JP2003026575A - Medicinal composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medicinal composition of an anthranillic acid derivative having improved light stability and solubility. SOLUTION: This medical composition is characterized by containing at least one compound selected from compounds represented by the formula I or their pharmacologically permissible salts and at least one compound selected from compounds represented by the formula II or their pharmacologically permissible salts.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical composition having improved photostability of a photolabile compound.

[0002]

Prior Art Formula II:

[Chemical 3] (In the formula, X represents a carbon atom or a nitrogen atom, and R ₄ and R ₅
Are each independently a hydrogen atom, a halogen, a carboxyl group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted acyl group, an optionally substituted aryl group. Or an anthranilic acid derivative represented by an optionally substituted heterocyclic group) is a therapeutic agent for allergic diseases or an antipyretic and anti-inflammatory analgesic agent,
It is known to be useful as a therapeutic agent for rheumatoid arthritis, etc., and they are widely applied clinically.

As a typical anthranilic acid derivative, tranilast (N- (3,4-dimethoxycinnamoyl))
Anthranilic acid). This drug is used as an orally administered drug for bronchial asthma, allergic rhinitis, etc. as a therapeutic agent for allergic diseases, and ophthalmologically, its usefulness in oral administration for spring catarrh and allergic conjunctivitis has been reported. And is now on the market as an eye drop for allergic diseases.

However, in general, since these anthranilic acid derivatives are extremely unstable to light, it is extremely important to ensure the stability of the preparation against exposure to light during production and after opening. . In order to stably store a preparation containing a pharmacologically active substance that is unstable to light, light-shielding means such as using a packaging material such as a brown container or a light-shielding bag is used. However, the light-shielding means may be insufficient, or a light-labile substance may be decomposed during manufacturing when a container or packaging material cannot be used. Further, even when applied, it is almost impossible to use it under light shielding. Especially for topical agents,
After removing the drug from the container and applying it to the skin and mucous membranes,
Usually, the drug will be exposed to light and will be subject to photolysis at the site of application. Therefore, stabilization of these photolabile drugs has been strongly desired.

As a method for improving the photostability of a drug in a preparation, generally known is a method of suppressing hydrolysis by using an antioxidant or by setting the pH in a stable pH range of the drug. ing. Regarding a drug exhibiting protein binding property such as tranilast, Japanese Patent No. 2654445 describes that photostability is improved by incorporating natural albumin. However, these methods cannot sufficiently improve the photostability of anthranilic acid derivatives such as tranilast.

[0006]

The object of the present invention is to provide a pharmaceutical composition in which the photostability of an anthranilic acid derivative is improved. Another object of the present invention is to provide a pharmaceutical composition which has improved solubility of an anthranilic acid derivative and can be stably used in a wide variety of dosage forms.

[0007]

The present inventors have found that an anthranilic acid derivative of the formula II is dramatically stabilized against light in the presence of a xanthine derivative of the formula I. This has led to the completion of the present invention. That is,
The present invention provides formula I:

[Chemical 4] (Wherein R ₁ , R ₂ and R ₃ each independently represent a hydrogen atom or an optionally substituted alkyl group) and at least a pharmacologically acceptable salt thereof. One compound and formula II:

[Chemical 5] A pharmaceutical composition comprising a compound represented by the formula (wherein X, R ₄ and R ₅ are as defined above) or at least one compound selected from pharmaceutically acceptable salts thereof. It is to provide things.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION Caffeine, which is one of the xanthine compounds represented by the formula I, has a central excitatory action, and is used in pharmaceuticals and food compositions for improving drowsiness, mainly as a composition for internal use and as an external preparation. It is also included in. Further, JP-A-7-228532 discloses that caffeine can be used to improve the solubility and photostability of argininamides in water and reduce eye irritation.
0-279503 discloses the use of caffeine, theobromine, theophylline and the like as a stabilizer for arylcarboxylic acids. However, there is no known pharmaceutical composition in which a xanthine derivative is mixed with an anthranilic acid derivative. The pharmaceutical composition of the present invention comprises a compound of formula I (compound I) and a compound of formula II (compound I).
The compound (I) is added to enhance the photostability of the compound II, thereby making it possible to more effectively utilize the excellent effect of the compound II.

The terms used in connection with the present invention are defined below. The “alkyl group” means a C _1-6 alkyl group, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl group and hexyl group. Preferred alkyl groups include methyl and propyl groups.

These alkyl groups may have one or more substituents. The substituent is, for example, a halogen atom (chlorine, fluorine, bromine atom, etc.), a hydroxyl group,
Alkoxy group (C such as methoxy, ethoxy, butoxy group
_1-4 alkoxy group, etc.), aryloxy group, carboxyl group, alkoxycarbonyl group (C _1-4 alkoxy-carbonyl group, etc.), aryloxycarbonyl group, acyl group (formyl, acetyl, propionyl group, etc., C _1-4 Alkyl-carbonyl group, aryl-carbonyl group such as benzoyl group), oxo group, nitro group, amino group, N-
One or more may be independently selected from a substituted amino group (mono or di C _1-4 alkylamino group and the like), a cyano group and the like.

The "cycloalkyl group" has 3 to 9 carbon atoms.
Cyclic alkyl groups, such as cyclopropyl,
Examples thereof include cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. These cycloalkyl groups may have one or more substituents, and examples of the substituents are the same as those described above for the “alkyl group”.

The term "acyl group" means a C ₁ -C ₁₂ acyl derived from an aliphatic carboxylic acid, for example, a formyl group,
Examples thereof include an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, a benzoyl group, a naphthoyl group, a toluoyl group, a salicyloyl group and a cinnamoyl group.

These acyl groups may have one or more substituents. Substituents are, for example, alkyl (methyl, ethyl, propyl, etc.); alkoxy (methoxy, ethoxy, propoxy, etc.); alkylthio (methylthio, ethylthio, etc.); alkylamino (methylamino, ethylamino, propylamino, etc.); cycloalkyl , For example, cyclo (C ₃ -C ₆ ) alkyl (for example, cyclopentyl, cyclohexyl, etc.); cycloalkenyl, for example, cyclo (C ₃ -C ₆ ) alkenyl (for example, cycloxenyl, cyclohexadienyl, etc.); halogen (fluorine, Chlorine, bromine, iodine); amino; amino protecting groups; hydroxy; protected hydroxy; cyano; nitro; carboxy; protected carboxy; sulfo; sulfamoyl; imino; oxo; aminoalkyl (aminomethyl, aminoethyl, etc.); Carbamoyloxy; hi One or more can be independently selected from droxyalkyl (hydroxymethyl, 1- or 2-hydroxyethyl, 1- or 2- or 3-hydroxypropyl etc.) and the like.

