JP2002037735A - Method for stabilizing caffeines and composition to be applied to mucous membrane - Google Patents

Abstract

PROBLEM TO BE SOLVED: To improve the stabilities of caffeines and a composition (e.g. an aqueous liquid preparation) containing the caffeines. SOLUTION: An aminoalkanesulfonic acid (e.g. taurine) or a derivative thereof is formulated with a compound (caffeines) represented by formula (1) (wherein, R1, R2 and R3 are each hydrogen atom or an alkyl group) or a salt thereof to prevent the deactivation or precipitation of the caffeines or the salt thereof and to stabilize an aqueous composition. The aqueous composition is useful as a composition to be applied to a mucous membrane, e.g. an aqueous preparation (e.g. a nasal drop, an eye lotion or an eye wash) to be applied to ocular- mucous membrane or nasal mucous membrane.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for stabilizing caffeine and a composition containing the same (aqueous composition and the like) and a stabilized composition for mucosal application (mucosal preparation).

[0002]

2. Description of the Related Art Caffeine has a central nervous system stimulating effect and can improve drowsiness. Therefore, caffeine is widely used in pharmaceuticals and food compositions. For example, it is known to add caffeine to eye drops (Japanese Patent Application Laid-Open No. Hei 7-228532).

[0003] The solubility of caffeine in water has a temperature of 8
At 0 ° C, it is 15% by weight or more, but at room temperature (15-20 ° C).
About 2% by weight (MERCK INDEX No. 13)
Plate), the solubility of caffeine varies greatly with temperature. In addition, coexisting substances also affect the solubility of caffeine. Therefore, in an aqueous solution containing caffeine, acicular crystals of caffeine hydrate are precipitated as the solubility decreases due to the ambient temperature. As described above, in the liquid preparation containing caffeine, it is necessary to consider not only the stability at room temperature but also the stability at low temperature.

[0004] Therefore, taking advantage of the fact that the solubility of caffeine varies not only with temperature changes but also with the concentration of salts coexisting in a liquid preparation, it is necessary to suppress the precipitation of caffeine by lowering the concentration of salts. Is possible. However, in topical administration, especially in liquid preparations such as eye drops, if the osmotic pressure is different from that of tears, irritation and pain may occur in the eyes.Therefore, controlling the solubility of caffeine by the concentration of salts substantially restricts it. Accompany.

[0005] Further, in order to improve the solubility of caffeine, sodium benzoate caffeine has been widely used in oral preparations. However, since sodium benzoate caffeine is strongly irritating to the mucous membrane, it is different from the outer skin such as the scalp, especially when used in formulations such as eye drops and nasal drops applied to sensitive ocular and nasal mucosa. Is limited in usage.

[0006] A method using a solubilizer is also known. For example, the solubility of caffeine can be improved by blending paraben. However, in this method, although the stability at low temperature can be imparted by assisting the dissolution of caffeine, paraben is a strong preservative, so it must be used in a limited manner in consideration of safety. In particular, in the preparation applied directly to the mucous membrane, the strong irritation of paraben becomes a problem.

Japanese Patent Application Laid-Open No. 9-48729 discloses an ophthalmic solution in which tetrahydrozoline hydrochloride and taurine are blended as eye drops stabilizing tetrahydrozoline hydrochloride even at a pH close to tears, and the pH is 6.5 to 7.7. An agent is disclosed. Japanese Patent Application Laid-Open No. Hei 9-151128 discloses that a container containing a resin selected from polyethylene and an ethylene-vinyl acetate copolymer contains a buffer agent or taurine in an ophthalmic solution having a content of 2 ml or less containing a sulfur agent. An ophthalmic solution stably containing a sulfur agent by adjusting the pH to 7.8 to 8.9 is disclosed. JP-A-62-190122 discloses an aqueous solution in which scopolamine hydrobromide is stabilized by adding taurine as an essential component at pH 5 to 6. Further, JP-A-56-75438 discloses a method for stabilizing an aqueous cyanocobalamin solution by adding taurine.

The above-mentioned taurine (aminoethylsulfonic acid)
Is a kind of amino acid and is known to have a cell activating effect. However, these documents do not disclose the role of caffeines and aminoethylsulfonic acid in stabilizing eye drops and the like.

[0009]

Accordingly, an object of the present invention is to provide a method for stabilizing caffeine and a composition containing caffeine.

[0010] Another object of the present invention is to provide a composition (or a composition (or formulation) for mucosal application such as eye drops, an aqueous composition for mucosal application, etc.) that can stabilize caffeine and suppress irritation to mucous membranes. To provide.

[0011]

Means for Solving the Problems The inventors of the present invention have made intensive studies to achieve the above object, and as a result, have found that caffeine and a composition containing caffeine can be stabilized by combination with aminoethylsulfonic acid. And completed the present invention.

That is, in the method of the present invention, aminoalkanesulfonic acid or a derivative thereof is blended,
The compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof is stabilized.

[0013]

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(Wherein, R ¹ , R ² and R ³ may be the same or different and each represent a hydrogen atom or an optionally substituted alkyl group). _The compounds represented by the formula (1) include _1-4 alkanesulfonic acids and the like, and the compounds represented by the formula (1) include caffeine, theophylline, diprofylline, theobromine, proxylphyrin, pentoxifylline and the like. The composition may be an aqueous solution.

