Aqueous composition containing atropine and buffering agent

Abstract

The present invention provides: an aqueous composition, containing atropine or a salt thereof as an active ingredient at a concentration of 0.001-0.1% (w / v) and a buffering agent, with suppressed mydriatic effect and having a pH of 6.0 or less, wherein the content of the buffering agent is an amount whereby the pH becomes 7.3 or less when the aqueous composition and BSS Plus are mixed at a volume ratio of 7:1; and a method for suppressing a mydriatic effect thereof.

Description

Aqueous composition containing atropine and a buffer

[0001] The present invention relates to a preparation in which the mydriatic effect is suppressed by adjusting the content of the buffer in an aqueous composition containing atropine or a salt thereof (hereinafter sometimes simply referred to as "atropine") and a buffer, and a method for suppressing the mydriatic effect thereof. More specifically, the present invention provides a preparation with suppressed mydriatic effect and a method for suppressing the mydriatic effect thereof, by adjusting the content of the buffer based on the pH when the aqueous composition and BSS Plus are mixed at a volume ratio of 7:1. Hereinafter, these preparations and methods are sometimes simply referred to as "the preparation of the present invention" and "the method of the present invention".

[0002] Atropine is a drug known to have the property of inhibiting the elongation of axial length. For example, Patent Document 1 discloses that a composition containing less than 0.025% atropine suppresses or prevents the progression of myopia. In addition, Patent Document 2 discloses an atropine-containing aqueous composition having an effect of suppressing axial length elongation and an effect of improving refractive error. On the other hand, atropine eye drops are used as mydriatics and also reduce accommodation. When atropine eye drops are instilled, the pupillary sphincter muscle of the iris is relaxed, thereby causing mydriasis which causes glare. This persists while the effect of the atropine eye drops is maintained, and also reduces the accommodation of the crystalline lens, leading to decreased near vision, which can even impair daily activities. Therefore, there has been a great demand for a medicament for suppressing or preventing the progression of myopia that induces a lower mydriatic effect, a smaller reduction in accommodation, and improves quality of life (QOL) (for example, Patent Document 2).

[0003] Heretofore, it has not been known that the mydriatic effect can be suppressed by adjusting the content of the buffer in an aqueous composition containing atropine and a buffer based on the pH when the aqueous composition and BSS Plus are mixed at a volume ratio of 7:1, and none of any documents describes or suggests this at all.

[0004] WO2012 / 161655 WO2017 / 204262

[0005] The inventors have surprisingly discovered that in an aqueous composition containing atropine and a buffering agent, the pupillary dilation effect can be suppressed by adjusting the buffering agent content based on the pH when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:1. Until now, it has not been known that the pupillary dilation effect can be suppressed in an aqueous composition containing atropine and a buffering agent by adjusting the buffering agent content based on the pH when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:1, and such an aqueous composition containing atropine and a buffering agent is extremely significant in the development of safer pharmaceutical formulations. Furthermore, providing such a method for suppressing pupillary dilation is also extremely significant in the development of atropine-containing pharmaceutical formulations. Therefore, the object of the present invention is to provide an aqueous composition containing atropine and a buffering agent in which the pupillary dilation effect is suppressed by adjusting the buffering agent content in the aqueous composition containing atropine and a buffering agent based on the pH when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:1, and a method for suppressing the pupillary dilation effect.

[0006] The present inventors diligently studied how to solve the problem of suppressing the pupillary dilation effect in an aqueous composition containing atropine and a buffering agent. As a result, they discovered that by adjusting the amount of the buffering agent based on the pH when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:1, it is possible to provide an aqueous composition containing atropine and a buffering agent with suppressed pupillary dilation and a method for suppressing its pupillary dilation effect, thus completing the present invention.

[0007] Specifically, the present invention provides the following: (Item A-1) An aqueous composition having a pH of 6.0 or less, comprising a concentration of 0.001 to 0.1% (w / v) of atropine or a salt thereof and a buffer as an active ingredient, characterized in that the amount of buffer is such that the pH when the aqueous composition is mixed with BSS Plus in a volume ratio of 7:1 is 7.3 or less. (Item A-2) The aqueous composition according to Item A-1, wherein the buffer is at least one selected from the group consisting of glutamate buffer, citrate buffer, acetate buffer, borate buffer, carbonate buffer, EDTA buffer, and trometamol. (Item A-3) The aqueous composition according to Item A-1 or A-2, wherein the amount of buffer is such that the pH when the aqueous composition is mixed with BSS Plus in a volume ratio of 7:1 is 4.1 to 7.0. (Item A-4) The aqueous composition according to Item A-1 or A-2, wherein the amount of buffering agent is such that the pH when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:1 is 4.1 to 6.1. (Item A-5) The aqueous composition according to Item A-1 or A-2, wherein the amount of buffering agent is such that the pH when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:1 is 4.1 to 5.1. (Item A-6) The aqueous composition according to Item A-1, wherein the buffering agent is a glutamate buffering agent, and the amount of buffering agent is such that the pH when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:1 is 4.1 to 7.0. (Item A-7) The aqueous composition according to Item A-1, wherein the buffering agent is a citric acid buffering agent, and the amount of buffering agent is such that the pH when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:1 is 4.2 to 7.2. (Item A-8) The aqueous composition according to Item A-1, wherein the buffering agent is an acetic acid buffering agent, and the amount of buffering agent is such that the pH when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:1 is 4.2 to 7.1. (Item A-9) The aqueous composition according to Item A-1, wherein the buffering agent is trometamol, and the amount of buffering agent is such that the pH when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:1 is 5.8 to 7.1.(Item A-10) The aqueous composition according to Item A-1, wherein the buffering agent is a boric acid buffering agent, and the amount of buffering agent is such that the pH when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:1 is 5.7 to 7.0. (Item A-11) The aqueous composition according to Item A-1, wherein the buffering agent is an edetate buffering agent, and the amount of buffering agent is such that the pH when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:1 is 5.7 to 6.6. (Item A-12) The aqueous composition according to Item A-1, wherein the buffering agent is a carbonate buffering agent, and the amount of buffering agent is such that the pH when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:1 is 7.2. (Item A-13) The aqueous composition according to any one of Items A-1 to A-12, further containing an isotonic agent. (A-14) The aqueous composition according to A-13, wherein the isotonic agent is at least one selected from the group consisting of glycerin, mannitol, propylene glycol, polyethylene glycol, glucose, sorbitol, xylitol, trehalose, and sodium chloride. (A-15) The aqueous composition according to A-13, wherein the isotonic agent is at least one selected from the group consisting of glycerin, sodium chloride, and mannitol. (A-16) The aqueous composition according to any one of A-13 to A-15, wherein the concentration of the isotonic agent is 0.05 to 2.4% (w / v). (A-17) The aqueous composition according to any one of A-1 to A-16, wherein the pH of the aqueous composition is 4.0 to 6.0. (A-18) The aqueous composition according to any one of A-1 to A-16, wherein the pH of the aqueous composition is 4.0 to 5.0. (Clause A-19) An aqueous composition according to any one of Clauses A-1 to A-16, wherein the pH of the aqueous composition is 4.0 to 4.5. (Clause A-20) An aqueous composition according to any one of Clauses A-1 to A-19, wherein the concentration of atropine or a salt thereof is 0.001 to 0.025% (w / v). (Clause A-21) An aqueous composition according to any one of Clauses A-1 to A-19, wherein the concentration of atropine or a salt thereof is 0.01 to 0.025% (w / v).(Item A-22) The aqueous composition according to any one of items A-1 to A-21, wherein the atropine or salt thereof is atropine sulfate or its hydrate. (Item A-23) The aqueous composition according to any one of items A-1 to A-22, substantially free of hydroxyethylcellulose, hydroxypropylmethylcellulose, or carboxyvinyl polymer as a water-soluble polymer. (Item A-24) The aqueous composition according to any one of items A-1 to A-22, substantially free of a water-soluble polymer. (Item A-25) The aqueous composition according to any one of items A-1 to A-24, substantially free of sodium dihydrogen phosphate, epsilon-aminocaproic acid, sodium citrate hydrate, or acetic acid as a buffer. (Item A-26) The aqueous composition according to any one of items A-1 to A-24, substantially free of phosphate buffer, epsilon-aminocaproic acid, citrate buffer, or acetic acid buffer as a buffer. (A-27) The aqueous composition according to any one of A-1 to A-22, substantially free of sodium dihydrogen phosphate, epsilon-aminocaproic acid, sodium citrate hydrate, or acetic acid as a buffer, and substantially free of hydroxyethylcellulose as a water-soluble polymer. (A-28) The aqueous composition according to any one of A-1 to A-22, substantially free of sodium dihydrogen phosphate as a buffer, and substantially free of hydroxyethylcellulose, hydroxypropyl methylcellulose, or carboxyvinyl polymer as a water-soluble polymer. (A-29) The aqueous composition according to any one of A-1 to A-28, substantially free of benzalkonium chloride. (A-30) The aqueous composition according to any one of A-1 to A-28, containing less than 100 ppm of benzalkonium chloride. (A-31) The aqueous composition according to any one of A-1 to A-30, contained in a unit dose type container. (Section A-32) An aqueous composition according to any one of Sections A-1 to A-31, wherein the aqueous composition is an aqueous eye drop. (Section A-33) An aqueous composition according to any one of Sections A-1 to A-32 for inhibiting and / or preventing the progression of myopia.(Section A-34) Use of an aqueous composition according to any one of sections A-1 to A-32 in the manufacture of a drug for inhibiting and / or preventing the progression of myopia. (Section A-35) An aqueous composition according to any one of sections A-1 to A-32 for use in inhibiting and / or preventing the progression of myopia.

