JP5301069B2 - Azulene-containing aqueous solution - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a stable aqueous solution containing azulenes, improved in light stability, by preventing an insoluble substance from forming, and to provide a preparation enhanced in transferability of the azulenes and berberines to organismic tissue. <P>SOLUTION: This aqueous solution is obtained by making (C) a buffer agent and (D) a nonionic surfactant contained in an aqueous solution containing (A) the azulenes and (B) berberines. The aqueous solution thus obtained is improved in the light stability, prevents the insoluble substance from forming, and therefore is excellent in long-term stability. Further, lipophilicity of the azulenes and the berberines which are pharmacologically active components is improved, so that the transferability thereof to the organismic tissue is enhanced. Therefore, the aqueous solution is useful as the external preparation, especially, as an ophthalmic preparation. <P>COPYRIGHT: (C)2006,JPO&amp;NCIPI

Description

The present invention relates to an aqueous liquid preparation containing azulene and excellent in stability.

  Azulenes such as sodium azulene sulfonate and guaiazulene sulfonic acid are drugs having a wide range of effects such as anti-inflammatory and anti-allergic effects, and are mainly used as oral anti-inflammatory agents and eye drops as anti-inflammatory agents. However, these azulenes are unstable with respect to light, and azulenes are easily decomposed at the stage of production and distribution. As the product decomposes, the color tone of the product changes and the quality deteriorates. In particular, since azulenes are extremely unstable to light in the presence of water, it is important for aqueous liquids containing azulene to ensure stability in the manufacturing process and market distribution process.

  In general, as means for stably holding a composition containing a pharmacologically active substance that is unstable to light, light shielding means by a packaging material containing the composition, for example, an auxiliary for shielding light from a container containing the preparation A light-shielding means such as a typical light-shielding bag or a brown container or an aluminum container is used as a container for storing the preparation. However, there are many cases where the patient does not use the auxiliary light shielding bag. On the other hand, in the manufacturing process in which the container or the packaging material cannot be used, there is a possibility that decomposition by light may proceed.

  Various methods for improving the photostability of azulene in an aqueous solution preparation containing azulene have been studied so far. For example, a method of stabilizing sodium azulenesulfonate in an aqueous solution in the presence of a polyhydric alcohol (Patent Document 1), or a method of stabilizing azulene in an aqueous solution in the presence of a xanthine derivative (Patent Document 2). ) Is disclosed.

On the other hand, when azulene is added to a solution containing a substance having a quaternary ammonium group such as berberine sulfate or benzalkonium chloride, an insoluble substance may be formed depending on the concentration or mixing ratio of both, resulting in white turbidity. It is known that there is. As a method for solving this problem, a method of adding glycyrrhizic acid or a salt thereof (Patent Document 3, Patent Document 4), a method of adding alkylpolyaminoethylglycine and a nonionic surfactant (Patent Document 5) are known. .

Although a method for improving the photostability of azulene in an aqueous solution and a method for suppressing the formation of an insoluble material between azulene and a compound having a quaternary ammonium group are known, There is no known method for simultaneously solving the problem, that is, improving the photostability of an aqueous liquid preparation containing azulene and suppressing the formation of insoluble substances.

Therefore, the present inventor has intensively studied to improve the long-term stability of the aqueous liquid preparation containing azulene. (A) The aqueous liquid preparation containing azulene is (B) berberine, (C) a buffer, D) The inclusion of nonionic surface activity improves the photostability of azulene in an aqueous solution, suppresses the formation of insoluble substances, and provides an aqueous solution with improved stability over a long period of time. The present invention has been completed by discovering that an aqueous liquid preparation with improved migration of living tissues and berberines can be obtained.

Patent No.2724943 JP2003-128537 Registration No. 2893807 JP 2004-59479 A Japanese Patent Publication No.8-25874

An object of the present invention is to provide an aqueous liquid agent that is excellent in stability over a long period of time by improving the light stability of azulene in an aqueous liquid agent and suppressing the formation of insoluble substances. Furthermore, it is providing the aqueous liquid agent which improved the biological tissue transferability of azulenes and berberine. Another object of the present invention is to provide a method for improving the stability of azulenes to light and a method for suppressing the formation of insoluble substances in an aqueous liquid preparation containing azulenes and berberines.

  The present invention relates to a stabilized aqueous solution containing (A) azulenes, (B) berberines, (C) a buffer, and (D) a nonionic surfactant, and an aqueous solution containing azulenes. A method for improving light stability, and (A) an aqueous solution containing azulenes and (B) berberines, (C) a buffering agent and (D) a nonionic surfactant. The present invention relates to a method for suppressing generation.

That is, the present invention is an aqueous liquid preparation described below, a method for improving photostability, and a method for improving biological tissue migration.
(1) (A) at least one selected from the group consisting of azulenesulfonic acid and a pharmacologically or physiologically acceptable salt thereof,
(B) at least one selected from the group consisting of berberine and pharmacologically or physiologically acceptable salts thereof;
(C) one or more selected from the group consisting of boric acid, citric acid, phosphoric acid, and pharmacologically or physiologically acceptable salts thereof , and (D) a polyoxyethylene-polyoxypropylene block copolymer, One or more selected from the group consisting of polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, and polyoxyethylene hydrogenated castor oil , wherein 1 part by weight of the component (A) in contrast, (B) component 0.1 to 50 parts by weight der is, component (a) and (B) the total amount 1 part by weight of component (D) component 0.1 to 300 parts by weight aqueous solutions for ophthalmology, characterized in der Rukoto.
(2 ) The content of at least one selected from the group consisting of (A) azulenesulfonic acid and a pharmacologically or physiologically acceptable salt thereof is 0.0001 to 0.1 W / V%, (1 ) Symbol placement of aqueous solutions.
( 3 ) The content of at least one selected from the group consisting of (B) berberine and a pharmacologically or physiologically acceptable salt thereof is 0.0005 to 0.5 W / V%, (1) or (2) The aqueous liquid preparation described .
(4 ) (A) at least one selected from the group consisting of azulenesulfonic acid and a pharmacologically or physiologically acceptable salt thereof, (C) boric acid, citric acid, phosphoric acid, and their pharmacological properties Or one or more selected from the group consisting of physiologically acceptable salts , and (D) polyoxyethylene-polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, and polyoxyethylene cured In an aqueous solution containing one or more selected from the group consisting of castor oil , (B) berberine, and at least one selected from the group consisting of pharmacologically or physiologically acceptable salts thereof are contained, (A) A method for improving the light stability of the component.
( 5 ) (A) at least one selected from the group consisting of azulenesulfonic acid and pharmacologically or physiologically acceptable salts thereof, (C) boric acid, citric acid, phosphoric acid, and their pharmacological properties Or one or more selected from the group consisting of physiologically acceptable salts , and (D) polyoxyethylene-polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, and polyoxyethylene cured In an aqueous solution containing one or more selected from the group consisting of castor oil , (B) berberine, and at least one selected from the group consisting of pharmacologically or physiologically acceptable salts thereof are contained, (A) The method of preparing the aqueous liquid agent with which the biological tissue transferability of the component and (B) component improved.

