Atropin contains aqueous components.

Abstract

This invention provides an atropine-containing aqueous composition that has excellent effects in suppressing axial length elongation and improving refractive errors. [Solution] An aqueous composition is provided which contains atropine or a salt thereof in a concentration of 0.001 to 0.1% (w / v), a water-soluble polymer, and a first buffer, and has a pH in the range of 6 or less, wherein the first buffer is at least one selected from the group consisting of phosphate buffer, aminocarboxylic acid buffer, carbonate buffer, acetate buffer, tartaric acid buffer, boric acid buffer, and trometamol.

Description

[Technical Field]

[0001] The present invention relates primarily to aqueous compositions containing atropine or a salt thereof (hereinafter also simply referred to as "atropine"). [Background technology]

[0002] Myopia is a type of refractive error in which light entering the eye from a distance focuses not on the retina, but in front of it, causing objects to appear blurry. Myopia is known to be caused by either an axial length (the distance from the cornea to the retina) being longer than normal (axial myopia) or excessive refractive power of the cornea or lens (refractive myopia).

[0003] Atropine is known to have properties that suppress the elongation of the axial length of the eye. For example, Patent Document 1 discloses that a composition containing less than 0.025% atropine suppresses or prevents the progression of myopia.

[0004] On the other hand, atropine eye drops are used as a pupillary dilator and also reduce accommodation. When atropine eye drops are instilled, the pupillary sphincter muscle of the iris relaxes, causing pupillary dilation that leads to glare. This effect persists as long as the atropine eye drops are active, reducing the lens's ability to adjust distances and resulting in decreased near vision. This can interfere with daily activities. Therefore, there has been a great desire for a medicine to suppress or prevent the progression of myopia that induces a smaller reduction in accommodation with a lower pupillary dilation effect, thereby improving quality of life (QOL). [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] WO2012 / 161655 [Overview of the project] [Problems that the invention aims to solve]

[0006] The object of the present invention is to find an atropine-containing aqueous composition that has excellent effects in suppressing axial length elongation and improving refractive errors. A key objective is to find an atropine-containing aqueous composition that induces a lower decrease in accommodation with a lower pupillary dilation effect. Another object of the present invention is to find an atropine-containing aqueous composition in which the viscosity does not decrease over time and in which atropine or a salt thereof is stable. [Means for solving the problem]

[0007] The inventors, after diligently studying to solve the above problems, have surprisingly found that an aqueous composition containing atropine or a salt thereof at a concentration of 0.001-0.1% (w / v), a water-soluble polymer, and a first buffer, with a pH in the range of 6 or less, wherein the first buffer is at least one selected from the group consisting of phosphate buffer, aminocarboxylic acid buffer, carbonate buffer, acetate buffer, tartaric acid buffer, boric acid buffer, and trometamol, has excellent inhibitory effects on axial length elongation and improvement of refractive errors without exacerbating the mydriatic effect of atropine. Furthermore, the inventors have also found that by not containing benzalkonium chloride, or by containing a limited amount of benzalkonium chloride, a low mydriatic effect can be observed. Furthermore, the inventors have found that by including a nonionic isotonic agent in an aqueous composition containing atropine or a salt thereof and a water-soluble polymer, and having a pH of 6 or less, the decrease in viscosity of the aqueous composition imparted by the water-soluble polymer over time can be suppressed, and the stability of atropine or a salt thereof can be maintained. The aqueous composition of the present invention is expected to be optimal in terms of quality of life by suppressing or preventing the progression of myopia, reducing pupillary dilation, and reducing the decrease in accommodation.

[0008] In other words, the present invention relates to the following:

[0009] (Section 1) An aqueous composition comprising atropine or a salt thereof at a concentration of 0.001 to 0.1% (w / v), a water-soluble polymer, and a first buffering agent, and having a pH of 6 or lower, wherein the first buffering agent is at least one selected from the group consisting of a phosphate buffering agent, an aminocarboxylic acid buffering agent, a carbonate buffering agent, an acetate buffering agent, a tartaric acid buffering agent, a boric acid buffering agent, and trometamol.

[0010] (Claim 2) The aqueous composition according to Item 1, wherein the first buffering agent is at least one selected from the group consisting of a phosphate buffering agent, an aminocarboxylic acid buffering agent, a carbonate buffering agent, and an acetate buffering agent.

[0011] (Claim 3) The aqueous composition according to Item 1 or 2, wherein the first buffering agent is a phosphate buffering agent.

[0012] (Claim 4) The aqueous composition according to Item 1 or 2, wherein the aminocarboxylic acid buffering agent is at least one selected from the group consisting of epsilon-aminocaproic acid, a glutamic acid buffering agent, and an aspartic acid buffering agent.

[0013] (Claim 5) The phosphate buffering agent is derived from at least one selected from the group consisting of sodium hydrogen phosphate hydrate, sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate, sodium dihydrogen phosphate dihydrate, potassium dihydrogen phosphate, sodium hydrogen phosphate heptahydrate, trisodium phosphate, and dipotassium phosphate, The carbonate buffering agent is derived from at least one selected from the group consisting of carbonic acid, sodium hydrogen carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, and magnesium carbonate, The acetate buffering agent is derived from at least one selected from the group consisting of acetic acid, ammonium acetate, potassium acetate, calcium acetate, and sodium acetate, The tartaric acid buffering agent is derived from at least one selected from the group consisting of sodium tartrate and potassium tartrate, The boric acid buffer is derived from at least one selected from the group consisting of boric acid, sodium borate, potassium borate, potassium tetraborate, potassium metaborate, ammonium borate, and borax, the glutamic acid buffer is derived from at least one selected from the group consisting of glutamic acid, sodium glutamate, and potassium glutamate, and / or the aspartic acid buffer is derived from at least one selected from the group consisting of aspartic acid, sodium aspartate, and magnesium aspartate, The aqueous composition according to any one of Items 1 to 4.

[0014] (Item 6) The aqueous composition according to any one of Items 1 to 5, further comprising a citrate buffer as a second buffer.

[0015] (Item 7) The aqueous composition according to Item 6, wherein the citrate buffer is derived from at least one selected from the group consisting of citric acid hydrate, sodium citrate, sodium citrate hydrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, and disodium citrate.

[0016] (Item 8) The aqueous composition according to any one of Items 1 to 7, wherein the water-soluble polymer is at least one selected from the group consisting of cellulose derivatives, carboxyvinyl polymer, and sodium alginate.

[0017] (Item 9) The aqueous composition according to claim 8, wherein the cellulose derivative is at least one selected from the group consisting of hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hypromellose acetate succinate, hypromellose phthalate, carboxymethylethylcellulose, and cellulose acetate phthalate.

[0018] (Section 10) The aqueous composition according to claim 8 or 9, wherein the cellulose derivative is at least one selected from the group consisting of hydroxyethylcellulose and hydroxypropylmethylcellulose.