The composition of the present invention contains an aminoalkanesulfonic acid or a derivative thereof as a stabilizer for the compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof. Further, the composition (formulation or pharmaceutical composition) of the present invention comprises a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof, and an aminoalkanesulfonic acid or a pharmaceutically acceptable salt thereof. Contains. In addition, the composition contains other components (for example, a decongestant, an antihistamine,
Antiallergic agents, antibacterial agents, sulfa agents, solubilizers, thickeners, chelating agents, stabilizers, etc.). Such a composition can stabilize the compound (1) or a salt thereof, has no irritation to the mucous membrane, and is useful as a mucosal composition (mucosal pharmaceutical preparation) applied to mucous membranes sensitive to irritation. is there. This composition is useful as eye drops, eyewashes, nasal drops and the like. The content of aminoalkanesulfonic acid or a derivative thereof is, for example, 0.0
It may be about 01 to 10% by weight (or (W / V)%). The ratio of the aminoalkanesulfonic acid or a derivative thereof to the compound of the formula (1) may be an effective amount or more for stabilization. For example, the compound represented by the formula (1) in terms of aminoalkanesulfonic acid It is about 0.01 to 5000 parts by weight based on 100 parts by weight.

In the present specification, the term "composition"
“Pharmaceutical composition”, “formulation”, and “mucosal preparation” may be simply referred to as “composition” or “formulation”.

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, a compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof (hereinafter may be simply referred to as caffeine) and an aminoalkanesulfonic acid or a derivative thereof ( In the following, the compound represented by the formula (1) or a salt thereof is stabilized by combining the compound with aminoalkanesulfonic acids.

In the above formula (1), examples of the alkyl group include C _1-6 alkyl groups (particularly C _1-4 alkyl groups) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and t-butyl groups. it can. Preferred alkyl groups include a methyl group and an ethyl group.

These alkyl groups may be substituted, for example,
Halogen atom (chlorine, bromine, fluorine atom, etc.), hydroxyl group, alkoxy group (C _1-4 alkoxy group such as methoxy, ethoxy, butoxy group, etc.), aryloxy group, carboxyl group, alkoxycarbonyl group (C _1-4
An alkoxy-carbonyl group), an aryloxycarbonyl group, an acyl group (a C _1-4 alkyl-carbonyl group such as formyl, acetyl, propionyl group, an aryl-carbonyl group such as benzoyl group), a nitro group, an amino group, an N- group It may have a substituted amino group (such as a mono- or di-C _1-4 alkylamino group) and a cyano group.

The compound (1) can also be used as a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include, for example, organic acid salts (eg, acetate, trifluoroacetate, fumarate, maleate, tartrate, citrate, methanesulfonate, toluenesulfonate and the like) ), Inorganic acid salts (eg, hydrochloride, hydrobromide, sulfate, phosphate, etc.), salts with organic bases (such as tertiary amines such as trimethylamine, triethylamine, triethanolamine, pyridine, picoline and the like) And salts with inorganic bases (ammonium salts, alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, and salts with aluminum and the like).

Specific examples of caffeines include xanthine derivatives such as caffeine, theophylline, oxtriphylline, diphyllin, diisobutylaminobenzoyloxypropyl theophylline, theobromine, diprofylline, proxyphyllin, pentoxifylline and the like. These compounds can be used alone or in combination of two or more. Among the xanthine derivatives, caffeine, theophylline, theobromine (particularly,
Caffeine) is preferred. Caffeine also includes anhydrous caffeine.

The caffeine includes substances used in the form of a mixture of caffeine. For example,
Sodium benzoate caffeine, a mixture with sodium benzoate, and caffeine citrate, a mixture of caffeine and citric acid, are mixtures containing caffeine, so they have essentially the same effect as caffeine. Show. In addition, aminophylline, which is a mixture of theophylline and ethylenediamine, and bufirin, which is a mixture of theophylline and aminoisobutanol, are also a mixture containing theophylline, and thus exhibit essentially the same action as theophylline. Similarly, calcium theobromate and sodium theobromine, which are a mixture of theobromine and salicylate, and sodium theobromine, which is a mixture of theobromine and sodium acetate, are also mixtures containing theobromine, and therefore have essentially the same action as theobromine. Is shown. That is, these mixtures are included in caffeine, theophylline, and theobromine in the present invention.

The aminoalkanesulfonic acid is not particularly limited as long as caffeine can be stabilized.
Examples thereof include amino C _1-10 alkanesulfonic acids such as aminomethanesulfonic acid, aminoethanesulfonic acid (or aminoethylsulfonic acid), aminopropanesulfonic acid, aminobutanesulfonic acid, aminopentanesulfonic acid, and aminohexanesulfonic acid. .

The aminoalkanesulfonic acid may be used as a derivative equivalent to the aminoalkanesulfonic acid in stabilizing caffeine. Examples of such derivatives include salts of aminoalkanesulfonic acids (particularly pharmacologically acceptable salts) [eg, organic acids, inorganic acids (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.), organic bases, inorganic bases, and the like. A salt with a base (such as an alkali metal such as sodium or potassium) or a compound derived from aminoalkanesulfonic acid [for example, N-acylaminoalkanesulfonic acid (for example, N-C ₁ -such as N-acetylaminoethanesulfonic acid); ₄ an acyl-aminoethanesulfonic acid), such as N-C _1-4 alkylamino -C _1-4 alkanesulfonic acids such as N- alkylamino alkanesulfonic acid (N- methylaminoethyl acid), N, N- dialkyl Aminoalkanesulfonic acid (N, N-dimethylaminoethylsulfonic acid and other N,
N-di C _1-4 alkylamino-C _1-4 alkanesulfonic acid, etc.), aminoalkanesulfinic acid (amino C _1-4 alkanesulfinic acid such as hypotaurine, etc.), taurocholic acid or a salt thereof (sodium salt, etc.) , Taurocyanine phosphate, taurobetaine, etc.].

These compounds or derivatives thereof can be used alone or in combination of two or more. Preferred aminoalkanesulfonic acids are amino C _1-4 alkanesulfonic acids, especially aminoethylsulfonic acid (taurine).