[0008] Furthermore, two or more of the configurations described in items A-1 to A-35 can be arbitrarily selected and combined.

[0009] The present invention also provides the following: (Item B-1) A method for suppressing the pupillary dilation effect when an aqueous composition containing atropine or a salt thereof at a concentration of 0.001 to 0.1% (w / v) and a buffering agent as an active ingredient, and having a pH of 6.0 or less, is instilled into the eye, characterized in that the amount of buffering agent in the aqueous composition is such that the pH becomes 7.3 or less when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:1. (Item B-2) The method according to Item B-1, wherein the buffering agent is at least one selected from the group consisting of glutamate buffering agent, citrate buffering agent, acetate buffering agent, borate buffering agent, carbonate buffering agent, EDTA buffering agent, and trometamol. (Item B-3) The method according to Item B-1 or B-2, wherein the amount of buffering agent is such that the pH becomes 4.1 to 7.0 when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:1. (Item B-4) The method according to Item B-1 or B-2, wherein the amount of buffering agent is such that the pH becomes 4.1 to 6.1 when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:1. (Item B-5) The method according to Item B-1 or B-2, wherein the amount of buffering agent is such that the pH becomes 4.1 to 5.1 when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:1. (Item B-6) The method according to Item B-1, wherein the buffering agent is a glutamate buffering agent, and the amount of buffering agent is such that the pH becomes 4.1 to 7.0 when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:1. (Item B-7) The method according to Item B-1, wherein the buffering agent is a citric acid buffering agent, and the amount of buffering agent is such that the pH becomes 4.2 to 7.2 when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:1. (Item B-8) The method according to Item B-1, wherein the buffering agent is an acetic acid buffering agent, and the amount of buffering agent is such that the pH becomes 4.2 to 7.1 when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:1. (Item B-9) The method according to Item B-1, wherein the buffering agent is trometamol, and the amount of buffering agent is such that the pH becomes 5.8 to 7.1 when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:1.(Item B-10) The method according to Item B-1, wherein the buffer is a boric acid buffer, and the amount of the buffer is such that the pH becomes 5.7 to 7.0 when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:1. (Item B-11) The method according to Item B-1, wherein the buffer is an edetate buffer, and the amount of the buffer is such that the pH becomes 5.7 to 6.6 when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:1. (Item B-12) The method according to Item B-1, wherein the buffer is a carbonate buffer, and the amount of the buffer is such that the pH becomes 7.2 when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:1. (Item B-13) The method according to any one of Items B-1 to B-12, wherein the aqueous composition further contains an isotonic agent. (Item B-14) The method according to item B-13, wherein the isotonic agent is at least one selected from the group consisting of glycerin, mannitol, propylene glycol, polyethylene glycol, glucose, sorbitol, xylitol, trehalose, and sodium chloride. (Item B-15) The method according to item B-13, wherein the isotonic agent is at least one selected from the group consisting of glycerin, sodium chloride, and mannitol. (Item B-16) The method according to any one of items B-13 to B-15, wherein the concentration of the isotonic agent is 0.05 to 2.4% (w / v). (Item B-17) The method according to any one of items B-1 to B-16, wherein the pH of the aqueous composition is 4.0 to 6.0. (Item B-18) The method according to any one of items B-1 to B-16, wherein the pH of the aqueous composition is 4.0 to 5.0. (Item B-19) The method according to any one of items B-1 to B-16, wherein the pH of the aqueous composition is 4.0 to 4.5. (Item B-20) The method according to any one of items B-1 to B-19, wherein the concentration of atropine or a salt thereof is 0.001 to 0.025% (w / v). (Item B-21) The method according to any one of items B-1 to B-19, wherein the concentration of atropine or a salt thereof is 0.01 to 0.025% (w / v). (Item B-22) The method according to any one of items B-1 to B-21, wherein the atropine or a salt thereof is atropine sulfate or its hydrate.(Item B-23) The method according to any one of items B-1 to B-22, wherein the aqueous composition substantially does not contain hydroxyethylcellulose, hydroxypropylmethylcellulose, or carboxyvinyl polymer as a water-soluble polymer. (Item B-24) The method according to any one of items B-1 to B-22, wherein the aqueous composition substantially does not contain a water-soluble polymer. (Item B-25) The method according to any one of items B-1 to B-24, wherein the aqueous composition substantially does not contain sodium dihydrogen phosphate, epsilon-aminocaproic acid, sodium citrate hydrate, or acetic acid as a buffer. (Item B-26) The method according to any one of items B-1 to B-24, wherein the aqueous composition substantially does not contain phosphate buffer, epsilon-aminocaproic acid, citrate buffer, or acetic acid buffer as a buffer. (Item B-27) The method according to any one of items B-1 to B-22, wherein the aqueous composition substantially does not contain sodium dihydrogen phosphate, epsilon-aminocaproic acid, sodium citrate hydrate, or acetic acid as a buffer, and substantially does not contain hydroxyethylcellulose as a water-soluble polymer. (Item B-28) The method according to any one of items B-1 to B-22, wherein the aqueous composition substantially does not contain sodium dihydrogen phosphate as a buffer, and substantially does not contain hydroxyethylcellulose, hydroxypropyl methylcellulose, or carboxyvinyl polymer as a water-soluble polymer. (Item B-29) The method according to any one of items B-1 to B-28, wherein the aqueous composition substantially does not contain benzalkonium chloride. (Item B-30) The method according to any one of items B-1 to B-28, wherein the aqueous composition contains less than 100 ppm of benzalkonium chloride. (Section B-31) The method according to any one of Sections B-1 to B-30, wherein the aqueous composition is contained in a unit dose container. (Section B-32) The method according to any one of Sections B-1 to B-31, wherein the aqueous composition is an aqueous eye drop solution.

[0010] Furthermore, two or more of the components in items B-1 to B-32 can be arbitrarily selected and combined.

