TW201617056A - Method for stabilizing dibutylhydroxytoluene - Google Patents

Abstract

The objective of the present invention is to provide a technique for increasing the thermal stability of dibutylhydroxytoluene and suppressing a decrease in the content thereof over time in a liquid drug that includes dibutylhydroxytoluene and pranoprofen and/or a salt thereof. By mixing, into the liquid drug that includes dibutylhydroxytoluene and pranoprofen and/or a salt thereof, at least one selected from the group consisting of cromoglycic acid, allantoin, glycyrrhizinic acid, chlorpheniramine, and pharmaceutically acceptable salts of these, and by employing a resin including polybutylene terephthalate as a resin that constitutes an inner wall surface (such as the wall surface of an interior space in a spout portion and/or a lid wall surface facing a spout opening in the spout portion) of an accommodating container, the thermal stability of the dibutylhydroxytoluene in the liquid drug can be increased, adsorption of the dibutylhydroxytoluene to the container can be suppressed, and a decrease in the dibutylhydroxytoluene content over time can be suppressed.

Description

Stabilization method of dibutylhydroxytoluene (1) Field of invention

The present invention relates to an article which maintains stability of dibutylhydroxytoluene in a liquid containing dibutylhydroxytoluene and pranoprofen and/or a salt thereof. Furthermore, the present invention relates to a method for stabilizing a liquid containing dibutylhydroxytoluene and pranoprofen and/or a salt thereof.

Background of the invention

In recent years, preparations having various efficacies have been developed in the fields of medicine, food, and cosmetics. In these preparations, in order to prevent oxidation of the contained components, the combination with the antioxidant is desired.

To date, dibutylhydroxytoluene (BHT) has been known as a representative compound of a fat-soluble antioxidant. 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, and In the field of cosmetics and other fields.

Further, there have been reports on preparation techniques using dibutylhydroxytoluene. For example, dibutylhydroxytoluene has been reported to stabilize pranoprofen and/or its salt (see Patent Document 1). However, in Patent Document 1, attention is paid to the stability of pranoprofen and/or its salt, and The stability of dibutylhydroxytoluene was not reviewed. In addition, it has been reported that the aqueous composition containing pranoprofen and/or its salt and dibutylhydroxytoluene has a low thermal stability, but it is possible to suppress yellowing by further mixing a sulfonamide (see Patent Document 2). . However, Patent Document 2 focuses on the yellowing inhibition of the aqueous composition, and does not review the stability of the dibutylhydroxytoluene itself.

On the other hand, in the fields of medicines, foods, cosmetics, and the like, a container equipped with a polyethylene nozzle as a storage preparation is generally used. However, it has been reported that a plastic container containing a polyethylene injection portion (nozzle, inner plug nozzle, opening inner plug, etc.) and a lid portion is once used to contain a solution containing dibutylhydroxytoluene. In the agent, dibutylhydroxytoluene in the liquid agent is adsorbed and accumulated in the above-mentioned injection portion (Patent Document 3). Therefore, it is reported in Patent Document 3 that a specific resin such as polybutylene terephthalate is used as a wall surface of a container constituting a liquid containing dibutylhydroxytoluene (the wall surface of the internal space of the injection portion and/or The resin in the wall portion of the lid portion opposite to the injection port of the injection portion can suppress the adsorption of dibutylhydroxytoluene on the inner wall surface and stably maintain the content of dibutylhydroxytoluene in the liquid preparation.

Advanced technical literature Patent literature

Patent Document 1: Japanese Patent Laid-Open Publication No. Hei 7-304670

Patent Document 2: Japanese Patent Laid-Open Publication No. 2011-98960

Patent Document 3: International Publication No. 2013/99861

Summary of invention

As a result of reviewing the practical use of a solution containing dibutylhydroxytoluene and pranoprofen and/or a salt thereof, the present inventors faced a new problem: if the liquid agent is contained in a currently used container In this case, the decrease in the content of dibutylhydroxytoluene over time can be quite significant. Further, Patent Document 2 reports that by mixing a sulfonamide agent, it is possible to improve the heat stability of an aqueous composition containing pranoprofen and/or a salt thereof and dibutylhydroxytoluene, and to suppress yellow of the aqueous composition. However, the yellowing of the aqueous composition is different from the thermal destabilization of the dibutylhydroxytoluene itself, and Patent Document 2 does not disclose a technique for improving the thermal stability of the dibutylhydroxytoluene itself.

Further, in the liquid preparation containing dibutylhydroxytoluene and pranoprofen and/or a salt thereof, the amount of dibutylhydroxytoluene added may be increased to compensate for the decrease in the amount of time, but The increase in the amount of the hydroxytoluene mixed is a cause of irritation when it is applied to a liquid preparation such as an eye drop, and thus it is not practical. Therefore, for a liquid preparation containing dibutylhydroxytoluene and pranoprofen and/or a salt thereof, it is necessary to develop a technique capable of suppressing a decrease in the content of dibutylhydroxytoluene.

Accordingly, an object of the present invention is to provide a technique for suppressing the decrease in the content of dibutylhydroxytoluene over time for a liquid preparation containing dibutylhydroxytoluene and pranoprofen and/or a salt thereof.