The amount of aminoalkanesulfonic acid used is as follows:
As long as it is an effective amount or more for stabilization of caffeine, caffeine can be effectively stabilized even in a small amount. Therefore, the amount of aminoalkanesulfonic acid used is 0.01 parts by weight or more (for example, 0.01 to 5000 parts by weight) based on 100 parts by weight of caffeine in terms of free compound (aminoalkanesulfonic acid). The amount can be selected from the range, preferably 0.1 part by weight or more (for example, 0.3 to 1000 parts by weight), more preferably 1 part by weight or more (for example, 1 to 1000 parts by weight), particularly 10 parts by weight or more ( For example, about 10 to 500 parts by weight),
Usually, 0.1 to 5000 parts by weight, preferably 1 to 300 parts by weight.
It is about 0 parts by weight (particularly 5 to 1000 parts by weight).

The aminoalkanesulfonic acid functions as a stabilizer for caffeine (a deactivation inhibitor and / or a precipitation inhibitor), and not only prevents the deactivation of caffeine but also the precipitation of caffeine. Or to prevent separation,
Stabilizes compositions containing caffeine. That is, aminoalkanesulfonic acids function as a stabilizer,
When aminoalkanesulfonic acids are added to a composition or a preparation containing caffeine, the caffeine and the composition containing caffeine can be reliably stabilized for a long period of time. Furthermore, the caffeines not only can effectively impart a high refreshing feeling, but also greatly improve (reduce or reduce) the sensitivity to mucous membranes (such as mucous membrane irritation). Therefore, the composition of the present invention contains caffeine and aminoalkanesulfonic acid as a stabilizer for the caffeine.

The composition or preparation of the present invention comprises a compound represented by the formula (1) (a xanthine derivative or the like) or a pharmaceutically acceptable salt thereof, and an aminoalkanesulfonic acid (amino C)
_(1-4 alkanesulfonic acid, etc.) or a derivative thereof, as a composition (mucosal composition or preparation) to be applied to mucous membranes, especially mucous membranes sensitive to irritation (such as ocular mucosa and nasal mucosa) It is suitable. The “mucosa” includes, for example, ocular mucosa such as cornea and conjunctiva, nasal mucosa, gums, tongue, lips, oral mucosa, pharyngeal mucosa, anal mucosa, rectal mucosa, vulvar mucosa, vaginal mucosa and the like.

Preferred compositions for mucosal application include ophthalmic compositions (eye drops, eyewashes, intraocular perfusates, agents for contact lenses, etc.), nasal compositions, oral compositions and the like. The composition (or preparation) of the present invention is particularly suitable for nasal drops, eye drops,
It is useful as an eyewash, a contact lens agent and the like.

[0030] The dosage form of the composition or preparation of the present invention is usually
It is an aqueous preparation (or an aqueous composition). The proportion of the aqueous component of the aqueous preparation is not particularly limited as long as the composition contains the aqueous component, and the composition contains an oil component together with the aqueous component, for example, an aqueous suspension composition (O / W type liquid, W / O solution), an aqueous viscous composition or the like. Further, they may be used in the form of solutions, suspensions, emulsions, extracts, syrups, creams, ointments, lotions and other liquids or semisolids.

In the composition or preparation of the present invention, the amount of the caffeine used may be, for example,
0.0001 to 10 (e.g.,
0.001 to 5)% by weight (or (W / V)%), preferably selected from the range of about 0.01 to 3 (for example, 0.1 to 2)% by weight (or (W / V)%). it can. In the present invention, the concentration of caffeine in the composition or the preparation is such a high concentration that caffeine is crystallized, for example, the amount used is 0.4% by weight (or (W / V)%). [For example,
About 0.4 to 10% by weight (or (W / V)%)], preferably 0.5% by weight (or (W / V)%) or more [for example, 0.5 to 10% by weight (or (W / V)%). / V)%)],
More preferably, it is 0.6% by weight (or (W / V)%) or more (for example, 0.6 to 10% by weight (or (W / V)%)).
Degree], particularly, about 0.6 to 5% by weight, caffeine can be efficiently stabilized.

Further, the content of the aminoalkanesulfonic acid is 0.001 to 10% by weight in terms of the free compound (aminoalkanesulfonic acid) based on the whole composition.
(Or (W / V)%), preferably 0.005 to 5% by weight (or (W / V)%), more preferably 0.01 to 5% by weight.
2% by weight (or (W / V)%), especially 0.1-1% by weight
(Or (W / V)%). The ratio between the caffeine and the aminoalkanesulfonic acid is as described above.

The types of components (pharmacologically active or physiologically active components) that can be further incorporated into the composition or preparation are not particularly limited, and various active ingredients may be selected depending on the use and type of the preparation.
For example, anti-inflammatory drug component, anti-allergic drug component, antipyretic analgesic component, psychotropic drug component, anti-hypertensive drug component, diuretic component,
Antitussive component, expectorant component, antiasthmatic component, stomachic component, digestive component, ulcer remedy component, anemia component, astringent component, antibacterial or bactericidal component, antitumor component, hormone, protein or Peptides, vitamins, amino acids and the like can be used.

Suitable components in the composition or preparation of the present invention include, for example, the following components.

Decongestants (vasoconstrictors or sympathomimetics): α-adrenergic agonists, such as imidazoline derivatives (naphazoline, tetrahydrozoline, etc.), β
-Phenylethylamine derivatives (phenylephrine, epinephrine, ephedrine, methylephedrine, etc.) and their salts (eg, naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, etc.)

Ocular muscle regulatory component: a cholinesterase inhibitor having an active center similar to acetylcholine, for example,
Quaternary ammonium compounds such as neostigmine methyl sulfate

Anti-inflammatory (or anti-inflammatory) or astringent: For example, epsilon-aminocaproic acid, berberine, azulene sulfonic acid, glycyrrhizic acid, anti-inflammatory enzyme agents (such as lysozyme), methyl salicylate, allantoin, zinc and salts thereof (chloride Berberine, berberine sulfate, sodium azulene sulfonate, dipotassium glycyrrhizinate, lysozyme chloride, zinc sulfate, zinc lactate), etc.

