JPH10152438A - Stabilization of 1-azaxanthone derivative or its salt and 1-azaxanthone derivative-containing composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a clinically advantageous pharmaceutical composition by adding a phenolic hydroxyl group-containing compound to the subject specific derivative or its salt. SOLUTION: This composition is obtained by adding 0.001-1(W/V)% compound selected from p-hydroxybenzoic acid, phenol, cresol and dibutylhydroxytoluene to 0.01-2.0(W/V)% compound of the formula (A ring may be substituted; R1 is H or an amino group; R2 is a group capable of releasing proton) or its salt. The composition is stabilized in the compound of the formula and excellent in feeling to user and useful as a pharmaceutical preparation for administration for local part of an eye. When the composition is administered as an eye drop to adult, the composition is administered in a daily dose of one or several drops one to several times per day according to the symptom as an aqueous eye drop containing about 0.01-2.0% compound of the formula or its salt.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a compound represented by the following general formula [I]:
And a method for stabilizing a 1-azaxanthone derivative or a salt thereof represented by the formula: and a composition containing the derivative.

[0002]

[Prior art]

 General formula [I]

[0003]

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Wherein the ring A may be substituted;
₁ represents hydrogen or an amino group which may be protected, R ₂
Represents a group capable of releasing a proton.] A 1-azaxanthone derivative (hereinafter, also referred to as a 1-azaxanthone derivative [I]) represented by, for example, JP-A-61-1058.
No. 7 describes that it has a strong antiallergic action and antiinflammatory action. Also, Japanese Patent Application Laid-Open No. 7-2580
No. 83 describes that the 1-azaxanthone derivative of the present invention exhibits a myopia preventing / treating effect based on ciliary muscle relaxing action. One of the derivatives, the following formula [II
I]

[0005]

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The compound represented by the formula amlexanox, chemical name 2-amino-7-isopropyl-1-azaxanthone-3-carboxylic acid (or 2-amino-7-isopropyl-5-oxo-5H- [1] benzopyrano [ 2,3-
b] Pyridine-3-carboxylic acid) is commercially available under the trade name of ELIX ophthalmic solution (registered trademark). However, there is a problem that the 1-azaxanthone derivative [I] is unstable in an aqueous solution state and is gradually decomposed. For this reason, conventionally, it has been stabilized by mixing parabens such as methyl parahydroxybenzoate and propyl parahydroxybenzoate with an aqueous solution of the derivative. However, since these parabens are not stable, and irritate the eyes clinically, particularly when used in the ophthalmic field, parabens are excellent in stability and clinical usability. The use of alternative stabilizers is desired.

[0007]

SUMMARY OF THE INVENTION An object of the present invention is to provide a 1-azaxanthone derivative [I] or a 1-azaxanthone derivative [I] by adding a stabilizing agent having a low irritancy, a good clinical feeling in use, and excellent stability. It is to provide a method for stabilizing a salt. Another object of the present invention is to provide a low-irritant and stable composition containing the 1-azaxanthone derivative [I] or a salt thereof.

[0008]

Means for Solving the Problems The present inventors have conducted intensive studies in order to achieve the above object, and have been seeking various compounds in order to obtain a stabilizer having low irritation, good feeling in use, and excellent stability. Searched. As a result, the present inventors have found that by adding a phenolic hydroxyl group-containing compound such as parahydroxybenzoic acid, phenol, cresol, and dibutylhydroxytoluene, the stability of the 1-azaxanthone derivative [I] or a salt thereof is remarkably increased. It has been found that the phenolic hydroxyl group-containing compound is improved with low irritation and has excellent stability, and the present invention has been completed.

That is, the present invention relates to (1) a phenolic hydroxyl group-containing compound represented by the general formula [I]:

[0010]

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Wherein the ring A may be substituted;
₁ represents hydrogen or an amino group which may be protected, R ₂
Represents a group capable of releasing a proton.] A method for stabilizing a 1-azaxanthone derivative or a salt thereof, which is added to an aqueous solution of a 1-azaxanthone derivative or a salt thereof represented by the following formula: (2) Ring A Is substituted with a halogen atom, a nitro group, an alkyl group, an alkoxy group, or a butadienylene group (-CH = CH-CH = CH-) which forms a benzene ring with two adjacent carbon atoms at positions 6,7,8,9. (1) The method for stabilizing a 1-azaxanthone derivative or a salt thereof according to (1), (3) the 1-aza according to (1), wherein the group capable of releasing a proton is a carboxyl group or a tetrazolyl group. (4) A method for stabilizing a xanthone derivative or a salt thereof, wherein (1) the 1-azaxanthone derivative has a general formula [II]

[0012]

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Wherein R represents an alkyl group, R ₁ represents hydrogen or an amino group which may be protected, and R ₂ represents a group capable of releasing a proton. 1-
A method for stabilizing an azaxanthone derivative or a salt thereof,
(5) The method for stabilizing a 1-azaxanthone derivative or a salt thereof according to (4), wherein the alkyl group is an alkyl group having 1 to 6 carbon atoms, and (6) the method according to (4), wherein the alkyl group is an isopropyl group. A method for stabilizing a 1-azaxanthone derivative or a salt thereof, (7) wherein R ₁ is an amino group (1)
Or (1) a method for stabilizing a 1-azaxanthone derivative or a salt thereof according to (4), (8) stabilization of a 1-azaxanthone derivative or a salt thereof according to (1) or (4), wherein R ₂ is a carboxyl group. (9) The 1-azaxanthone derivative has the formula [III]