  In the present invention, (A) an aqueous solution containing an azulene further contains (C) a buffer, (D) a nonionic surfactant and (B) a berberine, so that the aqueous solution containing an azulene is an aqueous solution. However, an aqueous solution having excellent light stability and stable for a long period in which the generation of insoluble substances is suppressed can be obtained. Furthermore, according to the present invention, an aquatic solution in which the ability of azulenes and berberines to migrate to living tissues is improved is obtained. In the method of the present invention, the light stability of an aqueous liquid preparation containing azulene can be improved to a high degree.

Specific examples of the azulene in the aqueous liquid preparation of the present invention include dimethylisopropylazulene (also referred to as guaiazulene, 1,4-dimethyl-7-isopropylazulene), azulenesulfonic acid (guaiazulenesulfonic acid, 1,4-dimethyl- 7-isopropylazulene-3-sulfonic acid), dimethylethylazulene (also called camazulene, 1,4-dimethyl-7-ethylazulene), 1,4-dimethyl-7-ethylazulene-3-sulfonic acid (camazulene) Sulfonic acid), and pharmacologically or physiologically acceptable salts thereof.
In the present invention, pharmacologically or physiologically acceptable salts include, for example, organic acid salts (for example, lactate, acetate, butyric acid, trifluoroacetate, fumarate, maleate, tartrate, citric acid, Acid salt, succinate, malonate, methanesulfonate, toluenesulfonate, tosylate, palmitate, stearate, etc., inorganic acid salt (eg hydrochloride, sulfate, nitrate, odor) Hydrohalates, phosphates, etc.), salts with organic bases (eg, salts with organic amines such as methylamine, triethylamine, triethanolamine, morpholine, piperazine, pyrrolidine, amino acids, tripyridine, picoline, etc.), inorganic Salts with bases (eg ammonium salts, alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, And salts with metals such as aluminum), and others.
Azulenes may be used alone or in combination of two or more. When the aqueous liquid preparation of the present invention is an ophthalmic composition, azulene sulfonic acid or a salt thereof is preferred.

  The content of azulene in the aqueous liquid preparation of the present invention is 0.0001 to 0.1 W / V% (hereinafter, unless otherwise specified, “W / V%” is simply indicated as “%”), preferably For example, in the case of an ophthalmic preparation, it is usually 0.0004 to 0.05%, preferably 0.001 to 0.03%, and more preferably 0.004 to 0. It is about 0.02%. Needless to say, the dose can be increased or decreased depending on the patient's weight, symptoms, administration frequency, administration method, and the like.

  Examples of berberine in the aqueous liquid preparation of the present invention include berberine and pharmacologically or physiologically acceptable salts. Specific examples include hydrochlorides and sulfates such as berberine sulfate and berberine chloride, and extracts of herbal medicines containing berberines such as duck and auren may be used. Moreover, you may use berberine individually or in combination of 2 or more types.

The content of berberine in the aqueous liquid of the present invention is usually 0.0005 to 0.5%, preferably 0.001 to 0.1%. For example, in the case of an ophthalmic preparation, the composition of berberine Content in a thing is 0.001-0.1% normally, More preferably, it is 0.001-0.05%, Most preferably, it is about 0.005-0.025%. In the case of using an extract of Acer aurium or the like, it can be prepared and used so that the content of berberine in the composition is as described above. Needless to say, the dose can be increased or decreased depending on the patient's weight, symptoms, administration frequency, administration method, and the like.

  The ratio of berberine to azulene in the aqueous liquid preparation of the present invention is usually 0.1 to 50 parts by weight, preferably 0.2 to 10 parts by weight, more preferably 0 to 1 part by weight of azulene. It can be selected from a range of about 25 to 7 parts by weight. In addition, if it deviates significantly from this range, the light stabilization effect obtained by the present invention tends to be reduced.

  Examples of the buffer in the aqueous liquid preparation of the present invention include boric acids, phosphoric acids, carbonic acids, citric acids, acetic acids, and Good buffer. As boric acids, boric acid and pharmacologically or physiologically acceptable salts thereof can be used. Specifically, boric acid, potassium tetraborate, sodium borate, borax, potassium metaborate, etc. Alkali metal salts of boric acid, alkaline earth metal salts of boric acid such as calcium borate and magnesium borate. These borates can also be used as hydrates. As phosphoric acids, phosphoric acid and pharmacologically or physiologically acceptable salts thereof can be used. Specifically, phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, Alkali metal salts of phosphoric acid such as dipotassium hydrogen phosphate, alkaline earth metal salts of phosphoric acid such as calcium phosphate and magnesium phosphate, and the like can be used. These phosphates may be used as hydrates. Carbonic acid and pharmacologically or physiologically acceptable salts thereof can be used as the carbonic acid, and specific examples thereof include sodium hydrogen carbonate and sodium carbonate. Citric acid and pharmacologically or physiologically acceptable salts thereof can be used as citric acids, and specific examples include citric acid, sodium citrate, potassium citrate and the like. As acetic acid, acetic acid and a pharmacologically or physiologically acceptable salt thereof can be used, and specific examples include acetic acid, potassium acetate, sodium acetate and the like. As a good buffering agent, MES, MOPS, PIPES, HEPES, BES, TES, etc. can be used. These buffering agents can be used alone or in combination. Preferred buffering agents are boric acids, phosphoric acids, carbonic acids, citric acids, and Good buffering agents, and more preferred buffering agents are boric acids, phosphoric acids, and citric acids. Particularly preferred buffering agents include boric acid, sodium borate, borax, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, citric acid, sodium citrate, citric acid Potassium, sodium carbonate, sodium bicarbonate.

