TWI644663B - Method for stabilizing dibutylhydroxytoluene, and products containing dibutylhydroxytoluene (1) - Google Patents

Abstract

The object of the present invention is to provide a technique for improving the thermal stability of dibutylhydroxytoluene and preventing its content from decreasing with time for a liquid agent containing dibutylhydroxytoluene and praprofen and / or its salts.

It is selected from the group consisting of cromolyn, allantoin, glycyrrhizic acid, clofamine, and their pharmaceuticals by mixing in a liquid containing dibutylhydroxytoluene and praprofen and / or its salts At least one of the group consisting of allowable salts, and the contained container uses a resin containing polybutylene terephthalate as the container to form the inner wall surface (the inner space wall surface of the injection part and / or the lid part and the The wall surface of the injection port opposite the injection port, etc.), that is, while improving the thermal stability of dibutylhydroxytoluene in the liquid, it can inhibit the adsorption of dibutylhydroxytoluene to the container, and effectively suppress its content. Reduced over time.

Description

Method for stabilizing dibutylhydroxytoluene, and products containing dibutylhydroxytoluene (1) Field of invention

The present invention relates to a product which can stabilize dibutylhydroxytoluene in a liquid agent containing dibutylhydroxytoluene and praprofen and / or its salts. Furthermore, the present invention relates to a method for stabilizing a liquid agent containing dibutylhydroxytoluene, praprofen and / or a salt thereof.

Background of the invention

In recent years, in the fields of medicine, food, perfumery, etc., preparations with various effects have been developed. In these preparations, in order to prevent the oxidation of the contained ingredients, the combination with antioxidants is desired.

So far, dibutylhydroxytoluene (BHT) has been known as a representative compound of fat-soluble antioxidants. Tocopherol, butyl hydroxyanisole, etc. are also known as fat-soluble antioxidants. However, compared with other fat-soluble antioxidants, dibutylhydroxytoluene has a strong antioxidant effect, so it is widely used in medicine, food, Fragrance cosmetics and other fields.

In addition, there are reports on preparation technology using dibutylhydroxytoluene. For example, it has been reported to use dibutylhydroxytoluene to stabilize pranoprofen and / or its salts (see Patent Document 1). However, Patent Document 1 focuses on the stability of praprofen and / or its salts, and The stability of dibutylhydroxytoluene has not been reviewed. It has also been reported that an aqueous composition containing praprofen and / or its salts and dibutylhydroxytoluene has low thermal stability, but by further mixing a sulfonamide, yellowing can be suppressed (see Patent Document 2) . However, Patent Document 2 focuses on the yellowing suppression of the aqueous composition, and does not review the stability of dibutylhydroxytoluene itself.

On the other hand, in the fields of medicine, food, cosmetics, etc., a polyethylene nozzle is generally used as a container for containing a preparation. However, it has been reported that the currently widely used plastic containers equipped with polyethylene injection parts (nozzles, inner plug nozzles, opening inner plugs, etc.) and lids, once containing liquid containing dibutylhydroxytoluene When the agent is used, dibutylhydroxytoluene in the liquid agent is adsorbed and accumulated in the injection part (Patent Document 3). Therefore, it is reported in Patent Document 3 that the use of specific resins such as polybutylene terephthalate as the inner wall surface of the container (the wall surface of the internal space of the injection part and / or Or the wall surface of the lid opposite the injection port of the injection part, etc.) can suppress the adsorption of dibutylhydroxytoluene on the inner wall surface, and can stably maintain the content of dibutylhydroxytoluene in the liquid agent.

Advance technical literature Patent literature

Patent Literature 1: Japanese Patent Publication No. 7-304670

Patent Literature 2: Japanese Patent Laid-Open No. 2011-98960

Patent Literature 3: International Publication No. 2013/99861

Summary of the invention

As a result of the review conducted by the present inventors on the practical use of liquid agents containing dibutylhydroxytoluene, praprofen and / or salts thereof, they faced a new problem: if this liquid agent is contained in a container currently in general use In the case, the dibutylhydroxytoluene content will decrease significantly over time. Furthermore, Patent Document 2 reports that by mixing a sulfonamide agent, the thermal stability of an aqueous composition containing praprofen and / or its salt and dibutylhydroxytoluene can be improved, and yellowing of the aqueous composition can be suppressed However, the yellowing of the aqueous composition is different from the thermal destabilization of dibutylhydroxytoluene itself, and Patent Document 2 does not disclose a technique for improving the thermal stability of dibutylhydroxytoluene itself.

In addition, in the liquid agent containing dibutylhydroxytoluene and praprofen and / or its salt, the amount of dibutylhydroxytoluene can also be increased to compensate for the decrease in its content over time, but due to dibutyl An increase in the mixing amount of hydroxytoluene may cause irritation when it is applied to liquid solutions such as eye drops, so it is not practical. Therefore, for a liquid agent containing dibutylhydroxytoluene and praprofen and / or a salt thereof, it is necessary to develop a technology capable of preventing a decrease in the content of dibutylhydroxytoluene.

Therefore, the object of the present invention is to provide a technique for preventing the dibutylhydroxytoluene content from decreasing with time for a liquid agent containing dibutylhydroxytoluene, praprofen and / or a salt thereof.

As a result of the efforts of the present inventors to solve the aforementioned problems, they found the following knowledge: by mixing the liquid agent containing dibutylhydroxytoluene with praprofen and / or its salt, the Glycolic acid, allantoin, At least one member of the group consisting of glycyrrhizic acid, clofphenamine, and their pharmaceutically acceptable salts, and the container containing the resin containing polybutylene terephthalate as the container to form the inner wall surface ( The internal space wall surface of the injection part and / or the wall surface of the cover opposite the injection port of the injection part, etc.), that is, the thermal stability of dibutylhydroxytoluene in the liquid agent can be improved and dibutyl can be suppressed The absorption of hydroxytoluene to the container effectively suppresses the decrease of its content over time. The present invention is based on this knowledge and has been completed after further review.