[0019] (Section 11) The aqueous composition according to any one of claims 8 to 10, wherein the cellulose derivative is hydroxyethylcellulose.

[0020] (Section 12) An aqueous composition containing atropine or a salt thereof in a concentration of 0.001 to 0.1% (w / v), hydroxyethylcellulose, and a first buffer, wherein the pH is in the range of 6 or less, and the first buffer is a phosphate buffer.

[0021] (Section 13) Furthermore, the aqueous composition according to item 12 further contains a citrate buffer as a second buffer.

[0022] (Section 14) An aqueous composition according to any one of items 1 to 13, comprising benzalkonium chloride at a concentration of less than 50 ppm.

[0023] (Section 15) An aqueous composition according to any one of claims 1 to 14, which is substantially free of benzalkonium chloride.

[0024] (Section 16) Furthermore, the aqueous composition according to any one of claims 1 to 15, further comprising a nonionic isotonic agent.

[0025] (Section 17) The aqueous composition according to claim 16, wherein the nonionic isotonic agent is at least one selected from the group consisting of glycerin, mannitol, propylene glycol, polyethylene glycol, glucose, sorbitol, xylitol, and trehalose.

[0026] (Section 18) The aqueous composition according to claim 16 or 17, wherein the nonionic isotonic agent is at least one selected from the group consisting of glycerin and mannitol.

[0027] (Section 19) The aqueous composition according to any one of claims 16 to 18, wherein the nonionic isotonic agent is glycerin.

[0028] (Section 20) An aqueous composition according to any one of items 1 to 19, wherein the concentration of the buffering agent is 0.001 to 10% (w / v).

[0029] (Section 21) An aqueous composition according to any one of items 6 to 11 and 13 to 20, wherein the concentration of the citrate buffer is 0.001 to 1.0% (w / v).

[0030] (Section 22) The aqueous composition according to item 21, wherein the concentration of the citrate buffer is 0.01 to 0.05% (w / v).

[0031] (Section 23) An aqueous composition according to any one of items 1 to 22, wherein the concentration of the water-soluble polymer is 0.01 to 5% (w / v).

[0032] (Section 24) An aqueous composition according to any one of claims 16 to 23, wherein the concentration of the nonionic isotonic agent is 0.01 to 10% (w / v).

[0033] (Section 25) An aqueous composition containing atropine or a salt thereof at a concentration of 0.001 to 0.1% (w / v), a water-soluble polymer, and a buffering agent, with a pH in the range of 5 or less.

[0034] (Section 26) The aqueous composition according to claim 25, wherein the buffering agent is at least one selected from the group consisting of phosphate buffering agents, citrate buffering agents, aminocarboxylic acid buffering agents, carbonate buffering agents, acetate buffering agents, tartaric acid buffering agents, borate buffering agents, and trometamol.

[0035] (Section 27) The aqueous composition according to item 25 or 26, wherein the buffering agent is a citrate buffering agent.

[0036] (Section 28) An aqueous composition containing atropine or a salt thereof at a concentration of 0.001 to 0.1% (w / v), and a phosphate buffer, with a pH of 6 or less.

[0037] (Section 29) The aqueous composition according to item 28, further containing a water-soluble polymer.

[0038] (Section 30) The aqueous composition according to claim 29, wherein the water-soluble polymer is at least one selected from the group consisting of hydroxyethylcellulose, carboxyvinyl polymer, hydroxypropyl methylcellulose, and sodium alginate.

[0039] (Section 31) The aqueous composition according to item 29 or 30, wherein the water-soluble polymer is hydroxyethylcellulose.

[0040] (Section 32) An aqueous composition according to any one of items 1 to 24 and 28 to 31, wherein the pH is in the range of 4 to 6.

[0041] (Section 33) An aqueous composition according to any one of items 1 to 32, wherein the concentration of the phosphate buffer is 0.01 to 1.0% (w / v).

[0042] (Section 34) An aqueous composition according to any one of items 1 to 33, wherein the concentration of atropine or a salt thereof is 0.001 to 0.025% (w / v).

[0043] (Section 35) An aqueous composition according to any one of items 1 to 34, wherein the concentration of atropine or a salt thereof is 0.001 to 0.01% (w / v).

[0044] (Section 36) The aqueous composition according to any one of claims 1 to 35, wherein atropine or a salt thereof is atropine sulfate or its hydrate.

[0045] (Section 37) An aqueous composition according to any one of items 1 to 36, contained in a unit dose container.

[0046] (Section 38) The aqueous composition according to any one of claims 1 to 37, wherein the aqueous composition is an eye drop.

[0047] (Section 39) An aqueous composition according to any one of items 1 to 38 for inhibiting and / or preventing the progression of myopia.

[0048] (Section 40) Use of an aqueous composition according to any one of items 1 to 38 in the manufacture of a drug for inhibiting and / or preventing the progression of myopia.

[0049] (Section 41) A method for inhibiting and / or preventing the progression of myopia, comprising administering to a patient an aqueous composition described in any one of items 1 to 38.

[0050] (Section 42) An aqueous composition according to any one of items 1 to 38, for use in inhibiting and / or preventing the progression of myopia.

[0051] (Section 43) A method for suppressing viscosity reduction of an aqueous composition by adding a nonionic isotonic agent to an aqueous composition containing atropine or a salt thereof at a concentration of 0.001 to 0.1% (w / v) and a water-soluble polymer, and having a pH in the range of 6 or less.

[0052] (Section 44) A method for stabilizing atropine or a salt thereof by adding a nonionic isotonic agent to an aqueous composition containing atropine or a salt thereof at a concentration of 0.001 to 0.1% (w / v) and a water-soluble polymer, and having a pH in the range of 6 or less. [Effects of the Invention]

[0053] As is evident from the test results described later, an aqueous composition containing atropine or a salt thereof at a concentration of 0.001-0.1% (w / v), a water-soluble polymer, and a first buffer, with a pH in the range of 6 or less, wherein the first buffer is at least one selected from the group consisting of phosphate buffer, aminocarboxylic acid buffer, carbonate buffer, acetate buffer, tartaric acid buffer, borate buffer, and trometamol, was shown to have excellent inhibitory effects on axial length elongation and improvement of refractive errors without exacerbating the mydriatic effect of atropine. It was also shown that by not containing benzalkonium chloride, or by containing a limited amount of benzalkonium chloride, a low mydriatic effect was achieved. Furthermore, it was shown that by including a nonionic isotonic agent in an aqueous composition containing atropine or a salt thereof and a water-soluble polymer, with a pH in the range of 6 or less, the decrease in viscosity of the aqueous composition imparted by the water-soluble polymer over time can be suppressed, and the stability of atropine or its salt can be maintained. Therefore, this aqueous composition is expected to be optimal in terms of quality of life by suppressing or preventing the progression of myopia, reducing pupillary dilation, and minimizing the reduction in accommodation. Furthermore, a further advantage associated with the composition of the present invention, such as a composition containing an isotonic agent, is that the composition can maintain its initial viscosity (or substantial proportion thereof) over time. [Brief explanation of the drawing]

[0054] [Figure 1] Figure 1 shows the viscosity measurement results in Test 5. [Figure 2] Figure 2 shows the results of the stability test in Test 5. [Figure 3] Figure 3 shows the results of Examples 23-25 ​​in the viscosity measurement of Test 6. [Figure 4] Figure 4 shows the results of Examples 26-28 in the viscosity measurement of Test 6. [Modes for carrying out the invention]

[0055] The aqueous composition of the present invention contains "atropine or a salt thereof" as an active ingredient.

