JP2009132732A - Ketotifen-containing composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To improve the photostability of a composition containing ketotifens. <P>SOLUTION: The photostability of the composition containing the ketotifen or its salt (an aqueous composition applied for mucous membrane) is improved by blending an amino acid expressed by the following formula (1). The ratio of the amino acid may be 0.01 pt.wt. to 10,000 pts.wt. based on 1 pt.wt. ketotifen or its salt. Such the composition is especially useful as an eye drop agent, an eye-washing agent, a nasal drop agent and a contact lens agent. H<SB>2</SB>N-(CH<SB>2</SB>)<SB>n</SB>-COOH (1) [wherein, (n) is an integer of 1 to 4]. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a composition (for example, an aqueous composition, a composition applied to mucosa, etc.) having improved stability to light over a long period of time even when containing ketotifen or a salt thereof which is unstable to light.

  Ketotifen or its salt has pharmacological actions such as chemical mediator release inhibition and eosinophil activation inhibition in addition to antihistaminic action, and as an antiallergic agent for oral, eye drops, and nasal drops. Widely used. However, ketotifen or its salt is unstable to light. In particular, since it becomes extremely unstable in light in an aqueous solution, it is important for an aqueous composition to ensure stability in the manufacturing process and market distribution process and long-term stability after opening.

  In general, as a means for stably holding a preparation containing a pharmacologically active substance that is unstable to light, a light shielding means by a packaging material containing the preparation, for example, an auxiliary light shielding means for shielding a container containing the preparation. Light-shielding means such as a method of using a light-shielding bag incidentally and a method of using a brown container or an aluminum container as a container for storing a preparation are employed. However, there are many cases where the user does not use the auxiliary light shielding bag, and in the manufacturing process in which the container or the packaging material cannot be used, there is a high risk of the substance being decomposed by light. Furthermore, in the production process of the aqueous composition, when an opaque or low-transparency container such as an aluminum container or a dark brown container is used, it is difficult to inspect foreign matters from the outside after filling the container with the preparation. It becomes.

  Furthermore, it is almost impossible to use the preparation under light shielding when applying the preparation. In particular, when a topical agent is taken out of a container and applied to the skin or mucous membrane, the drug is usually exposed to light, and it is difficult to avoid photolysis of the drug at the application site. Thus, methods for improving the photostability of ketotifen or a salt thereof have been known so far.

  For example, JP-A-10-152439 discloses a pharmaceutical composition containing ketotifen fumarate and glycyrrhizic acid or a salt thereof, and a pharmaceutical composition containing ketotifen fumarate, a formulation aid and glycyrrhizic acid or a salt thereof. It is disclosed that the photostability of ketotifen fumarate is improved.

  JP-T-2002-510627 discloses an aqueous ophthalmic composition containing pharmaceutically active ingredients such as ketotifen, retinoic acid, retinol, retinol acetate and salts thereof, and a polymer containing an antioxidant such as Irganox 1330. It is disclosed to stabilize the composition (stabilized against heat, light, and / or oxygen exposure, etc.) by contacting it, for example by containing it in a container of material.

  Japanese Patent Laid-Open No. 7-324034 discloses (a) boric acid, (b) boric acid and a chelating agent, (c) boric acid, a chelating agent and amino acids (ε-aminocaproic acid, glutarate). An eye drop having excellent stability and low irritation containing an acid or a sodium salt thereof, aminoethyl sulfonic acid and the like is disclosed. This document discloses that the residual ratio of ketotifen fumarate is high even when stored at a high temperature for a long time.

JP-A-10-152439 Japanese translation of PCT publication No. 2002-510627 JP 7-324034 A

  Accordingly, an object of the present invention is to provide a composition (an aqueous composition or a composition applied to mucous membranes) having a highly improved light stability even when containing ketotifen or a salt thereof.

  Another object of the present invention is to provide an aqueous composition having improved stability to light even in an aqueous solution and being stable for a long period of time.

  Still another object of the present invention is to provide a safe composition for applying to mucosa that is not only improved in stability to light but also has no irritation when applied to mucous membranes.

  Another object of the present invention is to provide a method capable of improving the light stability of ketotifen or a salt thereof.

  As a result of intensive investigations to achieve the above-mentioned problems, the present inventors have found that a composition in which a specific amino acid is blended with ketotifen or a salt thereof can improve the light stability of ketotifen or a salt thereof, and light over a long period of time. It was found that the composition was stable, and the present invention was completed.

Accordingly, the present invention provides the following.
Item 1. A stabilized composition comprising ketotifen or a salt thereof and an amino acid represented by the following formula (1) or a salt thereof.
_{H 2 N- (CH 2) n} -COOH (1)
(In the formula, n represents an integer of 1 to 4)
Item 2. An aqueous composition comprising ketotifen or a salt thereof and the amino acid represented by formula (1) according to item 1.
Item 3. A mucosa-applied composition comprising ketotifen or a salt thereof and the amino acid represented by formula (1) according to item 1.
Item 4. Item 4. The composition according to any one of Items 1 to 3, wherein n is an integer of 2 to 4 in Formula (1).
Item 5. Item 4. The composition according to any one of Items 1 to 3, comprising 0.01 to 10,000 parts by weight of the amino acid represented by Formula (1) with respect to 1 part by weight of ketotifen or a salt thereof.
Item 6. Item 4. The composition according to any one of Items 1 to 3, further comprising at least one selected from a nonionic surfactant, a chelating agent, and sorbic acid or a salt thereof.
Item 7. Item 4. The composition according to any one of Items 1 to 3, which is contained in a light transmissive container.
Item 8. Item 4. The composition according to any one of Items 1 to 3, which is an eye drop, an eye wash, a nasal drop, or a contact lens agent.
Item 9. A method for improving the photostability of ketotifen or a salt thereof by blending the amino acid represented by formula (1) according to item 1 with ketotifen or a salt thereof.

