JP6800265B2 - How to stabilize dibutylhydroxytoluene - Google Patents

Description

The present invention relates to a product capable of stably maintaining dibutylhydroxytoluene in a liquid preparation containing dibutylhydroxytoluene and pranoprofen and / or a salt thereof. Furthermore, the present invention relates to a method for stabilizing a liquid preparation containing dibutylhydroxytoluene and pranoprofen and / or a salt thereof.

In recent years, preparations having various effects have been developed in the fields of medicine, food, cosmetics and the like. In these preparations, in order to prevent the oxidation of the contained components, it is required to add an antioxidant.

Conventionally, dibutylhydroxytoluene (BHT) is known as a typical compound of a fat-soluble antioxidant. Butylated hydroxyanisole and the like are also known as fat-soluble antioxidants, but dibutylhydroxytoluene has a stronger antioxidant effect than other fat-soluble antioxidants, and is used in fields such as pharmaceuticals, foods, and cosmetics. Widely used in.

In addition, a formulation technology using dibutylhydroxytoluene has also been reported. For example, it has been reported that dibutylhydroxytoluene stabilizes pranoprofen and / or a salt thereof (see Patent Document 1). However, Patent Document 1 focuses on the stability of pranoprofen and / or a salt thereof, and has not studied the stability of dibutylhydroxytoluene. Further, although the thermal stability is lowered in the aqueous composition containing pranoprofen and / or a salt thereof and dibutylhydroxytoluene, it has been reported that yellowing can be suppressed by further adding a sulfa agent (Patent Document 2). reference). However, Patent Document 2 also pays attention to the suppression of yellowing of the aqueous composition, and the stability of the dibutylhydroxytoluene itself has not been investigated.

On the other hand, in the fields of medicine, food, cosmetics, etc., a plastic container equipped with a polyethylene nozzle is generally used as a container for storing a preparation. However, when a liquid agent containing dibutylhydroxytoluene is contained in a plastic container equipped with a polyethylene injection part (nozzle, inner plug nozzle, perforated inner plug, etc.) and a lid, which are generally used in the past, the liquid agent is used. It has been reported that the dibutylhydroxytoluene contained therein is adsorbed and accumulated in the pouring portion (Patent Document 3). Then, in Patent Document 3, the inner wall surface of the container containing the liquid agent containing dibutylhydroxytoluene (the wall surface of the internal space of the pouring portion and / or the wall surface of the lid portion facing the pouring outlet of the pouring portion, etc.) is configured. It has been reported that by adopting a specific resin such as polybutylene terephthalate as the resin to be used, the adsorption of dibutylhydroxytoluene on the inner wall surface can be suppressed and the content of dibutylhydroxytoluene in the liquid preparation can be stably maintained. There is.

Japanese Unexamined Patent Publication No. 7-304670 Japanese Unexamined Patent Publication No. 2011-98960 International Publication No. 2013/99861

The present inventor conducted a study aiming at practical use of a liquid preparation containing dibutylhydroxytoluene and pranoprofen and / or a salt thereof. When the liquid preparation was contained in a container which has been generally used in the past, it contained dibutylhydroxytoluene. We faced a new challenge in which the amount declined significantly over time. Further, in Patent Document 2, by blending a sulfa agent, the stability of the aqueous composition containing planoprofene and / or a salt thereof and dibutylhydroxytoluene to heat is improved, and the yellowing of the aqueous composition is suppressed. Although it has been reported that this can be done, the yellowing of the aqueous composition and the thermal instability of the dibutylhydroxytoluene itself are different events, and Patent Document 2 discloses a technique for improving the thermal stability of the dibutylhydroxytoluene itself. It's not a thing.

Further, in a liquid preparation containing dibutylhydroxytoluene and pranoprofen and / or a salt thereof, the decrease in the content over time can be compensated by increasing the addition amount of dibutylhydroxytoluene, but the dibutylhydroxytoluene Increasing the blending amount is not realistic because it causes irritation in the case of a liquid agent applied to the mucous membrane such as eye drops. Therefore, it is necessary to develop a technique capable of suppressing a decrease in the content of dibutylhydroxytoluene in a liquid preparation containing dibutylhydroxytoluene and pranoprofen and / or a salt thereof.

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

The present inventor has conducted diligent studies in order to solve the above problems, and found that a liquid preparation containing dibutylhydroxytoluene and planoprofen and / or a salt thereof contains chondroitin sulfate ester, aspartic acid, alginic acid, and alginic acid derivatives, and those As a container for blending and containing at least one selected from the group consisting of pharmaceutically acceptable salts, cyanocobalamine, pantenol, tocopherol, and tocopherol derivatives, the inner wall surface (internal space of the pouring portion). By adopting a resin containing polybutylene terephthalate as the resin constituting the wall surface and / or the wall surface facing the injection port of the injection portion on the lid portion, the thermal stability of dibutylhydroxytoluene in the liquid preparation is enhanced. At the same time, it has been found that the adsorption of dibutylhydroxytoluene on a container can be suppressed and the decrease in the content over time can be effectively suppressed. The present invention has been completed by further studies based on such findings.

