Ophthalmic liquid agent which is suppressed in decrease of dibutylhydroxytoluene content

Abstract

To solve the problem in which: the content of dibutylhydroxytoluene blended as an antioxidant in an ophthalmic liquid agent decreases in the ophthalmic liquid agent due to the volatility, adsorbability and degradability thereof.SOLUTION: The present invention provides an ophthalmic liquid agent which is suppressed in decrease of dibutylhydroxytoluene content by blending dibutylhydroxytoluene together with at least one thickening agent that is selected from the group consisting of xanthane gum, gelatin and carrageenan.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an ophthalmic solution containing a thickener and dibutylhydroxytoluene (BHT), in which a decrease in the dibutylhydroxytoluene (BHT) content in the ophthalmic solution is suppressed. [Background technology]

[0002] Dibutylhydroxytoluene is known as a representative compound of fat-soluble antioxidants, and is incorporated into aqueous ophthalmic liquid preparations such as eye drops for the purpose of stabilizing the active ingredients (Patent Document 1: JP 07-304670 A).

[0003] On the other hand, polysaccharides such as xanthan gum can increase viscosity by mixing with water, and are used as thickeners. Xanthan gum is used in food and cosmetics, and its safety has been confirmed. In pharmaceuticals, natural polymers such as xanthan gum are also blended into compositions as thickeners and stabilizers, but these compositions are mainly intended to stabilize active ingredients (Patent Document 2: JP 2008-195714 A). Such pharmaceutical compositions are formulated into various preparations, and are formulated into jellies and liquids that utilize high viscosity. A personal care composition that is applied to the skin is known as a composition that blends xanthan gum and dibutylhydroxytoluene (Patent Document 3: US / 2010 / 0150971), but has not been formulated into an ophthalmic liquid. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Japanese Patent Application Publication No. 07-304670 [Patent Document 2] JP 2008-195714 A [Patent Document 3] US Patent Application Publication No. 2010 / 0150971 Summary of the Invention [Problem to be solved by the invention]

[0005] The objective of the present invention is to develop an ophthalmic solution in which the decrease in the dibutylhydroxytoluene content is suppressed. [Means for solving the problem]

[0006] The present inventors conducted extensive research to obtain an ophthalmic solution in which a reduction in the dibutylhydroxytoluene content was suppressed, and discovered that a reduction in the dibutylhydroxytoluene content could be achieved by blending a thickener selected from the group consisting of xanthan gum, gelatin, and carrageenan, thereby completing the present invention.

[0007] Therefore, the present invention relates to the following inventions: [1] An ophthalmic solution comprising (A) dibutylhydroxytoluene and (B) one or more thickeners selected from the group consisting of xanthan gum, gelatin and carrageenan. [2] The ophthalmic solution according to item 1, further comprising (C) a nonionic surfactant. [3] (C) The ophthalmic solution according to item 2, wherein the nonionic surfactant is one or more surfactants selected from the group consisting of polysorbate 80, polyoxyethylene hydrogenated castor oil 60, and polyethylene glycol monostearate. [4] The ophthalmic solution according to any one of items 1 to 3, wherein the concentration of the thickener (B) is 0.03 to 0.3 w / v %. [5] The ophthalmic solution according to item 4, wherein the concentration of the thickener (B) is 0.05 to 0.3 w / v %. [6] The ophthalmic solution according to any one of items 1 to 5, wherein the concentration of (A) dibutylhydroxytoluene is 0.0005 to 0.005 w / v %. [7] (B) The ophthalmic solution according to any one of items 1 to 6, wherein the thickener is xanthan gum. [8] The ophthalmic solution according to any one of items 1 to 7, which has a viscosity of 2 to 100 mPa s when measured at a rotation speed of 10 rpm. [9] The ophthalmic solution according to any one of items 1 to 8, which has a pH of 6 to 8.

[10] The ophthalmic solution according to any one of items 1 to 9, wherein the ophthalmic solution is an aqueous solution.

[11] (A) 0.0005 to 0.005 w / v% dibutylhydroxytoluene, (B) 0.05 to 0.3 w / v% of one or more thickeners selected from the group consisting of xanthan gum, gelatin, and carrageenan; (C) containing 0.01 to 0.5 w / v % of one or more nonionic surfactants selected from the group consisting of polysorbate 80, polyoxyethylene hydrogenated castor oil 60, and polyethylene glycol monostearate; pH is 6-8; Ophthalmic solutions.

