RU2712031C2 - Method for stabilizing dibutylhydroxytoluene - Google Patents

Abstract

FIELD: medicine; pharmaceuticals.SUBSTANCE: group of inventions refers to medicine, namely to ophthalmology, and is intended to maintain stability of dibutylhydroxytoluene in a liquid preparation. Ophthalmic product in the form of a container contains a liquid preparation containing dibutylhydroxytoluene, pranoprofen and/or a pharmaceutically acceptable salt thereof and at least one compound selected from a group consisting of a chondroitin sulphate ester, aspartic acid, alginic acid, alginic acid derivative and their pharmaceutically acceptable salts and cyanocobalamin, panthenol, tocopherol and tocopherol derivative. Components are used in claimed amounts. Container comprises a housing, a nozzle having an outlet, and a cap for closing the outlet. At least one of the surfaces of the walls of the inner space of the spout and the surfaces of the cap walls facing the outlet has a resin which contains polybutylene terephthalate. Also provided is a method of stabilizing dibutylhydroxytoluene in a liquid preparation.EFFECT: use of the group of inventions makes it possible to increase thermal stability of dibutylhydroxytoluene and to suppress reduction of its content over time in the liquid preparation.16 cl, 8 tbl, 6 dwg, 5 ex

Description

FIELD OF THE INVENTION

The present invention relates to a product that allows you to maintain the stability of dibutylhydroxytoluene in a liquid preparation containing dibutylhydroxytoluene and pranoprofen and / or its salt. Further, the present invention relates to a method for stabilizing a liquid preparation containing dibutylhydroxytoluene, as well as pranoprofen and / or its salt.

State of the art

In recent years, drugs have been developed with various properties in the field of medicines, nutrition, cosmetics and others. To prevent oxidation of the ingredients in these preparations, the presence of antioxidants in them is necessary.

Dibutylhydroxytoluene (BHT) is known as a typical compound from a number of fat-soluble antioxidants. Tocopherol, butyl hydroxyanisole, and others are also known as fat-soluble antioxidants. Dibutylhydroxytoluene has a stronger antioxidant activity than other fat-soluble antioxidants, and is widely used in the field of medicines, nutrition, cosmetics and other fields.

In addition, there are reports of methods for preparing drugs using dibutylhydroxytoluene. For example, it was noted that stabilization of pranoprofen and / or its salt is achieved using dibutylhydroxytoluene (see Patent Document 1). However, Patent Document 1 mainly focuses on the stability of pranoprofen and / or its salt, and the stability of dibutylhydroxytoluene is not discussed. It has also been reported that since the aqueous composition, including pranoprofen and / or its salts and dibutylhydroxytoluene, has reduced thermal stability, the formation of a yellow color in the aqueous composition can be suppressed by the additional addition of a sulfamide agent (see Patent Document 2). However, Patent Document 2 also mainly focuses on preventing yellow formation of aqueous compositions, and the stability of dibutylhydroxytoluene itself is not discussed.

On the other hand, in the field of medicines, nutrition, cosmetics and other fields, plastic containers with a tip attached to them made of polyethylene are usually used as a container for drugs. However, it was noted that when a liquid preparation containing dibutylhydroxytoluene is placed in a plastic container with a nozzle (such as a tip, an internal nozzle or a hollow plug) and a cap made of polyethylene, which are commonly used widely, then dibutylhydroxytoluene is adsorbed in the liquid preparation and accumulates on the spout (Patent Document 3). Patent Document 3 states that a specific resin, for example polybutylene terephthalate, can be used as a resin forming the surface of the inner wall (such as the surface wall of the inner space of the spout and / or the wall surface of the cap facing the outlet from the spout) of the liquid container containing dibutylhydroxytoluene; while the adsorption of dibutylhydroxytoluene on the inner surface of the walls is suppressed, and the content of dibutylhydroxytoluene in the liquid preparation remains stable.

BACKGROUND OF THE INVENTION PATENT DOCUMENTS

Patent Document 1: Japanese Patent Laid-Open Publication No. Hei 7-304670 (1995)

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

Patent Document 3: International Publication No. WO 2013/99861

SUMMARY OF THE INVENTION

The tasks solved by the invention

In a study of the practical use of a liquid preparation containing dibutylhydroxytoluene, as well as pranoprofen and / or its salt, the present inventors faced a new problem in that when the liquid preparation is placed in a traditional and commonly used container, there is a significant decrease in the content dibutylhydroxytoluene over time. In addition, in Patent Document 2, it was noted that a sulfanilamide agent can be added to an aqueous composition containing pranoprofen and / or its salt and dibutylhydroxytoluene to increase the thermal stability of the aqueous composition, thereby counteracting the yellow color of the aqueous composition. However, the development of the yellow color of the aqueous composition and the thermal destabilization of dibutylhydroxytoluene are different phenomena, and thus, Patent Document 2 does not disclose a method for improving the thermal stability of dibutylhydroxytoluene per se.

In liquid preparations containing dibutylhydroxytoluene, as well as pranoprofen and / or its salt, it is possible to compensate for the decrease over time of the content of dibutylhydroxytoluene by increasing the amount of dibutylhydroxytoluene added, but increasing the amount of dibutylhydroxytoluene in the mixture causes irritation in the case of applying liquid drops such as eye drops mucous membranes, and thus unacceptable. Therefore, there is a need to develop a method by which it is possible to suppress a decrease in the content of dibutylhydroxytoluene in a liquid preparation containing dibutylhydroxytoluene, as well as pranoprofen and / or its salt.

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

Means for solving the task

The inventors of the present invention carried out thorough studies to solve the above problem, and finally found that when using at least one compound selected from the group consisting of ester of chondroitin sulfate, aspartic acid, alginic acid, a derivative of alginic acid, and a pharmaceutically acceptable salt thereof and cyanocobalamin, panthenol, tocopherol, and a tocopherol derivative added to a liquid preparation containing dibutylhydroxytoluene, as well as pranoprofen and / or its salt, and using and for a resin container for a liquid preparation of a resin including polybutylene terephthalate, as the resin forming the inner wall surface (which is the surface wall of the inner space of the nozzle and / or the wall surface of the cap facing the outlet of the nozzle) of the container, the thermal stability of dibutylhydroxytoluene in the liquid preparation increases, in at the same time, the adsorption of dibutylhydroxytoluene on the container is suppressed, and thus the reduction in dibu content over time is effectively suppressed tilhydroxytoluene. The present invention has been carried out through the following studies based on these observations.

Accordingly, the present invention provides a product comprising dibutylhydroxytoluene and a method for stabilizing dibutylhydroxytoluene, specific aspects of which are listed below.