[0014]

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(1) The method for stabilizing a 1-azaxanthone derivative or a salt thereof according to (1), wherein (10) the phenolic hydroxyl group-containing compound comprises parahydroxybenzoic acid, phenol, cresol, and dibutylhydroxytoluene. (1) a method for stabilizing a 1-azaxanthone derivative or a salt thereof according to (1) selected from the group; (11) a 1-azaxanthone derivative according to (10), wherein the phenolic hydroxyl group-containing compound is parahydroxybenzoic acid; (13) the method for stabilizing a 1-azaxanthone derivative or a salt thereof according to (10), wherein the phenolic hydroxyl group-containing compound is phenol;
The phenolic hydroxyl group-containing compound is cresol (1
0) The method for stabilizing a 1-azaxanthone derivative or a salt thereof according to 0), (14) the compound according to 10), wherein the phenolic hydroxyl group-containing compound is dibutylhydroxytoluene.
-A method for stabilizing an azaxanthone derivative or a salt thereof,
(15) a phenolic hydroxyl group-containing compound in an amount of 0.001 to 0.001;
The method for stabilizing a 1-azaxanthone derivative or a salt thereof according to (1), wherein the method is added at a concentration of 1 (W / V)%
6) The 1-azaxanthone derivative according to (1), which contains the 1-azaxanthone derivative represented by the general formula [I] or a salt thereof at a concentration of 0.01 to 2.0 (W / V)% or (17) A method for stabilizing a salt thereof, (17) adding 1-azaxanthone derivative represented by the general formula [I] or a salt thereof to 0.1 to
1 (1) described in (1), which is contained at a concentration of 1.0 (W / V)%.
-A method for stabilizing an azaxanthone derivative or a salt thereof,
(18) General formula [I]

[0016]

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Wherein the ring A may be substituted;
₁ represents hydrogen or an amino group which may be protected, R ₂
Represents a group capable of releasing a proton], a 1-azaxanthone derivative or a salt thereof, and a 1-azaxanthone derivative-containing composition containing a phenolic hydroxyl group-containing compound, (19) a ring A having a halogen atom, A nitro group, an alkyl group, an alkoxy group or a butadienylene group (-CH = CH-CH = CH-) forming a benzene ring with two adjacent carbon atoms at positions 6,7,8,9 (1) The composition containing a 1-azaxanthone derivative according to (18), (20) the compound according to (18), wherein the group capable of releasing a proton is a carboxyl group or a tetrazolyl group.
A composition containing an azaxanthone derivative, (21) a 1-azaxanthone derivative represented by the general formula [II]:

[0018]

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Wherein R represents an alkyl group, R ₁ represents hydrogen or an amino group which may be protected, and R ₂ represents a group capable of releasing a proton. 1
-Azaxantone derivative-containing composition, (22) the 1-azaxanthone derivative-containing composition according to (21), wherein the alkyl group is an alkyl group having 1 to 6 carbon atoms, and (23) the alkyl group is an isopropyl group ( 1) described in 21)
The composition containing an azaxanthone derivative, (24) the composition containing a 1-azaxanthone derivative according to (18) or (21), wherein R ₁ is an amino group, or (25) the composition (18) wherein R ₂ is a carboxyl group or The composition containing the 1-azaxanthone derivative according to (21), (26) the 1-azaxanthone derivative represented by the formula [III]

[0020]

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(18) The composition containing a 1-azaxanthone derivative according to (18), wherein (27) the phenolic hydroxyl group-containing compound is selected from the group consisting of parahydroxybenzoic acid, phenol, cresol, and dibutylhydroxytoluene. (18) The composition containing a 1-azaxanthone derivative according to (18), (28) the compound according to (27), wherein the phenolic hydroxyl group-containing compound is parahydroxybenzoic acid.
The composition containing a azaxanthone derivative, (29) the composition containing a 1-azaxanthone derivative according to (27), wherein the phenolic hydroxyl group-containing compound is phenol, and (30) the phenolic hydroxyl group-containing compound is cresol (2).
7) The composition containing a 1-azaxanthone derivative according to 7),
(31) The 1-azaxanthone derivative-containing composition according to (27), wherein the phenolic hydroxyl group-containing compound is dibutylhydroxytoluene, and (32) the phenolic hydroxyl group-containing compound in an amount of 0.001 to 1 (W / V)%. (18) the 1-azaxanthone derivative-containing composition according to (18), which is added at a concentration, (33) a form of a formulation for topical administration to the eye,
The composition containing a 1-azaxanthone derivative described in (3), (3
4) The 1-azaxanthone derivative-containing composition according to (33), which is in the form of eye drops, (35) the 1-azaxanthone derivative-containing composition, according to (34) which is in the form of aqueous eye drops, (36) ) The 1-azaxanthone derivative represented by the general formula [I] or a salt thereof is used in an amount of 0.01 to 2.0 (W / V).
(35), a composition containing (1-37) a 1-azaxanthone derivative represented by the general formula (I) or a salt thereof.
1- described in (35), which is contained at a concentration of 0 (W / V)%.
An azaxanthone derivative-containing composition.