[12] The ophthalmic solution according to item 11, having a viscosity of 2 to 100 mPa s when measured at a rotation speed of 10 rpm.

[13] The ophthalmic solution according to any one of items 1 to 12, The container includes a container body that contains a liquid medicine, a pouring part having a pouring outlet for pouring out the liquid medicine contained in the container body, and a lid that closes the pouring outlet, An ophthalmic solution product contained in a container, at least one of a wall surface of the internal space of the pouring portion and a wall surface of the lid portion facing the pouring outlet being made of a resin containing polybutylene terephthalate.

[14] A method for suppressing a decrease in the dibutylhydroxytoluene content in an ophthalmic solution containing dibutylhydroxytoluene, the method comprising blending one or more thickeners selected from the group consisting of xanthan gum, gelatin, and carrageenan. Effect of the Invention

[0008] In an ophthalmic solution containing dibutylhydroxytoluene and a thickener selected from the group consisting of xanthan gum, gelatin, and carrageenan, a decrease in the dibutylhydroxytoluene content can be suppressed. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] The present invention relates to an ophthalmic solution containing (A) dibutylhydroxytoluene and (B) one or more thickeners selected from the group consisting of xanthan gum, gelatin and carrageenan.

[0010] In the present invention, the ophthalmic solution may be any formulation that is administered to the eye, and examples thereof include eye drops and eye washes. From the viewpoint of formulation as an ophthalmic solution, it is preferable that all components contained in the formulation are dissolved, and it is also preferable that the formulation is an aqueous solution. The ophthalmic solution can be prepared at any acceptable pH from the viewpoint of achieving stability of the components contained in the solution, and can be prepared in the range of, for example, pH 3 to 9. In addition, from the viewpoint of eye irritation, the upper limit is preferably pH 8.5 or less, more preferably pH 8 or less, while the lower limit is preferably pH 4 or more, more preferably pH 5 or more, and even more preferably pH 6 or more. The ophthalmic solution may contain a buffer to adjust the pH of the solution to the above-mentioned range.

[0011] (A) Dibutylhydroxytoluene (BHT) is also called 2,6-di-tert-butyl-4-methylphenol. Dibutylhydroxytoluene is blended into ophthalmic solutions as a compound that stabilizes active ingredients, and its content can be selected arbitrarily depending on the formulation. From the viewpoint of blending into ophthalmic solutions, it can be blended in the range of 0.00001 to 2.0 w / v%. On the other hand, from the viewpoint of irritation, the content of (A) dibutylhydroxytoluene is preferably 0.01 w / v% or less, more preferably 0.005 w / v% or less. From the viewpoint of fully exerting its effect as an antioxidant, the content of (A) dibutylhydroxytoluene is preferably 0.0005 w / v% or more, more preferably 0.0025 w / v% or more.

[0012] (A) Dibutylhydroxytoluene (BHT) is known as a fat-soluble antioxidant, and is known to have a higher antioxidant power than other fat-soluble antioxidants, such as tocopherol and butylhydroxyanisole. In other words, dibutylhydroxytoluene is highly reactive, and its content decreases due to natural decomposition in the formulation. In addition, containers equipped with an extraction port (nozzle) are commonly used as containers for storing ophthalmic solutions, but adsorption and volatilization of dibutylhydroxytoluene occur depending on the material and shape of the container and extraction port. Not only natural decomposition but also adsorption and volatilization are thought to be factors in the decrease in the content of dibutylhydroxytoluene. Dibutylhydroxytoluene generally has low adsorption to glass, but is thought to have high adsorption to plastic containers. In addition, the material of the nozzle is thought to be involved in the volatilization of dibutylhydroxytoluene.

[0013] It is known that the content of dibutylhydroxytoluene is significantly reduced in a liquid preparation. Therefore, it has been disclosed that by using a specific polymer such as polybutylene terephthalate on the inner wall surface of the inside of a container that contains a liquid preparation, the adsorption of dibutylhydroxytoluene to the container can be suppressed, and the dibutylhydroxytoluene content in the preparation can be stably maintained (JP Patent Publication No. 2014-196349). It has also been disclosed that by blending an organic amine or a citrate salt and using the specific container, the thermal stability of dibutylhydroxytoluene in the aqueous composition can be increased, and by adopting a resin containing polybutylene terephthalate on the inner wall surface of the container, the adsorption to the container can be suppressed, and the decrease in the content over time can be effectively suppressed (JP Patent Publication No. 2015-187102).