[0056] In the present invention, the term "atropine or its salt" also includes (i) hydrates of atropine or its salt, (ii) organic solvent dihydrates of atropine or its salt, and (iii) mixtures of hydrates and organic solvent dihydrates.

[0057] Atropine salts include atropine sulfate or its hydrate, preferably atropine sulfate hydrate.

[0058] Atropine sulfate hydrate is a compound represented by the following structural formula. JPEG2026139734000001.jpg45123

[0059] 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 states of the production, crystallization, and storage of those crystals, but also mixtures of crystalline forms obtained at two or more stages.

[0060] 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).

[0061] 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 0.001 to 0.01% (w / v). More specifically, the concentrations are preferably 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), and 0.0050% (w / v). The percentages are 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), 0.0090%(w / v), 0.0095%(w / v), or 0.010%(w / v).

[0062] In this invention, the term "aqueous composition" means a composition containing water as a solvent.

[0063] In the present invention, the "water-soluble polymer" may be any pharmaceutically acceptable polymer that is soluble in water. Examples of such polymers, though not particularly limited, include celluloses and their derivatives (e.g., methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, cellulose acetate phthalate, ethylcellulose, hydroxymethylcellulose, hydroxyethyl methylcellulose, hypromellose acetate succinate, and hypromellose phthalate), synthetic polymers (e.g., polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, 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), and polymers and saccharides derived from natural products (e.g., gum arabic, sodium alginate, propylene glycol alginate, agar, gelatin, tragacanth, and xanthan gum). Among these, preferred water-soluble polymers used in the present invention are cellulose and its derivatives, carboxyvinyl polymers, and sodium alginate. Among these, more preferred water-soluble polymers used in the present invention are hydroxyethylcellulose, carboxyvinyl polymers, and hydroxypropylmethylcellulose.

[0064] The aqueous composition of the present invention may contain one or more water-soluble polymers.

[0065] In the present invention, the concentration of the water-soluble polymer in the aqueous composition is determined by adjusting the content of the water-soluble polymer to reflect, if necessary, the effects of the water-soluble polymer on the pharmaceutical substance (active ingredient), other additives, pH, osmotic pressure, and / or viscosity. However, the concentration of the water-soluble polymer in the aqueous composition of the present invention is preferably 0.01 to 5% (w / v), more preferably 0.1 to 2% (w / v).

[0066] 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%.

[0067] In the present invention, when the water-soluble polymer is hydroxyethylcellulose, the concentration of hydroxyethylcellulose is preferably 0.1 to 1.0% (w / v), and more preferably 0.1 to 0.6% (w / v).

[0068] In the present invention, when the water-soluble polymer is a carboxyvinyl polymer, the concentration of the carboxyvinyl polymer is preferably 0.04 to 0.4% (w / v), and more preferably 0.08 to 0.4% (w / v).

[0069] In the present invention, when the water-soluble polymer is hydroxypropyl methylcellulose, the concentration of hydroxypropyl methylcellulose is preferably 0.1 to 1.0% (w / v), and more preferably 0.1 to 0.6% (w / v).

[0070] In the present invention, when the water-soluble polymer is sodium alginate, the concentration of sodium alginate is preferably 0.1 to 2% (w / v), more preferably 0.5 to 2% (w / v).

[0071] In the present invention, the term "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, trometamol, etc. Examples of aminocarboxylic acid buffers include aspartate buffers, glutamate buffers, epsilon-aminocaproic acid, etc. These buffers may be used individually or in any combination of two or more components. Among these buffers, phosphate buffers, citrate buffers, carbonate buffers, acetate buffers, and aminocarboxylic acid buffers are preferred, phosphate buffers, citrate buffers, acetate buffers, and aminocarboxylic acid buffers are more preferred, phosphate buffers and / or citrate buffers are even more preferred, and phosphate buffers and citrate buffers are particularly preferred.

[0072] In the present invention, the concentration of the buffer in the aqueous composition is determined by adjusting the buffer content to reflect, if necessary, the effect of the buffer on the pharmaceutical substance (active ingredient), other additives, pH, osmotic pressure, and / or viscosity. However, the concentration of the buffer in the aqueous composition of the present invention is preferably 0.001 to 10% (w / v), more preferably 0.01 to 5% (w / v), even more preferably 0.01 to 3% (w / v), even more preferably 0.01 to 1% (w / v), particularly preferably 0.01 to 0.5% (w / v), and most particularly preferably 0.01 to 0.1% (w / v), where the weight of the buffer represents the weight of the buffering agent used as a raw material.

[0073] In the present invention, the phosphate buffer may be derived from (or used as a raw material for) any pharmaceutically acceptable phosphate buffering agent. Examples of such phosphate buffering agents, though not particularly limited, include phosphoric acid; phosphates such as alkali metal phosphates and alkaline earth metal phosphates; and their hydrates. More specifically, these include sodium hydrogen phosphate hydrate (referred to as "sodium hydrogen phosphate" or "sodium phosphate"), sodium dihydrogen phosphate (referred to as "monosodium phosphate"), sodium dihydrogen phosphate monohydrate (referred to as "monosodium phosphate"), sodium dihydrogen phosphate dihydrate (referred to as "monosodium phosphate"), potassium dihydrogen phosphate (referred to as "monosodium phosphate"), sodium hydrogen phosphate heptahydrate, trisodium phosphate, dipotassium phosphate, and the like.

[0074] In the present invention, the concentration of the phosphate buffer in the aqueous composition is determined by adjusting the content of the phosphate buffer to reflect, if necessary, the effects of the phosphate buffer on the pharmaceutical substance (active ingredient), other additives, pH, osmotic pressure, and / or viscosity. However, the concentration of the phosphate buffer in the aqueous composition of the present invention is preferably 0.01 to 1.0% (w / v), more preferably 0.05 to 1.0% (w / v), and even more preferably 0.05 to 0.5% (w / v), where the weight of the phosphate buffer represents the weight of the raw material phosphate buffering agent.

