Atropine-containing aqueous composition

Abstract

To provide an aqueous composition comprising atropine which has a potent action for inhibiting the elongation of eye axial length and improving the refractive error; further to provide an aqueous composition comprising atropine which induces a lesser degree of mydriasis and a lesser loss of accommodation; and also to provide an aqueous composition comprising atropine whose viscosity does not decrease with time and wherein atropine or a salt thereof is stable.SOLUTION: Disclosed herein is an aqueous composition comprising atropine or a salt thereof in a concentration range of 0.001-0.1%(w / v), a water-soluble polymer, and a first buffer, which is at a pH range of 6 or lower, wherein the first buffer is at least one selected from a group consisting of a phosphate buffer, an aminocarboxylate buffer, a carbonate buffer, an acetate buffer, a tartrate buffer, a borate buffer, and trometamol.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention mainly relates to an aqueous composition containing atropine or a salt thereof (hereinafter, also simply referred to as "atropine").

Background Art

[0002] Myopia is a type of refractive error, referring to a state where light entering the eye from afar forms an image in front of the retina instead of on the retina, and objects appear blurred. It is known that myopia is caused by an eye axial length (the length from the cornea to the retina) that is longer than normal (axial myopia), or a refractive power of the cornea or lens that is too strong (refractive myopia).

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

[0004] On the other hand, atropine eye drops are used as a mydriatic, and the ability to accommodate for near and far vision also decreases. When atropine eye drops are instilled, the pupillary sphincter of the iris relaxes, causing mydriasis, which is the cause of glare, and persists while the effect of the atropine eye drops is maintained. The ability to accommodate for near and far vision of the lens also decreases, resulting in a decrease in near vision. This can also be an obstacle to daily activities. Therefore, there has been a strong desire for a medicine for suppressing or preventing the progression of myopia that has a lower mydriatic effect, induces a lower decrease in the ability to accommodate for near and far vision, and improves the quality of life (QOL).

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0006] An object of the present invention is to find an atropine-containing aqueous composition having an excellent effect of suppressing axial length elongation and an effect of improving refractive errors. An important goal is to find an atropine-containing aqueous composition that induces a lower decrease in near and far accommodation with a lower mydriatic 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 atropine or its salt is stable. Means for Solving the Problems

[0007] As a result of intensive studies to solve the above problems, the present inventors surprisingly found that an aqueous composition containing atropine or its salt at a concentration of 0.001 to 0.1% (w / v), a water-soluble polymer, and a first buffering agent, and having a pH in the range of 6 or less, wherein the first buffering agent is at least one selected from the group consisting of phosphate buffer, aminocarboxylic acid buffer, carbonate buffer, acetate buffer, tartrate buffer, borate buffer, and tromethamine, has an excellent effect of suppressing axial length elongation and an effect of improving refractive errors without worsening the mydriatic effect of atropine. The present inventors also found that by not containing benzalkonium chloride or containing a limited amount of benzalkonium chloride, a low mydriatic effect is exhibited. Furthermore, the present inventors found that in an aqueous composition containing atropine or its salt and a water-soluble polymer and having a pH in the range of 6 or less, by containing a nonionic isotonic agent, a decrease in the viscosity of the aqueous composition imparted by the water-soluble polymer over time can be suppressed, and furthermore, the stability of atropine or its salt can be maintained. The aqueous composition of the present invention is expected to be optimal for the quality of life by suppressing or preventing the progression of myopia, reducing the mydriatic effect, and reducing the decrease in near and far accommodation.

[0008] That is, the present invention relates to the following.

[0009] (Item 1) 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 first buffer, and having a pH in the range of 6 or less, wherein the first buffer is at least one selected from the group consisting of a phosphate buffer, an aminocarboxylic acid buffer, a carbonate buffer, an acetate buffer, a tartrate buffer, a borate buffer, and tromethamine.

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

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

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

[0013] (Item 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 hydrogen carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, 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 tartrate buffer 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) Furthermore, the aqueous composition according to any one of items 1 to 5, which contains a citric acid buffer as a second buffer.

[0015] (Item 7) The citric acid buffer of the aqueous composition according to item 6 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 water-soluble polymer of the aqueous composition according to any one of items 1 to 7 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 item 8, wherein the cellulose derivative is at least one selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hypromellose acetate succinate, hypromellose phthalate, carboxymethyl ethyl cellulose, and cellulose acetate phthalate.

[0018] (Item 10) The aqueous composition according to item 8 or 9, wherein the cellulose derivative is at least one selected from the group consisting of hydroxyethyl cellulose and hydroxypropyl methyl cellulose.

[0019] (Item 11) The aqueous composition according to any one of items 8 to 10, wherein the cellulose derivative is hydroxyethyl cellulose.