[0022]

BEST MODE FOR CARRYING OUT THE INVENTION In the general formula [I], the substituent on ring A is, for example, a halogen atom, a nitro group, an alkyl group, an alkoxy group, or two adjacent groups at positions 6,7,8,9. Butadienylene group (-CH = CH-CH = CH-) forming a benzene ring with a carbon atom. Here, examples of the halogen atom include chlorine, bromine, fluorine and the like. The alkyl group is preferably a linear or branched alkyl group having 1 to 6 carbon atoms. Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl. The alkyl group is more preferably a straight-chain or branched alkyl group having 1 to 3 carbon atoms.
The alkoxy group is preferably an alkoxy group having 1 to 4 carbon atoms. Examples of the alkoxy group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,
tert-butoxy and the like. One or more substituents on the ring A may be the same or different and may be substituted on any position of the ring A.

In the general formulas [I] and [II], examples of the protecting group in the optionally protected amino group represented by R ₁ include (1) (a) a halogen atom (eg, chlorine, bromine, Fluorine, etc.), (b) an alkanoyl group having 1 to 7 carbon atoms (eg,
Formyl, acetyl, propionyl, isopropionyl, n-butyryl, isobutyryl, n-valeryl, isovaleryl, pivaloyl, n-hexanoyl, etc.) and (c)
An alkanoyl group having 2 to 7 carbon atoms which may have 1 to 3 substituents selected from nitro group and the like (eg, acetyl, propionyl, isopropionyl, n-butyryl, isobutyryl, n-valeryl, isovaleryl, Pivaloyl, n-hexanoyl, etc.), (2) an arylcarbonyl group having 7 to 11 carbon atoms which may have 1 to 3 substituents selected from the above (a), (b) and (c) (Eg, benzoyl, p-toluoyl, 1-naphthoyl,
2-naphthoyl, etc.), (3) an alkoxycarbonyl group having 2 to 7 carbon atoms which may have 1 to 3 substituents selected from the above (a), (b) and (c) (e.g., Methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, etc.), and (4) one to three substituents selected from (a), (b) and (c) above. (5) 1 to 3 substituents selected from the above (a), (b) and (c), which may have an aryloxycarbonyl group having 7 to 11 carbon atoms (eg, phenoxycarbonyl, etc.) (6) 1 to 3 aralkylcarbonyl groups having 8 to 13 carbon atoms (eg, benzylcarbonyl, phenethylcarbonyl, etc.) which may have (6) the above (a), (b) and (c) 8 to 13 carbon atoms which may have a substituent Aralkyloxycarbonyl group (eg, benzyloxycarbonyl, phenethyloxycarbonyl, etc.), (7) above (a),
(b) and a phthaloyl group optionally having 1 to 3 substituents selected from (c) and the like, (8) the above (a), (b) and
(c) an arylsulfonyl group having 6 to 10 carbon atoms optionally having 1 to 3 substituents selected from (c) and the like (eg, phenylsulfonyl, tosyl, etc.), (9) the above (a)
, (B) and (c), etc., which may have 1 to 3 substituents, and may have 1 to 6 carbon atoms, such as an alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, n
-Propylsulfonyl, etc.), (10) above (a), (b), (c)
And an alkyl group having 1 to 6 carbon atoms which may have 1 to 3 substituents selected from amino groups and the like (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- Butyl, tert-butyl, n-pentyl, n-hexyl, etc.), (11) above (a), (b) and (c)
And an aralkyl group having 7 to 19 carbon atoms optionally having 1 to 3 substituents selected from the group consisting of benzyl,
Phenethyl, benzhydryl, trityl and the like).

The protecting group in the amino group is preferably one to three substituents selected from the group consisting of (a) a halogen atom, (b) an alkanoyl group having 1 to 7 carbon atoms and (c) a nitro group. Each of which may have a C2 to C7 alkanoyl group, a C7 to C11 arylcarbonyl group, a C2 to C7 alkoxycarbonyl group, a C7 to C11 aryloxycarbonyl group, 8 to 13 aralkylcarbonyl groups,
And an aralkyloxycarbonyl group having 8 to 13 carbon atoms. R ₁ is preferably an unsubstituted amino group.

In the general formulas [I] and [II], the group capable of releasing a proton represented by R ₂ is, for example, a carboxyl group, a tetrazolyl group, a trifluoromethanesulfonylamino group (—NHSO ₂ CF ₃₎ ), A phosphono group, a sulfo group, etc., which can easily anionize by releasing H ⁺ , and these groups are an alkyl group optionally substituted by a suitable substituent (eg, methyl, n-butyl) Or an optionally substituted acyl group (eg, an alkanoyl group having 2 to 4 carbon atoms such as acetyl and propionyl which may be substituted with a halogen atom, etc.), and a halogen atom , A benzoyl group which may be substituted with amino, etc.)
Under biological or physiological conditions (eg in vivo reactions such as oxidation / reduction or hydrolysis by in vivo enzymes)
Or a group capable of chemically releasing a proton or a group capable of changing the proton. The group capable of releasing a proton is preferably a carboxyl group, a tetrazolyl group or the like, and a carboxyl group is particularly preferred.

In the general formula [II], the alkyl group represented by R is preferably a linear or branched alkyl group having 1 to 6 carbon atoms. Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n
-Butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n
-Hexyl and the like. R is more preferably a straight-chain or branched alkyl group having 1 to 3 carbon atoms. R is particularly preferably an isopropyl group.

