。
　クロルヘキシジン又はその塩としては、例えば、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などが挙げられる。
　ソルビン酸又はその塩としては、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などが挙げられる。 In the present invention, the preservative is benzalkonium chloride, benzalkonium bromide, benzethonium chloride, chlorhexidine or a salt thereof, sorbic acid or a salt thereof, methyl parahydroxybenzoate, propyl parahydroxybenzoate or chlorobutanol.
Examples of chlorhexidine or a salt thereof include chlorhexidine, chlorhexidine gluconate, chlorhexidine hydrochloride, chlorhexidine acetate and the like.
As sorbic acid or a salt thereof, sorbic acid, sodium sorbate, potassium sorbate and the like can be mentioned.
　本発明において、「防腐剤を含有しない」とは、水性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、防腐剤を「実質的に含有しない」とは、上記防腐剤を含まないこと、又は上記防腐剤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る。
　本発明において、「防腐効力を有する」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、水性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有することを指す。なお、水性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, "preservative-free" means that the aqueous pharmaceutical composition does not substantially contain the above-mentioned preservative. As used herein, "substantially free of preservatives" means that the preservatives are not contained, or that the preservatives are contained in a range that does not exhibit the preservative efficacy required for pharmaceutical compositions. Is intended.
In the present invention, "having preservative efficacy" refers to the action of preventing the growth and growth of microorganisms such as bacteria and fungi, and "having preservative efficacy without containing preservatives" means an aqueous pharmaceutical composition. It has antiseptic efficacy even if it does not contain the above-mentioned preservative. The degree of antiseptic efficacy of the aqueous pharmaceutical composition can be confirmed, for example, by conducting a test according to the preservation efficacy test method described in the 17th revised Japanese Pharmacopoeia, and preferably the 17th revised Japan It refers to preservative efficacy compatible with the test based on the preservation efficacy test method described in the pharmacopoeia.
　本発明の水性医薬組成物は、経口または非経口（例えば、局所）投与することができる。本発明の水性医薬組成物の非経口投与経路としては、医薬品として許容される局所投与経路、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、注射投与などが挙げられる。 The aqueous pharmaceutical composition of the present invention can be administered orally or parenterally (eg, topically). The parenteral administration route of the aqueous pharmaceutical composition of the present invention includes pharmaceutically acceptable topical administration route, for example, topical administration to the eye (for example, eye drop administration), nasal administration (transnasal) administration, topical application to the ear Administration (for example, ear drop administration), inhalation administration, spray administration, transdermal administration, dermal administration, injection administration and the like.
　本発明の水性医薬組成物は、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、その剤形は、医薬品として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、液剤、懸濁剤等の経口投与剤、点眼剤、点鼻剤、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）等の局所投与剤が挙げられる。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り、より好ましくは点眼剤又は眼科用注射剤であり、さらに好ましくは点眼剤である。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。 The aqueous pharmaceutical composition of the present invention can be used as an ophthalmic preparation, an otolaryngological preparation, an inhalation preparation, a percutaneous absorption preparation, and the dosage form is particularly limited as long as it can be used as a pharmaceutical. It is not a thing. As the dosage form, for example, orally administered agents such as solution, suspension, eye drops, nasal drops, ear drops, inhalant, (inhalable powder, inhalable liquid, inhalable aerosol), ointment, cream , Gel, transdermal preparation, patch (tape, patch), external solution (lotion, liniment), external solid (external powder), spray (pump spray, external aerosol), Locally administered agents such as injections (transfusions, implanted injections, sustained injections) and the like can be mentioned. The eye drop, nasal drop, ear drop, inhalant, cream, lotion, patch, ophthalmic transdermal preparation or ophthalmic injection is preferred, and eye drops or ophthalmic injection is more preferred. More preferably, it is an eye drop. These can be prepared according to the usual methods in the art.
　本発明の水性医薬組成物は、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、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。 The aqueous pharmaceutical composition of the present invention may optionally contain a pharmaceutical additive. For example, a buffering agent, a tonicity agent, a thickening agent, a surfactant, and the like to satisfy the requirements as an ophthalmic composition, an otolaryngological composition, an inhalable composition, and a transdermal absorption composition. 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 combination as appropriate, and an appropriate amount can be blended.
　本発明の水性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、これらの水和物又は溶媒和物であってもよい。
　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、これらの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、これらの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、これらの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、これらの水和物であってもよい。
　炭酸又はその塩としては、炭酸、炭酸ナトリウム、炭酸水素ナトリウム等が挙げられ、これらの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、これらの水和物であってもよい。
　本発明の水性医薬組成物に緩衝剤を配合する場合、緩衝剤は、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。また緩衝剤を２以上一緒に用いてもよい。
　本発明の水性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。 Examples of buffers that can be incorporated into the aqueous 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 Its salts, ε-aminocaproic acid, trometamol and the like may be mentioned, and these may be hydrates or solvates.