That is, the present invention provides a product containing dibutylhydroxytoluene and a stabilizing method according to the following aspects.
Item 1. (A) Dibutylhydroxytoluene and
(B) Pranoprofen and / or its pharmaceutically acceptable salt,
(C) At least one selected from the group consisting of chondroitin sulfate ester, aspartic acid, alginic acid, derivatives of alginic acid, pharmaceutically acceptable salts thereof, cyanocobalamin, panthenol, tocopherol, and tocopherol derivatives.
The liquid agent containing the dibutylhydroxytoluene is a product containing dibutylhydroxytoluene contained in a container.
The container includes a container main body portion for accommodating the liquid agent, an injection portion having a spout for pouring out the liquid agent contained in the container main body portion, and a lid portion for blocking the spout.
At least one of the wall surface of the internal space of the pouring portion and the wall surface of the lid portion facing the pouring outlet is made of a resin containing polybutylene terephthalate.
Products containing dibutylhydroxytoluene.
Item 2. Item 2. The product containing dibutylhydroxytoluene according to Item 1, wherein the liquid preparation further contains taurine.
Item 3. Item 2. The dibutylhydroxytoluene according to Item 1 or 2, wherein the pouring portion is a nozzle for pouring the liquid agent in the form of droplets, and the wall surface of the internal space of the nozzle is made of a resin containing polybutylene terephthalate. Containing product.
Item 4. Item 2. The product containing dibutylhydroxytoluene according to any one of Items 1 to 3, wherein the container body is made of a resin containing polyethylene terephthalate.
Item 5. Item 2. The product containing dibutylhydroxytoluene according to any one of Items 1 to 4, wherein the liquid agent further contains a boric acid buffer.
Item 6. Item 2. Dibutyl according to any one of Items 1 to 5, wherein the component (C) is at least one selected from the group consisting of chondroitin sulfate ester, aspartic acid, pharmaceutically acceptable salts thereof, and cyanocobalamin. Products containing hydroxytoluene.
Item 7. Item 6. The item according to any one of Items 1 to 6, wherein the component (C) includes chondroitin sulfate and / or a pharmaceutically acceptable salt thereof, and aspartic acid and / or a pharmaceutically acceptable salt thereof. Products containing dibutylhydroxytoluene.
Item 8. In the liquid preparation, the component (A) is 0.00001 to 0.005 w / v%, the component (B) is 0.005 to 0.5 w / v%, and the component (C) is 0.0005 to 5 w. Item 2. The product containing dibutylhydroxytoluene according to any one of Items 1 to 7, which contains / v%.
Item 9. Item 2. The product containing dibutylhydroxytoluene according to any one of Items 1 to 8, wherein the liquid agent is an eye drop.
Item 10. (A) Dibutylhydroxytoluene and
(B) Pranoprofen and / or its pharmaceutically acceptable salt,
This is a method for stabilizing dibutylhydroxytoluene in a liquid preparation containing
At least one selected from the group consisting of (C) chondroitin sulfate ester, aspartic acid, alginic acid, a derivative of alginic acid, a pharmaceutically acceptable salt thereof, cyanocobalamin, pantenol, tocopherol, and a tocopherol derivative in the solution. The dispenser is provided with a container main body portion for blending and containing the liquid agent, an injection portion having a spout for pouring out the liquid agent contained in the container main body portion, and a lid portion for blocking the spout. The liquid agent is contained in a container in which at least one of the wall surface of the internal space of the portion and the wall surface of the lid portion facing the spout is made of a resin containing polybutylene terephthalate.
Stabilization method.
Item 11. Item 10. The stabilization method according to Item 10, wherein taurine is further added to the liquid preparation.
Item 12. Item 10. The stabilization method according to Item 10 or 11, wherein the pouring portion is a nozzle for pouring out the liquid agent in the form of droplets, and the wall surface of the internal space of the nozzle is made of a resin containing polybutylene terephthalate. ..
Item 13. Item 2. The stabilization method according to any one of Items 10 to 12, wherein the container body is made of a resin containing polyethylene terephthalate.
Item 14. Item 8. The stabilization method according to any one of Items 10 to 13, wherein the liquid agent further contains a boric acid buffer.
Item 15. Item 2. The stability according to any one of Items 10 to 14, wherein the component (C) is at least one selected from the group consisting of chondroitin sulfate ester, aspartic acid, pharmaceutically acceptable salts thereof, and cyanocobalamin. How to make it.
Item 16. Item 6. The item according to any one of Items 10 to 15, wherein the component (C) includes chondroitin sulfate and / or a pharmaceutically acceptable salt thereof, and aspartic acid and / or a pharmaceutically acceptable salt thereof. Stabilization method.
Item 17. In the liquid preparation, the component (A) is 0.00001 to 0.005 w / v%, the component (B) is 0.005 to 0.5 w / v%, and the component (C) is 0.0005 to 5 w. The stabilization method according to any one of Items 10 to 16, which comprises / v%.
Item 18. Item 8. The stabilization method according to any one of Items 10 to 17, wherein the liquid agent is an eye drop.

According to the present invention, while containing dibutylhydroxytoluene and pranoprofen and / or a salt thereof, it is possible to improve the thermal stability of dibutylhydroxytoluene and suppress its adsorption to the container, and the content of dibutylhydroxytoluene is contained. The amount can be kept stable.

Further, in eye drops, nasal drops and the like, dibutylhydroxytoluene is set to a low content close to the threshold amount required for exerting an antioxidant effect, and in the prior art, planoprofene and / or its content is set. In the coexistence with the salt, the thermal stability of the dibutylhydroxytoluene was significantly impaired, and the loss of the antioxidant effect due to the decrease in the content tended to be remarkable. On the other hand, according to the present invention, dibutylhydroxytoluene and pranoprofen and / or a salt thereof coexist in liquid preparations such as eye drops and nasal drops, overcoming such drawbacks of the prior art. Even in this case, the decrease in the content can be effectively suppressed, and the antioxidant action can be effectively maintained in the liquid preparation.

FIG. 1 shows a cross-sectional view of an example of an eye drop container used in the present invention. FIG. 2 shows a partially enlarged cross-sectional view of the eye drop container shown in FIG. FIG. 3 shows a cross-sectional view of an example of an eye drop container used in the present invention. FIG. 4 shows a cross-sectional view of an example of an eye drop container used in the present invention. FIG. 5 shows a partially enlarged cross-sectional view of the eye drop container shown in FIG. FIG. 6 shows a cross-sectional view of an example of an eye wash container used in the present invention.

As used herein, the term "stabilization" or "stability" of dibutylhydroxytoluene means to prevent the content of dibutylhydroxytoluene from decreasing over time due to decomposition of dibutylhydroxytoluene or adsorption to a container. It means that the content is stably maintained, or its characteristics. Further, in the present specification, the "thermal stability" of dibutylhydroxytoluene means a property of suppressing decomposition of dibutylhydroxytoluene by heat. Further, in the present specification, the "dibutylhydroxytoluene-containing product" means a product in which a liquid agent containing the components (A) to (C) described later is contained in a container, and is referred to as a "BHT-containing product". It may be abbreviated. Further, in the present specification, the unit "w / v%" refers to the mass-to-volume percentage in the 16th revised Japanese Pharmacopoeia, and is synonymous with g / 100 mL.