Examples of the "aryl group" include phenyl, phenethyl, cinnamyl, benzyl, tolyl, styryl, anthryl, naphthyl and the like. These aryl groups may have one or more substituents. The substituent is, for example, a hydroxyl group, a halogen atom, an aliphatic alkyl group which may be substituted with a halogen atom, an aromatic alkyl group, an aliphatic carboxylic acid group, an aromatic carboxylic acid group, an aliphatic carboxylic acid ester group, an aromatic group. Carboxylic ester group,
One or more independently from an aliphatic ether group, an aromatic ether group, an aliphatic alcohol group, an aromatic alcohol group, an aliphatic aldehyde group, an aromatic aldehyde group, an aliphatic amino group, an aromatic amino group, etc. Can be selected.

The "heterocyclic group" is a group containing at least one hetero atom selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom and is saturated or It includes unsaturated monocyclic or polycyclic heterocyclic groups. The following are mentioned as a preferable heterocyclic group. 3-6 containing 1-4 nitrogen atoms
Membered unsaturated heteromonocyclic groups such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (eg 4H-
1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl etc.), tetrazolyl (eg 1H-tetrazolyl, 2H-tetrazolyl etc.), triazinyl (eg 1,2. , 4-triazinyl etc.) etc .: 3 to 7 membered saturated heteromonocyclic group containing 1 to 4 nitrogen atoms such as pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, homopiperazinyl, piperidylethyl etc .; 1 to 4 nitrogen atoms A saturated heteropolycyclic group containing, for example, quinuclidinyl and the like; an unsaturated heteropolycyclic group containing 1 to 5 nitrogen atoms, for example, indolyl,
Isoindolyl, 3H-indolyl, indolizinyl,
Benzimidazolyl, quinolyl, isoquinolyl, indazolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzotriazolyl, tetrazolopyridazinyl (eg tetrazolo [1,
5-b] pyridazinyl etc.), pteridinyl, carbazolyl, phenanthridinyl, acridinyl, perimidyl, etc .; 3-6 membered unsaturated heteromonocyclic group containing 1-3 nitrogen atoms and 1-2 oxygen atoms. , For example, oxazolyl, isoxazolyl, oxadiazolyl (eg 1,2,4
-Oxadiazolyl, 1,3,4-oxadiazolyl,
1,2,5-oxadiazolyl etc.); etc .; 3-6 membered saturated heteromonocyclic group containing 1-3 nitrogen atoms and 1-2 oxygen atoms, for example, morpholinyl, sydnolyl, etc .; 1-3
Unsaturated condensed heterocyclic group containing 1 nitrogen atom and 1 to 2 oxygen atoms, for example, benzoflazanyl, benzoxazolyl, benzoxazinyl, benzooxadiazolyl, etc .; 1 to 3 nitrogen atoms 3 to 6 membered unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms, for example, thiazolyl,
Isothiazolyl, thiadiazolyl (eg 1,2,4-
Thiadiazolyl, 1,3,4-thiadiazolyl, 1,
2,5-thiadiazolyl etc.); 3-6 membered saturated heteromonocyclic group containing 1-3 nitrogen atoms and 1-2 sulfur atoms (eg thiazolidinyl etc.); 1-3 nitrogen atoms And an unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms (for example, benzothiazolyl, benzothiadiazolyl, etc.); 3 to 6-membered unsaturated heterocyclic group containing one oxygen atom, for example, furyl , Pyranyl, etc .; 3- to 6-membered unsaturated heteromonocyclic groups containing 1-2 sulfur atoms, such as thienyl, dihydrothienyl, etc .; unsaturated fused heterocyclic groups containing 1-2 sulfur atoms (eg, Benzothienyl etc.) etc.
These heterocyclic groups may have, for example, one or more substituents independently selected from the substituents described for the aryl group above.

The compounds of formula I can be used as pharmaceutically (pharmaceutically) acceptable salts. Examples of the pharmacologically acceptable salt include, for example, organic acid salts (for example, lactate,
Acetate, butyric acid, trifluoroacetate, fumarate, maleate, tartrate, citrate, succinate, malonate, methanesulfonate, toluenesulfonate, tosylate, palmitic acid, Stearic acid etc.), inorganic acid salts (eg hydrochloride, sulfate, nitrate, hydrobromide, phosphate etc.), salts with organic bases (eg morpholine, piperazine, pyrrolidine, amino acids, trimethylamine,
Triethylamine, triethanolamine, pyridine,
Examples include salts with organic amines such as picoline), salts with inorganic bases (eg, ammonium salts, alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, salts with aluminum, etc.), etc. it can.

Specific examples of the compound represented by the formula I include caffeine, theophylline, theobromine, diprophylline, proxyphylline and pentoxifylline. These compounds can be used alone or in combination of two or more. Preferred compounds are caffeine, theophylline, theobromine, with caffeine being especially preferred. Caffeine also includes anhydrous caffeine.

Further, the compound I may be contained in the composition of the present invention in the form of a mixture consisting of the compound I and other substances. As an example of such a mixture, sodium caffeine benzoate which is a mixture of caffeine and sodium benzoate, caffeine citrate which is a mixture of caffeine and citric acid, aminophylline which is a mixture of theophylline and ethylenediamine, Examples thereof include bufilin, which is a mixture of theophylline and aminoisobutanol, calcium theobromine salicylate, which is a mixture of theobromine and salicylate, sodium theobromine salicylate, and sodium theobromine acetate, which is a mixture of theobromine and sodium acetate.

The concentration of Compound I or a pharmacologically acceptable salt thereof in the composition of the present invention varies depending on the type and dosage form of Compound I used, but in the case of a systemically administered pharmaceutical composition, it is administered daily. The amount is 50 to 500 mg, and in the case of a pharmaceutical composition for topical administration, the daily dose is 0.01.
It is preferable to appropriately design the formulation so that the dose is about 50 mg. For example, when the pharmaceutical composition is a solution such as eye drops, when 0.1 ml is administered to both eyes by a single eye drop four times a day, the formula I in the composition may be used. The concentration of the compound is 0.001 to 10% (hereinafter,% is W
/ V%), preferably 0.01 to 3%, particularly preferably 0.1 to 3.0%.