[0011] The present invention also provides the following: (C-1) An aqueous composition containing atropine or a salt thereof in a concentration of 0.001 to 0.1% (w / v) as an active ingredient, and a buffer in a concentration of 0.001 to 10% (w / v) (provided that (1) when the buffer is sodium dihydrogen phosphate, it does not contain hydroxyethylcellulose, hydroxypyropyrmethylcellulose, or carboxyvinyl polymer as a water-soluble polymer, and (2) when the buffer is epsilon-aminocaproic acid, sodium citrate hydrate, or acetic acid, it does not contain hydroxyethylcellulose as a water-soluble polymer). (C-2) The aqueous composition according to C-1, wherein the buffer is at least one selected from the group consisting of glutamate buffer, citrate buffer, acetate buffer, borate buffer, carbonate buffer, EDTA buffer, and trometamol. (Item C-3) The aqueous composition according to Item C-1 or C-2, wherein the concentration of the buffering agent is 0.005 to 5.0% (w / v). (Item C-4) The aqueous composition according to Item C-1 or C-2, wherein the concentration of the buffering agent is 0.006 to 3.4% (w / v). (Item C-5) The aqueous composition according to Item C-1, wherein the buffering agent is a glutamate buffer and the concentration of the buffering agent is 0.02 to 1.0% (w / v). (Item C-6) The aqueous composition according to Item C-1, wherein the buffering agent is a citrate buffer and the concentration of the buffering agent is 0.005 to 3.0% (w / v). (Item C-7) The aqueous composition according to Item C-1, wherein the buffering agent is an acetate buffer and the concentration of the buffering agent is 0.005 to 2.0% (w / v). (C-8) The aqueous composition according to C-1, wherein the buffering agent is trometamol and the concentration of the buffering agent is 0.05 to 3.4% (w / v). (C-9) The aqueous composition according to C-1, wherein the buffering agent is boric acid buffer and the concentration of the buffering agent is 0.019 to 1.9% (w / v). (C-10) The aqueous composition according to C-1, wherein the buffering agent is edetate buffer and the concentration of the buffering agent is 0.05 to 0.3% (w / v). (C-11) The aqueous composition according to C-1, wherein the buffering agent is carbonate buffer and the concentration of the buffering agent is 0.2% (w / v). (C-12) The aqueous composition according to any one of C-1 to C-11, further containing an isotonic agent.(C-13) The aqueous composition according to C-12, wherein the isotonic agent is at least one selected from the group consisting of glycerin, mannitol, propylene glycol, polyethylene glycol, glucose, sorbitol, xylitol, trehalose, and sodium chloride. (C-14) The aqueous composition according to C-12, wherein the isotonic agent is at least one selected from the group consisting of glycerin, sodium chloride, and mannitol. (C-15) The aqueous composition according to any one of C-12 to C-14, wherein the concentration of the isotonic agent is 0.05 to 2.4% (w / v). (C-16) The aqueous composition according to any one of C-1 to C-15, wherein the pH of the aqueous composition is 5.5 or less. (C-17) The aqueous composition according to any one of C-1 to C-15, wherein the pH of the aqueous composition is 5.0 or less. (C-18) An aqueous composition according to any one of C-1 to C-15, wherein the pH of the aqueous composition is 3.5 to 5.0. (C-19) An aqueous composition according to any one of C-1 to C-15, wherein the pH of the aqueous composition is 4.0 to 4.5. (C-20) An aqueous composition according to any one of C-1 to C-19, wherein the concentration of atropine or a salt thereof is 0.001 to 0.025% (w / v). (C-21) An aqueous composition according to any one of C-1 to C-19, wherein the concentration of atropine or a salt thereof is 0.01 to 0.025% (w / v). (C-22) An aqueous composition according to any one of C-1 to C-21, wherein the atropine or a salt thereof is atropine sulfate or its hydrate. (C-23) An aqueous composition according to any one of C-1 to C-22, substantially free of hydroxyethylcellulose, hydroxypropylmethylcellulose, or carboxyvinyl polymer as a water-soluble polymer. (C-24) An aqueous composition according to any one of C-1 to C-22, substantially free of a water-soluble polymer. (C-25) An aqueous composition according to any one of C-1 to C-24, substantially free of sodium dihydrogen phosphate, epsilon-aminocaproic acid, sodium citrate hydrate, or acetic acid as a buffer.(C-26) The aqueous composition according to any one of C-1 to C-24, substantially free of phosphate buffers, epsilon-aminocaproic acid, citrate buffers, or acetate buffers as buffers. (C-27) The aqueous composition according to any one of C-1 to C-22, substantially free of sodium dihydrogen phosphate, epsilon-aminocaproic acid, sodium citrate hydrate, or acetic acid as buffers, and substantially free of hydroxyethylcellulose as a water-soluble polymer. (C-28) The aqueous composition according to any one of C-1 to C-22, substantially free of sodium dihydrogen phosphate as a buffer, and substantially free of hydroxyethylcellulose, hydroxypropyl methylcellulose, or carboxyvinyl polymer as a water-soluble polymer. (C-29) The aqueous composition according to any one of C-1 to C-28, substantially free of benzalkonium chloride. (C-30) An aqueous composition according to any one of C-1 to C-28, containing less than 100 ppm of benzalkonium chloride. (C-31) An aqueous composition according to any one of C-1 to C-30, contained in a unit dose container. (C-32) An aqueous composition according to any one of C-1 to C-31, wherein the aqueous composition is an aqueous eye drop. (C-33) An aqueous composition according to any one of C-1 to C-32, for inhibiting and / or preventing the progression of myopia. (C-34) An aqueous composition according to any one of C-1 to C-32, in the manufacture of a drug for inhibiting and / or preventing the progression of myopia. (C-35) An aqueous composition according to any one of C-1 to C-32, for use in inhibiting and / or preventing the progression of myopia.

[0012] Furthermore, two or more of the configurations in items C-1 to C-35 can be arbitrarily selected and combined.

[0013] According to the present invention, in an aqueous composition containing atropine and a buffering agent, the pupillary dilation effect can be suppressed by adjusting the amount of the buffering agent based on the pH when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:1. Furthermore, the present invention provides a method for suppressing the pupillary dilation effect when an atropine-containing aqueous composition is instilled into the eye.

[0014] The present invention will be described in detail below.

[0015] The aqueous composition of the present invention contains "atropine or a salt thereof" as an active ingredient. "Atropine or a salt thereof" also includes (i) a hydrate of atropine or a salt thereof, (ii) an organic solvent hydrate of atropine or a salt thereof, and (iii) a mixture of the hydrate and the organic solvent hydrate. The atropine salt includes atropine sulfate (also referred to as "atropine sulfate") or its hydrate, preferably atropine sulfate hydrate.

[0016] The aqueous composition of the present invention may contain atropine or a salt thereof as the sole active ingredient, or it may contain pharmaceutically acceptable active ingredients other than atropine or a salt thereof. One embodiment of the aqueous composition of the present invention is an aqueous composition containing atropine or a salt thereof as the sole active ingredient. Another embodiment is an aqueous composition containing atropine or a salt thereof and other pharmaceutically acceptable active ingredients as active ingredients.

[0017] Atropine sulfate hydrate is a compound represented by the following structural formula.

[0018] If atropine or its salts have crystalline polymorphs and groups of crystalline polymorphs (polymorphic systems), then these crystalline polymorphs and groups of crystalline polymorphs (polymorphic systems) are also included within the scope of the present invention. Here, a group of crystalline polymorphs (polymorphic systems) means not only the individual crystalline forms obtained at each stage when the crystalline form changes depending on the conditions and state of the production, crystallization, storage, etc. of those crystals, but also mixtures of crystalline forms obtained at two or more stages.

[0019] Atropine or its salts can be prepared according to common methods in the field of organic synthesis chemistry, or commercially available products can be used. For example, atropine sulfate hydrate is commercially available from Tokyo Chemical Industry Co., Ltd. (product code: A0550).

[0020] In the present invention, "% (w / v)" means the mass (g) of the target component contained in 100 mL of the aqueous composition of the present invention. For example, if a salt of atropine is contained in the present invention, the value is the content of the salt of atropine. Also, if atropine or a salt oftropine or a salt of atropine or atropine or a salt of atropine or atropine or a salt of atropine or atropine or atropine or a salt of atropine or atropine or atropine or atropine or atropine or atropine or atropine or atropine or atropine or atropine or atropine or atropine or atropine or atropine or atrop

[0021] In the present invention, the concentration of atropine or its salt is preferably 0.001 to 0.1% (w / v), more preferably 0.001 to 0.05% (w / v), even more preferably 0.001 to 0.025% (w / v), and particularly preferably 0.01 to 0.025% (w / v). More specifically, the concentrations are 0.0010% (w / v), 0.0015% (w / v), 0.0020% (w / v), 0.0025% (w / v), 0.0030% (w / v), 0.0035% (w / v), 0.0040% (w / v), 0.0045% (w / v), 0.0050% (w / v), 0.0055% (w / v), 0.0060% (w / v), 0.0065% (w / v), 0.0070% (w / v), 0.0075% (w / v), 0.0080% (w / v), 0.0085% (w / v), 0 Examples include 0.0090% (w / v), 0.0095% (w / v), 0.010% (w / v), 0.011% (w / v), 0.012% (w / v), 0.013% (w / v), 0.014% (w / v), 0.015% (w / v), 0.016% (w / v), 0.017% (w / v), 0.018% (w / v), 0.019% (w / v), 0.020% (w / v), 0.021% (w / v), 0.022% (w / v), 0.023% (w / v), 0.024% (w / v), or 0.025% (w / v). Furthermore, one embodiment of the concentration of atropine or its salt is 0.026% (w / v), 0.027% (w / v), 0.028% (w / v), 0.029% (w / v), 0.030% (w / v), 0.031% (w / v), 0.032% (w / v), 0.033% (w / v), 0.034% (w / v), 0.035% (w / v), 0.036% (w / v), 0.037% (w / v). Examples of w / v values ​​include 0.038% (w / v), 0.039% (w / v), 0.040% (w / v), 0.041% (w / v), 0.042% (w / v), 0.043% (w / v), 0.044% (w / v), 0.045% (w / v), 0.046% (w / v), 0.047% (w / v), 0.048% (w / v), 0.049% (w / v), or 0.050% (w / v).

