JPWO2013099861A1 - Dibutylhydroxytoluene-containing preparation and method for stabilizing dibutylhydroxytoluene - Google Patents

Abstract

The objective of this invention is providing the technique which suppresses the fall of content of the dibutylhydroxytoluene in a formulation, and improves the stability. In a container containing a preparation containing dibutylhydroxytoluene, as a resin constituting its inner wall surface (the wall surface of the inner space of the pouring portion and / or the wall surface facing the pouring port of the pouring portion in the lid portion), By adopting one containing at least one polymer selected from the group consisting of butylene terephthalate, polyethylene terephthalate, polystyrene, acrylonitrile butadiene styrene, polycarbonate, polymethyl methacrylate, and ethylene vinyl alcohol copolymer, The adsorption of dibutylhydroxytoluene to the part can be suppressed, and the dibutylhydroxytoluene content in the preparation can be stably maintained.

Description

  The present invention relates to a preparation capable of stably holding dibutylhydroxytoluene. Furthermore, the present invention relates to a method for stabilizing dibutylhydroxytoluene.

  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, the addition of an antioxidant is required.

  Conventionally, dibutylhydroxytoluene (BHT) is known as a typical compound of a fat-soluble antioxidant. As fat-soluble antioxidants, tocopherol and butylhydroxyanisole are also known, but dibutylhydroxytoluene has a stronger antioxidant effect than other fat-soluble antioxidants, such as pharmaceuticals, foods, and cosmetics. Widely used in the field. Until now, many reports have been made on pharmaceutical technology using dibutylhydroxytoluene. For example, by using dibutylhydroxytoluene, stabilization of pranoprofen (see Patent Document 1), stabilization of apigenin (see Patent Document 2), prevention of coloring of a liquid agent containing minoxidil and carpronium chloride (see Patent Document 3), Improvement of thermal stability of L-ascorbic acid-2-O-maleic acid-α-tocopherol ester or a salt thereof (see Patent Document 4), thermal stabilization of sucralose (see Patent Document 5), flavin adenine dinucleotide (FAD) ) And pyridoxine-containing preparations (eye drops) are reported to be stabilized against photolysis (see Patent Document 6), solubilized vitamin A aqueous solution (see Patent Documents 7 to 9), and the like. .

  On the other hand, in the fields of medicine, food, cosmetics and the like, a plastic container equipped with a polyethylene nozzle is generally used as a container for storing a preparation. However, when a preparation containing dibutylhydroxytoluene is contained in such a plastic container, there is a problem that the dibutylhydroxytoluene content in the preparation decreases with time. In particular, in preparations that are administered directly to mucous membranes, such as eye drops and nasal drops, dibutylhydroxytoluene is set to a low content close to the threshold amount required to exert its antioxidant action, and its content The decrease in the amount tends to make the deterioration of the preparation due to oxidation remarkable.

  Despite the enormous number of reports on formulation technology using dibutylhydroxytoluene, the cause of the decrease in dibutylhydroxytoluene content has not yet been fully elucidated. The present condition is that the formulation technology which improves stability is not developed. Dibutylhydroxytoluene has an excellent antioxidant effect compared to other fat-soluble antioxidants, and if it can improve its stability over time, it can be used for the development of formulations that require the addition of antioxidant effects. It can make a great contribution.

US Pat. No. 5,856,345 European Patent Application No. 2444061 JP 2010-018555 A JP 2004-250413 A US Patent Application Publication No. 2005/0142271 Japanese Patent No. 3734521 Japanese Patent Application Laid-Open No. H05-17350 Japanese Patent No. 3199475 Japanese Patent No. 3802328

  An object of this invention is to provide the technique which suppresses the fall of content of dibutylhydroxytoluene in a formulation, and improves the stability.

  The present inventor has made extensive studies to solve the above problems, and as a result, a commonly used polyethylene pouring part (nozzle, inner plug nozzle, perforated inner plug, etc.) and a plastic with a lid attached. When a preparation containing dibutylhydroxytoluene is stored in a container, dibutylhydroxytoluene in the preparation is volatilized in the gas phase (gas space) in the container, and it is adsorbed and accumulated in the dispensing part of the container. It was found out that a decrease in the content of the preparation was caused.

  Furthermore, as a result of repeated investigations, the present inventor has found that the inner wall surface of the container containing the preparation containing dibutylhydroxytoluene (the wall outlet of the inner space of the outlet portion and / or the outlet of the outlet portion of the outlet portion). At least one selected from the group consisting of polybutylene terephthalate, polyethylene terephthalate, polystyrene, acrylonitrile butadiene styrene, polycarbonate, polymethyl methacrylate, and an ethylene vinyl alcohol copolymer. It has been found that by adopting a polymer-containing material, adsorption of dibutylhydroxytoluene on the inner wall surface can be suppressed and the dibutylhydroxytoluene content in the preparation can be stably maintained. The present invention has been completed based on such findings.

