TW201540292A - 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 item selected from the group consisting of a chondroitin sulfate ester, aspartic acid, alginic acid, an alginic acid derivative, pharmaceutically acceptable salts of these, cyanocobalamin, panthenol, a tocopherol, and a tocopherol derivative, 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 (2) 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. Butteryl hydroxyanisole is also known as a fat-soluble antioxidant. However, compared with other fat-soluble antioxidants, dibutylhydroxytoluene has a strong antioxidation effect, so it is widely used in medicine, food, and cosmetics. In the field.

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 present inventors have found that a mixture of dibutylhydroxytoluene and pranoprofen and/or a salt thereof is selected from chondroitin. Sulfate, day At least one of a group consisting of aspartic acid, alginic acid, a derivative of alginic acid, a pharmaceutically acceptable salt thereof, a cyanocobalamin, a panthenol, a reproductive phenol, and a reproductive phenol derivative, and is contained in a group The container is made of a resin containing polybutylene terephthalate as a resin constituting the inner wall surface of the container (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), that is, The adsorption stability of the dibutylhydroxytoluene to the container can be suppressed while the thermal stability of the dibutylhydroxytoluene in the liquid agent is increased, and the content is effectively suppressed 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 is obtained by accommodating a liquid agent in a container, which comprises: (A) dibutylhydroxytoluene, (B) Pula洛芬 and/or its pharmaceutically acceptable salt, (C) is selected from the group consisting of chondroitin sulfate, aspartic acid, alginic acid, derivatives of alginic acid, pharmaceutically acceptable salts thereof, cyanocobalamin At least one of the group consisting of panthenol, reproductive phenol, and a reproductive phenol derivative, and the container has a container body portion that houses the liquid agent, and a dispensing portion that can be housed in the container body a liquid injection outlet of the liquid portion, and a lid portion that seals the injection port, and the inner space wall surface of the injection portion and the cover portion and the aforementioned note At least one of the opposite wall surfaces of the outlet is composed of a resin containing polybutylene terephthalate.

Item 2. The dibutylhydroxytoluene-containing article of item 1, wherein the liquid agent further comprises taurine.

Item 3. The product containing dibutylhydroxytoluene according to Item 1 or 2, wherein the above-mentioned injection portion is a nozzle for injecting the liquid agent in a droplet shape, and the inner space wall surface of the nozzle is a poly(p-phenylene) It is composed of a resin of butylene dicarboxylate.

The dibutylhydroxytoluene-containing article according to any one of items 1 to 3, wherein the container body portion is composed of a polyethylene terephthalate-containing resin.

The dibutylhydroxytoluene-containing article according to any one of items 1 to 4, wherein the liquid agent further contains a boric acid buffer.

The dibutylhydroxytoluene-containing product according to any one of items 1 to 5, wherein the component (C) is selected from the group consisting of chondroitin sulfate, aspartic acid, and the like. And at least one of the group consisting of cyanocobalamin.

The dibutylhydroxytoluene-containing product according to any one of items 1 to 6, wherein the component (C) comprises chondroitin sulfate and/or a pharmaceutically acceptable salt thereof, and aspartic acid and/or Or a pharmaceutically acceptable salt thereof.

The dibutylhydroxytoluene-containing product according to any one of items 1 to 7, wherein the liquid preparation contains 0.00001 to 0.005 w/v% of the component (A) and 0.005 of the component (B) ~0.5w/v%, and containing the above (C) component 0.0005~5w/v%.

Item 9. The product containing dibutylhydroxytoluene according to any one of items 1 to 8, Wherein the liquid agent is an eye drop agent.

Item 10. 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 agent is mixed (C) selected from the group consisting of chondroitin sulfate, aspartic acid, alginic acid, alginic acid derivatives, pharmaceutically acceptable salts thereof, cyanocobalamin, pan At least one of the group consisting of an alcohol, a retort phenol, and a reproductive phenol derivative, and the liquid preparation is contained in a container having a container body portion containing a liquid agent and a liquid to be contained in the container body portion The injection portion of the injection port and the cover portion for sealing the injection port, and at least one of the inner space wall surface of the injection portion and the wall surface of the cover portion facing the injection port are included It is composed of a resin of polybutylene terephthalate.

Item 11. The method of stabilizing according to item 10, wherein the liquid agent is further mixed with taurine.

Item 12. The method for stabilizing the item 10 or 11, 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 a polybutylene terephthalate-containing material. Made of resin.

The method of any one of clauses 10 to 12, wherein the container body portion is made of a resin containing polyethylene terephthalate.

