Atropine-containing aqueous composition

Abstract

To provide an atropine-containing aqueous composition that induces a lower mydriatic effect and a lower reduction in accommodation.SOLUTION: Provided is an aqueous composition for suppressing and / or preventing progression of myopia comprising atropine or a salt thereof at a concentration of 0.001 to 0.1% (w / v), wherein the aqueous composition is characterized by substantially not containing benzalkonium chloride, thereby reducing a mydriatic effect.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention primarily relates to an aqueous composition 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 forms an image in front of the retina rather than on the retina, causing objects to appear blurred. Myopia is known to be caused by either a longer than normal axial length (the length from the cornea to the retina) (axial myopia) or by excessive refractive power of the cornea or lens (refractive myopia).

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

[0004] On the other hand, atropine eye drops are used as a mydriatic drug and also reduce accommodation. When atropine eye drops are applied to the eye, they relax the pupillary sphincter muscle of the iris, causing mydriasis, which causes glare. This dilation persists as long as the effect of atropine eye drops is maintained, reducing accommodation in the lens and resulting in reduced near vision. This can also impair daily activities. Therefore, there is a great need for a drug to slow or prevent the progression of myopia that has a weaker mydriatic effect, induces a smaller loss of accommodation, and improves quality of life (QOL). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] WO2012 / 161655 Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to find an aqueous atropine-containing composition that has excellent effects of inhibiting axial length elongation and improving refractive errors. An important goal is to find an aqueous atropine-containing composition that has a lower mydriatic effect and induces a smaller decrease in accommodation. Another object of the present invention is to find an aqueous atropine-containing composition whose viscosity does not decrease over time and in which atropine or a salt thereof is stable. [Means for solving the problem]

[0007] The present inventors conducted extensive research to solve the above-mentioned problems and 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 buffer, the aqueous composition having a pH 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, tartrate buffer, borate buffer, and trometamol, exhibits excellent effects of inhibiting axial elongation and improving refractive errors without exacerbating the mydriatic effect of atropine. Furthermore, the present inventors also found that an aqueous composition containing no benzalkonium chloride or a limited amount of benzalkonium chloride exhibits low mydriatic effect. Furthermore, the present inventors have found that by adding a nonionic tonicity agent to an aqueous composition containing atropine or its salt and a water-soluble polymer and having a pH of 6 or less, the decrease in viscosity of the aqueous composition over time imparted by the water-soluble polymer can be suppressed and the stability of atropine or its salt can be maintained. The aqueous composition of the present invention is expected to suppress or prevent the progression of myopia, reduce mydriatic effect, reduce loss of accommodation, and be optimal in terms of quality of life.

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

[0009] (Section 1) An aqueous composition having a pH of 6 or less, 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, 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 trometamol.

[0010] (Section 2) Item 1. 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] (Section 3) Item 3. The aqueous composition according to item 1 or 2, wherein the first buffer is a phosphate buffer.

[0012] (Section 4) Item 3. 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, glutamic acid buffer, and aspartic acid buffer.

[0013] (Section 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 tartrate buffer is 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 aspartic acid buffer is derived from at least one selected from the group consisting of aspartic acid, sodium aspartate, and magnesium aspartate; Item 5. The aqueous composition according to any one of items 1 to 4.

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

[0015] (Section 7) Item 7. The aqueous composition according to Item 6, wherein the citrate buffer is 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] (Section 8) 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 polymers, and sodium alginate.

[0017] (Section 9) 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 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.

[0018] (Section 10) 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] (Section 11) Item 11. The aqueous composition according to any one of items 8 to 10, wherein the cellulose derivative is hydroxyethyl cellulose.

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

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

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

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

[0024] (Section 16) Item 16. The aqueous composition according to any one of items 1 to 15, further comprising a non-ionic tonicity agent.

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

[0027] (Section 19) Item 19. The aqueous composition according to any one of items 16 to 18, wherein the non-ionic tonicity agent is glycerin.

[0028] (Section 20) 20. The 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) 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] (Section 22) 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] (Section 23) 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] (Section 24) 24. The aqueous composition according to any one of items 16 to 23, wherein the concentration of the nonionic tonicity agent is 0.01 to 10% (w / v).

[0033] (Section 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.

[0034] (Section 26) Item 26. The aqueous composition according to Item 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.