[0022] In this invention, "BSS Plus" refers to the diluted solution of BSS Plus® 500 Ocular Irrigation Solution 0.0184% (Japanese manufacturing approval number: 22000AMX00581000, manufacturer / distributor (importer): Alcon Japan Co., Ltd.). More specifically, BSS Plus® 500 Ocular Irrigation Solution 0.0184% is sold as a set of oxyglutathione solution and diluent, but only the diluent is used. This diluent contains thorium chloride, potassium chloride, sodium hydrogen phosphate hydrate, sodium bicarbonate, and a pH adjuster as additives, and is used as a pseudo-tear solution in this invention. Furthermore, in this invention, the diluted solution used has a pH of 7.28 and an osmotic pressure ratio of 1.0 to 1.1. The pH and osmotic pressure ratio of this diluted solution can be measured and calculated by conventional methods. For example, it can be measured and calculated according to the methods described in the "pH measurement method" and "osmotic pressure measurement method (osmolality measurement method)" of the 18th edition of the Japanese Pharmacopoeia. In the present invention, it is preferable to use the diluent immediately after opening, for example. It is more preferable to use the diluent within at least 24 hours of opening, even more preferable to use it within 12 hours of opening, even more preferable to use it within 8 hours of opening, particularly preferable to use it within 4 hours of opening, and most preferable to use it within 2 hours of opening.

[0023] In the present invention, "buffering capacity" is an indicator of buffering action and can be calculated as the pH value when BSS Plus (0.5 mL) is mixed with the aqueous composition of the present invention (3.5 mL).

[0024] In the present invention, the "buffering capacity" is 7.3 or less. Preferably, the buffering capacity is 7.0 or less, more preferably 6.8 or less, even more preferably 6.4 or less, even more preferably 6.1 or less, particularly preferably 5.8 or less, even more preferably 5.1 or less, most preferably 4.9 or less, and most preferably 4.4 or less. One embodiment of the buffering capacity is 4.1 to 7.0, 4.1 to 6.8, 4.1 to 6.4, 4.1 to 6.1, 4.1 to 6.0, 4.1 to 5.8, 4.1 to 5.1, 4.1 to 4.9, and 4.1 to 4.4. More specifically, examples of buffering capacity include 7.3, 7.2, 7.1, 7.0, 6.9, 6.8, 6.7, 6.6, 6.5, 6.4, 6.3, 6.2, 6.1, 6.0, 5.9, 5.8, 5.7, 5.6, 5.5, 5.4, 5.3, 5.2, 5.1, 5.0, 4.9, 4.8, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2, and 4.1.

[0025] In the present invention, "aqueous composition" means a composition containing water as a solvent.

[0026] In the present invention, the "buffering agent" is not particularly limited as long as it is pharmaceutically acceptable, and examples include phosphate buffers, citrate buffers, borate buffers, carbonate buffers, acetate buffers, tartaric acid buffers, aminocarboxylic acid buffers, EDTA buffers, trometamol, etc. Examples of aminocarboxylic acid buffers include aspartate buffers, glutamate buffers, epsilon-aminocaproic acid, etc. Preferably, buffers include glutamate buffers, citrate buffers, acetate buffers, borate buffers, carbonate buffers, EDTA buffers, and trometamol. More preferably, glutamate buffers, borate buffers, carbonate buffers, EDTA buffers, and trometamol are used, and even more preferably, glutamate buffers, borate buffers, EDTA buffers, and trometamol are used. These buffers may be used individually or in any combination of two or more components.

[0027] In the present invention, the amount of buffering agent in the aqueous composition of the present invention is such that it provides the aqueous composition of the present invention with a predetermined buffering capacity (for example, 7.3 or less), and preferably, it is such that when the aqueous composition of the present invention and BSS Plus are mixed in a volume ratio of 7:1, the pH becomes 7.3 or less. In the present invention, the concentration of the buffering agent can be appropriately adjusted depending on the type of buffering agent, but is preferably 0.001 to 10% (w / v), more preferably 0.005 to 5% (w / v), and even more preferably 0.006 to 3.4% (w / v). One embodiment of the buffering agent concentration is 0.01 to 2% (w / v), 0.01 to 0.3% (w / v), 0.01 to 0.1% (w / v), etc.

[0028] Examples of "phosphate buffers" include phosphates such as phosphoric acid, alkali metal phosphates, and alkaline earth metal phosphates, as well as their hydrates. More specifically, examples include sodium hydrogen phosphate hydrate (also called "sodium hydrogen phosphate" or "sodium phosphate"), sodium dihydrogen phosphate (also called "monosodium phosphate"), sodium dihydrogen phosphate monohydrate (also called "monosodium phosphate"), sodium dihydrogen phosphate dihydrate (also called "monosodium phosphate"), potassium dihydrogen phosphate (also called "monosodium phosphate"), sodium hydrogen phosphate heptahydrate, trisodium phosphate, and dipotassium phosphate.

[0029] Examples of "citric acid buffers" include citrates such as citric acid, alkali metal citrate, and alkaline earth metal citrate, as well as their hydrates. More specifically, examples include citric acid hydrate, sodium citrate, sodium citrate hydrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, and disodium citrate. Sodium citrate hydrate is preferably used as a "citric acid buffer."

[0030] When the buffering agent is a citrate buffer, its buffering capacity can be, for example, 4.2 to 7.2, 4.2 to 7.0, 4.2 to 6.8, 4.2 to 6.3, 4.2 to 5.9, 4.2 to 5.6, 4.2 to 4.9, or 4.2 to 4.3, with 4.2 to 7.0, 4.2 to 6.8, 4.2 to 5.9, or 4.2 to 4.9 being preferred. When the buffering agent is a citrate buffer, one embodiment of its buffering capacity can be 4.2, 4.3, 4.9, 5.6, 5.9, 6.3, 6.8, 7.0, or 7.2. Another embodiment can be 4.2, 4.9, 5.9, 6.8, or 7.0. When the buffering agent is a citrate buffer, one embodiment of its buffering capacity is, for example, 4.2 to 7.0, 4.2 to 6.7, 4.2 to 6.1, and 4.2 to 4.9, preferably 4.2 to 7.0, 4.2 to 6.7, and 4.2 to 6.1. When the buffering agent is a citrate buffer, one embodiment of its buffering capacity is 4.2, 4.9, 6.1, 6.7, and 7.0. Another embodiment is 4.2, 6.1, 6.7, and 7.0. When the buffering agent is a citrate buffer, one embodiment of its buffering capacity is, for example, 5.4 to 6.1. When the buffering agent is a citrate buffer, one embodiment of its buffering capacity is 5.4 and 6.1.

[0031] When the buffering agent is a citrate buffer, its concentration can be, for example, 0.005 to 3% (w / v), and more preferably 0.006 to 3% (w / v). When the buffering agent is a citrate buffer, one embodiment of its concentration can be 0.005% (w / v), 0.006% (w / v), 0.01% (w / v), 0.02% (w / v), 0.03% (w / v), 0.06% (w / v), 0.1% (w / v), 0.2% (w / v), 0.3% (w / v), 1.5% (w / v), or 3% (w / v). Another embodiment can be 0.006% (w / v), 0.02% (w / v), 0.06% (w / v), 0.2% (w / v), or 3% (w / v). Another embodiment includes concentrations of 0.006% (w / v), 0.02% (w / v), 0.06% (w / v), and 3% (w / v).

[0032] Examples of "boric acid buffers" include boric acid or its salts, borax, etc. More specifically, examples include boric acid, sodium borate, potassium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc. Boric acid is preferred as a "boric acid buffer."