That is, the ketotifen-containing composition of the present invention is a stabilized composition containing ketotifen or a salt thereof (hereinafter sometimes simply referred to as ketotifen) and an amino acid represented by the following formula (1).
_{H 2 N- (CH 2) n} -COOH (1)
(In the formula, n represents an integer of 1 to 4)
In the formula (1), n may be an integer of 2 to 4. The ketotifen and amino acid salts include physiologically acceptable salts and pharmaceutically acceptable salts (particularly pharmaceutically acceptable salts), respectively. The composition may contain 0.01 to 10,000 parts by weight of the amino acid with respect to 1 part by weight of ketotifens. The composition may further contain at least one selected from a nonionic surfactant, a chelating agent, and sorbic acid or a salt thereof.

  The composition of the present invention can be used as various compositions based on the pharmacological action of ketotifens, and is an aqueous composition and a composition applied to mucosa, for example, eye drops, eye wash, nasal drops, contact lens preparations, etc. There may be. The contact lens includes all types of contact lenses such as a soft contact lens, a hard contact lens, and an oxygen permeable hard contact lens.

  Moreover, since the light stability etc. are improved, the composition of this invention is suitable for accommodating in a light transmissive container (For example, glass or a plastic container etc.).

  The present invention also includes a method for improving the light stability of ketotifens by blending the amino acids with ketotifens.

  In the present specification, “salt” means a pharmacologically or physiologically acceptable salt. And ketotifen or its salt can be used with the form of a hydrate.

  In the present invention, a specific amino acid is blended with ketotifen to improve the light stability of ketotifen (and a composition containing ketotifen).

(Ketotifens)
Ketotifen, ie, 4,9-dihydro-4- (1-methyl-4-piperidylidene) -10H-benzo [4,5] cyclohepta [1,2-b] thiophen-10-one, is a known compound, It may be synthesized by a known method or obtained as a commercial product.

  As the salt of ketotifen, a pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable salt can be used. Examples of such salts include organic acid salts [for example, monocarboxylate (acetate, trifluoroacetate, butyrate, palmitate, stearate, etc.), polyvalent carboxylate (fumarate, maleate). Acid salt), oxycarboxylate (lactate, tartrate, citrate, succinate, malonate, etc.), organic sulfonate (methanesulfonate, toluenesulfonate, tosylate, etc.) Etc.], inorganic acid salts (eg, hydrochloride, sulfate, nitrate, hydrobromide, phosphate, etc.), salts with organic bases (eg, methylamine, triethylamine, triethanolamine, morpholine, piperazine, Salts with organic amines such as pyrrolidine, tripyridine, picoline), salts with inorganic bases [eg ammonium salts; alkali metals (sodium, potassium, etc.), Alkaline earth metals (calcium, magnesium etc.) and salts with metals such as aluminum or the like].

  Of the ketotifens, organic acid salts, particularly ketotifen fumarate is preferred.

  The ketotifens can be used alone or in combination of two or more.

  The proportion of ketotifen in the composition can be appropriately selected according to the dosage form and the like, for example, so that the daily application amount (adult) is about 0.01 to 15 mg. For example, the ratio (concentration) of ketotifens is 0.0001 to 10% by weight (W / W%), preferably 0.0001 to 5 W / W%, more preferably 0.001%, based on the entire stabilized composition. It is about 0001 to 1 W / W%. Further, for example, when used as an aqueous composition or a composition applied to mucous membranes, 0.0001 to 1 W / V% (hereinafter referred to as “W / V%” unless otherwise specified) with respect to the entire composition. ], Preferably 0.001 to 1%, more preferably 0.001 to 0.1%, particularly about 0.01 to 0.1%.

(Amino acid represented by formula (1))
The amino acid represented by the formula (1) includes amino acids having n of 1 to 4, for example, glycine (n = 1), β-alanine (n = 2), γ-aminobutyric acid (γ-amino-n -Butanoic acid) (n = 3) and γ-aminovaleric acid (5-amino-n-pentanoic acid) (n = 4).

  Of these amino acids, amino acids where n is 2 to 4 are preferred.

  The amino acids can be used alone or in combination of two or more.

  The ratio of amino acids is about 0.001 to 20 W / W%, preferably 0.001 to 10 W / W%, and more preferably about 0.001 to 5 W / W% with respect to the entire stabilized composition. Further, for example, when used as an aqueous composition or a composition applied to mucous membranes, 0.001 to 10%, preferably 0.01 to 5%, more preferably 0.1 to 5%, based on the entire composition. (For example, about 2 to 5%).