[0014] (B) Examples of the thickener include xanthan gum, gelatin, and carrageenan. These substances may be blended alone or in combination. The concentration of the thickener can be selected arbitrarily within a range that can suppress the decrease in the content of dibutylhydroxytoluene. From the viewpoint of blending as an ophthalmic solution, it can be blended in the range of 0.005 to 1.0 w / v%. On the other hand, from the viewpoint of the usability of the ophthalmic solution, the thickener is preferably used at 0.6 w / v% or less, more preferably 0.3% w / v% or less. From the viewpoint of exerting the effect of suppressing the decrease in the content of dibutylhydroxytoluene, the thickener is preferably 0.05 w / v% or more, more preferably 0.1 w / v% or more. The lower limit of the concentration of the thickener can be changed depending on the container used. When a PET container equipped with a PE nozzle or a PBT nozzle is used, the lower limit is preferably 0.05 w / v% or more.

[0015] (B) The viscosity of the solution increases by adding a thickener to the ophthalmic solution. The viscosity of the solution can be measured, for example, by the 2.1.3 cone-plate type rotational viscometer (cone-plate type viscometer) of the 17th revised Japanese Pharmacopoeia General Test Method, Viscosity Measurement Method, Method 2, Rotational Viscometer Method. The viscosity of the solution can vary depending on the dissolving conditions of the thickener, but when measured under the conditions of a measurement temperature of 20°C (±0.1°C), a rotor of 0.8°×R24 used, and a rotation speed of 10 rpm, the viscosity of the ophthalmic solution of the present invention is usually 2 to 100 mPa·s. From the viewpoint of the feeling of use of the ophthalmic solution or the ratio of the thickener to be blended, the lower limit of the viscosity range is 2 mPa·s, preferably 3 mPa·s, more preferably 10 mPa·s, and even more preferably 33 mPa·s. The upper limit of the viscosity range is 100 mPa·s, preferably 80 mPa·s, more preferably 60 mPa·s, even more preferably 50 mPa·s, and particularly preferably 41 mPa·s. The lower and upper limits can be arbitrarily selected to determine the numerical range. As an example, when xanthan gum is blended at 0.3 w / v% as a thickener, the viscosity can be 30 to 50 mPa·s, particularly 33 to 41 mPa·s. If the desired viscosity is not obtained, a thickener, thickener, or thickener other than the thickener of the present invention, such as sodium chondroitin sulfate, can be added.

[0016] In the present invention, the content mass ratio of (A) dibutylhydroxytoluene (BHT) to (B) thickener may be any ratio as long as it can suppress the decrease in the BHT content, and can be arbitrarily set by a person skilled in the art. As an example, (A) dibutylhydroxytoluene (BHT) / (B) thickener can be used at 0.00001 to 400, and from the viewpoint of suppressing the decrease in the BHT content, 0.001 to 10 is preferable. The lower limit of the content mass ratio is more preferably 1 / 60 from the viewpoint of suppressing the decrease in the BHT content, and more preferably 1 / 30. The upper limit of the content mass ratio is preferably 1 from the viewpoint of suppressing the decrease in the BHT content, and more preferably 1 / 10.

[0017] Xanthan gum is a polysaccharide mainly composed of glucose, mannose, and glucuronic acid, and is produced by fermenting starch with bacteria (such as Xanthomonas campestris). Xanthan gum has a molecular weight of 2 to 50 million Da depending on the product, and when dissolved in water, it imparts properties such as thickening, emulsion and suspension stability, and pseudoplasticity. Depending on the purification method, xanthan gum may be a salt with an inorganic base, and may include potassium salt, sodium salt, magnesium salt, and / or calcium salt. Since xanthan gum has pseudoplasticity, it is preferable to incorporate it into ophthalmic solutions in terms of the feeling of use after application.