As a result of the development of the above-mentioned problems, the inventors of the present invention have found that the liquid is selected from the group consisting of dibutylhydroxytoluene and pranoprofen and/or a salt thereof. Glycolic acid, allantoin, At least one of the group consisting of glycyrrhizic acid, chlorpheniramine, and the like, and the container for containing is made of a resin containing polybutylene terephthalate as the inner wall surface of the container ( The resin in the inner space wall surface of the injection portion and/or the wall surface of the lid portion opposite to the injection port of the injection portion can improve the thermal stability of the dibutylhydroxytoluene in the liquid agent and suppress the dibutyl The adsorption of the hydroxytoluene on the container, and effectively suppressing the content thereof, is reduced over time. The present invention has been completed based on this knowledge and has been further reviewed.

That is, the present invention provides a dibutylhydroxytoluene-containing article and a stabilization method as disclosed below.

Item 1. A product containing dibutylhydroxytoluene, which comprises a liquid preparation comprising: (A) dibutylhydroxytoluene, (B) pranoprofen and/or a pharmaceutically acceptable salt thereof, (C) selected from the group consisting of cromolyn, allantoin, glycyrrhizic acid, chlorpheniramine, and the like, and at least one of the group consisting of The container includes a container body portion that accommodates the liquid agent, a dispensing portion that has a spout that can eject the liquid agent stored in the container body portion, and a lid portion that closes the spout port and the above-described note At least one of the inner space wall surface of the outlet portion and the wall surface of the lid portion facing the injection port is made of a resin containing polybutylene terephthalate.

Item 2. The product containing dibutylhydroxytoluene according to Item 1, wherein the injection portion is a nozzle for injecting the liquid agent in a droplet shape, and the inner space wall surface of the nozzle is poly(p-phenylene) Resin structure of butylene dicarboxylate to make.

Item 3. The product containing dibutylhydroxytoluene according to Item 1 or 2, wherein the container body portion is made of a resin containing polyethylene terephthalate.

The dibutylhydroxytoluene-containing article according to any one of items 1 to 3, wherein the liquid agent further comprises a boric acid buffer.

The dibutylhydroxytoluene-containing product according to any one of items 1 to 4, wherein the component (A) contains 0.00001 to 0.005 w/v%, and the component (B) It contains 0.005 to 0.5 w/v%, and the above component (C) contains 0.0005 to 5 w/v%.

The dibutylhydroxytoluene-containing article according to any one of items 1 to 5, wherein the liquid agent is an eye drop.

Item 7. A method for stabilizing a dibutylhydroxytoluene containing (A) dibutylhydroxytoluene and (B) pranoprofen and/or a pharmaceutically acceptable salt thereof The method, characterized in that the liquid mixture (C) is at least one selected from the group consisting of pharmaceutically acceptable salts of cromolyn, allantoin, glycyrrhizic acid, chlorpheniramine, and the like, Further, the liquid agent is housed in a container body portion containing a liquid agent, a discharge portion having a discharge port for discharging a liquid agent accommodated in the container body portion, and a cover for sealing the discharge port At least one of the inner space wall surface of the injection portion and the wall surface of the lid portion facing the injection port is made of a resin containing polybutylene terephthalate.

The stabilization method according to Item 7, wherein the injection portion is a nozzle for injecting the liquid agent in a droplet shape, and the inner space wall surface of the nozzle is containing polybutylene terephthalate. Made of resin.

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

The stabilization method according to any one of items 7 to 9, wherein the liquid agent further comprises a boric acid buffer.

The stabilization method according to any one of items 7 to 10, wherein, in the liquid preparation, the component (A) contains 0.00001 to 0.005 w/v%, and the component (B) contains 0.005 to 0.5. w/v%, and the aforementioned component (C) contains 0.0005 to 5 w/v%.

The stabilization method according to any one of items 7 to 11, wherein the liquid agent is an eye drop.

According to the present invention, it is possible to improve the thermal stability of dibutylhydroxytoluene and the adsorption inhibition property to the container while containing dibutylhydroxytoluene and pranoprofen and/or a salt thereof, and to stabilize Maintain the content of dibutylhydroxytoluene.

Further, in eye drops, nasal drops, and the like, dibutylhydroxytoluene is set to a low level close to the threshold amount required to exert an antioxidant action, and in the prior art, with pranoprofen and/or When the salt or the salt thereof is coexisted, the thermal stability of dibutylhydroxytoluene is remarkably lowered, and the loss of the antioxidation effect tends to be remarkable due to the decrease in the content. In contrast, according to the present invention, the disadvantages of such prior art can be overcome, in liquid medicines such as eye drops or nose drops, even When dibutylhydroxytoluene is coexisted with pranoprofen and/or a salt thereof, the amount of dibutylhydroxytoluene and its salt can be effectively suppressed, and the antioxidant effect in the liquid preparation can be effectively maintained.

1‧‧‧Container body

2‧‧‧Note Department

3‧‧‧ Cover

4‧‧‧Extracted internal space

5‧‧‧Drawing the wall of the internal space of the Ministry

6‧‧‧The wall opposite the injection opening of the injection section in the cover

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a cross-sectional view showing an example of a state of the eye container used in the present invention.

Figure 2 is a partially enlarged cross-sectional view showing the eyedrop container of Figure 1.

Fig. 3 is a cross-sectional view showing an example of a state of the eye container used in the present invention.

Fig. 4 is a cross-sectional view showing an example of a state of the eye container used in the present invention.