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

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

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

[0038] (Section 30) 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] (Section 31) Item 31. The aqueous composition according to Item 29 or 30, wherein the water-soluble polymer is hydroxyethyl cellulose.

[0040] (Section 32) Item 32. The 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) 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] (Section 34) 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] (Section 35) 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] (Section 36) Item 36. The aqueous composition according to any one of items 1 to 35, wherein the atropine or a salt thereof is atropine sulfate or a hydrate thereof.

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

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

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

[0048] (Section 40) Item 39. Use of the aqueous composition according to any one of items 1 to 38 in the manufacture of a medicament for inhibiting and / or preventing the progression of myopia.

[0049] (Section 41) Item 39. A method for inhibiting and / or preventing the progression of myopia, comprising administering to a patient the aqueous composition according to any one of items 1 to 38.

[0050] (Section 42) Item 39. The 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 a decrease in viscosity of an aqueous composition, the method comprising adding a nonionic tonicity agent to the aqueous composition, the 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 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. [Effects of the Invention]

[0053] As is evident from the test results described below, 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 buffer, and having a pH 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, tartrate buffer, borate buffer, and trometamol, was shown to have excellent effects of inhibiting axial length elongation and improving refractive errors without exacerbating the mydriatic effect of atropine. It was also shown that the absence of benzalkonium chloride or the inclusion of a limited amount of benzalkonium chloride resulted in a low mydriatic effect. Furthermore, it was also shown that the inclusion of a nonionic tonicity agent in an aqueous composition containing atropine or its salt and a water-soluble polymer and having a pH of 6 or less inhibits the decrease in viscosity of the aqueous composition over time imparted by the water-soluble polymer and maintains the stability of atropine or its salt. Thus, the aqueous compositions are expected to slow or prevent myopia progression, provide lower mydriatic effects, and reduce loss of accommodation, resulting in optimal quality of life. A further advantage associated with compositions of the present invention, such as compositions containing a tonicity agent, is the ability of the composition to maintain its initial viscosity (or a substantial proportion thereof) over time. [Brief explanation of the drawings]

[0054] [Figure 1] FIG. 1 shows the results of the viscosity measurements in Test 5. [Figure 2] FIG. 2 shows the results of the stability test in Study 5. [Figure 3] FIG. 3 shows the results of Examples 23 to 25 in the viscosity measurement of Test 6. [Figure 4] FIG. 4 shows the results of Examples 26 to 28 in the viscosity measurement of Test 6. DETAILED DESCRIPTION OF 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" also 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 the hydrate and the organic solvate.

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

[0058] Atropine sulfate hydrate is a compound represented by the following structural formula: JPEG2025176149000001.jpg45123

[0059] When atropine or a salt thereof has crystalline polymorphs and crystalline polymorphic systems, these crystalline polymorphs and crystalline polymorphic systems (crystalline polymorphic systems) are also included within the scope of the present invention. Here, the crystalline polymorphic system (crystalline polymorphic system) refers not only to the individual crystalline forms obtained at each stage when the crystalline form changes depending on the conditions and states of the production, crystallization, storage, etc. of the crystals, but also to a mixture of crystalline forms obtained at two or more stages.

[0060] Atropine or a salt thereof can be produced by a conventional method in the field of organic synthetic chemistry, or a commercially available product 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), or 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 that contains water as a solvent.

[0063] In the present invention, a "water-soluble polymer" can be any pharmaceutically acceptable polymer that is soluble in water. Non-limiting 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 polymers), and naturally occurring polymers and saccharides (e.g., gum arabic, sodium alginate, propylene glycol alginate, agar, gelatin, tragacanth, and xanthan gum). Among these, preferred ones for use as the water-soluble polymer in the present invention are cellulose and its derivatives, carboxyvinyl polymers, and sodium alginate. Of these, more preferred ones for use as the water-soluble polymer in the present invention are hydroxyethyl cellulose, carboxyvinyl polymers, and hydroxypropyl methyl cellulose.