Item 1. A product containing dibutylhydroxytoluene, including a liquid preparation, placed in a container, where the liquid preparation contains:

(A) dibutylhydroxytoluene,

(B) pranoprofen and / or its pharmaceutically acceptable salt, and

(C) at least one compound selected from the group consisting of chondroitin sulfate ester, aspartic acid, alginic acid, alginic acid derivative, and pharmaceutically acceptable salts thereof, and cyanocobalamin, panthenol, tocopherol, and tocopherol derivative,

where the container includes a container body for accommodating a liquid preparation; a nozzle having an outlet through which the liquid preparation contained in the container body is to be poured; and a cap for closing the outlet; and

at least one surface of the walls of the inner space of the spout and the surface of the walls of the cap facing the outlet of the spout contains a resin comprising polybutylene terephthalate.

Item 2. A product containing dibutylhydroxytoluene according to claim 1, wherein the liquid preparation further comprises taurine.

Item 3. A product containing dibutylhydroxytoluene according to claims 1 or 2, where the spout is a tip through which a liquid preparation is poured in the form of drops; and the wall surface of the inner part of the tip is made of resin containing polybutylene terephthalate.

Item 4. A product containing dibutylhydroxytoluene according to any one of paragraphs. 1-3, where the container body is made of resin containing polyethylene terephthalate.

Item 5. A product containing dibutylhydroxytoluene according to any one of paragraphs. 1-4, where the liquid preparation further includes a borate buffer.

Item 6. A product containing dibutylhydroxytoluene according to any one of paragraphs. 1-5, where component (C) is at least one selected from the group consisting of chondroitin sulfate ester, aspartic acid, and pharmaceutically acceptable salts thereof, and cyanocobalamin.

Item 7. A product containing dibutylhydroxytoluene according to any one of paragraphs. 1-6, where the liquid preparation contains, as component (C), a chondroitin sulfate ester and / or a pharmaceutically acceptable salt thereof, and aspartic acid and / or a pharmaceutically acceptable salt thereof.

Item 8. A product containing dibutylhydroxytoluene according to any one of paragraphs. 1-7, where the liquid preparation contains component (A) in an amount of from 0.00001 to 0.005 wt./about. %, component (B) in an amount of from 0.005 to 0.5 wt./about. %, and component (C) in an amount of from 0.0005 to 5 wt./about. %

Item 9. A product containing dibutylhydroxytoluene according to any one of paragraphs. 1-8, where the liquid preparation is eye drops.

Item 10. A method for stabilizing dibutylhydroxytoluene in a liquid preparation containing:

(A) dibutylhydroxytoluene, and

(B) pranoprofen and / or its pharmaceutically acceptable salt,

where the method includes:

- mixing in a liquid preparation (C) at least one compound selected from the group consisting of chondroitin sulfate ester, aspartic acid, alginic acid derivative, alginic acid derivative, and their pharmaceutically acceptable salts, and cyanocobalamin, panthenol, tocopherol, and tocopherol derivative ; and

- placing a liquid preparation in a container, including: a container body for containing a liquid preparation; a nozzle having an outlet through which a liquid preparation is poured contained in the container body; and a cap for closing the outlet; and where at least one of the surfaces of the walls of the inner space of the nozzle and the surface of the walls of the cap facing the outlet, contains a resin comprising polybutylene terephthalate.

Clause 11. The method of claim 10, wherein the liquid preparation further comprises taurine.

Paragraph 12. The method according to p. 10 or 11, where the spout is a tip through which a liquid preparation is poured in the form of drops; and the wall surface of the inner part of the tip is made of resin containing polybutylene terephthalate.

Clause 13. The method according to any one of paragraphs. 10-12, where the container body is made of resin containing polyethylene terephthalate.

Clause 14. The method according to any one of paragraphs. 10-13, where the liquid preparation further includes a borate buffer.

Clause 15. The method according to any one of paragraphs. 10-14, where component (C) is at least one selected from the group consisting of chondroitin sulfate ester, aspartic acid, and pharmaceutically acceptable salts thereof, and cyanocobalamin.

Clause 16. The method according to any one of paragraphs. 10-15, where the liquid preparation contains, as component (C), a chondroitin sulfate ester and / or a pharmaceutically acceptable salt thereof, and aspartic acid and / or a pharmaceutically acceptable salt thereof.

Clause 17. The method according to any one of paragraphs. 10-16, where the liquid preparation contains component (A) in an amount of from 0.00001 to 0.005 wt./about. %, component (B) in an amount of from 0.005 to 0.5 wt./about. %, and component (C) in an amount of from 0.0005 to 5 wt./about. %

Clause 18. The method according to any one of paragraphs. 1-8, where the liquid preparation is eye drops.

Advantages of the Invention

In accordance with the present invention, when the container contains a liquid preparation containing dibutylhydroxytoluene, pranoprofen and / or its salt, the container improves the thermal stability of dibutylhydroxytoluene in the liquid preparation and controls its adsorption on the container, thereby allowing the dibutylhydroxytoluene content to be stably maintained.

Since eye drops, nasal drops, and the like contain dibutylhydroxytoluene, the amount of which is necessary to provide an antioxidant effect, is low, approaching the threshold, conventional methods tend to significantly disrupt the thermal stability of dibutylhydroxytoluene when combined with pranoprofen and / or its salt, which leads to a noticeable loss of the antioxidant effect of dibutylhydroxytoluene due to a decrease in its content. In accordance with the present invention, this drawback of conventional techniques can be overcome; and in liquid preparations containing dibutylhydroxytoluene, such as eye drops and nasal drops, the decrease in the content of dibutylhydroxytoluene is effectively suppressed even when combined with pranoprofen and / or its salt, and the antioxidant effect of dibutylhydroxytoluene in the liquid preparation is effectively preserved.

Brief Description of the Drawings

FIG. 1 is a cross-sectional view of an eye drop container for use in one aspect of the present invention.

FIG. 2 is an enlarged cross-sectional view of an eye drop container illustrated in FIG. 1.

FIG. 3 is a cross-sectional view of an eye drop container for use in another aspect of the present invention.

FIG. 4 is a cross-sectional view of an eye drop container for use in another aspect of the present invention.

FIG. 5 is an enlarged cross-sectional view of an eye drop container illustrated in FIG. 4.

FIG. 6 is a cross-sectional view of an eye lotion container for use in one aspect of the present invention.

Embodiments of the present invention

As used herein, “stabilizing” or “stability” of dibutylhydroxytoluene in a liquid preparation containing dibutylhydroxytoluene means suppressing a decrease over time of the content of dibutylhydroxytoluene in the liquid preparation due to the degradation or adsorption of dibutylhydroxytoluene in the container, or the like, and property. In addition, as used herein, the “thermal stability” of dibutylhydroxytoluene means a property in which the degradation of dibutylhydroxytoluene lol is suppressed by temperature. Further, as used herein, “a product containing dibutylhydroxytoluene” means a product in which a liquid preparation containing components (A) to (C) described below is placed in a container and may be referred to as a “BHT-containing product”. Further, in the present description, the unit "weight./about. % ”Represents the percentage by weight, determined by the Japanese Pharmacopoeia, 16th edition, and has the same meaning as g / 100 ml.