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

[0021] (Item 13) The aqueous composition according to item 12, further containing a citrate buffer as a second buffer.

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

[0023] (Item 15) The aqueous composition according to any one of items 1 to 14, substantially free of benzalkonium chloride.

[0024] (Item 16) Furthermore, the aqueous composition according to any one of items 1 to 15, which contains a nonionic isotonic agent.

[0025] (Item 17) The aqueous composition according to item 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] (Item 18) The aqueous composition according to item 16 or 17, wherein the nonionic isotonic agent is at least one selected from the group consisting of glycerin and mannitol.

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

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

[0029] (Item 21) The 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] (Item 22) The aqueous composition according to item 21, wherein the concentration of the citrate buffer is 0.01 to 0.05% (w / v).

[0031] (Item 23) The 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] (Item 24) The aqueous composition according to any one of items 16 to 23, wherein the concentration of the nonionic isotonic agent is 0.01 to 10% (w / v).

[0033] (Item 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 buffer, and having a pH in the range of 5 or less.

[0034] (Item 26) The aqueous composition according to Item 25, wherein the buffer is at least one selected from the group consisting of a phosphate buffer, a citrate buffer, an aminocarboxylic acid buffer, a carbonate buffer, an acetate buffer, a tartrate buffer, a borate buffer, and tromethamine.

[0035] (Item 27) The aqueous composition according to Item 25 or 26, wherein the buffer is a citrate buffer.

[0036] (Item 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, and having a pH in the range of 6 or less.

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

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

[0039] (Item 31) The aqueous composition according to Item 29 or 30, wherein the water-soluble polymer is hydroxyethyl cellulose.

[0040] (Item 32) The aqueous composition according to any one of Items 1 to 24 and 28 to 31, having a pH in the range of 4 to 6.

[0041] (Item 33) The 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] (Item 34) The 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] (Item 35) The 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] (Item 36) The aqueous composition according to any one of items 1 to 35, wherein atropine or a salt thereof is atropine sulfate or a hydrate thereof.

[0045] (Item 37) The aqueous composition according to any one of items 1 to 36, which is contained in a unit dose type container.

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

[0047] (Item 39) The aqueous composition according to any one of items 1 to 38, which is for suppressing and / or preventing the progression of myopia.

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

[0049] (Item 41) A method for suppressing and / or preventing the progression of myopia, which comprises administering the aqueous composition according to any one of items 1 to 38 to a patient.

[0050] (Item 42) An aqueous composition according to any one of claims 1 to 38 for use in suppressing and / or preventing the progression of myopia.

[0051] (Claim 43) A method for suppressing the 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] (Claim 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. [Effect of the Invention]

[0053] As is clear from the test results described below, 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 first buffer, and having 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, tartrate buffers, borate buffers, and tromethamine, has been shown to have an excellent effect of suppressing the elongation of the eye axis and an effect of improving refractive errors without worsening the mydriatic action of atropine. Further, it has also been shown that by not containing benzalkonium chloride or containing a limited amount of benzalkonium chloride, it has a low mydriatic action. Furthermore, in an aqueous composition containing atropine or a salt thereof and a water-soluble polymer and having a pH in the range of 6 or less, by containing a nonionic isotonic agent, a decrease in the viscosity of the aqueous composition imparted by the water-soluble polymer over time can be suppressed, and furthermore, the stability of atropine or a salt thereof 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 the mydriatic action, and reducing the decrease in near and far accommodation. A further advantage associated with the compositions of the present invention, such as those containing an isotonic agent, is that the composition can maintain its initial viscosity (or a substantial proportion thereof) over time.

Brief Description of the Drawings

[0054]

Figure 1

Figure 2

Figure 3

Figure 4

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 a salt thereof" includes (i) a hydrate of atropine or a salt thereof, (ii) an organic solvate of atropine or a salt thereof, and (iii) a mixture of a hydrate and an organic solvate.

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

[0058] Atropine sulfate hydrate is a compound represented by the following structural formula. JPEG2025084921000001.jpg45123

[0059] If crystal polymorphs and crystal polymorph groups (crystal polymorph systems) exist in atropine or a salt thereof, those crystal polymorphs and crystal polymorph groups (crystal polymorph systems) are also included in the scope of the present invention. Here, the crystal polymorph group (crystal polymorph system) means not only the individual crystal forms obtained at each stage when the crystal form changes depending on conditions and states such as the production, crystallization, and storage of those crystals, but also a mixture of crystal forms obtained at two or more stages.

[0060] Atropine or a salt thereof can be produced according to ordinary methods in the field of organic synthetic 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 a salt thereof 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 concentration is 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), 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), 0.0090% (w / v), 0.0095% (w / v), or 0.010% (w / v).

