Ophthalmic liquid preparation for inhibiting reduction of dibutylated hydroxytoluene content

Abstract

The present invention relates to an ophthalmic liquid preparation for inhibiting a decrease in the content of dibutylated hydroxytoluene. Dibutylated hydroxytoluene blended as an antioxidant in a liquid preparation for ophthalmology has a reduced content in the liquid preparation for ophthalmology due to its volatility, adsorbability, decomposability, and the like. The present invention provides an ophthalmic liquid preparation in which dibutylated hydroxytoluene and one or more thickeners selected from the group consisting of xanthan gum, gelatin and carrageenan are blended to suppress a decrease in the content of dibutylated hydroxytoluene.

Description

[0001] This application is a divisional application of Chinese patent application No. 201980035430.8 with the same invention name. The original international application number is PCT / JP2019 / 021849, and the international application date is May 31, 2019. Technical Field

[0002] The present invention relates to an ophthalmic liquid preparation containing a thickener and butylated hydroxytoluene (BHT), in which a decrease in the content of butylated hydroxytoluene (BHT) in the ophthalmic liquid preparation is suppressed. Background Art

[0003] It is known that dibutylhydroxytoluene is a representative compound of fat-soluble antioxidants and is incorporated into aqueous liquid preparations for ophthalmology such as eye drops for the purpose of stabilizing the active ingredient (Patent Document 1: Japanese Patent Application Laid-Open No. 07-304670).

[0004] On the other hand, polysaccharides such as xanthan gum can promote 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 addition, in medicines, natural polymers such as xanthan gum are formulated in compositions as thickening stabilizers, and their main purpose is to stabilize the active ingredients in these compositions (Patent Document 2: Patent Publication No. 2008-195714). Such pharmaceutical compositions are made into various preparations, but are made into jelly or liquid preparations utilizing high viscosity. As a composition formulated with xanthan gum and butylated hydroxytoluene, a personal care composition suitable for skin is known (Patent Document 3: US / 2010 / 0150971), but there is no dosage form made into an ophthalmic liquid preparation.

[0005] Prior art literature

[0006] Patent Literature

[0007] Patent Document 1: Japanese Patent Application Publication No. 07-304670

[0008] Patent Document 2: Japanese Patent Application Publication No. 2008-195714

[0009] Patent Document 3: U.S. Patent Application Publication No. 2010 / 0150971 Summary of the invention

[0010] Problems to be solved by the invention

[0011] An object of the present invention is to develop an ophthalmic liquid preparation in which a decrease in the content of butylated hydroxytoluene is suppressed.

[0012] Means of solving problems

[0013] The present inventors conducted intensive studies to obtain an ophthalmic liquid preparation that suppresses the reduction of the butylated hydroxytoluene content. As a result, they found that the reduction of the butylated hydroxytoluene content can be suppressed by adding a thickener selected from xanthan gum, gelatin and carrageenan, thereby completing the present invention.

[0014] Therefore, the present invention relates to the following inventions:

[0015] [1] An ophthalmic liquid preparation comprising:

[0016] (A) butylated hydroxytoluene; and

[0017] (B) at least one thickener selected from the group consisting of xanthan gum, gelatin and carrageenan.

[0018] [2] The ophthalmic liquid preparation according to item 1, further comprising (C) a nonionic surfactant.

[0019] [3] The ophthalmic liquid preparation according to item 2, wherein the (C) nonionic surfactant is one or more surfactants selected from the group consisting of polysorbate 80, polyoxyethylene hydrogenated castor oil 60, and polyethylene glycol monostearate.

[0020] [4] The ophthalmic liquid preparation according to any one of items 1 to 3, wherein the concentration of the thickener (B) is 0.03 to 0.3 w / v%.

[0021] [5] The ophthalmic liquid preparation according to item 4, wherein the concentration of the thickener (B) is 0.05 to 0.3 w / v%.

[0022] [6] The ophthalmic liquid preparation according to any one of items 1 to 5, wherein the concentration of (A) butylated hydroxytoluene is 0.0005 to 0.005 w / v%.