Figure 5 shows a partially enlarged cross-sectional view of the eyedrop container shown in Figure 4.

Fig. 6 is a cross-sectional view showing an example of a state of the eye wash container used in the present invention.

Detailed description of the preferred embodiment

In the present specification, "stabilization" or "stability" of dibutylhydroxytoluene means suppressing the decrease in the content of the liquid in the liquid by decomposing dibutylhydroxytoluene or adsorbing the container, and the like. Keep this content stable, or such a property. In the present specification, the "thermal stability" of dibutylhydroxytoluene means a property of suppressing decomposition of dibutylhydroxytoluene by heat. In the present specification, the "product containing dibutylhydroxytoluene" means a liquid containing a component (A) to (C) described below and stored in a container, and is also referred to as "a BHT-containing product". In addition, in the present specification, the unit "w/v%" refers to the percentage of mass to volume in the sixteenth revised Japanese Pharmacopoeia, which is synonymous with g/100mL.

1. Containing BHT products

The BHT-containing product of the present invention is characterized in that it is empty inside the injection portion The wall surface of the partition wall and/or the lid portion opposite to the injection port of the injection portion is a container made of a resin containing polybutylene terephthalate, and contains a liquid agent containing the following: (A) Butyl hydroxytoluene, (B) pranoprofen and/or its pharmaceutically acceptable salt, and (C) are selected from the group consisting of cromolyn, allantoin, glycyrrhizic acid, chlorpheniramine and the like. At least one of the groups consisting of the allowed salts. Hereinafter, the BHT-containing product of the present invention will be described in detail.

Liquid agent

In the BHT-containing product of the present invention, the liquid agent contained in the container contains dibutylhydroxytoluene (also referred to as component (A)). Dibutylhydroxytoluene is also known as 2,6-di-t-butyl-4-methylphenol, BHT, DBPC, etc., and is a compound well known as an antioxidant. In the liquid preparation, dibutylhydroxytoluene is a component which exhibits an antioxidant effect in the liquid preparation while improving the thermal stability of pranoprofen and/or a salt thereof, and also contributes to the visual effect. The stability of the pharmacological ingredients or additives that need to be added is improved.

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

The liquid preparation used in the present invention further contains pranoprofen and/or a salt thereof (also referred to as a component (B)). In the liquid preparation, pranoprofen and/or a salt thereof is obtained by using dibutylhydroxytoluene to improve light stability.

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

Further, the salt of pranoprofen is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include a metal salt such as a sodium salt, a potassium salt, a calcium salt, a magnesium salt or an aluminum salt; and a triethylamine salt; Diethylamine salt, whallin salt, piperazine An organic salt or the like such as a salt. These salts of pranoprofen may be used singly or in combination of two or more.

In the liquid preparation to be used in the present invention, one type of pranoprofen and a salt thereof may be used alone or two or more types may be used in combination. However, in the component (B), it is preferably as pranoprofen.

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

The liquid preparation used in the present invention further comprises at least one selected from the group consisting of pharmaceutically acceptable salts of cromolyn, allantoin, glycyrrhizic acid, chlorpheniramine, and the like (also indicated As component (C)). The liquid preparation used in the present invention can be significantly reduced in the presence of pranoprofen and/or a salt thereof by mixing the component (C) and storing it in a specific container to be described later. Effectively suppressed.

Chromic acid, also known as 5,5'-[(2-hydroxy-1,3-propanediyl) bisoxy) bis(4-oxooxy-4H-1-benzopipene-2-carboxylic acid), CROMOLYN and DSCG are well-known compounds which are also used for the purpose of anti-allergic or anti-inflammatory.

The salt of the cromolyn is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include an alkali metal salt such as a sodium salt or a potassium salt; an alkaline earth metal salt such as a calcium salt or a magnesium salt. Among the salts of such cromolic acids, alkali metal salts It is better, and the sodium salt is better. These salts of cromolic acid may be used singly or in combination of two or more.

Further, cromolyn and/or a salt thereof can also be used in the form of a hydrate.

Allantoin, also known as 5-ureidohydantoin, is also a well-known compound used for the purpose of anti-allergy, anti-inflammatory, promotion of granulation formation, promotion of tissue repair and the like.

The salt of allantoin is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include bishydroxyaluminum allantoin and chlorohydrin allantoin. These salts of allantoin may be used singly 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 Aldehyde]oxy]-11-sideoxy-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 known compound which is also used for anti-allergic or anti-inflammatory purposes.

The salt of glycyrrhizic acid is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include an alkali metal salt such as a sodium salt or a potassium salt; an alkaline earth metal salt such as a calcium salt or a magnesium salt; and an ammonium salt. Among these salts of glycyrrhizic acid, an alkali metal salt is preferred, and a potassium salt is more preferred. These salts of glycyrrhizic acid may be used singly or in combination of two or more.

Chlorpheniramine, also known as 3-(4-chlorophenyl)-N,N-dimethyl-3-pyridin-2-yl-propan-1-amine, is also used for antihistamine purposes. Public knowledge Compound.

The salt of chlorpheniramine is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include organic acid salts such as maleate and fumarate; and inorganic acid salts such as hydrochloride and sulfate. Among these salts of chlorpheniramine, maleate is preferred.

Further, the chlorpheniramine and/or its salt may be in the form of a solvate such as a hydrate, or may be either a d-form or a d-form.