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

[0063] In the present invention, the "water-soluble polymer" can be any pharmaceutically acceptable polymer that is soluble in water. Without particular limitation, examples of such polymers include celluloses and their derivatives (e.g., methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, cellulose acetate phthalate, ethylcellulose, hydroxymethylcellulose, hydroxyethylmethylcellulose, 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 ones used as the water-soluble polymer in the present invention are cellulose and its derivatives, carboxyvinyl polymer, and sodium alginate. Among these, more preferred ones used as the water-soluble polymer in the present invention are hydroxyethylcellulose, carboxyvinyl polymer, 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 and, if necessary, reflecting the influence 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), still 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 hydroxyethyl cellulose, the concentration of hydroxyethyl cellulose is preferably 0.1 to 1.0% (w / v), 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), 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), 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 "buffer" is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include phosphate buffers, citrate buffers, borate buffers, carbonate buffers, acetate buffers, tartrate buffers, aminocarboxylic acid buffers, tromethamine, and the like. Examples of aminocarboxylic acid buffers include aspartic acid buffers, glutamic acid buffers, epsilon-aminocaproic acid, and the like. These buffers may be used alone 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 content of the buffer and reflecting the influence of the buffer on the pharmaceutical substance (active ingredient), other additives, pH, osmotic pressure, and / or viscosity as necessary. 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), still more preferably 0.01 to 1% (w / v), particularly preferably 0.01 to 0.5% (w / v), and even more particularly preferably 0.01 to 0.1% (w / v), where the weight of the buffer represents the weight of the buffering agent as the raw material.

[0073] In the present invention, the phosphate buffer can be derived from (can be used as a raw material) any pharmaceutically acceptable phosphate buffering agent. Although not particularly limited, examples of such phosphate buffering agents include phosphoric acid; phosphates such as alkali metal phosphates and alkaline earth metal phosphates; and hydrates thereof. More specifically, sodium hydrogen phosphate hydrate (referred to as "sodium hydrogen phosphate" or "sodium phosphate"), sodium dihydrogen phosphate (referred to as "sodium primary phosphate"), sodium dihydrogen phosphate monohydrate (referred to as "sodium primary phosphate"), sodium dihydrogen phosphate dihydrate (referred to as "sodium primary phosphate"), potassium dihydrogen phosphate (referred to as "potassium primary 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 and reflecting the influence of the phosphate buffer on the pharmaceutical substance (active ingredient), other additives, pH, osmotic pressure, and / or viscosity as necessary. 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 phosphate buffering agent as the raw material.

[0075] In the present invention, the "citrate buffer" can be derived from (can be used as a raw material) a citrate buffering agent that is not particularly limited as long as it is pharmaceutically acceptable. Examples of the citrate buffering agent include citric acid; citrates such as alkali metal citrates and alkaline earth metal citrates; and hydrates thereof. More specifically, citric acid hydrate, sodium citrate, sodium citrate hydrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, disodium citrate, and the like.

[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 and reflecting the influence of the citrate buffer on the pharmaceutical substance (active ingredient), other additives, pH, osmotic pressure, and / or viscosity as necessary. 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), still 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 buffer agent as a raw material.

[0077] In the present invention, the "boric acid buffer" can be derived from (can be used as a raw material for) a boric acid buffering agent. Examples of the boric acid buffering agent include boric acid or its salts, and borax. More specifically, they are boric acid, sodium borate, potassium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, and the like. The "carbonate buffer" can be derived from (can be used as a raw material for) a carbonate buffering agent. Examples of the carbonate buffering agent include carbonic acid or its salts. More specifically, they are carbonic acid, sodium hydrogen carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium hydrogen carbonate, magnesium carbonate, and the like. The "acetic acid buffer" can be derived from (can be used as a raw material for) an acetic acid buffering agent. Examples of the acetic acid buffering agent include acetic acid or its salts. More specifically, they are acetic acid, ammonium acetate, potassium acetate, calcium acetate, sodium acetate, and the like. The "tartaric acid buffer" can be derived from (can be used as a raw material for) a tartaric acid buffering agent. Examples of the tartaric acid buffering agent include tartaric acid or its salts. More specifically, they are sodium tartrate, potassium tartrate, and the like. The "aspartic acid buffer" can be derived from (can be used as a raw material for) an aspartic acid buffering agent. Examples of the aspartic acid buffering agent include aspartic acid or its salts. More specifically, they are sodium aspartate, magnesium aspartate, and the like. The "glutamic acid buffer" can be derived from (can be used as a raw material for) a glutamic acid buffering agent. Examples of the glutamic acid buffering agent include glutamic acid or its salts. More specifically, they are sodium glutamate, potassium glutamate, and the like.