[0018] Gelatin can be prepared by subjecting animal bones, skin, ligaments, or tendons to acid or alkali treatment to obtain crude collagen, which is then extracted by heating, and purified. Gelatin is used as a thickening agent.

[0019] Carrageenan is a polysaccharide obtained by extraction from red algae such as the family Gigartinaceae, and is mainly composed of D-galactose and sulfuric acid. Carrageenan is obtained by extracting red algae with dilute alkaline hot water or alcohol. Carrageenan is called κ, ι, or λ carrageenan depending on the type of red algae used as the raw material. In the present invention, it is preferable to use λ carrageenan because it does not gel and has only a thickening effect.

[0020] (A) dibutylhydroxytoluene is lipophilic, and therefore has low water solubility. When preparing an ophthalmic solution containing dibutylhydroxytoluene, it is preferable to further include (C) a nonionic surfactant. (C) nonionic surfactant can be blended in the range of 0.001 to 5 w / v% from the viewpoint of blending as an ophthalmic solution. On the other hand, in the present invention, from the viewpoint of the effect as a solubilizing agent for dibutylhydroxytoluene, the upper limit of the content of (C) nonionic surfactant is preferably 1 w / v% or less, more preferably 0.5 w / v% or less, and the lower limit is preferably 0.01 w / v% or more, more preferably 0.1 w / v% or more.

[0021] (C) The nonionic surfactant may be selected arbitrarily as long as it does not cause a decrease in the dibutylhydroxytoluene content. For example, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyethylene glycol monostearate (40E.O.), etc. may be used.

[0022] The ophthalmic solution of the present invention may contain any component used in ophthalmic solutions in addition to (A) dibutylhydroxytoluene, (B) a thickener, and (C) a nonionic surfactant. The optional components used in ophthalmic solutions include, but are not limited to, active ingredients, aqueous bases, buffers, isotonicity agents, solubilizing agents, thickening agents, viscosifying agents, refreshing agents, pH adjusters, stabilizers, preservatives, and chelating agents.

[0023] The active ingredient used in the ophthalmic solution of the present invention may be any ingredient that can use dibutylhydroxytoluene as a stabilizer. Examples of active ingredients that can be used include pranoprofen, apigenin, minoxidil, carpronium chloride, L-ascorbic acid-2-O-maleic acid-α-tocopherol ester or its salt, sucralose, flavin adenine dinucleotide (FAD), pyridoxine, vitamin A, etc., but are not intended to be limited thereto.

[0024] The container in which the ophthalmic solution of the present invention is stored is composed of a container body that stores the solution, an outlet that includes an outlet for pouring out the solution stored in the container body, and a lid that covers the outlet. The outlet has a through hole to form an extraction port, and the solution inside the container is poured out to the outside of the container through the through hole. The extraction part has a nozzle shape, and the solution does not leak even when the container is inverted, but when pressure is applied to the container in the inverted state, the solution flows out from the through hole and falls as droplets. The lid can contact and cover the through hole of the extraction part, thereby suppressing leakage and volatilization of the solution and suppressing the intrusion of substances and bacteria from the outside. The outlet may be formed integrally with the main body from the same material, but may usually be formed from a material different from the main body and attached to the container body. The lid may generally be formed from the same material as the extraction part, and may include a lid outer shell formed from a different material to facilitate handling. In the present invention, the container in which the ophthalmic solution is stored may be made of a resin containing polyethylene terephthalate. In order to suppress a decrease in the BHT content, it is preferable that at least one or both of the wall surface of the internal space of the extraction part and the wall surface facing the spout in the lid part are made of a resin containing polybutylene terephthalate.

[0025] In a further aspect of the present invention, the present invention relates to a method for suppressing the decrease in the content of dibutylhydroxytoluene in an ophthalmic liquid preparation containing dibutylhydroxytoluene. The method of the present invention includes blending one or more thickeners selected from the group consisting of xanthan gum, gelatin, and carrageenan. The method of suppressing the decrease in the BHT content of the present invention further includes blending a surfactant. In addition, since the thickener is considered to suppress the adsorption of BHT to the container wall, a step of applying an aqueous solution containing the thickener to the container before putting the liquid preparation in may be included. As the concentrations of dibutylhydroxytoluene, thickener, and surfactant used in the method of suppressing the decrease in the BHT content of the present invention, the concentrations used in the ophthalmic liquid preparation described in this specification can be appropriately used.