The content of the buffer in the aqueous liquid preparation of the present invention is usually 0.001 to 10.0%, preferably 0.01 to 5.0%, more preferably about 0.1 to 3.0%. .
When the content of the buffer is significantly lower than this concentration range, it is difficult to obtain a sufficient effect in the present invention.

  The nonionic surfactant in the aqueous liquid preparation of the present invention may be any nonionic surfactant having surface activity, and is polyoxyethylene (hereinafter also referred to as POE) -polyoxypropylene (hereinafter also referred to as POP). .) Block copolymers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, and the like can be used. Examples of the POE-POP block pocolimer include poloxamers such as poloxamer 407, poloxamer 235, and poloxamer 188. Examples of the polyoxyethylene sorbitan fatty acid ester include polysorbates such as polysorbate 20, polysorbate 60, polysorbate 80, and the like. Examples of the polyoxyethylene castor oil include polyoxyethylene (35) castor oil. Examples of the polyoxyethylene hydrogenated castor oil include polyoxyethylene hydrogenated castor oil 60 (HCO 60) and polyoxyethylene hydrogenated castor oil 40 (HCO 40). ) And the like. These nonionic surfactants may be used alone or in combination of two or more. For example, in the case of an ophthalmic preparation, poloxamer, polysorbate, polyoxyethylene hydrogenated castor oil is preferable, and poloxamer 407, polysorbate 80, polyoxyethylene hydrogenated castor oil 60 is particularly preferable.

Moreover, content of the nonionic surfactant in the composition of this invention is 0.001-5% normally, Preferably it is 0.01-2%, More preferably, it is about 0.05-2%. When the content of the nonionic surfactant is remarkably lower than this concentration range, it is difficult to obtain a sufficient effect in the present invention, and when the content is extremely high, eye irritation tends to occur particularly in the case of an ophthalmic composition. is there.

  In the aqueous liquid preparation of the present invention, the ratio of (A) azulene and (B) berberine to (C) buffer and (D) nonionic surfactant is usually 1 part by weight of the total amount of azulene and berberine. In contrast, 0.2 to 600 parts by weight of buffer, 0.1 to 300 parts by weight of nonionic surfactant, preferably 2 to 400 parts by weight of buffer, and 1 to 200 parts by weight of nonionic surfactant. You can choose. In addition, when it deviates from this range remarkably, the production | generation suppression effect of the insoluble substance obtained by this invention tends to reduce.

  The aqueous liquid preparation of the present invention can be used, for example, in an internal or external form depending on the purpose. As an internal form, it can be provided as a topical preparation for various uses such as ophthalmic use, dental use, otolaryngology use, dermatology use, etc. Therefore, it is suitable for a preparation in which the generation of foreign matters is particularly problematic, and is particularly useful as an ophthalmic preparation. The ophthalmic preparation is not limited to a pharmaceutical preparation but can be used as a non-pharmaceutical preparation such as a contact lens preparation. For example, eye drops (also referred to as eye drops, including eye drops that can also be used while wearing contact lenses), eye wash (also referred to as eye drops, including eye drops that can also be used while wearing contact lenses), contact lens mounting solutions , Contact lens agents (cleaning solution, preserving solution, rinsing solution, disinfecting solution, multi-purpose solution, etc.). In this specification, the contact lens includes all types of contact lenses such as hard contact lenses (including oxygen permeable hard contact lenses) and soft contact lenses.

  Since the aqueous liquid preparation of the present invention has high stability to light, it is packaged in a form to be administered multiple times and is continuously used by the user, such as multi-dose aqueous liquid preparations such as eye drops, eye wash, nose It is also useful as a washing liquid, oral medicine (oropharyngeal medicine, gargle medicine, etc.), ear drops, nasal drops, liquid internal medicine (liquid gastrointestinal medicine, liquid cold medicine, etc.), skin external medicine and the like.

  For example, the aqueous liquid preparation of the present invention is preferably acidic to neutral (for example, about pH 3.0 to 7.5) for internal use liquid preparations. In the outer skin composition, it can usually be selected from the range of about pH 2.0 to 7.5, preferably from pH 3.0 to 7.5, more preferably from the viewpoint of low irritation to the skin and good skin feeling. Is preferably weakly acidic to neutral (for example, about pH 3.0 to 6.5). In the case of a composition applied to mucous membranes such as eye drops, eye wash, etc., the pH is usually 5.0 to 8.5, preferably pH 6.0 to 8.5, more preferably about pH 7.0 to 8.0. In this case, the pH is usually about 3.0 to 7.5, preferably about 3.5 to 8.0, and more preferably about 3.5 to 7.5. In addition, from the viewpoint of improving the light stability and suppressing the generation of insoluble substances, the pH of the aqueous liquid preparation of the present invention is preferably set within the range of pH 5.0 to 9.0, more preferably pH 6.5 to 8.5. Stability is further improved.

  According to the method for improving light stability of the present invention, (B) berberine is contained in an aqueous solution containing (A) azulenes, (C) a buffer and (D) a nonionic surfactant. Berberine can be defined as a photostabilizer for azulene because it improves the photostability of azulene.

  Further, in the present invention, it is possible to suppress the generation of insoluble substances caused by containing azulenes and berberines in an aqueous liquid preparation at a specific ratio and concentration by containing a buffer and a nonionic surfactant, It is possible to provide a more stable aqueous solution over a long period of time.

The aqueous liquid preparation of the present invention is a combination of various components (including pharmacologically active ingredients and physiologically active ingredients) in addition to azulenes, berberines, buffers and nonionic surfactants, as long as the effects of the present invention are not hindered. May be contained. The type of such components is not particularly limited, and examples thereof include, for example, a decongestant component, an eye regulator component, an anti-inflammatory component or an astringent component, an antihistamine component or an antiallergic component, vitamins, amino acids, and antibacterial agents. Examples include components, bactericidal components, saccharides, polysaccharides or derivatives thereof, cellulose or derivatives or salts thereof, water-soluble polymers other than those described above, local anesthetic components, steroid components, and glaucoma therapeutic agents. Examples of suitable components in the present invention include the following components.