Examples of phosphoric acid or salts thereof include phosphoric acid, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, etc. It may be a hydrate.
The boric acid or a salt thereof includes boric acid, sodium borate, potassium borate and the like, and may be a hydrate of these.
Citric acid or a salt thereof includes citric acid, sodium citrate, disodium citrate and the like, and may be a hydrate of these.
Acetic acid or a salt thereof includes acetic acid, sodium acetate, potassium acetate and the like, and may be a hydrate of these.
Carbonic acid or a salt thereof includes carbonic acid, sodium carbonate, sodium hydrogencarbonate and the like, and may be a hydrate of these.
As tartaric acid or a salt thereof, tartaric acid, sodium tartrate, potassium tartrate and the like can be mentioned, and their hydrates may be used.
When a buffer is incorporated into the aqueous pharmaceutical composition of the present invention, the buffer is more preferably phosphoric acid or a salt thereof, boric acid or a salt thereof, further preferably phosphoric acid or a salt thereof, sodium dihydrogenphosphate, phosphorus Particular preference is given to disodium hydrogen oxide or hydrates thereof. Also, two or more buffers may be used together.
The content of the buffer in the case of incorporating the buffer into the aqueous pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of buffer etc., but preferably 0.001 to 10% (w / v), 0.01 to 5% (w / v) is more preferable, 0.1 to 3% (w / v) is more preferable, and 0.2 to 1.5% (w / v) is most preferable.
　本発明の水性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。
　本発明の水性医薬組成物に等張化剤を配合する場合、等張化剤は、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。また等張化剤を２以上一緒に用いてもよい。
　本発明の水性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。 Examples of tonicity agents that can be added to the aqueous pharmaceutical composition of the present invention include ionic tonicity agents, non-ionic tonicity agents, and the like.
Examples of the ionic tonicity agent include sodium chloride, potassium chloride, calcium chloride, magnesium chloride and the like.
As the nonionic tonicity agent, glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose and the like can be mentioned.
When the isotonizing agent is added to the aqueous pharmaceutical composition of the present invention, the tonicity agent is more preferably an ionic tonicity agent, particularly preferably sodium chloride. Also, two or more tonicity agents may be used together.
The content of the tonicity agent in the case of incorporating the tonicity agent into the aqueous pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of tonicity agent etc., but it is 0.001 to 10% (w / V) is preferred, 0.01 to 5% (w / v) is more preferred, 0.1 to 2% (w / v) is more preferred, 0.2 to 1% (w / v) is most preferred .
　本発明の水性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。
　本発明の水性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。 Examples of thickening agents which can be incorporated into the aqueous pharmaceutical composition of the present invention include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium And hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, carboxymethyl ethyl cellulose, cellulose acetate phthalate, polyvinyl pyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, polyethylene glycol, sodium hyaluronate and the like.
The content of the thickening agent in the case of incorporating the thickening agent into the aqueous pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the thickening agent, etc., but 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 more preferable.
　本発明の水性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。
　本発明の水性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、０．０５～２％（ｗ／ｖ）がさらに好ましく、０．０５～０．２％（ｗ／ｖ）が特に好ましい。 Examples of surfactants which can be incorporated into the aqueous pharmaceutical composition of the present invention include cationic surfactants, anionic surfactants, nonionic surfactants and the like.
Examples of cationic surfactants include alkylamine salts, alkylamine polyoxyethylene adducts, fatty acid triethanolamine monoester salts, acylaminoethyl diethylamine salts, fatty acid polyamine condensates, alkyl imidazolines, 1-acylaminoethyl-2 And -alkyl imidazoline, 1-hydroxy ethyl 2-alkyl imidazoline and the like. However, benzalkonium chloride has the property of a cationic surfactant, but it is not included.
Examples of anionic surfactants include phosphate lipids such as lecithin.
Examples of nonionic surfactants include polyoxyethylene fatty acid esters such as polyoxyl stearate and the like; polysorbate 80, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate, polysorbate 65 and the like Polyoxyethylene sorbitan fatty acid ester; polyoxyethylene hydrogenated castor oil such as polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60; polyoxyl 5 castor oil Polyoxyl castor oil such as polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 castor oil, etc .; polyoxyethylene (160) Lyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, Polyoxyethylene (20) polyoxypropylene (20) glycol and the like; sucrose fatty acid ester such as sucrose stearate; tocopherol polyethylene glycol 1000 succinate (vitamin E TPGS) etc. Be
The content of the surfactant in the case of incorporating the surfactant into the aqueous pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the surfactant, etc., but it is 0.01 to 10% (w / V) is preferable, 0.05 to 5% (w / v) is more preferable, 0.05 to 2% (w / v) is further preferable, and 0.05 to 0.2% (w / v) is Particularly preferred.