[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, taking into account 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 or a derivative thereof, the concentration of cellulose or a derivative thereof 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 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 hydroxypropylmethylcellulose, the concentration of hydroxypropylmethylcellulose 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 buffer, citrate buffer, borate buffer, carbonate buffer, acetate buffer, tartrate buffer, aminocarboxylic acid buffer, trometamol, etc. Examples of aminocarboxylic acid buffers include aspartic acid buffer, glutamic acid buffer, and epsilon-aminocaproic acid. These buffers may be used alone or in any combination of two or more components. Among these buffers, phosphate buffer, citrate buffer, carbonate buffer, acetate buffer, and aminocarboxylic acid buffer are preferred, phosphate buffer, citrate buffer, acetate buffer, and aminocarboxylic acid buffer are more preferred, phosphate buffer and / or citrate buffer are even more preferred, and phosphate buffer and citrate buffer are particularly preferred.

[0072] In the present invention, the concentration of the buffering agent in the aqueous composition is determined by adjusting the content of the buffering agent, if necessary, to reflect the effects of the buffering agent on the pharmaceutical substance (active ingredient), other additives, pH, osmolality, and / or viscosity. However, the concentration of the buffering agent 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 even more particularly preferably 0.01 to 0.1% (w / v), where the weight of the buffering agent refers to the weight of the buffering agent as a raw material.

[0073] In the present invention, the phosphate buffer may be derived from any pharmaceutically acceptable phosphate buffering agent (can be made from such a raw material). Examples of such phosphate buffering agents include, but are not limited to, phosphoric acid; phosphate salts such as alkali metal phosphates and alkaline earth metal phosphates; and hydrates thereof. More specifically, sodium hydrogen phosphate hydrate (also referred to as "sodium hydrogen phosphate" or "sodium phosphate"), sodium dihydrogen phosphate (also referred to as "monosodium phosphate"), sodium dihydrogen phosphate monohydrate (also referred to as "monosodium phosphate"), sodium dihydrogen phosphate dihydrate (also referred to as "monosodium phosphate"), potassium dihydrogen phosphate (also referred to as "monopotassium phosphate"), sodium hydrogen phosphate heptahydrate, trisodium phosphate, dipotassium phosphate, etc.

[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, if necessary, to reflect 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 refers to the weight of the phosphate buffer as a raw material.

[0075] In the present invention, the "citric acid buffer" may be derived from (or may be made from) any citric acid buffering agent, without particular limitation, as long as it is pharmaceutically acceptable. Examples of citrate buffering agents include citric acid; citrate salts such as alkali metal citrates and alkaline earth metal citrates; and hydrates thereof. More specifically, these 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, if necessary, to reflect the effects of the citrate buffer on the pharmaceutical substance (active ingredient), other additives, pH, osmolality, 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 refers to the weight of the citrate buffer as a raw material.

[0077] In the present invention, the term "borate buffer" may be derived from (or may be made from) a borate buffering agent, and examples of the borate buffering agent include boric acid or its salts, and borax. More specific examples include boric acid, sodium borate, potassium borate, potassium tetraborate, potassium metaborate, ammonium borate, and borax. The term "carbonate buffer" may be derived from (or may be made from) a carbonate buffering agent, and examples of the carbonate buffering agent include carbonic acid or its salts. More specific examples include carbonic acid, sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, and magnesium carbonate. The term "acetate buffer" may be derived from (or may be made from) an acetate buffering agent, and examples of the acetate buffering agent include acetic acid or its salts. More specific examples include acetic acid, ammonium acetate, potassium acetate, calcium acetate, and sodium acetate. "Tartaric acid buffers" may be derived from (or may be made from) tartaric acid buffers, and examples of tartaric acid buffers include tartaric acid or its salts. More specifically, sodium tartrate, potassium tartrate, etc. "Aspartic acid buffers" may be derived from (or may be made from) aspartic acid buffers, and examples of aspartic acid buffers include aspartic acid or its salts. More specifically, sodium aspartate, magnesium aspartate, etc. "Glutamic acid buffers" may be derived from (or may be made from) glutamic acid buffers, and examples of glutamic acid buffers 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 buffer as the only buffer, or may contain the first buffer and the second buffer as the only buffers, or may contain an additional buffer in addition to the first buffer and the second buffer.

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

[0080] In the present invention, the "second buffer" is a citrate buffer. The definition and preferred concentration range of the citrate buffer are as explained above in the section "Buffer."

[0081] The viscosity of the aqueous composition of the present invention is adjusted to be preferably in the range of 3 to 500 mPa·s, more preferably in the range of 6 to 70 mPa·s, and is measured by an E-type viscometer (25°C; 50 s -1 It is measured at a shear rate of 1 / 2.