The 1-azaxanthone derivative represented by the general formula [I] is preferably a compound represented by the general formula [II], particularly preferably a compound represented by the formula [III].

The 1-azaxanthone derivative represented by the general formula [I] is, for example, a compound represented by the general formula [IV]

[0029]

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It is produced by reacting a compound represented by the formula (1) with an active methylene compound or an acetylene carboxylic acid derivative, followed by hydrolysis. Examples of the active methylene compound include methyl acetoacetate, ethyl acetoacetate, methyl cyanate, ethyl cyanate, cyanoacetamide, malononitrile, oxaloacetate ethyl ester, malonic acid diethyl ester, malonic acid dimethyl ester, benzoyl acetate ethyl, methyl 3 -Oxo-n-caproate and the like. The amount of these active methylene compounds to be used is usually based on 1 mol of the starting compound [IV] or a salt thereof.
Practically, it is about 1 to 10 times mol. Examples of the acetylene carboxylic acid derivative include dimethyl acetylene dicarboxylate, diethyl acetylene dicarboxylate, methyl propiolate, and ethyl propiolate. When a propiolic acid ester is used, the intermediate amino acrylate derivative can be isolated, but the ring closure reaction can be carried out without isolation. The amount of these acetylene carboxylic acid derivatives used is
Usually, it is about 1 to 10 moles per 1 mole of the starting compound [IV] or a salt thereof.

In general, the reaction is preferably carried out in the presence of a base. Examples of the base used include organic amines. Examples of the organic amines include primary amines such as n-butylamine, benzylamine and aniline, diethylamine and dipropylamine. , Dibutylamine, piperidine, pyrrolidine, morpholine and the like secondary amines, tertiary amines such as 1,8-diazabicyclo [5,4,0] -7-undecene and triethylamine, imidazole and 2-methylimidazole Heterocyclic bases. The amount of the organic base to be used is usually about a catalytic amount to about 5 times the molar amount of 1 mol of the starting compound [IV] or a salt thereof. In general, the reaction is preferably carried out in an organic solvent. Examples of the solvent include alcohols such as methanol, ethanol, propanol and butanol, aromatic hydrocarbons such as benzene and toluene, and dimethylformamide. The other reaction conditions such as the reaction temperature and the reaction time are not particularly limited, but the reaction is generally performed at room temperature (0 to 30 ° C.) to near the boiling point of the solvent used for about 1 to 24 hours. In the present production process, a protection reaction of the amino group of cyanoacetamide, which is an active methylene compound, may be performed, if desired. The protection reaction can be performed according to a conventional method in this technical field. As a condition for the hydrolysis, a usual acidic hydrolysis method is used. For example, sulfuric acid, hydrochloric acid, phosphoric acid or the like is used in excess, and the acid alone or together with an organic solvent such as organic acids such as formic acid and acetic acid or alcohols such as methanol, ethanol, propanol and butanol is usually used in an amount of 50 to 150. It is performed by heating at around ° C. The reaction time varies depending on the compound, but is usually about 1 hour to several days.

The 1-azaxanthone derivative [I] can be used as a pharmacologically acceptable salt. Examples of such salts include salts with bases such as inorganic bases and organic bases, and acid addition salts such as inorganic acids, organic acids, basic or acidic amino acids. Examples of the inorganic base include alkali metals such as sodium and potassium; alkaline earth metals such as calcium and magnesium; and aluminum and ammonium. Examples of the organic base include primary amines such as ethanolamine, secondary amines such as diethylamine, diethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, trimethylamine, triethylamine, pyridine, picoline, and triethanolamine. And tertiary amines. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Examples of organic acids include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid,
Examples thereof include citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. Examples of basic amino acids include arginine,
Lysine, ornithine and the like can be mentioned. Examples of acidic amino acids include aspartic acid and glutamic acid. The salt of the 1-azaxanthone derivative [I] is described in, for example, JP-A-61-10587 and JP-A-61-10.
It can be produced by the method described in JP-A-588, JP-A-54-48798, JP-A-54-88298, or the like, or a method analogous thereto.

The method for stabilizing a 1-azaxanthone derivative or a salt thereof of the present invention is carried out by adding a phenolic hydroxyl group-containing compound to an aqueous solution of the above-mentioned 1-azaxanthone derivative [I] or a salt thereof. The phenolic hydroxyl group-containing compound used is not particularly limited, but it is preferable to use parahydroxybenzoic acid, phenol, cresol, or dibutylhydroxytoluene, and particularly preferably to use parahydroxybenzoic acid.

When a phenolic hydroxyl group-containing compound is added to the 1-azaxanthone derivative [I] or a salt thereof,
The addition concentration is, for example, 0.001 to 1 (W / V)%, preferably 0.001 to 0.1 (W / V)%.

The composition of the present invention containing the 1-azaxanthone derivative [I] or a salt thereof and a phenolic hydroxyl group-containing compound exhibits an antiallergic effect, an antiinflammatory effect, a preventive / therapeutic effect for myopia, and a low irritation. Excellent in stability and stability.

The composition of the present invention has low toxicity and can be safely orally or parenterally administered to mammals (eg, human, rabbit, dog, cat, cow, horse, monkey, etc.). Can be.