The method of any one of clauses 10 to 13, wherein the liquid agent further comprises a boric acid buffer.

The method of any one of clauses 10 to 14, wherein the aforementioned (C) The component is selected from at least one selected from the group consisting of chondroitin sulfate, aspartic acid, pharmaceutically acceptable salts thereof, and cyanocobalamin.

The method of any one of clauses 10 to 15, wherein the component (C) comprises chondroitin sulfate and/or a pharmaceutically acceptable salt thereof, and aspartic acid and/or pharmaceutically acceptable thereof salt.

The method according to any one of items 10 to 16, wherein the liquid component comprises 0.00001 to 0.005 w/v% of the component (A) and 0.005 to 0.5 w/v% of the component (B). And containing the above (C) component 0.0005~5w/v%.

The method of any one of items 10 to 17, 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 The content of dibutylhydroxytoluene is stably maintained.

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. On the other hand, according to the present invention, it is possible to overcome the disadvantages of such conventional techniques, in the case of a liquid agent such as an eye drop or a nasal spray, even if dibutylhydroxytoluene is coexisted with pranoprofen and/or a salt thereof. In the case, it can effectively suppress the low content of the content, and can effectively maintain the antioxidant effect in the liquid agent.

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 the wall surface of the inner space wall surface and/or the lid portion of the injection portion opposite to the injection port of the injection portion is made of a resin containing polybutylene terephthalate. Contained in the container a liquid agent: (A) dibutylhydroxytoluene, (B) pranoprofen and/or a pharmaceutically acceptable salt thereof, and (C) selected from the group consisting of chondroitin sulfate, aspartic acid, At least one of a group consisting of alginic acid, a derivative of alginic acid, a pharmaceutically acceptable salt thereof, a cyanocobalamin, a panthenol, a reproductive phenol, and a reproductive phenol derivative. 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 a pharmaceutically acceptable salt selected from the group consisting of chondroitin sulfate, aspartic acid, alginic acid, alginic acid, and the like, cyanocobalam, panthenol, and reproduction. At least one of the group consisting of a phenol and a reproductive phenol derivative (also referred to as a 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.

Chondroitin sulfate is a polysaccharide in which a sugar chain composed of D-glucuronic acid and N-ethinyl-D-galactoside is bonded to sulfuric acid. As the chondroitin sulfate, any of natural or synthetic products can be used as the pharmaceutically acceptable one. For example, the chondroitin sulfate may be derived from a cartilage of a fish such as a shark, or may be derived from a mammal.

The salt of the chondroitin sulfate 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; a calcium salt; An alkaline earth metal salt such as a magnesium salt. Among these salts of chondroitin sulfate, an alkali metal salt is preferred, and a sodium salt is more preferred. These salts of the chondroitin sulfate may be used alone or in combination of two or more.

Aspartic acid is a well-known amino acid also known as 2-aminosuccinic acid. Aspartic acid may be any of D type, L type, and DL type, and is preferably L type.

The salt of aspartic acid 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. Among the salts of such aspartic acid, it is preferably an alkali metal salt, more preferably a potassium salt. These aspartic acid salts may be used alone or in combination of two or more.

Alginic acid is a polysaccharide composed of β-D-mannuronic acid and α-L-guluronic acid. As the alginic acid, any of natural and synthetic products can be used as long as it is pharmaceutically acceptable. For example, as alginic acid, it may be derived from algae or may be derived from microorganisms. In addition, the derivative of the alginic acid is not particularly limited as long as it is pharmaceutically acceptable, and an ester derivative such as propylene glycol alginate may be used.

The salt of the alginic acid and the derivative thereof 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; and an alkaline earth metal salt such as a calcium salt or a magnesium salt. Among these salts of alginic acid, an alkali metal salt is preferred, and a sodium salt is more preferred. These salts of the alginic acid may be used alone or in combination of two or more.

Cyanocobalamin is a well-known compound known as vitamin B12.

Ubiquinol, also known as (R)-2,4-dihydroxy-N-(3-hydroxypropane) A well-known compound such as -3,3-dimethylbutyramine or provitamin B5. The panthenol may be any of the D type, the L type, and the DL type, and may suitably be a D type.