[0082] The aqueous composition of the present invention may further contain an isotonicity adjusting agent. The isotonicity adjusting agent used in the present invention may be any pharmaceutically acceptable isotonicity adjusting agent. Although not particularly limited, examples of such isotonicity adjusting agents include non-ionic isotonicity adjusting agents such as glycerin, mannitol, propylene glycol, polyethylene glycol, glucose, sorbitol, xylitol, and trehalose. In the present invention, non-ionic isotonicity adjusting agents are preferred. As non-ionic isotonicity adjusting 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 isotonicity agent used in the present invention, the above-mentioned isotonicity agents may be used alone or in combination of two or more.

[0084] In the present invention, the concentration of the isotonicity agent in the aqueous composition is determined by adjusting the content of the isotonicity agent and, if necessary, taking into account the effects of the isotonicity agent on the pharmaceutical substance (active ingredient), other additives, pH, osmolality, and / or viscosity. However, the concentration of the isotonicity 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 tonicity 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 contain pharmaceutically acceptable additives, if necessary. Additives can be mixed with other components of the aqueous composition of the present invention using commonly used techniques. If necessary, additives may be selected from surfactants such as polyoxyethylene sorbitan monooleate, polyoxyl 40 stearate, and polyoxyethylene hydrogenated castor oil; stabilizers such as edetate disodium; preservatives such as benzalkonium chloride and boric acid; and pH adjusters such as hydrochloric acid and sodium hydroxide.

[0087] Benzalkonium chloride is generally used as a preservative. As described below, the present invention suggests 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, the aqueous composition of the present invention preferably contains no benzalkonium chloride or a limited amount of benzalkonium chloride. Here, "limited amount" refers to an 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] The term "unit-dose container" as used herein refers to an eye drop container in which a cap is fused to the mouth of the bottle and the fused portion between the cap and the bottle-shaped body is broken and opened at the time of use. The unit-dose container may contain an amount of aqueous composition for a single use, or may contain an amount of aqueous composition for several uses in a day.

[0089] The term "multi-dose container" as used in the present invention refers to an eye drop container comprising a container body and a cap that can be attached to the container body, and the cap can be freely opened and resealed. Such a multi-dose container usually 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. When the aqueous composition of the present invention is substantially free of a preservative such as benzalkonium chloride, it is preferably contained 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 around 4 or 5. More specifically, for example, pH 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 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 the 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 affected to some extent by the amount of drugs and additives in the aqueous composition. In the present invention, the osmotic pressure can be adjusted to fall within the above range by appropriately adjusting the amounts of these substances that can affect the osmotic pressure. 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 the "Osmotic Pressure Measurement Method (Osmolality Measurement Method)" in the 15th Edition of the Japanese Pharmacopoeia.

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

[0094] The dosage of the aqueous composition administered in the present invention is not particularly limited as long as it is sufficient to achieve the desired medicinal effect, and is preferably administered in the form of 1 to 3 drops at a time, 1 to 5 times a day, more preferably 1 to 2 drops at a time, 2 to 4 times a day, and most preferably 1 drop at a time, once a day before going to bed.

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

[0096] The term "inhibiting or preventing the progression of myopia" as used herein may mean slowing the progression of myopia or reducing the progression of myopia. The term "preventing myopia" as used herein may mean preventing the onset of myopia or slowing the onset of myopia. [Example]

[0097] The following test results and formulation examples are presented for a better understanding of the present invention, but should not be construed as limiting the scope of the present invention 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 their mydriatic activity.

[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 the resulting solution was adjusted to pH 5 by adding hydrochloric acid and sodium hydroxide as necessary, and the total volume was adjusted 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 formulations shown in Table 1, in the same manner as in Example 1. TIFF2025176149000002.tif73169

[0102] (Test Method) A single dose (50 μl volume) of each aqueous composition was instilled into each rabbit's eye (four eyes of four rabbits or six eyes of six rabbits for each aqueous composition). Images of the rabbit's pupils before and one hour after instillation were captured using optical coherence tomography (OCT) and then analyzed using image analysis software to calculate the rabbit's pupil area and mydriasis rate. The mydriasis rate was calculated using the following formula: Mydriatic rate (%)=((ba) / a)×100 In the formula, a is the average pupil area (mm 2 ), and a is 16.8 (mm 2 ) and b is the pupil area value 1 hour after administration.