That is, this invention provides the stabilization method of the aspect hung up below, the product containing dibutylhydroxytoluene, and the preservation | save method.
Item 1. A method for stabilizing dibutylhydroxytoluene, comprising:
At least one portion of the region constituting the inner wall of the container is at least one selected from the group consisting of polybutylene terephthalate, polyethylene terephthalate, polystyrene, acrylonitrile butadiene styrene, polycarbonate, polymethyl methacrylate, and ethylene vinyl alcohol copolymer. In a container constituted by a resin containing a polymer,
A stabilization method characterized by containing a preparation containing dibutylhydroxytoluene.
Item 2. Item 2. The stabilization method according to Item 1, wherein at least a part of a region constituting the inner wall of the container is made of a resin containing polybutylene terephthalate.
Item 3. When the container is set upright with the pouring part for pouring out the contained preparation facing upward, the region composed of the resin containing the polymer is formed so as not to come into contact with the contained preparation. Item 3. The stabilization method according to Item 1 or 2, wherein
Item 4. The container includes a container main body that contains a preparation containing dibutylhydroxytoluene, a pouring part that has a spout for pouring out the preparation contained in the container main body, and a lid that closes the spout.
Item 5. The stabilization according to any one of Items 1 to 3, wherein at least one of a wall surface of the internal space of the extraction portion and a wall surface facing the outlet in the lid portion is made of a resin containing the polymer. Method.
Item 5. Item 5. The stabilization method according to item 4, wherein both the wall surface of the internal space of the extraction portion and the wall surface facing the injection port in the lid portion are made of a resin containing the polymer.
Item 6. Item 6. The stabilization method according to Item 4 or 5, wherein the dispensing unit is a nozzle that dispenses the preparation in the form of droplets, and a wall surface of an internal space of the nozzle is made of a resin containing the polymer.
Item 7. Item 7. The stabilization method according to any one of Items 1 to 6, wherein the preparation further contains a surfactant.
Item 8. Item 8. The stabilization method according to any one of Items 1 to 7, wherein the preparation further comprises pranoprofen or a pharmaceutically acceptable salt thereof.
Item 9. Item 9. The stabilization method according to any one of Items 1 to 8, wherein the preparation further contains a chelating agent.
Item 10. Item 10. The stabilization method according to any one of Items 1 to 9, wherein the content of dibutylhydroxytoluene in the preparation is 0.00001 to 2.0 w / w%.
Item 11. Item 11. The stabilization method according to any one of Items 1 to 10, wherein the formulation is a liquid formulation.
Item 12. Item 12. The stabilization method according to any one of Items 1 to 11, wherein the preparation is an eye drop.
Item 13. A preparation containing dibutylhydroxytoluene is a product containing dibutylhydroxytoluene contained in a container,
The container includes a container main body for storing the preparation, a pouring part having a spout for pouring out the preparation contained in the container main body, and a lid for closing the spout;
At least one of the wall surface of the internal space of the pouring portion and the wall surface facing the pouring port in the lid portion is polybutylene terephthalate, polyethylene terephthalate, polystyrene, acrylonitrile butadiene styrene, polycarbonate, polymethyl methacrylate, and ethylene vinyl. It is composed of a resin containing at least one polymer selected from the group consisting of alcohol copolymers,
Products containing dibutylhydroxytoluene.
Item 14. Item 14. The dibutylhydroxytoluene-containing product according to Item 13, wherein both the wall surface of the inner space of the extraction portion and the wall surface facing the outlet in the lid portion are made of a resin containing the polymer.
Item 15. Item 15. The dibutylhydroxytoluene-containing product according to item 13 or 14, wherein at least one of a wall surface of the internal space of the extraction portion and a wall surface facing the outlet in the lid portion is made of a resin containing polybutylene terephthalate. Product.
Item 16. The dibutyl according to any one of Items 13 to 15, wherein the pouring part is a nozzle for pouring the preparation in the form of droplets, and the wall surface of the internal space of the nozzle is made of a resin containing the polymer. Products containing hydroxytoluene.
Item 17. Item 17. The dibutylhydroxytoluene-containing product according to any one of Items 13 to 16, wherein the preparation further contains a surfactant.
Item 18. Item 18. The dibutylhydroxytoluene-containing product according to any one of Items 13 to 17, wherein the preparation further comprises pranoprofen or a pharmaceutically acceptable salt thereof.
Item 19. Item 19. The product containing dibutylhydroxytoluene according to any one of Items 13 to 18, wherein the preparation further contains a chelating agent.
Item 20. Item 20. The dibutylhydroxytoluene-containing product according to any one of Items 13 to 19, wherein the content of dibutylhydroxytoluene in the preparation is 0.00001 to 2.0 w / w%.
Item 21. Item 20. The dibutylhydroxytoluene-containing product according to any one of Items 13 to 20, wherein the formulation is a liquid formulation.
Item 22. Item 22. The dibutylhydroxytoluene-containing product according to any one of Items 13 to 21, wherein the preparation is an eye drop.
Item 23. A method for preserving a preparation containing dibutylhydroxytoluene,
At least one portion of the region constituting the inner wall of the container is at least one selected from the group consisting of polybutylene terephthalate, polyethylene terephthalate, polystyrene, acrylonitrile butadiene styrene, polycarbonate, polymethyl methacrylate, and ethylene vinyl alcohol copolymer. In a container constituted by a resin containing a polymer,
A storage method, characterized by containing a preparation containing dibutylhydroxytoluene.
Item 24. Item 24. The storage method according to Item 23, wherein at least a part of the region constituting the inner wall of the container is made of a resin containing polybutylene terephthalate.
Item 25. When the container is set upright with the pouring part for pouring out the contained preparation facing upward, the region composed of the resin containing the polymer is formed so as not to come into contact with the contained preparation. Item 25. The storage method according to Item 23 or 24, wherein:
Item 26. The container includes a container main body that contains a preparation containing dibutylhydroxytoluene, a pouring part that has a spout for pouring out the preparation contained in the container main body, and a lid that closes the spout.
Item 26. The storage method according to any one of Items 23 to 25, wherein at least one of a wall surface of the internal space of the extraction portion and a wall surface facing the injection port in the lid portion is made of a resin containing the polymer. .
Item 27. Item 27. The storage method according to any one of Items 23 to 26, wherein both the wall surface of the internal space of the extraction portion and the wall surface facing the outlet in the lid portion are made of a resin containing the polymer.
Item 28. The storage according to any one of Items 23 to 27, wherein the extraction part is a nozzle for discharging the preparation in the form of droplets, and a wall surface of an internal space of the nozzle is made of a resin containing the polymer. Method.
Item 29. Item 30. The storage method according to any one of Items 23 to 29, wherein the preparation further contains a surfactant.
Item 30. Item 30. The storage method according to any one of Items 23 to 29, wherein the preparation further comprises pranoprofen or a pharmaceutically acceptable salt thereof.
Item 31. Item 31. The storage method according to any one of Items 23 to 30, wherein the preparation further contains a chelating agent.
Item 32. Item 32. The storage method according to any one of Items 23 to 31, wherein the content of dibutylhydroxytoluene in the preparation is 0.00001 to 2.0 w / w%.
Item 33. Item 33. The storage method according to any one of Items 23 to 32, wherein the formulation is a liquid formulation.
Item 34. Item 34. The storage method according to any one of Items 23 to 33, wherein the preparation is an eye drop.

  According to the present invention, the dibutylhydroxytoluene content in the preparation can be stably maintained over time.

  In particular, in eye drops, nasal drops and the like, dibutylhydroxytoluene is set to a low content, and in the prior art, the loss of the antioxidant effect due to the decrease in the content tends to be remarkable. On the other hand, according to the present invention, it is possible to overcome such disadvantages of the prior art and effectively suppress a decrease in the content of dibutylhydroxytoluene in eye drops, nasal drops, etc. It is possible to maintain it effectively.

FIG. 1 shows a cross-sectional view of an embodiment 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 sectional view of the eye drop container shown in FIG. FIG. 6 shows a cross-sectional view of one example of an eyewash container used in the present invention. FIG. 7 is a view showing the states of the glass ampoule container 10, the resin film 11, and the liquid preparation 12 when left standing for 2 weeks at a temperature of 50 ° C. in Test Example 6. FIG. 7 shows a state where the resin film 11 is sealed in the glass ampule container 10 so as not to come into contact with the liquid preparation 12.