Reproductive phenol is a well-known compound known as vitamin E. Further, the derivative of the reproductive phenol is not particularly limited as long as it is pharmaceutically acceptable, and may be an esterified product with a carboxylic acid such as acetic acid, nicotinic acid or succinic acid or a diesterified product of phosphoric acid. These derivatives of the reproductive phenol may be used singly or in combination of two or more. Among the derivatives of these reproductive phenols, a carboxylic acid ester of a reproductive phenol is preferable, and a regenerating phenol acetate is more preferable. Further, the reproductive phenol and its derivative may be any of the d-type, the l-form, and the dl-type, and may suitably be a d-form. Further, the reproductive phenol and its derivative may be any of α type, β type, γ type, and δ type, and may be, for example, α type.

In the liquid preparation used in the present invention, as the component (C), a pharmaceutically acceptable salt such as chondroitin sulfate, aspartic acid, alginic acid, alginic acid, or the like, cyanocobalamin or pan One of the alcohol, the reproductive phenol, and the reproductive phenol derivative may be used alone or in combination of two or more. Further, among the components (C), from the viewpoint of further effectively suppressing the decrease in the content of dibutylhydroxytoluene, it is suitable to be, for example, chondroitin sulfate, aspartic acid, alginic acid, alginic acid derivative. And pharmaceutically acceptable salts thereof, cyanocobalamin and panthenol; preferably such as chondroitin sulfate, aspartic acid, alginic acid, alginic acid derivatives, pharmaceutically acceptable salts thereof, cyanocobalamin More preferably, it is a pharmaceutically acceptable salt such as chondroitin sulfate, aspartic acid, and the like. In particular, the combination of chondroitin sulfate and/or a salt thereof and aspartic acid and/or a salt thereof can particularly effectively suppress the content of dibutylhydroxytoluene to be reduced, and thus it is suitably used in the present invention.

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

When chondroitin sulfate and/or a salt thereof is used, it is preferably 0.005 to 5 w/v%, more preferably 0.01 to 1 w/v%, and particularly preferably 0.05 to 0.5 w/v%.

When aspartic acid and/or its salt is used , it is preferably 0.01 to 5 w/v%, more preferably 0.05 to 2 w/v%, and particularly preferably 0.1 to 1 w/v%.

In the case of using a salt of alginic acid, a derivative thereof and/or the like, it is preferably 0.001 to 1 w/v%, more preferably 0.005 to 0.2 w/v%, particularly preferably 0.01 to 0.1 w/v%.

In the case of using cyanocobalamin, it is preferably 0.001 to 0.1 w/v%, more preferably 0.002 to 0.05 w/v%, and particularly preferably 0.004 to 0.02 w/v%.

In the case of using panthenol: it is preferably 0.001 to 1 w/v%, more preferably 0.005 to 0.5 w/v%, and particularly preferably 0.01 to 0.1 w/v%.

When reproductive phenol and/or its derivative is used, it is preferably 0.0005 to 1 w/v%, more preferably 0.001 to 0.1 w/v%, and particularly preferably 0.005 to 0.05 w/v%.

When chondroitin sulfate and/or a salt thereof is used in combination with aspartic acid and/or a salt thereof, the chondroitin sulfate and/or its salt is preferably 0.005 to 5 w/v%, more preferably 0.05 to 0.5 w. /v%; and the aspartic acid and/or its salt is preferably from 0.01 to 5 w/v%, more preferably from 0.1 to 1 w/v%.

The liquid preparation used in the present invention may contain, in addition to the above components (A) to (C), taurine and/or a pharmaceutically acceptable salt thereof. By further containing taurine, the content of dibutylhydroxytoluene can be further effectively suppressed to be reduced. In particular, the use of chondroitin sulfate, aspartic acid and/or When the salt is used as the component (C), the content of dibutylhydroxytoluene is particularly remarkably suppressed by containing taurine and/or a salt thereof.

Taurine, also known as aminoethyl sulfonic acid, has the chemical name 2-aminoethanesulfonic acid. In the field of ophthalmology, well-known compounds for the purpose of promoting eye metabolism and the like are also used.

The salt of the taurine 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. These salts of the taurine may be used alone or in combination of two or more.

In the liquid preparation used in the present invention, the content of taurine and/or a salt thereof is, for example, 0.01 to 5 w/v%, preferably 0.05 to 2 w/v%, more preferably 0.1 to 1 w/v%.

The liquid preparation used in the present invention may contain a buffering agent in addition to the above components 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 further containing a chelating agent, it can be further effectively inhibited The content of dibutylhydroxytoluene is reduced.

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. Further, examples of the pharmaceutically acceptable salt of ethylenediaminetetraacetic acid include alkali metal salts such as sodium salts and potassium salts; and alkaline earth metal salts such as calcium salts and magnesium salts.