　本発明の水性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。
　本発明の水性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。 Examples of stabilizers that can be incorporated into the aqueous pharmaceutical composition of the present invention include edetic acid or salts thereof.
Examples of edetic acid or salts thereof include edetic acid, disodium edetate, tetrasodium edetate and the like.
The content of the stabilizer in the case of incorporating the stabilizer into the aqueous pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the stabilizer etc., but 0.001 to 5% (w / v) Is preferred, 0.01 to 3% (w / v) is more preferred, and 0.1 to 2% (w / v) is even more preferred.
　本発明の水性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、亜硫酸ナトリウム等が挙げられる。
　本発明の水性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。 Examples of the antioxidant that can be incorporated into the aqueous pharmaceutical composition of the present invention include ascorbic acid, tocopherol, dibutylhydroxytoluene, sodium sulfite and the like.
The content of the antioxidant in the case of incorporating the antioxidant into the aqueous pharmaceutical composition of the present invention can be appropriately adjusted depending on the type of the antioxidant etc., but it is 0.001 to 5% (w / v) Is preferred, 0.01 to 3% (w / v) is more preferred, and 0.1 to 2% (w / v) is even more preferred.
　本発明の水性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。
　本発明の水性医薬組成物の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。特に、本発明の水性医薬組成物が眼科用組成物である場合は、水性医薬組成物のｐＨは眼科製剤に許容される範囲内にあればよく、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。また、６．７、６．８、６．９、７．０、７．１、７．２、７．３もさらにより好ましい。 The pH adjuster which can be incorporated into the aqueous pharmaceutical composition of the present invention is an acid or a base. Examples of the acid include hydrochloric acid, phosphoric acid, citric acid, acetic acid and the like, and examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate and the like.
The pH of the aqueous pharmaceutical composition of the present invention is preferably in the range of 4.0 to 8.5, more preferably 6.0 to 8.0. In particular, when the aqueous pharmaceutical composition of the present invention is an ophthalmic composition, the pH of the aqueous pharmaceutical composition may be within the range acceptable for the ophthalmic preparation, preferably 4.0 to 8.5, 0 to 8.0 is more preferable, 6.5 to 7.5 is more preferable, and 6.7 to 7.3 is particularly preferable. Also, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3 are even more preferred.
　本発明の水性医薬組成物の浸透圧比は、０．５～２．０の範囲内が好ましい。特に、本発明の水性医薬組成物が眼科用組成物である場合は、水性医薬組成物の浸透圧比は眼科製剤に許容される範囲内にあればよく、例えば０．５～２．０であり、０．７～１．６が好ましく、０．８～１．４がより好ましく、０．９～１．２がさらに好ましい。 The osmotic pressure ratio of the aqueous pharmaceutical composition of the present invention is preferably in the range of 0.5 to 2.0. In particular, when the aqueous pharmaceutical composition of the present invention is an ophthalmic composition, the osmotic pressure ratio of the aqueous pharmaceutical composition may be within the range acceptable for the ophthalmic preparation, for example, 0.5 to 2.0. 0.7 to 1.6 is preferable, 0.8 to 1.4 is more preferable, and 0.9 to 1.2 is more preferable.
　本発明において、水性医薬組成物とは水を含有する医薬組成物を指す。本発明の水性医薬組成物に含まれる水の含有量は、医薬組成物として使用可能な量であれば特に制限はされないが、水性医薬組成物の総重量に対して、１０％（ｗ／ｖ）以上が好ましく、３０％（ｗ／ｖ）以上がより好ましく、５０％（ｗ／ｖ）以上がさらに好ましい。特に、好ましくは７０％（ｗ／ｖ）以上であり、より好ましくは９０％（ｗ／ｖ）以上であり、さらに好ましくは９５％（ｗ／ｖ）以上である。　本発明の水性医薬組成物は、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。本発明の水性医薬組成物は、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。 In the present invention, the aqueous pharmaceutical composition refers to a pharmaceutical composition containing water. The content of water contained in the aqueous pharmaceutical composition of the present invention is not particularly limited as long as it can be used as a pharmaceutical composition, but 10% (w / v) based on the total weight of the aqueous pharmaceutical composition. Or more is preferable, 30% (w / v) or more is more preferable, and 50% (w / v) or more is more preferable. In particular, it is preferably 70% (w / v) or more, more preferably 90% (w / v) or more, and still more preferably 95% (w / v) or more. The aqueous pharmaceutical composition of the present invention may have all the components dissolved or partially suspended, and may be in the form of an emulsion or semisolid. The aqueous pharmaceutical composition of the present invention is more preferably in the form of a solution in which all the components are dissolved, and most preferably in the form of an aqueous solution. The solvent or dispersion medium is, but not limited to, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol etc.), preferably water.