[0033] When the buffering agent is a borate buffer, its buffering capacity can be, for example, 5.9 to 7.0, 5.9 to 6.8, 5.9 to 6.7, or 5.9 to 6.3, with 5.9 to 6.8 or 5.9 to 6.7 being preferred. When the buffering agent is a borate buffer, one embodiment of its buffering capacity can be 5.9, 6.3, 6.7, 6.8, or 7.0. Another embodiment can be 5.9, 6.7, or 6.8. When the buffering agent is a borate buffer, one embodiment of its buffering capacity can be, for example, 5.7 to 6.8 or 5.7 to 6.6. When the buffering agent is a borate buffer, one embodiment of its buffering capacity can be 5.7, 6.6, or 6.8. When the buffering agent is a borate buffer, one embodiment of its buffering capacity can be, for example, 6.1 to 6.2. When the buffering agent is a boric acid buffering agent, one aspect of its buffering capacity is described in sections 6.1 and 6.2.

[0034] When the buffering agent is a boric acid buffer, its concentration can be, for example, 0.019 to 1.9% (w / v), and more preferably 0.05 to 1.9% (w / v). When the buffering agent is a boric acid buffer, one embodiment of its concentration can be 0.019% (w / v), 0.05% (w / v), 0.1% (w / v), 0.19% (w / v), 0.2% (w / v), 0.95% (w / v), or 1.9% (w / v). Another embodiment can be 0.019% (w / v), 0.05% (w / v), 0.2% (w / v), or 1.9% (w / v). Yet another embodiment can be 0.019% (w / v), 0.05% (w / v), or 1.9% (w / v).

[0035] Examples of "carbonic acid buffers" include carbonic acid or its salts. More specifically, examples include carbonic acid, sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, magnesium carbonate, etc. Carbonic acid is preferred as the "carbonic acid buffer."

[0036] When the buffering agent is carbonic acid, its buffering capacity can be given as, for example, 7.2.

[0037] If the buffering agent is carbonic acid, its concentration can be, for example, 0.2% (w / v).

[0038] Examples of "acetic acid buffers" include acetic acid or its salts. More specifically, examples include acetic acid, ammonium acetate, potassium acetate, calcium acetate, sodium acetate, and sodium acetate hydrate. Sodium acetate hydrate is preferred as an "acetic acid buffer."

[0039] When the buffering agent is an acetic acid buffer, its buffering capacity can be, for example, 4.2 to 7.1, 4.2 to 7.0, 4.2 to 6.8, 4.2 to 6.7, 4.2 to 6.1, 4.2 to 5.9, 4.2 to 5.1, or 4.2 to 4.6, with 4.2 to 7.1, 4.2 to 6.8, 4.2 to 5.9, or 4.2 to 4.6 being preferred. When the buffering agent is an acetic acid buffer, one embodiment of its buffering capacity can be 4.2, 4.6, 5.1, 5.9, 6.1, 6.7, 6.8, 7.0, or 7.1. Another embodiment can be 4.2, 4.6, 5.9, 6.8, or 7.1. When the buffering agent is an acetic acid buffer, one embodiment of its buffering capacity is, for example, 4.2 to 7.0, 4.2 to 6.7, 4.2 to 5.8, and 4.2 to 4.6, preferably 4.2 to 7.0, 4.2 to 6.7, and 4.2 to 5.8. When the buffering agent is an acetic acid buffer, one embodiment of its buffering capacity is 4.2, 4.6, 5.8, 6.7, and 7.0. Another embodiment is 4.2, 5.8, 6.7, and 7.0. When the buffering agent is an acetic acid buffer, one embodiment of its buffering capacity is, for example, 5.5 to 6.0. When the buffering agent is an acetic acid buffer, one embodiment of its buffering capacity is 5.5 and 6.0.

[0040] When the buffering agent is an acetate buffer, its concentration can be, for example, 0.005 to 2% (w / v), and more preferably 0.006 to 2% (w / v). When the buffering agent is an acetate buffer, one embodiment of its concentration can be 0.005% (w / v), 0.006% (w / v), 0.01% (w / v), 0.02% (w / v), 0.04% (w / v), 0.06% (w / v), 0.1% (w / v), 0.2% (w / v), 1% (w / v), or 2% (w / v). Another embodiment can be 0.006% (w / v), 0.02% (w / v), 0.06% (w / v), 0.2% (w / v), or 2% (w / v). Another embodiment includes concentrations of 0.006% (w / v), 0.02% (w / v), 0.06% (w / v), and 2% (w / v).

[0041] Examples of "EDTA buffering agents" include EDTA (ethylenediaminetetraacetic acid) or its salts. More specifically, examples include EDTA, disodium EDTA, trisodium EDTA, etc. EDTA is preferred as the "EDTA buffering agent."

[0042] When the buffering agent is an EDTA buffer, its buffering capacity can be, for example, 5.7 to 6.6, 5.7 to 6.4, 5.7 to 6.3, or 5.7 to 6.1. When the buffering agent is an EDTA buffer, one embodiment of its buffering capacity can be 5.7, 6.1, 6.3, 6.4, or 6.6. When the buffering agent is an EDTA buffer, one embodiment of its buffering capacity can be, for example, 5.8 to 6.6, 5.8 to 6.3, or 5.8 to 6.0, preferably 5.8 to 6.6 or 5.8 to 6.3. When the buffering agent is an EDTA buffer, one embodiment of its buffering capacity can be 5.8, 6.0, 6.3, or 6.6. Another embodiment can be 5.8, 6.3, or 6.6. When the buffering agent is an EDTA buffer, one embodiment of its buffering capacity can be, for example, 6.0 to 6.2. When the buffering agent is an EDTA buffering agent, one aspect of its buffering capacity is described in 6.0 and 6.2.

[0043] When the buffer is an edetic acid buffer, the concentration thereof is, for example, 0.05 to 0.3% (w / v). When the buffer is an edetic acid buffer, one embodiment of the concentration includes 0.05% (w / v), 0.1% (w / v), 0.15% (w / v), 0.2% (w / v), and 0.3% (w / v). As another embodiment, 0.05% (w / v), 0.1% (w / v), 0.2% (w / v), and 0.3% (w / v) are mentioned. As still another embodiment, 0.05% (w / v), 0.1% (w / v), and 0.3% (w / v) are mentioned.

[0044] Examples of the "tartaric acid buffer" include tartaric acid or a salt thereof, and the like. More specifically, sodium tartrate, potassium tartrate, and the like are mentioned.

[0045] Examples of the "aspartic acid buffer" include aspartic acid or a salt thereof, and the like. More specifically, sodium aspartate, magnesium aspartate, and the like are mentioned.

[0046] Examples of the "glutamic acid buffer" include glutamic acid or a salt thereof, and the like. More specifically, sodium glutamate, potassium glutamate, and the like are mentioned. Preferred as the "glutamic acid buffer" is sodium glutamate.

[0047] When the buffering agent is a glutamate buffering agent, its buffering capacity can be, for example, 4.1 to 7.0, 4.1 to 6.5, 4.1 to 5.9, 4.1 to 5.1, or 4.1 to 4.4, and preferably 4.1 to 7.0, 4.1 to 6.5, or 4.1 to 5.1. When the buffering agent is a glutamate buffering agent, one embodiment of its buffering capacity can be 4.1, 4.4, 5.1, 5.9, 6.5, or 7.0. Another embodiment can be 4.1, 5.1, 6.5, or 7.0. When the buffering agent is a glutamate buffering agent, one embodiment of its buffering capacity can be, for example, 4.4 to 6.9, 4.4 to 6.5, or 4.4 to 5.1, and preferably 4.4 to 6.9 or 4.4 to 6.5. When the buffering agent is a glutamate buffering agent, one embodiment of its buffering capacity is 4.4, 5.1, 6.5, and 6.9. Another embodiment is 4.4, 6.5, and 6.9. When the buffering agent is a glutamate buffering agent, one embodiment of its buffering capacity is, for example, 6.0 to 6.6. When the buffering agent is a glutamate buffering agent, one embodiment of its buffering capacity is 6.0 and 6.6.

[0048] When the buffering agent is a glutamate buffer, its concentration can be, for example, 0.02 to 1% (w / v). When the buffering agent is a glutamate buffer, one embodiment of its concentration can be 0.02% (w / v), 0.05% (w / v), 0.06% (w / v), 0.1% (w / v), 0.2% (w / v), 0.5% (w / v), or 1% (w / v). Another embodiment can be 0.02% (w / v), 0.06% (w / v), 0.2% (w / v), or 1% (w / v). Yet another embodiment can be 0.02% (w / v), 0.06% (w / v), or 1% (w / v).