[0078] The aqueous composition of the present invention can contain the first buffer as the sole buffer, or can contain the first buffer and the second buffer as the sole buffer. Further, the aqueous composition of the present invention can contain, in addition to the first buffer and the second buffer, still another buffer.

[0079] In the present invention, the term "first buffer" refers to at least one selected from the group consisting of phosphate buffers, aminocarboxylic acid buffers, carbonate buffers, acetate buffers, tartrate buffers, borate buffers, and tromethamine. The definition and preferred concentration range of each buffer are as described in the previous section on "buffers".

[0080] In the present invention, the "second buffer" is a citrate buffer. The definition and preferred concentration range of the citrate buffer are as described in the previous section on "buffers".

[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 is measured with an E-type viscometer (25 °C; 50 s -1 shearing rate).

[0082] The aqueous composition of the present invention may further contain an isotonic agent. The isotonic agent used in the present invention can be any pharmaceutically acceptable isotonic agent. Without particular limitation, examples of such isotonic agents include non-ionic isotonic agents such as glycerin, mannitol, propylene glycol, polyethylene glycol, glucose, sorbitol, xylitol, and trehalose. In the present invention, non-ionic isotonic agents are preferred as the isotonic agent. As non-ionic isotonic agents, glycerin, mannitol, propylene glycol, polyethylene glycol, glucose, sorbitol, xylitol, and trehalose are preferred, glycerin and mannitol are more preferred, and glycerin is particularly preferred.

[0083] As the isotonic agent used in the present invention, the above isotonic agents may be used alone 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 and reflecting, if necessary, the influence 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), still 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), still 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 contain, if necessary, pharmaceutically acceptable additives. Additives are a widely used technology and can be mixed with other components of the aqueous composition of the present invention. Additives can be selected, if necessary, for example, surfactants such as polyoxyethylene sorbitan monooleate, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil; stabilizers such as disodium edetate; preservatives such as benzalkonium chloride, boric acid; pH regulators such as hydrochloric acid, sodium hydroxide, and the like.

[0087] Generally, benzalkonium chloride is used as a preservative. In the present invention, as described hereinafter, it has been suggested that an atropine-containing aqueous composition not containing benzalkonium chloride has a lower mydriatic effect than an atropine-containing aqueous composition containing benzalkonium chloride. Therefore, the aqueous composition of the present invention preferably does not contain benzalkonium chloride or contains a limited amount of benzalkonium chloride. Here, the "limited amount" means an amount of benzalkonium chloride that does not deteriorate 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] The term "unit-dose type container" used in the present invention refers to an eye drop container in which a cap is fusion-sealed to the bottle mouth portion and is intended to be broken and opened at the fusion portion between the cap and the bottle-shaped body during use. The unit-dose type container may contain an aqueous composition for one use for single use, or may contain an aqueous composition for several uses for one-day use.

[0089] The term "multi-dose type container" used in the present invention refers to an eye drop container provided with a container body and a cap that can be attached to the container body, and the cap can be freely opened and resealed. The multi-dose type container usually contains an eye drop solution for a plurality of times for use over a certain period.

[0090] The aqueous composition in the present invention can be contained in a unit-dose type container or a multi-dose type container. When the aqueous composition in the present invention is substantially free of a preservative such as benzalkonium chloride, it is preferably contained in a unit-dose type 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 in the range of 4 to 6, even more preferably in the range of 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, and 5.3 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 the living body. 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 significantly affected by the amounts of drugs and additives in the aqueous composition. In the present invention, the osmotic pressure can be adjusted to be within the above range by appropriately adjusting the amounts of these substances that can affect the osmotic pressure. It should be noted that the osmotic pressure of the aqueous composition of the present invention can be measured by ordinary methods. For example, the osmotic pressure of the aqueous composition of the present invention can be measured according to the method described in the "Osmotic Pressure Measurement Method (Osmolality Measurement Method)" of the Fifteenth Revised Japanese Pharmacopoeia.

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

[0094] The dosage and administration method of the aqueous composition administered in the present invention are not particularly limited as long as they are sufficient to exhibit the desired pharmaceutical effect, and preferably 1 to 3 drops once, 1 to 5 times a day, more preferably 1 to 2 drops once, 2 to 4 times a day, and most preferably 1 drop once, and can be instilled into the eyes before going to bed once a day.

[0095] The aqueous composition of the present invention is preferably used for suppressing or preventing the progression of myopia, preventing myopia, and / or treating myopia, and more preferably for suppressing or preventing the progression of myopia in schoolchildren.

[0096] As used herein, the term "suppressing or preventing the progression of myopia" may mean delaying the progression of myopia or reducing the progression of myopia. As used herein, the term "preventing 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 present invention should not be limited thereto.