　本発明の水性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 aqueous pharmaceutical composition of the present invention is an emulsion, it is a water-in-oil emulsion (even an oil-in-water emulsion (emulsion comprising an aqueous phase as a continuous phase and an aqueous phase and dispersed oily droplets)). The oil phase may be an emulsion composed of an oil and dispersed aqueous droplets as the continuous phase. The average size of the oily droplets or aqueous droplets is 20 to 3000 nm, preferably 30 to 1000 nm, more preferably 50 to 600 nm, and still more preferably 100 to 300 nm.
　本発明の水性医薬組成物がエマルションである場合、その油相の例としては、例えばトリグリセリド、モノグリセリド、ジグリセリド等の中鎖もしくは長鎖のトリグリセリド、ヒマシ油、ゴマ油等の植物油、またはパラフィン系炭化水素等の鉱油等が挙げられる。また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、０．１～５０％（ｗ／ｖ）であり、好ましくは１～３０％（ｗ／ｖ）である。本発明の水性医薬組成物がエマルションである場合、そ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、外用エアゾール剤などに用いられてもよい。 When the aqueous pharmaceutical composition of the present invention is an emulsion, examples of the oil phase thereof include medium- or long-chain triglycerides such as triglycerides, monoglycerides and diglycerides, vegetable oils such as castor oil and sesame oil, or paraffin hydrocarbons Etc. mineral oil etc. are mentioned. The amount of the oil phase in the emulsion is, for example, 0.1 to 50% (w / v), preferably 1 to 30% (w / v) in the case of an oil-in-water emulsion. When the aqueous pharmaceutical composition of the present invention is an emulsion, it takes advantage of its physicochemical properties to produce ointments, creams, lotions, gels, liniments, transdermal preparations, tapes, patches, It may be used for external powder, pump spray, external aerosol and the like.
　本発明において、水性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。特に、本発明の水性医薬組成物が眼科用組成物である場合は、水性医薬組成物を収容する容器は点眼容器が好ましく、その点眼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、本発明の水性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。マルチドーズ型水性医薬組成物とは、マルチドーズ型容器に入れられた水性医薬組成物を指す。 In the present invention, the container for containing the aqueous pharmaceutical composition is not particularly limited to the size and shape of the container body. In particular, when the aqueous pharmaceutical composition of the present invention is an ophthalmic composition, the container for containing the aqueous pharmaceutical composition is preferably an eye drop container, and the eye drop container is a multi-dose container, a single dose unit dose container Although it may be any of a PFMD (Preservative Free Multi Dose) container, a multi-dose container is particularly preferable because the aqueous pharmaceutical composition of the present invention has preservative efficacy. A multi-dose type container is a container in which opening and closing of a cap and the like can be freely performed for the purpose of multiple use, can be used for a certain period after opening, and is easy to carry. A multidose aqueous pharmaceutical composition refers to an aqueous pharmaceutical composition contained in a multidose container.
　本発明において、水性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、本発明の水性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 for containing the aqueous pharmaceutical composition is not particularly limited as long as it conforms to the form of the container, and resin containers, aluminum containers, glass containers, etc. may be mentioned. In particular, when the container for containing the aqueous pharmaceutical composition of the present invention is an eye drop container, a resin container is preferable. The material of the resin container is, for example, polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET), polybutylene terephthalate, polypropylene-polyethylene copolymer, polyvinyl chloride, acrylic resin, polystyrene, cyclic olefin polymer, cyclic olefin copolymer Etc. Furthermore, polyethylene is classified according to its density and includes low density polyethylene (LDPE), medium density polyethylene (MDPE), high density polyethylene (HDPE) and the like.
　本発明の水性医薬組成物は、特に断りのない限り、アルカフタジン又はその塩以外の医薬活性成分を含んでいてもよい。特に、本発明の水性医薬組成物が眼科用組成物である場合は、アルカフタジン又はその塩以外の点眼剤に用いられる医薬活性成分を含んでいてもよい。アルカフタジン又はその塩以外の他の医薬活性成分としては、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、局所麻酔剤等が挙げられる。他の医薬活性成分は、水性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。 The aqueous pharmaceutical composition of the present invention may contain a pharmaceutically active ingredient other than alcaftadine or a salt thereof, unless otherwise specified. In particular, when the aqueous pharmaceutical composition of the present invention is an ophthalmic composition, it may contain a pharmaceutically active ingredient to be used for eye drops other than alkaftadine or a salt thereof. As other pharmaceutically active ingredients other than alcaftadine or a salt thereof, for example, anti-inflammatory agent, antibacterial agent, antiviral agent, vitamin agent, vasoconstrictor, mydriatic agent, miotic agent, intraocular pressure reducing agent, dry eye treatment Agents, local anesthetics and the like. Other pharmaceutically active ingredients may be formulated, for example, in an amount of 0.001 to 5% (w / v) based on the total weight of the aqueous pharmaceutical composition. Moreover, you may use these in combination of 2 or more types.