[0026] In this specification, the unit "w / v%" refers to a percentage by mass to volume, and is synonymous with g / 100 ml. In addition, since the density of an ophthalmic solution is generally the same as the density of water, it is synonymous with w / w%. As for the formulations used in this specification, those that are easy to foam may be prepared in w / w%.

[0027] All documents mentioned herein are incorporated by reference in their entirety.

[0028] The following examples of the present invention are for illustrative purposes only and do not limit the technical scope of the present invention. The technical scope of the present invention is limited only by the claims. The present invention can be modified, for example, by adding, deleting, and replacing the constituent elements of the present invention, without departing from the spirit of the present invention. EXAMPLES

[0029] Test Example 1: Effect of xanthan gum on the decrease in dibutylhydroxytoluene (BHT) content in ophthalmic solutions containing BHT Dibutylhydroxytoluene (BHT) (Wako Pure Chemical Industries, Ltd.) and polysorbate 80 (NOF Corporation) were dissolved in hot water to prepare a BHT-containing solution. Separately, borax and xanthan gum (XA) (Echo Gum T, DSP Gokyo Food & Chemical Co., Ltd.) were dissolved in purified water at high temperature, cooled, and then boric acid was added to prepare a xanthan gum solution, borax and hypromellose (HPMC) (65SH4000, Shin-Etsu Chemical Co., Ltd.) were dissolved in purified water at high temperature, cooled, and then boric acid was added to prepare a hypromellose solution, and boric acid and borax were dissolved to prepare a base solution. The density of all liquid preparations was approximately 1 g / cm 3 It is.

[0030] The BHT-containing solution was added to the xanthan gum solution, hypromellose solution and base solution to give respective specified concentrations, and the pH was adjusted to obtain each of the test solutions of Examples 1 to 3 and Comparative Examples 1 to 6. [Table 1] These test solutions were filled into glass ampoules to prepare test samples. Each test sample was stored at 60°C for two weeks, and then the BHT content of each was measured using HPLC. The ratio of the BHT content of each test sample stored at 60°C to the BHT content of the sample stored at 4°C was shown as the residual rate (%). The results are shown in Table 2 below. [Table 2] At each pH range (pH 6 to 8), hypumellose had no inhibitory effect on the decrease in BHT content, whereas xanthan gum exhibited an extremely high inhibitory effect on the decrease in BHT content.

[0031] Test Example 2: Effect of dibutylhydroxytoluene (BHT) concentration on suppressing the decrease in BHT content in ophthalmic solutions containing BHT According to the preparation method of [Test Example 1], each test liquid shown in Table 3 was prepared and filled into a container to prepare a test sample. [Table 3] These test solutions were filled into glass ampoules to prepare test samples. Each test sample was stored at 60°C for 2 or 4 weeks, and then the BHT content of each was measured using HPLC. The ratio of the BHT content of the test sample stored at 60°C to the BHT content of the sample stored at 4°C was shown as the residual rate (%). The results are shown in Table 4 below. [Table 4] At BHT concentrations of more than 0.0005%, xanthan gum exerts an effect of suppressing the decrease in BHT content.

[0032] Test Example 3: Effect of xanthan gum concentration on the decrease in dibutylhydroxytoluene (BHT) content in ophthalmic solutions containing BHT According to the preparation method of [Test Example 1], each test liquid shown in Table 5 was prepared and filled into a container to prepare a test sample. [Table 5]

[0033] After storing each test sample at 60°C for 2 and 4 weeks, the BHT content of each was measured using HPLC. The ratio of the BHT content of each test sample stored at 60°C to the BHT content of the sample stored at 4°C was shown as the residual rate (%). [Table 6] In a liquid formulation containing 0.005% BHT, xanthan gum was effective in suppressing the decrease in BHT content at 0.05% (w / v) or more, and this effect increased in a concentration-dependent manner. The suppression of the decrease in BHT content was observed when xanthan gum was blended in an amount 10 times or more that of BHT.