[0049] When the buffering agent is trometamol, its buffering capacity can be, for example, 5.8 to 7.1, 5.8 to 6.9, 5.8 to 6.8, 5.8 to 6.6, or 5.8 to 6.1, with 5.8 to 7.1, 5.8 to 6.9, or 5.8 to 6.8 being preferred. When the buffering agent is trometamol, one embodiment of its buffering capacity can be 5.8, 6.1, 6.6, 6.8, 6.9, or 7.1. Another embodiment can be 5.8, 6.8, 6.9, or 7.1. When the buffering agent is trometamol, one embodiment of its buffering capacity can be, for example, 5.9 to 7.0 or 5.9 to 6.9. When the buffering agent is trometamol, one embodiment of its buffering capacity can be 5.9, 6.9, or 7.0. When the buffering agent is trometamol, one embodiment of its buffering capacity can be, for example, 6.0 to 6.1. When the buffering agent is trometamol, one aspect of its buffering capacity is described in 6.0 and 6.1.

[0050] When the buffering agent is trometamol, its concentration can be, for example, 0.05 to 3.4% (w / v). When the buffering agent is trometamol, one embodiment of its concentration can be 0.05% (w / v), 0.1% (w / v), 0.2% (w / v), 0.34% (w / v), 1.7% (w / v), or 3.4% (w / v). Another embodiment can be 0.05% (w / v), 0.1% (w / v), 0.2% (w / v), or 3.4% (w / v). Yet another embodiment can be 0.05% (w / v), 0.1% (w / v), or 3.4% (w / v).

[0051] In the present invention, additives may be used in the aqueous composition as needed. These additives may include water-soluble polymers, isotonic agents, surfactants, stabilizers, preservatives, antioxidants, high molecular weight polymers, pH adjusters, and bases. These may be used individually or in combination of two or more as appropriate, and appropriate amounts may be added.

[0052] Examples of the aqueous composition of the present invention include eye drops or aqueous eye solutions.

[0053] The aqueous composition of the present invention may appropriately contain water-soluble polymers that can be used as pharmaceutical additives. In the present invention, "water-soluble polymer" means any water-soluble, pharmaceutically acceptable polymer used to increase the viscosity of the aqueous composition, and is also referred to as a viscosity enhancer. Examples of water-soluble polymers of the present invention include celluloses and their derivatives (e.g., methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (hypromellose; HPMC), hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, carboxymethylcellulose sodium (carmellose sodium; CMCNa), cellulose acetate phthalate, ethylcellulose, hydroxymethylcellulose, hydroxyethylmethylcellulose, hypromellose acetate succinate, and Examples include hypromellose phthalate, synthetic polymers (e.g., polyethylene glycol (macrogol; PEG), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, and carboxyvinyl polymer (CVP)), and polymers and saccharides derived from natural products (e.g., gum arabic, duran gum, sodium alginate, propylene glycol alginate, agar, gelatin, tragacanth, and xanthan gum). One embodiment of a water-soluble polymer includes cellulose and its derivatives, carboxyvinyl polymer, and sodium alginate. Another embodiment includes hydroxyethylcellulose, carboxyvinyl polymer, hydroxypropyl methylcellulose, and sodium carboxymethylcellulose. Another embodiment includes hydroxyethylcellulose, hydroxypropyl methylcellulose, and sodium carboxymethylcellulose.Another embodiment includes hydroxyethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, carboxyvinyl polymer, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, gellan gum, and sodium alginate. These water-soluble polymers may be used individually or in any combination of two or more components.

[0054] When the aqueous composition of the present invention contains a water-soluble polymer, the concentration of the water-soluble polymer can be appropriately adjusted depending on the type of water-soluble polymer, but is preferably 0.01 to 20% (w / v), more preferably 0.05 to 10% (w / v), even more preferably 0.1 to 5% (w / v), and particularly preferably 0.1 to 2% (w / v).

[0055] In the present invention, when the water-soluble polymer is cellulose and its derivatives, the concentration of cellulose and its derivatives is preferably 0.01 to 5% (w / v), more preferably 0.1 to 2% (w / v), even more preferably 0.1 to 1% (w / v), and particularly preferably 0.1 to 0.6% (w / v). For example, when the water-soluble polymer is at least one selected from the group consisting of hydroxyethylcellulose (HEC), hydroxypropyl methylcellulose (HPMC), and sodium carboxymethylcellulose (CMCNa), the concentration of each is preferably 0.1 to 1% (w / v), and more preferably 0.1 to 0.6% (w / v). For example, when the water-soluble polymer is carboxyvinyl polymer (CVP), the concentration is preferably 0.04 to 0.4% (w / v), and more preferably 0.08 to 0.4% (w / v). For example, when the water-soluble polymer is polyethylene glycol, its concentration is preferably 0.01 to 20% (w / v), and more preferably 0.1 to 20% (w / v). For example, when the water-soluble polymer is polyvinyl alcohol (PVA), its concentration is preferably 0.01 to 20% (w / v), and more preferably 0.05 to 10% (w / v). For example, when the water-soluble polymer is polyvinylpyrrolidone (PVP), its concentration is preferably 0.01 to 5% (w / v), and more preferably 0.1 to 5% (w / v). For example, when the water-soluble polymer is gellan gum, its concentration is preferably 0.1 to 2% (w / v), and more preferably 0.1 to 1% (w / v). For example, when the water-soluble polymer is sodium alginate, its concentration is preferably 0.1 to 2% (w / v), and more preferably 0.1 to 1% (w / v).

[0056] The aqueous composition of the present invention may optionally contain an isotonic agent that can be used as an additive to pharmaceuticals. In the present invention, the "isotonic agent" is not particularly limited as long as it is pharmaceutically acceptable, and examples include nonionic isotonic agents such as glycerin, mannitol, propylene glycol, polyethylene glycol, glucose, sorbitol, xylitol, and trehalose. Preferred nonionic isotonic agents include glycerin, mannitol, propylene glycol, polyethylene glycol, glucose, sorbitol, xylitol, and trehalose, more preferably glycerin and mannitol, and particularly preferably glycerin. One embodiment of the isotonic agent is glycerin, sodium chloride, and mannitol. Another embodiment of the isotonic agent is sodium chloride. These isotonic agents may be used individually or in any combination of two or more components.

[0057] When the aqueous composition of the present invention contains an isotonic agent, the concentration of the isotonic agent can be appropriately adjusted depending on the type of isotonic agent, but is preferably 0.01 to 10% (w / v), more preferably 0.05 to 5% (w / v), even more preferably 0.1 to 5% (w / v), even more preferably 0.5 to 5% (w / v), and particularly preferably 1 to 5% (w / v). For example, when the isotonic agent is glycerin, its concentration is preferably 0.5 to 5% (w / v), more preferably 1 to 3% (w / v), and even more preferably 1.2 to 2.4% (w / v). For example, when the isotonic agent is sodium chloride, its concentration is preferably 0.01 to 1% (w / v), more preferably 0.03 to 0.5% (w / v), and even more preferably 0.05 to 0.1% (w / v).

[0058] The pH of the aqueous composition of the present invention is not limited to a specific value as long as it is within a pharmaceutically acceptable range. Preferably, the pH is in the range of 6 or less, more preferably in the range of 3 to 6, even more preferably in the range of 4 to 6, even more preferably in the range of 4 to 5.5, particularly preferably in the range of 4 to 5, and most preferably in the vicinity of 4 or 5. More specifically, examples include pH 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, etc.

[0059] The osmotic pressure of the aqueous composition of the present invention is not limited to a specific value, but is within a range acceptable to living organisms. Examples of osmotic pressures of the aqueous composition of the present invention include 100 to 1000 mOsm. Preferably, the osmotic pressure of the aqueous composition of the present invention is 200 to 500 mOsm, and more preferably 250 to 350 mOsm. Generally, the osmotic pressure of an aqueous composition is affected to some extent by the amount of drugs and additives in the aqueous composition. In the present invention, the osmotic pressure can be adjusted to fall within the above range by appropriately adjusting the amounts of these substances that can affect the osmotic pressure. The osmotic pressure of the aqueous composition of the present invention is measured by conventional methods. For example, the osmotic pressure of the aqueous composition of the present invention can be measured according to the method described in "Osmotic Pressure Measurement Method (Osmolar Concentration Measurement Method)" of the 18th edition of the Japanese Pharmacopoeia.