That is, the present invention provides a product containing dibutylhydroxytoluene and a stabilizing method as disclosed below.

Item 1. A product containing dibutylhydroxytoluene, which is prepared by containing a liquid agent in a container, the liquid agent containing: (A) dibutylhydroxytoluene, (B) praprofen and / or The pharmaceutically acceptable salt thereof, (C) is selected from at least one selected from the group consisting of cromoglycic acid, allantoin, glycyrrhizic acid, clofiphenamine, and pharmaceutically acceptable salts thereof, and the foregoing The container includes: a container body portion that houses the liquid agent; an injection portion that has an injection port that can inject the liquid agent contained in the container body portion; and a lid portion that closes the injection port and the injection hole At least one of the wall surface of the internal space of the outlet portion and the wall surface of the lid portion opposite to the injection port is composed of a resin containing polybutylene terephthalate.

Item 2. The product containing dibutylhydroxytoluene as described in Item 1, wherein the injection part is a nozzle for injecting the liquid agent in the form of droplets, and the wall of the inner space of the nozzle is made of polyparaphenylene Framed by resins of butane dicarboxylate to make.

Item 3. The product containing dibutylhydroxytoluene as described in Item 1 or 2, wherein the body of the container is made of resin containing polyethylene terephthalate.

Item 4. The product containing dibutylhydroxytoluene as described in any one of Items 1 to 3, wherein the aforementioned liquid agent further contains a boric acid buffer.

Item 5. The product containing dibutylhydroxytoluene as described in any one of Items 1 to 4, in the aforementioned liquid preparation, the aforementioned (A) component contains 0.00001 to 0.005 w / v%, and the aforementioned (B) component Contains 0.005 ~ 0.5w / v%, and the aforementioned (C) component contains 0.0005 ~ 5w / v%.

Item 6. The product containing dibutylhydroxytoluene as described in any one of Items 1 to 5, wherein the aforementioned liquid agent is an eye drop.

Item 7. A stabilizing method which stabilizes dibutylhydroxytoluene in a liquid agent containing (A) dibutylhydroxytoluene and (B) praprofen and / or pharmaceutically acceptable salts thereof The method is characterized in that the liquid solution is mixed with (C) at least one selected from the group consisting of cromolyn, allantoin, glycyrrhizic acid, clofamine, and pharmaceutically acceptable salts thereof, The liquid agent is contained in the following container: a container body portion for containing the liquid agent, an injection portion having an injection outlet for injecting the liquid agent contained in the container body portion, and a cap for sealing the injection hole At least one of the inner space wall surface of the injection part and the wall surface opposite to the injection port of the lid part is composed of a resin containing polybutylene terephthalate.

Item 8. The stabilization method according to Item 7, wherein the injection part is a nozzle for injecting the liquid agent in the form of droplets, and the inner wall surface of the nozzle is made of polybutylene terephthalate. Of resin.

Item 9. The stabilization method according to Item 7 or 8, wherein the container body is made of a resin containing polyethylene terephthalate.

Item 10. The stabilization method according to any one of Items 7 to 9, wherein the liquid solution further includes a boric acid buffer.

Item 11. The stabilization method as described in any one of Items 7 to 10, wherein in the liquid agent, the (A) component contains 0.00001 to 0.005 w / v%, and the (B) component contains 0.005 to 0.5 w / v%, and the aforementioned (C) component contains 0.0005 to 5 w / v%.

Item 12. The stabilization method as described in any one of Items 7 to 11, wherein the aforementioned liquid preparation is an eye drop.

According to the present invention, while containing dibutylhydroxytoluene and praprofen and / or its salts, it is possible to improve the thermal stability of dibutylhydroxytoluene and its adsorption inhibition on the container, and stabilize Maintain the content of dibutylhydroxytoluene.

In addition, in eye drops or nose drops, dibutylhydroxytoluene is set at a low content close to the threshold amount required for the anti-oxidation effect, and in the conventional technology, in combination with praprofen and / Under the coexistence of the salt or the salt, the thermal stability of dibutylhydroxytoluene significantly decreases, and the loss of the antioxidant effect due to the decrease in the content thereof tends to become significant. In contrast, according to the present invention, the shortcomings of such conventional techniques can be overcome. In liquid preparations such as eye drops or nasal drops, even The coexistence of dibutylhydroxytoluene and praprofen and / or its salts can still effectively suppress the reduction of its content, while effectively maintaining the antioxidant effect in the liquid.

1‧‧‧Container body

2‧‧‧Department

3‧‧‧ Cover

4‧‧‧Extract the internal space of the department

5‧‧‧The wall surface of the internal space of the drawer

6‧‧‧The wall surface of the cover opposite the injection port of the injection part

FIG. 1 shows a cross-sectional view of an example of an eye-drop container used in the present invention.

FIG. 2 shows a partially enlarged cross-sectional view of the eye drop container shown in FIG. 1.

FIG. 3 shows a cross-sectional view of an example of an eyedrop container used in the present invention.

FIG. 4 shows a cross-sectional view of an example of an eye-drop container used in the present invention.

5 shows a partially enlarged cross-sectional view of the eye drop container shown in FIG. 4.

FIG. 6 is a cross-sectional view showing an example of an eyewash container used in the present invention.