Examples of the anti-inflammatory (or anti-inflammatory) agent include aromatic carboxylic acid derivatives such as aryl carboxylic acids (ibuprofen, ketoprofen, naproxen, suprofen, indomethacin, planoprofen, mefenamic acid, diclofenac, bromfenac) , 2-
Examples thereof include naphthylacetic acid, 2-naphthoxyacetic acid, salicylic acid, and the like, and pyridonecarboxylic acids (such as lomefloxane, norfloxacin, ofloxacin, enoxacin, ciprofloxacin, and tosfloxacin).

Antihistamines: For example, chlorpheniramine, diphenhydramine, iproheptin, ketotifen, emedastine, clemastine, azelastine, levocabastine, olobatadine, and salts thereof (diphenhydramine hydrochloride, iproheptin hydrochloride, azelastine hydrochloride, levavaclosine hydrochloride, oleavaclosine hydrochloride, oleovaclosine hydrochloride, oleovaclosine hydrochloride, oleovaclosine hydrochloride Lamin, ketotifen fumarate, emedastine fumarate, clemastine fumarate)

Antiallergic agents: for example, cromoglycic acid, amlexanox, ibudilast, suplatast,
Pemirolast, tranilast and their salts (such as sodium cromoglycate and suplatast tosilate)

Antibacterial agents or sulfa drugs: for example, sulfonamides [sulfamethoxazole, sulfisoxazole, or salts thereof (sulfamethoxazole sodium, sulfisomidine sodium, etc.) and the like], acrinol, Quaternary ammonium or a salt thereof (benzalkonium (benzalkonium salt such as benzalkonium chloride, etc.), benzethonium (benzethonium salt such as benzethonium chloride, benzethonium bromide, etc.), cetylpyridium (cetyl such as cetylpyridinium chloride) Pyridium salt), alkylpolyaminoethylglycine, ofloxacin, norfloxacin, etc.

Vitamins: For example, vitamin B ₂ (or flavin adenine dinucleotide sodium), vitamin B ₆ (or pyridoxine hydrochloride), vitamin B ₁₂ (or cyanocobalamin), retinol acetate (vitamin A acetate), retinol palmitate, acetic acid Tocopherol (vitamin E acetate), d-α-tocopherol acetate, panthenol, sodium pantothenate, calcium pantothenate, etc.

Amino acids: for example, L-aspartic acid or a salt thereof (potassium L-aspartate, magnesium L-aspartate, potassium magnesium L-aspartate, etc.), etc.

Myopia treatment / prevention agents: for example, tropicamide, cyclopentolate, endothelin and the like

Ocular hypotensives: for example, pilocarpine or a salt thereof (such as pilocarpine hydrochloride), isopropyl unoprostone, distigmine bromide, carbacomal, carteolol hydrochloride, befnolol hydrochloride, timolol maleate, dipivefrin hydrochloride, ecothiopart iodide, diclofenamide , And β receptor blockers, etc.

Saccharides: For example, monosaccharides (eg, glucose), disaccharides (eg, trehalose, lactose, fructose), cellulose or its derivatives (eg, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose) or salts thereof, high molecular weight saccharides or these Salts (such as sodium chondroitin sulfate and sodium hyaluronate) and sugar alcohols (such as mannitol, xylitol, and sorbitol)

Other components: polyvinyl alcohol, polyvinylpyrrolidone, etc. Further, if necessary depending on the application, a local anesthetic (oxybuprocaine, lidocaine, lidocaine hydrochloride, etc.), a soothing agent (procaine hydrochloride, etc.), etc. Various active ingredients may be used.

In general, among these components, at least one component selected from the following group or a pharmaceutically acceptable salt thereof can be used.

Naphazoline, phenylephrine, epinephrine, ephedrine, methylephedrine, tetrahydrozoline, methylneostigmine sulfate, epsilon-aminocaproic acid, berberine, azulenesulfonic acid, glycyrrhizic acid, lysozyme, allantoin, zinc, chlorpheniramine, diphenhydramine, iproheptin Emedastine, clemastine, azelastine, levocabastine, olobatadine, cromoglycic acid, amlexanox, ibudilast, splatast, pemirolast, tranilast, sulfamethoxazole, sulfisoxazole, sulfisomidine, acrynol, benzethonium, cetylpyridinine, aminopolyxylethyl glyrosine , Norfloxacin, hula Down adenine dinucleotide, pyridoxine, cyanocobalamin, retinol, tocopherol, panthenol, pantothenic acid, aspartic acid,
Glucose, chondroitin sulfate, hyaluronic acid, and polyvinyl alcohol These components can be used alone or in combination of two or more.

The content of these components can be selected according to the type of preparation, the type of active ingredient, and the like. For example, 0.0001 to 30% by weight (or (W / V) based on the whole preparation)
%), Preferably 0.001 to 10% by weight (or (W /
V)%), more preferably in the range of about 0.01 to 10% by weight (or (W / V)%).

More specifically, in the aqueous preparation (ophthalmic solution or nasal solution) suitable for the present invention, the content of each component [unit:% by weight (or (W / V)%)] is, for example, Is as follows.

Decongestant (vasoconstrictor or sympathomimetic): For example, an effective amount (eg, 0.0001) to 0.
5, preferably about 0.0005 to 0.3, more preferably about 0.001 to 0.1

Ocular muscle regulating component: for example, an effective amount (eg, 0.0001) to 0.01, preferably 0.0002 to
0.05, more preferably 0.0003 to 0.005
degree

Anti-inflammatory (or anti-inflammatory) or astringent: for example, an effective amount (eg, 0.001) to 10, preferably 0.005 to 5, more preferably 0.01 to 3

Antihistamines: for example, an effective amount (eg, 0.0001) to 0.1, preferably 0.0005 to
0.07, more preferably about 0.001 to 0.05

Antiallergic agent: for example, an effective amount (eg, 0.001) to 10, preferably 0.005 to 5, more preferably about 0.01 to 5

Antibacterial agent or sulfa agent: for example, an effective amount (eg, 0.001) to 10, preferably 0.003 to
10, more preferably about 0.01 to 10

Vitamin: For example, an effective amount (for example, 0.
0001) to 0.5, preferably 0.0005 to 0.5.
3, more preferably about 0.001 to 0.1

Amino acids: For example, an effective amount (eg,
0001) to 5, preferably about 0.0005 to 3, and more preferably about 0.001 to 2.