本発明の水性医薬組成物は、アレルギー性疾患の治療剤として有用である。アレルギー性疾患の治療には、アレルギー症状のあらゆる治療（例えば、改善、軽減、進行の抑制等）及びその予防が含まれる。本発明の水性医薬組成物は、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、改善、軽減、進行の抑制等）及びその予防が含まれる。 The aqueous pharmaceutical composition of the present invention is useful as a therapeutic agent for allergic diseases. Treatment of allergic disease includes any treatment (eg, amelioration, reduction, suppression of progression, etc.) of the allergic condition and its prevention. The aqueous pharmaceutical composition of the present invention is more preferably used as a therapeutic agent for ophthalmic allergic diseases, and particularly useful as a therapeutic agent for allergic conjunctivitis. Treatment of allergic conjunctivitis includes all treatments (eg, amelioration, reduction, suppression of progression, etc.) of allergic conjunctivitis and its symptoms and the prevention thereof.
　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。 In the present invention, "patient" means not only human but also other animals such as dogs, cats, horses and the like. The patient is preferably a mammal, more preferably a human. In the present invention, "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, etc., as compared to an untreated subject.
　本発明の水性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に特に制限されるものではない。本発明の水性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回に分けて点眼することができ、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。コンタクトレンズは、ハードコンタクトレンズまたはソフトコンタクトレンズであってもよい。
　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 the aqueous pharmaceutical composition of the present invention is administered, it is not particularly limited to the dosage regimen as long as it is sufficient to produce the desired medicinal effect. When the aqueous pharmaceutical composition of the present invention is an ophthalmic composition, it is divided into one drop once a day, 1 to 6 times a day, preferably 1 to 4 times a day, more preferably 1 to 2 times a day It can be instilled and can be used even when wearing a contact lens. The contact lens may be a hard contact lens or a soft contact lens.
As a soft contact lens, a contact lens which has hydroxyethyl methacrylate as a main component, a silicone hydrogel contact lens, etc. are mentioned, for example.
The type of the soft contact lens to which the present invention is applied is not particularly limited, and may be any of ionic, nonionic, water-containing or non-water-containing. For example, in addition to lenses used repeatedly, it is applicable to all commercially available soft contact lenses such as daily disposable lenses, one week disposable lenses, and two week disposable lenses.
　また、本発明の水性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、本発明の水性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、本発明の水性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。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回眼瞼皮膚に投与することができる。 In addition, when the aqueous pharmaceutical composition of the present invention is a composition for nasal use, it is possible for one drop to several drops, or one spray to several sprays, 1 to 6 times a day, preferably 1 to a day. It can be instilled four times, more preferably once to three times a day, and when the aqueous pharmaceutical composition of the present invention is a composition for eardrops, one drop to several drops per day, one day It can be divided into 1 to 6 times, preferably 1 to 4 times a day, more preferably 1 to 3 times a day, and when the aqueous pharmaceutical composition of the present invention is an inhalable composition, It can be inhaled by dividing into one spray to several sprays, 1 to 6 times a day, preferably 1 to 4 times a day, more preferably 1 to 3 times a day. When the pharmaceutical composition of the present invention is an ophthalmic transdermal absorption type preparation, 1 mg to 1 g of once administered 1 to 4 times a day, preferably twice a day, more preferably once a day to the eyelid skin can do.
　本発明の水性医薬組成物に防腐効力を付与する方法は、水性医薬組成物にアルカフタジン又はその塩を配合することを含む。 The method for imparting preservative efficacy to the aqueous pharmaceutical composition of the present invention comprises incorporating alkaftadine or a salt thereof into the aqueous pharmaceutical composition.
　本発明の水性医薬組成物の防腐効力を維持する方法は、水性医薬組成物にアルカフタジン又はその塩を配合することを含む。 The method of maintaining the preservative efficacy of the aqueous pharmaceutical composition of the present invention comprises incorporating alkaftadine or a salt thereof into the aqueous pharmaceutical composition.