1. OSH-containing products

BHT-containing products according to the present invention are characterized in that the liquid preparation containing (A) dibutylhydroxytoluene, (B) pranoprofen and / or its pharmaceutically acceptable salt, and (C) at least one compound selected from the group consisting of ester chondroitin sulfate, aspartic acid, alginic acid, an alginic acid derivative, and pharmaceutically acceptable salts thereof, and cyanocobalamin, panthenol, tocopherol, and a tocopherol derivative are placed in a container in which the inner wall surface its space the spout and / or the wall surface of the cap facing the outlet nozzle are made of a resin containing polybutylene terephthalate. In the following description, OSH-containing products according to the present invention are discussed in detail.

Liquid preparations

In the BHT-containing product of the present invention, the liquid preparation placed in the container contains dibutylhydroxytoluene, which may be designated as component (A). Dibutylhydroxytoluene is also referred to as 2,6-di-tert-butyl-4-methylphenol, BHT, or DBPK, and is a compound known as an antioxidant. In a liquid preparation, dibutylhydroxytoluene is a component that improves the thermal stability of pranoprofen and / or its salt when it exhibits antioxidant effects in a liquid preparation and contributes to the stability of the optionally added pharmacological component (s), additives, and others.

The content of component (A) in the liquid preparation is not specifically limited, and it is only required that the content is determined as necessary, for example, depending on the use of the liquid preparation. For example, the content of component (A) in a liquid preparation is from 0.00001 to 0.005 wt./about. %, preferably from 0.00005 to 0.005 wt./about. %, and more preferably from 0.0001 to 0.005 wt./about. %

The liquid preparation used in the present invention further comprises pranoprofen and / or its salt, which may be designated as component (B). In a liquid preparation, pranoprofen and / or its salt have increased resistance to light due to dibutylhydroxytoluene.

Pranoprofen is also referred to as α-methyl-5H- [1] benzopyrano [2,3-b] pyridin-7-acetic acid, and is a compound with known anti-inflammatory activity in the field of ophthalmology.

Pranoprofen salts are not limited in any way, provided that they are pharmaceutically acceptable, and examples thereof include metal salts such as sodium salts, potassium salts, calcium salts, magnesium salts and aluminum salts; and organic base salts such as triethylamine salts, diethylamine salts, morpholine salts, and piperazine salts. These pranoprofen salts may be used alone, or two or more of them may be used in combination.

In the liquid preparation that is used in the present invention, as component (B), one of pranoprofen and its salts can be selected and used separately, or two or more of them can be used in combination. Among them, pranoprofen is preferred as component (B).

The content of component (B) in the liquid preparation is not specifically limited, and it is only required that the content is determined as necessary, for example, depending on the use of the liquid preparation. For example, the content of component (B) in a liquid preparation is from 0.005 to 0.5% w / v. %, preferably from 0.05 to 0.1 wt./about. %, and more preferably 0.05 wt./about. %

The liquid preparation used in the present invention further comprises at least one selected from the group consisting of an ester of chondroitin sulfate, aspartic acid, alginic acid, a derivative of alginic acid, and pharmaceutically acceptable salts thereof, and cyanocobalamin, panthenol, tocopherol, and a derivative tocopherol, which can be designated as component (C). In the liquid preparation used in the present invention, it is possible to suppress a significant reduction in the dibutylhydroxytoluene content caused by the presence of pranoprofen and / or its salt by adding component (s) (C) to the liquid preparation and then placing it in a specific container described below.

Chondroitin sulfate ester is a polysaccharide in which sulfuric acid is bound to the carbohydrate chain of D-glucuronic acid and N-acetyl-D-galactosamine. As the chondroitin sulfate ester, any type of chondroitin sulfate ester, natural or synthetic, can be used, provided that it is pharmaceutically acceptable. For example, chondroitin sulfate ester can be obtained from cartilage of fish, such as sharks, or from mammals.

Chondroitin sulfate ester salts are not limited in any way, provided that they are pharmaceutically acceptable, and include, for example, alkali metal salts such as sodium salts and potassium salts, and alkaline earth metal salts such as calcium salts of magnesium salts. Among these chondroitin sulfate ester salts, alkali metal salts are preferred, and the sodium salt is more preferred. These chondroitin sulfate ester salts can be used individually, or in combination of two or more of them.

Aspartic acid is a known amino acid, which is referred to as 2-aminobutanedioic acid. Aspartic acid may be in any of the forms selected from the D-form, L-form and DL-form, with the L-form being preferred.

Salts of aspartic acid include, for example, alkali metal salts such as sodium salts and potassium salts, and alkaline earth metal salts such as calcium salts and magnesium salts. Among these salts of aspartic acid, alkali metal salts are preferred, and a potassium salt is more preferred. These salts of aspartic acid may be used alone, or two or more of them may be used in combination.

Alginic acid is a polysaccharide comprising β-D-mannuronic acid and α-L-glucuronic acid. As alginic acid, any type of alginic acid, natural or synthetic, can be used, provided that it is pharmaceutically acceptable. For example, alginic acid can be obtained from algae or from bacteria. Derivatives of alginic acid are not limited in any way, provided that they are pharmaceutically acceptable, and include, for example, ester derivatives, such as propylene glycol alginate.

Salts of alginic acid and its derivatives are not limited in any way, provided that they are pharmaceutically acceptable, and include, for example, alkali metal salts such as sodium salts and potassium salts, and alkaline earth metal salts such as calcium salts and magnesium salts . Among these salts of alginic acid, alkali metal salts are preferred, and the sodium salt is more preferred. These alginic acid salts may be used alone, or two or more of them may be used in combination.

Cyanocobalamin is a known compound, also referred to as vitamin B12.

Panthenol is a known compound, which is also referred to as (R) -2,4-dihydroxy-N- (3-hydroxypropyl) -3,3-dimethylbutyramide, provitamin B5, etc. Panthenol may be in any of the forms selected from the D-form, L-form and DL-form, with the D-form being preferred.

Tocopherol is a known compound, also known as vitamin E. Tocopherol derivatives are not limited in any way, provided that they are pharmaceutically suitable, and include, for example, esters with carboxylic acids such as acetic acid, nicotinic acid, and succinic acid and diesters with phosphoric acid. These tocopherol derivatives can be used individually, or two or more of them can be used in combination. Among these tocopherol derivatives, tocopherol carboxylic esters are preferred, and tocopheryl acetate is more preferred. Tocopherol and its derivatives may be in any of the forms selected from the D-form, L-form and DL-form, with the D-form being preferred. In addition, tocopherol and its derivatives may be in any of the α-form, β-form, γ-form and δ-form, with the α-form being preferred.