  The ratio of amino acid to ketotifen is usually 0.01 to 10,000 parts by weight of amino acid (eg 0.05 to 10,000 parts by weight), preferably 0.1 to 3 parts per 1 part by weight of ketotifen. , 500 parts by weight (for example, 0.5 to 1,000 parts by weight), and more preferably from about 0.1 to 1,000 parts by weight. The ratio is 1 to 200 parts by weight, preferably 5 to 100 parts by weight (for example, 10 to 80 parts by weight), and more preferably about 15 to 80 parts by weight with respect to 1 part by weight of ketotifen. Also good.

  The composition of the present invention may further contain at least one selected from a nonionic surfactant, a chelating agent, and sorbic acid or a salt thereof. By combining such components, the photostability of ketotifens can be further improved.

  Nonionic surfactants include, for example, polyoxyethylene (POE) -polyoxypropylene (POP) block copolymers (for example, poloxamer 407, poloxamer 235, poloxamer 188, poloxamine, etc.); monolauric acid POE (20) sorbitan ( POE sorbitan fatty acid esters such as polysorbate 20) and monooleic acid POE (20) sorbitan (polysorbate 80); POE castor oil such as POE (60) castor oil, POE (60) hydrogenated castor oil or hydrogenated castor oil; POE ( 9) POE alkyl ethers such as lauryl ether; POE (20) POP (4) POE / POP alkyl ethers such as cetyl ether; POE alkyl phenyl ethers such as POE (10) nonylphenyl ether and the like can be used. In addition, the number in a parenthesis shows addition mole number (average addition mole number). These nonionic surfactants can be used alone or in combination of two or more. Among the nonionic surfactants, polyoxyethylene-polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil or hydrogenated castor oil, and polyoxyethylene alkyl ether are preferable.

  The ratio (concentration) of the nonionic surfactant is usually about 0.001 to 10 W / W%, preferably about 0.001 to 5 W / W% in the stabilized composition. In the aqueous composition or the composition applied to mucosa, the ratio is about 0.001 to 1%, preferably about 0.01 to 1%, more preferably about 0.05 to 1% in the composition.

  Examples of the chelating agent include edetic acid (ethylenediaminetetraacetic acid, EDTA), ethylenediaminediacetic acid (EDDA), diethylenetriaminepentaacetic acid (DTPA), N- (2-hydroxyethyl) ethylenediaminetriacetic acid (HEDTA), N- ( Examples include 2-hydroxyethyl) iminodiacetic acid (HIDA), citric acid, tartaric acid, succinic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1-hydroxyethane-1,1-diphosphonic acid, and the like. These chelating agents can be used alone or in combination of two or more.

  The chelating agent can also be used as a pharmacologically or physiologically acceptable salt (for example, the salt exemplified in the section of ketotifen).

  Among the chelating agents, ethylenediaminetetraacetic acid, citric acid and salts thereof [ethylenediaminetetraacetic acid disodium, ethylenediaminetetraacetic acid disodium dihydrate (sodium edetate), etc.] are preferable.

  The ratio (concentration) of the chelating agent is usually about 0.0001 to 10 W / W%, preferably about 0.001 to 5 W / W% in the stabilized composition. In the case of an aqueous composition or a composition applied to mucosa, the ratio is 0.0001 to 1%, preferably 0.001 to 0.5%, more preferably about 0.005 to 0.3% in the composition. It is.

  Examples of the sorbic acid salt include salts exemplified in the section of ketotifen. In particular, a salt with an inorganic base, for example, an alkali metal salt or alkaline earth metal salt of sorbic acid such as potassium sorbate is preferable. Sorbic acid or a salt thereof can be used alone or in combination of two or more.

  The ratio (concentration) of sorbic acid or a salt thereof is usually about 0.00005 to 10 W / W%, preferably about 0.0001 to 10 W / W% in the stabilized composition. Moreover, in the aqueous composition or the composition applied to mucosa, the ratio is 0.00005 to 10% (for example, 0.0001 to 10%), preferably 0.0005 to 5%, more preferably 0 in the composition. About 0.001 to 5%.

  In the present invention, the addition of the specific amino acid as described above can greatly improve the light stability of the composition containing ketotifen, and there is almost no irritation even when applied to the mucous membrane. Therefore, the composition of the present invention can be formulated in combination with various carriers (aqueous carrier, hydrophilic carrier, oily carrier, liquid carrier, granular carrier, etc.), and may be a non-aqueous composition. In particular, the composition of the present invention is useful as an aqueous composition because high light stability is obtained even in an aqueous medium.

  The composition of this invention can be provided with various forms according to the objective, for example, various dosage forms, such as a solid agent, a semi-solid agent, and a liquid agent. For example, solid preparations (tablets, powders, granules, capsules, etc.), semi-solid preparations (ointments (hard ointments, ointments etc.), creams, etc.), liquid preparations (eye drops, lotions, extracts, Suspensions, emulsions, syrups, injections (including injections prepared at the time of use), aerosols, soft capsules, drinks, etc.]. As long as it is an aqueous composition, it may be an aqueous semi-solid preparation such as a liquid, an ointment, or a cream. Furthermore, the composition of the present invention can be used not only as a pharmaceutical composition but also as a non-pharmaceutical composition such as a cleaning liquid, a contact lens preparation, food, and cosmetics.