[0075] In the present invention, "citric acid buffer" may be derived from (or used as a raw material for) any pharmaceutically acceptable citrate buffering agent, which is not particularly limited. Examples of citrate buffering agents include citric acid; citrates such as alkali metal citrate and alkaline earth metal citrate; and their hydrates. More specifically, examples include citric acid hydrate, sodium citrate, sodium citrate hydrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, and disodium citrate.

[0076] In the present invention, the concentration of the citrate buffer in the aqueous composition is determined by adjusting the content of the citrate buffer to reflect, if necessary, the effects of the citrate buffer on the pharmaceutical substance (active ingredient), other additives, pH, osmotic pressure, and / or viscosity. However, the concentration of the citrate buffer in the aqueous composition of the present invention is preferably 0.001 to 1.0% (w / v), more preferably 0.005 to 0.5% (w / v), even more preferably 0.01 to 0.1% (w / v), even more preferably 0.01 to 0.05% (w / v), and particularly preferably 0.02 to 0.04% (w / v), where the weight of the citrate buffer represents the weight of the citrate buffering agent used as a raw material.

[0077] In the present invention, the "boric acid buffer" may be derived from (or used as a raw material for) a boric acid buffering agent, and examples of boric acid buffering agents include boric acid or its salts and borax. More specifically, these include boric acid, sodium borate, potassium borate, potassium tetraborate, potassium metaborate, ammonium borate, and borax. The "carbonic acid buffer" may be derived from (or used as a raw material for) a carbonate buffering agent, and examples of carbonate buffering agents include carbonic acid or its salts. More specifically, these include carbonic acid, sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, and magnesium carbonate. The "acetic acid buffer" may be derived from (or used as a raw material for) an acetic acid buffering agent, and examples of acetic acid buffering agents include acetic acid or its salts. More specifically, these include acetic acid, ammonium acetate, potassium acetate, calcium acetate, and sodium acetate. "Tartarate buffering agents" may be derived from (or made from) tartarate buffering agents, and examples of tartarate buffering agents include tartaric acid or its salts. More specifically, sodium tartrate, potassium tartrate, etc. "Aspartate buffering agents" may be derived from (or made from) aspartate buffering agents, and examples of aspartate buffering agents include aspartic acid or its salts. More specifically, sodium aspartate, magnesium aspartate, etc. "Glutamate buffering agents" may be derived from (or made from) glutamate buffering agents, and examples of glutamate buffering agents include glutamic acid or its salts. More specifically, sodium glutamate, potassium glutamate, etc.

[0078] The aqueous composition of the present invention may contain the first buffering agent as the sole buffering agent, or it may contain the first buffering agent and the second buffering agent as the sole buffering agent. Furthermore, the aqueous composition of the present invention may contain another buffering agent in addition to the first buffering agent and the second buffering agent.

[0079] In the present invention, the term "first buffering agent" refers to at least one selected from the group consisting of phosphate buffering agents, aminocarboxylic acid buffering agents, carbonate buffering agents, acetate buffering agents, tartaric acid buffering agents, boric acid buffering agents, and trometamol. The definition and preferred concentration range of each buffering agent are as described in the preceding section on "buffering agents."

[0080] In this invention, the "second buffering agent" is a citrate buffering agent. The definition of the citrate buffering agent and its preferred concentration range are as described in the "buffering agent" section above.

[0081] The viscosity of the aqueous composition of the present invention is preferably adjusted to be in the range of 3 to 500 mPa·s, more preferably in the range of 6 to 70 mPa·s, and measured using an E-type viscometer (25°C; 50s). -1 It is measured by shear rate.

[0082] The aqueous composition of the present invention may further contain an isotonic agent. The isotonic agent used in the present invention may be any pharmaceutically acceptable isotonic agent. Examples of such isotonic agents, though not particularly limited, include nonionic isotonic agents such as glycerin, mannitol, propylene glycol, polyethylene glycol, glucose, sorbitol, xylitol, and trehalose. In the present invention, nonionic isotonic agents are preferred as isotonic agents. Preferred nonionic isotonic agents include glycerin, mannitol, propylene glycol, polyethylene glycol, glucose, sorbitol, xylitol, and trehalose, with glycerin and mannitol being more preferred, and glycerin being particularly preferred.

[0083] The isotonic agents used in the present invention may be used individually or in combination of two or more.

[0084] In the present invention, the concentration of the isotonic agent in the aqueous composition is determined by adjusting the content of the isotonic agent to reflect, if necessary, the effects of the isotonic agent on the pharmaceutical substance (active ingredient), other additives, pH, osmotic pressure, and / or viscosity. However, the concentration of the isotonic agent in the aqueous composition of the present invention 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).

[0085] In the present invention, when the isotonic agent is glycerin, the concentration of glycerin is preferably 0.1 to 5.0% (w / v), more preferably 0.1 to 3.0% (w / v), even more preferably 0.5 to 3.0% (w / v), and particularly preferably 1.0 to 3.0% (w / v).

[0086] The aqueous composition of the present invention may optionally contain pharmaceutically acceptable additives. These additives can be mixed with other components of the aqueous composition of the present invention using widely practiced techniques. The additives may optionally include, for example, surfactants such as polyoxyethylene sorbitan monooleate, polyoxyl 40 stearate, and polyoxyethylene hydrogenated castor oil; stabilizers such as disodium edetate; preservatives such as benzalkonium chloride and boric acid; and pH adjusters such as hydrochloric acid and sodium hydroxide.

[0087] Generally, benzalkonium chloride is used as a preservative. In the present invention, as will be described later, it has been suggested that an atropine-containing aqueous composition that does not contain benzalkonium chloride has a lower mydriatic effect than an atropine-containing aqueous composition that contains benzalkonium chloride. Therefore, it is preferable that the aqueous composition of the present invention does not contain benzalkonium chloride or contains a limited amount of benzalkonium chloride. Here, "limited amount" means the amount of benzalkonium chloride that does not worsen the mydriatic effect of the atropine-containing aqueous composition of the present invention. Specifically, the concentration of benzalkonium chloride is preferably less than 100 ppm, more preferably less than 50 ppm, and even more preferably substantially free of benzalkonium chloride.

[0088] In this invention, the term "unit-dose container" refers to an eye drop container in which a cap is fused and sealed at 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 before use. The unit-dose container may contain an aqueous composition for single use, or it may contain an aqueous composition for several uses, intended for use throughout the day.

[0089] In this invention, the term "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. This multi-dose container typically contains multiple doses of eye drops for use over a certain period of time.

[0090] The aqueous composition of the present invention can be contained in a unit-dose container or a multi-dose container. If the aqueous composition of the present invention substantially does not contain preservatives such as benzalkonium chloride, it is preferable to contain it in a unit-dose container.