1. 1. BHT-Containing Products The BHT-containing products of the present invention include (A) dibutylhydroxytoluene, (B) planoprofen and / or pharmaceutically acceptable salts thereof, and (C) chondroitin sulfate, aspartic acid, alginic acid, A liquid preparation containing at least one selected from the group consisting of derivatives of aspartic acid, pharmaceutically acceptable salts thereof, cyanocobalamin, pantenol, tocopherol, and tocopherol derivatives can be applied to the wall surface of the internal space of the dispensing portion and /. Alternatively, the wall surface of the lid portion facing the injection port of the injection portion is housed in a container made of a resin containing polybutylene terephthalate. 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 (sometimes referred to as component (A)). Dibutylhydroxytoluene, also referred to as 2,6-di-tert-butyl-4-methylphenol, BHT, and DBPC, is a compound known as an antioxidant. In the liquid preparation, dibutylhydroxytoluene improves the thermal stability of pranoprofen and / or its salt, exhibits an antioxidant effect in the liquid preparation, and is used as a pharmacological component or additive to be added as necessary. It is a component that also contributes to the improvement of stability.

The content of the component (A) in the liquid agent is not particularly limited and may be appropriately set according to the intended use of the liquid agent. For example, 0.00001 to 0.005 w / v%, preferably 0. 0005 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 (sometimes referred to as component (B)). In the solution, pranoprofen and / or a salt thereof is improved in stability to light by dibutylhydroxytoluene.

Pranoprofen is also called α-methyl-5H- [1] benzopyrano [2,3-b] pyridine-7-acetic acid, and is a known compound known to have an anti-inflammatory effect in the field of ophthalmology. ..

The salt of planoprofene is not particularly limited as long as it is pharmaceutically acceptable, but for example, metal salts such as sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt; triethylamine salt, diethylamine, etc. Examples thereof include organic base salts such as salts, morpholin salts and piperazine salts. These pranoprofen salts may be used alone or in combination of two or more.

In the liquid preparation used in the present invention, as the component (B), one type may be selected from pranoprofen and a salt thereof and used alone, or two or more types may be used in combination. .. Among the components (B), pranoprofen is preferably mentioned.

The content of the component (B) in the liquid preparation is not particularly limited and may be appropriately set according to the intended use of the liquid preparation, for example, 0.005 to 0.5 w / v%, preferably 0. 05 to 0.1 w / v%, more preferably 0.05 w / v%.

The solution used in the present invention is further selected from the group consisting of chondroitin sulfate, aspartic acid, alginic acid, derivatives of alginic acid, pharmaceutically acceptable salts thereof, cyanocobalamin, panthenol, tocopherol, and tocopherol derivatives. Contains at least one type (sometimes referred to as component (C)). In the liquid preparation used in the present invention, the content of dibutylhydroxytoluene caused in the presence of pranoprofen and / or a salt thereof by blending the component (C) and storing it in a specific container described later. It becomes possible to effectively suppress a significant decrease in.

Chondroitin sulfate ester is a polysaccharide in which sulfuric acid is bound to a sugar chain composed of D-glucuronic acid and N-acetyl-D-galactosamine. As the chondroitin sulfate ester, either a natural product or a synthetic product may be used as long as it is pharmaceutically acceptable. For example, the chondroitin sulfate ester may be derived from the cartilage of fish such as sharks, or may be derived from mammals.

The salt of chondroitin sulfate is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include alkali metal salts such as sodium salt and potassium salt; and alkaline earth metal salts such as calcium salt and magnesium salt. Can be mentioned. Among these chondroitin sulfate salts, an alkali metal salt is preferable, and a sodium salt is more preferable. These chondroitin sulfate salts may be used alone or in combination of two or more.

Aspartic acid is a known amino acid also called 2-aminobutanedioic acid. Aspartic acid may be any of D-form, L-form, and DL-form, but L-form is preferable.

Examples of the salt of aspartic acid include alkali metal salts such as sodium salt and potassium salt; and alkaline earth metal salts such as calcium salt and magnesium salt. Among these aspartic acid salts, an alkali metal salt is preferable, and a potassium salt is more preferable. 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-gluuronic acid. As the alginic acid, either a natural product or a synthetic product may be used as long as it is pharmaceutically acceptable. For example, alginic acid may be derived from algae or microorganisms. The alginic acid derivative is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include an ester derivative such as alginic acid propylene glycol ester.

The salt of alginic acid and its derivative is not particularly limited as long as it is pharmaceutically acceptable, but for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt and the like. Can be mentioned. Among these alginic acid salts, an alkali metal salt is preferable, and a sodium salt is more preferable. These alginic acid salts may be used alone or in combination of two or more.

Cyanocobalamin is a known compound known as Vitamin B12.

Panthenol is a known compound also referred to as (R) -2,4-dihydroxy-N- (3-hydroxypropyl) -3,3-dimethylbutylamide, provitamin B5 and the like. The panthenol may be any of D-form, L-form, and DL-form, but D-form is preferable.

Tocopherol is a known compound known as Vitamin E. The derivative of tocopherol is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include an ester form with a carboxylic acid such as acetic acid, nicotinic acid, and succinic acid, and a diester form with phosphoric acid. These tocopherol derivatives may be used alone or in combination of two or more. Among these tocopherol derivatives, a carboxylic acid ester of tocopherol is preferable, and a tocopherol acetate is more preferable. Further, tocopherol and its derivative may be any of d-form, l-form, and dl-form, but d-form is preferable. Further, tocopherol and its derivative may be any of α-form, β-form, γ-form and δ-form, but α-form is preferable.