[0098] The meanings of the abbreviations are as follows. BAK: Benzalkonium Chloride CVP: Carboxyvinyl Polymer HEC: Hydroxyethyl Cellulose HPMC: Hydroxypropyl Methylcellulose

[0099] Test 1 Several aqueous compositions were evaluated for 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 hydroxyethyl cellulose, 0.1 g of sodium dihydrogen phosphate, and 2.4 g of concentrated glycerin were dissolved in purified water, and hydrochloric acid and sodium hydroxide were added to the resulting solution as necessary to adjust the pH to 5, and the total volume was made to 100 ml.

[0101] (Examples 2 to 3 and Comparative Examples 1 to 3) The aqueous compositions of Examples 2 to 3 and Comparative Examples 1 to 3 were prepared according to the formulation shown in Table 1 in the same manner as in Example 1. TIFF2025084921000002.tif73169

[0102] (Test method) The single-dose amount (volume of 50 μl) of each aqueous composition was instilled into one eye of a rabbit (4 eyes of 4 rabbits or 6 eyes of 6 rabbits for each aqueous composition). Images of the rabbit's pupil before and 1 hour after instillation were captured by optical coherence tomography (OCT), and then analyzed with image analysis software to calculate the pupil area and mydriasis rate of the rabbit. The mydriasis rate was calculated by the following formula. Mydriasis rate (%) = ((b - a) / a) × 100 In the formula, a is the average value of the pupil area before instillation in each test of Comparative Examples 1 to 3 and Examples 1 to 3 (mm 2 ), and 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 the average value of the data obtained from the results of 4 or 6 eyes. The mydriatic effect of this aqueous composition was determined according to the following evaluation criteria. A: The pupil area value 1 hour after instillation is less than 30.0 mm 2 (less than) B: The pupil area value 1 hour after instillation is 30.0 mm or more and less than 35.0 mm 2 (35.0 mm) 2 (less than) C: The pupil area value 1 hour after instillation is 35.0 mm or more and less than 40.0 mm 2 (40.0 mm) 2 (less than) D: The pupil area value 1 hour after instillation is 40.0 mm or more 2 (or more) TIFF2025084921000003.tif46139

[0104] (Discussion) As is clear from Table 2, it was shown that an aqueous composition containing (i) atropine or a salt thereof, (ii) having a pH in the range of 6 or less, and (iii) further containing a phosphate buffer has a lower mydriasis induced than a composition not containing a phosphate buffer.

[0105] Test 2 Some aqueous compositions of the present invention were evaluated for mydriatic action.

[0106] (Sample preparation method) (Examples 4 to 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 (volume of 50 μl) of each aqueous composition was instilled into a single eye of a rabbit (4 eyes of 4 rabbits or 6 eyes of 6 rabbits for each aqueous composition). Images of the rabbit's pupils 1 hour after instillation were captured by optical coherence tomography (OCT) and then analyzed with image analysis software to calculate the pupil area of the rabbit.

[0108] (Test results) The results of Examples 4 to 11 are shown in Table 3. Each value in Table 3 is the average value of data obtained from the results of 4 or 6 eyes. The mydriatic action of this aqueous composition was determined according to the following evaluation criteria. A: The pupil area value 1 hour after instillation is less than 30.0 mm 2 less than B: The pupil area value 1 hour after instillation is 30.0 mm or more and less than 35.0 mm 2 30.0 mm or more and less than 35.0 mm 2 less than C: The pupil area value 1 hour after instillation is 35.0 mm or more and less than 40.0 mm 2 35.0 mm or more and less than 40.0 mm 2 less than D: The pupil area value 1 hour after instillation is 40.0 mm or more 2 40.0 mm or more TIFF2025084921000004.tif84166

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

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

[0111] (Sample preparation method) (Examples 12 to 14) The aqueous compositions of Examples 12 to 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 (volume of 50 μl) of each aqueous composition was instilled into one eye of a rabbit (4 eyes of 4 rabbits for each aqueous composition). The image of the rabbit's pupil 1 hour after instillation was captured by optical coherence tomography (OCT), and then analyzed with image analysis software to calculate the pupil area of the rabbit.

[0113] (Test results) The results of Examples 12 to 14 are shown in Table 4. Each value in Table 4 is the average value of the data obtained from the results of 4 eyes. The mydriatic effect of this aqueous composition was determined according to the following evaluation criteria. A: The pupil area value 1 hour after instillation is less than 30.0 mm 2 less than B: The pupil area value 1 hour after instillation is 30.0 mm or more and less than 35.0 mm 2 30.0 mm or more and less than 35.0 mm 2 less than C: The pupil area value 1 hour after instillation is 35.0 mm or more and less than 40.0 mm 2 35.0 mm or more and less than 40.0 mm 2 less than D: The pupil area value 1 hour after instillation is 40.0 mm or more 2 40.0 mm or more TIFF2025084921000005.tif68131

[0114] (Discussion) Even when the aqueous composition contained 0.005% (w / v) of atropine, the mydriatic effect was low when the aqueous composition contained a phosphate buffer as the first buffer (Example 12). Further, 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 benzalkonium chloride, which is generally used as a preservative, on the mydriatic effect of the aqueous composition of the present invention was examined.