Myopia treatment / prevention agent: for example, an effective amount (eg, 0.001) to 5, preferably 0.005 to 3, more preferably about 0.001 to 1.

Ocular hypotensive agent: For example, an effective amount (eg,
001) to 10, preferably about 0.001 to 5, and more preferably about 0.001 to 3.

Saccharides [eg, monosaccharides (eg, glucose), disaccharides (eg, trehalose, lactose, fructose, etc.)]: eg, 0.0001 to 5, preferably 0.001 to 5, more preferably 0.01 to 5 About 2

Cellulose or a derivative thereof (hydroxypropylmethylcellulose, methylcellulose, hydroxypropylethylcellulose and the like) or a salt thereof: for example, about 0.001 to 5, preferably about 0.001 to 3, and more preferably about 0.01 to 1.

Polymeric saccharides or salts thereof (such as sodium chondroitin sulfate and sodium hyaluronate): for example, about 0.0001 to 2, preferably about 0.01 to 2, and more preferably about 0.01 to 1.

Polyvinyl pyrrolidone, polyvinyl alcohol: for example, 0.001 to 10, preferably 0.00
1-5, more preferably about 0.01-3.

The composition (or preparation) of the present invention can be prepared using various bases and additives according to the type of preparation. For example, water, vegetable oils (olive oil, soybean oil, sesame oil, cottonseed oil, etc.), (poly) ethylene glycol, propylene glycol, liquid paraffin, vaseline, wax, macrogol, cetanol, higher fatty acid esters, cellulose derivatives, carboxyvinyl polymer, poly It can be prepared using oxyethylene-polyoxypropylene block copolymers, gums and the like.

Compositions such as aqueous preparations (aqueous liquids and the like) may contain solubilizers (or emulsifiers), thickeners, chelating agents and the like.

As a solubilizing agent (or emulsifier), for example, polyoxyethylene (POE) -polyoxypropylene (POP) block copolymer (BASF Wyandotte C)
oproration), polysorbate, polyoxyethylene sorbitan fatty acid ester (polyoxyethylene sorbitan monooleate), polyoxyethylene oxystearate triglyceride, polyoxyethylene mono higher fatty acid ester (polyoxyethylene monostearate), polyethylene glycol, poly Nonionic surfactants such as oxyethylene hydrogenated castor oil can be exemplified. Further, if necessary, a cationic surfactant (a quaternary ammonium salt such as benzalkonium chloride, an alkylenediamine (such as ethylenediamine))
POE-POP block-substituted alkylenediamines (eg, BASF Wyandotte Coproration, Tetronic) to which a block chain composed of a POE block and a POP block has been added, anionic surfactants (eg, alkylbenzene sulfonates, alkyl sulfates), and the like. An amphoteric surfactant (such as alkyl polyaminoethyl glycine hydrochloride) may be used.

Examples of the thickener include polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone (K25, K30, K90, etc.), polysaccharides or derivatives thereof [cellulose derivatives (hydroxyethylcellulose,
Hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose (2208,290
6,2910), celluloses such as carboxymethylcellulose, or salts thereof), gum arabic powder, sodium chondroitin sulfate, powdered tragacanth, etc.), sugars (glucose, sorbitol, dextran 7).
0), carboxyvinyl polymer, macrogol 4
000 and the like. A block copolymer containing the polyoxyethylene block and the polyoxypropylene block (BASF Wyandotte Coproration, Pluronic, Tetronic, etc.) can also be used as a thickener. Among these thickeners, usually, polyvinyl alcohol, polyvinylpyrrolidone, cellulose derivatives (hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose,
Or salts thereof).

Examples of the chelating agent include ethylenediaminetetraacetate, edetic acid or a salt thereof (eg, an alkali metal salt such as disodium edetate, trisodium edetate, and tetrasodium edetate, or an alkaline earth such as calcium edetate). Metal salt), nitrilotriacetic acid or a salt thereof, sodium hexametaphosphate, citric acid and the like.

The composition of the present invention comprises various components, inorganic salts, buffers, tonicity agents, preservatives or preservatives, stabilizers, pH adjusters, fresheners, antioxidants, coloring agents Agents, flavors or fragrances.

Examples of the inorganic salts include sodium chloride, potassium chloride, sodium carbonate, dried sodium carbonate, sodium hydrogen carbonate, calcium chloride, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, Examples thereof include sodium thiosulfate. In addition, these inorganic salts may be used as a buffer component or a tonicity component.

Examples of the buffer include a phosphate buffer,
Examples thereof include a borate buffer, a carbonate buffer, a citrate buffer, a tartrate buffer, an acetate buffer, and an amino acid (epsilon aminocaproic acid, aspartate and the like).
Among them, phosphate buffers, borate buffers, carbonate buffers, and citrate buffers (particularly, borate buffers, phosphate buffers, and citrate buffers) that more effectively exhibit a stimulus-reducing effect are available. preferable.

Examples of the tonicity agent include sugars (sorbitol, glucose, mannitol, etc.), polyhydric alcohols (glycerin, polyethylene glycol, propylene glycol, etc.), and inorganic salts (sodium chloride, potassium chloride, etc.). Can be illustrated.