[0034] Test Example 4: Effect of type of thickener on suppressing the decrease in BHT content in ophthalmic solutions containing BHT According to the preparation method of [Test Example 1], each test solution shown in Table 7 was prepared as a test sample. The test sample was filled into a glass ampoule. Gelatin manufactured by Nacalai Tesque, Inc., sodium alginate manufactured by Funakoshi Co., Ltd., carrageenan manufactured by Tokyo Kasei Kogyo Co., Ltd., and gellan gum manufactured by Kanto Kagaku Co., Ltd. were used. [Table 7]

[0035] In Reference Example 1, the quantitative sample gelled, making it impossible to measure. After storing each test sample at 60°C for 2 and 4 weeks, the BHT content of each was measured using HPLC. The ratio of the BHT content of the sample stored at 60°C to the BHT content of the sample stored at 4°C for each test sample was shown as the residual rate (%). [Table 8]

[0036] All thickeners were effective in suppressing the decrease in BHT content, but xanthan gum, gelatin, and carrageenan were particularly effective in suppressing the decrease in BHT content.

[0037] Test Example 5: Selection of a container for enclosing an ophthalmic solution containing BHT and xanthan gum According to the preparation method of [Test Example 1], each test liquid shown in Table 9 was prepared and filled into glass, a polyethylene terephthalate (PET) container equipped with a polyethylene (PE) nozzle, and a PET container equipped with a polybutylene terephthalate (PBT) nozzle to prepare test samples. [Table 9]

[0038] After storing each test sample at 60°C for 2 and 4 weeks, the BHT content of each was measured using HPLC. The ratio of the BHT content of each test sample stored at 60°C to the BHT content of the sample stored at 4°C was shown as the residual rate (%). [Table 10]

[0039] In glass vials, a BHT stabilizing effect was observed at a xanthan gum concentration of 0.1% (w / v) or higher. On the other hand, in PET containers equipped with PE nozzles and PET containers equipped with PBT nozzles, an effect of suppressing the decrease in BHT content was observed at a concentration of 0.05% (w / v) or higher. The effect of suppressing the decrease in BHT content varied depending on the nozzle material, and PET containers equipped with PBT nozzles were the most effective in stabilizing BHT.

[0040] Test Example 6: Selection of surfactants in ophthalmic solutions containing BHT and xanthan gum According to the preparation method of [Test Example 1], the polysorbate 80 of Example 2 was replaced with the same nonionic surfactant, polyoxyethylene hydrogenated castor oil 60 (abbreviated as HCO-60) or polyethylene glycol monostearate (40E.O.) (abbreviated as MYS-40), to prepare the test solutions of Examples 17 and 18. These were filled into a PET container equipped with a polybutylene terephthalate (PBT) nozzle to prepare test samples. Both HCO-60 and MYS-40 were manufactured by Nikko Chemicals Co., Ltd. After storing each test sample at 60°C for 4 weeks, the BHT content of each was measured using HPLC. The ratio of the BHT content of the sample stored at 60°C to the BHT content of the sample stored at 4°C in the measurement results of each test sample was shown as the residual rate. As a result, the residual rate of BHT after storage at 60°C for 4 weeks was 101.6% in Example 17, in which HCO-60 was added, and 93.0% in Example 18, in which MYS-40 was added. This indicates that the stabilizing effect of xanthan gum on BHT was observed when HCO-60 or MYS-40 was used as the nonionic surfactant, similar to when polysorbate 80 was used.

[0041] Test Example 7: Viscosity of ophthalmic solutions containing BHT and xanthan gum According to the preparation method of [Test Example 1], Examples 2, 11, 10, and 19 shown in Table 11 were prepared, and the rotational viscosity was measured using a cone-plate type rotational viscometer (cone-plate type viscometer, TV-25 type, Toki Sangyo) according to the Japanese Pharmacopoeia General Test Method Viscosity Measurement Method Method 2 Rotational Viscometer Method. The measurement temperature was 20°C (±0.1°C), the rotor used was (0.8°×R24), and the rotation speed was 10 rpm. Sodium chondroitin sulfate manufactured by Maruha Nichiro Corporation was used. [Table 11]