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 Agents, anti-anxiety agents, antipsychotic drugs, antibiotics, antitumor agents, antihyperlipidemic drugs, antitussive expectorants, muscle relaxants, antiepileptic drugs, antiulcer drugs, antidepressants, cardiotonics, arrhythmia Therapeutic agents, vasodilators, hypertension diuretics, diabetes therapeutic agents, anti-tuberculosis drugs, anesthetic antagonists, skin disease medications, dental oral medications, diagnostic medications, public health medications, and the like.

Among these pharmacological ingredients, when it is a preparation for ophthalmology or otolaryngology such as an eye drop, an eye wash, a nasal spray, or an ear lotion, specifically, the following components may be mentioned: dipotassium glycyrrhizinate , allantoin, ε-aminocaproic acid, bromfenac, ketorolac tromethamine, nepafenac, berberine, berberine, hydrazine Anti-inflammatory agents such as sodium sulfonate, zinc sulfate, zinc lactate, lysozyme hydrochloride; anti-histidines such as chlorpheniramine maleate and bishydroxyhydroxylamine hydrochloride; sodium cromoglycate, ketotifen fumarate Anti-allergic to salt (Ketotifen Fumarate), Acitazanolast, amlexanox, Pemirolast Potassium, Tranilast, Ibudilast, etc. Agents; antibacterial agents such as Norfloxacin, ofloxacin, lomefloxacin, levofloxacin, gentamicin, gatifloxacin; ascorbic acid, flavin Adenine dinucleotide sodium, pyridoxine hydrochloride, retinol acetate, retinyl palmitate, Vitamins such as calcium pantothenate and sodium pantothenate; anti-cholinesterase agents such as neostigmine methyl sulfate; naphazoline, tetrahydrozole, epinephrine, ephedrine, go Vasoconstrictor such as phenylephrine and dl-methylephedrine; therapeutic agent for isotonic conjunctival epithelial barrier of sodium hyaluronate; sulfadiazine, sulfisoxazole, sulfisomidine, Sulfadimethoxine, sulfamethoxine (sulfamethoxypyridazine), sulfamethoxazole, sulfaethidole, sulfamethomidine, sulfaphenazole, sulfaguanidine, phthalylsulfathiazole ), sulfonamides 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, and chondroitin sulfur. Water-soluble polymer such as sodium acid ester or sodium hyaluronate; Hyporomellose, hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl Cellulose such as cellulose sodium. These viscous bases may be used alone or in combination of two or more.

Examples of the cooling agent include 1-menthol, borneol, camphor, and eucalyptus oil. These cooling agents may be used alone or in combination of two or more.

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.

Examples of the preservative include sorbic acid or a salt thereof, benzoic acid or a salt thereof, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, chlorobutanol, and lohexedine gluconate. (chlorhexidine gluconate), boric acid, dehydroacetic acid or its salt, acetic acid or its salt, benzalkonium chloride, benzethonium chloride, benzyl alcohol, zinc chloride, p-chloro-m-xylenol, chlorine Cresol, phenylethyl alcohol, 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, and ethylenediaminetetraacetate. 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, and poly An oxyethylene sorbitan fatty acid ester, a nonionic surfactant such as octoxynol; an amphoteric surfactant such as an alkyldiaminoethylglycine or a lauryl dimethylaminoacetic acid betaine; Anionic surfactants such as alkyl sulfates, N-mercapto taurates, polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyl ether sulfates; alkyl pyridinium salts, alkyl ammonium salts and the like Sexual surfactants, etc. These surfactants may be used alone or in combination of two or more.

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 the case of medicine, it can be produced by the method described in the sixteenth revised Japanese Pharmacopoeia preparations.

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 injection portion may be configured such that the liquid agent contained in the container body portion can be injected from the injection outlet to the outside of the container, and the structure is There is no particular limitation, and for example, it can be configured such that the liquid agent can be ejected in the form of droplets, or can be configured to eject the liquid agent 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.

Some or all of the above-mentioned injection portions may be integrally formed with the container body portion. 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 is injected from the injection port to the outside of the container through the internal space 4 of the dispensing portion 2. 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, for cheaper, insert Entered the imaginary line (dashed line). 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 eyewash container, the liquid agent contained in the container 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 special feature. 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 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. It may be composed of a blend of polybutylene terephthalate 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, if a portion for discharging the liquid agent in a non-drop form is used, for example, dibutyl hydroxy group can be more effectively inhibited. From the viewpoint of the low content of the toluene, it is preferred that at least the wall surface of the lid portion opposite to the injection port of the injection portion is made of a resin containing polybutylene terephthalate, more preferably the inside of the injection portion. The wall surface of the space and the wall surface of the lid portion opposite to the injection port of the injection portion are made of a resin containing polybutylene terephthalate.