  In this specification, “stabilization” or “stability” of dibutylhydroxytoluene means that the dibutylhydroxytoluene content in the preparation is suppressed from decreasing with time, and the content is kept stable, or Means a characteristic. Further, in the present specification, the “formulation” means contents contained in a container. Further, in the present specification, “dibutylhydroxytoluene-containing product” means a product in a state where the preparation is contained in a container, and may be abbreviated as “BHT-containing product”. In the present specification, the unit “w / w%” means mass percentage and is synonymous with weight%. Further, in this specification, the unit “w / v%” means a mass to volume percentage and is synonymous with g / 100 mL.

1. BHT-containing product In the BHT-containing product of the present invention, the preparation containing dibutylhydroxytoluene contains a specific polymer on the wall surface of the inner space of the pouring part and / or the wall surface facing the pouring port of the pouring part in the lid part. It is housed in a container made of resin. Hereinafter, the BHT-containing product of the present invention will be described in detail.

Formulation The formulation used in the present invention contains dibutylhydroxytoluene. Dibutylhydroxytoluene is also known as 2,6-di-tert-butyl-4-methylphenol, BHT, etc., and is a known compound as an antioxidant.

  The content of dibutylhydroxytoluene in the preparation is not particularly limited, and may be appropriately set according to the use of the preparation, the form of preparation, the purpose of blending dibutylhydroxytoluene, and the like. If the specific standard of the content of dibutylhydroxytoluene in the preparation is given, for example, the total amount of the preparation is 0.00001 to 2.0 w / w%, preferably 0.0001 to 1.0 w of dibutylhydroxytoluene. / w%.

  More specifically, when the preparation is a liquid pharmaceutical preparation such as an eye drop, an eye wash, a nasal drop, an ear drop, and an injection, dibutylhydroxytoluene is 0.00001 per total amount of the preparation. -0.1 w / v%, preferably 0.0001-0.01 w / v%, more preferably 0.0001-0.009 w / v%, more preferably 0.0001-0.005 w / v%. It is done. In particular, when the preparation is a liquid pharmaceutical preparation and contains pranoprofen and / or a salt thereof, the preparation is effective from the viewpoint of effectively imparting the photostability of pranoprofen and / or a salt thereof. The total amount of dibutylhydroxytoluene is preferably 0.00001 to 0.005 w / v%, more preferably 0.00005 to 0.005 w / v%, particularly preferably 0.0005 to 0.005 w / v%. Can be mentioned.

  The preparation may further contain a surfactant. In the preparation, when a surfactant is contained, it is possible to more effectively suppress a decrease in the content of dibutylhydroxytoluene.

  Specific examples of the surfactant include polyoxyethylene sorbitan fatty acid esters (polysorbate 20, polysorbate 60, polysorbate 65, polysorbate 80, etc.), tyloxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer ( Pluronic), octoxynol, polyoxyl stearate 40, polyoxyl stearate 45, polyoxyl stearate 55, and the like; amphoteric surfactants such as alkyldiaminoethylglycine and lauryl dimethylaminoacetic acid betaine; alkyl sulfates Anionic surfactants such as N-acyl taurine salts, polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyl ether sulfates; alkyl pyridiniums , Alkylamine salts, benzalkonium chloride, benzethonium cationic surfactants such as chloride, and the like. These surfactants may be used individually by 1 type, and may be used in combination of 2 or more type. Among these surfactants, nonionic surfactants are preferable, and polyoxyethylene sorbitan fatty acid esters are more preferable, from the viewpoint of more effectively suppressing the decrease in the content of dibutylhydroxytoluene.

  When the preparation contains a surfactant, the content is appropriately set according to the use of the preparation, the form of preparation, etc. For example, the surfactant is 0.001 to 20 w per total amount of the preparation. / w%, preferably 0.005 to 10 w / w%. More specifically, when the preparation is a liquid pharmaceutical preparation such as an eye drop, an eye wash, a nasal drop, an ear drop, an injection, the surfactant is 0.001 per total amount of the preparation. ~ 5 w / v%, preferably 0.01-1 w / v% or 0.1-1 w / v%, more preferably 0.01-0.5 w / v%, particularly preferably 0.05-0.5 w / v%, most preferably 0.1 to 0.2 w / v%.

  In addition, the preparation may further contain a chelating agent. In the preparation, when the chelating agent is contained, preferably when both the surfactant and the chelating agent are contained, it is possible to more effectively suppress the content of dibutylhydroxytoluene.

  Specific examples of chelating agents include edetic acid, citric acid, succinic acid, ascorbic acid, trihydroxymethylaminomethane, nitrilotriacetic acid, 1-hydroxyethane-1,1-diphosphonic acid, polyphosphoric acid, metaphosphoric acid, hexametalin. Examples thereof include acids and pharmaceutically acceptable salts thereof. These chelating agents may be used individually by 1 type, and may be used in combination of 2 or more type. Among these chelating agents, edetic acid and pharmaceutically acceptable salts thereof are preferable from the viewpoint of more effectively suppressing the decrease in the content of dibutylhydroxytoluene.

  When the preparation contains a chelating agent, the content is appropriately set according to the use of the preparation, the form of the preparation, etc., for example, the chelating agent is 0.00005-1 w / per total amount of the preparation. w%, preferably 0.0001 to 0.5 w / w%. More specifically, when the preparation is a liquid pharmaceutical preparation such as an eye drop, an eye wash, a nasal drop, an ear drop, an injection, the chelating agent is 0.0005 per total amount of the preparation. 0.2 w / v%, preferably 0.001 to 0.15 w / v%, more preferably 0.01 w / v%.

  In addition to the above components, the preparation can contain pharmacological components depending on the use of the preparation. The pharmacological component used is not particularly limited, but for example, anti-inflammatory drugs, anti-inflammatory drugs, chemotherapeutic drugs, antibacterial drugs, antiviral drugs, hormone drugs, vitamin drugs, anti-cataract drugs, angiogenesis inhibitors, immunity Suppressor, protease inhibitor, aldose reductase inhibitor, antihistamine, antiallergic agent, anxiety agent, antipsychotic agent, antibiotic, antitumor agent, antihyperlipidemic agent, antitussive / an expectorant, muscle relaxant, anti Antiepileptic drugs, antiulcer drugs, antidepressants, cardiotonic drugs, arrhythmia drugs, vasodilators, hypertension diuretics, antidiabetic drugs, antituberculosis drugs, anesthetic antagonists, skin disease drugs, dental and oral drugs, diagnostic It can be used by appropriately selecting from conventionally known pharmacological components such as drugs and public health drugs.