[0023] [7] The ophthalmic liquid preparation according to any one of items 1 to 6, wherein the thickener (B) is xanthan gum.

[0024] [8] The ophthalmic liquid preparation 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.

[0025] [9] The ophthalmic liquid preparation according to any one of items 1 to 8, wherein the pH thereof is 6 to 8.

[0026]

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

[0027]

[11] An ophthalmic liquid preparation comprising:

[0028] (A) 0.0005 to 0.005 w / v% of butylated hydroxytoluene,

[0029] (B) 0.05 to 0.3 w / v% of at least one thickener selected from the group consisting of xanthan gum, gelatin and carrageenan, and

[0030] (C) 0.01 to 0.5 w / v% of one or more nonionic surfactants selected from polysorbate 80, polyoxyethylene hydrogenated castor oil 60 and polyethylene glycol monostearate;

[0031] Its pH is 6-8.

[0032]

[12] The ophthalmic liquid preparation according to item 11, wherein the viscosity when measured at a rotation speed of 10 rpm is 2 to 100 mPa·s.

[0033]

[13] An ophthalmic liquid preparation product, comprising the ophthalmic liquid preparation according to any one of items 1 to 12 contained in a container, wherein the container comprises:

[0034] The container body for containing the liquid preparation,

[0035] a pouring portion having a pouring spout for pouring out the liquid preparation contained in the container body, and

[0036] a cover portion covering the pouring opening;

[0037] 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 port is formed of a resin containing polybutylene terephthalate.

[0038]

[14] A method for suppressing a decrease in the content of butylated hydroxytoluene, characterized in that at least one thickener selected from the group consisting of xanthan gum, gelatin and carrageenan is added to an ophthalmic liquid preparation containing butylated hydroxytoluene.

[0039] Effects of the Invention

[0040] In an ophthalmic liquid preparation containing dibutylhydroxytoluene and a thickener selected from the group consisting of xanthan gum, gelatin and carrageenan, a decrease in the content of dibutylhydroxytoluene can be suppressed. DETAILED DESCRIPTION

[0041] The present invention relates to an ophthalmic liquid preparation, which contains (A) butylated hydroxytoluene and (B) at least one thickener selected from the group consisting of xanthan gum, gelatin and carrageenan.

[0042] In the present invention, the ophthalmic liquid preparation can be any preparation as long as it can be applied to the eye. As one example, eye drops, eye washes, etc. can be cited. From the perspective of making an ophthalmic liquid preparation as a dosage form, it is preferred that all the components contained in the preparation are dissolved. In addition, an aqueous liquid preparation (aqueous liquid preparation) is preferred. As an ophthalmic liquid preparation, from the perspective of achieving the stability of the components contained in the liquid preparation, it can be modulated at any allowable pH, for example, it can be modulated in the range of pH 3 to 9. In addition, from the perspective of irritation to the eye, the upper limit may preferably be below pH 8.5, more preferably below pH 8, on the other hand, the lower limit may preferably be above pH 4, more preferably above pH 5, and further preferably above pH 6. In order to adjust the pH of the liquid preparation to the above range, a buffer may be used in the ophthalmic liquid preparation.

[0043] (A) Butylated hydroxytoluene (BHT) is called 2,6-di-tert-butyl-4-methylphenol. Butylated hydroxytoluene is formulated in ophthalmic liquid preparations as a compound of a stabilizing active ingredient, and its content can be arbitrarily selected according to the preparation. From the viewpoint of being formulated in ophthalmic liquid preparations, it can be formulated in a range of 0.00001 to 2.0 w / v%. On the other hand, from the viewpoint of irritation, the content of (A) Butylated hydroxytoluene is preferably less than 0.01 w / v%, more preferably less than 0.005 w / v%. From the viewpoint of fully exerting its effectiveness as an antioxidant, the content of (A) Butylated hydroxytoluene is preferably more than 0.0005 w / v%, more preferably more than 0.0025 w / v%.