The composition of the present invention in the form of a preparation can be prepared, for example, by adding 1-
It can be produced by mixing the azaxanthone derivative [I] or a salt thereof, and a phenolic hydroxyl group-containing compound with a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers include various organic or inorganic carrier materials commonly used as pharmaceutical materials. In solid preparations, excipients, lubricants, binders, disintegrants, etc. are used. A solubilizing agent, a suspending agent, a thickening agent, a tonicity agent, a buffering agent, a soothing agent and the like are appropriately compounded. Also,
If necessary, pharmaceutical additives such as preservatives, chelating agents, antioxidants, coloring agents, sweeteners, flavoring agents, fragrances and the like may be used according to ordinary methods. Preferred examples of the excipient include lactose, sucrose, mannitol, starch, crystalline cellulose, light anhydrous silicic acid, and the like. Preferred examples of the lubricant include, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferred examples of the binder include, for example, sucrose, mannitol, maltitol, starch, gelatin, acacia, tragacanth gum, crystalline cellulose, dextrin,
Examples include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, sodium alginate, chitin, chitosan and the like. Preferred examples of the disintegrant include, for example, starch, carboxymethylcellulose, carboxymethylcellulose calcium,
Croscarmellose sodium, sodium carboxymethyl starch, chitin, chitosan and the like.

Preferred examples of the solvent include water for injection, alcohols (eg, ethanol, propylene glycol, macrogol, glycerin, etc.), oils and fats (eg, olive oil, sesame oil, peanut oil, cottonseed oil, castor oil,
Corn oil). Preferred examples of the dissolution aid include, for example, polyvinylpyrrolidone, cyclodextrin, caffeine, polyethylene glycol, propylene glycol, mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate And the like. Preferable examples of the suspending agent include, for example, stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, glyceryl monostearate, and polysorbate 80.
Surfactants such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose,
Hydrophilic polymers such as hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, gum arabic, gelatin, and albumin are exemplified. Preferred examples of the thickener include, for example, egg yolk lecithin, gelatin, gum arabic, gum tragacanth, methylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, sodium polyacrylate, sodium alginate, pectin and the like. . Preferable examples of the tonicity agent include sorbitol, glycerin, polyethylene glycol, propylene glycol, glucose, sodium chloride and the like. Preferred examples of the buffer include, for example, a phosphate buffer,
Examples include borate buffer, citrate buffer, tartrate buffer, acetate buffer and the like. Preferred examples of the soothing agent include benzyl alcohol and the like.

Preferable examples of the preservative include, for example, paraoxybenzoic acid esters, benzalkonium chloride, benzethonium chloride, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid or a salt thereof, and parachloromethaxinol Chlorcresol, thimerosal and the like. Preferable examples of the chelating agent include sodium edetate, sodium citrate, condensed sodium phosphate and the like. Preferred examples of the antioxidant include, for example, sulfite, ascorbic acid, α-tocopherol, cysteine and the like. Preferable examples of the coloring agent include, for example, tar dye, licorice extract, riboflavin, zinc oxide and the like. Suitable examples of the sweetener include, for example, glucose, sucrose, fructose, honey, saccharin, licorice and the like. Suitable examples of the flavoring agent include, for example, vanillin, menthol, rose oil and the like. Preferable examples of the fragrance include fennel oil, borneol, menthol and the like. In addition to the above, pharmaceutically acceptable carriers include, for example, agar, casein, collagen and the like.

When the preparation of the present invention is used in the form of an aqueous solution, the pH is preferably 4 to 9 in consideration of the stability of the 1-azaxanthone derivative [I] or a salt thereof.

Formulations for oral administration include, for example, powders,
Examples include solid preparations such as granules, tablets and capsules, and liquid preparations such as emulsions, syrups and suspensions. For example, the tablet is a 1-azaxanthone derivative [I] or a salt thereof, and the above-mentioned excipient to the phenolic hydroxyl group-containing compound,
A disintegrant, a binder, a lubricant or the like is appropriately added, and the mixture is compression-molded. At this time, if desired,
Subsequent to the compression molding, the above-mentioned sweetener, flavoring agent, fragrance and the like may be further added, or coating may be performed by a method known per se for the purpose of enteric coating or persistence. As a coating agent used for coating, for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate,
Hydroxypropyl methylcellulose acetate succinate, ethylcellulose and the like are used. The suspension is
For example, a 1-azaxanthone derivative [I] or a salt thereof,
And a phenolic hydroxyl group-containing compound can be produced by suspending the compound in the solvent described above. At this time, if necessary, the above-mentioned suspending agent or the like may be appropriately used.

Examples of preparations for parenteral administration include injections and preparations for topical ocular administration. Injections
It includes subcutaneous injections, intravenous injections, intramuscular injections, and the like. The injection may be an aqueous or non-aqueous injection, and may be a solution or a suspension. Examples of the preparation for topical administration to the eye include eye drops, eye ointments, gels, and the like, and particularly preferable are eye drops. The eye drop may be an aqueous or non-aqueous eye drop, and may be a solution or a suspension. The preparation of the present invention is preferably used for topical administration to the eye, and is more preferably used as an eye drop, particularly an aqueous eye drop.