In the liquid preparation used in the present invention, as component (C), one form of an ester of chondroitin sulfate, aspartic acid, alginic acid, a derivative of alginic acid, and their pharmaceutically acceptable salts, and cyanocobalamin, panthenol, tocopherol, and a tocopherol derivative may be selected and applied individually, or two or more of them may be used in combination. Among them, as component (C), chondroitin sulfate ester, aspartic acid, alginic acid, an alginic acid derivative, and pharmaceutically acceptable salts thereof, and cyanocobalamin and panthenol are preferred; more preferred are chondroitin sulfate ester, aspartic acid, alginic acid, an alginic acid derivative, and pharmaceutically acceptable salts thereof, and cyanocobalamin; even more preferred are chondroitin sulfate ester, aspartic acid, and pharmaceutically acceptable salts thereof, from the point of view of more effectively suppressing the reduction of dibutylhydroxytoluene. In particular, the combination of the chondroitin sulfate ester and / or its salt and aspartic acid and / or its salt is suitably used in the present invention, since this combination can lead to a particularly significant inhibition of the reduction of dibutylhydroxytoluene.

The content of component (s) (C) in a liquid preparation for use in the present invention is, for example, from 0.0005 to 5% w / v. %, preferably from 0.001 to 2 wt./about. % In particular, the content of each of the components (C) is in the following range:

In the case of the use of an ester of chondroitin sulfate and / or its salt: preferably from 0.005 to 5 wt./about. %, more preferably from 0.01 to 1 wt./about. %, particularly preferably from 0.05 to 0.5 mass. %

In the case of the use of aspartic acid and / or its salt: preferably from 0.01 to 5 wt./about. %, more preferably from 0.05 to 2 wt./about. %, particularly preferably from 0.1 to 1 mass. %

In the case of the use of alginic acid, its derivative and / or salt of alginic acid or its derivative: preferably from 0.001 to 1 wt./about. %, more preferably from 0.005 to 0.2 wt./about. %, particularly preferably from 0.01 to 0.1 mass. %

In the case of the use of cyanocobalamin: preferably from 0.001 to 0.1 wt./about. %, more preferably from 0.002 to 0.05 wt./about. %, particularly preferably from 0.004 to 0.02 mass. %

In the case of panthenol: preferably from 0.001 to 1 wt./about. %, more preferably from 0.005 to 0.5 wt./about. %, particularly preferably from 0.01 to 0.1 mass. %

In the case of the use of tocopherol and / or its derivative: preferably from 0.0005 to 1 wt./about. %, more preferably from 0.001 to 0.1 wt./about. %, particularly preferably from 0.005 to 0.05 mass. %

In the case of the use of an ester of chondroitin sulfate and / or its salt and aspartic acid and / or its salt: preferably from 0.005 to 5 wt./about. %, more preferably from 0.05 to 0.5 wt./about. % ester of chondroitin sulfate and / or its salt, and preferably from 0.01 to 5 wt./about. %, more preferably from 0.1 to 1 wt./about. % for aspartic acid and / or its salt.

The liquid preparation used in the present invention may contain, in addition to components (A) to (C), taurine and / or its pharmaceutically acceptable salt. The most effective inhibition of dibutylhydroxytoluene reduction can be achieved by the additional addition of taurine. In particular, when chondroitin sulfate ester, aspartic acid and / or its salt are used as component (C), a decrease in the content of dibutyl hydroxytoluene can be particularly effectively suppressed by the addition of taurine and / or its salt.

Taurine is also referred to as aminoethyl sulfonic acid, and has the chemical name 2-aminoethanesulfonic acid. In the field of ophthalmology, taurine is a known compound used, for example, to stimulate metabolism in the eye.

Taurine salts are not limited in any way, provided that they are pharmaceutically acceptable, and include, for example, salts with alkali metals such as sodium salt and potassium salt. One of these salts may be used alone, or two or more of them may be used in combination.

The content of taurine and / or its salt in a liquid preparation for use in the present invention is, for example, from 0.01 to 5% w / v. %, preferably from 0.05 to 2 wt./about. %, and more preferably from 0.1 to 1 wt./about. %

The liquid preparation used in the present invention may contain, in addition to the components described above, a buffer so that the liquid preparation has a buffer activity. Examples of the buffer include, but are not limited to, borate buffer, phosphate buffer, nitrate buffer, tartrate buffer, acetate buffer, Tris buffer, amino acid (such as glutamic acid), etc. These buffers can be used individually, or two or more of them can be used in combination. Among these buffers, the borate buffer has a buffer capacity in the pH range in which pranoprofen and / or its salt are soluble in the liquid preparation, and are suitable for use in the present invention.

It is only required that the buffer content in the liquid preparation used in the present invention be determined as necessary, in the range of quantities at which the buffer is able to provide the necessary buffering effect, depending on the type of buffer used, and is, for example, from 0.001 to 5 weight. /about. %, preferably from 0.05 to 3 wt./about. %, more preferably from 0.1 to 2 wt./about. %

The liquid preparation used in the present invention may further comprise a chelating agent, in addition to the components described above. It is possible that in the presence of a chelating agent, a decrease in the content of dibutylhydroxytoluene is more effectively suppressed.

Examples of a chelating agent include, in particular, edetic acid, citric acid, succinic acid, ascorbic acid, tris (hydroxymethyl) aminomethane, nitrilotriacetic acid, 1-hydroxyethane-1,1-diphosphonic acid, polyphosphoric acid, metaphosphoric acid, and and their pharmaceutically acceptable salts. These chelating agents can be used individually or in combination of two or more of them. Among these chelating agents, edetic acid and its pharmaceutically acceptable salts are preferred from the point of view of more effectively suppressing the reduction of dibutylhydroxytoluene. Pharmaceutically acceptable salts of edetic acid include, for example, alkali metal salts such as sodium salts, potassium salts, and alkaline earth metal salts such as calcium salts and magnesium salts.

When the liquid preparations used in the present invention contain a chelating agent, it is only required that the content of the chelating agent is determined as necessary, for example, depending on the use of the liquid preparation, and should be, for example, from 0.0005 to 0.5% w / v . %, preferably from 0.001 to 0.2 wt./about. %, more preferably from 0.005 to 0.13 wt./about. %

A liquid preparation for use in the present invention may contain a pharmacological component in addition to the above components, in accordance with the use of a liquid preparation. The pharmacological component used is not limited specifically, and can be selected, as necessary, from conventional known pharmacological components, such as vasoconstrictors, anti-cholesterase agents, anti-inflammatory drugs, therapeutic agents for keratoconjunctival epithelial disorders, anti-inflammatory analgesics, chemotherapeutic agents, anti-bacterial drugs, , hormonal drugs, vitamins, amino acids, anti-cataracts, inhibitor angiogenesis, immunosuppressive agents, protease inhibitors, aldose reductase inhibitors, antihistamines, anti-allergic agents, anxiety disorder agents, antipsychotics, antibiotics, antitumor agents, antihyperlipidemic agents, cough and antiepileptic drugs, antipyretic drugs antidepressants, cardiotonic drugs, antiarrhythmic drugs, vasodilators, antihypertensive diuretics, an thidiabetic agents, anti-tuberculosis drugs, antagonists of narcotic analgesics, skin diseases, dentifrice and oral care products, diagnostic tools, and hygiene products.