In the pharmaceutical composition of the present invention, the compound represented by the above formula I or a pharmaceutically acceptable salt thereof is dissolved to improve the solubility in an aqueous solution and form a stable aqueous composition. Adjuvants can be used. Such solubilizers include benzoic acid, citric acid, ethylenediamine,
Examples thereof include aminoisobutanol, taurine and salts thereof, surfactants, and polyhydric alcohols such as propylene glycol.

The compound represented by the above formula II can also be used as a pharmacologically acceptable salt. The pharmaceutically acceptable salts can include those similar to those described for the compound of formula I.

Among the compounds represented by the formula II, preferred compounds are those in which X is a carbon atom or a nitrogen atom, R ₄ is a hydrogen atom, an optionally substituted aryl group or an optionally substituted hetero group. A ring group, a compound in which R ₅ is a hydrogen atom, an optionally substituted alkyl group or an optionally substituted heterocyclic group, or a pharmaceutically acceptable salt thereof.

Particularly preferred compounds are shown below. 1) A compound in which X is a carbon atom, R ₄ is a hydrogen atom, and R ₅ is an optionally substituted alkyl group, for example, R ₅ is pyridocaine which is an alkyl group substituted with a heterocyclic group, and R ₅ is an alkyl group. Certain methylanthranilates, cinnamylanthranilates in which R ₅ is an aryl group, and the like. 2) X is a carbon atom, compounds wherein R ₄ optionally substituted aryl group, R ₅ is a hydrogen atom for example, aryl R ₄ is substituted with an optionally substituted aliphatic alkyl group with a halogen atom Group mefenamic acid, flufenamic acid, meclofenamic acid or tolfenamic acid, enfenamic acid in which R ₄ is an aryl group,
Lobenzarit and the like in which R ₄ is an aryl group substituted with a halogen atom and an aliphatic carboxylic acid.

3) A compound in which X is a carbon atom, R ₄ is an optionally substituted aryl group, and R ₅ is an optionally substituted alkyl group, for example, R ₄ is an aliphatic group optionally substituted with a halogen atom. An aryl group substituted with an alkyl group, R
Telofenamate in which ₅ is substituted with an alkoxy group,
R ₄ is an aryl group substituted by an aliphatic alkyl group which may be substituted by a halogen atom, and R ₅ is etofenamate substituted by an alkoxy group and a hydroxy group.

4) A compound in which X is a carbon atom, R ₄ is a heterocyclic group which may be substituted, and R ₅ is an alkyl group which may be substituted, for example, a heterocyclic group in which R ₄ is substituted with a halogen atom. Wherein R ₅ is graphenin, which is an alkyl group substituted with a hydroxy group, R ₄ is a heterocyclic group substituted with an aliphatic alkyl group which may be substituted with a halogen atom, and R ₅ is substituted with piperazinyl. Is an anthraphenine which is a substituted alkyl group, R ₄ is a heterocyclic group which is substituted with an aliphatic alkyl group which may be substituted with a halogen atom, and R ₅ is an alkyl group which is substituted with a hydroxy group. Floctaphenin etc. 5) X is a nitrogen atom, compounds wherein R ₄ optionally substituted aryl group, R ₅ is a hydrogen atom for example, aryl R ₄ is substituted with an optionally substituted aliphatic alkyl group with a halogen atom The bases are niflumic acid, clonixin and flunixin. 6) X is a carbon atom, R ₄ is an optionally substituted acyl group,
Compounds in which R ₅ is a hydrogen atom, such as tranilast in which R ₄ is an acyl group substituted with a lower alkoxy group. Among them, a particularly preferable compound is a compound in which X is a carbon atom, R ₄ is an optionally substituted acyl group, and R ₅ is a hydrogen atom.

Specific examples of the compound represented by the formula II include:
Tranilast, floctafenin, mefenamic acid, flufenamic acid, tolfenamic acid, enfenamic acid, niflumic acid, pyridocaine, cinnamyl anthranilate,
Lobenzarit, clonixin,
Flunixin, meclofenamic acid (mecl
ofenamic acid), methyl anthranilate
thranilate), telophenamate (terofenamate), etofenamate (etofenamete), graphenin (glafe)
nine), anthraphenine or a pharmacologically acceptable salt thereof. Preferred compounds are tranilast, floctafenine, mefenamic acid,
Flufenamic acid, tolfenamic acid, enfenamic acid, niflumic acid, pyridocaine, cinnamyl anthranilate, lobenzarit, and tranilast are particularly preferable.

The concentration of the compound represented by the formula II or a pharmaceutically acceptable salt thereof in the composition of the present invention varies depending on the kind and dosage form of the compound, but in the pharmaceutical composition to be systemically administered, The daily dose is 50-500 mg,
For topically administered pharmaceutical compositions, as a daily dosage,
The formulation can be appropriately designed so as to be 0.01 to 50 mg. For example, when used as an aqueous composition, 0.01 to 20%, preferably 0.
01 to 10%, more preferably 0.1 to 5%, and particularly preferably 0.1 to 3%.

The compounding ratio of the compound represented by the formula I or a pharmaceutically acceptable salt thereof and the compound represented by the formula II or a pharmaceutically acceptable salt thereof depends on the kind of the compound. Is usually 0.001 to 20: by weight.
1, preferably 0.01 to 10: 1, more preferably 0.1 to 5, and particularly preferably 0.1 to 3: 1. Moreover, in order to impart the compound II stability to light and further good solubility, the compound represented by the formula I or a pharmaceutically acceptable salt thereof, and the compound represented by the formula II or the The compounding ratio with a pharmacologically acceptable salt varies depending on the type of compound and the solubilizing agent used in combination, but is usually 0.5 to 20: 1, preferably 1.0 to 20: by weight. 1, particularly preferably 1.5 to 20: 1.

The pharmaceutical composition of the present invention comprises a compound of formula I or a pharmaceutically acceptable salt thereof in an aqueous solution of a compound of formula II or a pharmaceutically acceptable salt thereof. It is not always necessary to use another solubilizing agent because it can improve the solubility of the solubilizing agent, but a solubilizing agent may be used to obtain a stable aqueous composition. Examples of such a solubilizing agent include surfactants such as polyvinylpyrrolidone, trometamol and polysorbate, and polyhydric alcohols such as propylene glycol. Particularly, polyvinylpyrrolidone and trometamol are preferable because they enhance the effect of improving the photostabilization of tranilast by caffeine.