[0091] The pH of the aqueous composition of the present invention is not limited to a specific value, but is within a pharmaceutically acceptable range. However, the pH of the aqueous composition of the present invention is preferably in the range of 6 or less, more preferably 4 to 6, even more preferably 4 to 5, and particularly preferably in the vicinity of 4 or 5. More specifically, for example, pH values ​​of 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, and 6.0 are preferred, and pH values ​​of 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, and 5.4 are more preferred.

[0092] Furthermore, 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. The osmotic pressure of the aqueous composition of the present invention is, for example, 100 to 1000 mOsm, preferably 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 may affect the osmotic pressure. It should be noted that the osmotic pressure of the aqueous composition of the present invention can be 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 15th edition of the Japanese Pharmacopoeia.

[0093] Examples of formulations of the aqueous composition of the present invention include eye drops or aqueous eye solutions.

[0094] The dosage and administration of the aqueous composition administered in this 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.

[0095] The aqueous composition of the present invention is preferably used to inhibit or prevent the progression of myopia, to prevent myopia, and / or to treat myopia, and more preferably to inhibit or prevent the progression of myopia in school-aged children.

[0096] As used in this invention, the term "suppression or prevention of myopia progression" may mean slowing down or reducing the progression of myopia. As used in this invention, the term "prevention of myopia" may mean preventing the onset of myopia or delaying the onset of myopia. [Examples]

[0097] The following test results and formulation examples are provided for a better understanding of the present invention, but the scope of the invention should not be limited thereto.

[0098] The meanings of the abbreviations are as follows: BAK: Benzalkonium chloride CVP: Carboxyvinyl polymer HEC: Hydroxyethylcellulose HPMC: Hydroxypropylmethylcellulose

[0099] Test 1 Several aqueous compositions were evaluated for their mydriatic effect.

[0100] (Sample preparation method) (Example 1) The aqueous composition of Example 1 was prepared according to the formulation shown in Table 1. Specifically, 0.01 g of atropine sulfate hydrate, 0.32 g of hydroxyethylcellulose, 0.1 g of sodium dihydrogen phosphate, and 2.4 g of concentrated glycerin were dissolved in purified water. Hydrochloric acid and sodium hydroxide were added to the resulting solution as needed to adjust the pH to 5, and the total volume was made 100 ml.

[0101] (Examples 2-3 and Comparative Examples 1-3) The aqueous compositions of Examples 2-3 and Comparative Examples 1-3 were prepared according to the formulations shown in Table 1, in the same manner as in Example 1. TIFF2026139734000002.tif73169

[0102] (Test Method) A single dose (volume of 50 µl) of each aqueous composition was instilled into one eye of a rabbit (4 eyes from 4 rabbits or 6 eyes from 6 rabbits for each aqueous composition). Images of rabbit pupils before instillation and 1 hour after instillation were captured by optical coherence tomography (OCT), then analyzed with image analysis software, and the pupil area and mydriasis rate of rabbits were calculated. The mydriasis rate was calculated by the following formula. Mydriasis rate (%) = ((b - a) / a) × 100 In the formula, a is the average value of pupil area (mm 2 ) before instillation in each test of Comparative Examples 1 to 3 and Examples 1 to 3, a is 16.8 (mm 2 ), and b is the pupil area value 1 hour after instillation.

[0103] (Test Results) The results of Examples 1 to 3 and Comparative Examples 1 to 3 are shown in Table 2. Each value in Table 2 is an average value of data obtained from the results of 4 or 6 eyes. The mydriatic effect of the present aqueous composition was determined according to the following evaluation criteria. A: The pupil area value 1 hour after instillation is 30.0 mm 2 less than B: The pupil area value 1 hour after instillation is 30.0 mm 2 or more and less than 35.0 mm 2 less than C: The pupil area value 1 hour after instillation is 35.0 mm 2 or more and less than 40.0 mm 2 less than D: The pupil area value 1 hour after instillation is 40.0 mm 2 or more TIFF2026139734000003.tif46139

[0104] (Discussion) As is clear from Table 2, aqueous compositions containing (i) atropine or a salt thereof, (ii) a pH of 6 or less, and (iii) a phosphate buffering agent induced less pupillary dilation than compositions without a phosphate buffering agent.

[0105] Test 2 Several aqueous compositions of the present invention were evaluated for their mydriatic effect.

[0106] (Sample preparation method) (Examples 4-11) The aqueous compositions of Examples 4 to 11 were prepared according to the formulations shown in Table 3, in the same manner as in Example 1.

[0107] (Test method) A single dose (50 μl) of each aqueous composition was instilled into the monocular eye of a rabbit (four eyes of four rabbits or six eyes of six rabbits for each aqueous composition). One hour after instillation, images of the rabbits' pupils were captured using optical coherence tomography (OCT), and then analyzed using image analysis software to calculate the pupil area of ​​each rabbit.

[0108] (Test results) The results for Examples 4-11 are shown in Table 3. Each value in Table 3 is the average value of data obtained from four or six eyes. The pupil-dilating effect of this aqueous composition was evaluated according to the following criteria. A: The pupil area value one hour after instillation was 30.0 mm. 2 less than B: The pupil area value one hour after instillation was 30.0 mm. 2 35.0mm 2 less than C: Pupil area value 35.0 mm after 1 hour of eye drop application. 2 40.0 mm 2 less than D: Pupil area value 40.0 mm² 1 hour after instillation. 2 That's all. TIFF2026139734000004.tif84166

[0109] (Consideration) When the aqueous composition contained a phosphate buffer as the first buffer, the pupillary dilation effect was low (Example 4). Furthermore, when the aqueous composition contained a citrate buffer as a second buffer in addition to the phosphate buffer, the pupillary dilation effect was even lower (Examples 6-8).

[0110] Test 3 Several aqueous compositions of the present invention were evaluated for their mydriatic effect.

[0111] (Sample preparation method) (Examples 12-14) The aqueous compositions of Examples 12-14 were prepared according to the formulations shown in Table 4, in the same manner as in Example 1.

[0112] (Test method) A single dose (50 μl) of each aqueous composition was instilled into the monocular eye of a rabbit (four eyes of four rabbits, one for each aqueous composition). One hour after instillation, images of the rabbits' pupils were captured using optical coherence tomography (OCT), and then analyzed using image analysis software to calculate the pupil area of ​​each rabbit.