[0060] The viscosity of the aqueous composition of the present invention is not limited to a specific value, but for example, it is 5 to 70 mPa·s. Preferably, the viscosity of the aqueous composition of the present invention is 5 to 60 mPa·s, more preferably 8 to 50 mPa·s, even more preferably 10 to 45 mPa·s, particularly preferably 10 to 40 mPa·s, and most preferably 15 to 35 mPa·s. One embodiment of the viscosity of the aqueous composition of the present invention is 5 to 57 mPa·s, 15 to 48 mPa·s, 15 to 30 mPa·s, 20 to 48 mPa·s, 20 to 30 mPa·s, or 27 to 68 mPa·s. Generally, the viscosity of an aqueous composition is affected to some extent by the amount of drugs and additives in the aqueous composition. In the present invention, the viscosity can be adjusted to fall within the above range by appropriately adjusting the amount of these substances that can affect the viscosity. The viscosity of the aqueous composition of the present invention is measured by conventional methods. For example, the viscosity of the aqueous composition of the present invention can be measured according to the method described in the second method, "rotational viscometer method," of the "viscosity measurement method" in the 18th edition of the Japanese Pharmacopoeia.

[0061] In the present invention, "substantially absent" means that the aqueous composition of the present invention does not contain any of the components, or that a certain component is contained in an amount that does not exert its effects and side effects on its own. For example, "substantially absent water-soluble polymers" means that the aqueous composition does not contain any water-soluble polymers, or that a water-soluble polymer is contained in an amount that does not exert its effects and side effects as a water-soluble polymer on its own.

[0062] One embodiment of the aqueous composition of the present invention is an aqueous composition that substantially does not contain hydroxyethylcellulose, hydroxypropylmethylcellulose, or carboxyvinyl polymer as the water-soluble polymer. Another embodiment is an aqueous composition that substantially does not contain the water-soluble polymer.

[0063] One embodiment of the aqueous composition of the present invention is an aqueous composition that substantially does not contain sodium dihydrogen phosphate, epsilon-aminocaproic acid, sodium citrate hydrate, or acetic acid as a buffering agent. Another embodiment is an aqueous composition that substantially does not contain phosphate buffering agent, epsilon-aminocaproic acid, citrate buffering agent, or acetic acid buffering agent as a buffering agent.

[0064] One embodiment of the aqueous composition of the present invention is an aqueous composition that substantially does not contain sodium dihydrogen phosphate, epsilon-aminocaproic acid, sodium citrate hydrate, or acetic acid as a buffering agent, and substantially does not contain hydroxyethylcellulose as a water-soluble polymer. Another embodiment is an aqueous composition that substantially does not contain sodium dihydrogen phosphate as a buffering agent, and substantially does not contain hydroxyethylcellulose, hydroxypropyl methylcellulose, or carboxyvinyl polymer as a water-soluble polymer.

[0065] One embodiment of the aqueous composition of the present invention is an aqueous composition that is substantially free of benzalkonium chloride. Another embodiment is an aqueous composition that contains less than 100 ppm of benzalkonium chloride.

[0066] In the present invention, the aqueous composition can be administered orally or parenterally. Administration routes include oral administration, intravenous administration, transdermal administration, and local ocular administration (e.g., eye drops, conjunctival sac administration, intravitreous administration, subconjunctival administration, sub-Tenon's capsule administration).

[0067] The aqueous composition of the present invention can be contained in a package. A package means one that directly or indirectly contains the aqueous composition of the present invention. The aqueous composition of the present invention is not particularly limited as long as it can be contained in a package, and can be used in dosage forms for eye disease preparations, such as eye drops, eye gels, and injections. The aqueous composition of the present invention is particularly preferred for use as eye drops. These dosage forms can be manufactured according to conventional methods in the art. The package can be any type commonly expected for pharmaceutical preparations, and its airtightness is not particularly limited. Furthermore, the means of containing the aqueous composition in the package can be filled by conventional methods according to the form of the package, etc.

[0068] When the aqueous composition of the present invention is used as an eye drop, the eye drop container may be composed of one component or of multiple components. In the present invention, the aqueous composition may be contained in, for example, a one-piece eye drop container composed of one component, a two-piece eye drop container composed of two components, or a three-piece eye drop container composed of three components. For example, a three-piece eye drop container is formed from three components: a container body for containing the aqueous composition, an inner stopper, and a cap. A one-piece molded container in which blow molding and drug solution filling are performed simultaneously is also included in the above eye drop container according to the number of components. When the container is formed from multiple components, the components may be made of the same material or of different materials.

[0069] When the aqueous composition of the present invention is used as eye drops, it may be contained in a multi-dose container, a single-use unit-dose container, or a PFMD (Preservative Free Multi-Dose) container.

[0070] In the present invention, "multi-dose container" refers to an eye drop container comprising a container body and a cap that can be attached to the container body, wherein the cap can be freely opened and resealed. The multi-dose container typically contains multiple doses of eye drops for use over a certain period of time.

[0071] In the present invention, "unit dose type container" refers to an eye drop container in which a cap is fused and sealed to the neck of the bottle, and which is intended to be opened by breaking the fused portion between the cap and the bottle-shaped body when in use. The unit dose type container may contain an aqueous composition for single use, or it may contain an aqueous composition for several uses, intended for use in a day.

[0072] In the present invention, a "PFMD (Preservative Free Multi-Dose) container" refers to a container whose physical structure ensures sterility within the container even without containing preservatives. Examples of PFMD containers include containers that exhibit a preservative effect by having a backflow prevention valve in the discharge hole, and containers that exhibit a preservative effect by being a delaminated bottle with a filter. Furthermore, PFMD containers also include eye drop containers in which the inner stopper (nozzle) and cap are integrated into a single component until the first opening, and after opening, the inner stopper (nozzle) and cap separate into two components.

[0073] The dosage and administration of the aqueous composition of the present invention are not particularly limited as long as they are sufficient to produce the desired pharmacological effect. Preferably, 1 to 3 drops are administered once to 5 times a day, more preferably 1 to 2 drops are administered twice to 4 times a day, and most preferably 1 drop is administered once a day before bedtime.

[0074] The aqueous compositions of the present invention can be used, for example, to inhibit or prevent the progression of myopia, and / or to treat myopia. More preferably, they can be used to inhibit or prevent the progression of myopia in school-aged children. "Inhibiting or preventing the progression of myopia" means slowing down or reducing the progression of myopia. "Preventing myopia" means preventing the onset of myopia or delaying the onset of myopia.

[0075] The present invention also provides a method for suppressing pupillary dilation by adjusting the amount of a buffer in an aqueous composition containing atropine and a buffer based on the pH when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:1.

[0076] Examples and test examples are shown below, but these are for the purpose of better understanding the present invention and do not limit the scope of the invention.

[0077] Preparation of the Test Formulation (1) Preparation of Example 1A-8 The aqueous composition of Example 1A-8 was prepared according to the formulation shown in Table 3. Specifically, concentrated glycerin (14.4 g) and atropine sulfate hydrate (0.15 g) were mixed with 250 mL of purified water and stirred to dissolve. Then, purified water was added to adjust the total volume to 300 mL, and the mixture was thoroughly mixed to prepare a 0.05% atropine sulfate hydrate / 4.8% concentrated glycerin solution (2x concentrated solution). Purified water (15 mL) and sodium citrate hydrate (0.1 g) were added to the 2x concentrated solution (25 mL), and the pH was adjusted to 4.3. Further purified water was added to adjust the total volume to 50 mL, and the pH was confirmed to be 4.3 to prepare Example 1A-8. (2) Preparation of Examples and Comparative Examples in Tables 1 to 18 In accordance with the preparation of Example 1A-8 in (1) above, Examples 1A-1 to 7 and 9 to 11, Examples 1B-1 to 10, Examples 1C-1 to 7, Examples 1D-1 to 5, Examples 1E-1 to 6, Examples 1F-1 to 8, Example 1G-1, Examples 2A-1 to 5, Examples 2B-1 to 5, Examples 2C-1 to 4, Examples 2D-1 to 4, Examples 2E-1 to 4 and Examples 2F-1 to 4, as well as Comparative Examples 1 to 2, were prepared according to the formulations shown in Tables 19 to 24 below. At that time, the pH was adjusted to 5.5. (4) Preparation of Examples 4A to 4F Examples 4A to 4F were prepared in accordance with the preparation of Example 1A-8 in (1) above, according to the formulations shown in Tables 19 to 24 below. At that time, the pH was adjusted to 6.0.