Since the pharmaceutical composition of the present invention contains both Compound I and Compound II together, it is stable against light and highly safe, and therefore can be provided in various dosage forms depending on the purpose. For example, lotion, extract, suspension,
Emulsions, syrups, injectables (including injectable preparations at the time of use), aerosols, liquids such as soft capsules, tablets, granules, powders, chewing agents, solid capsules such as hard capsules, oily ointment It can be used in the form of semisolid preparations such as aqueous ointments, creams, poultices and gels. Further, as described in Test Examples below, in the presence of the compound of formula I, the solubility of the compound of formula II is improved, and the stability in an aqueous solution is enhanced. Alternatively, it is also useful as a pharmaceutical composition containing water (aqueous pharmaceutical composition) in a dosage form such as a semi-solid preparation. In addition, if desired, it is possible to provide a composition having stability against light and good solubility without using a solubilizing agent for compound II other than compound I, so that it can be widely used depending on the purpose. It can be used in dosage forms.

As an example of the pharmaceutical composition of the present invention, an injection drug,
Examples include suppositories, internal medicines, inhalation preparations, etc., which are useful as a topically applied pharmaceutical composition which is stable to light and is easily exposed to light when applied to a patient. In addition, since it is safe with no or little irritation, it is not only applied to the skin but also mucous membranes that are susceptible to irritation (ocular mucosa such as cornea and conjunctiva, gums, tongue, lip, oral mucosa, nasal mucosa, pharyngeal mucosa, etc. ) Is also useful. For example, among topically applied pharmaceutical compositions, as a composition applied to the skin, an ointment for the outer skin, a cream for the outer skin, a gel for the outer skin,
As a composition to be applied to mucous membranes such as a poultice, it is useful as an eye drop, an eye wash, an eye ointment, a contact lens mounting solution, a nasal drop, an oral preparation, an ear drop, a nasal wash and the like.

The pharmaceutical composition of the present invention is preferably an aqueous pharmaceutical composition that is topically applied, but in particular, an aqueous composition that is applied to the mucous membrane, for example, an ophthalmic composition (eye drops, contact lens wear). Liquids, eyewashes, etc.), otolaryngological compositions (nasal drops, ear drops, nasal washes, etc.), oral compositions and the like.

The aqueous pharmaceutical composition of the present invention includes, for example, tranilast or a pharmacologically acceptable salt thereof and a compound represented by the formula I or a pharmacologically acceptable salt thereof,
Various components can be contained in combination. Examples of components that can be combined include decongestant components, anti-inflammatory drug components, antihistamine drug components, astringent drug components, bactericidal drug components, antitumor drug components, hormones, proteins or peptides, vitamins, amino acids. Etc. can be used. Examples of suitable components in the present invention include the following components.

Decongestant components: epinephrine, ephedrine, tetrahydrozoline, naphazoline, phenylephrine, methylephedrine and salts thereof.

Ocular muscle regulator component: A cholinesterase inhibitor having an active center similar to acetylcholine, for example, quaternary ammonium compounds such as neostigmine methylsulfate and salts thereof.

Anti-inflammatory drug component: celecoxib
b), rofecoxib, indomethacin, diclofenac, pranoprofen, piroxicam, meloxicam, epsilon-aminocaproic acid, berberine, azulene sulfonic acid, glycyrrhizic acid, lysozyme, methyl salicylate, allantoin and pharmacologically acceptable Salt (for example, berberine chloride, berberine sulfate, sodium diclofenac, sodium azulene sulfonate, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, lysozyme chloride).
Astringent component: zinc and their salts (eg, zinc sulfate,
Zinc lactate) etc.

Antihistamine drug component: for example, chlorpheniramine, diphenhydramine, iproheptin, ketotifen, emedastine, clemastine, azelastine, levocabastine, olopatadine, cromoglicic acid,
Amlexanox, mequitazine, loratadine (loratadi
ne), fexofenadine, cetirizine, ibudilast, suplatast, pemirolast, and pharmacologically acceptable salts (eg, chlorpheniramine maleate, diphenhydramine hydrochloride, iproheptin hydrochloride, ketotifen fumarate, fumar). Acid emedastine, clemastine fumarate, azelastine hydrochloride, levocabastine hydrochloride, olopatadine hydrochloride, sodium cromoglycate, etc.) and the like.

Bactericidal ingredients: 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 agents (lomefloxacin, levofloxacin, ciprofloxacin hydrochloride, ofloxacin) , Norfloxacin, etc.) etc.

Vitamin: For example, vitamin A (eg, retinal, retinol, retinoic acid, carotene, dehydroretinal, lycopene and pharmacologically acceptable salts thereof (eg, retinol acetate, retinol palmitate, etc.)), etc. , Vitamins B (for example, thiamine, thiamine disulfide, dicetiamine, octothiamine, shicotiamine, bisbutyamine, bisbentiamine, prosultiamine, benfotiamine, fursultiamine, riboflavin, flavin adenine dinucleotide, pyridoxine, pyridoxal, Hydroxocobalamin, cyanocobalamin, methylcobalamin, deoxyadenocobalamin, folic acid, tetrahydrofolic acid, dihydrofolic acid, nicotinic acid, nicotinamide, nicotinic alcohol, pant Phosphate, panthenol, biotin,
Choline, inositol and their pharmacologically acceptable salts thereof (for example, thiamine hydrochloride, thiamine nitrate, dicetiamine hydrochloride, fursultiamine hydrochloride, riboflavin butyrate, flavin adenine dinucleotide sodium, pyridoxine hydrochloride, pyridoxal phosphate, phosphate Pyridoxal calcium, hydroxocobalamin hydrochloride, hydroxocobalamin acetate, calcium pantothenate, sodium pantothenate, etc.), vitamin Cs (ascorbic acid and its derivatives, erythorbic acid and its derivatives and pharmacologically acceptable salts thereof (eg, , Sodium ascorbate, sodium erythorbate, etc.), etc.
Vitamin Ds (eg, ergocalciferol, cholecalciferol, hydroxycholecalciferol,
Vitamin Es (eg, tocopherol and its derivatives, ubiquinone derivatives and their pharmacologically acceptable salts (tocopherol acetate, nicotine), such as dihydroxycholecalciferol, dihydrotaxosterol and pharmacologically acceptable salts thereof, etc. Acid tocopherol, tocopherol succinate, tocopherol calcium succinate, etc.)) and other vitamins (eg, carnitine,
Ferulic acid, γ-oryzanol, orotic acid, rutin,
Eriocitrin, hesperidin and their pharmacologically acceptable salts (carnitine chloride, etc.) and the like.