  The composition of the present invention is useful as an aqueous composition. Such aqueous compositions include, for example, skin ointments, skin creams, skin liquids, eye drops (eye drops), eye wash (eye wash), eye ointments, contact lens mounting liquids, contact lens agents. (Cleaning solution, preservative solution, bactericidal solution, multipurpose solution), nasal drops (nasal drops), nasal rinses, oropharyngeal drugs, mouthwashes, ear drops, cosmetics and the like.

  Furthermore, since the composition of the present invention is safe with little or no irritation, it can be applied to the lips and mucous membranes (eye mucous membranes such as cornea and conjunctiva, oral mucosa, nasal mucosa, pharyngeal mucosa, etc.) that are susceptible to irritation. Useful for application. Examples of such mucosa-applied compositions include ophthalmic compositions [eye drops (including eye drops that can be used while wearing contact lenses), contact lens mounting liquids, and eye wash (eye drops that can also be used while wearing contact lenses). Drugs), contact lens preparations (cleaning solution, preservative solution, bactericidal solution, multipurpose solution, etc.), otolaryngological compositions (nasal drops, ear drops, nasal washing solutions, etc.), oral compositions (oropharynx Medicines, gargles, etc.). In this specification, the contact lens includes all types of contact lenses such as hard contact lenses (including oxygen permeable hard contact lenses) and soft contact lenses.

  Furthermore, a composition (particularly an aqueous composition) that is packaged in a form to be administered multiple times and used continuously by a user (particularly an aqueous composition), for example, an ointment for an outer skin, an outer skin, because it is highly stable to light. It is also useful for creams, skin solutions, eye drops, eye wash, nasal drops, gargles, contact lens preparations (cleaning solution, preservative solution, bactericidal solution, multipurpose solution).

  The composition of the present invention (aqueous composition, composition applied to mucous membranes) is combined with various components (including pharmacologically active components and physiologically active components) in addition to the above-described components as long as the photostability is not impaired. You may contain. The type of such components is not particularly limited, and examples thereof include, for example, a decongestant component, an anti-inflammatory component, an astringent component, an antipyretic analgesic component, a stomachic component, a digestive component, an ulcer therapeutic component, an antibacterial agent or a bactericidal agent. Ingredients, antitumor drug ingredients, hormones, proteins or peptides, amino acids, vitamins and the like can be exemplified. Examples of suitable components in the present invention include the following components.

  Decongestant: epinephrine, ephedrine, tetrahydrozoline, naphazoline, phenylephrine, methylephedrine and their salts. For example, α-adrenergic agonists such as imidazoline derivatives (naphazoline, tetrahydrozoline, etc.), β-phenylethylamine derivatives (phenylephrine, epinephrine, ephedrine, methylephedrine, etc.), and pharmaceutically or physiologically acceptable salts thereof ( For example, inorganic acid salts such as naphazoline hydrochloride, naphazoline nitrate, tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, phenylephrine hydrochloride, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride; and organic acid salts such as epinephrine hydrogen tartrate).

  Eye muscle modulator component: Cholinesterase inhibitor having an active center similar to acetylcholine, for example, quaternary ammonium compounds such as neostigmine methyl sulfate and salts thereof.

  Anti-inflammatory components: celecoxib, rofecoxib, indomethacin, diclofenac, pranoprofen, piroxicam, meloxicam, berberine, glycyrrhizic acid, lysozyme, methyl salicylate, allantoin, azulene sulfonic acid and their pharmacology Pharmaceutically acceptable salts such as berberine chloride, berberine sulfate, diclofenac sodium, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, lysozyme chloride, sodium azulene sulfonate and the like.

  Astringent ingredients: zinc and their salts (eg, zinc sulfate, zinc lactate) and the like.

  Antihistamine component or antiallergic component: for example, chlorpheniramine, diphenhydramine, iproheptin, emedastine, clemastine, azelastine, levocabastine, olopatadine, cromoglycic acid, tranilast, amlexanox, mequitazine, loratadine (loratadine) Cetirizine, ibudilast, suplatast, pemirolast, and pharmacologically acceptable salts (eg, chlorpheniramine maleate, diphenhydramine hydrochloride, iproheptine hydrochloride, emedastine fumarate, clemastine fumarate, azelastine hydrochloride, levocabastine hydrochloride, Olopatadine hydrochloride, cromoglycate sodium, etc.).

  Antibacterial or bactericidal components: For example, sulfonamides (eg, sulfamethoxazole, sulfisoxazole, sulfisomidine and pharmacologically acceptable salts (sulfamethoxazole sodium, sulfisomidine sodium) Etc.), acrinol, quaternary ammonium compounds (eg benzalkonium, benzethonium, cetylpyridinium) and pharmacologically acceptable salts (benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, cetylpyridinium bromide) Etc.), alkylpolyaminoethylglycine, new quinolone (lomefloxacin, levofloxacin, ciprofloxacin, ofloxacin, norfloxacin, ciprofloxacin hydrochloride, etc.), biguanides (polyhexamethylene biguanide, black Hexidine or a salt thereof), berberine or a salt thereof, polydronium chloride, Glokill (trade name, manufactured by Rhodia, for example, Glokill PQ), polydiallyldimethylammonium chloride, poly [oxyethylene (dimethyliminio) ethylene- (dimethyli Minio) ethylene dichloride], parabens (such as methyl aminobenzoate, ethyl aminobenzoate).