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

[0117] (Test method) A single dose (volume of 50 μl) of each aqueous composition was instilled into a single eye of a rabbit (4 eyes of 4 rabbits for each aqueous composition). The image of the pupil of the rabbit 1 hour after instillation was captured by optical coherence tomography (OCT), and then analyzed with image analysis software to calculate the pupil area of the rabbit.

[0118] (Test results) The results of Examples 15 to 17 are shown in Table 5. Each value in Table 5 is the average value of the data obtained from the results of 4 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 less than 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 and less than 45.0 mm 2 less than E: Pupil area value 1 hour after eye drop is 45.0 mm 2 or more TIFF2025084921000006.tif63133

[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 an aqueous composition containing atropine and a water-soluble polymer, the effect of the isotonic agent on the viscosity of the aqueous composition and the stability of atropine was examined.

[0121] (Sample preparation method) (Examples 18 - 22) The aqueous compositions of Examples 18 - 22 were prepared according to the formulation shown in Table 6 in the same manner as in Example 1. The prepared samples were filled into polyethylene eye drop containers at 5 mL each, equipped with inner stoppers, sealed with caps, and stored at 60 °C for 4 weeks under light shielding. TIFF2025084921000007.tif62161

[0122] (Test method) (1) Viscosity measurement test 1 According to the 16th revised Japanese Pharmacopoeia, "Method 2: Rotational viscometer method", the viscosity of each aqueous composition immediately after preparation and at 1, 2, and 4 weeks after preparation was measured using a cone - plate rotational viscometer. The measurement conditions are shown below. · Measuring instrument: Rotational rheometer (Kinexus pro+) · Rotation speed (S -1 ): 50 / sec · Measurement temperature: 25 °C

[0123] (2) Stability test 1 Atropine decomposes to produce tropic acid. In this test, to evaluate the stability of atropine, high-performance liquid chromatography was used to quantify the content of tropic acid 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] (Discussion) (1) Viscosity measurement test 1 As shown in Figure 1, the aqueous compositions containing atropine and hydroxyethyl cellulose and no isotonic agent (Example 18, "not contained" in Figure 1), the aqueous composition containing sodium chloride as an isotonic agent (Example 19, "NaCl" in Figure 1), and the aqueous composition containing boric acid as an isotonic agent (Example 20, "boric acid" in Figure 1) had their viscosities decreased over time. On the other hand, the aqueous compositions containing atropine and hydroxyethyl cellulose and containing glycerin as an isotonic agent (Example 21, "glycerin" in Figure 1) and the aqueous composition containing mannitol as an isotonic agent (Example 22, "mannitol" in Figure 1) maintained their viscosities, and the decrease in viscosity over time was suppressed.

[0126] (2) Stability test 1 As shown in Figure 2, the aqueous compositions containing atropine and hydroxyethyl cellulose and containing mannitol or boric acid as an isotonic agent produced more tropic acid than the other aqueous compositions. From the above, in the aqueous composition containing atropine and hydroxyethyl cellulose, it was shown that the addition of mannitol or boric acid as an isotonic agent is not preferable from the viewpoint of the stability of atropine. Also, from the results of the above viscosity measurement test 1 and stability test 1, in the aqueous composition containing atropine and hydroxyethyl cellulose, in order to suppress the decrease in viscosity over time and maintain the stability of atropine, it was shown that it is preferable to add glycerin as an isotonic agent.

[0127] Test 6 (Viscosity Measurement Test 2) In an aqueous composition containing atropine and a water-soluble polymer, the effect of an isotonic agent on the viscosity of the aqueous composition was examined.

[0128] (Sample Preparation Method) (Examples 23 to 28) The aqueous compositions of Examples 23 to 28 were prepared according to the formulations shown in Table 7 in the same manner as in Example 1. The prepared samples were filled into polyethylene eye drop containers at 5 mL each. After attaching the middle stopper, they were sealed with a cap and stored at 60°C for 4 weeks under light shielding. TIFF2025084921000008.tif57151

[0129] (Test Method) (Viscosity Measurement Test 2) According to the "Second Method: Rotary Viscometer Method" in the 16th Revised Japanese Pharmacopoeia, the viscosity of each aqueous composition immediately after preparation and at 1, 2, and 4 weeks after preparation was measured using a cone-plate type rotary viscometer. The measurement conditions are shown below. · Measuring instrument: Rotary rheometer (Kinexus pro+) · Rotation speed (S -1 ): 50 / sec · Measurement temperature: 25°C