[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 data obtained from the results of four or six eyes. The mydriatic effect of this aqueous composition was evaluated according to the following criteria. A: Pupil area was 30.0mm 1 hour after administration 2 less than B: Pupil area was 30.0mm 1 hour after administration 2 Over 35.0mm 2 less than C: Pupil area 35.0mm 1 hour after instillation 2 Over 40.0mm 2 less than D: Pupil area 40.0mm 1 hour after instillation 2 End TIFF2025176149000003.tif46139

[0104] (Consideration) As is clear from Table 2, aqueous compositions (i) containing atropine or a salt thereof, (ii) having a pH in the range of 6 or less, and (iii) further containing a phosphate buffer were shown to induce less mydriasis than compositions not containing a phosphate buffer.

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

[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 (50 μl volume) of each aqueous composition was instilled into each rabbit's eye (four eyes of four rabbits or six eyes of six rabbits for each aqueous composition). Images of the rabbit's pupils one hour after instillation were captured using optical coherence tomography (OCT) and then analyzed using 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 four or six eyes. The mydriatic effect of this aqueous composition was evaluated according to the following criteria. A: Pupil area was 30.0mm 1 hour after administration 2 less than B: Pupil area was 30.0mm 1 hour after administration 2 Over 35.0mm 2 less than C: Pupil area 35.0mm 1 hour after instillation 2 Over 40.0mm 2 less than D: Pupil area 40.0mm 1 hour after instillation 2 End TIFF2025176149000004.tif84166

[0109] (Consideration) When the aqueous composition contained a phosphate buffer as the first buffer, the mydriatic effect was low (Example 4). Furthermore, 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 Several aqueous compositions of the present invention were evaluated for their mydriatic activity.

[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 (50 μl volume) of each aqueous composition was instilled into each eye of a rabbit (four eyes of four rabbits for each aqueous composition). Images of the rabbit's pupils one hour after instillation were captured using optical coherence tomography (OCT) and then analyzed using 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 four eyes. The mydriatic effect of this aqueous composition was evaluated according to the following criteria. A: Pupil area was 30.0mm 1 hour after administration 2 less than B: Pupil area was 30.0mm 1 hour after administration 2 Over 35.0mm 2 less than C: Pupil area 35.0mm 1 hour after instillation 2 Over 40.0mm 2 less than D: Pupil area 40.0mm 1 hour after instillation 2 End TIFF2025176149000005.tif67131

[0114] (Consideration) Even if 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). Also, 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 13 and 14).

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

[0116] (Sample preparation method) (Examples 15 to 17) The aqueous compositions of Examples 15 to 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 volume) of each aqueous composition was instilled into each eye of a rabbit (four eyes of four rabbits for each aqueous composition). Images of the rabbit's pupils one hour after instillation were captured using optical coherence tomography (OCT) and then analyzed using 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 four eyes. The mydriatic effect of this aqueous composition was evaluated according to the following criteria. A: Pupil area was 30.0mm 1 hour after administration 2 less than B: Pupil area was 30.0mm 1 hour after administration 2 Over 35.0mm 2 less than C: Pupil area 35.0mm 1 hour after instillation 2 Over 40.0mm 2 less than D: Pupil area 40.0mm 1 hour after instillation 2 Over 45.0mm 2 less than E: Pupil area 45.0mm 1 hour after instillation 2 End TIFF2025176149000006.tif62134

[0119] (Consideration) As is clear from Table 5, the aqueous composition not containing benzalkonium chloride (Example 15) exhibited 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) The effects of an isotonic agent on the viscosity of an aqueous composition containing atropine and a water-soluble polymer and the stability of atropine were investigated.