In case the liquid preparation is a liquid preparation for use in ophthalmology or otology, such as eye drops, eye lotions, nose drops or ear drops, specific examples of the pharmacological component include anti-inflammatory agents such as dipotassium glycyrrhizinate, allantoin, epsilon-aminocaprona acid, bromfenac, ketorolac tromethamine, nepafenac, berberine chloride, berberine sulfate, sodium azulene sulfonate, zinc sulfate, zinc lactate and lysozyme hydrochloride; antihistamines such as chlorpheniramine maleate and diphenhydramine hydrochloride; antiallergic agents such as sodium cromoglycate, ketotifen fumarate, acitazanolast, amlexanox, pemirolast potassium, tranylast and ibudilast; antibacterial agents such as norfloxacin, ofloxacin, lomefloxacin, levofloxacin, gentamicin and gatifloxacin; vitamins such as ascorbic acid, flavin adenine sodium dinucleotide, pyridoxine hydrochloride, retinol acetate, retinol palmitate, calcium pantothenate and sodium pantothenate; anticholinesterase agents, such as neostigmine methyl sulfate; vasoconstrictors such as naphazoline, tetrahydrozoline, epinephrine, ephedrine, phenylephrine and d1-methylephedrine; treatments for keratoconjunctival diseases, such as sodium hyaluronate; and sulfamide preparations such as sulfadiazine, sulfisoxazole, sulfisomidine, sulfadimethoxine, sulfamethoxypyridazine, sulfamethoxazole, sulfaethiolide, sulfamethomidine, sulfafenazole, sulfaguanidine, phthalyl sulfathiazole and succinyl sulfathiazole. Each of these compounds illustrated in this application may be in the form of a salt, provided that the salts are pharmaceutically acceptable.

The appropriate content of pharmacological components is determined appropriately, depending on the type of pharmacological components, the use of a liquid preparation, etc.

The liquid preparation used in the present invention may optionally contain, in addition to the components described above, additives such as tonicity agents, solubilizing agents, viscosity agents, cooling agents, pH adjusters, preservatives, stabilizers and surfactants.

Examples of tonicity agents include saccharides such as sorbitol, glucose and mannitol; polyhydric alcohols such as glycerin and propylene glycol; salts such as sodium chloride; and boric acid. These tonicity agents can be used individually or in combination of two or more of them.

Examples of solubilizing agents include nonionic surfactants such as polyoxyethylene sorbitan monooleate, polyoxyethylene hydrogenated castor oil, tyloxapol and pluronics; and polyhydric alcohols, such as glycerin and macrogol. These solubilizing agents can be used individually or in combination of two or more of them.

Examples of viscous agents include water-soluble macromolecules such as polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, carboxyvinyl polymer, xanthan gum, sodium chondroitin sulfate, and sodium hyaluronate; and celluloses such as hypromellose, hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and sodium carboxymethyl cellulose. These viscous agents can be used individually or in combination of two or more of them.

Examples of cooling agents include 1-menthol, borneol, camphor, and eucalyptus oil. These cooling agents can be used individually or in combination of two or more of them.

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

Examples of preservatives include sorbic acid and its salt, benzoic acid and its salts, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, chlorhexidine gluconate, boric acid, dehydroacetic acid and its benzene chloride, benzoyl chloride, benzene, benzene chloride, benzal chloride zinc chloride, parachloromethaxylene, chlorocresol, phenethyl alcohol, polydronium chloride, thiomersal and polyhexamethylene biguanide. These preservatives can be used individually or in combination of two or more of them.

Examples of stabilizers include polyvinylpyrrolidone, sulfites, monoethanolamine, glycerin, propylene glycol, cyclodextrin, dextran, ascorbic acid and edetates. These stabilizers can be used individually or in combination of two or more of them.

Examples of surfactants include nonionic surfactants such as tyloxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymers, polyoxyethylene sorbitan fatty acid esters, and octoxynol; amphoteric surfactants such as alkyl diaminoethyl glycine and betaine lauryl dimethylaminoacetate; anionic surfactants such as alkyl sulfate, N-acyl-taurine salts, polyoxyethylene alkyl ether phosphate and polyoxyethylene alkyl ether sulfate; and cationic surfactants, such as alkyl pyridinium salts and alkyl amine salts. These surfactants can be used individually or in combination of two or more of them.

The appropriate concentrations of these additives are determined appropriately, depending on the type of additives, the use of a liquid preparation, etc.

The form of the liquid preparation for use in the present invention is not particularly limited, provided that it contains water as a solvent. For example, the liquid preparation may be any form of an aqueous solution, suspension, emulsion and the like, but is preferably in the form of an aqueous solution.

The pH of the liquid preparation used in the present invention is not specifically limited, and it is only necessary that the pH is set appropriately, for example, depending on the use of the liquid preparation, and the value is, for example, from 5.0 to 9.0, preferably from 6.5 to 8.5.

The use of a liquid preparation for use in the present invention is not particularly limited, and includes, for example, the use of contact lenses as medicaments and products. Specific examples of medications include, for example, ophthalmic liquid preparations, such as eye drops (including eye drops for contact lenses, useful even when contact lenses are worn) and lotions for the eyes; otological liquid preparations such as nasal drops and ear drops; and preparations for oral administration, injection, and for external use. Specific examples of contact lens care products include, for example, a contact lens wearable solution and a multipurpose contact lens solution. Among these uses of liquid preparations, ophthalmic liquid preparations, otological liquid preparations and contact lens care products are preferred, and eye drops are more preferred.

The liquid preparation for use in the present invention can be loaded into a multi-dose container containing multiple doses of the liquid preparation and intended for repeated use, or alternatively, in a single dose container containing a single dose of the liquid preparation and intended for single use.

The liquid preparation for use in the present invention can be obtained in accordance with a known production method, in accordance with the form, use, etc., and for example, can be obtained by mixing the components in an aqueous base, such as water or saline. For example, if the liquid preparation is a medicine, it can be obtained by the methods established in the General Rules for the Preparation of the Japanese Pharmacopoeia, 16th edition.

Containers

A BHT-containing product according to the present invention includes a container comprising a container body for receiving a liquid preparation, a spout and a cap. The container is designed so that the surface wall of the inner space of the spout and / or the wall surface of the cap facing the outlet of the spout includes a resin containing polybutylene terephthalate.

<Container Structure>

The container body, which is part of the container, is part to accommodate the liquid preparation. The shape and size of the container body are not limited in any way, and they can be selected in accordance with the type and volume of the liquid product to be contained.

The spout, which is part of the container, is a part having an internal space through which the container body and the outer side of the container body communicate with each other, and contains an outlet through which the preparation contained in the container body is poured, and which is configured to communicate with an opening of the container body, and is designed for pouring (unloading) the drug from the container through the outlet from the inner space. The spout is not limited in any way by its structure, provided that the spout is designed so that the drug can pour out of the container body through the outlet. For example, the spout may be designed so that the drug spills out in the form of a drop, or so that the drug spills out not in the form of a drop. From the point of view of more successfully achieving the effects of the present invention, the nozzle is preferably a tip designed so that the preparation is poured in the form of a drop. The spout may have an inner plug, for example, an inner tip or a hollow plug inside.