  Vitamins: For example, vitamins A [eg, retinal, retinol, retinoic acid, carotene, dehydroretinal, lycopene and pharmacologically acceptable salts thereof (eg, retinol acetate, retinol palmitate, etc.), vitamin B [E.g. thiamine, thiamine disulfide, dicetiamine, octothiamine, chicotiamine, bisbutiamine, bisbenchamine, prosultiamine, benfotiamine, fursultiamine, riboflavin, flavin adenine dinucleotide, pyridoxine, pyridoxal, hydroxocobalamin, Cyanocobalamin, methylcobalamin, deoxyadenocobalamin, folic acid, tetrahydrofolic acid, dihydrofolic acid, nicotinic acid, nicotinamide, nicotinic alcohol, pantothenic acid, Ntenol, biotin, choline, inositol and pharmacologically acceptable salts thereof (for example, thiamine hydrochloride, thiamine nitrate, dicetiamine hydrochloride, fursultiamine hydrochloride, riboflavin butyrate, sodium flavin adenine dinucleotide, pyridoxine hydrochloride, pyridoxal phosphate, Pyridoxal calcium phosphate, hydroxocobalamin hydrochloride, hydroxocobalamin acetate, calcium pantothenate, sodium pantothenate etc.)], vitamin C [ascorbic acid and derivatives thereof, erythorbic acid and derivatives thereof and pharmacologically acceptable salts thereof (Eg, sodium ascorbate, sodium erythorbate, etc.)], vitamin D [eg, ergocalciferol, cholecalciferol, hydroxycholecalcif Roll, dihydroxycholecalciferol, dihydrotaxosterol and pharmacologically acceptable salts thereof], vitamin E [eg, tocopherol and derivatives thereof, ubiquinone derivatives and pharmacologically acceptable salts thereof (tocopherol acetate, Tocopherol nicotinate, tocopherol succinate, calcium tocopherol succinate, etc.)], other vitamins [eg carnitine, ferulic acid, γ-oryzanol, orotic acid, rutin, eriocitrin, hesperidin and their pharmacologically acceptable Salts (such as carnitine chloride)].

  Amino acids: For example, monoamino monocarboxylic acid [leucine (2-amino-4-methylvaleric acid), isoleucine (2-amino-3-methylvaleric acid), valine (2-amino-3-methylbutyric acid), methionine (2-amino-4-methylthiobutyric acid), threonine (2-amino-3-hydroxybutyric acid), phenylalanine, tryptophan, serine, proline, hydroxyproline, tyrosine, cysteine, etc.], diaminomonocarboxylic acid (lysine, hydroxylysine, Asparagine, glutamine, ornithine, etc.), monoaminodicarboxylic acid (aspartic acid, glutamic acid), histidine, glycylglycine, aminoethylsulfonic acid (taurine), and pharmacologically acceptable salts thereof (for example, potassium aspartate, Magne aspartate Umm, such as cysteine hydrochloride) and the like.

  Sugars: monosaccharides (eg glucose), disaccharides (eg trehalose, lactose, fructose etc.), oligosaccharides (eg lactulose, raffinose, pullulan etc.), cellulose or derivatives thereof (eg methylcellulose, ethylcellulose, hydroxyethylcellulose) , Hydroxypropylcellulose, carboxymethylcellulose, carboxyethylcellulose, etc.), high molecular sugars (eg, chondroitin sulfate, hyaluronic acid, etc.) and pharmacologically acceptable salts thereof (eg, chondroitin sulfate sodium, sodium hyaluronate, etc.), sugars Alcohols (for example, mannitol, xylitol, sorbitol, etc.).

  Local anesthetic components: lidocaine, oxybuprocaine, dibucaine, procaine, ethyl aminobenzoate, meprilucaine, and salts thereof (such as lidocaine hydrochloride and oxybuprocaine hydrochloride).

Steroid component: Hydrocortisone, prednisolone, and salts thereof Other components: Polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, etc.

  The content of these components can be selected according to the type of preparation, the type of active ingredient, etc., for example, from 0.0001 to 30%, preferably from about 0.001 to 10% of the whole preparation. You can choose.

  More specifically, in the preferred aqueous composition in the present invention, the content of each component is, for example, as follows.

Decongestant component (vasoconstrictor or sympathomimetic agent): For example, 0.0001 to 0.5%, preferably 0.0005 to 0.3%, more preferably about 0.001 to 0.1%. Regulator component: For example, 0.0001 to 0.5%, preferably about 0.001 to 0.1% Anti-inflammatory component or astringent component: For example, 0.0001 to 10%, preferably 0.0001 to About 5% Antihistamine component: For example, 0.0001 to 10%, preferably about 0.001 to 5% Bactericidal component: For example, 0.001 to 10%, preferably about 0.01 to 10% Vitamins Class: For example, about 0.0001 to 1%, preferably about 0.0001 to 0.5% Amino acid: For example, about 0.0001 to 10%, preferably about 0.001 to 3% Sugar: For example, about 0.001%. 0001-5%, good Preferably about 0.001 to 5%, more preferably about 0.01 to 2% Cellulose or a derivative thereof or a salt thereof: for example, 0.001 to 5%, preferably about 0.01 to 1%. Or a salt thereof: For example, 0.0001 to 2%, preferably 0.001 to 2%, more preferably about 0.01 to 2% (for example, 0.01 to 1%). Polyvinylpyrrolidone, polyvinyl alcohol: For example, 0.001 to 10%, preferably 0.001 to 5%, more preferably about 0.01 to 3%.