In the liquid preparation used in the present invention, among the components (C), chondroitin sulfate, aspartic acid, alginic acid, derivatives of alginic acid, pharmaceutically acceptable salts thereof, cyanocobalamin, panthenol, tocopherol, and tocopherol derivatives. Therefore, one type may be selected and used alone, or two or more types may be used in combination. Further, among these (C) components, from the viewpoint of more effectively suppressing the decrease in the content of dibutylhydroxytoluene, preferably, chondroitin sulfate, aspartic acid, aspartic acid, derivatives of alginic acid, and their pharmaceuticals. Acceptable salts, cyanocobalamin, and pantenol; more preferably chondroitin sulfate, aspartic acid, aspartic acid, derivatives of alginic acid, pharmaceutically acceptable salts thereof, cyanocobalamin; more preferably chondroitin sulfate, aspartic acid. Acids and their pharmaceutically acceptable salts are included. In particular, a combination of chondroitin sulfate and / or a salt thereof and aspartic acid and / or a salt thereof can remarkably suppress a decrease in the content of dibutylhydroxytoluene, and is therefore preferably used in the present invention.

Examples of the content of the component (C) in the liquid preparation used in the present invention include 0.0005 to 5 w / v%, preferably 0.001 to 2 w / v%. More specifically, the content of each type of component (C) includes the following range.
When chondroitin sulfate ester and / or a salt thereof is used: 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 a salt thereof is used: preferably 0.01 to 5 w / v%, more preferably 0.05 to 2 w / v%, particularly preferably 0.1 to 1 w / v%.
When using alginic acid, its derivatives and / or salts thereof: 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%.
When cyanocobalamin is used: preferably 0.001 to 0.1 w / v%, more preferably 0.002 to 0.05 w / v%, particularly preferably 0.004 to 0.02 w / v%.
When panthenol is used: preferably 0.001 to 1 w / v%, more preferably 0.005 to 0.5 w / v%, particularly preferably 0.01 to 0.1 w / v%.
When tocopherol and / or a derivative thereof is used: 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: Chondroitin sulfate and / or a salt thereof is preferably 0.005 to 5 w / v%, more preferably 0. 05 to 0.5 w / v%, and aspartic acid and / or a salt thereof is preferably 0.01 to 5 w / v%, more preferably 0.1 to 1 w / v%.

The liquid preparation used in the present invention may contain taurine and / or a pharmaceutically acceptable salt thereof in addition to the components (A) to (C). Further, by containing taurine, the decrease in the content of dibutylhydroxytoluene can be suppressed more effectively. In particular, when chondroitin sulfate, aspartic acid, and / or salts thereof are used as the component (C), the content of dibutylhydroxytoluene is significantly reduced by containing taurine and / or a salt thereof. Can be suppressed.

Taurine is also referred to as aminoethyl sulfonic acid, and its chemical name is 2-aminoethane sulfonic acid. In the field of ophthalmology, it is a known compound that is also used for the purpose of promoting the metabolism of the eye.

The salt of taurine is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include alkali metal salts such as sodium salt and potassium salt. These taurine salts may be used alone or in combination of two or more.

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

In addition to the above-mentioned components, the liquid preparation used in the present invention may contain a buffering agent in order to provide a buffering action. The buffering agent is not particularly limited, and examples thereof include borate buffering agent, phosphoric acid buffering agent, citric acid buffering agent, tartrate buffering agent, acetate buffering agent, Tris buffering agent, amino acid (glutamic acid, etc.) and the like. These buffering agents may be used alone or in combination of two or more. Among these buffers, borate buffer has a buffering ability in a pH range in which pranoprofen and / or a salt thereof can be dissolved, and is preferably used in the present invention.

The content of the buffering agent in the liquid agent used in the present invention may be appropriately set within a range capable of imparting a desired buffering action according to the type of the buffering agent used. For example, 0.001 to 5w. / V%, preferably 0.05 to 3 w / v%, more preferably 0.1 to 2 w / v%.

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

Specific examples of the chelating agent include edetic acid, citric acid, succinic acid, ascorbic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1-hydroxyethane-1,1-diphosphonic acid, polyphosphoric acid, metaphosphoric acid, and hexametallin. Examples include acids, their pharmaceutically acceptable salts and the like. These chelating agents may be used alone or in combination of two or more. Among these chelating agents, edetic acid and a pharmaceutically acceptable salt thereof are preferably mentioned from the viewpoint of more effectively suppressing the decrease in the content of dibutylhydroxytoluene. Examples of the pharmaceutically acceptable salt of edetonic acid include alkali metal salts such as sodium salt and potassium salt; and alkaline earth metal salts such as calcium salt and magnesium salt.

When the liquid agent used in the present invention contains a chelating agent, the content thereof may be appropriately set according to the intended use of the liquid agent, and is preferably 0.0005 to 0.5 w / v%, for example. Is 0.001 to 0.2 w / v%, more preferably 0.005 to 0.13 w / v%.

In addition to the above components, the liquid agent used in the present invention may contain a pharmacological component depending on the use of the liquid agent. The pharmacological components used are not particularly limited, but are, for example, vasoconstrictors, anticholinesterases, anti-inflammatory agents, corneal epithelial disorders therapeutic agents, anti-inflammatory analgesics, chemotherapeutic agents, antibacterial agents, antiviral agents, hormone agents. , Vitamin drugs, amino acids, anti-cataract drugs, angiogenesis inhibitors, immunosuppressants, protease inhibitors, aldose reductase inhibitors, antihistamines, antiallergic agents, anxiety agents, antipsychiatric agents, antibiotics, antitumor agents, Antihyperlipidemic, antitussive / expectorant, muscle relaxant, antiepileptic, antiulcer, antidepressant, cardiotonic, arrhythmia, vasodilator, hypertensive diuretic, antidiabetic, antituberculous , Antiseptic agents, skin disease agents, dental and oral agents, diagnostic agents, public hygiene agents and the like, which can be appropriately selected and used from conventionally known pharmacological components.