  Among these pharmacological components, when it is a preparation used in the ophthalmic or otolaryngological field such as eye drops, eye wash, nasal drops, ear drops, specifically, pranoprofen, dipotassium glycyrrhizinate, Anti-inflammatory agents such as allantoin, epsilon aminocaproic acid, bromfenac, ketorolac tromethamine, nepafenac, berberine chloride, berberine sulfate, sodium azulenesulfonate, zinc sulfate, zinc lactate, lysozyme hydrochloride; chlorpheniramine maleate, diphenhydramine hydrochloride Antihistamines such as salts; antiallergic agents such as cromoglycate sodium, ketotifen fumarate, acitazanolast, amlexanox, pemirolast potassium, tranilast, ibudilast; norfloxacin, ofloxacin, lomefloxacin, levofloxa Antibacterial agents such as ascorbic acid, flavin adenine dinucleotide, cyanocobalamin, pyridoxine hydrochloride, tocopherol acetate, retinol acetate, retinol palmitate, panthenol, calcium pantothenate, sodium pantothenate Vitamins such as aspartic acid, taurine, sodium chondroitin sulfate, etc., anticholinesterase agents such as neostigmine methyl sulfate, vasoconstrictors such as naphazoline, tetrahydrozoline, epinephrine, ephedrine, phenylephrine, dl-methylephedrine; hyaluronic acid Drugs for treating keratoconjunctival epithelial disorders such as sodium; sulfadiazine, sulfisoxazole, sulfisomidine, sulfadime Xing, sulfamethoxazole methoxy pyridazine, sulfamethoxazole, sulfamethoxazole ethyl Doll, sulfamethoxazole meth spermidine, sulfaphenazole, sulfaguanidine, phthalidyl Rusuru phosphatidyl azole, sulfa drugs such as succinyl Rusuru phosphatidyl azoles are exemplified. The compounds exemplified here may be in the form of a salt or other salts as long as they are pharmaceutically acceptable.

  By maintaining a stable dibutylhydroxytoluene content in the preparation, the oxidative degradation of the pharmacological component contained in the preparation is suppressed, and as a result, the thermal stability, light stability, and stability during long-term storage of the pharmacological component. Can be improved. Among the pharmacological components, the components that can be stabilized by dibutylhydroxytoluene are specifically, pranoprofen, pranoprofen salts, berberine chloride, flavin adenine dinucleotide sodium, pyridoxine hydrochloride, retinol acetic acid. Examples thereof include esters, retinol palmitate, cyanocobalamin, and sodium azulene sulfonate.

  Among the pharmacological components, pranoprofen and / or its salt, in particular, can be provided with a significantly superior light stability by maintaining a stable content of dibutylhydroxytoluene in the formulation. It is particularly suitable as a pharmacological component. Here, the salt of pranoprofen 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 And organic base salts such as salts, morpholine salts, piperazine salts and the like. These pranoprofen salts may be used alone or in combination of two or more.

  The content of these pharmacological components is appropriately set according to the type of pharmacological component to be used, the purpose of the preparation, the form of preparation, etc., for example, 0.001 to 1.0 w / per total amount of the preparation w%, preferably 0.005 to 0.5 w / w%. In particular, when pranoprofen and / or a salt thereof is used as a pharmacological component and the preparation is a liquid pharmaceutical preparation, the content of pranoprofen and / or a salt thereof is preferably 0.005 to 0.005. 5 w / v%, more preferably 0.05 to 0.1 w / v%, and most preferably 0.05 w / v%.

  Furthermore, the said formulation is suitably formulated so that a desired formulation form and physical property may be provided by mix | blending a pharmaceutically acceptable base or additive other than the said component as needed. Such a base or additive is not particularly limited. For example, in the case of a liquid preparation, an aqueous base, a buffer, an isotonic agent, a solubilizing agent, a viscous base, a cooling agent, Examples include pH adjusters, preservatives, stabilizers and the like.

  Examples of the aqueous base include water and physiological saline.

  Examples of the buffer include phosphate buffer, borate buffer, citrate buffer, tartaric acid buffer, acetate buffer, Tris buffer, amino acid, and the like.

  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; boric acid and the like.

  Examples of solubilizers include nonionic surfactants such as polyoxyethylene sorbitan monooleate, polyoxyethylene hydrogenated castor oil, tyloxapol, pluronic, and polyoxyl stearate; polyhydric alcohols such as glycerin and macrogol. Can be mentioned.

  Examples of the viscous base include water-soluble polymers such as polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, carboxyvinyl polymer, polyacrylic acid, sodium hyaluronate, sodium chondroitin sulfate, xanthan gum, sodium alginate; hydroxyethyl cellulose, methyl cellulose, hydroxy Examples thereof include celluloses such as propylcellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose.

  Examples of the refreshing agent include terpenes such as l-menthol, borneol, camphor, and eucalyptus oil.

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

  Examples of preservatives include sorbic acid, potassium sorbate, sodium benzoate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, chlorohexidine gluconate, boric acid, dehydroacetic acid, dehydro Examples include sodium acetate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, zinc chloride, parachlormetaxylenol, chlorcresol, phenethyl alcohol, polydronium chloride, and thimerosal.

  Examples of the stabilizer include polyvinyl pyrrolidone, sodium sulfite, monoethanolamine, glycerin, propylene glycol, cyclodextrin, dextran, ascorbic acid, taurine, tocopherol and the like.

  About content of these bases or additives, it sets suitably according to the use, formulation form, etc. of the said formulation.

  The form of the preparation is not particularly limited, and any of liquid forms such as aqueous solutions, suspensions, and emulsions; semisolid forms such as gels and ointments; solid forms such as powders, fine granules, and granules It may be. In particular, liquid preparations have a strong tendency to decrease the dibutylhydroxytoluene content in relation to plastic containers that are widely used in the prior art. According to the present invention, even in liquid preparations, dibutylhydroxytoluene The content reduction can be effectively suppressed. In view of such effects of the present invention, among these preparation forms, a liquid preparation is mentioned as a suitable preparation form.

  The use of the preparation is not particularly limited, and examples thereof include pharmaceuticals, contact lens care products, cosmetics, and foods. Among these uses, preferably, pharmaceuticals and contact lens care products are used. Specific examples of pharmaceuticals include ophthalmic preparations such as eye drops (including eye drops for contact lenses that can be instilled even when a contact lens is worn), eyewashes, etc .; otorhinological preparations such as nasal drops and ear drops Injections and the like, preferably ophthalmic preparations, and more preferably eye drops. Specific examples of contact lens care products include contact lens mounting liquids, contact lens multipurpose solutions, and the like. Specifically, cosmetics include lotion, milky lotion, cream, cosmetic liquid, UV care cosmetics, face wash, foundation, lipstick, eye shadow, mascara, hair cream, shampoo, conditioner, body shampoo, bath preparation, perfume. And skin cleansing agents.

  In the BHT-containing product of the present invention, the preparation may be a multi-dose type that is filled with a plurality of doses and used repeatedly, or a unit that is filled with a single dose and is used up once. A dose type may also be used.