  In the composition of the present invention, various components and additives used for pharmaceuticals, quasi-drugs, etc. are arbitrarily selected according to the form of the preparation, as long as the effects of the invention are not impaired. It is possible to formulate it in combination.

  For example, for solid preparations, binders (hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, etc.), excipients (sucrose, lactose, starch, corn starch, crystalline cellulose, light anhydrous Silicic acid etc.), lubricants (magnesium stearate etc.), disintegrants (croscarmellose sodium etc.) etc. can be used. Moreover, in the semi-solid preparation, a base according to the type of preparation, for example, an ointment base (for example, hydrocarbon base such as petrolatum, liquid paraffin, wax, cetanol, higher fatty acid ester, etc.), gel base ( For example, carboxyvinyl polymer, polyoxyethylene polyoxypropylene block copolymer, gum, etc.), oily base (vegetable oil such as olive oil, soybean oil, sesame oil, cottonseed oil, propylene glycol, etc.) can be used. Furthermore, in the liquid agent, a solvent or water as a base, an oily base, a solubilizing agent, a suspending or emulsifying agent, an isotonic agent, a buffering agent and the like can be used.

  Moreover, you may add antiseptic | preservative, antioxidant, a sweetening agent, a sour agent, a coloring agent, a fragrance | flavor, etc. to these compositions as needed.

  Below, although the typical component used for the aqueous composition which is 1 aspect of this invention is illustrated, it is not limited to these components.

  Sugars: for example, glucose, fructose, galactose, mannose, ribose, ribulose, arabinose, xylose, lyxose, deoxyribose, maltose, trehalose, sucrose, cellobiose, lactose, pullulan, lactulose, raffinose, maltitol and the like Acceptable salts.

  Thickeners: for example, polysaccharides or derivatives thereof (gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guayac fat, quince seed, dalman gum, tragacanth, benzoin gum, locust bean gum, casein, agar, alginic acid, dextrin, dextran, Carrageenan, gelatin, collagen, pectin, starch, polygalacturonic acid, chitin and derivatives thereof, chitosan and derivatives thereof, elastin, heparin, heparinoid, heparin sulfate, heparan sulfate, hyaluronic acid, chondroitin sulfate, etc.), ceramide, cellulose or derivatives thereof (Cellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carbo Methyl cellulose, carboxyethyl cellulose, etc.), polyvinyl alcohol (completely or partially saponified product), polyvinyl pyrrolidone, macrogol, polyvinyl (meth) acrylate, polyacrylic acid, carboxyvinyl polymer, polyethyleneimine, ribonucleic acid, deoxyribonucleic acid, and the like Pharmacologically acceptable salts.

  Surfactant: Surfactant other than the nonionic surfactant, for example, amphoteric surfactants such as glycine type such as alkyldiaminoethyl glycine, betaine acetate type such as lauryldimethylaminoacetic acid betaine, imidazoline type; POE ( 10) POE alkyl ether phosphates and salts thereof such as sodium lauryl ether phosphate, N-acyl amino acid salts such as sodium lauroylmethylalanine, alkyl ether carboxylates, N-acyl taurine salts such as sodium N-cocoylmethyl taurate, Anionic surfactants such as sulfonates such as sodium tetradecenesulfonate, alkyl sulfates such as sodium lauryl sulfate, POE alkyl ether sulfates such as POE (3) sodium lauryl ether sulfate, α-olefin sulfonates; Cationic surfactants such as alkylamine salts, alkyl quaternary ammonium salts (such as benzalkonium chloride and benzethonium chloride), and alkylpyridinium salts (such as cetylpyridinium chloride and cetylpyridinium bromide). The numbers in parentheses indicate the number of added moles.

  Preservatives, bactericides or antibacterial agents: for example, paraoxybenzoic acid esters (methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, etc.), acrinol, methylrosaniline chloride, benzalkonium chloride, benzethonium chloride , Cetylpyridinium chloride, cetylpyridinium bromide, chlorhexidine, polyhexamethylene biguanide, alkylpolyaminoethylglycine, benzyl alcohol, phenethyl alcohol, chlorobutanol, isopropanol, ethanol, phenoxyethanol, sulfur, zirconium phosphate silver, zinc, zinc oxide, etc. Supports, silver zinc aluminosilicate, mercurochrome, thimerosal, povidone iodine, dehydroacetic acid, chloroxylenol, creso , Chlorophene, phenol, resorcin, orthophenylphenol, isopropylmethylphenol, thymol, hinokitiol, sulfamine, lysozyme, lactoferrin, triclosan, 8-hydroxyquinoline, undecylenic acid, caprylic acid, propionic acid, benzoic acid, sorbic acid, sorbin Potassium acid, sodium sorbate, triclocarban sorbate, halocarban, thiabendazole, polymyxin B, 5-chloro-2-methyl-4-isothiazolin-3-one, 2-methyl-4-isothiazolin-3-one, polylysine, Hydrogen peroxide, polydronium chloride, Glokill (trade name, manufactured by Rhodia, for example, Glokill PQ), polydiallyldimethylammonium chloride, poly [oxyethylene (dimethyliminio) ethylene - (dimethyliminio) ethylene dichloride], etc., and the like pharmacologically acceptable salts.

  pH adjuster: For example, inorganic acid (hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, boric acid, etc.), organic acid (acetic acid, propionic acid, oxalic acid, gluconic acid, fumaric acid, lactic acid, citric acid, tartaric acid, malic acid , Succinic acid, etc.), gluconolactone, ammonium acetate, inorganic bases (sodium bicarbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, etc.), organic bases (monoethanolamine, triethanol) Amine, diisopropanolamine, triisopropanolamine, etc.), borax, and pharmacologically acceptable salts thereof.