The spout, in whole or in part, can be formed integrally with the container body. Alternatively, the spout may be inserted into the opening of the container body or attached to the outside of the opening of the container body.

The container cap is the part covering the outlet. The cap may have a structure adapted to the container body and / or outlet. In particular, in the case where the BHT-containing product of the present invention is a multi-dose product, the cap may have a structure that is adapted to be detached from the container body and / or outlet. In the case where the BHT-containing product of the present invention is a single dose product, the cap may have a structure adapted to be removed from the container body and / or outlet. One suitable example of a structure selected to be detachable from the container body and / or outlet includes a cap that is screwed so that it can be detached to the container body and / or nozzle. In the case where the cap is screwed so that it can be detached to the container body and / or nose, the cap may have a threaded portion so that it is screwed onto the container body and / or nose.

The shape of the container is determined appropriately, in accordance with the use of the BHT-containing product, for containing the liquid preparation. Specific application examples include eye drop containers, eye lotion containers, and nose drop containers.

FIG. 1-6 illustrate examples of specific aspects of a container for use in the present invention.

FIG. 1 is a cross-sectional view of an eye drops container from one aspect, and FIG. 2 is an enlarged cross-sectional view of an eye drops container illustrated in FIG. 1. In accordance with the eye drop container shown in FIG. 1, a spout 2 through which a liquid preparation in the form of a drop can pour out is inserted inside the opening of the container body 1, and the cap 3 is screwed so that it can be disconnected to the container body 1 so as to close the outlet of the spout 2. In accordance with the container for eye drops, the liquid preparation placed in the container body 1 is poured out of the container through an outlet from the inner space 4 of the nozzle 2. The eye drop container illustrated in FIG. 1 can be used to host a single dose liquid preparation, but can be used to hold a multi-dose liquid preparation.

FIG. 3 is a cross-sectional view of an eye drop container from one aspect. The eye drop container illustrated in FIG. 3 is such that the container body 1 and the nozzle 2 are made of the same material and form a unit with each other without binding or mechanical connection, and are designed so that a liquid preparation in the form of a droplet can pour out of the container through the outlet from the inner space 4 of the spout 2. In FIG. 3, the cap is not shown, and for convenience is depicted by a dashed line (dashed line). In the eye drop container shown in FIG. 3, the part of the container below the dashed line corresponds to the body of the container 1, and the part of the container above the dashed line corresponds to the spout 2. The eye drop container illustrated in FIG. 3 can be used to hold a single dose liquid preparation, but can also be used to hold a multi-dose liquid preparation.

FIG. 4 is a cross-sectional view of an eye drop container from one aspect, and FIG. 5 is an enlarged partial cross-sectional view of the eye drop container illustrated in FIG. 4. The eye drop container illustrated in FIG. 4 is such that the container body 1, the spout 2 and the cap 3 are formed integrally with each other. Spout 2 and cap 3 are connected to each other. When the nozzle 2 and the cap 3 are separated from each other, the liquid preparation placed in the container body 1 can pour out of the container through the outlet from the inner space 4 of the nozzle 2. For convenience, in FIG. 4 and 5 dashed lines (dashed lines) are drawn. In each of FIG. 4 and 5, the portion of the container between the two dashed lines corresponds to the spout 2, and the space between the two dashed lines corresponds to the inner space 4 of the spout 2. The eye drop container illustrated in FIG. 4 is suitably used to contain a single dose liquid preparation.

FIG. 6 is a cross-sectional view of an eye lotion container. The eye lotion container illustrated in FIG. 6 is such that the body of the container 1 and the spout 2 are formed integrally with each other. The eye lotion container is designed so that a liquid preparation placed in the container body 1 is poured out of the container through the outlet from the inner space 4 from the nozzle 2. For convenience, in FIG. 6 a dashed line is drawn (dashed line).

FIG. 1-6 illustrate specific aspects of an eye drop container and an eye lotion container. However, it is noted that the present invention is not limited to such structures and forms. The present invention is applicable to containers other than eye drop containers and eye lotion containers, provided that the containers have predetermined characteristics.

<Container Material>

In the container, at least one of the surfaces of the walls of the inner space and the nose and the wall surface of the cap facing the outlet includes a resin containing polybutylene terephthalate (PBT). As indicated in this application, the “cap surface facing the outlet” corresponds to the portion of the inner wall of the cap that closes the outlet when the cap is attached to the container body and / or nozzle. In particular, for example, in the case of FIG. 2, 5 and 6, each of the surfaces indicated by reference number 5 corresponds to a “surface of the walls of the inner space of the spout”, and each of the surfaces indicated by reference number 6 corresponds to a “surface of the walls of the cap facing the outlet”.

Since the surface wall of the inner space of the spout and / or the wall surface of the cap facing the outlet of the spout is made of a resin containing polybutylene terephthalate, in combination with the composition used in the liquid preparation of the present invention, the adsorption and accumulation of dibutylhydroxytoluene on the spout and / or cap effectively suppressed, and thus, the content of dibutylhydroxytoluene in the liquid preparation can remain stable.

The resin constituting the wall surface of the inner space of the spout and / or the wall surface of the cap facing the outlet of the spout may be made of polybutylene terephthalate, or may be made of a blended polymer containing polybutylene terephthalate and some other polymer. In the case where the resin constituting the surface of the walls of the nozzle and / or the surface of the walls of the cap facing the outlet of the nozzle is a mixed polymer containing polybutylene terephthalate and some other polymer, the mixing ratio is not limited specifically, provided that effects are achieved according to the present invention. It is necessary that the percentage of polybutylene terephthalate relative to the total amount of the mixed polymer is not less than 50 mass. %, preferably not less than 60 wt. %, more preferably not less than 70 mass. %, even more preferably not less than 80 mass. %, and in particular not less than 90 mass. %

In the container, it is only necessary that at least one of the walls of the inner space of the nozzle and the surface of the walls of the cap facing the outlet of the nozzle contain polybutylene terephthalate. For example, if a nozzle is used through which a liquid preparation in the form of a drop is poured (for example, a tip designed to remove a liquid preparation in the form of drops), from the point of view of effectively suppressing a decrease in the content of dibutylhydroxytoluene, it is preferable that at least the surface of the walls of the inner the space of the spout was made of a resin containing polybutylene terephthalate, and it is more preferable that both the surface wall of the inner space of the spout and the surface of the walls of the cap, facing the nozzle outlet, was made of resin containing polybutylene terephthalate. For example, if a nozzle is used through which the liquid preparation is discharged in a non-droplet form, from the point of view of effectively suppressing the reduction in dibutylhydroxytoluene content, it is preferable that at least the surface of the cap walls facing the nozzle outlet is made of resin, containing polybutylene terephthalate, and it is more preferable that both the surface wall of the inner space of the spout and the surface of the walls of the cap facing the outlet of the spout be made of resin containing polybutylene terephthalate.