  Decongestant: α-adrenergic drugs such as imidazoline derivatives (oxymetazoline, tetrahydrozoline, naphazoline, etc.), β-phenylethylamine derivatives (epinephrine, ephedrine, phenylephrine, methylephedrine, etc.), and their pharmacologically or physiologically (E.g., epinephrine hydrochloride, ephedrine hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, epinephrine hydrogen tartrate, tetrahydrozoline nitrate, naphazoline nitrate; epinephrine hydrogen tartrate; Etc.). These may be d-form, l-form or dl-form.

Ocular muscle modulator component: Cholinesterase inhibitor having an active center similar to acetylcholine, for example, quaternary ammonium compounds such as neostigmine methylsulfate, atropine, tropicamide, herenien, and pharmaceutically or physiologically acceptable salts thereof ( For example, atropine sulfate).

Anti-inflammatory component or astringent component: Zinc salt (for example, zinc sulfate, zinc lactate, etc.), aspirin, acemetacin, allantoin, ibuprofen, epsilon-aminocaproic acid, indomethacin, indomethacin farnesyl, lysozyme chloride, thiaramide hydrochloride, glycyrrhizic acid, salicylic acid Methyl, diclofenac, silver nitrate, celecoxib, thiaprofenic acid, piroxicam, pranoprofen, bromfenac, mefenamic acid, meloxicam, lysozyme, loxoprofen sodium, rofecoxib, and the like and pharmaceutically or physiologically acceptable salts thereof (for example, glycyrrhizic acid Dipotassium, ammonium glycyrrhizinate, diclofenac sodium, bromfenac sodium) and the like.

Antihistamine component or antiallergic component: for example, acitazanolast, astemizole, azelastine, amlexanox, ibudilast, iproheptin, emedastine, ebastine, epinastine, oxatomide, olopatadine, clemastine, cromoglycic acid, chlorpheniramine, ketothiphene, ketotifen , Cetirizine, tazanolast, terfenadine, tranilast, fexofenadine, bepotastine, pemirolast, mequitazine, repirinast, levocabastine, loratadine, or a salt thereof (e.g., azelastine hydrochloride, iproheptin hydrochloride, olopatadine hydrochloride, levomethadine hydrochloride, levomethine hydrochloride, levomethamine hydrochloride, Cremastine fumarate, ketotifen fumarate, chromog Sodium click acid, pemirolast potassium, chlorpheniramine maleate) and the like.

Vitamins: For example, vitamins A [eg, carotene, dehydroretinal, lycopene, retinal, retinol, retinoic acid and pharmacologically acceptable salts thereof (eg, retinol acetate, retinol palmitate, etc.), vitamin B [Dicetiamine hydrochloride, thiamine hydrochloride, pyridoxine hydrochloride, fursultiamine hydrochloride, octothiamine, chicotiamine, dicetiamine, thiamine nitrate, bistiamine nitrate, thiamine, thiamine disulfide, thiamine dicetyl nitrate, bisibutamine, bisbenchamine, full Sultiamine, prosultiamine, benfotiamine, flavin adenine dinucleotide, flavin adenine dinucleotide sodium, riboflavin butyrate, riboflavin, riboflavin sodium phosphate, pyri Doxin, pyridoxal, pyridoxal phosphate, pyridoxal calcium phosphate, hydroxocobalamin hydrochloride, hydroxocobalamin acetate, cyanocobalamin, hydroxocobalamin, deoxyadecocobalamine, methylcobalamin, dihydrofolate, tetrahydrofolate, folate, nicotinic alcohol, nicotinic acid, nicotinic acid Amide, panthenol, pantothenic acid, calcium pantothenate, sodium pantothenate, inositol, choline, biotin, etc.], vitamin C [ascorbic acid and its derivatives, erythorbic acid and its derivatives and pharmacologically acceptable salts thereof ( For example, sodium ascorbate, sodium erythorbate, etc.)], vitamin Ds [eg ergocalciferol, cholecalciferol, Dihydroxycholecalciferol, dihydrotaxosterol, hydroxycholecalciferol and pharmacologically acceptable salts thereof, etc.]], vitamin E [for example, tocopherol and derivatives thereof, ubiquinone derivatives and pharmacologically acceptable salts thereof Salts (tocopherol succinate, tocopherol calcium succinate, tocopherol acetate, tocopherol nicotinate, etc.)], other vitamins [eg, eriocitrin, orotic acid, carnitine, γ-oryzanol, ferulic acid, hesperidin, rutin and its drugs Physically acceptable salts (such as carnitine chloride, methyl hesperidin, etc.)].

  Amino acids: for example, asparagine, aspartic acid, aminoethylsulfonic acid (taurine), alanine, isoleucine, ornithine, glycylglycine, glycine, glutamine, glutamic acid, creatinine, chondroitin sulfate, cysteine, serine, tyrosine, tryptophan, threonine, valine , Histidine, hydroxyproline, hydroxylysine, phenylalanine, proline, methionine, lysine, leucine or a salt thereof (eg, potassium aspartate, magnesium aspartate, magnesium / aspartate mixture, cysteine hydrochloride, sodium glutamate, sodium chondroitin sulfate, etc.) . These may be d-form, l-form or dl-form.