  Isotonizing agents: for example, polyhydric alcohols such as glycerin and propylene glycol, saccharides (buty sugar, mannitol, sorbitol, etc.).

  Inorganic salts: For example, sodium chloride, potassium chloride, sodium carbonate, sodium bicarbonate, calcium chloride, magnesium sulfate, sodium hydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium thiosulfate, sodium acetate and the like.

  Furthermore, a fragrance or a refreshing agent (for example, menthol, camphor, borneol, geraniol, eucalyptus oil, bergamot oil, fennel oil, mint oil, cinnamon oil, rose oil, peppermint oil, etc.) can be added as necessary. .

  The aqueous composition (or aqueous solution) needs to be adjusted to a pH and / or osmotic pressure within a range acceptable to a living body, if necessary. The acceptable pH is usually preferably acidic to neutral (for example, about pH 3.0 to 7.5) for an internal drink. In the outer skin composition, the pH can be usually selected from a range of about 2.0 to 7.5, preferably from pH 3.0 to 7.5, more preferably from the viewpoint of low irritation to the skin and good skin feeling. Is preferably weakly acidic to neutral (for example, about pH 3.0 to 6.5). In the mucosa-applied composition, for example, in the case of eye drops and eye wash, the pH is usually 4.0 to 7.5, preferably pH 4.5 to 7.5, more preferably about pH 4.5 to 6.5. In the case of nasal drops, the pH is usually about 3.0 to 7.5, preferably about 3.5 to 7.5, more preferably about pH 3.5 to 6.5.

  The osmotic pressure is about 100 to 1200 mOsm, preferably about 100 to 600 mOsm, particularly preferably about 150 to 400 mOsm, and the osmotic pressure ratio with respect to physiological saline is usually 0.3 to 4.1, preferably 0.3 to 2. 1, particularly preferably about 0.5 to 1.4. The pH and osmotic pressure can be adjusted using a buffer, the pH adjuster, an isotonic agent, salts and the like.

  Examples of the buffer include known borate buffers, phosphate buffers, carbonate buffers, citrate buffers, acetate buffers, Good buffers, and the like. Preferred buffers are Good buffer, borate buffer, phosphate buffer, carbonate buffer and citrate buffer. Particularly preferred buffers are Good buffer, borate buffer or phosphate buffer. “Good buffering agent” is a general term for aminoethanesulfonic acid derivatives and aminopropanesulfonic acid derivatives having a zwitterionic structure having buffering ability, and is a buffering agent devised by Good et al. Examples of the good buffer include MES, MOPS, PIPES, HEPES, BES, and TES. Examples of the boric acid buffer include borates such as boric acid, alkali metal borates, and alkaline earth metal borates, and combinations of boric acid and borates. Examples of the phosphate buffer include phosphates such as phosphoric acid, alkali metal phosphates, and alkaline earth metal phosphates, and combinations of phosphoric acid and phosphates. Moreover, you may use the borate or the hydrate of a phosphate as a borate buffer or a phosphate buffer. More specifically, boric acid or a salt thereof (sodium borate, potassium tetraborate, potassium metaborate, etc.), phosphoric acid or a salt thereof (sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, etc.) , Carbonic acid or a salt thereof (sodium hydrogencarbonate, sodium carbonate, etc.). When a borate buffer or a phosphate buffer is used as the buffer, the concentration of these buffers in the aqueous composition of the present invention is, for example, about 0.0001 to 10.0%.

  The composition of this invention can be manufactured by a well-known method. The solid preparation can be prepared, for example, by kneading or granulating each component, and adding an additive as necessary to perform tableting. A semi-solid agent and a liquid agent can be prepared by mixing a base and each component, and if necessary, sterilizing by filtration and filling a container. More specifically, in the case of an eye drop of an aqueous composition, for example, ketotifens and amino acids are dissolved using distilled water or purified water and an additive, adjusted to a predetermined osmotic pressure and pH, and an aseptic environment. Then, it can be produced by sterilizing by filtration and aseptically filling a container that has been sterilized by washing.

  The composition of the present invention has high light stability and can maintain high light stability over a long period of time. Therefore, it is excellent in light-transmitting containers, glass or plastic containers, particularly squeeze and portability. It can be packaged or accommodated in a plastic container or the like in a form that can be used repeatedly. Furthermore, since the composition of the present invention can be packaged or housed in a highly light permeable container such as a plastic container, foreign matter contamination can be reliably determined from the outside of the container, and a foreign matter confirmation test is easily performed. In addition, it is possible to reliably perform process control and quality control of an aqueous composition (aqueous preparations such as eye drops, eyewashes, injections, infusions, beverages, foods, and cosmetics).