The constituent materials of parts other than the wall surfaces are not limited in any way, provided that the surface wall of the inner space of the spout and / or the surface of the walls of the cap facing the outlet of the spout is made of resin containing polybutylene terephthalate. For example, parts other than wall surfaces may be made of resin containing polybutylene terephthalate, or may be made of a material other than polybutylene terephthalate.

If the container has a container body and a spout molded as a unit, the container body is made of the same resin as the spout.

If the container consists of a container body and a spout inserted inside the opening of the container body for attachment, or connected outside the opening of the container body, the container body may be made of glass or plastic. Preferably, the container body is made of plastic. In the event that the container body of one aspect is made of plastic, the type of resin forming the container body is not limited in any way, and examples thereof include polyethylene terephthalate, polybutylene terephthalate, polystyrene and acrylonitrile butadiene styrene. Among them, polyethylene terephthalate is capable of suppressing the adsorption of dibutylhydroxytoluene, and at the same time has excellent ductility, and thus is suitable as a resin for forming the container body.

2. Methods of stabilization

The method for stabilizing dibutylhydroxytoluene in accordance with the present invention is characterized in that the dibutylhydroxytoluene-containing preparation is a liquid preparation containing (A) dibutylhydroxytoluene and (B) pranoprofen and / or a pharmaceutically acceptable salt thereof with which component (C) is mixed, which is at least one selected from the group consisting of chondroitin sulfate ester, aspartic acid, alginic acid, alginic acid derivative, and pharmaceutically acceptable salts thereof, and cyanocoba amine, panthenol, tocopherol and tocopherol derivative, and placed in a container, wherein the inner space of the wall surface of the spout and / or the wall surface of the cap facing the outlet spout is made of resin containing polybutylene terephthalate.

In the stabilization method according to the present invention, the types and amounts of components (A) to (C) contained in the liquid preparation and additional components that can optionally be mixed with them, and the use of the liquid preparation are the same as in the liquid preparation used in OSH-containing product described above. The container used in the stabilization method according to the present invention is the same as the container used in the OSH-containing product described above.

In a liquid preparation containing dibutylhydroxytoluene and pranoprofen and / or its salt, the stabilization method according to the present invention increases the thermal stability of dibutylhydroxytoluene by controlling the adsorption of dibutylhydroxytoluene on the container, thus making it possible to effectively suppress the decrease in the dibutylhydrohydrolhydrohydrolhydrohydrolhydrohydolhydrohydolhydrohydol hydrochloride concentration and thus , can be used as a method for storing liquid preparations.

Examples

The present invention has been described in detail with reference to examples which are not intended to limit the present invention in any way.

Experimental example 1. Assessment of changes in the content of dibutylhydroxytoluene over time.

The liquid preparations shown in Table 2 were prepared and poured and stored in various types of containers. The changes in the dibutylhydroxytoluene content over time during storage were determined. In particular, the liquid preparations shown in Table 2 were prepared in accordance with the usual method and stored by placing them in containers shown in Table 1, which were hermetically sealed and left for two weeks under conditions of protection from light at 40 ° C and 75 % OV. The amount of liquid preparation was 10 ml for containers 2 and 3, and 5 ml for container 1. In the case of containers 2 and 3, the container was left in the upright position so that the cap was on the upper side and the bottom of the container was on the lower side. Before starting storage and one and two weeks after starting storage, samples were taken so that the liquid preparation in the container did not come into contact with the nozzle and the content of dibutylhydroxytoluene in the liquid preparation was determined by HPLC, thus assessing the thermal stability of dibutylhydroxytoluene. The stability of dibutylhydroxytoluene was calculated as a percentage of the remaining dibutylhydroxytoluene (%), which, in particular, was determined by the ratio of dibutylhydroxytoluene before and after storage. Container 3 is an example of an eye drop container that has been commonly used in the prior art. It is known that glass weakly adsorbs conventional drugs; container 1 is an example of containers on which dibutylhydroxytoluene is poorly adsorbed.

The results obtained are shown in Table 2. As can be seen from the control results, it can be concluded that the combined presence of dibutylhydroxytoluene and pranoprofen in a liquid preparation leads to a significant decrease in the content of dibutylhydroxytoluene. In addition, it was observed that in liquid preparations containing dibutylhydroxytoluene and pranoprofen, in which pyridoxine hydrochloride, a type of vitamin was added, a decrease in the content of dibutylhydroxytoluene could not be sufficiently suppressed (Comparative Example 1). Conversely, a decrease in dibutylhydroxytoluene content could be effectively suppressed in liquid preparations containing dibutylhydroxytoluene and pranoprofen, to which sodium chondroitin sulfate, potassium L-aspartate, sodium alginate, cyanocobalamin, panthenol or D-α-tocopherol 2 were added, and a tip made of polybutylene terephthalate (Examples 1-7).

Experimental example 2. Assessment of changes in the content of dibutylhydroxytoluene over time (in the case of low concentrations of dibutylhydroxytoluene).

The liquid preparations shown in Table 3 were prepared in accordance with the usual method. The same method was used as in Experimental Example 1 to dispense and store these liquid preparations in the containers shown in Table 1, and to measure the dibutylhydroxytoluene content in the liquid preparation by HPLC. Based on the data obtained, the percentage of remaining dibutylhydroxytoluene (%) was calculated in the same manner as in Experimental Example 1.

The results obtained are shown in Table 3. From these results, it was found that even when dibutylhydroxytoluene is at a concentration of 0.0001 wt./about. %, a decrease in the content of dibutylhydroxytoluene when combined with pranoprofen can be effectively suppressed by adding sodium chondroitin sulfate or potassium L-aspartate to the liquid preparation and placing it in container 2 with a tip made of polybutylene terephthalate.

In the table, the content of each component is expressed in "weight./about. % ".

Experimental Example 3. Evaluation of changes in the content of dibutylhydroxytoluene over time when combined with sodium chondroitin sulfate and / or potassium L-aspartate, and taurine.

The liquid preparations shown in Table 4 were prepared in accordance with the usual method. The same method was used as in Test Example 1 to dispense and store these liquid preparations in the containers shown in Table 1, except that the temperature during storage was changed to 50 ° C or 60 ° C, and for measurement the content of dibutylhydroxytoluene in the liquid preparation by HPLC. Based on the data obtained, the percentage of remaining dibutylhydroxytoluene (%) was calculated in the same manner as in Experimental Example 1.

The results are shown in Table 4. From these results, it was found that in liquid preparations containing dibutylhydroxytoluene and pranoprofen, the decrease in the content of dibutylhydroxytoluene was especially strongly suppressed when sodium chondroitin sulfate and potassium L-aspartate were used in combination, and when sodium chondroitin sulfate and / or potassium L-aspartate and taurine were used in combination.

In the table, the content of each component is expressed in "weight./about. % ".

Experimental Example 4. Assessing the effect of pH on the change in dibutylhydroxytoluene content over time caused by pH.

The liquid preparations shown in Table 5 were prepared in accordance with the usual method. The same method was used as in Experimental Example 1 to dispense and store these liquid preparations in the containers shown in Table 1, and to measure the dibutylhydroxytoluene content in the liquid preparation by HPLC. Based on the data obtained, the percentage of remaining dibutylhydroxytoluene (%) was calculated in the same manner as in Experimental Example 1.