　以下に、製剤例および防腐効力試験の結果を示すが、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。 The following shows formulation examples and results of preservative efficacy tests, but these are for the purpose of better understanding 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。 [Formulation example]
The following are representative preparation examples of the present invention. In addition, the compounding quantity of each component is a content in 1 mL of formulation in the following formulation example.
製剤例１
　アルカフタジン　　　　　　　２．５ｍｇ
　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 1
Alcaftadine 2.5 mg
Sodium dihydrogen phosphate 5 mg
Sodium chloride 5 mg
Diluted hydrochloric acid, appropriate amount Sodium hydroxide, appropriate amount Purified water, appropriate amount
製剤例２
　アルカフタジン　　　　　　　　　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
Alcaftadine 5 mg
Sodium dihydrogen phosphate 5 mg
Sodium chloride 5 mg
Diluted hydrochloric acid, appropriate amount Sodium hydroxide, appropriate amount Purified water, appropriate amount
製剤例３
　アルカフタジン　　　　　　　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
Alcaftadine 2.5 mg
Sodium dihydrogen phosphate 5 mg
Disodium edetate 0.1 mg
Sodium chloride 5 mg
Diluted hydrochloric acid, appropriate amount Sodium hydroxide, appropriate amount Purified water, appropriate amount
製剤例４
　アルカフタジン　　　　　　　　　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
Alcaftadine 5 mg
1 mg boric acid
Sodium chloride 5 mg
Diluted hydrochloric acid, appropriate amount Sodium hydroxide, appropriate amount Purified water, appropriate amount
製剤例５
　アルカフタジン　　　　　　　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
Alcaftadine 2.5 mg
Polysorbate 80 1 mg
Polyethylene glycol 1 mg
Glycerin Appropriate amount Diluted hydrochloric acid Suitable amount Sodium hydroxide Appropriate amount Purified water Appropriate amount
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
　アルカフタジン（０．１５ｇ）、リン酸二水素ナトリウム（０．３ｇ）、塩化ナトリウム（０．３ｇ）を水に溶解して濾過滅菌を行い、ｐＨ調節剤と水を加えて全量を６０ｇとすることにより、実施例１の製剤を調製した。 Antiseptic efficacy test This test was conducted according to the preservation efficacy test method described in the 17th revised Japanese Pharmacopoeia.
1. Preparation of test preparation Alkaftadine (0.15 g), sodium dihydrogen phosphate (0.3 g) and sodium chloride (0.3 g) are dissolved in water and sterilized by filtration, pH adjuster and water are added to obtain the total amount. The formulation of Example 1 was prepared by adjusting to 60 g.
実施例１
１ｇ中
　アルカフタジン　　　　　　　　　　２．５ｍｇ
　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
　ｐＨ　　　　　　　　　　　　　　　　　７．０ Example 1
Alcaftadine 2.5mg in 1g
Sodium dihydrogen phosphate 5 mg
Sodium chloride 5 mg
Diluted hydrochloric acid, appropriate amount Sodium hydroxide, appropriate amount Purified water, appropriate amount pH 7.0
　実施例１の調製方法と同様の方法にて、実施例２および比較例１～４の製剤を調製した。なお、比較例３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４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。 The preparations of Example 2 and Comparative Examples 1 to 4 were prepared in the same manner as the preparation method of Example 1. In addition, levocetirizine hydrochloride used in Comparative Example 3 is an active ingredient of "Zysal (registered trademark) tablet 5 mg", and Bepotastine besilate used in Comparative Example 4 is 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
１ｇ中
　アルカフタジン　　　　　　　　　　　　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
　ｐＨ　　　　　　　　　　　　　　　　　７．０ Example 2
Alcaftadine 5mg in 1g
Sodium dihydrogen phosphate 5 mg
Sodium chloride 5 mg
Diluted hydrochloric acid, appropriate amount Sodium hydroxide, appropriate amount Purified water, appropriate amount pH 7.0
比較例１
１ｇ中
　（アルカフタジンは含有しない）
　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
In 1 g (does not contain alkaftadine)
Sodium dihydrogen phosphate 5 mg
Sodium chloride 5 mg
Diluted hydrochloric acid, appropriate amount Sodium hydroxide, appropriate amount Purified water, appropriate amount pH 7.0
比較例２
１ｇ中
　アルカフタジン　　　　　　　　　　１．５ｍｇ
　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
　ｐＨ　　　　　　　　　　　　　　　　　７．０ Comparative example 2
Alcaftadine 1.5mg in 1g
Sodium dihydrogen phosphate 5 mg
Sodium chloride 5 mg
Diluted hydrochloric acid, appropriate amount Sodium hydroxide, appropriate amount Purified water, appropriate amount pH 7.0
比較例３
１ｇ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 3
Levogetirizine hydrochloride 2.85mg in 1g
(Equivalent to 2.4 mg of levocetirizine free form)
Sodium dihydrogen phosphate 5 mg
Sodium chloride 5 mg