[0044] It is known that (A) butylated hydroxytoluene (BHT) is a fat-soluble antioxidant, and it is known that it has a high antioxidant power compared with other fat-soluble antioxidants, such as tocopherol or butylated hydroxyanisole. In other words, butylated hydroxytoluene is highly reactive and will naturally decompose in the preparation, resulting in a decrease in its content. In addition, as a container for containing ophthalmic liquid preparations, a container with an extraction port (nozzle) is generally used. Depending on the material and shape of the container and the extraction port, butylated hydroxytoluene will be adsorbed or volatilized. It is believed that not only natural decomposition, but also adsorption and volatilization are one of the reasons for the reduction in the content of butylated hydroxytoluene. It is believed that butylated hydroxytoluene generally has low adsorption to glass, but on the other hand, it has high adsorption in plastic containers. It is also believed that the material of the nozzle is related to the volatilization of butylated hydroxytoluene.

[0045] It is known that the content of butylated hydroxytoluene in liquid preparations will be significantly reduced. Therefore, the following contents are disclosed: by using a specific polymer such as polybutylene terephthalate on the inner wall surface of the container inside the liquid preparation, butylated hydroxytoluene is inhibited from being adsorbed by the container, so that the content of butylated hydroxytoluene in the preparation can be stably maintained (Japanese Patent Publication No. 2014-196349). In addition, the following contents are disclosed: by combining an organic amine or a citrate and using the above-mentioned specific container, the thermal stability of butylated hydroxytoluene in an aqueous composition can be improved, and at the same time, by using a resin containing polybutylene terephthalate on the inner wall surface of the container, it is possible to inhibit adsorption by the container and effectively inhibit the decrease in content over time (Japanese Patent Publication No. 2015-187102).

[0046] As (B) thickeners, xanthan gum, gelatin, and carrageenan can be mentioned. These substances can be formulated alone or in combination. The concentration of the thickener can be arbitrarily selected within the range that can suppress the reduction of the content of dibutylhydroxytoluene. From the viewpoint of being formulated in an ophthalmic liquid preparation, it can be formulated in the range of 0.005 to 1.0 w / v%. On the other hand, from the viewpoint of the feel of the ophthalmic liquid preparation, the amount of the thickener used is preferably 0.6 w / v% or less, more preferably 0.3 w / v% or less. From the viewpoint of exerting the effect of suppressing the reduction of the dibutylhydroxytoluene content, 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 vary depending on the container used. In the case of using a PET container with a PE nozzle or a PBT nozzle, the lower limit is preferably 0.05 w / v% or more.

[0047] By adding (B) a thickener to an ophthalmic liquid preparation, the viscosity of the liquid preparation increases. As an example, the viscosity of the liquid preparation can be measured by "2.1.3 Cone-plate type rotational viscometer (cone-plate type viscometer) of the 17th edition of the Japanese Pharmacopoeia General Test Methods Viscosity Measurement Method Method 2 Rotational Viscometer Method". The viscosity of the liquid preparation varies depending on the dissolution conditions of the thickener. When measured at a measurement temperature of 20°C (±0.1°C), using a rotor of 0.8°×R24, and a rotation speed of 10 rpm, the viscosity of the ophthalmic liquid preparation of the present invention is generally 2 to 100 mPa·s. From the perspective of the feel of the ophthalmic liquid preparation or the perspective of the proportion of the thickener to be formulated, the lower limit of the viscosity range can be 2 mPa·s, preferably 3 mPa·s, more preferably 10 mPa·s, and further preferably 33 mPa·s. The upper limit of the viscosity range can be 100mPa·s, preferably 80mPa·s, more preferably 60mPa·s, further preferably 50mPa·s, and particularly preferably 41mPa·s. The lower limit and the upper limit can be arbitrarily selected to determine the numerical range. As an example, when 0.3w / v% xanthan gum is used as a thickener, the viscosity can be 30 to 50mPa·s, particularly 33 to 41mPa·s. When the desired viscosity cannot be obtained, a thickener, a viscosifier or a viscous agent other than the thickener of the present invention, such as sodium chondroitin sulfate, etc. can also be added.