  In addition, when a formulation containing dibutylhydroxytoluene is contained in a conventionally used plastic container, the higher the proportion of the gas phase (gas space) in the container, the more the dibutylhydroxytoluene content decreases. Has been confirmed by the present inventors (see Test Example 5 described later). In other words, in a multi-dose type formulation that is used repeatedly multiple times, the amount of the contained formulation decreases with repeated use due to the relationship with the plastic container that is widely used in the prior art, and accordingly, the amount of dibutylhydroxytoluene is reduced. There is a problem that the decrease in the content becomes remarkable. On the other hand, according to this invention, the content fall of dibutylhydroxytoluene can be suppressed effectively, without being influenced by the ratio for which the gaseous phase (gas space) in a container accounts. In view of such an effect of the present invention, a multi-dose type preparation is mentioned as a suitable example of the preparation used in the present invention.

  The preparation may be manufactured according to a preparation method known per se, depending on the preparation form, use, etc. For example, in the case of a medicine, the method described in the 16th revised Japanese Pharmacopoeia General Rules for Preparation is used. Can be manufactured.

Container The BHT-containing product of the present invention comprises a container main body, a pouring part, and a lid part in order to accommodate the preparation, and the pouring part is poured in the wall surface and / or the lid part of the internal space of the pouring part. A container in which the wall surface facing the outlet is made of a resin containing a specific polymer is used.

<Container structure>
The container main body which comprises the said container is a site | part which accommodates the said formulation. The shape and size of the container main body are not particularly limited, and are set as appropriate according to the type of formulation to be stored.

  The pouring part constituting the container has an internal space that communicates between the container main body and the outside of the container main body, and includes a pouring outlet for pouring out the preparation contained in the container main body. The outlet is provided so as to communicate with the opening of the container main body, and is a part for dispensing (discharging) the preparation contained in the container main body from the pouring outlet to the outside of the container through the internal space. The structure of the dispensing unit is not particularly limited as long as it is configured so that the formulation contained in the container body can be poured out of the container body from the spout, and for example, the formulation is in the form of droplets. It may be configured to be poured out, or it may be configured so that the preparation is discharged in a non-droplet form. From the viewpoint of more effectively achieving the effects of the present invention, the dispensing section is preferably a nozzle configured to dispense the preparation in the form of droplets. Moreover, the said extraction | pouring part may be provided with the inside stopper like an inside stopper nozzle or a perforated inside stopper, for example.

  One part or all part of the said extraction part may be integrally molded with the container main body. Moreover, the said extraction | pouring part may be attached to the lumen | bore of the opening part of a container main body, or it is made to attach to the outer side, and is attached.

  Moreover, the cover part which comprises the said container is a site | part which blocks the said spout. The said lid part should just be equipped with the structure fitted with the container main body and / or the spout. More specifically, when the BHT-containing product of the present invention is a multi-dose type, it may be of a structure that can be detachably fitted to the container body and / or the spout, and the BHT-containing product of the present invention. In the case of a unit dose type, any structure may be used as long as it is detachably fitted from the container body and / or the spout. As a suitable example of the structure detachably fitted to the container main body and / or the spout, there is a lid portion that is detachably attached to the container main body and / or the extraction portion by screw fitting. When the lid and the container main body and / or the extraction portion are detachably attached by screw fitting, the lid is provided with a screw portion that is screwed with the screw portion of the container main body and / or the extraction portion. Just do it.

  In the BHT-containing product of the present invention, in order to effectively suppress the adsorption of dibutylhydroxytoluene volatilized in the gas phase (gas space) in the container to the inner wall of the container, the container was accommodated in the container body. It is desirable that the drug product has a shape that can be left standing in a state where it is not in contact with the dispensing part, specifically a shape that can stand upright while the dispensing part is facing upward. In addition, the BHT-containing product of the present invention is such that the container itself is in a state in which the pouring part faces upward even if the container itself is not shaped to stand upright with the pouring part facing upward. In the case of distribution and storage, the adsorption of dibutylhydroxytoluene volatilized in the gas phase in the container to the inner wall of the container can be effectively suppressed. Therefore, as another preferred example of the BHT-containing product of the present invention, there is one in which the extraction part is held in an upward state at the distribution and storage stages.

  The shape of the said container is suitably set according to the use of the BHT containing formulation to accommodate. Specifically, an eye drop container, an eye wash container, an nasal drop container, etc. are mentioned.

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

  1 is a cross-sectional view of an embodiment of an eye drop container, and FIG. 2 is a partially enlarged cross-sectional view of the eye drop container shown in FIG. In the ophthalmic container shown in FIG. 1, a dispensing part 2 capable of dispensing the preparation in the form of droplets is inserted into the lumen of the opening of the container body 1, and a lid 3 is further attached to the container body 1. It is detachably attached by screw fitting, and the spout of the spout part 2 is blocked. In the eye drop container, the preparation contained in the container 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 preparation, but is preferably used for accommodating a multi-dose type preparation.

  FIG. 3 is a cross-sectional view of one embodiment of an eye drop container. In the eye drop container shown in FIG. 3, the container main body 1 and the extraction portion 2 are integrally formed of the same material regardless of adhesion or mechanical joining, and the internal space 4 of the extraction portion 2 is interposed. The preparation can be poured out of the container from the spout. In FIG. 3, the lid 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 body 1, and the container member above the virtual line corresponds to the extraction part 2. The eye drop container shown in FIG. 3 may be used for accommodating a unit dose type preparation, but is preferably used for accommodating a multi-dose type preparation.

  4 is a cross-sectional view of one embodiment 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 drop shown in FIG. 4, the container main body 1, the extraction part 2, and the cover part 3 are integrally molded. The dispensing part 2 and the lid part 3 are connected to each other, but the preparation contained in the container body 1 is separated through the internal space 4 of the dispensing part 2 by separating them during use. Can be poured out of the container. 4 and 5, a virtual line (dotted line) is inserted for convenience. 4 and 5, the container member between two virtual lines corresponds to the extraction part 2, and the space between the two virtual lines corresponds to the internal space 4 of the extraction part 2. The eye drop container shown in FIG. 4 is suitably used for housing a unit dose type BHT-containing preparation.

  FIG. 6 is a cross-sectional view of the eyewash container. In the eyewash container shown in FIG. 6, a part of the container body 1 and the extraction part 2 are integrally formed. In the said eyewash container, the said formulation accommodated in the container main body 1 is poured out of a container from a spout through the internal space 4 of the extraction | pouring part 2. FIG. In FIG. 6, a virtual line (dotted line) is inserted 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 predetermined containers may be used other than the eye drop container and the eye wash container. It can be used as long as it has the features of

<Container material of container>
In the container, at least one of a wall surface of the internal space of the extraction portion and a wall surface facing the outlet in the lid portion is polybutylene terephthalate (PBT), polyethylene terephthalate (PET), polystyrene (PS), acrylonitrile. It is comprised by resin containing the at least 1 sort (s) of polymer selected from the group which consists of a butadiene styrene (ABS), a polycarbonate (PC), a polymethyl methacrylate (PMMA), and an ethylene vinyl alcohol copolymer (EVOH). 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 FIGS. 2, 5, and 6 as an example, the surface portion indicated by reference numeral 5 corresponds to the “wall surface of the internal space of the extraction portion”, and the surface portion indicated by reference numeral 6 is “the lid”. It corresponds to “a wall surface facing the spout” in the section.