Detailed description of the preferred embodiment

In this specification, "stabilization" or "stability" of dibutylhydroxytoluene means that dibutylhydroxytoluene will be suppressed in the liquid formulation due to decomposition or adsorption to the container over time, and Keep the content stable, or this characteristic. In addition, in this specification, the "thermal stability" of dibutylhydroxytoluene means the characteristic which suppresses the decomposition of dibutylhydroxytoluene by heat. In addition, in this specification, the "product containing dibutylhydroxytoluene" refers to a liquid containing the components (A) to (C) described later in a state of being contained in a container, and is also referred to as "product containing BHT". In this manual, the unit "w / v%" refers to the percentage of mass to volume in the 16th revised Japanese Pharmacopoeia, which is synonymous with g / 100mL.

1. Products containing BHT

The BHT-containing product of the present invention is characterized in that the interior of the injection part is empty The wall surface of the partition wall and / or the wall opposite to the injection port of the injection part is a container composed of a resin containing polybutylene terephthalate, containing the following liquid agent: (A) 2 Butylhydroxytoluene, (B) praprofen and / or pharmaceutically acceptable salts thereof, and (C) selected from the group consisting of cromolyn, allantoin, glycyrrhizic acid, clofamine and the like Allow at least one salt in the group. Hereinafter, the BHT-containing product of the present invention will be described in detail.

Liquid

In the BHT-containing product of the present invention, the liquid contained in the container contains dibutylhydroxytoluene (also expressed as component (A)). Dibutylhydroxytoluene is also known as 2,6-di-tert-butyl-4-methylphenol, BHT, DBPC, etc. It is a well-known compound as an antioxidant. In this solution, dibutylhydroxytoluene is an ingredient as follows: while seeking to improve the thermal stability of praprofen and / or its salts, it also exerts an antioxidant effect in the solution and also helps to visualize The stability of pharmacological ingredients or additives that need to be added is improved.

The content of the (A) component in the liquid preparation is not particularly limited, and it may be appropriately set depending on the use of the liquid preparation, for example, 0.00001 ~ 0.005w / v%, preferably 0.00005 ~ 0.005w / v %, More preferably 0.0001 ~ 0.005w / v%.

The liquid preparation used in the present invention further contains praprofen and / or its salt (also expressed as component (B)). In this solution, pranoprofen and / or its salts use dibutylhydroxytoluene to improve light stability.

Pranoprofen, also known as α-methyl-5H- [1] benzopyran [2,3-b] pyridine-7-acetic acid, is a well-known compound known to have anti-inflammatory effects in the field of ophthalmology.

The pranoprofen salt is not particularly limited as long as it is pharmaceutically acceptable. Examples include metal salts such as sodium salt, potassium salt, calcium salt, magnesium salt, and aluminum salt; Diethylamine salt, morpholin salt, piper Organic salts such as salt. These pranoprofen salts can be used alone or in combination of two or more.

In the liquid preparation used in the present invention, as the component (B), one kind may be selected from pranoprofen and its salts and used alone, or two or more kinds may be used in combination. However, in component (B), it should be Ruprafen.

The content of the component (B) in the liquid preparation is not particularly limited, and it may be appropriately set depending on the use of the liquid preparation, etc. However, for example, 0.005 to 0.5 w / v%, preferably 0.05 to 0.1 w / v %, More preferably 0.05w / v%.

The liquid agent used in the present invention further includes at least one selected from the group consisting of cromoglycic acid, allantoin, glycyrrhizic acid, clofiphenamine, and pharmaceutically acceptable salts thereof (also express (Component (C)). The liquid agent used in the present invention can reduce the content of dibutylhydroxytoluene in the presence of praprofen and / or its salts by mixing the component (C) and storing it in a specific container described later. It is effectively suppressed.

Cromolyn, also known as 5,5 '-[(2-hydroxy-1,3-propanediyl) dioxy) bis (4-oxo-4H-1-benzopiperan-2-carboxylic acid), CROMOLYN and DSCG are well-known compounds that are also used for anti-allergy or anti-inflammatory purposes.

The salt of cromoglycic acid is limited to the pharmaceutically acceptable limit, and is not particularly limited, but examples thereof include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt. Among the salts of cromoglycic acid, alkali metal salts can be cited Preferably, sodium salt is better. These cromolyn salts can be used alone or in combination of two or more.

Furthermore, cromoglycic acid and / or its salts can also be used in the form of hydrates.

Allantoin, also known as 5-ureidohydantoin, is also a well-known compound used for purposes such as anti-allergy, anti-inflammatory, granulation formation, and tissue repair.

The salt of allantoin is limited to pharmacologically acceptable ones, and is not particularly limited, but examples include dihydroxy aluminum allantoin, aluminum chlorohydrin allantoin, and the like. These allantoin salts can be used alone or in combination of two or more.

Glycyrrhizic acid, also known as 3β-[[2-O- (6-O-potassium-β-D-glucopyranuronic acid) -6-O-potassium-α-D-glucopyranose Aldoxy] oxy] -11- pendant-olean-12-ene-30-acid (ie 3β-{(2-O- (6-O-potassio-β-D-glucopyranuronosyl) -6 -O-potassio-α-D-glucopyranuronosyl] oxy} -11-oxo-olean-12-en-30-oic acid) is a well-known compound used for the purpose of anti-allergy or anti-inflammatory.

The salt of glycyrrhizic acid is limited to the pharmacologically acceptable limit, and is not particularly limited, but examples thereof include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; Among these glycyrrhizic acid salts, alkali metal salts are preferred, and potassium salts are more preferred. These glycyrrhizic acid salts can be used alone or in combination of two or more.

Clofiphenamine, also known as 3- (4-chlorophenyl) -N, N-dimethyl-3-pyridin-2-yl-propan-1-amine, is also used for antihistamine and other purposes Publicization of Compound.

The salt of clofiphenamine is not limited to pharmacologically acceptable ones, and examples include organic acid salts such as maleate and fumarate; inorganic acid salts such as hydrochloride and sulfate. Among these clofiphene salts, maleate is preferred.