[0048] In the present invention, the content mass ratio of (A) butylated hydroxytoluene (BHT) to (B) thickener can be any ratio as long as the reduction in BHT content can be suppressed, and can be set arbitrarily by a person skilled in the art. As an example, as the ratio of (A) butylated hydroxytoluene (BHT) / (B) thickener, 0.00001 to 400 can be adopted, and from the viewpoint of suppressing the reduction in BHT content, 0.001 to 10 is preferably used. As the lower limit of the content mass ratio, from the viewpoint of suppressing the reduction in BHT content, 1 / 60 is preferably used, and 1 / 30 is more preferably used. As the upper limit of the content mass ratio, from the viewpoint of suppressing the reduction in BHT content, 1 is preferably used, and 1 / 10 is more preferably used.

[0049] Xanthan gum is a polysaccharide mainly composed of glucose, mannose and glucuronic acid, produced by fermenting starch with bacteria (Xanthomonas campes tris, etc.). Xanthan gum varies according to the product, with a molecular weight of 2 million to 50 million Da, and when dissolved in water, it imparts properties such as thickening, emulsification and suspension stability, and pseudoplasticity. For xanthan gum, according to the refining method, it can be a salt with an inorganic base, and it can also contain potassium salt, sodium salt, magnesium salt and / or calcium salt. Since xanthan gum has pseudoplasticity, it is preferred from the perspective of the use feeling after eye drops when it is combined in an ophthalmic liquid preparation.

[0050] Gelatin can be purified by heating and extracting crude collagen obtained by treating animal bones, skins, ligaments or tendons with acid or alkali, and used as a thickener.

[0051] Carrageenan refers to a polysaccharide extracted from red algae such as the Taxaceae family, and is mainly composed of D-galactose and sulfuric acid. Carrageenan is obtained by extracting red algae with dilute alkali hot water or alcohol. Carrageenan is called κ-type, ι-type, and λ-type carrageenan according to the type of red algae used as the raw material. In the present invention, λ-carrageenan is preferably used because it does not gel and only has a thickening effect.

[0052] Since (A) butylated hydroxytoluene is fat-soluble, it has low water solubility. When preparing an ophthalmic liquid preparation containing butylated hydroxytoluene, it is preferably also contained (C) a nonionic surfactant. From the viewpoint of being formulated in an ophthalmic liquid preparation, the (C) nonionic surfactant can be formulated in a range of 0.001 to 5 w / v%. On the other hand, in the present invention, from the viewpoint of the effect of butylated hydroxytoluene as a cosolvent, the upper limit of the content of the (C) nonionic surfactant is preferably less than 1 w / v%, more preferably less than 0.5 w / v%, and the lower limit is preferably more than 0.01 w / v%, more preferably more than 0.1 w / v%.

[0053] (C) The nonionic surfactant may be arbitrarily selected as long as it does not cause a decrease in the content of butylated hydroxytoluene, and examples thereof include polysorbate 80, polyoxyethylene hydrogenated castor oil 60, and polyethylene glycol (40 EO) monostearate.

[0054] The ophthalmic liquid preparation of the present invention may contain any component used in ophthalmic liquid preparations in addition to (A) butylated hydroxytoluene, (B) a thickener, and (C) a nonionic surfactant. The optional component that can be used in ophthalmic liquid preparations includes, but is not limited to, active ingredients, aqueous bases, buffers, isotonic agents, solubilizers, thickeners, thickeners, cooling agents, pH adjusters, stabilizers, preservatives, chelating agents, and the like.

[0055] As the active ingredient used in the ophthalmic liquid preparation of the present invention, any ingredient that can use butylated hydroxytoluene as a stabilizer can be used in combination. As an example of an active ingredient that can be combined, pranoprofen, apigenin, minoxidil, carpronium chloride, L-ascorbic acid-2-O-maleic acid-α-tocopheryl ester or its salt, sucralose, flavin adenine dinucleotide (FAD), pyridoxine, vitamin A, etc. can be cited, but it is not limited to this.