[0121] (Sample preparation method) (Examples 18 to 22) The aqueous compositions of Examples 18 to 22 were prepared according to the formulations shown in Table 6, in the same manner as in Example 1. 5 mL of the prepared samples were filled into polyethylene eye dropper containers, which were then fitted with inner stoppers, sealed with caps, and stored in the dark at 60°C for 4 weeks. TIFF2025176149000007.tif62161

[0122] (Test Method) (1) Viscosity measurement test 1 According to the Japanese Pharmacopoeia, 16th Edition, "Method 2: Rotational Viscometer Method," the viscosity of each aqueous composition was measured immediately after preparation and 1, 2, and 4 weeks after preparation using a cone-and-plate rotational viscometer. The measurement conditions are shown below. Measurement equipment: Rotational 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 content of tropic acid was quantified using high-performance liquid chromatography immediately after preparation and 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, the viscosity of the aqueous composition containing atropine and hydroxyethyl cellulose but no tonicity agent (Example 18, "Nothing" in Figure 1), the aqueous composition containing sodium chloride as a tonicity agent (Example 19, "NaCl" in Figure 1), and the aqueous composition containing boric acid as a tonicity agent (Example 20, "Boric Acid" in Figure 1) decreased over time. On the other hand, the viscosity of the aqueous composition containing atropine and hydroxyethyl cellulose and glycerin as a tonicity agent (Example 21, "Glycerin" in Figure 1), and the aqueous composition containing mannitol as a tonicity agent (Example 22, "Mannitol" in Figure 1) were maintained, 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, it was demonstrated that the addition of mannitol or boric acid as an isotonic agent is not preferable in aqueous compositions containing atropine and hydroxyethyl cellulose from the viewpoint of atropine stability. Furthermore, the results of the above-mentioned Viscosity Measurement Test 1 and Stability Test 1 indicated that in an aqueous composition containing atropine and hydroxyethyl cellulose, it is preferable to add glycerin as an isotonic agent in order to suppress a 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 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. 5 mL of the prepared samples were filled into polyethylene eye dropper containers, which were then fitted with inner stoppers, sealed with caps, and stored in the dark at 60°C for 4 weeks. TIFF2025176149000008.tif57151

[0129] (Test Method) (Viscosity measurement test 2) According to the Japanese Pharmacopoeia, 16th Edition, "Method 2: Rotational Viscometer Method," the viscosity of each aqueous composition was measured immediately after preparation and 1, 2, and 4 weeks after preparation using a cone-and-plate rotational viscometer. The measurement conditions are shown below. Measurement equipment: Rotational rheometer (Kinexus pro+) Rotation speed (S -1 ): 50 / sec ·Measurement temperature: 25℃

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

[0131] (Consideration) (Viscosity measurement test 2) As shown in Figure 3, the viscosity of the aqueous composition containing atropine and hydroxypropyl methylcellulose but not a tonicity agent (Example 23, "Nothing" in Figure 3) decreased over time. On the other hand, the viscosity of the aqueous compositions containing glycerin or mannitol as a tonicity agent (Examples 24 and 25, "Glycerin" or "Mannitol" in Figure 3) was maintained, and the decrease in viscosity over time was suppressed. Furthermore, as shown in Figure 4, the viscosity of the aqueous composition containing atropine and a carboxyvinyl polymer but not a tonicity agent (Example 26, "Not Contained" in Figure 4) decreased over time. On the other hand, the viscosity of the aqueous compositions containing glycerin or mannitol as a tonicity agent (Examples 27 and 28, "Glycerin" or "Mannitol" in Figure 4) was maintained, and the decrease in viscosity over time was suppressed.

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

[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. TIFF2025176149000009.tif46149

[0134] (Test Method) Experimental Myopia Mouse Model: A spectacle-lens-induced myopia model was created by attaching a -10D lens to the right eye of a mouse (C57BL / 6J) at 24 days of age. The experimental eye was used. A -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 temporarily glued to a Velcro® ring (8 mm base curve). One piece of this lens was then attached to Velcro® glued to the hair around the experimental right eye using cyanoacrylate. Through this setup, a 1.5 mm gap was confirmed between the posterior part of the lens and the anterior corneal surface.

[0135] Ocular biometry: Ocular biometry, such as axial length and refractive error measurements, was performed using an in vivo Optical Low Coherence Interferometry (OLCI-AcMaster) and an automated eccentric photorefractor, respectively. Axial length was measured on postnatal days 38 and 66, while refraction of the animals' eyes was measured on postnatal days 52 and 66. Drug treatment: Atropine sulfate (at a concentration of 0.01%) was administered once daily, with or without hydroxyethylcellulose, to a spectacle-lens-induced myopia model from postnatal day 39 to 66. 7 μL of each drug was administered topically to the right eye under dim red light each day.