In addition, the clofphenamine and / or its salt may be in the form of a solvate such as a hydrate, or it may be in either the d-type or dl-type.

In the liquid preparation used in the present invention, as component (C), cromolyn, allantoin, glycyrrhizic acid, clofamine, and other pharmaceutically acceptable salts can be selected and used alone. Two or more types can also be used in combination. Moreover, among these (C) components, from the viewpoint of continuing to effectively suppress the reduction of the content of dibutylhydroxytoluene and exerting an excellent anti-allergic effect, for example, cromolyn, allantoin, and glycyrrhizic acid are preferred , And other pharmaceutically acceptable salts, preferably cromolyn and its pharmaceutically acceptable salts, more preferably cromolyn, pharmaceutically acceptable salts, particularly preferably cromolyn.

In the liquid preparation used in the present invention, the content of the component (C) may be, for example, 0.0005 to 5 w / v%, and is preferably 0.001 to 2 w / v%. More specifically, the content of various types of component (C) includes the following ranges.

When using cromolyn and / or its salt: 0.1 to 5 w / v% is preferred, 0.5 to 3 w / v% is more preferred, and 1 to 2 w / v% is particularly preferred.

When using allantoin and / or its salts: 0.01 to 1 w / v% is preferred, 0.03 to 0.5 w / v% is more preferred, and 0.06 to 0.3 w / v% is particularly preferred.

When using glycyrrhizic acid and / or its salt: 0.005 ~ 1w / v% is preferred, 0.01 ~ 0.5w / v% is more preferred, and 0.05 ~ 0.25w / v% is particularly preferred.

When using clofiphene and / or its salt: 0.0005 ~ 1w / v% is preferred, 0.001 ~ 0.1w / v% is more preferred, and 0.006 ~ 0.03w / v% is particularly preferred.

In addition to the aforementioned components (A) to (C), the liquid agent used in the present invention may contain a buffering agent in order to have a buffering effect. The buffering agent is not particularly limited, but examples thereof include boric acid buffering agent, phosphoric acid buffering agent, citric acid buffering agent, tartaric acid buffering agent, acetic acid buffering agent, Tris buffering agent, amino acids (glutamic acid, etc.), and the like. These buffering agents can be used alone or in combination of two or more. Among these buffering agents, boric acid buffering agents have buffering energy in a pH range capable of dissolving praprofen and / or its salts, and are suitable for use in the present invention.

The content of the buffering agent in the liquid agent used in the present invention can be appropriately set in the range that can provide the desired buffering effect according to the type of buffering agent used, and can be, for example, 0.001 to 5 w / v%, preferably 0.05 ~ 3w / v%, more preferably 0.1 ~ 2w / v%.

Furthermore, the liquid agent used in the present invention may contain a chelating agent in addition to the aforementioned ingredients. By containing a chelating agent, the content of dibutylhydroxytoluene can be further effectively suppressed.

Specific examples of the chelating agent include ethylenediaminetetraacetic acid, citric acid, succinic acid, ascorbic acid, trimethylolaminomethane, nitrotriacetic acid, 1-hydroxy-ethane-1,1-diphosphonic acid , Polyphosphoric acid, metaphosphoric acid, hexametaphosphoric acid, or their pharmaceutically acceptable salts. These chelating agents may be used alone or in combination of two or more. Among these chelating agents, from the viewpoint of further effectively suppressing the decrease in the content of dibutylhydroxytoluene, preferred are ethylenediaminetetraacetic acid and pharmaceutically acceptable salts thereof. Also, the medicine of ethylenediaminetetraacetic acid The salts that are allowed in science include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt.

When the liquid agent used in the present invention contains a chelating agent, its content may be appropriately set depending on the use of the liquid agent, etc., but may be, for example, 0.0005 to 0.5 w / v%, preferably 0.001 ~ 0.2w / v%, more preferably 0.005 ~ 0.13w / v%.

The liquid preparation used in the present invention may contain pharmacological components according to the use of the liquid preparation in addition to the above-mentioned components. The pharmacological ingredients used are not particularly limited. For example, they can be appropriately selected from the following conventional pharmacological ingredients and used: vasoconstrictors, anticholinerase inhibitors, anti-inflammatory agents, corneal epithelial barrier treatment drugs, anti-inflammatory analgesics , Chemotherapeutics, antibiotics, antivirals, hormones, vitamins, amino acids, anti-cataract drugs, angiogenesis inhibitors, immunosuppressants, protease inhibitors, aldose reductase inhibitors, antihistamines, anti-allergy Agents, anti-anxiety agents, antipsychotic drugs, antibiotics, antitumor agents, antihyperlipidemic drugs, antitussive and expectorant drugs, muscle relaxants, antiepileptic drugs, antiulcer drugs, antidepressant drugs, cardiotonics, arrhythmia treatment agents , Vasodilators, hypertension diuretics, diabetes treatment agents, anti-tuberculosis drugs, anesthesia antagonists, skin disease drugs, dental oral drugs, diagnostic drugs, public health drugs, etc.