  Antibacterial component or bactericidal component: Acrinol, aminoglycoside antibacterial agent [kanamycin (for example, aminodeoxykanamycin sulfate, kanamycin sulfate, etc.), gentamicin (for example, gentamicin sulfate), sisomycin (for example, sisomycin sulfate), streptomycin (for example, , Streptomycin sulfate, etc.), tobramycin, micronomycin (eg, micronomycin sulfate, etc.), alkylpolyaminoethylglycine, chloramphenicol antibiotics (eg, chloramphenicol), sulfonamides [eg, Famethoxazole, sulfisoxazole, sulfisomidine and pharmacologically acceptable salts (sulfamethoxazole sodium, sulfisoxazole diethanolamine, sulfisoxazole) Sol monoethanolamine, sulfisomezole sodium, sulfisomidine sodium, etc.)], quaternary ammonium compounds [eg cetylpyridinium, benzalkonium, benzethonium and pharmacologically acceptable salts (cetylpyridinium chloride, Benzalkonium chloride, benzethonium chloride, cetylpyridinium bromide)], tetracycline antibiotics (tetracycline hydrochloride, oxytetracycline hydrochloride, etc.), new quinolones (ciprofloxacin hydrochloride, ofloxacin hydrochloride, ciprofloxacin, norfloxacin, levofloxacin, Lomefloxacin (eg, lomefloxacin hydrochloride)], β-lactam antibacterial [carbenicillin (eg, carbenicillin sodium), sulbenicillin (eg, sulbenicin) Thorium, etc.), cefmenoxime (eg, cefmenoxime hydrochloride, etc.), penicillin (eg, benzylpenicillin potassium)], polypeptide antibacterial agents (eg, colistin, colistin sodium metasulfonate), macrolide antibacterial agents [eg, erythromycin (eg, Erythromycin lactobionate, etc.), kitasamycin, spiramycin, etc.], fradiomycin (eg, fradiomycin sulfate), polymyxin (eg, polymyxin sulfate), dibekacin (eg, dibekacin sulfate), amikacin (eg, amikacin sulfate) Etc.). Antiviral drugs such as acyclovir, adenine arabinoside, iododeoxycytidine, idoxuridine, carbocyclic oxetanocin G, gancyclovir, cyclocytidine, cytosine arabinoside, cidophobia, trifluorothymidine, valacyclovir, bromo Examples of deoxyuridine, foscarnet, polyvinyl alcohol iodine, iodine, and antifungal agents include amphotericin B, isoconazole, itraconazole, econazole, clotrimazole, nystatin, pimaricin, fluorocytosine, fluconazole, flucytosine, miconazole and the like.

  Sugars: monosaccharides (eg glucose), disaccharides (eg trehalose, fructose, lactose etc.), oligosaccharides (eg pullulan, lactulose, raffinose etc.), sugar alcohols (eg xylitol, sorbitol, mannitol etc.) Such.

  Polysaccharides or derivatives thereof: gum arabic, alginic acid, elastin, casein, carrageenan, caraya gum, agar, xanthan gum, chitin and derivatives thereof, chitosan and derivatives thereof, carob gum, guar gum, guaiac fat, quince seed, collagen, chondroitin sulfate or salts thereof (Sodium alginate, sodium hyaluronate, sodium chondroitin sulfate, etc.), gelatin, dammar gum, dextran, dextrin, starch, tragacanth, hyaluronic acid, heparan sulfate, heparinoid, heparin, heparin sulfate, benzoin gum, pectin, locust bean gum, etc.

  Cellulose or a derivative thereof or a salt thereof: ethyl cellulose, carboxyethyl cellulose, carboxymethyl cellulose, cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, nitrocellulose, methylcellulose and the like.

Water-soluble polymers other than those described above: polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, and the like.

Local anesthetic ingredients: ethyl aminobenzoate, oxybuprocaine, cocaine, cornecaine, dibucaine, tetracaine, piperocaine, bupivacaine, procaine, proparacaine, hexothiocaine, mepivacaine, meprilucaine, lidocaine and their salts (oxybuprocaine hydrochloride, cocaine hydrochloride) , Cornecaine hydrochloride, Dibucaine hydrochloride, Tetracaine hydrochloride, Diethylaminoethyl parabutylaminobenzoate, Piperocaine hydrochloride, Procaine hydrochloride, Proparacaine hydrochloride, Hexothiocaine hydrochloride, Lidocaine hydrochloride, etc.).

Steroid components: cortisol, dexamethasone, triamcinolone, parameterzone, hydrocortisone, fluorometholone, prednisolone, betamethasone, methylprednisolone, hydroxymesterone and salts thereof (hydrocortisone caproate, prednisolone caproate, cortisone acetate, hydrocortisone acetate, prednisolone acetate, Dexamethasone sodium metasulfobenzoate, dexamethasone sodium sulfate, dexamethasone sodium phosphate, triamcinolone acetonide, betamethasone sodium phosphate, dexamethasone sodium metasulfobenzoate, methylprednisolone) and the like.

Glaucoma treatment ingredients: acetazolamide, unoprostone (eg, isopropyl unoprostone), epinephrine, apraclonidine hydrochloride, carteolol hydrochloride, dipivefrin hydrochloride, dorzolamide hydrochloride, pilocarpine hydrochloride, bunazosin hydrochloride, bupanolol hydrochloride, betaxolol hydrochloride, befnolol hydrochloride, carbachol, Levobunolol hydrochloride, epinephrine dipivalate, distigmine bromide, nipradilol, timolol maleate, metazolamide, latanoprost, and salts thereof.

Cataract treatment component: glutathione, cineraria martima, salivary gland hormone, thiopronin, pirenoxine, dihydro azapentacene disulfonate and salts thereof (for example, sodium 5,12-dihydroazapentacene disulfonate).

The amount of these components in the aqueous liquid is appropriately selected according to the type of formulation, the type of active ingredient, etc., and the amounts of various components in internal use, skin, and mucosa preparations are known in the art. is there. For example, it can be selected from the range of about 0.0001 to 30%, preferably about 0.001 to 10% with respect to the whole preparation.
More specifically, the content of each component in the aqueous liquid for ophthalmic mucosa application is, for example, as follows.