In the liquid preparation used in the present invention, one of the pharmaceutically acceptable salts of cromolyn, allantoin, glycyrrhizic acid, chlorpheniramine, and the like may be selected as the component (C), and may be used alone. Two or more types may be used in combination. Further, among these components (C), from the viewpoint of continuously suppressing the content of dibutylhydroxytoluene to be low and exhibiting an excellent antiallergic action, for example, cromolyn, allantoin, and glycyrrhizin are preferred. And pharmaceutically acceptable salts thereof, and preferably cromolyn and a pharmaceutically acceptable salt thereof, more preferably a pharmaceutically acceptable salt of cromolyn, particularly preferably sodium cromolyn.

In the liquid preparation used in the present invention, the content of the component (C) is, for example, 0.0005 to 5 w/v%, and preferably 0.001 to 2 w/v%. More specifically, the content of various components of the component (C) is as follows.

In the case of using cromolyn and/or a salt thereof, it is preferably 0.1 to 5 w/v%, more preferably 0.5 to 3 w/v%, and particularly preferably 1 to 2 w/v%.

When using allantoin and/or a salt thereof, it is preferably 0.01 to 1 w/v%, more preferably 0.03 to 0.5 w/v%, and particularly preferably 0.06 to 0.3 w/v%.

When glycyrrhizic acid and/or a salt thereof is used, it is preferably 0.005 to 1 w/v%, more preferably 0.01 to 0.5 w/v%, and particularly preferably 0.05 to 0.25 w/v%.

When chlorpheniramine and/or its salt is used, it is preferably 0.0005 to 1 w/v%, more preferably 0.001 to 0.1 w/v%, and particularly preferably 0.006 to 0.03 w/v%.

The liquid preparation used in the present invention may contain a buffering agent in addition to the above components (A) to (C) in order to have a buffering action. The buffering agent is not particularly limited, and examples thereof include a boric acid buffer, a phosphate buffer, a citrate buffer, a tartaric acid buffer, an acetate buffer, a Tris buffer, an amino acid (glutamic acid, etc.), and the like. These buffers may be used alone or in combination of two or more. Among these buffers, the boric acid buffer has a buffering energy in a pH range in which pranoprofen and/or a salt thereof can be dissolved, and is suitable for use in the present invention.

The content of the buffer in the liquid preparation used in the present invention may be appropriately set in accordance with the kind of the buffer to be used in a range capable of providing a desired buffering effect, and may be, for example, 0.001 to 5 w/v%, preferably such as 0.05~3w/v%, more preferably 0.1~2w/v%.

Further, the liquid preparation used in the present invention may contain a chelating agent in addition to the above components. By containing a chelating agent, it is possible to further effectively suppress the decrease in the content of dibutylhydroxytoluene.

Specific examples of the chelating agent include ethylenediaminetetraacetic acid, citric acid, succinic acid, ascorbic acid, trishydroxymethylaminomethane, nitrogen triacetic acid, and 1-hydroxy-ethane-1,1-diphosphonic acid. a pharmaceutically acceptable salt of polyphosphoric acid, metaphosphoric acid, hexametaphosphoric acid, or the like. 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, ethylenediaminetetraacetic acid and a pharmaceutically acceptable salt thereof are preferable. Also, the drug of ethylenediaminetetraacetic acid The salt which is acceptable for the study may, for example, be an alkali metal salt such as a sodium salt or a potassium salt; an alkaline earth metal salt such as a calcium salt or a magnesium salt.

In the case where the liquid preparation used in the present invention contains a chelating agent, the content thereof may be appropriately set depending on the use of the liquid agent, etc., and 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 a pharmacological ingredient in addition to the above components, depending on the use of the liquid preparation. The pharmacological component to be used is not particularly limited, and can be suitably selected, for example, from the following conventional pharmacological ingredients: vasoconstrictor, anticholinesterase inhibitor, anti-inflammatory agent, corneal epithelial disorder therapeutic drug, anti-inflammatory analgesic drug. Chemotherapeutics, antibiotics, antivirals, hormones, vitamins, amino acids, anti-cataracts, angiogenesis inhibitors, immunosuppressants, protease inhibitors, aldose reductase inhibitors, antihistamines, antiallergic Agent, anti-anxiety agent, antipsychotic drug, antibiotic, antitumor agent, antihyperlipidemic drug, antitussive expectorant, muscle relaxant, antiepileptic drug, antiulcer drug, antidepressant, cardiotonic, arrhythmia therapeutic agent , vasodilators, hypertension diuretics, diabetes treatment agents, anti-tuberculosis drugs, anesthetic antagonists, skin disease medications, dental oral medications, diagnostic medications, public health medications, etc.