Among these pharmacological ingredients, if it is a preparation used in ophthalmology or otolaryngology such as eye drops, eye wash, nose drops, ear drops, etc., specifically, the following ingredients may be mentioned: ε-amino Hexanoic acid, bromfenac, ketorolac tromethamine, nepafenac, phoshine, chrysopine sulfate, azuline sulfate, sodium azulene sulfonate, sulfuric acid Anti-inflammatory agents such as zinc, zinc lactate, lysozyme hydrochloric acid, etc .; antihistamines such as diphenylhydroxylamine hydrochloride; Ketotifen Fumarate, Acitazanolast, aminexanol (amlexanox), Pimirolast Potassium, Tranilast, Ibudilast and other anti-allergic agents; Norfloxacin, ofloxacin, Antibacterial agents such as lomefloxacin, levofloxacin, gentamicin, gatifloxacin; ascorbic acid, flavin adenine dinucleotide sodium, cyanocobalamin, pyridoxine hydrochloride , Tocopheryl acetate, retinyl acetate, retinyl palmitate, pantothenol, calcium pantothenate, sodium pantothenate and other vitamins; aspartic acid, taurine, chondroitin sulfate sodium and other amines Basic acids; anti-cholinesterases such as neostigmine methyl sulfate; naphazoline, tetrahydroazole, epinephrine, ephedrine, phenylephrine, dl- Vasoconstrictors such as methylephedrine; therapeutic agents for corneal conjunctival epithelial disorders such as sodium hyaluronate; sulfadiazine (sulfadi azine), sulfisoxazole, sulfisomidine, sulfadimethoxine, sulfadimethoxine, sulfamethoxypyridazine, sulfamethoxazole, sulfamethidazole ), Sulfamethomidine, sulfamethazole, sulfaphenazole, sulfaguanidine, phthalylsulfathiazole, succinylsulfathiazole and other sulfonamides. The compounds exemplified here are pharmaceutically acceptable as a limit, and may be in the form of salts or other salts.

The content of these pharmacological components can be appropriately set according to the type of pharmacological component or the use of the liquid.

In addition, the liquid agent used in the present invention may contain isotonic agents, dissolution aids, viscosity bases, cooling agents, pH adjusters, preservatives, stabilizers, in addition to the aforementioned components Additives such as surfactants.

Examples of isotonic agents include sugars such as sorbitol, glucose, and mannitol; polyhydric alcohols such as glycerin and propylene glycol; salts such as sodium chloride; boric acid. These isotonizing agents may be used alone or in combination of two or more.

Examples of the dissolution aid include nonionic surfactants such as polyoxyethylene sorbitan monooleate, polyoxyethylene hydrogenated castor oil, tetrabutyral, and PLURONIC®; glycerin and polyethylene glycol (macrogol) Etc. polyols. One type of these dissolution aids may be used alone, or two or more types may be used in combination.

Examples of the viscous base include polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, carboxyvinyl polymer, xanthan gum, chondroitin sulfate sodium, alginic acid or its salt, and sodium hyaluronate. Water-soluble polymer; cellulose such as hypromellose, hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, etc. . These adhesive bases may be used alone or in combination of two or more.

Examples of the cooling agent include l-menthol, borneol, camphor, and eucalyptus oil. These cooling agents can be used alone, or 2 More than one combination.

Examples of the pH adjuster include alkalis such as sodium hydroxide, potassium hydroxide, and borax; acids such as acetic acid, citric acid, hydrochloric acid, phosphoric acid, tartaric acid, and boric acid.

Examples of the preservatives include sorbic acid or its salts, benzoic acid or its salts, methyl paraben, ethyl paraben, propyl paraben, chlorobutanol, and chlorhexidine gluconic acid. Salt, boric acid, dehydroacetic acid or its salt, acetic acid or its salt, benzalkonium chloride, benzethonium chloride, benzyl alcohol, zinc chloride, p-chloro-m-xylenol, chlorocresol, Phenylethanol, Polidronium chloride, thimerosal, polyhexamethylene biguanide (PHMB), etc. These preservatives may be used alone or in combination of two or more.

Examples of the stabilizer include polyvinylpyrrolidone, sulfite, monoethanolamine, glycerin, propylene glycol, cyclodextrin, dextran, ascorbic acid, ethylenediaminetetraacetate, taurine, and tocopherol. These stabilizers may be used alone or in combination of two or more.

Examples of the surfactant include tyloxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, and octoxynol ) And other nonionic surfactants; amphoteric surfactants such as alkyl diamino ethyl glycine, lauryl dimethyl amino acetate betaine; alkyl sulfate, N-acetyl taurine, polyoxy Anionic surfactants such as ethylene alkyl ether phosphate and polyoxyethylene alkyl ether sulfate; cationic surfactants such as alkyl pyridinium salt and alkyl ammonium salt. These surfactants can also be used alone, also Can be used in combination of two or more.

The concentration of these additives can be appropriately set according to the type of additive or the use of the liquid.

The form of the liquid agent used in the present invention may be any one as long as it contains water as a base, and may be, for example, any of an aqueous solution, a suspension liquid, and an emulsion, and preferably, it may be an aqueous solution.

In addition, the pH of the liquid agent used in the present invention is not particularly limited, and may be appropriately set depending on the use of the liquid agent, etc., but may be, for example, 5.0 to 9.0, preferably 6.5 to 8.5.

The use of the liquid agent used in the present invention is not particularly limited, and examples thereof include medicine and contact lens care products. For medicine, specifically, ophthalmic solutions such as eyedrops (including eyedrops for contact lenses that can also be used when contact lenses are worn), eye wash, etc .; nasal drops, eardrops, etc. Department of liquid medicine; internal medicine, injection, external medicine, etc. In addition, in terms of contact lens care products, specifically, for example, a contact lens mounting solution, a multifunctional solution for contact lenses, etc. may be mentioned. Among the uses of these liquid preparations, liquid preparations for ophthalmology, liquid preparations for otolaryngology, and contact lens care products are preferred, and eye drops are more preferred.

In addition, the liquid formulation used in the present invention can be filled in a multi-dose type container (that is, filled with the usage amount of multiple portions and can be used repeatedly); and can also be filled in a single-dose type container which is used up once.

The liquid agent used in the present invention may be produced according to its well-known preparation method depending on its form or application. For example, it can be prepared by mixing each component in an aqueous base such as water or physiological saline. For example, in medicine In the case of the situation, it can be manufactured by the method described in the 16th revised edition of the General Pharmacopoeia of Japan.

container

In the BHT-containing product of the present invention, the following solution is used for accommodating the aforementioned liquid agent: the container body portion, the injection portion, and the lid portion, and the wall surface and / or the lid portion of the internal space of the injection portion The wall surface of the injection port facing the injection port is made of resin containing polybutylene terephthalate.