Amino acids: for example, leucine, isoleucine, valine, methionine, threonine, alanine,
Phenylalanine, tryptophan, lysine, glycine, asparagine, aspartic acid, serine, glutamine, glutamic acid, proline, tyrosine, cysteine,
Histidine, ornithine, hydroxyproline, hydroxylysine, glycylglycine, aminoethyl sulfonic acid (taurine) and pharmacologically acceptable salts thereof (eg potassium aspartate, magnesium aspartate, cysteine hydrochloride, etc.) and the like.

Sugars: monosaccharides (eg glucose),
Disaccharides (eg, trehalose, lactose, fructose, etc.), oligosaccharides (eg, lactulose, raffinose, pullulan, etc.), cellulose or derivatives thereof (eg, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,
Carboxymethyl cellulose, carboxyethyl cellulose, nitrocellulose, etc.), high molecular sugars (eg, chondroitin sulfate, hyaluronic acid) and their pharmacologically acceptable salts (eg, sodium chondroitin sulfate, sodium hyaluronate)), sugar alcohols (For example, mannitol, xylitol, sorbitol, etc.), antipruritic components (crotamiton, ictamol, moctamol, thymolic acid, etc.) and the like.

Other components: polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone and the like. The content of these components can be selected according to the type of formulation, the type of active ingredient, etc., and is, for example, 0.000 based on the total formulation.
It can be selected from the range of 1 to 30%, preferably about 0.001 to 10%.

More specifically, in the aqueous topical composition preferred in the present invention, the content of each component is, for example, as follows. Ocular muscle regulator component: For example, 0.0001 to 0.5%, preferably 0.001 to 0.1%. Anti-inflammatory drug component or astringent drug component: For example, 0.001-1
0%, preferably 0.01-3%. Antihistamine drug component: For example, 0.0001 to 10%,
Preferably 0.001 to 5%. Bactericidal component: for example, 0.001 to 10%, preferably 0.01 to 10% Vitamin: for example, 0.0001 to 1%, preferably 0.001 to 0.3%. Amino acids: For example, 0.0001 to 10%, preferably 0.001 to 3%.

In the pharmaceutical composition of the present invention, various components and additives used in pharmaceuticals, quasi-drugs and the like are arbitrarily selected and used in combination as needed within a range that does not impair the effects of the present invention. It is possible to formulate. Specific examples will be given below, but the present invention is not limited thereto. 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, and their pharmacological properties. The salts and the like that are permissible in.

Thickening agents: for example, gum arabic, karaya gum, xanthan gum, carob gum, guar gum, guaiac butter, 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 its derivatives, chitosan and its derivatives, elastin, heparin, heparinoid, heparin sulfate, heparan sulfate, hyaluronic acid, chondroitin sulfate, ceramide, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxy Methylcellulose, carboxyethylcellulose, cellulose, nitrocellulose, polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone, macrogol, polyvinylmethacrylate, polyacrylic acid, carboxyvinyl polymer, polyethyleneimine, ribonucleic acid, deoxyribonucleic acid, carboxyvinyl. Polymers and the like, and pharmacologically acceptable salts thereof and the like can be mentioned.

Surfactants: For example, POE / POP block copolymer (for example, poloxamer 407, poloxamer 235, poloxamer 188, etc.), monolauric acid POE (2
0) P of sorbitan (polysorbate 20), POE (60) sorbitan monostearate (polysorbate 60), POE (20) sorbitan monooleate (polysorbate 80), etc.
OE sorbitan fatty acid esters, POE (60) hydrogenated castor oil and other POE hydrogenated castor oil, POE (9) lauryl ether and other POE alkyl ethers, POE (20) POP
(4) POE / POP alkyl ethers such as cetyl ether, non-ionic surfactants such as POE alkylphenyl ethers such as POE (10) nonylphenyl ether,
Glycine type such as alkyldiaminoethylglycine, betaine acetate type such as lauryldimethylaminoacetic acid betaine,
Amphoteric surfactants such as imidazoline type, POE (10) sodium lauryl ether phosphate and other POE alkyl ether phosphates and salts thereof, N-acyl amino acid salts such as sodium lauroylmethylalanine, alkyl ether carboxylates and N-cocoyl N-acyl taurine salts such as sodium methyl taurine, sulfonates such as sodium tetradecene sulfonate, alkyl sulfates such as sodium lauryl sulfate, POE (3) POE alkyl ether sulfates such as sodium lauryl ether sulfate, α-olefins Examples thereof include anionic surfactants such as sulfonates. POE is an abbreviation for polyoxyethylene, and POP is an abbreviation for polyoxypropylene. The number in parentheses indicates the number of added moles.

Antiseptic / antibacterial / bactericidal agent: For example, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, acrinol, methylrosaniline chloride, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, odor. Cetylpyridinium chloride, chlorhexidine, polyhexamethylene biguanide, alkylpolyaminoethylglycine, benzyl alcohol, phenethyl alcohol, chlorobutanol, isopropanol, ethanol, phenoxyethanol, sulfur, zirconium phosphate silver, zinc, zinc oxide support, silver zinc Aluminosilicate, Mercurochrome, thimerosal, povidone iodine, dehydroacetic acid, chlorxylenol, cresol, chlorophene, phenol Resorcin, orthophenylphenol, isopropylmethylphenol, thymol, hinokitiol, sulfamine, lysozyme, lactoferrin, triclosan, 8-hydroxyquinoline, undecylenic acid, caprylic acid, propionic acid, benzoic acid, propionic acid, sorbic acid, triclocarban sorbate, Halocarban, thiabendazole, polymyxin B, 5-
Chloro-2-methyl-4-isothiazolin-3-one,
2-Methyl-4-isothiazolin-3-one, polylysine, hydrogen peroxide, quaternary ammonium polymer (polydronium chloride (polyquarterium-1), Glokill (trade name, manufactured by Rhodia), Unisense CP (trade name) , Poly (diallyldimethylammonium chloride), manufactured by Senka Co., Ltd., WSCP (trade name, poly [oxyethylene (dimethyliminio) ethylene- (dimethyliminio))
[Etrenji chloride] containing about 60% by weight, Backman
Laboratories)), biguanide compounds (Cosmocil CQ (trade name, containing about 20% by weight of polyhexamethylene biguanide hydrochloride, manufactured by Avicia)), and pharmacologically acceptable salts thereof.