Among these pharmacological ingredients, when it is a preparation for ophthalmology or otolaryology such as an eye drop, an eye wash, a nasal spray, or an ear lotion, specifically, the following components may be mentioned: ε-amino group Caproic acid, bromfenac, ketorolac tromethamine, nepafenac, berberine chloride, berberine sulfate, sodium sulfonate, sulfuric acid Anti-inflammatory agents such as zinc, zinc lactate, lysozyme hydrochloride; antihistidines such as bishydroxyhydroxylamine hydrochloride; Ketotifen Fumarate, Acitazanolast, Alemsino Anti-allergic agents (amlexanox), Pemirolast Potassium, Tranilast, Ibudilast, etc.; Norfloxacin, ofloxacin, Antibacterial agents such as lomefloxacin, levofloxacin, gentamicin, gatifloxacin; ascorbic acid, flavin adenine dinucleotide sodium, cyanocobalamin, pyridoxine hydrochloride , tocopherol acetate, retinol acetate, retinyl palmitate, ubiquinol, calcium pantothenate, sodium pantothenate and other vitamins; aspartic acid, taurine, chondroitin sulfate and other amines Anti-cholinesterase agents such as neostigmine methyl sulfate; naphazoline, tetrahydrozole, epinephrine, ephedrine, phenylephrine, dl- Vasoconstrictor such as methyl ephedrine; therapeutic agent for isotonic conjunctival epithelial barrier of sodium hyaluronate; sulfadi Azine), sulfisoxazole, sulfisomidine, sulfadimethoxine, sulfamethoxypyridazine, sulfamethoxazole, sulfaethidole , sulfamethomidine, sulfaphenazole, sulfaguanidine, phthalylsulfathiazole, sulfonamide such as succinylsulfathiazole. The compounds exemplified herein are limited to pharmaceutically acceptable, and may be in the form of a salt or in the form of other salts.

The content of the pharmacological components can be appropriately set depending on the type of the pharmacological component or the use of the liquid preparation.

Further, the liquid preparation used in the present invention may contain, in addition to the above components, an isotonic agent, a dissolution aid, a binder, a cooling agent, a pH adjuster, a preservative, a stabilizer, and the like. Additives such as surfactants.

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

Examples of the dissolution aid include polyoxyethylene sorbitan monooleate, polyoxyethylene hydrogenated castor oil, tetrabutyl phenol, and non-ionic surfactants such as PLURONIC®; glycerin and polyethylene glycol (macrogol). Such as polyols and the like. These dissolution aids may be used alone or in combination of two or more.

Examples of the adhesive base include polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, carboxyvinyl polymer, xanthan gum, sodium chondroitin sulfate, alginic acid or a salt thereof, sodium hyaluronate, and the like. Water-soluble polymer; hypromellose, hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, etc. . These viscous 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 in combination. The above combination is used.

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

As the preservative, for example, sorbic acid or a salt thereof, benzoic acid or a salt thereof, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, chlorobutanol, 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), and the like. 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, tocopherol, and the like. These stabilizers may be used alone or in combination of two or more.

As the surfactant, for example, tetrabutyl phenol (tyloxapol), polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, octoxynol (octoxynol) And other nonionic surfactants; alkyldiamine ethylglycine, amphoteric dimethylaminoacetic acid betaine and other amphoteric surfactants; alkyl sulfates, N-mercapto taurates, polyoxygen An anionic surfactant such as a vinyl alkyl ether phosphate or a polyoxyethylene alkyl ether sulfate; a cationic surfactant such as an alkylpyridinium salt or an alkylammonium salt. These surfactants can also be used alone or in combination. It can be used in combination of 2 or more types.

The concentration of these additives can be appropriately set depending on the type of the additive or the use of the liquid agent.

The form of the liquid preparation to be used in the present invention may be any one of aqueous solution, suspension, and emulsion, and may be, for example, an aqueous solution.

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

The use of the liquid preparation used in the present invention is not particularly limited, and examples thereof include medicines and contact lens care products. In the case of medicine, for example, eye drops (including eye drops for contact lenses which can also be used when wearing contact lenses), eye drops such as eye drops, and ear and nose such as nose drops and ear drops can be used. Liquid for use in the department; internal preparation, injection, external preparation, etc. Further, as the contact lens care product, specifically, a contact lens mounting liquid, a multifunctional solution for contact lenses, and the like can be given. Among these liquid preparations, preferred are ophthalmic liquid preparations, oto-nasal liquid preparations, and contact lens care products, and more preferred are eye drops.

Further, the liquid preparation used in the present invention can be filled in a multi-dose type container (that is, it can be used repeatedly by filling a plurality of portions), or can be filled in a single-dose type container which is used up once.

The liquid preparation to be used in the present invention may be produced according to a conventionally known preparation method depending on its form, use, and the like. For example, it may be prepared by mixing the components in an aqueous base such as water or physiological saline. For example, in medicine In the case of the case, it can be produced by the method described in the general provisions of the sixteenth revised Japanese Pharmacopoeia preparation.

container

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

<Construction of container>

The container body portion constituting the container is a portion for accommodating the liquid agent. The shape and size of the container main body portion are not particularly limited, and can be appropriately set depending on the type and capacity of the liquid agent to be contained.

The injection portion constituting the container is a portion having an internal space for communicating between the container body portion and the outside of the container, and a discharge port for discharging the liquid agent contained in the container body portion, the above-mentioned note The outlet is provided to communicate with the opening of the container body portion, and the liquid agent contained in the container body portion passes through the internal space and is discharged from the injection port to the outside of the container (discharge). The pouring portion is configured to be capable of pouring the liquid agent contained in the container body portion from the injection port to the outside of the container, and is not particularly limited in structure. For example, the liquid can be configured to The droplets are injected, or configured to flow out the liquid in a non-droplet form. From the viewpoint of further achieving the effects of the present invention, it is preferable that the above-mentioned injection portion is configured as a nozzle which can eject the liquid agent in a droplet form. Further, for the injection portion, for example, an inner plug such as an inner lid nozzle or a porous inner lid may be provided.