[0113] (Test results) The results for Examples 12-14 are shown in Table 4. Each value in Table 4 is the average value of the data obtained from the results of the four eyes. The pupil-dilating effect of this aqueous composition was evaluated according to the following criteria. A: The pupil area value one hour after instillation was 30.0 mm. 2 less than B: The pupil area value one hour after instillation was 30.0 mm. 2 35.0mm 2 less than C: Pupil area value 35.0 mm after 1 hour of eye drop application. 2 40.0 mm 2 less than D: Pupil area value 40.0 mm² 1 hour after instillation. 2 That's all. TIFF2026139734000005.tif67131

[0114] (Consideration) Even when the aqueous composition contained 0.005% (w / v) atropine, the mydriatic effect was low when the aqueous composition contained a phosphate buffer as the first buffer (Example 12). Furthermore, when the aqueous composition contained a citrate buffer as a second buffer in addition to the phosphate buffer, the mydriatic effect was even lower (Examples 13 and 14).

[0115] Test 4 The effect of the aqueous composition of the present invention on the pupil-dilating effect of benzalkonium chloride, which is commonly used as a preservative, was investigated.

[0116] (Sample preparation method) (Examples 15-17) The aqueous compositions of Examples 15-17 were prepared according to the formulations shown in Table 5, in the same manner as in Example 1.

[0117] (Test method) A single dose (50 μl) of each aqueous composition was instilled into the monocular eye of a rabbit (four eyes of four rabbits, one for each aqueous composition). One hour after instillation, images of the rabbits' pupils were captured using optical coherence tomography (OCT), and then analyzed using image analysis software to calculate the pupil area of ​​each rabbit.

[0118] (Test results) The results for Examples 15-17 are shown in Table 5. Each value in Table 5 is the average value of the data obtained from the results of the four eyes. The pupil-dilating effect of this aqueous composition was evaluated according to the following criteria. A: The pupil area value one hour after instillation was 30.0 mm. 2 less than B: The pupil area value one hour after instillation was 30.0 mm. 2 35.0mm 2 less than C: Pupil area value 35.0 mm after 1 hour of eye drop application. 2 40.0 mm 2 less than D: Pupil area value 40.0 mm² 1 hour after instillation. 2 45.0mm 2 less than E: Pupil area value 45.0 mm after 1 hour of eye drop application. 2 That's all. TIFF2026139734000006.tif62134

[0119] (Consideration) As is clear from Table 5, the aqueous composition without benzalkonium chloride (Example 15) showed a lower mydriatic effect than the aqueous compositions containing benzalkonium chloride (Examples 16 and 17).

[0120] Test 5 (Viscosity measurement test 1 and stability test 1) In aqueous compositions containing atropine and a water-soluble polymer, the effects of isotonic agents on the viscosity of the aqueous composition and the stability of atropine were investigated.

[0121] (Sample preparation method) (Examples 18-22) The aqueous compositions of Examples 18-22 were prepared in the same manner as in Example 1, according to the formulations shown in Table 6. The prepared samples were filled into polyethylene eye drop containers in 5 mL portions, sealed with inner stoppers and caps, and stored in the dark at 60°C for 4 weeks. TIFF2026139734000007.tif62161

[0122] (Test method) (1) Viscosity measurement test 1 In accordance with the "Method 2: Rotational Viscometer Method" of the 16th Revised Japanese Pharmacopoeia, the viscosity of each aqueous composition was measured immediately after preparation and at 1, 2, and 4 weeks after preparation using a cone-plate type rotational viscometer. The measurement conditions are as follows. • Measuring instrument: Rotary rheometer (Kinexus pro+) • Rotation speed (S -1 ): 50 / sec ·Measurement temperature: 25℃

[0123] (2) Stability Test 1 Atropine decomposes to produce tropic acid. In this study, to evaluate the stability of atropine, the tropic acid content was quantified using high-performance liquid chromatography immediately after preparation and at 1, 2, and 4 weeks after preparation.

[0124] (Test results) The results of viscosity measurement test 1 are shown in Figure 1. The results of stability test 1 are shown in Figure 2.

[0125] (Consideration) (1) Viscosity measurement test 1 As shown in Figure 1, aqueous compositions containing atropine and hydroxyethylcellulose but without an isotonic agent (Example 18, labeled "without" in Figure 1), aqueous compositions containing sodium chloride as an isotonic agent (Example 19, labeled "NaCl" in Figure 1), and aqueous compositions containing boric acid as an isotonic agent (Example 20, labeled "boric acid" in Figure 1) all showed a decrease in viscosity over time. On the other hand, aqueous compositions containing atropine and hydroxyethylcellulose and glycerin as an isotonic agent (Example 21, labeled "glycerin" in Figure 1), and aqueous compositions containing mannitol as an isotonic agent (Example 22, labeled "mannitol" in Figure 1) maintained their viscosity and suppressed a decrease in viscosity over time.

[0126] (2) Stability Test 1 As shown in Figure 2, aqueous compositions containing atropine and hydroxyethylcellulose, and containing mannitol or boric acid as an isotonic agent, produced more tropic acid compared to other aqueous compositions. Therefore, it was shown that the addition of mannitol or boric acid as an isotonic agent is undesirable in aqueous compositions containing atropine and hydroxyethylcellulose from the viewpoint of atropine stability. Furthermore, the results of the viscosity measurement test 1 and stability test 1 above indicate that, in an aqueous composition containing atropine and hydroxyethylcellulose, it is preferable to add glycerin as an isotonic agent in order to suppress the decrease in viscosity over time and maintain the stability of atropine.

[0127] Test 6 (Viscosity measurement test 2) The effect of an isotonic agent on the viscosity of an aqueous composition containing atropine and a water-soluble polymer was investigated.

[0128] (Sample preparation method) (Examples 23-28) The aqueous compositions of Examples 23-28 were prepared in the same manner as in Example 1, according to the formulations shown in Table 7. The prepared samples were filled into polyethylene eye drop containers in 5 mL portions, fitted with inner stoppers, sealed with caps, and stored in a light-shielded place at 60°C for 4 weeks. TIFF2026139734000008.tif57151

[0129] (Test method) (Viscosity measurement test 2) In accordance with the "Method 2: Rotational Viscometer Method" of the 16th Revised Japanese Pharmacopoeia, the viscosity of each aqueous composition was measured immediately after preparation and at 1, 2, and 4 weeks after preparation using a cone-plate type rotational viscometer. The measurement conditions are as follows. • Measuring instrument: Rotary rheometer (Kinexus pro+) • Rotation speed (S -1 ): 50 / sec ·Measurement temperature: 25℃

[0130] (Test results) The results of viscosity measurement tests in Examples 23-25 ​​are shown in Figure 3. The results of viscosity measurement tests in Examples 26-28 are shown in Figure 4.