Diluted hydrochloric acid, appropriate amount Sodium hydroxide, appropriate amount Purified water, appropriate amount pH 7.0
比較例４
１ｇ中
　ベポタスチンベシル酸塩　　　　　２１．１ｍｇ
　　（べ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 4
1 g of bepotastine besilate 21.1 mg
(Equivalent to 15 mg of free body of Bepotastine)
Sodium dihydrogen phosphate 5 mg
Sodium chloride 5 mg
Diluted hydrochloric acid, appropriate amount Sodium hydroxide, appropriate amount Purified water, appropriate amount 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 referred to as E. coli)
Pseudomonas aeruginosa ATCC 9027 (also referred to as P. aeruginosa)
Staphylococcus aureus, Staphylococcus aureus ATCC 6538 (also referred to as S. aureus)
Yeast and mold:
Candida albicans ATCC 10231 (also referred to as C. albicans)
Aspergillus niger, Aspergillus brasiliensis ATCC 16404 (also referred to as 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１～２及び比較例１～４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１ｍＬ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 inoculum was inoculated to the test sample such that the concentration of the culture solution in the test sample consisting of each preparation was 10 5 to 10 6 cells / mL (5 types of bacteria). Specifically, the inoculum is prepared to be 10 7 to 10 8 cfu / mL, and this inoculum is adjusted to 10 5 to 10 6 cfu / mL according to Examples 1 to 2 and Comparative Example. Test samples consisting of 1 to 4 formulations were inoculated with each inoculum, mixed uniformly, and used as samples. These samples were stored at 20-25 ° C. in the dark, and 1 mL was collected from each sample with a micropipette at each sampling point (7, 14, or 28 days), and the viable cell count was measured. At each sampling point, the lid of the sample solution was removed, sampling was performed, and the lid was closed.
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。
　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。 3. Test Results and Discussion The test results are shown in Table 1. The test results in Table 1 show the common logarithm value of the ratio (B / A) of the number of bacteria (B) at inoculation to the number of bacteria (A) when the number of viable bacteria is measured, for example, the value In the case of 1 ", it indicates that the number of viable bacteria at the time of examination decreased to 10% of the number of inoculated bacteria.
Regarding the pass / fail judgment of the test, for bacterial species (E. coli, P. aeruginosa, S. aureus), 1.0 or more 7 days after sowing, and 3.0 or more after 14 or 28 days, And for fungal species (C. albicans, A. brasiliensis), the values after 14 days or 28 days after sowing were not reduced compared with 7 days after sowing, and it was considered as satisfying when satisfying both.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
　表１に示されるように、アルカフタジン又はその塩を含有する実施例１～２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た。それに対して、比較例１～４の製剤は、十分な防腐効力を有さないことが示された。特に、アルカフタジン、レボセチリジン及びべポタスチンはいずれも抗アレルギー性疾患治療剤として使用されるが、防腐効力を有する化合物はアルカフタジンのみであることが示された。これにより、０．１５％（ｗ／ｖ）超の濃度のアルカフタジンまたはその塩を含有する本発明の水性医薬組成物は、防腐剤を含有しなくても、繰り返し容器を開閉して使用可能であることが示唆された。 As shown in Table 1, the formulations of Examples 1 and 2 containing alcaftadine or a salt thereof exhibited sufficient antiseptic efficacy against any bacteria despite containing no preservative. In contrast, it was shown that the formulations of Comparative Examples 1 to 4 do not have sufficient preservative efficacy. In particular, alcaftadine, levocetirizine and bepotastine are all used as antiallergic disease therapeutic agents, but it has been shown that only alkaftadine is a compound having preservative efficacy. Thus, the aqueous pharmaceutical composition of the present invention containing alcaftadine or a salt thereof at a concentration of more than 0.15% (w / v) can be used repeatedly by opening and closing the container without containing a preservative. It was suggested that there is.
　本発明は、０．１５％（ｗ／ｖ）超の濃度のアルカフタジン又はその塩を含有する水性医薬組成物であって、防腐剤を含有しないことを特徴とする、水性医薬組成物を提供する。 The present invention provides an aqueous pharmaceutical composition containing alkaftadine or a salt thereof at a concentration of more than 0.15% (w / v), which is characterized by containing no preservative. .

Claims (13)

  1. 　有効成分として０．１５％（ｗ／ｖ）超の濃度のアルカフタジン又はその塩を含有する水性医薬組成物であって、防腐剤を含有しないことを特徴とする、水性医薬組成物。 An aqueous pharmaceutical composition comprising as the active ingredient alcaftadine or a salt thereof at a concentration of more than 0.15% (w / v), which is characterized by containing no preservative.