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

[0131] (Discussion) (Viscosity Measurement Test 2) As shown in Figure 3, the viscosity of the aqueous composition containing atropine and hydroxypropylmethylcellulose and not containing an isotonic agent (Example 23, "not contained" in Figure 3) decreased over time. On the other hand, the viscosity of the aqueous composition containing glycerin or mannitol as an isotonic agent (Examples 24 and 25, "glycerin" or "mannitol" in Figure 3) was maintained, and the decrease in viscosity over time was suppressed. Also, as shown in Fig. 4, an aqueous composition containing atropine and a carboxyvinyl polymer and not containing an isotonic agent (Example 26, "not contained" in Fig. 4) showed a decrease in its viscosity over time. On the other hand, an aqueous composition containing glycerin or mannitol as an isotonic agent (Examples 27 and 28, "glycerin" or "mannitol" in Fig. 4) maintained its viscosity and the decrease in viscosity over time was suppressed.

[0132] Test 7 In a mouse myopia model, the effects of water-soluble polymers on the inhibitory effect of atropine on axial length elongation and the improvement effect on refractive abnormalities were investigated.

[0133] (Sample preparation method) (Examples A to 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. TIFF2025084921000009.tif46149

[0134] (Test method) Experimental myopia mouse model: A myopia model induced by a spectacle lens was created by attaching a -10D lens to the right eye of a mouse (C57BL / 6J) and used as the experimental eye on the 24th day after birth. A temporary -10D lens (blue PMMA spectacle lens, outer radius of curvature 8.5 mm, inner radius of curvature 8 mm, lens thickness 0.5 mm) was adhered to a Velcro (registered trademark) loop (with an 8 mm base curve). Then one piece of this was attached to Velcro (registered trademark) adhered to the hair around the experimental right eye using cyanoacrylate. Through this setup, it was confirmed that there was a 1.5 mm gap between the rear of the lens and the front surface of the cornea.

[0135] Ocular biometry: Ocular biometry, such as axial length measurement and refractive error measurement, was performed using an in vivo optical low coherence interferometry (OLCI - AcMaster) and an automated eccentric photorefractor, respectively. The axial length was measured on the 38th and 66th days after birth, while the refractive power of the animal's eyes was measured on the 52nd and 66th days. Drug treatment: Atropine sulfate (at a concentration of 0.01%) was administered once a day from the 39th to the 66th day after birth to a myopia model induced by spectacle lenses, either with or without hydroxyethyl cellulose. 7 μL of each drug was topically administered to the right eye in a dark red light each day.

[0136] (Test results) (1) Inhibitory effect on axial length elongation The results of Examples B - D are shown in Table 9. The ratio of the inhibitory effect on axial length elongation by each sample of the examples was calculated by the following formula. Difference in axial length (mm) = [Axial length on the 66th day] - [Axial length on the 38th day] Inhibitory rate of axial length elongation by the sample of Example B (%) = TIFF2025084921000010.tif13151 Inhibitory rate of axial length elongation by the sample of Example C (%) = TIFF2025084921000011.tif13151 Inhibitory rate of axial length elongation by the sample of Example D (%) = TIFF2025084921000012.tif13151 TIFF2025084921000013.tif3084

[0137] (2) Improvement effect on refractive error The results of Examples A - D are shown in Table 10. Change in refractive error (diopter) = [Refractive power on the 66th day (diopter)] - [Refractive power on the 52nd day (diopter)] TIFF2025084921000014.tif3586

[0138] Examination No inhibitory effect on axial eye length elongation was observed in the aqueous composition (Example B) containing a water-soluble polymer but not containing atropine. On the other hand, by adding a water-soluble polymer to the aqueous composition containing atropine (Example D), it was found that it exhibited a stronger inhibitory effect on axial eye length elongation than the aqueous composition (Example C) containing atropine but not containing a water-soluble polymer. Also, similar to the above inhibitory effect on axial eye length elongation, by adding a water-soluble polymer to the aqueous composition containing atropine (Example D), it was found that it exhibited a stronger refractive error improving effect than the aqueous composition (Example C) containing atropine but not containing a water-soluble polymer. As is also clear from the results of Examples 1 and 3 in Tables 1 and 2, since it has been shown that the addition of a water-soluble polymer does not affect the mydriatic effect of atropine, the aqueous composition containing atropine and a water-soluble polymer is expected to be a myopia progression inhibitor with a low mydriatic effect.

[0139] Formulation Example The medicament of the present invention will be further specifically described by way of formulation examples, but the present invention is not limited only to these formulation examples.