Among these pharmacological components, when the preparation is used in the field of ophthalmology or otolaryngology such as eye drops, eye wash, nasal drops, and ear drops, specifically, dipotassium glycyrrhizinate, allantin, and ephedrine aminocapron. Anti-inflammatory agents such as acid, bromfenac, ketrolactromethamine, nepafenac, berberine chloride, berberine sulfate, sodium azulene sulfonate, zinc sulfate, zinc lactate, lysoteam hydrochloride; antihistamines such as chlorpheniramine maleate, diphenhydramine hydrochloride Anti-allergic agents such as sodium cromoglycate, ketotiphen fumarate, acitazanolast, anlexanox, pemirolast potassium, tranilast, ibudilast; antibacterial agents such as norfloxacin, ofloxacin, romefloxacin, levofloxacin, gentamycin, gachifloxacin; ascorbic acid , Flavin adenine dinucleotide sodium, pyridoxin hydrochloride, retinol acetate, retinol palmitate, calcium pantothenate, sodium pantothenate and other vitamins; anticholinergic agents such as neostigmine methyl sulfate; nafazoline, tetrahydrozoline, ephedrine, ephedrine, Vascular contractile agents such as phenilefurin and dl-methylephedrine; therapeutic agents for keratoconjunctival epithelial disorders such as sodium hyaluronate; Examples thereof include sulfa agents such as dol, sulfamethomidin, sulfaphenazole, sulfaguanidine, phthalylsulfatiazole, and succinyl sulfatizol. The compounds exemplified herein may be in the form of salts or other salts, as long as they are pharmaceutically acceptable.

The content of these pharmacological components is appropriately set according to the type of the pharmacological component, the use of the liquid preparation, and the like.

In addition to the above-mentioned components, the liquid agent used in the present invention includes, if necessary, an tonicity agent, a dissolution aid, a viscous base, a cooling agent, a pH adjuster, a preservative, and a stabilizer. , Additives such as surfactants may be contained.

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

Examples of the solubilizing agent include nonionic surfactants such as polyoxyethylene sorbitan monooleate, polyoxyethylene hydrogenated castor oil, tyroxapol, and pluronic; and polyhydric alcohols such as glycerin and macrogol. These dissolution aids may be used alone or in combination of two or more.

Examples of the viscous base include water-soluble polymers such as polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, carboxyvinyl polymer, xanthan gum, sodium chondroitin sulfate, and sodium hyaluronate; hypromellose, hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, and hydroxy. Examples thereof include celluloses such as propylmethyl cellulose and sodium carboxymethyl cellulose. These viscous bases may be used alone or in combination of two or more.

Examples of the refreshing agent include l-menthol, borneol, camphor, eucalyptus oil and the like. These refreshing 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 borosand; acids such as acetic acid, citric acid, hydrochloric acid, phosphoric acid, tartaric acid and boric acid.

Examples of preservatives include sorbic acid or a salt thereof, benzoic acid or a salt thereof, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, chlorhexidine gluconate, boric acid, dehydroacetic acid or a salt thereof. , Benzylconium chloride, benzethonium chloride, benzyl alcohol, zinc chloride, parachlormethoxylenol, chlorhexidine, phenethyl alcohol, polydronium chloride, timerosal, polyhexamethylene biguanide and the like. These preservatives may be used alone or in combination of two or more.

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

Examples of the surfactant include nonionic surfactants such as tyroxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, and octoxinol; alkyldiaminoethylglycine, Amphoteric surfactants such as betaine lauryldimethylaminoacetate; anionic surfactants such as alkyl sulfates, N-acyltaurine salts, polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyl ether sulfates; alkyl pyridinium salts, Examples thereof include cationic surfactants such as alkylamine salts. These surfactants may be used alone or in combination of two or more.

The concentration of these additives is appropriately set according to the type of additive, the use of the liquid agent, and the like.

The liquid agent used in the present invention may be in the form of a liquid containing water as a base, and may be in the form of an aqueous solution, a suspension, an emulsion, or the like, but the aqueous solution is preferable. Can be mentioned.

The pH of the liquid agent used in the present invention is not particularly limited and may be appropriately set according to the intended use of the liquid agent, for example, 5.0 to 9.0, preferably 6.5 to 8. .5 can be mentioned.

The use of the liquid agent used in the present invention is also not particularly limited, and examples thereof include pharmaceuticals and contact lens care products. Specific examples of pharmaceuticals include eye drops (including eye drops for contact lenses that can be instilled even when wearing contact lenses), ophthalmic solutions such as eye wash; otolaryngological solutions such as nasal drops and ear drops. ; Examples include internal preparations, injections, and external preparations. Specific examples of contact lens care products include contact lens mounting solutions and multipurpose solutions for contact lenses. Among the uses of these liquids, preferably, ophthalmic liquids, otolaryngological liquids, contact lens care products, and more preferably eye drops are mentioned.

Further, the liquid agent used in the present invention may be filled in a multi-dose type container which is filled with a plurality of doses and used repeatedly, or is filled with a single dose and finished to be used once. It may be filled in a unit dose type container.

The liquid preparation used in the present invention may be produced according to a preparation method known per se, depending on its form, application, etc., and is prepared by, for example, blending each component with an aqueous base such as water or physiological saline. it can. For example, in the case of a drug, it can be manufactured by the method described in the 16th revised Japanese Pharmacopoeia General Regulations for Formulation.

Container The BHT-containing product of the present invention is provided with a container body, a pouring portion, and a lid for accommodating the liquid agent, and the pouring portion is provided on the wall surface and / or lid of the internal space of the pouring portion. A container whose wall surface facing the spout is made of a resin containing polybutylene terephthalate is used.

<Container structure>
The container main body portion constituting the container is a portion for accommodating the liquid agent. The shape and size of the container body are not particularly limited, and are appropriately set according to the type and volume of the liquid agent to be contained.

The pouring portion constituting the container has an internal space communicating between the container main body and the outside of the container, and is provided with a pouring outlet for pouring out the liquid agent contained in the container main body. An outlet is provided so as to communicate with the opening of the container main body, and the liquid agent contained in the container main body is poured (discharged) from the pouring outlet to the outside of the container through the internal space. The structure of the pouring portion is not particularly limited as long as the liquid agent contained in the container body can be poured out from the pouring port to the outside of the container. For example, the liquid agent is in the form of droplets. It may be configured to be dispensed, or the liquid agent may be configured to flow out in the form of non-droplets. From the viewpoint of more effectively exerting the effects of the present invention, it is preferable that the dispensing portion is a nozzle configured so that the liquid agent is dispensed in the form of droplets. Further, the pouring portion may be provided with an inner plug such as an inner plug nozzle or a perforated inner plug.