As the preservative or preservative, for example,
Quaternary ammonium or a salt thereof (benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, etc.), paraoxybenzoic acid ester (methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, etc.), benzyl alcohol, Examples include phenethyl alcohol, sorbic acid or a salt thereof (such as a potassium salt), alkyl polyaminoethyl glycine, thimerosal, chlorobutanol, sodium dehydroacetate, polymyxin B sulfate, polyquad, polyhexamethylene biguanide, and chlorhexidine.

Examples of the stabilizer include edetates (such as sodium edetate) and ethylenediaminetetraacetate.

As the pH adjusting agent, bases (hydroxides of alkali metals such as sodium hydroxide and potassium hydroxide,
Examples thereof include alkali metal carbonates or hydrogen carbonates such as sodium carbonate and the like, acids (organic acids such as acetic acid and citric acid, and inorganic acids such as hydrochloric acid and phosphoric acid), and borax.

Examples of the cooling agent include terpene compounds such as l-menthol, d-menthol, dl-menthol, d-camphor, dl-camphor, d-borneol, dl-borneol, and geraniol; eucalyptus oil, bergamot oil And essential oil components such as fennel oil, peppermint oil, rose oil and cool mint.

In the present invention, the pH of an aqueous solution (particularly, a solution for mucosal application, for example, an ophthalmic solution such as an eye drop, a nasal drop, or a contact lens agent) is usually 4 to 9 (from the viewpoint of irritation). For example, 4.6 to 7.6), preferably 5
To 7, more preferably about 5.5 to 7. The osmotic pressure is usually about 150 to 450 mOsm, and the osmotic pressure ratio to physiological saline is usually 0.6 to 1.6, preferably 0.7 to 1.5, particularly about 0.8 to 1.2. It is.

The composition of the present invention can be produced by a conventional method using the above-mentioned caffeines, aminoalkanesulfonic acids, the above-mentioned bases and additives. For example, the aqueous liquid preparation can be prepared by dissolving or suspending the caffeine and aminoalkanesulfonic acid using distilled water and additives, adjusting the osmotic pressure to a predetermined value, and sterilizing by filtration.

The usage and dosage of the composition of the present invention can be selected according to the type and form of the preparation, the condition and age of the patient. For example, the usage and dosage of an aqueous ophthalmic solution (such as eye drops) are usually about 1 to 6 times per day, and the number of drops per time is about 1 to 3 drops. In addition, eye ointments are usually
An appropriate amount can be applied to the conjunctival sac about 1 to 3 times a day.

[0082]

According to the present invention, since the caffeine and the aminoalkanesulfonic acid are combined, precipitation and separation can be prevented, and the caffeine can be stabilized. Also,
The composition (or preparation) of the present invention is safe without irritation to mucous membranes. Therefore, it is useful as a mucosal composition (aqueous preparation applied to mucous membranes such as ocular mucosa and nasal mucosa).

[0083]

The present invention will be described below in more detail with reference to Examples, but the present invention is not limited to these Examples.

Examples 1 to 6 and Comparative Example 1 (2% by weight caffeine aqueous solution) Anhydrous caffeine was dissolved in physiological saline (Japanese Pharmacopoeia),
A 2% by weight aqueous solution of caffeine was prepared. Aminoethylsulfonic acid was added to this aqueous caffeine solution to prepare an aqueous solution having an aminoethylsulfonic acid content of 0.01 to 2% by weight (Examples 1 to 6). As a control, a 2% by weight aqueous solution of caffeine was used without adding aminoethylsulfonic acid (Comparative Example 1).

After confirming that the obtained aqueous solution maintained a uniform solution state for 2 hours or more at room temperature,
It was left in a refrigerator set at a temperature of 4 ° C. for 1 hour, and the presence or absence of formation of a precipitate was observed. As a result, caffeine precipitation was observed in the test solution of Comparative Example 1, while the test solution containing 0.01 to 2% by weight of aminoethylsulfonic acid was
There was no precipitation of caffeine, and the solution remained stable and was stable. Table 1 shows the results.

[0086]

[Table 1]

Examples 7 to 13 and Comparative Example 2 (1% by weight caffeine aqueous solution) Anhydrous caffeine was dissolved in physiological saline (Japanese Pharmacopoeia).
A 1% by weight aqueous solution of caffeine was prepared. Aminoethylsulfonic acid was added to this aqueous caffeine solution to prepare an aqueous solution having an aminoethylsulfonic acid content of 0.003 to 2% by weight (Examples 7 to 13). As a control, a 1% by weight aqueous solution of caffeine was used without adding aminoethylsulfonic acid (Comparative Example 2).

After confirming that the obtained aqueous solution maintained a uniform solution state for 2 hours or more at room temperature,
It was left in a refrigerator set at a temperature of 4 ° C. for 1 hour, and the presence or absence of formation of a precipitate was observed. As a result, caffeine was precipitated in the test solution of Comparative Example 2, whereas in the test solution containing 0.003 to 2% by weight of aminoethylsulfonic acid, a clear solution state without caffeine was precipitated. Maintain
It was stable. Table 2 shows the results.

[0089]

[Table 2]

As is clear from Tables 1 and 2, by adding aminoethylsulfonic acid to caffeine,
Precipitation or separation of caffeine can be effectively suppressed.

Examples 14 to 27 and Comparative Examples 3 to 13 Using the components shown in Tables 3 and 4, the total volume was adjusted to 1 L with distilled water to prepare aqueous solutions having a pH of 4.6 to 7.6. It was left in a refrigerator set at a temperature of 4 ° C. for 1 hour, and the presence or absence of formation of a precipitate was observed. As a result, precipitation of caffeine was observed in the test solutions containing no aminoethylsulfonic acid (Comparative Examples 3 to 13). On the other hand, in the test solution containing aminoethylsulfonic acid (Examples 14 to 27),
A clear solution state was maintained without the precipitation of caffeine, indicating that aminoethylsulfonic acid was effective in stabilizing caffeine. The results are shown in Tables 3 and 4.