Part or all of the aforementioned injection portion may also be with the container body portion One-piece molding. Further, the injection portion may be disposed to be inserted into the inner cavity of the opening of the container main body or to be disposed outside the container.

Further, the lid portion constituting the container is a portion that closes the injection port. The lid portion may have a structure that fits into the container body portion and/or the injection port. More specifically, in the case where the BHT-containing product of the present invention is of a multi-dose type, it may be a fitting structure capable of attaching and detaching the container body portion and/or the injection port; and the BHT-containing article of the present invention is a single-dose type. In this case, it may be a fitting structure that can be detached from the container body portion and/or the detachment. A preferred example of the fitting structure capable of attaching and detaching the container main body portion and/or the injection port is a cover portion that is detachably attached to the container main body portion and/or the injection portion by screw fitting. When the cover portion and the container body portion and/or the injection portion are detachably assembled by screw fitting, the cover portion may be provided with a screw body portion of the container body portion and/or the injection portion. The screw part.

The shape of the container can be appropriately set in accordance with the use of the BHT-containing product contained therein. Specifically, an eye-drop container, an eye-washing container, a nose-nose container, etc. are mentioned.

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

1 is a cross-sectional view showing one aspect of an eye container; and FIG. 2 is a partially enlarged cross-sectional view showing the eye container shown in FIG. 1. In the eyedrop container shown in Fig. 1, a discharge portion 2 capable of injecting the liquid material in a droplet shape 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 The container body 1 is detachably attached to the container body 1 and the injection port of the injection unit 2 is closed. In the eye container, the liquid agent that has been accommodated in the container body portion 1 passes through the interior of the dispensing portion 2 The gap 4 is injected from the injection outlet to the outside of the container. The eyedrop container shown in Fig. 1 can also be used for accommodating a single-dose type liquid, but is suitable for containing a multi-dose type liquid agent.

Figure 3 is a cross-sectional view of one aspect of an eye container. In the eyedrop container shown in Fig. 3, the container body portion 1 and the dispensing portion 2 are integrally formed of the same material without using the subsequent or mechanical joining, and the liquid agent can be passed through the internal space 4 of the dispensing portion 2. The injection port is sprayed out of the container to the outside of the container. In Fig. 3, the cover portion is omitted, and an imaginary line (dashed line) is inserted for the sake of convenience. In the eyedrop container shown in Fig. 3, the container member below the imaginary line corresponds to the container body portion 1, and the container portion above the imaginary line corresponds to the dispensing portion 2. The eye-drop container shown in Fig. 3 can also be used for accommodating a single-dose type liquid, but is suitable for containing a multi-dose type liquid agent.

4 is a cross-sectional view showing one aspect of an eye container; and FIG. 5 is a partially enlarged cross-sectional view of the eye container shown in FIG. 4. In the eye drop shown in Fig. 4, the container body portion 1, the injection portion 2, and the lid portion 3 are integrally formed. The injection portion 2 and the lid portion 3 are connected to each other, and the liquid agent accommodated in the container body 1 can be passed through the internal space 4 of the injection portion 2 from the injection port by being disconnected during use. Mark out to the outside of the container. In Figures 4 and 5, an imaginary line (dashed line) is inserted for the sake of cheapness. In FIGS. 4 and 5, the container member between the two imaginary lines corresponds to the dispensing portion 2, and the space between the two imaginary lines corresponds to the internal space 4 of the dispensing portion 2. The eyedrop container shown in Figure 4 is suitable for containing a single dose type of liquid.

Figure 6 is a cross-sectional view of the eyewash container. In the eyewash container shown in Fig. 6, one portion of the container body portion 1 and the dispensing portion 2 is integrally formed. In the wash In the eye container, the liquid agent contained in the container main body portion 1 is injected from the injection port to the outside of the container through the internal space 4 of the injection portion 2. In Fig. 6, for the sake of cheapness, an imaginary line (dashed line) is inserted.

1 to 6, the specific aspects of the eye-drop container and the eye-washing container are listed, but the present invention is not limited to such a structure or shape, and even a container other than the eye-eye container and the eye-washing container has the above-described characteristics. be usable.

<Construction material of container>

At least one of the containers described above is composed of a resin containing polybutylene terephthalate (PBT): a wall surface of the inner space of the injection portion, and a wall surface opposite to the injection port in the lid portion . Here, the "wall surface of the lid portion facing the injection port" corresponds to an inner wall portion of the lid portion that closes the discharge port when the lid portion is attached to the container body portion and/or the injection portion. Specifically, in the case of FIG. 2, the surface portion indicated by the reference numeral 5 corresponds to the "wall surface of the internal space of the injection portion", and the surface portion indicated by the symbol 6 corresponds to "the cover portion is opposed to the above-mentioned injection port. The wall."