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 be composed of a resin containing polybutylene terephthalate, and the walls other than the walls may be The portion is not particularly limited in the constituent material. 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) selected from the group consisting of chondroitin sulfate, aspartic acid, alginic acid, derivatives of alginic acid, pharmaceutically acceptable salts thereof, cyanocobalamin, panthenol, reproductive phenol, and reproductive phenol derivatives At least one of the group consisting of the liquid agent (that is, a preparation containing dibutylhydroxytoluene) is housed in a container having a wall surface of the internal space of the injection portion and/or a portion of the lid portion and the injection portion The wall opposite to the outlet of the injection 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 type or content of the other compoundable component, and the use of the liquid agent are used in combination with the above-mentioned use. The case of the liquid preparation of the BHT 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: Review of the change over time of dibutylhydroxytoluene content price

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 storage capacity of the liquid agent was set to 10 mL; and in the case of the container 1, the storage capacity of the liquid agent 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.

#4: Polypropylene cover

The results obtained are shown in Table 2. As the results of the control group showed, it was found that if dibutylhydroxytoluene and pranoprofen were coexisted in the liquid agent, the dibutylhydroxytoluene content was significantly reduced. Further, when pyridoxal hydrochloride as one type of vitamin is combined with dibutylhydroxytoluene and pranoprofen, the decrease in the content of dibutylhydroxytoluene cannot be sufficiently suppressed (Comparative Example 1). In contrast, sodium chondroitin sulfate, potassium L-aspartate, sodium alginate, cyanocobalamin, panthenol, or d-alpha-reproductive phenol acetate with dibutylhydroxytoluene and pranoprofen The liquid agent which is combined and accommodated in the container 2 containing the nozzle made of polybutylene terephthalate can effectively suppress the decrease in the content of dibutylhydroxytoluene (Examples 1 to 7).

Test Example 2: Evaluation of the change with time of dibutylhydroxytoluene content (in the case of low concentration of dibutylhydroxytoluene)

The liquid agent shown in Table 3 was prepared in the usual manner to be the same as Test Example 1 described above. The method was carried out and stored in each container shown in Table 1, and the content of dibutylhydroxytoluene in the liquid was measured by HPLC. From the obtained measurement 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 Table 3. From this result, it was confirmed that even when dibutylhydroxytoluene was 0.0001 w/v%, sodium chondroitin sulfate or potassium L-aspartate was mixed in the liquid preparation, and it was contained therein. In the container 2 of the nozzle made of polybutylene terephthalate, the content of dibutylhydroxytoluene in the presence of pranoprofen is still effectively suppressed.

Test Example 3: Evaluation of the change of the content of dibutylhydroxytoluene by sodium chondroitin sulfate and/or potassium L-aspartate and taurine

The liquid preparations shown in Table 4 were prepared by the usual method, and were stored in the respective containers shown in Table 1 in the same manner as in Test Example 1 except that the temperature at the time of storage was changed to 50 ° C or 60 ° C, and determined by HPLC. Dibutylhydroxyl in liquid The content of toluene. From the obtained measurement 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 Table 4. From the results, it was confirmed that in the case of the solution containing dibutylhydroxytoluene and pranoprofen, when the chondroitin sulfate was combined with the potassium L-aspartate, and the chondroitin sulfate was used In the case where sodium ester and/or potassium L-aspartate is combined with taurine, the effect of suppressing the decrease in the content of dibutylhydroxytoluene is particularly remarkable.

Test Example 4: Evaluation of pH influence on dibutylhydroxytoluene content due to pH over time

The liquid agent shown in Table 5 was prepared in the usual manner to be the same as Test Example 1 described above. The method was carried out and stored in each container shown in Table 1, and the content of dibutylhydroxytoluene in the liquid was measured by HPLC. From the obtained measurement 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 Table 5. From this result, it was confirmed that the low-inhibition effect of the dibutylhydroxytoluene content of the present invention was successfully prevented from being affected by the pH.