  By forming the wall surface facing the spout of the pouring part in the wall surface and / or the lid of the pouring part with the resin containing such a polymer, the pouring part of dibutylhydroxytoluene and / or Adsorption and accumulation on the lid can be effectively suppressed, and the dibutylhydroxytoluene content in the preparation can be stably maintained. Among these polymers, PBT, PET, PS, ABS, and EVOH are preferable from the viewpoint of ease of molding and the like, and PBT and PET are more preferable.

  Among the polymers, polystyrene may be either general-purpose polystyrene (GPPS) or impact-resistant polystyrene (HIPS).

  The resin constituting the wall surface of the inner space of the pouring part and / or the wall surface facing the pouring port of the pouring part in the lid part may be composed of at least one of the polymers. It may be composed of a blend polymer of at least one of the above and a polymer other than the polymer. When using a blend polymer of at least one of the polymers and a polymer other than the polymer as a resin constituting the wall facing the outlet of the outlet in the wall and / or lid of the outlet, The mixing ratio is not particularly limited as long as the effects of the present invention are achieved, but the total amount of the blended polymer is 50 w / w% or more, preferably 70 w / w% or more, more preferably 90 w. It is desirable to occupy more than / w%.

  In the container, at least one of the wall surface of the internal space of the pouring portion and the wall surface facing the pouring port of the pouring portion in the lid portion only needs to contain the resin described above. For example, when adopting a pouring part (for example, a nozzle configured to drop the preparation in the form of droplets) where the preparation is poured out in the form of droplets, it is effective to reduce the content of dibutylhydroxytoluene. It is preferable that at least the wall surface of the internal space of the extraction portion is made of the resin described above, and the wall surface of the internal space of the extraction portion and the outlet of the extraction portion in the lid portion More preferably, both opposing wall surfaces are composed of the resin described above. In addition, for example, in the case of adopting a pouring part through which the preparation flows out in a non-droplet form, at least the pouring of the pouring part at the lid is effective from the viewpoint of effectively suppressing a decrease in the content of dibutylhydroxytoluene. It is preferable that the wall surface facing the outlet is made of the above-described resin, and both the wall surface of the inner space of the pouring portion and the wall surface facing the pouring port of the pouring portion in the lid portion are made of the resin described above. More preferably.

  As long as the wall surface of the internal space of the pouring part and / or the wall surface facing the pouring port of the pouring part in the lid part is made of the above-described resin, the constituent materials of the parts other than these wall surfaces are not particularly limited. . For example, parts other than these wall surfaces may be comprised with resin containing the said polymer, and may be comprised with raw materials other than the resin containing the said polymer. When the parts other than these wall surfaces are composed of the resin containing the polymer, each cross-sectional layer structure of the extraction part and / or the cover part is a single layer structure formed from the resin containing the polymer, When the portion other than the wall is made of a material other than the polymer, each cross-sectional layer structure of the pouring part and / or the lid is a laminated structure of a wall surface constituting layer made of the polymer and a base material layer made of another material. become.

  When the said container is integrally molded with the container main body and the extraction | pouring part, the container main body is comprised with the same resin as the extraction | pouring part.

  In addition, when the container is attached by inserting the extraction portion into the inner cavity of the opening of the container main body, the container main body may be made of glass or plastic. Further, in such a container, when the container body is made of plastic, it may be made of a resin different from the pouring part, but the content of dibutylhydroxytoluene in the preparation is further reduced. In view of effective suppression, it contains at least one polymer selected from the group consisting of polybutylene terephthalate, polyethylene terephthalate, polystyrene, acrylonitrile butadiene styrene, polycarbonate, polymethyl methacrylate, and ethylene vinyl alcohol copolymer. It is desirable that it is made of resin. About resin containing these polymers, about a specific aspect, a suitable thing, etc., it is the same as that of the case of resin which comprises the said extraction part.

2. Method for stabilizing dibutylhydroxytoluene In the method for stabilizing dibutylhydroxytoluene of the present invention, a preparation containing dibutylhydroxytoluene is accommodated in a container in which at least a part of the region constituting the inner wall of the container is made of a specific resin. It is characterized by this.

  The “preparation containing dibutylhydroxytoluene” used in the stabilization method of the present invention is the same as the preparation used in the BHT-containing product.

  Further, in the container used in the stabilization method of the present invention, at least a part of the region constituting the inner wall of the container is made of polybutylene terephthalate, polyethylene terephthalate, polystyrene, acrylonitrile butadiene styrene, polycarbonate, polymethyl methacrylate, and ethylene vinyl. It is a container constituted by a resin containing at least one polymer selected from the group consisting of alcohol copolymers. The region constituting the inner wall of the container is a wall surface region that forms the inner space of the container that accommodates the preparation. Specifically, the inner wall surface of the container body, the inner wall surface of the dispensing portion, and the inner wall surface of the lid portion Formed by. That is, in the container used in the stabilization method of the present invention, at least a part of the inner wall surface of the container body, the inner wall surface of the pouring part, and the inner wall surface of the lid part is made of the resin containing the polymer. Just do it. The inner wall surface of the extraction part is a wall surface part of the internal space of the extraction part. Further, the inner wall surface of the lid portion is a wall surface region of the lid portion facing the spout port of the extraction portion. The structural structure of the container main body, the extraction part, and the lid part is as described in the “Container” column of “1. BHT-containing product”.

  The container used in the stabilization method of the present invention is only required that at least a part of the region constituting the inner wall is made of the resin containing the polymer, but dibutyl vaporized in the gas phase (gas space) in the container. In order to effectively suppress the adsorption of hydroxytoluene on the inner wall of the container, the portion made of the resin containing the polymer is when the container is erected so that the pouring portion faces upward. A region that does not come into contact with the contained preparation (hereinafter sometimes referred to as a non-contact region) is preferable. Specifically, as the non-contact region of the container, the inner wall portion of the container main body (for example, around the opening of the container main body) that becomes the non-contact region when the preparation is filled at the time of manufacture, the inner wall surface of the dispensing portion And the inner wall surface of the lid.

  The container used in the stabilization method of the present invention may be a container used in the BHT-containing product, although at least a part of the region constituting the inner wall of the container may be composed of a resin containing the polymer. It is done.