A part or all of the pouring portion may be integrally molded with the container main body portion. Further, the pouring portion may be inserted into the cavity of the opening of the container main body or attached to the outside.

The lid portion constituting the container is a portion that closes the spout. The lid may have a structure fitted with the container body and / or the spout. More specifically, when the BHT-containing product of the present invention is a multi-dose type, it may have a structure that is detachably fitted to the container body and / or the spout, and also contains the BHT of the present invention. When the product is a unit dose type, the structure may be such that it is detachably fitted from the container body and / or the spout. A preferred example of a structure that is detachably fitted to the container body and / or the spout is a lid that is detachably attached to the container body and / or the spout by screw fitting. .. When the lid and the container body and / or the pouring part are detachably attached by screw fitting, the lid is provided with a screw part to be screwed with the screw part of the container body and / or the pouring part. It suffices if it is done.

The shape of the container is appropriately set according to the use of the BHT-containing product to be accommodated. Specific examples thereof include an eye drop container, an eye wash container, and a nasal drop container.

Examples of specific embodiments of the container used in the present invention are shown in FIGS. 1 to 6.

FIG. 1 is a cross-sectional view of one aspect of the eye drop container, and FIG. 2 is a partially enlarged cross-sectional view of the eye drop container shown in FIG. In the eye drop container shown in FIG. 1, an injection portion 2 capable of injecting the liquid agent in the form of droplets is inserted into the cavity of the opening of the container main body 1, and the lid 3 is a container main body. It is detachably attached to No. 1 by screw fitting, and the pouring outlet of the pouring portion 2 is blocked. In the eye drop container, the liquid agent contained in the container main body 1 is poured out of the container from the spout through the internal space 4 of the pouring part 2. The eye drop container shown in FIG. 1 may be used for accommodating a unit dose type liquid agent, but is preferably used for accommodating a multidose type liquid agent.

FIG. 3 is a cross-sectional view of one aspect of the eye drop container. In the eye drop container shown in FIG. 3, the container body 1 and the dispensing portion 2 are integrally formed of the same material regardless of adhesion or mechanical joining, and are formed through the internal space 4 of the dispensing portion 2. The liquid agent can be poured out in droplet form from the pouring outlet to the outside of the container. In FIG. 3, the lid portion is omitted, and a virtual line (dotted line) is inserted for convenience. In the eye drop container shown in FIG. 3, the container member below the virtual line corresponds to the container main body portion 1, and the container member above the virtual line corresponds to the pouring portion 2. The eye drop container shown in FIG. 3 may be used for accommodating a unit dose type liquid agent, but is preferably used for accommodating a multidose type liquid agent.

FIG. 4 is a cross-sectional view of one aspect of the eye drop container, and FIG. 5 is a partially enlarged cross-sectional view of the eye drop container shown in FIG. In the eye drops shown in FIG. 4, the container main body portion 1, the dispensing portion 2, and the lid portion 3 are integrally molded. The dispensing portion 2 and the lid portion 3 are in a connected state, but by separating them at the time of use, the liquid agent contained in the container main body portion 1 is injected through the internal space 4 of the dispensing portion 2. It becomes possible to pour out the container from the outlet. Virtual lines (dotted lines) are inserted in FIGS. 4 and 5 for convenience. In FIGS. 4 and 5, the container member between the two virtual lines corresponds to the pouring section 2, and the space between the two virtual lines corresponds to the internal space 4 of the pouring section 2. The eye drop container shown in FIG. 4 is suitably used for accommodating a unit dose type liquid preparation.

FIG. 6 is a cross-sectional view of the eye wash container. In the eye wash container shown in FIG. 6, a part of the container main body 1 and the pouring portion 2 is integrally molded. In the eye wash container, the liquid agent contained in the container main body 1 is poured out from the spout through the internal space 4 of the pouring part 2. A virtual line (dotted line) is inserted in FIG. 6 for convenience.

Although specific embodiments of the eye drop container and the eye wash container are shown in FIGS. 1 to 6, the present invention is not limited to these structures and shapes, and a container other than the eye drop container and the eye wash container is also specified. It can be used as long as it has the characteristics of.

<Container material>
In the container, at least one of the wall surface of the internal space of the pouring portion and the wall surface of the lid portion facing the pouring outlet is composed of a resin containing polybutylene terephthalate (PBT). Here, the “wall surface facing the spout in the lid” corresponds to the inner wall portion of the lid that covers the spout when the lid is attached to the container body and / or the spout. Specifically, taking FIG. 2 as an example, the surface portion indicated by reference numeral 5 corresponds to the “wall surface of the internal space of the injection portion”, and the surface portion indicated by reference numeral 6 corresponds to “the injection outlet in the lid portion”. Corresponds to the "wall surface facing".

As described above, the resin containing polybutylene terephthalate constitutes the wall surface of the internal space of the pouring portion and / or the wall surface of the lid portion facing the pouring outlet of the pouring portion, thereby forming a specific composition adopted in the liquid agent. In combination with this, it is possible to effectively suppress the adsorption and accumulation of dibutylhydroxytoluene on the pouring portion and / or the lid portion, and to stably maintain the content of dibutylhydroxytoluene in the liquid preparation. ..

The resin constituting the wall surface of the internal space of the pouring portion and / or the wall surface of the lid portion facing the pouring outlet of the pouring portion may be composed of polybutylene terephthalate alone, or may be composed of polybutylene terephthalate alone. It may consist of a blended polymer with another polymer. When a blended polymer of polybutylene terephthalate and another polymer is used as the resin constituting the wall surface and / or the wall surface of the pouring portion facing the pouring outlet of the pouring portion, the effect of the present invention is exhibited. The mixing ratio thereof is not particularly limited, but the polybutylene terephthalate is 50 w / w% or more, preferably 60 w / w% or more, more preferably 70 w / w% or more, based on the total amount of the blend polymer. More preferably, it occupies 80 w / w% or more, and particularly preferably 90 w / w% or more.