  Examples of the plastic container resin that can contain the composition include olefin resins (polyethylene, polypropylene, etc.), polyester resins, polyphenylene ether resins, polycarbonate resins, polysulfone resins, polyamide resins, and hard vinyl chloride resins. And styrene resins (polystyrene, acrylonitrile-styrene copolymer (AS resin), etc.), cellulose acetates and the like. Preferred resins are polyethylene, polypropylene, polyester resins, and polycarbonate resins, and particularly preferred resins are polyester resins.

As the polyester resin, a resin composed of a dicarboxylic acid component (such as an aromatic dicarboxylic acid component such as phthalic acid, terephthalic acid, or naphthalenedicarboxylic acid) and a diol component can be used. Specifically, aromatic polyester resins such as polyalkylene terephthalate [poly C _2-4 alkylene terephthalate such as polyethylene terephthalate (PET) and polybutylene terephthalate (PBT)], polyalkylene naphthalate [polyethylene naphthalate ( PEN), poly C _2-4 alkylene naphthalate such as polybutylene naphthalate, etc.], polycycloalkylene terephthalate [poly (1,4-cyclohexylenedimethylene terephthalate) (PCT) etc.], polyarylates (bisphenols ( Homopolyesters such as bisphenol-A) and phthalic acids (resins composed of phthalic acid and terephthalic acid). The polyester resin also includes a copolyester containing the homopolyester unit as a main component (for example, 50% by weight or more), a copolymer of the homopolyester (such as a copolymer of PET and PCT), and the like. . Of these, olefin resins (such as polyethylene), aromatic polyester resins (polyethylene terephthalate, polyethylene naphthalate, polyarylate, etc.) and polycarbonate resins are preferred.

  The polycarbonate-based resin is, for example, an aromatic polycarbonate based on bisphenols (such as bisphenol-A).

  The plastic container may be a polymer alloy (polymer blend or the like) as long as there is no real harm in cost performance, strength, light permeability, gas or water vapor barrier properties (moisture permeability), and the like. Preferred polymer alloys include polymer blends of a plurality of synthetic resins (such as polymer blends of PET and PEN).

  The resin is preferably a resin having good squeeze properties and durability against repeated pressing, and a transparent or translucent resin, and may be colored as necessary. In addition, by incorporating a component that can inhibit light transmission (such as an ultraviolet absorber or an infrared absorber) into the resin, or by applying a coating agent containing the component to the resin surface, the effect of the present invention is achieved. Thus, the light stability may be further improved.

  In the present invention, a specific amino acid is further added to the composition containing ketotifen, so that even a composition containing ketotifen (aqueous composition, composition applied to mucous membrane) is highly improved in light stability. it can. Moreover, even in an aqueous solution, the stability of the composition (aqueous composition) to light can be improved, and a stable aqueous composition can be obtained over a long period of time. Furthermore, not only the stability to light is improved, but a safe composition for applying to mucosa that is not irritating when applied to the mucosa can be obtained. In addition, the method of the present invention can improve the stability of ketotifen to light.

  Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.

Preparation Examples 1-24
The components shown in Tables 1 to 4 were dissolved in purified water at the ratios shown in the table to make 100 ml, and eye drops, eye washes, nasal drops, and contact lens preparations were prepared. In the table, the term “concentrated benzalkonium chloride 50” means a substance based on the Japanese Pharmacopoeia.

Examples 1-8 and Comparative Examples 1-2
(1) Preparation of test solution Test solutions prepared by dissolving ketotifen fumarate and the amino acids shown in Table 5 in purified water at the ratios shown in the table to make 100 ml were filled in colorless and transparent glass bottles and sealed. In the Examples, as amino acids, in the formula NH ₂ — (CH ₂ ) _n —COOH, n = 1: glycine, n = 2: β-alanine, n = 3: γ-amino-n-butanoic acid, and n = 4: 5-Amino-n-pentanoic acid was used.

  Moreover, the test solution was prepared similarly to the Example about the example (comparative example 1) which does not contain an amino acid, and the example (comparative example 2) which used aminoethylsulfonic acid as an amino acid.

(2) Light Stabilization Test Each test solution was tested for light stability according to the following procedure.

  Using a light stability tester (“Light-Tron LT-120 D3CJ type”, manufactured by Nagano Science Co., Ltd.), the obtained test solution was 5,000 lux at a room temperature of 25 ° C. using a D65 fluorescent lamp as a light source. The test solution was exposed to light with an integrated dose of about 200,000 lux · hr. Since ketotifen fumarate is decomposed by light and the test solution is colored brown, the test solution after light irradiation is 400 nm by an absorbance method using a spectrophotometer ("U-3300", manufactured by Hitachi, Ltd.). The degree of coloring was evaluated. The results are shown in Table 5.

  As is clear from the table, in Examples using specific amino acids, coloring of ketotifen due to light irradiation was suppressed.

Claims (1)

The composition stabilized with respect to the light containing ketotifen or its salt, and the amino acid or its salt represented by following formula (1).
_{H 2 N- (CH 2) n} -COOH (1)
(In the formula, n represents an integer of 1 to 4)