<Construction of container>

The container body for constructing the container is a portion for storing the liquid agent. The shape and size of the container body are not particularly limited, and can be appropriately set according to the type and volume of the liquid agent contained therein.

The injection part constituting the container is the following part: it has an internal space for communicating between the container body and the outside of the container, and is provided with an injection port for injecting the liquid contained in the container body. The outlet is provided so as to communicate with the opening of the container body, and allows the liquid agent contained in the container body to pass through the internal space and be poured out of the container through the injection port (discharge). As long as the injection part is configured to inject the liquid agent contained in the container body part from the injection port to the outside of the container, the structure is not particularly limited. For example, it can be configured to Those who are ejected in the form of droplets, or those configured to flow out the liquid in a non-droplet form. From the viewpoint that the effect of the present invention can be further achieved, the aforementioned injection portion is preferably configured as a nozzle capable of injecting the liquid agent in the form of droplets. In addition, an inner plug such as an inner cap nozzle and a porous inner cap may be provided in the injection part, for example.

Part or all of the aforementioned injection part may also be connected to the container body part One-piece. In addition, the injection part may be inserted into the inner cavity of the opening of the container body or installed outside.

In addition, the lid constituting the container is a portion that closes the injection port. The lid portion may have a structure that fits the container body portion and / or the spout. More specifically, in the case where the BHT-containing product of the present invention is a multi-dose type, it may be a fitting structure capable of attaching and detaching the container body and / or the injection port; in addition, the BHT-containing product of the present invention is a single-dose type In the case of, it may be a fitting structure that can be detached from the container body and / or the injection. An ideal example of a fitting structure capable of attaching and detaching the container body part and / or the spout can be given as follows: The container body part and / or the spouting part are screwed into the detachably assembled lid part. In the case where the lid part is detachably assembled with the container body part and / or the injection part by screw fitting, the lid part may also be provided with a screw part which is screwed with the container body part and / or the injection part The screw part.

The shape of the aforementioned container can be appropriately set according to the application of the BHT-containing product contained therein. Specific examples include eye drop containers, eye wash containers, and nose drop containers.

Examples of specific aspects of the container used in the present invention are shown in Figs. 1-6.

FIG. 1 is a cross-sectional view of an aspect of an eye-drop container; FIG. 2 is a partially enlarged cross-sectional view of the eye-drop container shown in FIG. 1. In the eye-drop container shown in FIG. 1, an injection portion 2 capable of injecting the liquid agent in the form of a droplet is inserted into the inner cavity of the opening portion of the container body portion 1; and the lid portion 3 is fitted by screws On the other hand, it is detachably attached to the container body 1 and closes the injection port of the injection part 2. In the eye drop container, the liquid agent that has been contained in the container body 1 passes through the empty part of the injection part 2 Room 4 is poured out of the container from the injection port. The eye drop container shown in Fig. 1 can also be used to contain single-dose liquids, but it is suitable for containing multiple-dose liquids.

Fig. 3 is a cross-sectional view of an aspect of an eye-drop container. In the eye-drop container shown in FIG. 3, the container body 1 and the injection part 2 are not integrated or mechanically joined, but are formed as one body using the same material, and the aforementioned liquid agent can pass through the internal space 4 of the injection part 2 The liquid is discharged from the outlet to the outside of the container. In FIG. 3, the cover portion is omitted, and an imaginary line (broken line) is inserted for convenience. In the eye-drop container shown in FIG. 3, the container material below the imaginary line corresponds to the container body 1, and the container portion above the imaginary line corresponds to the injection part 2. The eye drop container shown in FIG. 3 can be used to contain a single-dose liquid agent, but it is suitable for containing a multi-dose liquid agent.

4 is a cross-sectional view of an aspect of an eye-drop container; FIG. 5 is a partially enlarged cross-sectional view of the eye-drop container shown in FIG. 4. In the eye drops shown in FIG. 4, the container body portion 1, the injection portion 2 and the lid portion 3 are integrally formed. Although the injection part 2 and the lid part 3 are in a connected state, by disconnecting them during use, the liquid agent contained in the container body 1 can pass through the internal space 4 of the injection part 2 from the injection port Note out to the outside of the container. In Figs. 4 and 5, an imaginary line (broken line) is inserted for cheap operation. In FIGS. 4 and 5, the container material between the two imaginary lines corresponds to the injection part 2, and the space between the two imaginary lines corresponds to the internal space 4 of the injection part 2. The eye drop container shown in FIG. 4 is suitable for containing a single-dose liquid.

6 is a cross-sectional view of an eye wash container. In the eye wash container shown in FIG. 6, a part of the container body 1 and the injection part 2 are integrally formed. In the wash In the eye container, the liquid agent contained in the container body 1 is discharged from the injection port to the outside of the container through the internal space 4 of the injection part 2. In Fig. 6, an imaginary line (dashed line) is inserted for cheap operation.

Figures 1 to 6 list specific aspects of the eye-drop container and eye-wash container, but the present invention is not limited to these structures or shapes, and even containers other than the eye-drop container and eye-wash container as long as they have the above characteristics be usable.