The injection can be prepared as an aqueous injection by dissolving, for example, the 1-azaxanthone derivative [I] or a salt thereof, and a phenolic hydroxyl group-containing compound in the water for injection together with the above-mentioned preservative and isotonic agent. Alternatively, it can be produced as an oily injection by dissolving or suspending in propylene glycol, olive oil, sesame oil, cottonseed oil and the like.

The aqueous eye drops are prepared, for example, by heating purified water, dissolving the preservative, adding a solubilizing agent, and then adding a 1-azaxanthone derivative [I] or a salt thereof and a phenolic hydroxyl group-containing compound. It can be produced by completely dissolving. At this time, if necessary, a buffering agent, a tonicity agent, a chelating agent, a thickener, and the like may be used. The dissolution aid is preferably polyvinylpyrrolidone,
Examples thereof include cyclodextrin and caffeine, and particularly preferred is polyvinylpyrrolidone. When polyvinylpyrrolidone is used, the solubility of the 1-azaxanthone derivative [I] or a salt thereof is remarkably improved, and the stability of the 1-azaxanthone derivative [I] or a salt thereof is particularly increased. (Japanese Patent Application Laid-Open No.
For example, polyvinylpyrrolidone has an average molecular weight of about 250.
Those of from 00 to about 120,000, preferably about 40,000 (for example, polyvinylpyrrolidone K30) are used. The amount of polyvinylpyrrolidone added is usually 0.2 to 20 (W / V)%, preferably 0.5 to 15 (W / V)%, particularly preferably 1 to 10 (W / V).
/ V)%.

The buffer is particularly preferably a borate buffer. When a borate buffer is used as a buffer, a liquid with lower irritation can be obtained as compared with the case where another buffer, for example, a phosphate buffer is used. At this time, the added amount of boric acid is 0.2 to 4 (W / V)%, preferably 0.5 to 4 (W / V).
To 2 (W / V)%.

The aqueous suspension ophthalmic solution can be produced by appropriately selecting and using the above-mentioned suspending agents in addition to the additives used in the above aqueous ophthalmic solution. The pH of the above-mentioned aqueous eye drops and aqueous suspension eye drops is preferably from 4 to 9, particularly preferably from 5 to 8.

The non-aqueous eye drops are prepared by adding a 1-azaxanthone derivative [I] or a salt thereof and a phenolic hydroxyl group-containing compound to an aqueous solution of an alcohol (eg, ethanol, ethylene glycol, macrogol, propylene glycol, glycerin, etc.). It can be produced by dissolving or suspending in an oily solvent such as a basic solvent or oils (eg, olive oil, sesame oil, peanut oil, cottonseed oil, castor oil, corn oil, etc.).

The ophthalmic ointment can be produced, for example, by appropriately selecting and using vaseline, plastibase, liquid paraffin and the like as a base.

The ophthalmic gel can be produced, for example, by appropriately selecting and using a carboxyvinyl polymer, an ethylene maleic anhydride polymer, a polyoxyethylene-polyoxypropylene block copolymer, a gellan gum or the like as a base.

The dosage of the preparation of the present invention varies depending on the administration route, symptoms, age and weight of the patient.
For one eye, 1-azaxanthone derivative [I] or a salt thereof, which is an active ingredient, is administered in an amount of 0.01 to 2.0 (W
/ V)%, preferably about 0.1 to 1.0 (W / V)%, as an aqueous ophthalmic solution containing 1 to several drops once or several times a day, preferably 2 to 3 times a day, depending on the symptoms. It is desirable to administer about to 5 times.

Hereinafter, the present invention will be described in more detail by way of examples, and the effects of the present invention will be clarified by test examples. However, these are merely examples, and the scope of the present invention is limited by these examples. Not something.

[0052]

【Example】

Example 1 Compound [III], boric acid, borax, polyvinylpyrrolidone and parahydroxybenzoic acid are added and dissolved in a part of sterilized purified water, and 100 ml of the remaining sterilized purified water is added.
And This liquid is filled into a 5 ml polypropylene (PP) ophthalmic container.

Embodiment 2 Compound [III], boric acid, borax, polyvinylpyrrolidone, parahydroxybenzoic acid and sodium hydroxide are added to a part of the sterilized purified water to dissolve, and the remaining sterilized purified water is added to make 100 ml. This solution is filled into a 5 ml polyethylene (PE) ophthalmic container.

Embodiment 3 Compound [III], boric acid, dibutylhydroxytoluene, polyoxyethylene hydrogenated castor oil 60 and sodium hydroxide are added to a part of the sterilized purified water and dissolved, and the remaining sterilized purified water is added to make 100 ml. This solution is filled into a 5 ml PP ophthalmic container.

Test Example 1 Stability test of compound [III] (1) Basic formulation (compound [III] 0.5 g, boric acid 1.6 g,
Borax 0.7 g), parahydroxybenzoic acid, dibutylhydroxytoluene (hereinafter also referred to as BHT), polyoxyethylene hydrogenated castor oil 60, phenol, cresol, sodium hydroxide were blended according to the formulation shown in Table 1,
Sterile purified water was added to make up to 100 ml. Each of these solutions was filled in a 5 ml glass ampule.