Decongestant component (vasoconstrictor or sympathomimetic drug): For example, 0.0001 to 0.5%, preferably 0.0005 to 0.3%, more preferably 0.001 to 0.1%.
Eye muscle modulator component: For example, 0.0001 to 0.5%, preferably 0.0005 to 0.1%, more preferably 0.0005 to 0.01%.
Anti-inflammatory component or astringent component: for example, 0.0001-10%, preferably 0.0001-5%.
Antihistamine component or antiallergic agent component: for example, 0.0001 to 10%, preferably 0.001 to 5%.
Vitamins: For example, 0.0001 to 1%, preferably 0.0001 to 0.5%.
Amino acids: For example, 0.0001 to 10%, preferably 0.001 to 3%.
Antibacterial component or bactericidal component: For example, 0.00001 to 10%, preferably 0.0001 to 10%.
Saccharides: For example, 0.0001 to 5%, preferably 0.001 to 5%, more preferably 0.01 to 2%.
Polysaccharide or derivative thereof: for example, 0.0001 to 2%, preferably 0.01 to 2%, more preferably 0.01 to 1%.
Cellulose or a derivative thereof or a salt thereof: For example, 0.001 to 5%, preferably 0.01 to 1%.
Water-soluble polymers other than those described above: For example, 0.001 to 10%, preferably 0.001 to 5%, more preferably 0.01 to 3%.
Local anesthetic component: For example, 0.001-1%, preferably 0.01-1%.
Steroid component: For example, 0.001 to 1%, preferably 0.01 to 1%.
Glaucoma treatment component: for example, 0.001 to 5%, preferably 0.01 to 1%.
Cataract treatment component: for example, 0.0001 to 10%, preferably 0.001 to 5%.

  Further, in the aqueous liquid preparation of the present invention, as long as the effects of the invention are not impaired, various components and additives are appropriately selected according to the usage and form according to conventional methods, and one or more are used in combination. And may be contained. As those components or additives, for example, carriers (water, aqueous solvents, aqueous or oily bases, etc.) commonly used in the preparation of semi-solids and liquids, thickeners, sugars, nonionic surfactants There may be mentioned various additives such as surfactants, preservatives, bactericides or antibacterial agents, pH regulators, tonicity agents, fragrances or cooling agents, chelating agents, etc. other than the agents.

  Although the typical component used for the aqueous liquid preparation of this invention is illustrated below, it is not limited to these.

  Thickeners: for example, carboxyvinyl polymer, ceramide, cellulose derivatives (ethyl cellulose, carboxyethyl cellulose, carboxymethyl cellulose, cellulose, nitrocellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, etc.), polysaccharides or derivatives thereof (Arabia) Gum, alginic acid, elastin, casein, carrageenan, caraya gum, agar, xanthan gum, chitin and its derivatives, chitosan and its derivatives, carob gum, guar gum, guaiac fat, quince seed, collagen, chondroitin sulfate, gelatin, dammar gum, tragacanth gum, benzoin gum, Dextrin, dextran, starch, hyaluronic acid, pectin, hepara Sulfuric acid, heparinoid, heparin, heparin sulfate, polygalacturonic acid, locust bean gum, etc.), deoxyribonucleic acid, polyacrylic acid, polyethyleneimine, polyethylene oxide, polyethylene glycol, polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone, polyvinyl Methacrylate, macrogol, methyl vinyl ether / maleic anhydride copolymer, ribonucleic acid, and pharmacologically acceptable salts thereof (for example, sodium alginate, sodium chondroitin sulfate, etc.).

Sugars: for example, arabinose, galactose, xylose, glucose, cyclodextrin, sucrose, cellobiose, deoxyribose, trehalose, fructose, pullulan, maltitol, maltose, mannose, lactulose, lactose, raffinose, lyxose, ribulose, ribose Physically acceptable salts.
Sugar alcohols: For example, xylitol, sorbitol, mannitol and the like.
These may be d-form, l-form or dl-form.

Surfactant: Amphoteric surfactant such as glycine type such as alkyldiaminoethylglycine, betaine acetate type such as lauryldimethylaminoacetic acid betaine, imidazoline type; sulfonic acid such as alkyl ether carboxylate and sodium tetradecene sulfonate Salts, alkyl sulfates such as sodium lauryl sulfate, N-acyl taurine salts such as sodium N-cocoylmethyl taurate, POE alkyl ether phosphates such as POE (10) sodium lauryl ether phosphate and their salts, sodium lauroylmethylalanine, etc. N-acyl amino acid salts of POE (3) POE alkyl ether sulfates such as sodium lauryl ether sulfate, anionic surfactants such as α-olefin sulfonates; alkylamine salts, alkyl quaternary ammonium Cationic surfactants such as salts (such as benzalkonium chloride and benzethonium chloride) and alkylpyridinium salts (such as cetylpyridinium chloride and cetylpyridinium bromide) can be used. The numbers in parentheses indicate the number of added moles.

Preservatives, bactericides or antibacterial agents: for example, acrinol, alkylpolyaminoethylglycine (such as alkyldiaminoethylglycine hydrochloride), benzoic acid or its salts (such as sodium benzoate), isopropanol, isopropylmethylphenol, undecylenic acid, ethanol, chloride Cetylpyridinium, benzalkonium chloride, benzethonium chloride, polydronium chloride, methylrosaniline chloride, orthophenylphenol, hydrogen peroxide, caprylic acid, chlorxylenol, chlorhexidine or its salts (chlorhexidine hydrochloride, chlorhexidine gluconate, etc.), chlorophene, chlorobutanol , 5-chloro-2-methyl-4-isothiazolin-3-one, cetylpyridinium bromide, sulfamine, sorbic acid or a salt thereof (sorbic acid Potassium sorbate, sodium sorbate, triclocarban sorbate), thiabendazole, thimerosal, thymol, dehydroacetic acid, sodium dehydroacetate, triclosan, paraoxybenzoic acid ester (methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, Butyl paraoxybenzoate, etc.), halocarban, biguanide compounds (polyhexamethylene biguanide, 8-hydroxyquinoline (oxyquinoline sulfate), hinokitiol, phenethyl alcohol, phenoxyethanol, propanol, propionic acid, benzyl alcohol, popiyon iodine, etc., poly Diallyldimethylammonium chloride, poly [oxyethylene (dimethyliminio) ethylene- (dimethyliminio Ethylene dichloride], polyethylene polyamine / dimethylamine epichlorohydrin polycondensate (trade name, for example, Busan 1157, manufactured by Bachman), polymyxin B, polylysine, mercurochrome, 2-methyl-4-isothiazolin-3-one, lactoferrin, lysozyme, phosphoric acid Zirconium silver, resorcin, Glokil (trade name, for example, GlokilPQ, manufactured by Rhodia), and pharmacologically acceptable salts thereof.

pH adjuster: For example, inorganic acid (hydrochloric acid, sulfuric acid, etc.), organic acid (aspartic acid, aminoethylsulfonic acid, epsilon-aminocaproic acid, gluconic acid, glutamic acid, succinic acid, acetic acid, oxalic acid, tartaric acid, lactic acid, fumaric acid , Propionic acid, malic acid, etc.), gluconolactone, ammonium acetate, inorganic bases (calcium hydroxide, potassium hydroxide, sodium hydroxide, magnesium hydroxide, borax, etc.), organic bases (diisopropanolamine, triisopropanolamine) , Triethanolamine, monoethanolamine, lysine, etc.) and pharmacologically acceptable salts thereof.