PH adjusters: For example, hydrochloric acid, sulfuric acid, lactic acid,
Acetic acid, citric acid, tartaric acid, malic acid, succinic acid, oxalic acid, gluconic acid, fumaric acid, propionic acid, acetic acid, aspartic acid, epsilon aminocaproic acid, glutamic acid, aminoethylsulfonic acid, phosphoric acid, polyphosphoric acid, boric acid, Gluconolactone, ammonium acetate, sodium hydrogen carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide,
Examples include monoethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine, lysine, borax and the like, and pharmacologically acceptable salts thereof.

Tonicity agents: Examples include polyhydric alcohols such as glycerin and propylene glycol, sugars such as butter sugar, mannitol and sorbitol.

Chelating agents: eg, edetic acid, citric acid, polyphosphoric acid, hexametaphosphoric acid, metaphosphoric acid, ascorbic acid, succinic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1-hydroxyethane-1,
Examples thereof include 1-diphosphonic acid and the like, and pharmacologically acceptable salts thereof.

Water-soluble polymer substances: for example, gelatin, polyacrylic acid and salts thereof, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, sodium carboxymethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose,
Methyl vinyl ether / maleic anhydride copolymer, sodium alginate, polyethylene oxide, gum arabic, xanthan gum, tragacanth gum and the like,

Polyhydric alcohol: Examples include glycerin, sorbitol, propylene glycol, polyethylene glycol, 1,3-butylene glycol, ethylene glycol and the like. Crosslinking agent: For example, aluminum hydroxide, aluminum magnesium hydroxide, aluminum glycinate, dihydroxyaluminum aminoacetate, polyvalent metal compounds such as synthetic leather hydrotalcite, etc. may be mentioned. Swelling agent: Examples include kaolin, bentonite, titanium oxide, silicic acid anhydride, and the like.

Inorganic salts: For example, sodium chloride, potassium chloride, sodium carbonate, sodium hydrogen carbonate, calcium chloride, magnesium sulfate, sodium hydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate,
Examples thereof include sodium thiosulfate and sodium acetate.
Furthermore, if necessary, a fragrance or a cooling agent (for example, menthol, camphor, borneol, geraniol, eucalyptus oil, bergamot oil, fennel oil, peppermint oil, cinnamon oil, rose oil, peppermint oil, etc.), local anesthetic (for example, , Lidocaine, lidocaine hydrochloride, oxybuprocaine hydrochloride, etc.) and the like can be added.

When the pharmaceutical composition of the present invention is a preferred embodiment of an aqueous composition (in particular, eye drops, eye washes, ophthalmic compositions such as contact lens mounting solutions, nasal drops, etc.), if necessary, It is necessary to adjust the pH and / or osmotic pressure within the range that is acceptable to the living body. The acceptable pH is usually p
H5.0-9.0, preferably 5.5-8.5, particularly preferably 6.5
~ 7.5. The osmotic pressure is 100 to 1200 mOsm,
Preferably 100 to 600, particularly preferably 150 to 4
The osmotic pressure ratio to the physiological saline is usually 0.3 to 4.1, preferably 0.3 to 2.1, and particularly preferably 0.5 to 1.4. The adjustment of pH and osmotic pressure can be carried out by a method known in the art using the above-mentioned pH adjusting agent, tonicity adjusting agent, salts and the like.

The pharmaceutical composition of the present invention can be produced by a known method. For example, an aqueous composition is prepared by dissolving tranilast and the compound represented by the above formula I using distilled water or purified water, and an additive, adjusting the osmotic pressure and pH to a predetermined value, and sterilizing by filtration under a sterile environment. It can be manufactured by aseptically filling a container that has been treated and washed and sterilized.

[0056]

EXAMPLES The present invention will be described in detail below based on examples, but the present invention is not limited to these examples.

Example 1 (Artificial tear solution eye drop) Tranilast 0.50 g Boric acid 0.13 g Borax 0.75 g Anhydrous caffeine 0.50 g Potassium sorbate 0.10 g Sodium hydroxide solution Purified in appropriate amount An appropriate amount of water 100 mL, a clear eye drop having a pH of 7.4 and an osmotic pressure ratio of 1.0 was obtained.

Example 2 (ophthalmic solution) tranilast 0.50 g anhydrous caffeine 0.50 g sodium chloride 0.82 g hydrochloric acid solution appropriate amount sodium hydroxide solution appropriate amount purified water appropriate amount 100 mL pH 7.5 with an osmotic pressure ratio of 1.0 I got clear eye drops.

Example 3 (ophthalmic solution) tranilast 0.50 g boric acid 0.13 g borax 0.75 g anhydrous caffeine 0.50 g sodium hydroxide solution proper amount purified water proper amount 100 mL pH 7.9, osmotic pressure ratio 1 A clear eye drop of 0.0 was obtained.

Example 4 (Eye drops) Tranilast 0.05 g Anhydrous caffeine 0.1 g Boric acid 1.30 g Borax 0.75 g Potassium sorbate 0.10 g Sodium hydroxide solution Proper amount Purified water Proper amount 100 mL A clear eye drop having a pH of 7.9 and an osmotic pressure ratio of 1.1 was obtained.

Example 5 (eye drops) Tranilast 0.50 g Chlorpheniramine maleate 0.015 g Sodium dihydrogen phosphate 1.80 g Sodium chloride 0.50 g Anhydrous caffeine 0.50 g Chlorhexidine gluconate 0 0.005 g polysorbate 80 0.50 g sodium hydroxide solution proper amount purified water proper amount 100 mL A clear eye drop having a pH of 7.4 and an osmotic pressure ratio of 1.0 was obtained.

Example 6 (Eyewash) Tranilast 0.05 g Chlorpheniramine maleate 0.0015 g Boric acid 1.30 g Borax 0.75 g Aminophylline 0.10 g Chlorhexidine gluconate 0.005 g Polysorbate 80 0.20 g sodium hydroxide solution proper amount purified water proper amount 100 mL A clear eye wash having a pH of 7.7 and an osmotic pressure ratio of 1.0 was obtained.

Example 7 (nasal drops) Tranilast 0.50 g Chlorpheniramine maleate 0.25 g Boric acid 1.30 g Borax 0.75 g Anhydrous caffeine 2.00 g Benzalkonium chloride 0.01 g Polysorbate 80 0.20 g Hydrochloric acid solution Appropriate amount purified water Appropriate amount 100 mL A clear nasal drop having a pH of 6.5 and an osmotic pressure ratio of 1.3 was obtained.