[0140] Formulation Example 1: Eye drops (0.01% (w / v)) TIFF2025084921000015.tif4194 Add the atropine sulfate hydrate and other components listed above to sterilized purified water. Mix these components well to prepare the above eye drops.

[0141] Formulation Example 2: Eye drops (0.004% (w / v)) TIFF2025084921000016.tif4194 Add the atropine sulfate hydrate and other components listed above to sterilized purified water. Mix these components well to prepare the above eye drops.

Industrial Applicability

[0142] 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 first buffering agent, and having a pH in the range of 6 or less, 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 tartrate buffering agent, a borate buffering agent, and tromethamine, has been shown to have an excellent effect of suppressing the elongation of the eye axis and an effect of improving refractive errors without worsening the mydriatic action of atropine. It has also been shown to have a low mydriatic action by not containing benzalkonium chloride or containing a limited amount of benzalkonium chloride. Furthermore, in an aqueous composition containing atropine or a salt thereof and a water-soluble polymer and having a pH in the range of 6 or less, by containing a nonionic isotonic agent, a decrease in the viscosity of the aqueous composition imparted by the water-soluble polymer over time can be suppressed, and furthermore, the stability of atropine or a salt thereof can be maintained. This aqueous composition is expected to be optimal for quality of life by suppressing or preventing the progression of myopia, reducing the mydriatic action to a lower level, and reducing the decrease in near and far accommodation.

Claims

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 buffer, and having a pH in the range of 6 or less, wherein the first buffer is at least one selected from the group consisting of a phosphate buffer, an aminocarboxylic acid buffer, a carbonate buffer, an acetate buffer, a tartaric acid buffer, a borate buffer, and trometamol.

2. 2. The aqueous composition of 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. 3. The aqueous composition of claim 1, wherein the first buffer is a phosphate buffer.

4. 3. The aqueous composition according to claim 1, 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 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 dihydrogen phosphate heptahydrate, sodium phosphate trihydrate, and potassium phosphate dihydrate; 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 tartrate buffer is 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 aspartic acid buffer is derived from at least one selected from the group consisting of aspartic acid, sodium aspartate, and magnesium aspartate; 5. An aqueous composition according to any one of claims 1 to 4.

6. 6. The aqueous composition according to claim 1, further comprising a citrate buffer as a second buffer.

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

9. 9. The aqueous composition of claim 8, wherein the cellulose derivative is at least one selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hypromellose acetate succinate, hypromellose phthalate, carboxymethyl ethyl cellulose, and cellulose acetate phthalate.

10. 10. The aqueous composition according to claim 8, wherein the cellulose derivative is at least one selected from the group consisting of hydroxyethyl cellulose and hydroxypropyl methylcellulose.

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

12. 1. An aqueous composition comprising atropine or a salt thereof at a concentration of 0.001-0.1% (w / v), hydroxyethylcellulose, and a first buffering agent, the aqueous composition having a pH in the range of 6 or less, wherein the first buffering agent is a phosphate buffering agent.

13. 13. The aqueous composition of claim 12, further comprising a citrate buffer as a second buffer.

14. 14. The aqueous composition of claim 1, containing benzalkonium chloride at a concentration of less than 50 ppm.

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

16. 16. The aqueous composition of claim 1, further comprising a non-ionic tonicity agent.

17. 17. The aqueous composition of claim 16, wherein the non-ionic tonicity agent is at least one selected from the group consisting of glycerin, mannitol, propylene glycol, polyethylene glycol, glucose, sorbitol, xylitol and trehalose.

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

19. 19. The aqueous composition of any one of claims 16 to 18, wherein the non-ionic tonicity agent is glycerin.

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

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

23. 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. 24. The aqueous composition according to any one of claims 16 to 23, wherein the concentration of the non-ionic tonicity agent is from 0.01 to 10% (w / v).

25. 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 buffering agent, and having a pH in the range of 5 or less.

26. 26. The aqueous composition of claim 25, wherein the buffer is at least one selected from the group consisting of phosphate buffers, citrate buffers, aminocarboxylic acid buffers, carbonate buffers, acetate buffers, tartrate buffers, borate buffers, and trometamol.

27. 27. The aqueous composition of claim 25 or 26, wherein the buffer is a citrate buffer.

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

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

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

31. 31. The aqueous composition of claim 29 or 30, wherein the water-soluble polymer is hydroxyethyl cellulose.

32. 32. The aqueous composition of any one of claims 1 to 24 and 28 to 31, having a pH in the range of 4 to 6.

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

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

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

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

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

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

41. 40. 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. 39. 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 a decrease in viscosity of an aqueous composition, the method comprising adding a non-ionic tonicity agent to the aqueous composition, the aqueous composition comprising 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 non-ionic tonicity 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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