  Isotonizing agents: for example, inorganic salts (eg, sodium bisulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate , Disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, etc., polyhydric alcohols (eg, ethylene glycol, glycerin, 1,3-butylene glycol, propylene glycol, etc.) ), Sugars or sugar alcohols (eg, sorbitol, butter sugar, mannitol, etc.).

  Perfume or refreshing agent: terpenes (for example, anethole, eugenol, camphor, geraniol, cineol, borneol, menthol, limonene, ryuuno, etc. These may be any of d-form, l-form or dl-form) , Cool mint oil, cinnamon oil, spearmint oil, mint water, mint oil, peppermint oil, bergamot oil, eucalyptus oil, rose oil, etc.).

  Chelating agents: for example, ascorbic acid, edetic acid, citric acid, succinic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1-hydroxyethane-1,1-diphosphonic acid, hexametaphosphoric acid, polyphosphoric acid, metaphosphoric acid, and the like Pharmacologically acceptable salts and the like (for example, tetrasodium edetate, sodium edetate).

Stabilizer: Dibutylhydroxytoluene, trometamol, tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, etc.

Solubilizers: olive oil, sesame oil, soybean oil, camellia oil, corn oil, rapeseed oil, castor oil, plastibase, peanut oil, etc.

Thickener: 0.0005 to 50%, for example, preferably 0.001 to 10%
Saccharides: for example 0.001 to 10%, preferably 0.01 to 5%
Surfactant: For example, 0.0001 to 10%, preferably 0.005 to 5%
Preservative, bactericidal agent or antibacterial agent: for example, 0.00001-5%, preferably 0.0001-2%
pH regulator: for example, 0.00001-5%, preferably 0.0001-2%
Isotonizing agent: for example 0.001 to 10%, preferably 0.01 to 5%
Perfume or refreshing agent: for example, 0.00001-5%, preferably 0.0001-2%
Chelating agent: for example, 0.00001-5%, preferably 0.0001-2%

The aqueous liquid preparation of the present invention needs to be adjusted to an osmotic pressure ratio within a range that is acceptable to a living body, if necessary. The osmotic pressure ratio with respect to physiological saline is usually 0.3 to 4.1, preferably 0.3 to 2.1, and particularly preferably about 0.5 to 1.4. The osmotic pressure ratio can be adjusted using a buffer, the pH adjuster, an isotonic agent, salts, and the like.

  The aqueous liquid preparation of the present invention can be produced by a known method. However, as described above, an insoluble substance may be generated by containing azulenes and berberine at a specific ratio and concentration. Accordingly, the blending order of each component in the aqueous liquid may be considered. Specifically, it is preferable to prepare by adding azulene after dissolving berberine, a buffering agent and a nonionic surfactant. Further, when the ophthalmic preparation is an eye drop, an eye wash, etc., it can be prepared by mixing each component, subjecting to filtration sterilization treatment as necessary, and filling the container. More specifically, if the composition is an eye drop, for example, distilled water or purified water and additives are used to dissolve berberine, buffering agent, nonionic surfactant, and further azulene is dissolved. And adjusted to a predetermined osmotic pressure and pH, subjected to filtration sterilization treatment in an aseptic environment, and aseptically filled into a container that has been sterilized by washing.

  Since the aqueous liquid preparation of the present invention has high light stability and can maintain high light stability for a long period of time, it can be accommodated in a highly light-transmitting container such as a glass or plastic container. In particular, when used repeatedly, when housed in a plastic container or the like, it is excellent in squeeze and portability and easy to handle. Furthermore, since the aqueous liquid preparation of the present invention can be packaged or accommodated in a plastic container with high light transmittance, foreign matter contamination can be reliably determined from the outside of the container, and a foreign matter confirmation test can be easily performed. Since the production process management and quality control of an aqueous liquid preparation can be performed reliably, it is suitably used as an ophthalmic aqueous liquid preparation.

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

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

  In the present invention, the plastic container is a polymer alloy (polymer blend or the like) in consideration of the influence on quality such as strength, light transmission, gas or water vapor barrier properties (moisture permeability) and cost performance. Also good. Preferred polymer alloys include polymer blends of a plurality of synthetic resins (such as polymer blends of PET and PEN). The resin is preferably a resin having good squeeze properties and durability against repeated pressing, and a transparent or translucent resin, and may be colored as necessary. In addition, by incorporating a component that can inhibit light transmission (such as an ultraviolet absorber or an infrared absorber) into the resin, or by applying a coating agent containing the component to the resin surface, the effect of the present invention is achieved. Thus, the light stability may be further improved.