Example 8 (tablets) Tranilast 2 parts Anhydrous caffeine 100 parts d-Chlorpheniramine maleate 6 parts Belladonna total alkaloid 0.4 parts Aspartame 15 parts Mannit 992.6 parts Avicel 60 parts Menthol 12 parts Stearic acid Magnesium 12 parts Total amount 1200 parts According to the conventional method, after thoroughly mixed, tableted to give 1 tablet 400
A chewable tablet of mg / tablet was obtained.

Example 9 (soft capsule) Tranilast 100 g Sodium benzoate caffeine 333 g dl-Methylephedrine hydrochloride 200 g Lysozyme chloride 290 g (potency) Roto extract 120 g Medium chain fatty acid triglyceride 1279 g Salami beeswax 67 g Polysorbate 80 167 g Glycerin fatty acid ester 67 g Total amount 2590 g A gelatin film was filled according to a conventional method to obtain about 10000 soft capsules.

Example 10 (soft capsule) Tranilast 100 g Sodium benzoate caffeine 333 g dl-Methylephedrine hydrochloride 200 g Lysozyme chloride 290 g (potency) Roto extract 120 g Medium chain fatty acid triglyceride 1279 g Salami beeswax 67 g Polysorbate 80 167 g Glycerin fatty acid ester 67 g Total amount 2590 g A gelatin film was filled according to a conventional method to obtain about 10000 soft capsules.

Example 11 (Hard Capsule) Tranilast 100 g Anhydrous Caffeine 300 g Glycyrrhizic acid 200 g Lactose 300 g Potato starch 90 g Magnesium stearate 10 g Total amount 1000 g Hard capsules were filled according to a conventional method, and about 1000 capsules were prepared. To obtain a hard capsule.

[0068] Example 12 (ointment)         Tranilast 5 g         Anhydrous caffeine 10 g         Glycyrrhizic acid 100 g         Stearyl alcohol 100 g         Polyoxyethylene hydrogenated castor oil 1 g         Glyceryl stearate 1 g         White petrolatum 400 g         Purified water Suitable amount         Total amount 1000 g An ointment was obtained according to a conventional method.

Example 13 (Injection) Tranilast 5 g Anhydrous caffeine 10 g Sodium chloride 9 g Purified water Appropriate amount Total 1000 g An injection was obtained according to a conventional method. The injection may be dissolved in advance or may be dissolved before use.

Examples 14 to 20 In the same manner as in Examples 1 to 13 above, Table 1 (unit: g / 100)
mL) to obtain a pharmaceutical composition containing tranilast.

[0071]

[Table 1]

Example 21 (Poultice) Tranilast 0.5 g Caffeine 1.0 g Sodium polyacrylate 4.0 g Polyacrylic acid 8.0 g Glycerin 6.0 g Aluminum magnesium hydroxide 0.25 g Anhydrous Silicic acid 1.5 g Polysorbate 60 0.3 g Purified water Appropriate amount Total 100 g According to a conventional method, the above components are kneaded and homogenized to spread on a support to obtain a patch.

Example 22 (Poultice) Tranilast 0.5 g Anhydrous caffeine 1.0 g 1-Menthol 1.5 g Crotamiton 2.5 g Nonyl acid vanillyl amide 0.01 g Diisopropyl adipate 5.0 g Edetic acid Sodium 0.05 g Dry aluminum hydroxide gel 0.10 g Kaolin 5.0 g Polyacrylic acid partial hydrate 8.0 g Tartaric acid 1.0 g Propylene glycol 10.0 g Lauromacgrol 3.0 g Isopropanol 15 g Purified water proper amount total amount 100 g According to a conventional method, the above components are kneaded and homogenized to spread on a support to obtain a poultice.

Test Example 1 Tranilast with caffeine
Light Stabilization 1) Decomposition by UV and Visible Light and its Inhibition Test Various test liquids shown in Tables 2 and 3 were filled in a colorless quartz Mayer and closed with a quartz stopper. Further, a test solution (BB) which was covered with aluminum foil and completely shielded from light was prepared. These test solutions were irradiated with light at 25 ° C. and 5000 lux using a D65 fluorescent lamp as a light source (light stability tester Light-Tron LT-120 D3CJ type, manufactured by Nagano Scientific Co., Ltd.), and the total irradiation amount was 10,000 lux. hr, 25,000 lux ・ hr, and 50,000 lux ・ h
It was exposed to the light of r. After the light irradiation, the test solution was diluted 40 times, and the residual amount of tranilast was quantified by a high performance liquid chromatography method using a reverse phase column (Finepak SIL C18S, JASCO Corporation). Tranilast has a pH of 20
mM phosphate buffer / acetonitrile mixture (55: 4
Using 5) as a solvent, elution was carried out at a rate of 1 mL / min at 25 ° C., and the absorbance was measured at 339 nm for detection. The results are shown in Tables 2 and 3.

Table 2 Light stability of tranilast (quartz container)

[Table 2] Table 3 shows the optical stability of tranilast (quartz container), in which the precipitation of insoluble matter was not observed by visual observation, and the one was observed.

[Table 3] When the precipitation of the insoluble matter was not observed by visual observation, the mark was ◯, and when it was recognized, the mark was x.

2) Decomposition by visible light and its inhibition test The test solutions described in Table 4 were filled in a polyethylene plastic container and closed with a plastic cap. Furthermore, the test liquid (PC, PC1,
PC2, PT, PU) were prepared. For these test solutions, use a fluorescent lamp as a light source, 25 ° C, 2500lu
The light of x was similarly irradiated and exposed to the light of total illuminance of 50,000 lux · hr. After irradiation with light, the residual amount of tranilast was quantified in the same manner as in 1). The results are shown in Table 4.

Table 4 Light stability of tranilast (polyethylene plastic container)

[Table 4] When the precipitation of the insoluble matter was not observed by visual observation, the mark was ◯, and when it was recognized, the mark was x.

As a result of the test, in the aluminum light-shielding container (BB in Tables 2 and 3 and PC, PC1, PC2, PT, PU in Table 4), the total irradiation amount before the start of the test and up to 50,000 lux · hr was measured. Although no change was observed in the residual rate under light exposure, the residual rate was decreased in all other non-shaded containers. This indicates that tranilast is significantly decomposed by irradiation with ultraviolet light and visible light. Controls (Q, R in Tables 2 and 3) that do not contain compound I (caffeine, etc.) and samples that contain (Q1 to Q4 and R1 to R)
Comparison of 3) shows that caffeine suppresses the decomposition of tranilast by ultraviolet rays and visible rays in a concentration-dependent manner. Similarly, comparison of the sample PQ containing no compound I in Table 4 with the samples containing it (PB, PB1, PB2) confirms that the compound of formula I suppresses the degradation of tranilast by visible light.