[0056]

[Table 1]

The glass ampules filled with the respective liquids according to the formulation shown in Table 1 were kept at 60 ° C., and after 2 weeks and 4 weeks, the properties, pH, and content of the compound [III] of each liquid were measured. The content of the compound [III] was measured under the following measurement conditions. Table 2 shows the results. Column: YMC-Pack ODS-A A-302
(YMC) Column temperature: 35 ° C. Detector: SPD-10A (detection wavelength: 244 nm) Flow rate: 0.8 ml / min (adjusted so that the elution time of compound [III] becomes about 16 minutes). : 0.05 M ammonium dihydrogen phosphate: methanol = 45:55 (pH 5.0 with phosphoric acid) Sample injection volume: 10 μl

[0058]

[Table 2]

Regarding the appearance, No. 3 containing BHT was used. 3
At 60 ° C. for 2 weeks, it turned yellow and clear, and the other liquid turned to slightly yellow and clear at 60 ° C. for 4 weeks.
No change in pH was observed in any of the solutions. Compound [II
No. I] with respect to the residual ratio of No.
The residual ratio of No. 1 was about 50%. Regarding the stability of the solution containing the phenolic hydroxyl group-containing compound, the stability of the solution containing no. 2 at 60 ° C, about 9 in 2 weeks
0%, N with BHT, phenol and cresol
o. 3, 4 and 5 are solutions containing about 100% and buffer only (No.
As compared with 1), the value was almost stable. From the above results, it was shown that compound [III] can be stabilized by blending a compound having a phenolic hydroxyl group.

Test Example 2 Stability test of compound [III] (2) 0.5 g of compound [III] was added to 0.5 g of boric acid, borax, methyl parahydroxybenzoate, propyl parahydroxybenzoate, benzoic acid, BHT Oxyethylene hydrogenated castor oil 60, p-hydroxybenzoic acid, and sodium hydroxide were blended according to the formulation shown in Table 3, and sterilized purified water was added thereto to prepare a 100 m
l. Each of these solutions was filled in a 5 ml glass ampule.

[0061]

[Table 3]

The glass ampules filled with the respective liquids according to the formulations shown in Table 3 were kept at 60 ° C., and after 2 weeks and 4 weeks, the properties, pH, and content of the compound [III] of each liquid were measured. The content of the compound [III] was measured under the following measurement conditions. Table 4 shows the results. Column: YMC-Pack ODS-A A-302
(YMC) Column temperature: 35 ° C. Detector: SPD-10A (detection wavelength: 244 nm) Flow rate: 0.8 ml / min (adjusted so that the elution time of compound [III] becomes about 16 minutes). : 0.05 M ammonium dihydrogen phosphate: methanol = 45:55 (pH 5.0 with phosphoric acid) Sample injection volume: 10 μl

[0063]

[Table 4]

From these results, it was found that the compound containing 0.2% of parahydroxybenzoic acid had a stable residual ratio of the compound [III] of 98% after 4 weeks at 60 ° C. (measured in Test Example 1). The obtained parahydroxybenzoic acid was added to 0.
When 1% was blended, the residual ratio was 85.4%. ). With respect to those containing 0.005% and 0.0025% of BHT, the residual ratio of the compound [III] was stable at 98 ° C. for 4 weeks at 98% for both concentrations.

[0065]

By using the method of the present invention, it is possible to impart desired stability to an aqueous solution of the 1-azaxanthone derivative [I] or a salt thereof according to the present invention, and it is possible to store the aqueous solution for a long time. I do. In addition, the composition containing the 1-azaxanthone derivative [I] or a salt thereof and the phenolic hydroxyl group-containing compound obtained in the present invention is excellent in stability, hypoallergenic and has good clinical use feeling, It can be used clinically advantageously.

Claims (37)