[0056] The container for containing the ophthalmic liquid preparation of the present invention comprises: a container body for containing the liquid preparation, a pouring part including a pouring port for pouring out the liquid preparation contained in the container body, and a cover covering the pouring part. The pouring part is provided with a through hole to form an extraction port, and the liquid preparation inside the container is poured out to the outside of the container through the through hole. The extraction part is set in a nozzle shape, and the liquid preparation will not leak out even if the container is inverted. By applying pressure to the container in the inverted state, the liquid preparation flows out through the through hole and falls as droplets. The cover can contact the through hole covering the extraction part, thereby suppressing the leakage and volatilization of the liquid preparation, and at the same time, suppressing the invasion of substances and bacteria from the outside. The pouring part can be formed integrally with the body using the same material, but is usually formed of a material different from the body and can be installed on the container body. The cover can usually be formed of the same material as the extraction part, and for easy operation, it can contain a cover profile formed of a different material. In the present invention, the container for containing the ophthalmic liquid preparation may be composed of a resin containing polyethylene terephthalate. In addition, from the viewpoint of suppressing the reduction of the BHT content, it is preferred that at least one or both of the wall surface of the internal space of the extraction part and the wall surface of the cover part opposite to the pouring port are composed of a resin containing polybutylene terephthalate.

[0057] In various embodiments of the present invention, the present invention relates to a method for inhibiting the reduction of the content of butylated hydroxytoluene in an ophthalmic liquid preparation containing butylated hydroxytoluene. The method of the present invention includes combining one or more thickeners selected from xanthan gum, gelatin and carrageenan. The method for inhibiting the reduction of BHT content of the present invention also includes combining a surfactant. In addition, since it is believed that the thickener inhibits the adsorption of BHT by the wall of the container, before loading the liquid preparation, a step of applying (applying) an aqueous solution containing a thickener to the container may also be included. As the concentrations of butylated hydroxytoluene, thickener, and surfactant used in the method for inhibiting the reduction of BHT content of the present invention, the concentrations used for the ophthalmic liquid preparations described in this specification can be appropriately used.

[0058] In this specification, the unit "w / v%" means the percentage of mass to volume, and is synonymous with g / 100ml. In addition, the density of ophthalmic liquid preparations is usually the same as the density of water, so it is synonymous with w / w%. Regarding the prescriptions used in this specification, the prescriptions that are easy to foam can also be prepared in w / w%.

[0059] All documents mentioned in this specification are incorporated into this specification by reference in their entirety.

[0060] The embodiments of the present invention described below are only for illustration and do not limit the technical scope of the present invention. The technical scope of the present invention is limited only by the scope of the claims. Without departing from the gist of the present invention, the present invention may be modified, for example, by adding, deleting and replacing the constituent elements of the present invention.

[0061] Example

[0062] Test Example 1: BHT content of xanthan gum in ophthalmic liquid preparations containing butylated hydroxytoluene (BHT) Reduce the inhibitory effect

[0063] Butylated hydroxytoluene (BHT) (manufactured by Wako Pure Chemical Industries, Ltd.) and polysorbate 80 (manufactured by NOF Corporation) were dissolved in hot water to prepare a solution containing BHT. In addition, a solution prepared by dissolving borax and xanthan gum (XA) (Eco-Gum T, manufactured by DSP Gokyo Food and Chemical Co., Ltd.) in purified water at high temperature and adding boric acid after cooling was used as a xanthan gum solution. In addition, a solution prepared by dissolving borax and hydroxypropyl methylcellulose (HPMC) (65SH4000, manufactured by Shin-Etsu Chemical Co., Ltd.) in purified water at high temperature and then adding boric acid after cooling was used as a hydroxypropyl methylcellulose solution, and a solution dissolved with boric acid and borax was used as a base solution. It should be noted that the density of all liquid preparations is about 1 g / cm 3 .