[0131] (Consideration) (Viscosity measurement test 2) As shown in Figure 3, the aqueous composition containing atropine and hydroxypropyl methylcellulose but without an isotonic agent (Example 23, labeled "without" in Figure 3) showed a decrease in viscosity over time. On the other hand, the aqueous compositions containing glycerin or mannitol as an isotonic agent (Examples 24 and 25, labeled "glycerin" or "mannitol" in Figure 3) maintained their viscosity and suppressed the decrease in viscosity over time. Furthermore, as shown in Figure 4, the aqueous composition containing atropine and carboxyvinyl polymer but without an isotonic agent (Example 26, labeled "without" in Figure 4) showed a decrease in viscosity over time. On the other hand, the aqueous compositions containing glycerin or mannitol as an isotonic agent (Examples 27 and 28, labeled "glycerin" or "mannitol" in Figure 4) maintained their viscosity and suppressed the decrease in viscosity over time.

[0132] Test 7 In a mouse myopia model, we investigated the effects of water-soluble polymers on atropine's ability to inhibit axial length elongation and improve refractive errors.

[0133] (Sample preparation method) (Examples A-D) The aqueous compositions of Examples A to D were prepared according to the formulations shown in Table 8, in the same manner as in Example 1. TIFF2026139734000009.tif46149

[0134] (Test method) Experimental Myopia Mouse Model: A myopia model induced by spectacle lenses was created by attaching a -10D lens to the right eye of a mouse (C57BL / 6J), and used as the experimental eye at 24 days postnatal. The -10D lens (blue PMMA spectacle lens, lateral curvature radius 8.5 mm, medial curvature radius 8 mm, lens thickness 0.5 mm) was temporarily attached to a loop of Velcro (with an 8 mm base curve). One of these pieces was then attached to Velcro (registered trademark) that had been attached to the fur around the experimental right eye using cyanoacrylate. Throughout this setup, a 1.5 mm gap was confirmed to exist between the posterior part of the lens and the anterior part of the cornea.

[0135] Ocular biometry: Ocular biometry, such as axial length and refractive error measurement, was performed using an in vivo optical low coherence interferometry (OLCI-AcMaster) and an automated eccentric photorefractor, respectively. Axial length was measured at 38 and 66 days postnatally, while refractive error was measured at 52 and 66 days postnatally. Drug administration: Atropine sulfate (at a concentration of 0.01%) was administered once daily from day 39 to day 66 of life to a spectacle-lens-induced myopia model, with or without hydroxyethylcellulose. 7 μL of each drug was administered topically to the right eye under a dark red light each day.

[0136] (Test results) (1) Suppressive effect on axial lengthening The results for Examples B to D are shown in Table 9. The ratio of suppression of axial length elongation by each example sample was calculated using the following formula. Difference in axial length (mm) = [Axial length on day 66] - [Axial length on day 38] Suppression rate of axial length elongation by sample of Example B (%) = TIFF2026139734000010.tif13151 Suppression rate of axial length elongation by sample of Example C (%) = TIFF2026139734000011.tif13151 Suppression rate of axial length elongation by sample of Example D (%) = TIFF2026139734000012.tif13151 TIFF2026139734000013.tif2984

[0137] (2) Improvement of refractive errors The results for Examples A to D are shown in Table 10. Change in refractive error (diopters) = [Refractive index (diopters) on day 66] - [Refractive index (diopters) on day 52] TIFF2026139734000014.tif3586

[0138] (Consideration) An aqueous composition containing a water-soluble polymer but without atropine (Example B) did not exhibit any effect in inhibiting axial length elongation. On the other hand, it was found that adding a water-soluble polymer to an aqueous composition containing atropine (Example D) resulted in a stronger effect in inhibiting axial length elongation than an aqueous composition containing atropine but without a water-soluble polymer (Example C). Furthermore, similar to the axial length elongation inhibitory effect described above, it was found that adding a water-soluble polymer to an aqueous composition containing atropine (Example D) resulted in a stronger refractive error improvement effect than an aqueous composition containing atropine but without a water-soluble polymer (Example C). As is clear from the results of Examples 1 and 3 in Tables 1 and 2, the addition of water-soluble polymers does not affect the mydriatic effect of atropine. Therefore, aqueous compositions containing atropine and water-soluble polymers are expected to be myopia progression inhibitors with minimal mydriatic effect.

[0139] Examples of formulations The present invention will be described in more detail with reference to examples of formulations, but the present invention is not limited to these examples.

[0140] Formulation example 1: Eye drops (0.01% (w / v)) Add the atropine sulfate hydrate and other components listed above to sterile purified water. Mix these components well to prepare the eye drops described above.

[0141] Formulation example 2: Eye drops (0.004% (w / v)) Add the atropine sulfate hydrate and other components listed above to sterile purified water. Mix these components well to prepare the eye drops described above. [Industrial applicability]

[0142] An aqueous composition containing atropine or a salt thereof at a concentration of 0.001-0.1% (w / v), a water-soluble polymer, and a first buffer, with a pH in the range of 6 or less, wherein the first buffer is at least one selected from the group consisting of phosphate buffers, aminocarboxylic acid buffers, carbonate buffers, acetate buffers, tartaric acid buffers, boric acid buffers, and trometamol, was shown to have excellent inhibitory effects on axial length elongation and improvement of refractive errors without exacerbating the mydriatic effect of atropine. It was also shown that by not containing benzalkonium chloride, or by containing a limited amount of benzalkonium chloride, a low mydriatic effect was achieved. Furthermore, it was shown that by including a nonionic isotonic agent in an aqueous composition containing atropine or a salt thereof and a water-soluble polymer, with a pH in the range of 6 or less, the decrease in viscosity of the aqueous composition imparted by the water-soluble polymer over time can be suppressed, and the stability of atropine or its salt can be maintained. This aqueous composition is expected to be optimal in terms of quality of life by suppressing or preventing the progression of myopia, reducing pupillary dilation, and minimizing the reduction in accommodation.

Claims

1. An aqueous composition comprising atropine or a salt thereof in a concentration of 0.001 to 0.1% (w / v), a water-soluble polymer, and a first buffer, wherein the pH is in the range of 6 or less, and the first buffer is at least one selected from the group consisting of phosphate buffer, aminocarboxylic acid buffer, carbonate buffer, acetate buffer, tartaric acid buffer, boric acid buffer, and trometamol.

2. The aqueous composition according to claim 1, wherein the first buffer is at least one selected from the group consisting of phosphate buffers, aminocarboxylic acid buffers, carbonate buffers, and acetate buffers.

3. The aqueous composition according to claim 1 or 2, wherein the first buffering agent is a phosphate buffering agent.

4. The aqueous composition according to claim 1 or 2, wherein the aminocarboxylic acid buffer is at least one selected from the group consisting of epsilon-aminocaproic acid, glutamic acid buffer, and aspartic acid buffer.