Reference test example 1: Evaluation of the change of dibutylhydroxytoluene content over time

The liquid materials shown in Tables 6 and 7 were prepared by the usual methods, and stored 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. From the obtained measurement 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 6 and 7. From the results, it is clear that in Comparative Examples 2 to 15, the reduction in the content of dibutylhydroxytoluene which occurs when dibutylhydroxytoluene and pranoprofen are coexisted cannot be sufficiently suppressed. Or the dibutylhydroxytoluene content is further reduced. In other words, it has been confirmed from the present results that the inhibitory effect of the dibutylhydroxytoluene content which occurs when dibutylhydroxytoluene and pranoprofen coexist is selected to select chondroitin sulfate, aspartic acid, etc. The salt, cyanocobalamin and/or panthenol are mixed in to reveal the special effects.

Table 7

Formulation Example 1

The eye drops of the composition shown in Table 8 were prepared according to the usual method. Each eyedrop was placed in an eye drop container in which a nozzle made of polybutylene terephthalate was attached to a container body of polyethylene terephthalate.

Table 8

1‧‧‧Container body

2‧‧‧Note Department

3‧‧‧ Cover

Claims (16)

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) selected from the group consisting of chondroitin sulfate, aspartic acid, alginic acid, derivatives of alginic acid, pharmaceutically acceptable salts thereof, cyanocobalamin, panthenol At least one of the group consisting of a reproductive phenol and a reproductive phenol derivative, wherein the container has a container body portion that houses the liquid agent, and a dispensing portion that has a liquid that can be contained in the container body portion a dispensing outlet for dispensing the agent, and a lid portion sealing the injection opening, wherein at least one of the inner space wall surface of the injection portion and the wall surface of the lid portion opposite to the injection port is made of polyparaphenylene It is composed of a resin of butylene dicarboxylate. The preparation of dibutyl hydroxytoluene according to claim 1, wherein the liquid preparation further comprises taurine. The product containing dibutylhydroxytoluene according to claim 1 or 2, wherein the above-mentioned 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 terephthalate-containing It is composed of a resin of butylene ester. The product containing dibutylhydroxytoluene according to any one of claims 1 to 3, The container body portion is made of a resin containing polyethylene terephthalate. The dibutylhydroxytoluene-containing article according to any one of claims 1 to 4, wherein the liquid agent further contains a boric acid buffer. The product containing dibutylhydroxytoluene according to any one of claims 1 to 5, wherein the component (C) comprises chondroitin sulfate and/or a pharmaceutically acceptable salt thereof, and asparagine and/or A pharmaceutically acceptable salt. The product containing dibutylhydroxytoluene according to any one of claims 1 to 6, wherein the liquid agent comprises 0.00001 to 0.005 w/v% of the component (A) and 0.005 to 0.5 of the component (B). w/v%, and containing the above (C) component 0.0005~5w/v%. The dibutylhydroxytoluene-containing article according to any one of claims 1 to 7, wherein the liquid agent is an eye drop. A method for stabilizing a method comprising stabilizing dibutylhydroxytoluene in a liquid preparation of (A) dibutylhydroxytoluene and (B) pranoprofen and/or a pharmaceutically acceptable salt thereof, It is characterized in that the liquid mixture (C) is selected from the group consisting of chondroitin sulfate, aspartic acid, alginic acid, alginic acid derivatives, pharmaceutically acceptable salts thereof, cyanocobalamin, panthenol, At least one of a group consisting of a reproductive phenol and a reproductive phenol derivative, and storing the liquid agent in a container having a container body portion for containing a liquid agent and having a container body to be accommodated in the container a dispensing portion of the injection opening of the liquid portion of the body portion and a lid portion sealing the injection port, and at least one of an inner space wall surface of the injection portion and a wall surface of the lid portion facing the injection port It is composed of a resin containing polybutylene terephthalate. The stabilization method of claim 9, wherein the liquid agent is further mixed with taurine. The method for stabilizing the item 9 or 10, 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 a resin containing polybutylene terephthalate Composition. The method of any one of clauses 9 to 11, wherein the container body portion is made of a resin containing polyethylene terephthalate. The method of any one of clauses 9 to 12, wherein the liquid agent further contains a boric acid buffer. The method of any one of clauses 9 to 13, wherein the component (C) comprises chondroitin sulfate and/or a pharmaceutically acceptable salt thereof, and aspartic acid and/or a pharmaceutically acceptable salt thereof. The method of any one of the items 9 to 14, wherein the liquid agent comprises 0.00001 to 0.005 w/v% of the component (A), and 0.005 to 0.5 w/v% of the component (B), and Containing the above (C) component 0.0005~5w/v%. The method of any one of clauses 9 to 15, wherein the liquid agent is an eye drop.