[0064] A solution containing BHT was added to the xanthan gum solution, hydroxypropylmethylcellulose solution and base solution to a predetermined concentration, and the pH was adjusted to obtain test solutions of Examples 1 to 3 and Comparative Examples 1 to 6.

[0065] [Table 1]

[0066]

[0067] pH adjuster: hydrochloric acid and / or sodium hydroxide aqueous solution

[0068] In the table, the unit of the content of each component is "g / 100g".

[0069] These test solutions were filled into glass vials to serve as test specimens. After each test specimen was stored at 60°C for 2 weeks, the BHT content of each specimen was measured using HPLC. The ratio of the BHT content of the 60°C stored product to the BHT content of the 4°C stored product in the measurement results of each test specimen is shown as the residual rate (%). The results are shown in Table 2 below.

[0070] [Table 2]

[0071]

[0072] At each pH (pH 6 to 8), hydroxypropylmethylcellulose had no effect of suppressing a decrease in BHT content, whereas xanthan gum showed an extremely high effect of suppressing a decrease in BHT content.

[0073] Test Example 2: Concentration of butylated hydroxytoluene (BHT) in ophthalmic liquid preparations The resulting BHT content reduces the inhibitory effect

[0074] According to the preparation method of [Test Example 1], each test solution shown in Table 3 was prepared and filled into a container to prepare a test specimen.

[0075] [Table 3]

[0076]

[0077]

[0078] pH adjuster: hydrochloric acid and / or sodium hydroxide aqueous solution

[0079] In the table, the unit of the content of each component is "g / 100g".

[0080] These test solutions were filled into glass vials to serve as test specimens. Each test specimen was stored at 60°C for 2 weeks or 4 weeks, and then the BHT content of each specimen was measured using HPLC. The ratio of the BHT content of the 60°C stored product to the BHT content of the 4°C stored product, which shows the measurement results of each test specimen, was used as the residual rate (%). The results are shown in Table 4 below.

[0081] [Table 4]

[0082]

[0083]

[0084] When the BHT concentration is higher than 0.0005%, xanthan gum exhibits an effect of suppressing a decrease in the BHT content.

[0085] Test Example 3: Effect of Xanthan Gum Concentration in Ophthalmic Liquid Preparations Added with Butylated Hydroxytoluene (BHT) BHT content reduction inhibitory effect

[0086] According to the preparation method of [Test Example 1], each test solution shown in Table 5 was prepared and filled into a container to prepare a test specimen.

[0087] [Table 5]

[0088]

[0089] pH adjuster: hydrochloric acid and / or sodium hydroxide aqueous solution

[0090] In the table, the unit of the content of each component is "g / 100g".

[0091] Each test sample was stored at 60°C for 2 weeks and 4 weeks, and then the BHT content of each sample was measured using HPLC. The measurement results of each test sample are shown as the ratio of the BHT content of the sample stored at 60°C to the BHT content of the sample stored at 4°C as the residual rate (%).

[0092] [Table 6]

[0093]

[0094] In a liquid preparation containing 0.005% BHT, when xanthan gum is 0.05% (w / v) or more, the effect of suppressing the decrease in BHT content is exerted, and this effect increases in a concentration-dependent manner. The suppression of the decrease in BHT content can be confirmed when xanthan gum is added in an amount 10 times or more of BHT.

[0095] Test Example 4: BHT content reduction caused by different types of thickeners in ophthalmic liquid preparations containing BHT Low inhibitory effect

[0096] According to the preparation method of [Test Example 1], each test solution shown in Table 7 was prepared as a test specimen. The test specimen was filled into a glass vial. Gelatin was produced by Nakalai Test Co., Ltd., sodium alginate was produced by Funakossi Co., Ltd., carrageenan was produced by Tokyo Chemical Industry Co., Ltd., and gellan gum was produced by Kanto Chemical Co., Ltd.