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

Test example 1
Purified water, berberine sulfate, buffer (boric acid / borax, sodium citrate, disodium hydrogen phosphate), polysorbate 80 according to the formulations of Examples 1 to 3 and Comparative Examples 1 to 8 shown in Table 1 below (Trade name: TO-10M (manufactured by Nikko Chemicals Co., Ltd.)), sodium azulenesulfonate was added thereto, and the pH was adjusted to around 7 with sodium hydroxide and / or hydrochloric acid to make the total amount of the test solution 100 ml. . Each test solution was filled in a colorless and transparent glass bottle and sealed to obtain a test sample.
Each test sample was stored for 5 days immediately after production and at room temperature under light shielding, and the presence or absence of insoluble substances was visually observed. Among them, the test samples which were left to stand at room temperature for 5 days and did not recognize the formation of insoluble substances were tested for light stability according to the following procedure. Using a light stability tester (“Light-Tron LT-120 D3CJ type”, manufactured by Nagano Science Co., Ltd.), each test sample obtained was subjected to a D65 fluorescent lamp as a light source at 25 ° C. at 50,000. Lux light was continuously irradiated for 60 hours, and the test sample was exposed to light having an integrated irradiation amount of 300,000 lux · hr. Azulene is decomposed by light, and the test solution in the test sample is discolored. Therefore, before light irradiation (accumulated dose of 100,000 lux · hr) and after light irradiation (accumulated dose of 200,000 lux · hr, 300,000 lux · hr). ) Was measured for absorbance at a measurement wavelength of 577 nm using a spectrophotometer (“U-3300”, manufactured by Hitachi, Ltd.). About the light absorbency measurement value obtained about each test solution, the residual rate of the sodium azulenesulfonate in each test solution was calculated | required from the following formula | equation. Prior to the test, it was confirmed that sodium azulene sulfonate can be stably quantified by measuring the absorbance at the above wavelength. The results for each test sample are shown in Table 1. In addition, regarding the presence or absence of the generation of insoluble substances, the table shows “O” when the formation of the insoluble substance was not observed, and “X” when the formation of the insoluble substance was recognized.

  As apparent from Table 1, berberine sulfate, borate buffer (boric acid, borax) as buffer, sodium citrate, disodium hydrogen phosphate, and TO-10M as nonionic surfactant In Examples 1 to 6 used, the generation of insoluble substances and the decomposition of sodium azulenesulfonate by light irradiation could be remarkably suppressed. On the other hand, in Comparative Examples 1 to 8 which did not contain any of berberine sulfate, a buffering agent or a nonionic surfactant, decomposition of sodium azulenesulfonate and generation of an insoluble substance by light irradiation were observed.

Test example 2
In accordance with the formulation of Example 3 and Comparative Examples 9 and 10 shown in Table 2 below, purified water is berberine sulfate, boric acid, borax, polysorbate 80 (trade name: TO-10M (manufactured by Nikko Chemicals)). After dissolution, sodium azulene sulfonate was added thereto to make a total volume of 100 ml to obtain a test solution. Each test solution (15 mL) was dispensed into a stoppered test tube, and 1-octanol (15 mL) was added, followed by shaking with a shaker for 10 minutes. Next, after centrifugation at 2000 rpm for 10 minutes and reaching an equilibrium state, a spectrophotometer ("U-3300", manufactured by Hitachi, Ltd.) is used for the aqueous phase (lower layer) of each test solution obtained. The absorbance at wavelengths of 420 nm and 577 nm was measured. About the absorbance measurement value obtained for each test solution, the migration rate (%) of sodium azulenesulfonate and berberine sulfate to the oil phase in each test solution was determined from the following formula. Prior to the test, it was confirmed that stable quantification could be performed with absorbance measurements at 577 nm for sodium azulenesulfonate and 420 nm for berberine sulfate. The results for each test sample are shown in Table 2.

  As is clear from Table 2, in Example 4, compared to Comparative Example 9 not containing berberine sulfate and Comparative Example 10 not containing sodium azulene sulfonate, berberine sulfate and sodium azulene sulfonate were added to the oil phase. The migration rate was good. Therefore, in Example 4, compared with Comparative Examples 9 and 10, the fat solubility of berberine sulfate and sodium azulene sulfonate is improved, and the tissue transferability is improved.

  In accordance with the formulations shown in Tables 3 to 6 below, eye drops and eye washes are prepared by a conventional method, sterilized by filtration in a sterile environment, and sterilized eye drops containers (capacity 15 mL container material, main body: polyethylene terephthalate, nozzle: polyethylene) , Cap: polypropylene), eyewash container (capacity: 300 mL, container material, main body: polyethylene terephthalate, cap: polypropylene), and eye drops of Examples 5 to 22 and eye wash of Examples 23 and 24 were obtained.

Claims (5)

(A) at least one selected from the group consisting of azulenesulfonic acid and a pharmacologically or physiologically acceptable salt thereof,
(B) at least one selected from the group consisting of berberine and pharmacologically or physiologically acceptable salts thereof;
(C) one or more selected from the group consisting of boric acid, citric acid, phosphoric acid, and pharmacologically or physiologically acceptable salts thereof , and (D) a polyoxyethylene-polyoxypropylene block copolymer, One or more selected from the group consisting of polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil, and polyoxyethylene hydrogenated castor oil , wherein 1 part by weight of the component (A) in contrast, (B) component 0.1 to 50 parts by weight der is, component (a) and (B) the total amount 1 part by weight of component (D) component 0.1 to 300 parts by weight aqueous solutions for ophthalmology, characterized in der Rukoto. (A) azulene sulfonate, and at least one content is selected from the group consisting of a pharmaceutically or physiologically acceptable salt is 0.0001~0.1W / V%, according to claim 1 Aqueous solution. (B) berberine, and at least one content of 0.0005~0.5W / V%, according to claim 1 or 2 which is selected from a pharmaceutically or physiologically acceptable group consisting salt Aqueous solution. (A) Azulenesulfonic acid and at least one selected from the group consisting of pharmacologically or physiologically acceptable salts thereof, (C) boric acid, citric acid, phosphoric acid, and their pharmacological or physiological properties one or more selected from the acceptable group consisting of salt, and (D) a polyoxyethylene - polyoxypropylene block copolymers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil, and from polyoxyethylene hydrogenated castor oil And (B) berberine and at least one selected from the group consisting of pharmacologically or physiologically acceptable salts thereof are contained in an aqueous liquid preparation containing one or more selected from the group A method for improving the light stability of components. (A) Azulenesulfonic acid and at least one selected from the group consisting of pharmacologically or physiologically acceptable salts thereof, (C) boric acid, citric acid, phosphoric acid, and their pharmacological or physiological properties one or more selected from the acceptable group consisting of salt, and (D) a polyoxyethylene - polyoxypropylene block copolymers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil, and from polyoxyethylene hydrogenated castor oil And (B) berberine and at least one selected from the group consisting of pharmacologically or physiologically acceptable salts thereof are contained in an aqueous liquid preparation containing one or more selected from the group A method for preparing an aqueous liquid preparation having improved component and (B) component migration to a living tissue.