[0078] Test Example 1: Evaluation of Buffering Capacity Each of the example formulations (3.5 mL) prepared above was mixed with BSS Plus (0.5 mL), and the pH was measured to evaluate the buffering capacity of each example formulation. pH was measured in accordance with the method described in the "pH Measurement Method" of the General Test Methods of the 18th Edition of the Japanese Pharmacopoeia.

[0079] Test Example 2: Evaluation of Mydriatic Effect A single dose (10 μL) of each example formulation and comparative formulation was instilled into the monocular eye (6 eyes of 6 rabbits) of rabbits. Images of the rabbits' pupils before instillation and 30 minutes after instillation were captured by optical coherence tomography (OCT), and then analyzed using image analysis software to calculate the pupil area of ​​the rabbits. The rate of change in mydriatic area was the change in mydriatic area (mm²) before and after instillation of the comparative formulation. ２ The change in pupillary dilation area (mm²) before and after instillation of each example formulation, with the value of ) set to 1. ２ This represents the ratio of pupil dilation. Percentage change in pupil dilation = b / a In the formula, a represents the (pupil area 30 minutes after instillation - pupil area before instillation) of the comparative formulation containing the same concentration of atropine as the evaluated example formulation, and b represents the (pupil area 30 minutes after instillation - pupil area before instillation) of the evaluated example formulation. When measuring the percentage change in pupil dilation for each example formulation, the comparative formulation used for comparison is also evaluated for each test, and its value is calculated.

[0080]

[0081] The table above shows the pupil area before instillation and 30 minutes after instillation for Comparative Example 1 and Comparative Example 2, as well as the change in pupil area before and after instillation. From the results above, Comparative Example 1 and Comparative Example 2, which do not contain a buffering agent, showed a large change in pupil area before and after instillation, indicating that they have a strong mydriatic effect.

[0082]

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[0104]

[0105] The above results show that the atropine-containing aqueous composition containing a buffering agent and having buffering capacity (Example) exhibited a smaller rate of change in pupil dilation compared to the atropine-containing aqueous composition not containing a buffering agent and having no buffering capacity (Comparative Example). In other words, it was shown that the pupil dilation effect can be suppressed by providing the atropine-containing aqueous composition with appropriate buffering capacity.

[0106] The present invention provides an aqueous composition containing atropine and a buffering agent, wherein the pupillary dilation effect is suppressed by adjusting the content of the buffering agent based on the pH when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:1, and a method for suppressing the pupillary dilation effect of the aqueous composition containing atropine and a buffering agent.

Claims

1. An aqueous composition containing atropine or a salt thereof at a concentration of 0.001 to 0.1% (w / v) and a buffer as an active ingredient, and having a pH of 6.0 or lower, characterized in that the amount of buffer is such that the pH when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:1 becomes 7.3 or lower.

2. The aqueous composition according to claim 1, wherein the buffer is at least one selected from the group consisting of glutamate buffer, citrate buffer, acetate buffer, borate buffer, carbonate buffer, EDTA buffer, and trometamol.

3. The aqueous composition according to claim 1 or 2, wherein the amount of buffering agent is such that the pH when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:1 is between 4.1 and 7.

0.

4. The aqueous composition according to claim 1 or 2, wherein the amount of buffering agent is such that the pH of the aqueous composition when mixed with BSS Plus in a volume ratio of 7:1 is 4.1 to 6.

1.

5. The aqueous composition according to claim 1 or 2, wherein the amount of buffering agent is such that the pH of the aqueous composition when mixed with BSS Plus in a volume ratio of 7:1 is 4.1 to 5.

1.

6. The aqueous composition according to claim 1, wherein the buffering agent is a glutamate buffering agent, and the amount of buffering agent is such that the pH when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:1 is 4.1 to 7.

0.

7. The aqueous composition according to claim 1, wherein the buffer is a citrate buffer, and the amount of the buffer is such that the pH of the aqueous composition when mixed with BSS Plus in a volume ratio of 7:1 is 4.2 to 7.

2.

8. The aqueous composition according to claim 1, wherein the buffering agent is an acetic acid buffering agent, and the amount of the buffering agent is such that the pH when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:1 is 4.2 to 7.

1.

9. The aqueous composition according to claim 1, wherein the buffering agent is trometamol, and the amount of buffering agent is such that the pH of the aqueous composition when mixed with BSS Plus in a volume ratio of 7:1 is 5.8 to 7.

1.

10. The aqueous composition according to claim 1, wherein the buffering agent is a boric acid buffering agent, and the amount of buffering agent is such that the pH of the aqueous composition when mixed with BSS Plus in a volume ratio of 7:1 is 5.7 to 7.

0.

11. The aqueous composition according to claim 1, wherein the buffer is an edetate buffer, and the amount of the buffer is such that the pH when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:1 is 5.7 to 6.

6.

12. The aqueous composition according to claim 1, wherein the buffering agent is a carbonate buffering agent, and the amount of the buffering agent is such that the pH becomes 7.2 when the aqueous composition and BSS Plus are mixed in a volume ratio of 7:

1.

13. The aqueous composition according to any one of claims 1 to 12, further comprising an isotonic agent.

14. The aqueous composition according to claim 13, wherein the isotonic agent is at least one selected from the group consisting of glycerin, mannitol, propylene glycol, polyethylene glycol, glucose, sorbitol, xylitol, trehalose, and sodium chloride.

15. The aqueous composition according to claim 13, wherein the isotonic agent is at least one selected from the group consisting of glycerin, sodium chloride, and mannitol.

16. The aqueous composition according to any one of claims 13 to 15, wherein the concentration of the isotonic agent is 0.05 to 2.4% (w / v).

17. The aqueous composition according to any one of claims 1 to 16, wherein the pH of the aqueous composition is 4.0 to 6.

0.

18. The aqueous composition according to any one of claims 1 to 16, wherein the pH of the aqueous composition is 4.0 to 5.

0.

19. The aqueous composition according to any one of claims 1 to 16, wherein the pH of the aqueous composition is 4.0 to 4.

5.

20. The aqueous composition according to any one of claims 1 to 19, wherein the concentration of atropine or a salt thereof is 0.001 to 0.025% (w / v).

21. The aqueous composition according to any one of claims 1 to 19, wherein the concentration of atropine or a salt thereof is 0.01 to 0.025% (w / v).

22. The aqueous composition according to any one of claims 1 to 21, wherein atropine or a salt thereof is atropine sulfate or a hydrate thereof.

23. The aqueous composition according to any one of claims 1 to 22, wherein the water-soluble polymer is substantially free of hydroxyethylcellulose, hydroxypropylmethylcellulose, or carboxyvinyl polymer.

24. The aqueous composition according to any one of claims 1 to 22, which substantially does not contain a water-soluble polymer.

25. The aqueous composition according to any one of claims 1 to 24, which substantially does not contain sodium dihydrogen phosphate, epsilon-aminocaproic acid, sodium citrate hydrate, or acetic acid as a buffering agent.

26. The aqueous composition according to any one of claims 1 to 24, which substantially does not contain a phosphate buffer, epsilon-aminocaproic acid, a citrate buffer, or an acetate buffer as a buffering agent.

27. The aqueous composition according to any one of claims 1 to 22, which substantially does not contain sodium dihydrogen phosphate, epsilon-aminocaproic acid, sodium citrate hydrate, or acetic acid as a buffering agent, and substantially does not contain hydroxyethylcellulose as a water-soluble polymer.

28. The aqueous composition according to any one of claims 1 to 22, which substantially does not contain sodium dihydrogen phosphate as a buffering agent and substantially does not contain hydroxyethylcellulose, hydroxypropylmethylcellulose, or carboxyvinyl polymer as a water-soluble polymer.

29. The aqueous composition according to any one of claims 1 to 28, which is substantially free of benzalkonium chloride.

30. An aqueous composition according to any one of claims 1 to 28, containing less than 100 ppm of benzalkonium chloride.

31. An aqueous composition according to any one of claims 1 to 30, contained in a unit dose container.

32. The aqueous composition according to any one of claims 1 to 31, wherein the aqueous composition is an aqueous eye drop solution.

33. An aqueous composition according to any one of claims 1 to 32 for inhibiting and / or preventing the progression of myopia.

34. Use of the aqueous composition according to any one of claims 1 to 32 in the manufacture of a drug for inhibiting and / or preventing the progression of myopia.

35. An aqueous composition according to any one of claims 1 to 32, for use in inhibiting and / or preventing the progression of myopia.

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