<Construction material of container>

At least one of the following of the container is composed of a resin containing polybutylene terephthalate (PBT): the wall surface of the inner space of the injection part, and the wall surface opposite to the injection port in the lid part . Here, the "wall surface of the lid opposite to the injection port" refers to the portion of the inner wall of the lid that closes the injection port when the lid is attached to the container body and / or the injection part. Specifically, taking FIG. 2 as an example, the surface portion shown by symbol 5 is equivalent to "the wall surface of the internal space of the injection part"; the surface portion shown by symbol 6 is equivalent to "the cover part is opposite to the aforementioned injection port Wall. "

If the wall surface of the internal space of the injection part and / or the wall surface opposite to the injection port of the injection part in the cover part is formed by a resin containing polybutylene terephthalate, and used in the aforementioned liquid agent The specific composition complements each other, that is, it can effectively inhibit the adsorption and accumulation of dibutylhydroxytoluene to the injection part and / or the cover part, so that the content of dibutylhydroxytoluene in the liquid agent is kept stable.

The resin constituting the wall surface (that is, the wall surface of the internal space of the injection part and / or the wall surface of the cover part opposite to the injection port of the injection part) may be composed of polybutylene terephthalate alone, or Polyterephthalic acid It is composed of blended polymers of butanediol and other polymers. The resin constituting the wall surface (that is, the wall surface of the internal space of the injection part and / or the wall surface opposite to the injection port of the injection part in the cover part), when using polybutylene terephthalate and other polymers When the polymer is blended, the mixing ratio is not particularly limited under the limit of the effect of the invention, but ideally, relative to the total amount of the polymer blend, polybutylene terephthalate The diester accounts for more than 50w / w%, preferably more than 60w / w%, preferably more than 70w / w%, more preferably more than 80w / w%, and particularly preferably more than 90w / w%.

In the aforementioned container, at least one of the wall surface of the internal space of the injection part and / or the wall surface opposite to the injection port of the injection part may contain polybutylene terephthalate. For example, if an injection part for injecting a liquid agent in the form of droplets (for example, a nozzle configured to drop droplets in the form of droplets) is used, the content of dibutylhydroxytoluene can be more effectively suppressed From the point of view of reduction, it is preferable that at least the wall surface of the inner space of the injection portion is composed of a resin containing polybutylene terephthalate, and it is preferable that the wall surface of the inner space of the injection portion and the cover portion The opposite wall surface of the injection port of the outlet is made of resin containing polybutylene terephthalate. In addition, if, for example, the injection part in the form of a non-droplet effluent is used, from the viewpoint of more effectively suppressing the decrease in the content of dibutylhydroxytoluene, it is preferable that it is at least between the cap part and the injection part The wall surface opposite to the injection port is composed of a resin containing polybutylene terephthalate. More preferably, the wall surface of the internal space of the injection part and the wall surface opposite to the injection port of the injection part in the lid are The resin is composed of polybutylene terephthalate.

As long as the wall surface of the inner space of the injection part and / or the lid part The wall surface opposite to the injection port of the injection part may be composed of a resin containing polybutylene terephthalate, and parts other than these wall surfaces are not particularly limited in the constituent materials. For example, the parts other than the wall surfaces may be made of resin containing polybutylene terephthalate, or may be made of materials other than polybutylene terephthalate.

In the case where the container body portion and the injection portion are integrally formed, the container body portion is made of the same resin as the injection portion.

In addition, if the container is inserted into the inner cavity of the opening of the container body, or the injection part is installed outside the opening of the container body, the container body It may be made of glass or plastic, but it is preferably made of plastic, for example. In the container of the above aspect, when the container body is made of plastic, the type of resin forming the container body is not particularly limited, but examples thereof include polyethylene terephthalate and polyethylene Butyl phthalate, polystyrene, acrylonitrile-butadiene-styrene, etc. Among them, polyethylene terephthalate has excellent moldability and can suppress the adsorption of dibutylhydroxytoluene, so it is appropriate to use the resin that forms the container body.

2. Stabilization method

The method for stabilizing dibutylhydroxytoluene of the present invention is characterized by mixing in a liquid agent containing (A) dibutylhydroxytoluene, (B) praprofen and / or a pharmaceutically acceptable salt thereof (C) at least one member selected from the group consisting of cromolyn, allantoin, glycyrrhizic acid, clofamine, and pharmaceutically acceptable salts thereof, and the liquid solution (i.e. containing dibutyl (Formulation of hydroxytoluene) In the container: the wall surface of the inner space of the injection part and / or the wall surface of the lid opposite the injection port of the injection part is a container made of resin containing polybutylene terephthalate.

In the stabilization method of the present invention, the types or contents of the (A) to (C) components contained in the liquid agent, the types and contents of other compoundable ingredients, and the application of the liquid agent are used in the The situation of the liquid preparation of the product is the same. In addition, the container used in the stabilization method of the present invention is the same as the container used in the aforementioned BHT-containing product.

The stabilization method of the present invention is directed to a liquid agent containing dibutylhydroxytoluene and praprofen and / or its salts, by improving the thermal stability of dibutylhydroxytoluene and simultaneously suppressing dibutylhydroxytoluene The adsorption to the container can effectively suppress the decrease in the content of dibutylhydroxytoluene and improve the storage stability of dibutylhydroxytoluene, so it can also be implemented as a method of storing the liquid agent.

Examples

The following examples are given to illustrate the present invention, but the present invention is not limited by these examples.

Test Example 1: Evaluation of dibutylhydroxytoluene content over time

The liquid formulation shown in Table 2 was prepared, and the change in the content of dibutylhydroxytoluene over time when it was stored in various containers was measured. Specifically, the liquid formulation shown in Table 2 was prepared according to a normal method, stored in each container shown in Table 1 and sealed, and allowed to stand for 2 weeks under 40 ° C, 75% RH, and shading conditions to be stored. At this time, in the case of containers 2 and 3, the volume of the liquid agent is set to 10 mL; In the case of the container 1, the capacity of the liquid agent is set to 5 mL. Furthermore, in the case of the containers 2 and 3, the container is allowed to stand in an upright state with the lid portion on the upper surface and the bottom of the container body portion on the lower surface. Before the start of storage, one week and two weeks after the start of storage, the liquid in the container was sampled so that the nozzle did not contact the liquid, and the content of dibutylhydroxytoluene in the liquid was measured by HPLC to evaluate the two Thermal stability of butylhydroxytoluene. The stability of dibutylhydroxytoluene is specifically calculated by calculating the ratio of the content of dibutylhydroxytoluene after storage to the content of dibutylhydroxytoluene before storage as the residual ratio (%). In addition, the container 3 is an example of an eye drop container that is currently in general use. In addition, it is known that glass is not easy to adsorb general drugs, so the container 1 is an example of a container that is not easy to adsorb dibutylhydroxytoluene.