[0097] [Table 7]

[0098]

[0099] pH adjuster: hydrochloric acid and / or sodium hydroxide aqueous solution

[0100] In the table, the unit of the content of each component is "g / 100g".

[0101] The quantitative sample of Reference Example 1 gelled and could not be measured. After each test sample was stored at 60°C for 2 weeks and 4 weeks, the BHT content of each was measured using HPLC. The measurement results of each test sample are shown as the ratio of the BHT content of the 60°C stored product to the BHT content of the 4°C stored product as the residual rate (%).

[0102] [Table 8]

[0103]

[0104] All thickeners have the effect of suppressing the decrease in BHT content, but xanthan gum, gelatin, and carrageenan have a particularly high effect of suppressing the decrease in BHT content.

[0105] Test Example 5: Selection of a container for packaging an ophthalmic liquid preparation containing BHT and xanthan gumAccording to the preparation method of [Test Example 1], the test liquids shown in Table 9 were prepared and filled into glass containers, polyethylene terephthalate (PET) containers with polyethylene (PE) nozzles, and PET containers with polybutylene terephthalate (PBT) nozzles, respectively, as test specimens.

[0106] [Table 9]

[0107]

[0108] pH adjuster: hydrochloric acid and / or sodium hydroxide aqueous solution

[0109] In the table, the unit of the content of each component is "g / 100g".

[0110] Each test sample was stored at 60°C for 2 weeks and 4 weeks, and then the BHT content of each sample was measured using HPLC. The measurement results of each test sample are shown as the ratio of the BHT content of the sample stored at 60°C to the BHT content of the sample stored at 4°C as the residual rate (%).

[0111] [Table 10]

[0112] Glass

[0113]

[0114] PE nozzle + PET container

[0115]

[0116] PBT nozzle + PET container

[0117]

[0118] In a glass vial, when the concentration of xanthan gum was 0.1% (w / v) or more, a BHT stabilization effect was observed. On the other hand, in a PET container with a PE nozzle or a PET container with a PBT nozzle, when the concentration of xanthan gum was 0.05% (w / v) or more, an effect of suppressing the reduction of the BHT content was observed. The effect of suppressing the reduction of the BHT content varied depending on the material of the nozzle, and the PET container with a PBT nozzle was the most excellent in the stabilization effect of BHT.

[0119] Test Example 6: Selection of surfactants in ophthalmic liquid preparations containing BHT and xanthan gum

[0120] According to the preparation method of [Test Example 1], the polysorbate 80 of Example 2 is replaced with polyoxyethylene hydrogenated castor oil 60 (abbreviated as HCO-60) or polyethylene glycol (40E.O.) monostearate (abbreviated as MYS-40), which is also a nonionic surfactant. Prepare the test solutions of Examples 17 and 18. Fill them into a PET container equipped with a polybutylene terephthalate (PBT) nozzle as test specimens. Both HCO-60 and MYS-40 are products manufactured by Nikko Chemical Co., Ltd. After each test specimen was stored at 60°C for 4 weeks, the BHT content of each was determined using HPLC. The ratio of the BHT content of the 60°C stored product to the BHT content of the 4°C stored product, which shows the measurement results of each test specimen, is used 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 to which HCO-60 was added, and was 93.0% in Example 18 to which MYS-40 was added. The use of HCO-60 or MYS-40 as a nonionic surfactant confirmed the effect of xanthan gum in stabilizing BHT, as in the case of using polysorbate 80.

[0121] Test Example 7: Viscosity of ophthalmic liquid preparation containing BHT and xanthan gum

[0122] 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 by "2.1.3. Cone-plate type rotational viscometer (cone-plate type viscometer, TV-25 type, Toki Sangyo) of the Japanese General Test Method Viscosity Measurement 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. Chondroitin sodium sulfate used was a product manufactured by Maruhanichiro Co., Ltd.

[0123] [Table 11]

[0124]

[0125] pH adjuster: hydrochloric acid and / or sodium hydroxide aqueous solution

[0126] In the table, the unit of the content of each component is "g / 100g".