  Since the stabilization method of the present invention can effectively suppress a decrease in the content of dibutylhydroxytoluene and improve the storage stability of dibutylhydroxytoluene, it is implemented as a storage method for a preparation containing dibutylhydroxytoluene. You can also

  EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

Test Example 1: Evaluation of adsorptivity (liquid contact state) of various fat-soluble antioxidants Liquid preparations shown in Table 1 were prepared, and fat-soluble antioxidants against polyethylene or polybutylene terephthalate in contact with the liquid preparations. The adsorptivity of the agents (dibutylhydroxytoluene, butylhydroxyanisole, acetic acid d-α-tocopherol) was evaluated. Specifically, in a glass ampoule container containing 6 mL of liquid formulation, a polyethylene nozzle (nozzle for low-density polyethylene resin eye drops container; trade name “Novatec (registered trademark) LD LJ808”, Nippon Polyethylene Co., Ltd. ) Or a polybutylene terephthalate nozzle (nozzle for eye drops; trade name “Novaduran (registered trademark) 5010R5X”, manufactured by Mitsubishi Engineering Plastics) and seal the opening of the glass ampoule container Sealed. With the nozzle immersed in the liquid preparation, it was allowed to stand at 50 ° C. for 2 weeks. Subsequently, the sealed glass ampule container was opened, and the fat-soluble antioxidant content in the liquid preparation was measured by HPLC to calculate the residual ratio (%) of the fat-soluble antioxidant after storage. For comparison, a test was performed in the same manner as described above without inserting a nozzle.

  The results are shown in Table 1. As is clear from the results of Reference Examples 1-1 to 1-3 and 2-1 to 2-3, butylhydroxyanisole and d-α-tocopherol acetate were immersed in a nozzle made of polyethylene or polybutylene terephthalate. Even in this case, there was almost no change in the content in the preparation, and it was maintained stably. On the other hand, as is clear from the results of Comparative Example 1, the content of dibutylhydroxytoluene in the preparation was significantly reduced when a polyethylene nozzle was immersed. That is, it has been clarified that dibutylhydroxytoluene has a unique property of being adsorbed on a polyethylene nozzle. Further, since most of the constituent resins of the nozzles conventionally used in eye drops are polyethylene, it has been found that the drop in the content of dibutylhydroxytoluene is unavoidable in the eye drops used conventionally.

  On the other hand, as is clear from the results of Example 1, dibutylhydroxytoluene is stable with almost no decrease in the content in the preparation when a polybutylene terephthalate nozzle is immersed (Example 1). Was maintained.

Test Example 2: Evaluation of adsorbability (non-wetted state) of dibutylhydroxytoluene The liquid preparation shown in Table 2 was prepared, and the adsorbability of dibutylhydroxytoluene to the nozzle in a state not in contact with the liquid preparation was evaluated. Went. Specifically, after attaching a polyethylene or polybutylene terephthalate nozzle to the opening of a polyethylene terephthalate ophthalmic container body (capacity 9 mL; maximum fillable volume 11 mL) and filling the container with 10 mL of liquid preparation The sample was allowed to stand for 2 weeks at a temperature of 50 ° C. with a polypropylene cap (nozzle and liquid preparation in a non-contact state). Next, the dibutylhydroxytoluene content in the liquid preparation in the eye drop container was measured by HPLC, and the residual ratio (%) of dibutylhydroxytoluene after storage was calculated.

  The results are shown in Table 2. From this result, it was confirmed that an eye drop container equipped with a polyethylene nozzle causes a significant decrease in the dibutylhydroxytoluene content in the liquid formulation even when the nozzle is not in contact with the liquid formulation (Comparative Example). 3). That is, it was suggested that dibutylhydroxytoluene in the liquid preparation volatilizes in the container and is adsorbed and accumulated in a polyethylene nozzle. On the other hand, in the ophthalmic container equipped with a nozzle made of polybutylene terephthalate, the dibutylhydroxytoluene content was hardly decreased, and it was confirmed that dibutylhydroxytoluene in the liquid preparation can be stably retained (Example 2). ).

Test Example 3: Evaluation of the Effect of Surfactant on Dibutylhydroxytoluene Adsorbability (Non-Wetted State) A liquid formulation shown in Table 3 was prepared and contacted with the liquid formulation in the same manner as in Test Example 2 above. The adsorptivity of dibutylhydroxytoluene to the nozzle in a liquid-free state was evaluated.

  The results are shown in Table 3. From this result, in the case of using an eye drop container equipped with a nozzle made of polybutylene terephthalate, in the liquid preparation containing polysorbate 80 (Example 4 and Example 5), the liquid preparation not containing polysorbate 80 (Example 3) It became clear that the effect of suppressing the decrease in the content of dibutylhydroxytoluene in the liquid preparation was significant.

Test Example 4: Evaluation of the effect of the content of dibutylhydroxytoluene and surfactant on the adsorptivity (non-wetted state) of dibutylhydroxytoluene The liquid formulations shown in Tables 4 to 6 were prepared, and the same as in Test Example 2 above. By this method, the adsorptivity of dibutylhydroxytoluene to the nozzle in a state not in contact with the liquid preparation was evaluated.

  The results are shown in Tables 4-6. From this result, in the case of using an ophthalmic container equipped with a nozzle made of polybutylene terephthalate, 0.1-0.00001 w / v% dibutylhydroxytoluene and 0.1-1 w / v% polysorbate 80 are included. In the liquid preparations (Examples 6 to 19), it was revealed that the effect of suppressing the decrease in the dibutylhydroxytoluene content in the liquid preparation was significant.

Test Example 5: Evaluation of the influence of the liquid amount of the liquid preparation on the adsorptivity (non-wetted state) of dibutylhydroxytoluene Using the liquid preparation used in Example 2, the amount of liquid accommodated in the eye drop container was 2, 5 And dibutylhydroxytoluene with respect to the nozzle in a state not in contact with the liquid preparation in the same manner as in Test Example 2 except that the temperature condition during storage was changed to 25 ° C. The adsorptivity was evaluated.

  The results are shown in Table 7. From this result, the smaller the amount of the liquid preparation contained in the container, that is, the higher the proportion of the gas phase (gas portion) in the container body, the more remarkable the adsorption of dibutylhydroxytoluene to the polyethylene nozzle. Became clear. That is, from this result, it was suggested that in the multi-dose-type preparation that is used repeatedly, the dibutylhydroxytoluene content decreases remarkably as the amount of the preparation decreases with use.

  On the other hand, when a polybutylene terephthalate nozzle was used, it was confirmed that the decrease in the dibutylhydroxytoluene content can be effectively suppressed regardless of the amount of liquid preparation contained in the container.