[0136] (Test results) (1) Suppressive effect on axial lengthening The results of Examples B to D are shown in Table 9. The rate of inhibition 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] Inhibition rate of axial length elongation by the sample of Example B (%) = TIFF2025176149000010.tif13151 Inhibition rate of axial length elongation by the sample of Example C (%) = TIFF2025176149000011.tif13151 Inhibition rate of axial length elongation by sample of Example D (%) = TIFF2025176149000012.tif13151 TIFF2025176149000013.tif2984

[0137] (2) Refractive error improvement effect The results of Examples A to D are shown in Table 10. Change in refractive error (diopters) = [refractive index on day 66 (diopters)] - [refractive index on day 52 (diopters)] TIFF2025176149000014.tif3586

[0138] (Consideration) The aqueous composition containing a water-soluble polymer but not atropine (Example B) did not exhibit any inhibitory effect on axial elongation. On the other hand, it was found that the addition of a water-soluble polymer to an aqueous composition containing atropine (Example D) exhibited a stronger inhibitory effect on axial elongation than the aqueous composition containing atropine but not a water-soluble polymer (Example C). Furthermore, similar to the above-mentioned effect of inhibiting axial length elongation, it was found that adding a water-soluble polymer to an aqueous composition containing atropine (Example D) exhibited a stronger effect of improving refractive error than an aqueous composition containing atropine but not a water-soluble polymer (Example C). As is clear from the results of Examples 1 and 3 in Tables 1 and 2, it has been shown that the addition of a water-soluble polymer does not affect the mydriatic effect of atropine. Therefore, an aqueous composition containing atropine and a water-soluble polymer is expected to be a drug for inhibiting the progression of myopia with little mydriatic effect.

[0139] Formulation example The pharmaceutical agent of the present invention will be explained in more detail with reference to formulation examples, but the present invention is not limited to these formulation examples.

[0140] Formulation Example 1: Eye drops (0.01% (w / v)) TIFF2025176149000015.tif4094 Add the above-listed atropine sulfate hydrate and other ingredients to sterile purified water. Mix these ingredients well to prepare the above eye drops.

[0141] Formulation Example 2: Eye drops (0.004% (w / v)) TIFF2025176149000016.tif4094 Add the above-listed atropine sulfate hydrate and other ingredients to sterile purified water. Mix these ingredients well to prepare the above eye drops. [Industrial Applicability]

[0142] An aqueous composition containing atropine or its salt at a concentration of 0.001-0.1% (w / v), a water-soluble polymer, and a first buffer, and having a pH 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, tartrate buffer, borate buffer, and trometamol, has been shown to have excellent effects of inhibiting axial elongation and improving refractive errors without exacerbating the mydriatic effect of atropine. It has also been shown that the absence of benzalkonium chloride or the inclusion of a limited amount of benzalkonium chloride results in a low mydriatic effect. Furthermore, it has been shown that the inclusion of a nonionic tonicity agent in an aqueous composition containing atropine or its salt and a water-soluble polymer and having a pH of 6 or less inhibits the decrease in viscosity of the aqueous composition over time imparted by the water-soluble polymer and maintains the stability of atropine or its salt. The aqueous compositions are expected to slow or prevent the progression of myopia, provide lower mydriatic effects, lower loss of accommodation, and be optimal in terms of quality of life.

Claims

1. 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 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 a phosphate buffer, an aminocarboxylic acid buffer, a carbonate buffer, and an acetate buffer.

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 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 tartrate buffer is 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 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 according to 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 methyl cellulose.

11. 11. The aqueous composition of 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 to 0.1% (w / v), hydroxyethyl cellulose, and a first buffer, the aqueous composition having a pH in the range of 6 or less, wherein the first buffer is a phosphate buffer.

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

14. 14. The aqueous composition of any one of claims 1 to 13, 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 of any one of claims 1 to 19, wherein the concentration of the buffering agent is 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 of any one of claims 16 to 23, wherein the concentration of the non-ionic tonicity agent is 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 buffer, citrate buffer, aminocarboxylic acid buffer, carbonate buffer, acetate buffer, tartrate buffer, borate buffer, 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 of 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, wherein the pH is 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 its salt 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 its salt 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 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. 39. 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 nonionic tonicity agent to the aqueous composition, the 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 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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