[0042] Test Example 8: Effect of xanthan gum on suppressing the decrease in BHT content in the presence of drugs According to the preparation method of [Test Example 1], the active ingredient was further added to prepare each test solution shown in Table 12 below. Pranoprofen manufactured by API Corporation was used. Sodium cromoglycate manufactured by Fermion was used. Each test solution of Examples 20 and 21 and Comparative Example 26 was filled into a container made of PET with a polybutylene terephthalate (PBT) nozzle attached, and stored at 4°C and 60°C for 4 weeks, and then the BHT content of each was measured using HPLC. The ratio of the BHT content of the product stored at 60°C to the BHT content of the product stored at 4°C was shown as the residual rate (%). As a result, even when pranoprofen was contained as a drug, the stabilization effect of BHT was confirmed by adding xanthan gum. [Table 12]

[0043] Test Example 9: Viscosity of ophthalmic solutions containing BHT and xanthan gum The aqueous solution in which borax was dissolved was heated to about 80°C, and xanthan gum was added and dissolved for 1 hour, or hypromellose was added and dissolved for 2 hours. After cooling the liquid temperature to about 30°C, boric acid, polysorbate 80, and dibutylhydroxytoluene were added and dissolved, and the pH was adjusted to obtain the test liquids of Example 22 and Comparative Examples 27 and 28. Each of these test liquids was filled into a glass ampoule to obtain a test specimen. After storing each test specimen at 4°C for 7 weeks, the rotational viscosity was measured according to the viscosity measurement method of Test Example 7. However, the rotation speed was 100 rpm and 10 rpm. [Table 13] [Table 14]

Claims

1. (A) an ophthalmic solution containing dibutylhydroxytoluene and (B) xanthan gum as a thickener, and An ophthalmic solution product including a container for containing the ophthalmic solution, The container comprises a container body, a dispensing section having a spout for dispensing the liquid contained in the container body, and a lid for sealing the spout. The ophthalmic liquid product wherein at least one of the walls of the internal space of the dispensing portion and the wall of the lid portion facing the dispensing spout is made of a resin containing polybutylene terephthalate.

2. The ophthalmic solution product according to claim 1, wherein the ophthalmic solution further contains (C) a nonionic surfactant.

3. (C) The ophthalmic liquid product according to claim 2, wherein the nonionic surfactant is one or more surfactants selected from the group consisting of polysorbate 80, polyoxyethylene hydrogenated castor oil 60, and polyethylene glycol monostearate.

4. (B) An ophthalmic liquid product according to any one of claims 1 to 3, wherein the concentration of xanthan gum is 0.03 to 0.3 w / v%.

5. (B) The ophthalmic liquid product according to claim 4, wherein the concentration of xanthan gum is 0.05 to 0.3 w / v%.

6. (A) An ophthalmic liquid product according to any one of claims 1 to 5, wherein the concentration of dibutylhydroxytoluene is 0.0005 to 0.005 w / v%.

7. An ophthalmic liquid product according to any one of claims 1 to 6, wherein (A) the concentration of dibutylhydroxytoluene is 0.0005 to 0.005 w / v%, and (B) the concentration of xanthan gum is 0.03 to 0.3 w / v%.

8. An ophthalmic liquid product according to any one of claims 1 to 7, wherein the viscosity measured at a rotational speed of 10 rpm is 2 to 100 mPa·s.

9. An ophthalmic liquid product according to any one of claims 1 to 8, wherein the pH is 6 to 8.

10. The ophthalmic liquid product according to any one of claims 1 to 9, wherein the ophthalmic liquid is an aqueous liquid.

11. (A) 0.0005 to 0.005 w / v% dibutylhydroxytoluene, (B) 0.05 to 0.3 w / v% xanthan gum as a thickening agent, (C) Contains one or more nonionic surfactants selected from the group consisting of polysorbate 80, polyoxyethylene hydrogenated castor oil 60, and polyethylene glycol monostearate in an amount of 0.01 to 0.5 w / v%, The pH is between 6 and 8. Ophthalmic solutions, and Container for containing the ophthalmic solution An ophthalmic liquid product containing, The container comprises a container body, a dispensing section having a spout for dispensing the liquid contained in the container body, and a lid for sealing the spout. The ophthalmic liquid product wherein at least one of the walls of the internal space of the dispensing portion and the wall of the lid portion facing the dispensing spout is made of a resin containing polybutylene terephthalate.

12. The ophthalmic liquid product according to claim 11, wherein the viscosity measured at a rotational speed of 10 rpm is 2 to 100 mPa·s.