The wall surface of the internal space of the injection portion and/or the wall surface of the lid portion opposite to the injection port of the injection portion by the resin containing polybutylene terephthalate, and the liquid material used for the liquid preparation The specific components complement each other, that is, the adsorption and accumulation of the distillate portion and/or the lid portion of the dibutylhydroxytoluene can be effectively suppressed, 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 inner space of the injection portion and/or the wall surface of the lid portion facing the injection port of the injection portion) may be composed of polybutylene terephthalate alone. Polyterephthalic acid The admixture of butadiene ester and other polymers. The resin constituting the wall surface (that is, the wall surface of the inner space of the injection portion and/or the wall surface of the lid portion facing the injection port of the injection portion) is made of polybutylene terephthalate and other polymers. In the case of blending the polymer, the mixing ratio of the polymer is not particularly limited as far as the effect of the present invention is attained, but it is desirable that the polybutylene terephthalate is based on the total amount of the blended polymer. The diester is 50 w/w% or more, preferably 60 w/w% or more, preferably 70 w/w% or more, more preferably 80 w/w% or more, and particularly preferably 90 w/w% or more.

In the container, any one of the wall surface of the internal space of the injection portion and/or the wall surface of the lid portion facing the injection port of the injection portion may contain polybutylene terephthalate. For example, if a dispensing portion for ejecting a liquid droplet in the form of a droplet (for example, a nozzle configured to drop a droplet in a droplet shape) is used, the content of dibutylhydroxytoluene can be more effectively suppressed. From the viewpoint of low reduction, it is preferable that the wall surface of at least the inner space of the injection portion is made of a resin containing polybutylene terephthalate, preferably a wall surface of the inner space of the injection portion, and a lid portion The opposite wall of the outlet of the outlet is made of a resin containing polybutylene terephthalate. Further, when the injection portion for discharging the liquid agent in a non-droplet form is used, for example, it is preferable to reduce the content of dibutylhydroxytoluene more effectively, and it is preferable that at least the lid portion and the injection portion are The opposite wall surface of the injection port is made of a resin containing polybutylene terephthalate, and more preferably, the wall surface of the inner space of the injection portion is opposite to the wall surface of the lid portion opposite to the injection port of the injection portion. It is composed of a resin of polybutylene terephthalate.

As long as the wall of the internal space of the injection part, and/or the cover part The wall surface of the injection portion facing the outlet of the injection portion may be composed of a resin containing polybutylene terephthalate, and the portions other than the wall surfaces are not particularly limited as to the constituent materials. For example, the portion other than the wall surface may be composed of a resin containing polybutylene terephthalate or a material other than polybutylene terephthalate.

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

Further, in the container, the injection portion is inserted into the inner cavity of the opening of the container main portion, or the injection portion is attached to the outer side of the opening of the container main portion, the container main portion is It can be made of glass or plastic, but it is usually made of plastic. In the case of the container of the aspect, when the main body portion of the container is made of plastic, the type of the resin forming the main portion of the container is not particularly limited, and examples thereof include polyethylene terephthalate and poly-pair. Butylene phthalate, polystyrene, acrylonitrile-butadiene-styrene, and the like. Among them, polyethylene terephthalate has a good formability and can suppress the adsorption of dibutylhydroxytoluene, so that it is suitable to use a resin which forms a container main portion.

2. Stabilization method

A method for stabilizing dibutylhydroxytoluene of the present invention, which comprises mixing in a liquid preparation containing (A) dibutylhydroxytoluene, (B) pranoprofen and/or a pharmaceutically acceptable salt thereof (C) at least one selected from the group consisting of pharmaceutically acceptable salts of cromolyn, allantoin, glycyrrhizic acid, chlorpheniramine, and the like, and the aforementioned liquid agent (ie, containing dibutyl) Hydroxytoluene preparation) In the container, the wall surface of the internal space of the injection portion and/or the wall surface of the lid portion facing the injection port of the injection portion is a container made of a resin containing polybutylene terephthalate.

In the stabilization method of the present invention, the type or content of the components (A) to (C) contained in the liquid preparation, the content of other types which can be combined with the synthetic component, and the use of the liquid preparation are used in combination with the above-mentioned use in the presence of BHT. The case of the liquid preparation of the product is the same. Further, the container used in the stabilization method of the present invention is also the same as the container used in the above-mentioned BHT-containing product.

The stabilization method of the present invention is directed to a liquid preparation containing dibutylhydroxytoluene and pranoprofen and/or a salt thereof, which improves the thermal stability of dibutylhydroxytoluene and simultaneously suppresses dibutylhydroxytoluene The adsorption of the container can effectively suppress the content of dibutylhydroxytoluene and reduce the storage stability of dibutylhydroxytoluene, so that it can be carried out as a method for preserving the liquid agent.

Example

The invention is specifically illustrated by the following examples, but the invention is not limited by the examples.

Test Example 1: Evaluation of the change over time of dibutylhydroxytoluene content

The liquid preparation shown in Table 2 was prepared, and the change in the content of dibutylhydroxytoluene which was stored in various containers was measured over time. Specifically, the liquid materials shown in Table 2 were prepared by the usual methods, and they were housed in the respective containers shown in Table 1 and sealed, and allowed to stand for 2 weeks under the conditions of 40 ° C, 75% RH, and light-shielding, and stored. At this time, in the case of the containers 2 and 3, the liquid storage capacity is set to 10 mL; In the case of the container 1, the liquid storage capacity was set to 5 mL. Further, in the case of the containers 2 and 3, the container is placed in an upright state so that the lid portion is the upper surface and the bottom portion of the container body portion is below. Before the start of storage, one week after the start of storage and two weeks later, 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, thereby evaluating two. Thermal stability of butyl hydroxytoluene. The stability of dibutylhydroxytoluene is specifically calculated as the ratio of the content of dibutylhydroxytoluene after storage to the content of dibutylhydroxytoluene before storage as a residual ratio (%). Further, the container 3 is an example of a currently used eye-point container. Further, it is known that glass is less likely to adsorb a general drug, and therefore, the container 1 is an example of a container which does not easily adsorb dibutylhydroxytoluene.