[Claims] 1. A phenolic hydroxyl group-containing compound represented by the general formula [I]: Wherein the ring A may be substituted, R ₁ represents hydrogen or an amino group which may be protected, and R ₂ represents a group capable of releasing a proton. Or a method for stabilizing a 1-azaxanthone derivative or a salt thereof, which is added to an aqueous solution of the salt thereof. 2. A butadienylene group in which ring A forms a benzene ring with a halogen atom, a nitro group, an alkyl group, an alkoxy group or two adjacent carbon atoms at positions 6, 7, 8, and 9 (-CH = CH- The method for stabilizing a 1-azaxanthone derivative or a salt thereof according to claim 1, which may be substituted with CH = CH-). 3. The method for stabilizing a 1-azaxanthone derivative or a salt thereof according to claim 1, wherein the group capable of releasing a proton is a carboxyl group or a tetrazolyl group. 4. A 1-azaxanthone derivative represented by the general formula [I
I] 1-azaxanthone according to claim 1, wherein R represents an alkyl group, R ₁ represents hydrogen or an amino group which may be protected, and R ₂ represents a group capable of releasing a proton. A method for stabilizing a derivative or a salt thereof. 5. The method for stabilizing a 1-azaxanthone derivative or a salt thereof according to claim 4, wherein the alkyl group is an alkyl group having 1 to 6 carbon atoms. 6. The method for stabilizing a 1-azaxanthone derivative or a salt thereof according to claim 4, wherein the alkyl group is an isopropyl group. 7. The method according to claim 1, wherein R ₁ is an amino group.
The method for stabilizing a 1-azaxanthone derivative or a salt thereof according to the above. 8. The method for stabilizing a 1-azaxanthone derivative or a salt thereof according to claim 1, wherein R ₂ is a carboxyl group. 9. A 1-azaxanthone derivative represented by the formula [III]: The method for stabilizing a 1-azaxanthone derivative or a salt thereof according to claim 1, which is represented by the following formula: 10. The method for stabilizing a 1-azaxanthone derivative or a salt thereof according to claim 1, wherein the phenolic hydroxyl group-containing compound is selected from the group consisting of parahydroxybenzoic acid, phenol, cresol, and dibutylhydroxytoluene. 11. The method for stabilizing a 1-azaxanthone derivative or a salt thereof according to claim 10, wherein the phenolic hydroxyl group-containing compound is parahydroxybenzoic acid. 12. The method for stabilizing a 1-azaxanthone derivative or a salt thereof according to claim 10, wherein the phenolic hydroxyl group-containing compound is phenol. 13. The method for stabilizing a 1-azaxanthone derivative or a salt thereof according to claim 10, wherein the phenolic hydroxyl group-containing compound is cresol. 14. The method for stabilizing a 1-azaxanthone derivative or a salt thereof according to claim 10, wherein the phenolic hydroxyl group-containing compound is dibutylhydroxytoluene. 15. A phenolic hydroxyl group-containing compound containing 0.1 to 10.
The method for stabilizing a 1-azaxanthone derivative or a salt thereof according to claim 1, wherein the compound is added at a concentration of 001 to 1 (W / V)%. 16. The 1-azaxanthone derivative represented by the general formula [I] or a salt thereof is used in an amount of 0.01 to 2.0 (W /
The method for stabilizing a 1-azaxanthone derivative or a salt thereof according to claim 1, which is contained at a concentration of V)%. 17. A method for preparing a 1-azaxanthone derivative represented by the general formula [I] or a salt thereof from 0.1 to 1.0 (W / V)
The method for stabilizing a 1-azaxanthone derivative or a salt thereof according to claim 1, which is contained at a concentration of 1%. 18. A compound of the general formula [I] Wherein the ring A may be substituted, R ₁ represents hydrogen or an amino group which may be protected, and R ₂ represents a group capable of releasing a proton. Or a salt thereof, and a 1-azaxanthone derivative-containing composition containing a phenolic hydroxyl group-containing compound. 19. A butadienylene group in which ring A forms a benzene ring with a halogen atom, a nitro group, an alkyl group, an alkoxy group or two adjacent carbon atoms at positions 6, 7, 8, and 9 (-CH = CH- The 1-azaxanthone derivative-containing composition according to claim 18, which may be substituted with CH = CH-). 20. The method according to claim 18, wherein the group capable of releasing a proton is a carboxyl group or a tetrazolyl group.
An azaxanthone derivative-containing composition. 21. A 1-azaxanthone derivative represented by the following general formula [II]: The 1-azaxanthone according to claim 18, wherein R represents an alkyl group, R ₁ represents hydrogen or an amino group which may be protected, and R ₂ represents a group capable of releasing a proton. A derivative-containing composition. 22. The composition containing a 1-azaxanthone derivative according to claim 21, wherein the alkyl group is an alkyl group having 1 to 6 carbon atoms. 23. The 1-azaxanthone derivative-containing composition according to claim 21, wherein the alkyl group is an isopropyl group. 24. The 1-azaxanthone derivative-containing composition according to claim 18, wherein R ₁ is an amino group. 25. The method according to claim 1, wherein R ₂ is a carboxyl group.
22. The 1-azaxanthone derivative-containing composition according to 8 or 21. 26. A 1-azaxanthone derivative represented by the formula [III
[Formula 6] The 1-azaxanthone derivative-containing composition according to claim 18, which is represented by the following formula: 27. The 1-azaxanthone derivative-containing composition according to claim 18, wherein the phenolic hydroxyl group-containing compound is selected from the group consisting of parahydroxybenzoic acid, phenol, cresol, and dibutylhydroxytoluene. 28. The 1-azaxanthone derivative-containing composition according to claim 27, wherein the phenolic hydroxyl group-containing compound is parahydroxybenzoic acid. 29. The 1-azaxanthone derivative-containing composition according to claim 27, wherein the phenolic hydroxyl group-containing compound is phenol. 30. The composition containing a 1-azaxanthone derivative according to claim 27, wherein the phenolic hydroxyl group-containing compound is cresol. 31. The 1-azaxanthone derivative-containing composition according to claim 27, wherein the phenolic hydroxyl group-containing compound is dibutylhydroxytoluene. 32. A compound having a phenolic hydroxyl group content of 0.1%.
The 1-azaxanthone derivative-containing composition according to claim 18, which is added at a concentration of 001 to 1 (W / V)%. 33. The 1-azaxanthone derivative-containing composition according to claim 18, which is in the form of a preparation for topical administration to the eye. 34. The composition containing a 1-azaxanthone derivative according to claim 33, which is in the form of eye drops. 35. The 1-azaxanthone derivative-containing composition according to claim 34, which is in the form of an aqueous eye drop. 36. A 1-azaxanthone derivative represented by the general formula [I] or a salt thereof in an amount of 0.01 to 2.0 (W /
The 1-azaxanthone derivative-containing composition according to claim 35, which contains V) at a concentration of%. 37. A 1-azaxanthone derivative represented by the general formula [I] or a salt thereof in an amount of 0.1 to 1.0 (W / V)
The 1-azaxanthone derivative-containing composition according to claim 35, which is contained at a concentration of 1%.