The results obtained are shown in Table 2. As the results of the control group indicate, once dibutylhydroxytoluene and praprofen coexist in the liquid, the decrease in the content of dibutylhydroxytoluene is significant. In addition, if diethylhydroxytoluene and praprofen are combined with naphthyridine hydrochloride or neostigmine methyl sulfate, it can be confirmed that it cannot fully inhibit dibutyl The reduction of the content of hydroxytoluene may cause the content of dibutylhydroxytoluene to decrease further (Comparative Examples 1 and 2). On the other hand, sodium cromoglycate, allantoin, dipotassium glycyrrhizinate, or clofiphenamine maleate was combined in dibutylhydroxytoluene and praprofen, and it was housed in a parylene The liquid agent in the container 2 of a nozzle made of butylene formate can effectively suppress the decrease in the content of dibutylhydroxytoluene (Examples 1 to 5).

Reference Test Example 1: Evaluation of dibutylhydroxytoluene content over time

The liquid preparations shown in Tables 3 and 4 were prepared according to a normal method, and stored in each container shown in Table 1 in the same manner as in Test Example 1, and the content of dibutylhydroxytoluene in the liquid preparation was measured by HPLC. Based on the obtained measurement values, the residual rate of dibutylhydroxytoluene was calculated in the same manner as in the aforementioned Test Example 1. (%).

The results obtained are shown in Tables 3 and 4. From this result, it is clear that in Comparative Examples 3 to 16, the reduction in the content of dibutylhydroxytoluene that occurs when dibutylhydroxytoluene and praprofen are coexisted cannot be sufficiently suppressed, or dibutyl The content of hydroxytoluene is even lower. That is, from this result, it was confirmed that the suppression effect of the dibutylhydroxytoluene content reduction that occurs when dibutylhydroxytoluene and praprofen are coexisted is by selecting cromolyn, allantoin, and glycyrrhizic acid. And / or its salt and mixing it to exhibit the unique effect.

Table 4

Claims (12)

A product containing dibutylhydroxytoluene, characterized in that the product is prepared by containing a liquid agent in a container, and the liquid agent contains: (A) dibutylhydroxytoluene, (B) praprofen and / Or a pharmaceutically acceptable salt thereof, (C) at least one selected from the group consisting of cromoglycic acid, allantoin, glycyrrhizic acid, clofiphenamine, and pharmaceutically acceptable salts thereof, The container has a container body portion that contains the liquid agent, and an injection portion that has an injection port that can inject the liquid agent contained in the container body portion, and a lid portion that closes the injection port, and At least one of the wall surface of the internal space of the injection part and the wall surface of the cover part opposite to the injection port is composed of a resin containing polybutylene terephthalate. The product containing dibutylhydroxytoluene according to claim 1, wherein the injection part is a nozzle for injecting the liquid agent in the form of droplets, and the inner wall surface of the nozzle is polybutylene terephthalate Ester resin. The product containing dibutylhydroxytoluene as claimed in claim 1 or 2, wherein the body part of the container is made of resin containing polyethylene terephthalate. The product containing dibutylhydroxytoluene according to claim 1 or 2, wherein the aforementioned liquid agent further comprises boric acid buffer. For the product containing dibutylhydroxytoluene as claimed in claim 1 or 2, in the aforementioned liquid preparation, the aforementioned (A) component contains 0.00001 ~ 0.005w / v%, and the aforementioned (B) component contains 0.005 ~ 0.5w / v% And, the aforementioned (C) component contains 0.0005 to 5 w / v%. The product containing dibutylhydroxytoluene as claimed in claim 1 or 2, wherein the aforementioned liquid is an eye drop. A stabilizing method, which is a method of stabilizing dibutylhydroxytoluene in a liquid preparation containing (A) dibutylhydroxytoluene and (B) praprofen and / or a pharmaceutically acceptable salt thereof, which It is characterized by mixing (C) at least one kind selected from the group consisting of cromolyn, allantoin, glycyrrhizic acid, clofamine, and pharmaceutically acceptable salts thereof, and combining the aforementioned liquid The liquid agent is contained in a container having a container body part for storing the liquid agent, an injection part having an injection port for injecting the liquid agent contained in the container body part, and a lid part for sealing the injection port, and At least one of the inner space wall surface of the injection part and the wall surface opposite to the injection port of the lid part is composed of a resin containing polybutylene terephthalate. The stabilization method according to claim 7, wherein the injection part is a nozzle for injecting the liquid agent in the form of droplets, and the inner wall surface of the nozzle is composed of a resin containing polybutylene terephthalate . The stabilization method according to claim 7 or 8, wherein the container body is made of a resin containing polyethylene terephthalate. The stabilization method according to claim 7 or 8, wherein the aforementioned liquid agent further contains a boric acid buffer. The stabilization method according to claim 7 or 8, wherein in the aforementioned liquid preparation, the aforementioned (A) component contains 0.00001 ~ 0.005w / v%, and the aforementioned (B) component contains 0.005 ~ 0.5w / v%, and the aforementioned ( C) The composition contains 0.0005 ~ 5w / v%. The stabilization method according to claim 7 or 8, wherein the aforementioned liquid is an eye drop.