In the container, at least one of the wall surface of the internal space of the pouring portion and the wall surface of the lid portion facing the pouring outlet of the pouring portion may contain polybutylene terephthalate. For example, when an injection part (for example, a nozzle configured so that the liquid agent is dropped in the form of droplets) is adopted, the content of dibutylhydroxytoluene is further reduced. From the viewpoint of more effective suppression, it is preferable that at least the wall surface of the internal space of the dispensing portion is made of a resin containing polybutylene terephthalate, and the wall surface of the internal space of the dispensing portion and the lid portion are injected. It is more preferable that both the spout of the outlet and the wall surface facing the spout are made of a resin containing polybutylene terephthalate. Further, for example, when a pouring portion in which the liquid agent flows out in the form of non-droplets is adopted, at least the lid portion is dispensed from the viewpoint of more effectively suppressing the decrease in the content of dibutylhydroxytoluene. It is preferable that the wall surface facing the pouring outlet of the portion is made of a resin containing polybutylene terephthalate, and both the wall surface of the internal space of the pouring portion and the wall surface facing the pouring outlet of the pouring portion are poly. It is more preferably composed of a resin containing butylene terephthalate.

As long as the wall surface of the internal space of the pouring portion and / or the wall surface of the lid portion facing the pouring outlet of the pouring portion is made of a resin containing polybutylene terephthalate, the constituent materials of the parts other than these wall surfaces are used. There are no particular restrictions. For example, the parts other than these wall surfaces may be made of a resin containing polybutylene terephthalate, or may be made of a material other than polybutylene terephthalate.

When the container is integrally molded with the container main body and the pouring portion, the container main body is made of the same resin as the pouring portion.

Further, when the container is attached by inserting the dispensing portion into the cavity of the opening of the container main body, or by mounting and attaching the dispensing portion to the outside of the opening of the container main body. If so, the container body may be made of either glass or plastic, but plastic is preferable. In the container of this aspect, when the container body is made of plastic, the type of resin forming the container body is not particularly limited, but for example, polyethylene terephthalate, polybutylene terephthalate, polystyrene, acrylonitrile butadiene styrene, etc. Can be mentioned. Among these, polyethylene terephthalate is suitably used as a resin for forming a container body because it can suppress the adsorption of dibutylhydroxytoluene while having excellent moldability.

2. 2. Stabilization Method The method for stabilizing dibutylhydroxytoluene of the present invention is a liquid preparation containing (A) dibutylhydroxytoluene, (B) planoprofen and / or a pharmaceutically acceptable salt thereof, and (C) chondroitin. A liquid preparation containing at least one selected from the group consisting of sulfate esters, aspartic acid, alginic acid, derivatives of alginic acid, pharmaceutically acceptable salts thereof, cyanocobalamin, pantenol, tocopherol, and derivatives of tocopherol. The preparation containing dibutylhydroxytoluene is housed in a container in which the wall surface of the internal space of the pouring portion and / or the wall surface of the lid portion facing the pouring outlet of the pouring portion is made of a resin containing polybutylene terephthalate. It is characterized by that.

In the stabilization method of the present invention, the types and contents of the components (A) to (C) to be contained in the liquid preparation, the types and contents of other ingredients that can be blended, the uses of the liquid preparation, etc. are described in the BHT-containing product. This is the same as for the liquid agent used. Further, the container used in the stabilization method of the present invention is the same as the container used in the BHT-containing product.

The stabilizing method of the present invention is to enhance the thermal stability of dibutylhydroxytoluene and suppress the adsorption of dibutylhydroxytoluene to a container in a liquid preparation containing dibutylhydroxytoluene and planoprofene and / or a salt thereof. As a result, the decrease in the content of dibutylhydroxytoluene can be effectively suppressed and the storage stability of the dibutylhydroxytoluene can be improved, so that it can be carried out as a storage method for the liquid agent.

Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto.

Test Example 1: Evaluation of change over time in the content of dibutylhydroxytoluene The change in the content of dibutylhydroxytoluene over time was measured when the liquid preparation shown in Table 2 was prepared and stored in various containers. Specifically, the liquid preparation shown in Table 2 is prepared according to a conventional method, stored in each container shown in Table 1, sealed, and stored at 40 ° C., 75% RH, and allowed to stand for 2 weeks under light-shielding conditions. did. At that time, in the case of containers 2 and 3, the capacity of the liquid agent was 10 mL, and in the case of container 1, the capacity of the liquid agent was 5 mL. Further, in the case of the containers 2 and 3, the container was allowed to stand upright so that the lid portion was on the upper surface and the bottom portion of the container main body was on the lower surface. Before the start of storage, one week and two weeks after the start of storage, the liquid preparation in the container is sampled so as not to come into contact with the nozzle, and the content of dibutylhydroxytoluene in the liquid preparation is measured by HPLC to obtain dibutylhydroxy. The thermal stability of toluene was evaluated. Specifically, the stability of dibutylhydroxytoluene was calculated as the residual ratio (%) of the ratio of the dibutylhydroxytoluene content after storage to the dibutylhydroxytoluene content before storage. The container 3 is an example of a conventional eye drop container. Further, it is known that glass is difficult to adsorb general drugs, and container 1 is an example of a container to which dibutylhydroxytoluene is difficult to be adsorbed.

The results obtained are shown in Table 2. As can be seen from the control results, it was clarified that when dibutylhydroxytoluene and pranoprofen coexisted in the liquid preparation, the dibutylhydroxytoluene content decreased significantly. Moreover, when pyridoxine hydrochloride, which is one of the vitamins, was combined with dibutylhydroxytoluene and pranoprofen, the decrease in the dibutylhydroxytoluene content could not be sufficiently suppressed (Comparative Example 1). On the other hand, dibutylhydroxytoluene and planoprofene are combined with sodium chondroitin sulfate, potassium L-aspartate, sodium alginate, cyanocobalamin, panthenol, or d-α-tocopherol acetate, and a nozzle made of polybutylene terephthalate. The liquid agent contained in the attached container 2 was able to effectively suppress the decrease in the dibutylhydroxytoluene content (Examples 1 to 7).