The results obtained are shown in Table 5. From these results, it was found that the pH does not affect the effect of suppressing the reduction in dibutylhydroxytoluene content in accordance with the present invention.

Control Example 1. Evaluation of changes in the content of dibutylhydroxytoluene over time.

The liquid preparations shown in Tables 6 and 7 were prepared in accordance with the usual method. The same method was used as in Experimental Example 1 to dispense and store these liquid preparations in the containers shown in Table 1, and to measure the dibutylhydroxytoluene content in the liquid preparation by HPLC. Based on the data obtained, the percentage of remaining dibutylhydroxytoluene (%) was calculated in the same manner as in Experimental Example 1.

The results are shown in Tables 6 and 7. From these results, it was found that when dibutylhydroxytoluene and pranoprofen are co-present in liquid preparations, it was not possible in Comparative Examples 2-15 to sufficiently suppress the reduction in dibutylhydroxytoluene due to co-presence, or an additional decrease was noted. dibutylhydroxytoluene content. Thus, this result made it possible to establish that in the combined presence of dibutylhydroxytoluene and pranoprofen in a liquid preparation, the effect of suppressing the decrease in the content of dibutylhydroxytoluene due to the joint presence is a characteristic effect observed when choosing an ester of chondroitin sulfate, aspartic acid, its salt, cyanide, cyanide or panthenol, and mixing them in a liquid preparation.

Preparation Example 1

Eye drops having the composition shown in Table 8 were prepared in accordance with the usual method. Each of these eye drops was placed in an eye drop container in which the container body made of polyethylene terephthalate was attached to a tip made of polybutylene terephthalate.

Description of reference signs

1 - container body

2 - nose

3 - cap

4 - the inner surface of the spout

5 - the surface wall of the inner space of the nose

6 - the surface of the walls of the cap facing the outlet of the nozzle

Claims (25)

1. Ophthalmic product in the form of a container containing a liquid preparation containing dibutylhydroxytoluene, where the specified liquid preparation contains: (A) dibutylhydroxytoluene, (B) pranoprofen and / or a pharmaceutically acceptable salt thereof; and (C) at least one compound selected from the group consisting of an ester of chondroitin sulfate, aspartic acid, alginic acid, a derivative of alginic acid and their pharmaceutically acceptable salts and cyanocobalamin, panthenol, tocopherol and a tocopherol derivative, wherein said liquid preparation contains a complex chondroitin sulfate ester in an amount of 0.01-1% w / v, aspartic acid in an amount of 0.01-2% w / v, alginic acid, alginic acid derivative and / or pharmaceutically acceptable salts thereof in amounts about 0.01-0.2 weight / vol%, cyanocobalamin in an amount of 0.002-0.1 weight / vol%, panthenol in an amount of 0.01-0.1 weight / vol%, tocopherol and / or derivative of tocopherol in an amount of 0.005-0.1 wt./about., where the container comprises a container body for a liquid preparation, a nozzle having an outlet through which liquid preparation contained in the container body can pour, and a cap for closing the outlet; and at least one of the surfaces of the walls of the inner space of the nozzle and the surfaces of the walls of the cap facing the outlet contains a resin comprising polybutylene terephthalate. 2. A product containing dibutylhydroxytoluene according to claim 1, wherein the liquid preparation further comprises taurine. 3. The product containing dibutylhydroxytoluene according to claim 1 or 2, where the spout is a tip through which a liquid preparation in the form of drops can pour out, and the surface of the walls of the inner space of the tip is made of a resin containing polybutylene terephthalate. 4. The product containing dibutylhydroxytoluene according to any one of paragraphs. 1-3, where the container body is made of resin containing polyethylene terephthalate. 5. The product containing dibutylhydroxytoluene according to any one of paragraphs. 1-4, where the liquid preparation further includes a borate buffer. 6. The product containing dibutylhydroxytoluene according to any one of paragraphs. 1-5, where the liquid preparation contains, as component (C), a chondroitin sulfate ester and / or a pharmaceutically acceptable salt thereof and aspartic acid and / or a pharmaceutically acceptable salt thereof. 7. The product containing dibutylhydroxytoluene according to any one of paragraphs. 1-6, where the liquid preparation contains component (A) in an amount of from 0.00001 to 0.005 wt./about. %, component (B) in an amount of from 0.005 to 0.5 wt./about. % and component (C) in an amount of from 0.0005 to 5 wt./about. % 8. The product containing dibutylhydroxytoluene according to any one of paragraphs. 1-7, where the liquid preparation is eye drops. 9. A method for stabilizing dibutylhydroxytoluene in a liquid preparation containing: (A) dibutylhydroxytoluene; and (B) pranoprofen and / or its pharmaceutically acceptable salt, where the method includes: - mixing in a liquid preparation (C) at least one compound selected from the group consisting of an ester of chondroitin sulfate, aspartic acid, alginic acid, a derivative of alginic acid and their pharmaceutically acceptable salts and cyanocobalamin, panthenol, tocopherol and a tocopherol derivative, wherein said liquid preparation contains chondroitin sulfate ester in an amount of 0.01-1% w / v%, aspartic acid in an amount of 0.01-2% w / v%, alginic acid, a derivative of alginic acid and / or its pharmacist commercially acceptable salts in an amount of 0.01-0.2% w / v, cyanocobalamin in an amount of 0.002-0.1% w / v, panthenol in an amount of 0.01-0.1% w / v , tocopherol and / or tocopherol derivative in an amount of 0.005-0.1 wt./about.%; and - placing a liquid preparation in a container containing a container body for receiving a liquid preparation, a nozzle having an outlet through which liquid preparation contained in the container body can pour, and a cap for closing the outlet, and where at least one of the surfaces of the walls of the inner the space of the nozzle and the surface of the walls of the cap facing the outlet contains a resin containing polybutylene terephthalate. 10. The method of claim 9, wherein the liquid preparation further comprises taurine. 11. The method according to p. 9 or 10, where the spout is a tip through which a liquid preparation in the form of drops is poured, and the surface of the walls of the inner space of the tip is made of resin containing polybutylene terephthalate. 12. The method according to any one of paragraphs. 9-11, where the container body is made of resin containing polyethylene terephthalate. 13. The method according to any one of paragraphs. 9-12, where the liquid preparation further comprises a borate buffer. 14. The method according to any one of paragraphs. 9-13, where the liquid preparation contains, as component (C), a chondroitin sulfate ester and / or a pharmaceutically acceptable salt thereof and aspartic acid and / or a pharmaceutically acceptable salt thereof. 15. The method according to any one of paragraphs. 9-14, where the liquid preparation contains component (A) in an amount of from 0.00001 to 0.005% w / v, component (B) in an amount of from 0.005 to 0.5% w / v and component (C) in an amount of from 0.0005 to 5% w / v. 16. The method according to any one of paragraphs. 9-15, where the liquid preparation is eye drops.

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