[0127] Test Example 8: Effect of reducing the content of BHT produced by xanthan gum in the presence of drugs

[0128] According to the preparation method of [Test Example 1], the active ingredients were further added to prepare the test solutions shown in Table 12 below. Pranoprofen was a product manufactured by API. Sodium cromoglycate was a product manufactured by Fulmin Corporation. The test solutions of Examples 20 and 21 and Comparative Example 26 were filled into a PET container equipped with a nozzle made of polybutylene terephthalate (PBT), and after being stored at 4°C and 60°C for 4 weeks, 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 is shown as the residual rate (%). As a result, in the case of containing pranoprofen as a drug, the effect of stabilizing BHT by adding xanthan gum was confirmed.

[0129] [Table 12]

[0130]

[0131] pH adjuster: hydrochloric acid and / or sodium hydroxide aqueous solution

[0132] In the table, the unit of the content of each component is "g / 100g".

[0133] Test Example 9: Viscosity of ophthalmic liquid preparation containing BHT and xanthan gum

[0134] The aqueous solution dissolved with borax is heated to about 80°C, and xanthan gum is added to dissolve for 1 hour, or hydroxypropyl methylcellulose is added to dissolve for 2 hours. After the liquid temperature is cooled to about 30°C, boric acid, polysorbate 80 and butylated hydroxytoluene are added and dissolved, and the pH is adjusted to prepare the test solutions of Example 22 and Comparative Examples 27 and 28. These test solutions are filled into glass vials, respectively, as test specimens. After each test specimen is stored at 4°C for 7 weeks, the rotational viscosity is measured according to the viscosity measurement method of Test Example 7. Among them, the rotation speed is set to 100rpm and 10rpm, respectively.

[0135] [Table 13]

[0136]

[0137] pH adjuster: hydrochloric acid and / or sodium hydroxide aqueous solution

[0138] In the table, the unit of the content of each component is "g / 100g".

[0139] [Table 14]

[0140] Embodiment 22 Comparative Example 27 Comparative Example 28 Viscosity at 100 rpm (mPa·s) 8.9 1.0 7.8 Viscosity at 10rpm (mPa·s) 39.3 0.9 8.0

Claims

1. An ophthalmic liquid preparation comprising (A) butylated hydroxytoluene and (B) xanthan gum at a ratio of (A) / (B)=1 / 6 to 1 / 600.

2. The ophthalmic liquid preparation according to claim 1, comprising: (A) 0.0005 to 0.005 w / v% of butylated hydroxytoluene, and (B) 0.05-0.15 w / v% xanthan gum. 3 . The ophthalmic liquid preparation according to claim 1 , comprising (A) dibutylhydroxytoluene and (B) xanthan gum at a ratio of (A) / (B)=1 / 10 to 1 / 30.

4. An ophthalmic liquid preparation product, which is obtained by placing the ophthalmic liquid preparation according to any one of claims 1 to 3 in a container, The container has: a container body for containing the ophthalmic liquid preparation, a pouring portion having a pouring spout for pouring out the ophthalmic liquid preparation contained in the container body portion, and a cover portion covering the pouring opening; At least one of a wall surface of the internal space of the pouring part and a wall surface of the cover part facing the pouring port is made of a resin containing polybutylene terephthalate.

5. A method for suppressing a decrease in the content of butylated hydroxytoluene in an ophthalmic liquid preparation containing butylated hydroxytoluene, characterized in that: The ophthalmic liquid preparation is blended with one or more thickeners selected from the group consisting of xanthan gum, gelatin and carrageenan.

6. The method for suppressing the reduction of the content of butylated hydroxytoluene according to claim 5, wherein: (A) Butylhydroxytoluene and (B) xanthan gum are mixed in a ratio of (A) / (B)=1 / 6 to 1 / 600.

7. The method for suppressing the reduction of the content of butylated hydroxytoluene according to claim 5, wherein: (A) Butylhydroxytoluene and (B) xanthan gum are mixed in a ratio of (A) / (B)=1 / 10 to 1 / 30.

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