[0092]

[Table 3]

[0093]

[Table 4]

In Formulation Examples 1 to 18, aseptic preparations were prepared by conventional methods using the following components to obtain preparations. The pH of each obtained formulation is also shown below.

Formulation Example 1 (Eye drops) Caffeine anhydrous 0.6 g Aminoethylsulfonic acid 1.0 g Pyridoxine hydrochloride 0.1 g Boric acid 0.1 g Sodium chloride 0.6 g 1 N sodium hydroxide Appropriate amount Sterile purified water Appropriate amount 100 mL ( pH 6.5)

Formulation Example 2 (eye drops) Anhydrous caffeine 1.0 g Aminoethylsulfonic acid 1.0 g Neostigmine methyl sulfate 0.005 g Naphazoline hydrochloride 0.001 g Sodium chloride 0.7 g 1N Sodium hydroxide Appropriate amount Sterilized purified water qs Total 100mL (pH5.5)

Formulation Example 3 (Eye drops) Anhydrous caffeine 2.0 g Aminoethylsulfonic acid 1.0 g Dipotassium glycyrrhizinate 0.25 g Chlorpheniramine maleate 0.03 g Concentrated glycerin 3 mL 1N sodium hydroxide Appropriate sterilization Purified water qs 100mL (pH 6.0)

Formulation Example 4 (nasal drops) anhydrous caffeine 1.5 g aminoethylsulfonic acid 1.0 g methyl salicylate 0.03 g chlorpheniramine maleate 0.3 g dl-methylephedrine hydrochloride 0.3 g polysorbate 80 0.2 g benzalkonium chloride 0.01 g sodium chloride 0.6 g 1N sodium hydroxide qs sterile purified water qs total 100mL (pH 6.5)

Formulation Example 5 (artificial tear-type eye drops) anhydrous caffeine 0.05 g aminoethylsulfonic acid 1.0 g sodium chloride 0.5 g potassium chloride 0.1 g boric acid 0.5 g sodium edetate 0 0.05g Potassium sorbate 0.1g pH adjuster qs sterile purified water qs 100ml (pH 7.2)

Formulation Example 6 (artificial tear-type eye drops) Anhydrous caffeine 0.1 g aminoethylsulfonic acid 0.5 g l-menthol 0.01 g sodium chloride 0.5 g potassium chloride 0.1 g boric acid 1 0.0 g sodium edetate 0.05 g potassium sorbate 0.1 g polysorbate 80 0.1 g pH adjuster qs sterile purified water qs 100 mL (pH 6.5)

Formulation Example 7 (Disinfectant for contact lenses) Anhydrous caffeine 0.3 g polyhexamethylene biguanide 0.0001 g aminoethyl sulfonic acid 1.0 g sodium chloride 0.5 g boric acid 0.5 g hydroxyethyl cellulose 0 0.1 g Poloxamer 407 0.1 g Sodium edetate 0.05 g pH adjuster qs sterile purified water qs 100 mL (pH 6.0)

Formulation Example 8 (Disinfectant for contact lenses) Anhydrous caffeine 1.0 g l-menthol 0.005 g polyhexamethylene biguanide 0.0001 g aminoethylsulfonic acid 0.5 g sodium chloride 0.5 g boric acid 1.0 g Hydroxyethylcellulose 0.1 g Poloxamer 407 0.1 g Sodium edetate 0.05 g pH adjuster qs sterile purified water qs 100 mL (pH 7.0)

Formulation Example 9 (Cleaning and disinfecting preservative for contact lenses) Anhydrous caffeine 0.1 g polyhexamethylene biguanide 0.0001 g aminoethylsulfonic acid 1.0 g sodium chloride 0.5 g boric acid 0.5 g polyvinyl Pyrrolidone 2.0 g Poloxamer 407 0.1 g Sodium edetate 0.005 g pH adjuster qs sterile purified water qs 100 mL (pH 6.8)

Formulation Example 10 (Cleaning and disinfecting preservative for contact lenses) Anhydrous caffeine 0.1 g l-menthol 0.001 g polyhexamethylene biguanide 0.0001 g aminoethylsulfonic acid 0.5 g sodium chloride 0.5 g Boric acid 1.0 g polyvinylpyrrolidone 2.0 g poloxamer 407 0.1 g sodium edetate 0.005 g pH adjuster qs sterile purified water qs 100 mL (pH 7.3)

Formulation Example 11 (eyewash) Dipotassium glycyrrhizinate 0.025 g Chlorpheniramine maleate 0.003 g Pyridoxine hydrochloride 0.010 g Tocopherol acetate 0.005 g Potassium L-aspartate 0.100 g Aminoethyl sulfonic acid 0.100 g Sodium chondroitin sulfate 0.050 g Boric acid 1.700 g Borax 0.100 g Anhydrous caffeine 0.2 g Chlorobutanol 0.010 g Benzalkonium chloride 0.005 g Polysorbate 80 0.05 g pH adjuster Appropriate amount Sterilized purified water Appropriate amount 100 mL (pH 6.8)

Formulation Example 12 (eyewash) Dipotassium glycyrrhizinate 0.025 g Pyridoxine hydrochloride 0.010 g Tocopherol acetate 0.005 g Potassium L-aspartate 0.100 g Aminoethylsulfonic acid 0.100 g Sodium chondroitin sulfate 0.050 g Boric acid 1.550 g Borax 0.300 g Anhydrous caffeine 0.2 g 1-menthol 0.003 g dl-Camphor 0.003 g Eucalyptus oil 0.005 g Bergamot oil 0.002 g Alkyl polyaminoethyl glycine solution 0.050 g (10 W / W% ) Polysorbate 80 0.05 g pH adjuster qs sterile purified water qs 100 mL (pH 7.0)