5. The phosphate buffer is derived from at least one selected from the group consisting of sodium hydrogen phosphate hydrate, sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate, sodium dihydrogen phosphate dihydrate, potassium dihydrogen phosphate, sodium hydrogen phosphate heptahydrate, trisodium phosphate, and dipotassium phosphate. The carbonate buffer is derived from at least one selected from the group consisting of carbonic acid, sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, and magnesium carbonate. The acetate buffer is derived from at least one selected from the group consisting of acetic acid, ammonium acetate, potassium acetate, calcium acetate, and sodium acetate. The tartaric acid buffer is derived from at least one selected from the group consisting of sodium tartrate and potassium tartrate. The borate buffer is derived from at least one selected from the group consisting of boric acid, sodium borate, potassium borate, potassium tetraborate, potassium metaborate, ammonium borate, and borax. The glutamate buffer is derived from at least one selected from the group consisting of glutamic acid, sodium glutamate, and potassium glutamate, and / or The aspartate buffer is derived from at least one selected from the group consisting of aspartic acid, sodium aspartate, and magnesium aspartate. The aqueous composition according to any one of claims 1 to 4.

6. Furthermore, the aqueous composition according to any one of claims 1 to 5, further comprising a citric acid buffer as a second buffer.

7. The aqueous composition according to claim 6, wherein the citrate buffer is derived from at least one selected from the group consisting of citric acid hydrate, sodium citrate, sodium citrate hydrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, and disodium citrate.

8. The aqueous composition according to any one of claims 1 to 7, wherein the water-soluble polymer is at least one selected from the group consisting of cellulose derivatives, carboxyvinyl polymers, and sodium alginate.

9. The aqueous composition according to claim 8, wherein the cellulose derivative is at least one selected from the group consisting of hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hypromellose acetate succinate, hypromellose phthalate, carboxymethylethylcellulose, and cellulose acetate phthalate.

10. The aqueous composition according to claim 8 or 9, wherein the cellulose derivative is at least one selected from the group consisting of hydroxyethylcellulose and hydroxypropylmethylcellulose.

11. The aqueous composition according to any one of claims 8 to 10, wherein the cellulose derivative is hydroxyethylcellulose.

12. An aqueous composition containing atropine or a salt thereof in a concentration of 0.001 to 0.1% (w / v), hydroxyethylcellulose, and a first buffer, wherein the pH is in the range of 6 or less, and the first buffer is a phosphate buffer.

13. Furthermore, the aqueous composition according to claim 12 further contains a citric acid buffer as a second buffer.

14. The aqueous composition according to any one of claims 1 to 13, comprising benzalkonium chloride at a concentration of less than 50 ppm.

15. The aqueous composition according to any one of claims 1 to 14, which is substantially free of benzalkonium chloride.

16. Furthermore, the aqueous composition according to any one of claims 1 to 15, further containing a nonionic isotonic agent.

17. The aqueous composition according to claim 16, wherein the nonionic isotonic agent is at least one selected from the group consisting of glycerin, mannitol, propylene glycol, polyethylene glycol, glucose, sorbitol, xylitol, and trehalose.

18. The aqueous composition according to claim 16 or 17, wherein the nonionic isotonic agent is at least one selected from the group consisting of glycerin and mannitol.

19. The aqueous composition according to any one of claims 16 to 18, wherein the nonionic isotonic agent is glycerin.

20. The aqueous composition according to any one of claims 1 to 19, wherein the concentration of the buffering agent is 0.001 to 10% (w / v).

21. The aqueous composition according to any one of claims 6 to 11 and 13 to 20, wherein the concentration of the citrate buffer is 0.001 to 1.0% (w / v).

22. The aqueous composition according to claim 21, wherein the concentration of the citrate buffer is 0.01 to 0.05% (w / v).

23. The aqueous composition according to any one of claims 1 to 22, wherein the concentration of the water-soluble polymer is 0.01 to 5% (w / v).

24. The aqueous composition according to any one of claims 16 to 23, wherein the concentration of the nonionic isotonic agent is 0.01 to 10% (w / v).

25. An aqueous composition containing atropine or a salt thereof in a concentration of 0.001 to 0.1% (w / v), a water-soluble polymer, and a buffer, with a pH of 5 or less.

26. The aqueous composition according to claim 25, wherein the buffering agent is at least one selected from the group consisting of phosphate buffering agents, citrate buffering agents, aminocarboxylic acid buffering agents, carbonate buffering agents, acetate buffering agents, tartaric acid buffering agents, borate buffering agents, and trometamol.

27. The aqueous composition according to claim 25 or 26, wherein the buffering agent is a citric acid buffering agent.

28. An aqueous composition containing atropine or a salt thereof at a concentration of 0.001 to 0.1% (w / v), and a phosphate buffer, with a pH of 6 or less.

29. The aqueous composition according to claim 28, further containing a water-soluble polymer.

30. The aqueous composition according to claim 29, wherein the water-soluble polymer is at least one selected from the group consisting of hydroxyethylcellulose, carboxyvinyl polymer, hydroxypropyl methylcellulose, and sodium alginate.

31. The aqueous composition according to claim 29 or 30, wherein the water-soluble polymer is hydroxyethylcellulose.

32. An aqueous composition according to any one of claims 1 to 24 and 28 to 31, wherein the pH is in the range of 4 to 6.

33. The aqueous composition according to any one of claims 1 to 32, wherein the concentration of the phosphate buffer is 0.01 to 1.0% (w / v).

34. The aqueous composition according to any one of claims 1 to 33, wherein the concentration of atropine or a salt thereof is 0.001 to 0.025% (w / v).

35. The aqueous composition according to any one of claims 1 to 34, wherein the concentration of atropine or a salt thereof is 0.001 to 0.01% (w / v).

36. The aqueous composition according to any one of claims 1 to 35, wherein atropine or a salt thereof is atropine sulfate or a hydrate thereof.

37. An aqueous composition according to any one of claims 1 to 36, contained in a unit dose type container.

38. The aqueous composition according to any one of claims 1 to 37, wherein the aqueous composition is an eye drop.

39. An aqueous composition according to any one of claims 1 to 38 for suppressing and / or preventing the progression of myopia.

40. Use of the aqueous composition according to any one of claims 1 to 38 in the manufacture of a drug for inhibiting and / or preventing the progression of myopia.

41. A method for inhibiting and / or preventing the progression of myopia, comprising administering to a patient an aqueous composition according to any one of claims 1 to 38.

42. An aqueous composition according to any one of claims 1 to 38, for use in inhibiting and / or preventing the progression of myopia.

43. A method for suppressing viscosity reduction of an aqueous composition by adding a nonionic isotonic agent to an aqueous composition containing atropine or a salt thereof at a concentration of 0.001 to 0.1% (w / v) and a water-soluble polymer, and having a pH in the range of 6 or less.

44. A method for stabilizing atropine or a salt thereof by adding a nonionic isotonic agent to an aqueous composition containing atropine or a salt thereof at a concentration of 0.001 to 0.1% (w / v) and a water-soluble polymer, and having a pH in the range of 6 or less.

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