Diprophylline other than caffeine,
Pentoxifylline was also shown to inhibit photodegradation (see PT, PU in Table 4). In addition, polyvinylpyrrolidone and trometamol were shown to further enhance the effect of improving the photostabilization of tranilast by caffeine. (Q
3 and B, Q4 and S, R2 and B, R3 and S) Furthermore, samples containing no polyvinylpyrrolidone or trometamol which are solubilizing agents for tranilast (Tables 2 and 3).
The fact that the precipitation of insoluble matter is not observed in B and S) of Caffeine shows that caffeine is effective not only for photostabilization of tranilast but also for solubilization. In addition, regarding the compound represented by the formula II (caffeine and the like) and the composition containing no polyvinylpyrrolidone and trometamol (I in Table 5 below), the photostability was not measured because tranilast does not dissolve.

Test Example 2 Tranilast dissolution of the compound of formula I
Effect on Degradability Test solutions containing tranilast and various compounds of formula I, listed in Table 5, were prepared and tested for solubility. Each test solution was filtered through a 0.22 μm membrane filter, put into a glass container, and stored at room temperature. Immediately after preparation, visual observation was performed 7 days after storage at room temperature. The results are shown in Table 5.

[0081]

[Table 5] The case where the precipitation of insoluble matter was not observed was marked with ◯, and the case where it was recognized was marked with x. As a result of the test, none of the test solutions to which anhydrous caffeine or the other compound of the formula I was added was clear and no foreign matter was observed. On the other hand, in the solution to which the compound I was not added, precipitation was observed at the time of preparation in 0.1% of tranilast, and it was not dissolved.

Test Example 3 Soft contact lens size
Effect on Soft contact lens (SUREVUE ^R (manufactured by Johnson & Johnson, water content 58%)
% Group IV lens) was soaked for 3 minutes and the effect on the lens was evaluated by measuring the change in lens size. For the lens size, a universal projector (manufactured by Nikon Corporation, model V-12A) was used to measure the diameters at two points where the lenses intersect vertically, and the average value was calculated.
The change in lens size was within 0.5 mm, which complied with the standard. In addition, whether or not the size change of the contact lens is appropriate is determined by the American National Standards Institute ANSI (American National
Standards Institute) regarding contact lenses (ANSI Z80.8 (1986)) (if the allowable range of lens size change is within 0.5 mm, the standard is met).

Test Example 4 Soft contact lens absorption
Against eye drops 5mL of Chakushiken Example 3, contact lenses (SUREVUE ^R (Johnson & Johnson Co. moisture content 58
% Group IV lens)), and the contents of tranilast and caffeine in the immersion liquid after a certain period of time were measured by a high performance liquid chromatography method. As a result, it was found that the example of the present invention did not adsorb to the contact lens. Therefore, it was shown that the pharmaceutical composition of the present invention can be applied to contact lenses.

Test Example 5 Eye Irritation Test The eye irritation test was conducted by instilling the eye drops and the eye washes of Examples 1 to 6. In the examples of the present invention, irritation to the eye was not observed. Furthermore, in the same formulation as the eye drop of Example 2, pH = 5.5, 6.0, 6.5, 7.0,
Examples were adjusted to 7.5, 8.0, 8.5. pH
There was no eye irritation at any pH of 5.5 to 8.5.

[0085]

INDUSTRIAL APPLICABILITY The pharmaceutical composition of the present invention contains both the compound of formula I and the compound of formula II, thereby significantly improving the photostability of the compound of formula II and further improving the solubility thereof. The improvement makes it possible to more effectively and widely utilize the excellent effects of the compound II as an antiallergic agent and the like.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 11/02 A61P 11/02 27/02 27/02 37/08 37/08 (72) Inventor Yasuko Nishina 1-8-1, Tatsunishi, Ikuno-ku, Osaka-shi, Osaka Prefecture F-term within Rohto Pharmaceutical Co., Ltd. (reference) 4C076 AA06 AA12 AA36 AA54 AA56 AA72 BB01 BB11 BB24 BB25 CC07 CC10 CC15 DD50 EE16 FF63 4C086 AA02 CB07 MA02 MA34 MA03 MA03 MA03 MA03 ZA59 ZB13 4C206 AA02 GA07 GA33 KA01 MA02 MA03 MA04 MA05 MA29 NA03 ZA33 ZA34 ZA59 ZB13

Claims (8)

[Claims] 1. Formula I: (Wherein R ₁ , R ₂ and R ₃ each independently represent a hydrogen atom or an optionally substituted alkyl group) and at least a pharmacologically acceptable salt thereof. One compound and a compound of formula II: (In the formula, X represents a carbon atom or a nitrogen atom, and R ₄ and R ₅
Are each independently a hydrogen atom, a halogen, a carboxyl group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted acyl group, an optionally substituted aryl group. Or a compound represented by an optionally substituted heterocyclic group) or at least one compound selected from pharmaceutically acceptable salts thereof. 2. The compound of formula I is at least one compound selected from caffeine, pentoxifylline, theophylline, diprophylline, theobromine, proxyphilin or a pharmaceutically acceptable salt thereof.
The pharmaceutical composition according to. 3. The compound of formula II has the formula X
Is a carbon atom or a nitrogen atom, R ₄ is a hydrogen atom, an optionally substituted aryl group or an optionally substituted heterocyclic group, and R ₅ is a hydrogen atom, an optionally substituted alkyl group or a substituted The pharmaceutical composition according to claim 1 or 2, which is a compound represented by an optionally heterocyclic group. 4. The compound of formula II is tranilast, floctafenine, mefenamic acid, flufenamic acid, tolfenamic acid, enfenamic acid, niflumic acid, pyridocaine, cinnamyl anthranilate, lobenzarit, clonixin, flunixin, meclofenamic acid, methylanthraninic acid. The pharmaceutical composition according to claim 3, which is at least one compound selected from the group consisting of phenate, telofenamate, etofenamate, graphenin, anthraphenin and pharmaceutically acceptable salts thereof. 5. A compound of formula I to a compound of formula II
It is contained in a weight ratio of 0.001 to 20: 1.
5. The pharmaceutical composition according to any one of 4 to 4. 6. The pharmaceutical composition according to claim 1, further comprising polyvinylpyrrolidone and / or trometamol. 7. The pharmaceutical composition according to claim 1, which is an aqueous pharmaceutical composition. 8. The method according to claim 1, which is applied locally.
The pharmaceutical composition according to any one of 1.