Formulation Example 13 (eye drops) Anhydrous caffeine 0.075 g naphazoline hydrochloride 0.003 g allantoin 0.060 g aminoethylsulfonic acid 2.0 g sodium chloride 0.7 g potassium chloride 0.1 g boric acid 0.3 g Sodium edetate 0.05 g Poloxamer 407 0.100 g Sodium hyaluronate 0.05 g Epsilon-aminocaproic acid 0.750 g Benzalkonium chloride 0.005 g pH adjuster qs sterile purified water qs 100 mL (pH 6.0)

Formulation Example 14 (eye drops) Anhydrous caffeine 0.075 g naphazoline hydrochloride 0.003 g allantoin 0.060 g aminoethylsulfonic acid 0.5 g l-menthol 0.003 g d-borneol 0.001 g sodium chloride 0.7 g Potassium chloride 0.1 g Boric acid 0.5 g Sodium edetate 0.05 g Polysorbate 80 0.100 g Sodium hyaluronate 0.05 g Epsilon-aminocaproic acid 0.750 g Alkyl polyaminoethyl glycine solution 0.050 g (10 W / W%) pH adjuster qs sterile purified water qs qty 100mL (pH 7.4)

Formulation Example 15 (Eye drops) Caffeine anhydrous 1.0 g Sodium cromoglycate 1.00 g Chlorpheniramine maleate 0.015 g Aminoethylsulfonic acid 0.2 g Sodium chloride 0.5 g Potassium chloride 1 g Boric acid 0.3 g Sodium edetate 0.05 g Polyoxyethylene hydrogenated castor oil 0.100 g Benzalkonium chloride 0.005 g pH adjuster Appropriate amount Sterile purified water Appropriate amount 100 mL (pH 7.0)

Formulation Example 16 (eye drops) Anhydrous caffeine 0.8 g l-menthol 0.005 g sodium cromoglycate 1.00 g chlorpheniramine maleate 0.015 g aminoethylsulfonic acid 0.2 g sodium chloride 5 g Potassium chloride 0.1 g Boric acid 0.3 g Sodium edetate 0.05 g Polyoxyethylene hydrogenated castor oil 0.100 g Benzalkonium chloride 0.005 g pH adjuster qs sterile purified water qs 100 mL (pH 5. 5)

Formulation Example 17 (artificial tear-type eye drops) Anhydrous caffeine 0.03 g aminoethylsulfonic acid 1.5 g sodium chloride 0.5 g potassium chloride 0.1 g boric acid 0.3 g sodium edetate 0.05 g Alkyl polyaminoethyl glycine solution 0.100 g (10 W / W%) hydroxyethyl cellulose 0.050 g Poloxamer 407 0.100 g pH adjuster qs sterile purified water qs 100 mL (pH 6.0)

Formulation Example 18 (Artificial tear-type eye drops) Anhydrous caffeine 0.03 g l-menthol 0.003 g dl-camphor 0.002 g aminoethylsulfonic acid 1.0 g sodium chloride 0.7 g potassium chloride 0 0.1 g Boric acid 0.3 g Sodium edetate 0.05 g Alkyl polyaminoethyl glycine solution 0.100 g (10 W / W%) Hydroxyethyl cellulose 0.050 g Poloxamer 407 0.05 g Polysorbate 80 0.05 g pH adjuster Appropriate amount of sterilized purified water Appropriate amount Total amount 100mL (pH7.5)

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (reference) // A61P 25/26 A61P 25/26 F term (reference) 4C076 AA11 AA12 BB21 CC01 DD57 FF15 FF36 4C084 AA19 NA03 NA05 ZA36 ZB13 ZB35 ZB37 ZC44 ZC45 4C086 AA01 AA02 CB07 MA02 MA03 MA05 MA07 MA17 MA56 MA58 NA02 NA03 NA05 ZA02 ZA33

Claims (11)

[Claims] 1. A compound represented by the following formula (1) by mixing aminoalkanesulfonic acid or a derivative thereof. Wherein R ¹ , R ² and R ³ may be the same or different and each represent a hydrogen atom or an optionally substituted alkyl group, or a pharmaceutically acceptable compound thereof. Salt stabilization method. 2. The method according to claim 1, wherein the compound represented by the formula (1) is at least one selected from the group consisting of caffeine, theophylline, diprofylline, theobromine, proxylphyrin and pentoxifylline. 3. The method according to claim 1, wherein the aminoalkanesulfonic acid is amino C
The stabilizing method according to claim 1, which is an _1-4 alkanesulfonic acid. 4. A composition comprising an aminoalkanesulfonic acid or a derivative thereof as a stabilizer for the compound represented by the formula (1) according to claim 1 or a pharmaceutically acceptable salt thereof. 5. A composition for mucosal application comprising the compound represented by the formula (1) according to claim 1 or a pharmaceutically acceptable salt thereof, and aminoalkanesulfonic acid or a derivative thereof. 6. The composition according to claim 5, comprising a xanthine derivative and an amino C _1-4 alkanesulfonic acid. 7. The composition according to claim 5, comprising 0.001 to 10% by weight (or (W / V)%) of aminoalkanesulfonic acid or a derivative thereof based on aminoalkanesulfonic acid in terms of aminoalkanesulfonic acid. 8. The composition according to claim 5, which is a nasal drop, an eye drop or an eye wash. 9. A compound represented by the formula (1) according to claim 1 or a pharmaceutically acceptable salt thereof, relative to 100 parts by weight.
The composition according to claim 5, which contains 0.01 to 5000 parts by weight of aminoalkanesulfonic acid or a derivative thereof in terms of aminoalkanesulfonic acid. 10. A compound comprising the compound represented by the formula (1) according to claim 1 or a pharmaceutically acceptable salt thereof, an aminoalkanesulfonic acid or a derivative thereof, and at least one selected from the following group: Mucosal application composition. Decongestants, antihistamines, antiallergic agents, antibacterial agents, and sulfa drugs 11. The composition for applying to mucous membrane according to claim 5, further comprising at least one selected from a solubilizer, a thickener, a chelating agent, and a stabilizer.