Test Example 6: Evaluation of the influence of the resin constituting the nozzle on the adsorptivity (non-wetted state) of dibutylhydroxytoluene Using the liquid formulation used in Example 2, in a state where it was not in contact with the liquid formulation The adsorptivity of dibutylhydroxytoluene to various resins was evaluated. Specifically, one glass resin film (8 mm × 25 mm; thickness 0.5 mm) shown in Table 8 is placed above a glass ampoule container containing 6 mL of a liquid preparation so as not to come into contact with the glass ampule container. The ampule container was sealed by sealing the opening. Then, as shown in FIG. 7, the resin film was not in contact with the liquid preparation, and was allowed to stand at 50 ° C. for 2 weeks. Subsequently, the sealed glass ampoule container was opened, the dibutylhydroxytoluene content in the liquid preparation was measured by HPLC, and the residual ratio (%) of dibutylhydroxytoluene after storage was calculated.

  The results are shown in Table 8. From this result, polyvinyl chloride, linear low-density polyethylene, high-density polyethylene, low-density polyethylene, polyacetal, thermoplastic elastomer, and polypropylene have a strong action of adsorbing dibutylhydroxytoluene, and dibutylhydroxytoluene in liquid preparations. It was confirmed to reduce the content. On the other hand, polyethylene terephthalate, polycarbonate, polymethyl methacrylate, polybutylene terephthalate, ethylene vinyl alcohol copolymer, acrylonitrile butadiene styrene, impact polystyrene, and general-purpose polystyrene can suppress the adsorption of dibutylhydroxytoluene. It was confirmed that the content of dibutylhydroxytoluene in the mixture can be maintained stably.

Test Example 7: Evaluation of adsorptivity of dibutylhydroxytoluene (non-wetted state) and light stability of pranoprofen The liquid preparation shown in Table 9 was prepared, and the adsorptivity of dibutylhydroxytoluene to a polybutylene terephthalate nozzle And the photostability of pranoprofen was evaluated. Specifically, after filling 15 mL of a liquid preparation into a brown eye drop container body (capacity 16 mL) made of polyethylene terephthalate, a polybutylene terephthalate nozzle is attached to the opening of the eye drop container body, and a polypropylene cap Did. The total illuminance of 600 for the container-prepared preparation thus prepared was irradiated at 25 ° C. and 3,000 lx / hr using a light stability tester (LT-120A-WCD, manufactured by Nagano Science Co., Ltd.). Light exposure until it reaches 1,000, lx · hr, and the content of pranoprofen in the liquid preparation before and after the light exposure is measured by HPLC (n = 3), and the residual ratio of pranoprofen after light exposure (%) Was calculated.

  The results are shown in Table 9. From this result, it was confirmed that pranoprofen is stably held even by light exposure by accommodating a liquid preparation containing dibutylhydroxytoluene in a container having a nozzle made of polybutylene terephthalate. In particular, when the content of dibutylhydroxytoluene is 0.0001 to 0.005 w / v% (particularly 0.0005 to 0.005 w / v%), the light stability of the coexisting pranoprofen is remarkably high. It was also clarified from the results of this test.

DESCRIPTION OF SYMBOLS 1 Container main body 2 Extraction part 3 Lid part 4 Internal space of extraction part 5 Wall surface 6 of extraction part internal space Wall surface 10 which opposes the outflow part of extraction part in a cover part 10 Glass ampoule container 11 Resin film 12 Liquid preparation

Claims (20)

A method for stabilizing dibutylhydroxytoluene, comprising:
At least one portion of the region constituting the inner wall of the container is at least one selected from the group consisting of polybutylene terephthalate, polyethylene terephthalate, polystyrene, acrylonitrile butadiene styrene, polycarbonate, polymethyl methacrylate, and ethylene vinyl alcohol copolymer. In a container constituted by a resin containing a polymer,
A stabilization method characterized by containing a preparation containing dibutylhydroxytoluene.   The stabilization method according to claim 1, wherein at least a part of a region constituting the inner wall of the container is made of a resin containing polybutylene terephthalate.   When the container is set upright with the pouring part for pouring out the contained preparation facing upward, the region composed of the resin containing the polymer is formed so as not to come into contact with the contained preparation. The stabilization method according to claim 1, wherein The container includes a container main body that contains a preparation containing dibutylhydroxytoluene, a pouring part that has a spout for pouring out the preparation contained in the container main body, and a lid that closes the spout.
2. The stabilization method according to claim 1, wherein at least one of a wall surface of the internal space of the extraction portion and a wall surface facing the injection port in the lid portion is made of a resin containing the polymer.   5. The stabilization method according to claim 4, wherein both the wall surface of the internal space of the pouring part and the wall surface facing the pouring port in the lid part are made of a resin containing the polymer.   The stabilization method according to claim 4, wherein the dispensing unit is a nozzle that dispenses the preparation in the form of droplets, and a wall surface of an internal space of the nozzle is made of a resin containing the polymer.   The stabilization method according to claim 1, wherein the preparation further comprises a surfactant.   The stabilization method according to claim 1, wherein the preparation further comprises pranoprofen or a pharmaceutically acceptable salt thereof.   The stabilization method according to claim 1, wherein the preparation further comprises a chelating agent.   The stabilization method according to claim 1, wherein the preparation is a liquid preparation.   The stabilization method according to claim 1, wherein the preparation is an eye drop. A preparation containing dibutylhydroxytoluene is a product containing dibutylhydroxytoluene contained in a container,
The container includes a container main body for storing the preparation, a pouring part having a spout for pouring out the preparation contained in the container main body, and a lid for closing the spout;
At least one of the wall surface of the internal space of the pouring portion and the wall surface facing the pouring port in the lid portion is polybutylene terephthalate, polyethylene terephthalate, polystyrene, acrylonitrile butadiene styrene, polycarbonate, polymethyl methacrylate, and ethylene vinyl. It is composed of a resin containing at least one polymer selected from the group consisting of alcohol copolymers,
Products containing dibutylhydroxytoluene.   The dibutylhydroxytoluene-containing product according to claim 12, wherein both the wall surface of the inner space of the extraction portion and the wall surface facing the outlet in the lid portion are made of a resin containing the polymer.   13. The dibutylhydroxytoluene-containing product according to claim 12, wherein at least one of a wall surface of the inner space of the extraction portion and a wall surface facing the outlet in the lid portion is made of a resin containing polybutylene terephthalate. .   The dibutylhydroxytoluene-containing product according to claim 12, wherein the pouring part is a nozzle for pouring the preparation in the form of droplets, and the wall surface of the internal space of the nozzle is made of a resin containing the polymer. .   The product containing dibutylhydroxytoluene according to claim 12, wherein the formulation further comprises a surfactant.   The dibutylhydroxytoluene-containing product according to claim 12, wherein the formulation further comprises pranoprofen, or a pharmaceutically acceptable salt thereof.   The product containing dibutylhydroxytoluene according to claim 12, wherein the formulation further comprises a chelating agent.   The product containing dibutylhydroxytoluene according to claim 12, wherein the preparation is a liquid preparation.   The product containing dibutylhydroxytoluene according to claim 12, wherein the preparation is an eye drop.