Test Example 2: Evaluation of changes in the content of dibutylhydroxytoluene over time (in the case of low-concentration dibutylhydroxytoluene)
The liquid preparation shown in Table 3 was prepared according to a conventional method, stored in each container shown in Table 1 in the same manner as in Test Example 1, and the content of dibutylhydroxytoluene in the liquid preparation was measured by HPLC. .. Based on the obtained measured values, the residual ratio (%) of dibutylhydroxytoluene was calculated by the same method as in Test Example 1.

The results obtained are shown in Table 3. From this result, even when the amount of dibutylhydroxytoluene is 0.0001 w / v%, the liquid preparation is mixed with sodium chondroitin sulfate or potassium L-aspartate, and the container 2 is equipped with a polybutylene terephthalate nozzle. It was confirmed that the decrease in the content of dibutylhydroxytoluene in the coexistence of planoprofene can be effectively suppressed by accommodating in.

Test Example 3: Evaluation of change over time in the content of dibutylhydroxytoluene due to the combination of sodium chondroitin sulfate and / or potassium L-aspartate and taurine The liquid preparation shown in Table 4 was prepared according to a conventional method, and the temperature at the time of storage. The content of dibutylhydroxytoluene in the liquid preparation was measured by HPLC in the same manner as in Test Example 1 except that the temperature was changed to 50 ° C. or 60 ° C. in each container shown in Table 1. .. Based on the obtained measured values, the residual ratio (%) of dibutylhydroxytoluene was calculated by the same method as in Test Example 1.

The results obtained are shown in Table 4. From this result, in the liquid preparation containing dibutylhydroxytoluene and planoprofene, when sodium chondroitin sulfate and potassium L-aspartate were combined, and sodium chondroitin sulfate and / or potassium L-aspartate and taurine were added. It was confirmed that when combined, the suppression of the decrease in the content of dibutylhydroxytoluene became remarkably remarkable.

Test Example 4: Evaluation of the effect of pH on the change in the content of dibutylhydroxytoluene due to pH over time The liquid preparation shown in Table 5 was prepared according to a conventional method, and is shown in Table 1 in the same manner as in Test Example 1. It was stored in each container, and the content of dibutylhydroxytoluene in the solution was measured by HPLC. Based on the obtained measured values, the residual ratio (%) of dibutylhydroxytoluene was calculated by the same method as in Test Example 1.

The results obtained are shown in Table 5. From this result, it was confirmed that the effect of suppressing the decrease in the content of dibutylhydroxytoluene according to the present invention is exhibited without being affected by pH.

Reference Test Example 1: Evaluation of Changes in Dibutylhydroxytoluene Content Over Time The liquid preparations shown in Tables 6 and 7 were prepared according to a conventional method and stored in each container shown in Table 1 in the same manner as in Test Example 1. 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 by the same method as in Test Example 1.

The results obtained are shown in Tables 6 and 7. From this result, in Comparative Examples 2 to 15, the decrease in the dibutylhydroxytoluene content caused by the coexistence of dibutylhydroxytoluene and pranoprofen could not be sufficiently suppressed, or the dibutylhydroxytoluene content was further decreased. It became clear that it would happen. That is, from this result, the effect of suppressing the decrease in the dibutylhydroxytoluene content caused by the coexistence of dibutylhydroxytoluene and planoprofen is that chondroitin sulfate ester, aspartic acid, salts thereof, cyanocobalamin, and / or panthenol are used. It was confirmed that it is a peculiar effect recognized by selecting and blending this.

Formulation Example 1
Eye drops having the compositions shown in Table 8 were prepared according to a conventional method. Each eye drop was housed in an eye drop container equipped with a polybutylene terephthalate nozzle in a container body made of polyethylene terephthalate.

1 Container body 2 Dispensing part 3 Lid part 4 Internal space of the extraction part 5 Wall surface of the internal space of the extraction part 6 Wall surface of the lid part facing the spout of the spouting part

Claims (8)

(A) Dibutylhydroxytoluene and
(B) Pranoprofen and / or its pharmaceutically acceptable salt,
(C) 0.005-5 w / v% chondroitin sulfate and / or a pharmaceutically acceptable salt thereof , 0.01-5 w / v% aspartic acid and / or a pharmaceutically acceptable salt thereof , 0.001 to 1 w / v% aspartic acid, derivatives of aspartic acid and / or pharmaceutically acceptable salts thereof, 0.001 to 0.1 w / v% cyanocobalamin, 0.001 to 1 w / v% panthenol, as well as at least one selected from 0.0005~1w / v% of tocopherol及beauty / or the group consisting of a derivative thereof,
Liquid containing
A container main body, a pouring portion having a spout for pouring out the liquid agent contained in the container main body, and a lid portion for blocking the spout are provided, and the wall surface of the internal space of the pouring portion and the said A method for producing a product containing dibutylhydroxytoluene, wherein at least one of the wall surfaces of the lid portion facing the spout is housed in a container made of a resin containing polybutylene terephthalate. The method for producing a dibutylhydroxytoluene-containing product according to claim 1, wherein the liquid agent further contains taurine. The dibutylhydroxy according to claim 1 or 2, wherein the pouring portion is a nozzle for pouring out the liquid agent in the form of droplets, and the wall surface of the internal space of the nozzle is made of a resin containing polybutylene terephthalate. A method for producing a product containing toluene. The method for producing a product containing dibutylhydroxytoluene according to any one of claims 1 to 3, wherein the container body is made of a resin containing polyethylene terephthalate. The method for producing a dibutylhydroxytoluene-containing product according to any one of claims 1 to 4, wherein the liquid agent further contains a boric acid buffer. The invention according to any one of claims 1 to 5, wherein the component (C) includes a chondroitin sulfate ester and / or a pharmaceutically acceptable salt thereof, and aspartic acid and / or a pharmaceutically acceptable salt thereof. A method for producing a product containing dibutylhydroxytoluene. In the liquid, the component (A) 0.00001~0.005w / v%, the component (B) 0.005~0.5w / v% containing Murrell, to any one of claims 1 to 6 The method for producing a product containing dibutylhydroxytoluene according to the above method. The method for producing a dibutylhydroxytoluene-containing product according to any one of claims 1 to 7, wherein the liquid agent is an eye drop.