The results obtained are shown in Table 2. As indicated by the results of the control group, it was found that once dibutylhydroxytoluene and pranoprofen were coexisted in the liquid, the decrease in the content of dibutylhydroxytoluene was remarkable. Further, if dipyridylhydroxytoluene and pranoprofen are combined with naphthylpyrazine hydrochloride or neostigmine methyl sulfate, it is confirmed that it cannot sufficiently inhibit dibutylation. The low content of the hydroxytoluene content, or vice versa, led to a further decrease in the dibutylhydroxytoluene content (Comparative Examples 1 and 2). In contrast, dibutyl hydroxytoluene and pranoprofen were combined with sodium cromoglycate, allantoin, dipotassium glycyrrhizinate or chlorpheniramine maleate, and contained in polyphenylene terephthalate. The liquid agent in the container 2 of the 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 the change over time of dibutylhydroxytoluene content

The liquid materials shown in Tables 3 and 4 were prepared by the usual methods, and stored in the respective containers 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 measured values, the residual ratio of dibutylhydroxytoluene was calculated in the same manner as in the above Test Example 1. (%).

The results obtained are shown in Tables 3 and 4. It is clear from the results that in Comparative Examples 3 to 16, the reduction in the content of dibutylhydroxytoluene which occurs when dibutylhydroxytoluene and pranoprofen are coexisted, or the dibutyl group is not sufficiently suppressed. The hydroxytoluene content is even lower. That is, from the results, it was confirmed that the inhibitory effect of dibutylhydroxytoluene content which occurs when dibutylhydroxytoluene and pranoprofen coexist is selected by selecting cromolyn, allantoin, glycyrrhizic acid And / or its salt and mix it to show the unique effect.

Table 4

1‧‧‧Container body

2‧‧‧Note Department

3‧‧‧ Cover

Claims (12)

A product containing dibutylhydroxytoluene, characterized in that the product comprises a liquid agent contained in a container, the liquid agent comprising: (A) dibutylhydroxytoluene, (B) pranoprofen and / or a pharmaceutically acceptable salt thereof, (C) is at least one selected from the group consisting of cromolyn, allantoin, glycyrrhizic acid, chlorpheniramine, and the like, and a pharmaceutically acceptable salt thereof, Further, the container includes a container main portion accommodating the liquid agent, and a dispensing portion having a spout that can be used to discharge the liquid agent contained in the main body of the container, and a lid portion that closes the spout, and At least one of the inner space wall surface of the injection portion and the wall surface of the lid portion facing the injection port is made of a resin containing polybutylene terephthalate. The product containing dibutyl hydroxytoluene according to claim 1, wherein the injection portion is a nozzle for injecting the liquid agent in a droplet shape, and the inner space wall surface of the nozzle is composed of polybutylene terephthalate It is composed of an ester resin. The article containing dibutylhydroxytoluene according to claim 1 or 2, wherein the container body portion is composed of a resin containing polyethylene terephthalate. The dibutylhydroxytoluene-containing article according to any one of claims 1 to 3, wherein the liquid agent further comprises a boric acid buffer. The product containing dibutylhydroxytoluene according to any one of claims 1 to 4, In the liquid preparation, the component (A) contains 0.00001 to 0.005 w/v%, the component (B) contains 0.005 to 0.5 w/v%, and the component (C) contains 0.0005 to 5 w/v%. The dibutylhydroxytoluene-containing article according to any one of claims 1 to 5, wherein the liquid agent is an eye drop. A method for stabilizing dibutylhydroxytoluene containing (A) dibutylhydroxytoluene and (B) pranoprofen and/or a pharmaceutically acceptable salt thereof, which is stabilized And characterized in that the mixture (C) in the liquid agent is at least one selected from the group consisting of pharmaceutically acceptable salts of cromolyn, allantoin, glycyrrhizic acid, chlorpheniramine, and the like, and the foregoing The liquid agent is housed in a container body portion that houses the liquid agent, a discharge portion that has a discharge port for discharging the liquid agent stored in the container body portion, and a lid portion that closes the injection port, and At least one of the inner space wall surface of the injection portion and the wall surface facing the injection port in the lid portion is made of a resin containing polybutylene terephthalate. The stabilization method according to claim 7, wherein the injection portion is a nozzle for injecting the liquid agent in a droplet shape, and the inner space wall surface of the nozzle is composed of a resin containing polybutylene terephthalate. . The method of stabilizing the item 7 or 8, wherein the container body portion is made of a resin containing polyethylene terephthalate. The method of stabilizing according to any one of claims 7 to 9, wherein the liquid agent further comprises a boric acid buffer. The stabilization method according to any one of claims 7 to 10, wherein, in the liquid agent, the component (A) contains 0.00001 to 0.005 w/v%, and the component (B) contains 0.005 to 0.5 w/v%. And the component (C) contains 0.0005 to 5 w/v%. The method of stabilizing according to any one of claims 7 to 11, wherein the liquid agent is an eye drop.