  2. 　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に記載の水性医薬組成物。 The aqueous pharmaceutical composition according to claim 1, containing at least one selected from the group consisting of a buffer, a tonicity agent, a pH adjuster and a stabilizer as an additive.
  3. 　添加剤として緩衝剤、等張化剤及びｐＨ調節剤を含有する、請求項１または２に記載の水性医薬組成物。 The aqueous pharmaceutical composition according to claim 1 or 2, which contains a buffer, a tonicity agent and a pH adjuster as additives.
  4. 　さらに安定化剤を含有する、請求項３に記載の水性医薬組成物。 The aqueous pharmaceutical composition according to claim 3, further comprising a stabilizer.
  5. 　５％（ｗ／ｖ）以下の濃度のアルカフタジン又はその塩を含有する、請求項１～４のいずれか１項に記載の水性医薬組成物。 The aqueous pharmaceutical composition according to any one of claims 1 to 4, which contains alcaftadine or a salt thereof at a concentration of 5% (w / v) or less.
  6. 　０．２５％～５％（ｗ／ｖ）の濃度のアルカフタジン又はその塩を含有する、請求項１～４のいずれか１項に記載の水性医薬組成物。 The aqueous pharmaceutical composition according to any one of claims 1 to 4, which contains alcaftadine or a salt thereof at a concentration of 0.25% to 5% (w / v).
  7. 　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、請求項１～６のいずれか１項に記載の水性医薬組成物。 The aqueous pharmaceutical composition according to any one of claims 1 to 6, which is an ophthalmic composition, an otolaryngological composition, a composition for inhalation or a composition for percutaneous absorption.
  8. 　点眼剤である、請求項１～７のいずれか１項に記載の水性医薬組成物。 The aqueous pharmaceutical composition according to any one of claims 1 to 7, which is an eye drop.
  9. 　マルチドーズ型水性医薬組成物である、請求項１～８のいずれか１項に記載の水性医薬組成物。 The aqueous pharmaceutical composition according to any one of claims 1 to 8, which is a multidose aqueous pharmaceutical composition.
  10. 　防腐剤が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及びクロロブタノールからなる群より選択される少なくとも１種である、請求項１～９のいずれか１項に記載の水性医薬組成物。 The preservative is at least one selected from the group consisting of benzalkonium chloride, benzalkonium bromide, benzethonium chloride, chlorhexidine or salts thereof, sorbic acid or salts thereof, methyl parahydroxybenzoate, propyl parahydroxybenzoate and chlorobutanol The aqueous pharmaceutical composition according to any one of claims 1 to 9, which is
  11. 　有効成分として０．１５％（ｗ／ｖ）超の濃度のアルカフタジン又はその塩を含有する水性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、防腐剤を含有することなく防腐効力を有する、水性医薬組成物。 An aqueous pharmaceutical composition comprising alcaftadine or a salt thereof at a concentration of more than 0.15% (w / v) as an active ingredient, which comprises as an additive a buffer, an isotonicity agent, a pH regulator and a stabilizer An aqueous pharmaceutical composition comprising at least one selected from the group consisting of and having preservative efficacy without containing a preservative.
  12. 　アルカフタジン又はその塩を０．１５％（ｗ／ｖ）超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、アルカフタジン又はその塩を含有する水性医薬組成物に防腐効力を付与する方法。 By blending alcaftadine or a salt thereof at a concentration of more than 0.15% (w / v), it imparts preservative efficacy to an aqueous pharmaceutical composition containing alcaftadine or a salt thereof without containing a preservative as an additive. how to.
  13. 　アルカフタジン又はその塩を０．１５％（ｗ／ｖ）超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、アルカフタジン又はその塩を含有する水性医薬組成物の防腐効力を維持する方法。 By blending alcaftadine or a salt thereof at a concentration of more than 0.15% (w / v), the preservative efficacy of an aqueous pharmaceutical composition containing alcaftadine or a salt thereof is maintained without containing a preservative as an additive. how to.
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WO2021255622A1 (en) 2020-06-15 2021-12-23 Alkem Laboratories Limited Combination of alcaftadine and a corticosteroid
WO2022208146A1 (en) 2021-04-01 2022-10-06 Alkem Laboratories Limited Nasal compositions comprising alcaftadine

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021255622A1 (en) 2020-06-15 2021-12-23 Alkem Laboratories Limited Combination of alcaftadine and a corticosteroid
WO2022208146A1 (en) 2021-04-01 2022-10-06 Alkem Laboratories Limited Nasal compositions comprising alcaftadine

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