Atropine-containing aqueous pharmaceutical composition

Abstract

Provided is an aqueous pharmaceutical composition for treating, preventing, and / or inhibiting the progression of myopia. [Solution] The aqueous pharmaceutical composition contains atropine or a salt thereof at a concentration of 0.025% (w / v), and is intended to be administered to myopic patients aged 12 to 15 years.

Description

[Technical Field]

[0001] The present invention relates to an aqueous pharmaceutical composition containing atropine or a salt thereof. Specifically, the present invention relates to an aqueous pharmaceutical composition for treating, preventing, and / or inhibiting the progression of myopia, comprising atropine or a salt thereof at a concentration of 0.025% (w / v), the aqueous pharmaceutical composition being characterized in that the composition is administered to myopic patients aged 12 to 15. [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, causing objects to appear blurred. Myopia is thought to occur when the refractive power of the cornea or lens is too strong, causing distant objects to not be focused on the retina but to be focused in front of the retina (refractive myopia), or when the axial length (the length from the cornea to the retina) is elongated and longer than normal, causing distant objects to not be focused on the retina but to be focused in front of the retina even if the lens is made sufficiently thin (axial myopia).

[0003] Myopia is treated by surgery, correction with glasses or contact lenses, or drug therapy, but no fundamental treatment exists. In recent years, research into drug therapy has been actively conducted, and drugs that can slow or prevent the progression of myopia have been reported. Atropine is one of these drugs, and is known to have the property of inhibiting axial elongation. For example, Patent Document 1 discloses 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 and having a pH of 6 or less has an excellent effect of inhibiting axial elongation and improving refractive errors without exacerbating the mydriatic effect of atropine. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] WO2017 / 204262 Summary of the Invention [Problem to be solved by the invention]

[0005] Myopia generally develops during childhood and progresses at a rate of approximately 0.50 diopters per year until age 15-16. Furthermore, the onset of myopia at a young age or its rapid progression can lead to severe myopia in adulthood, accompanied by pathological myopic lesions that cause visual impairment. Therefore, when developing drugs that can improve myopia or slow its progression, it is extremely important to consider drugs for young myopic patients.

[0006] The present invention has been made in view of the above circumstances, and an object of the present invention is to find an atropine-containing aqueous pharmaceutical composition that is useful for treating, preventing, and / or inhibiting the progression of myopia. [Means for solving the problem]

[0007] The present inventors have conducted extensive research into aqueous compositions containing atropine and have surprisingly found that when an aqueous composition containing atropine or a salt thereof at a concentration of 0.025% (w / v) is administered to myopic patients aged 5 to 15, the change in spherical equivalent (SE) from before administration in 12 to 15-year-old myopic patients is 0.00 diopters (D) or more, even 12 months after the start of administration, thereby achieving a greater effect in inhibiting the progression of myopia, which led to the completion of the present invention.

[0008] Specifically, the present invention provides the following: (1) An aqueous pharmaceutical composition for the treatment, prevention, and / or suppression of the progression of myopia, comprising atropine or a salt thereof at a concentration of 0.025% (w / v), the aqueous pharmaceutical composition being used to administer to myopic patients aged 12 to 15. (2) The aqueous pharmaceutical composition according to (1) above, wherein the treatment, prevention, and / or inhibition of the progression of myopia is improvement of refractive error. (3) The aqueous pharmaceutical composition according to (1) or (2) above, characterized in that it is used in a myopic patient so that the change in spherical equivalent (SE) from before administration to 4 months after the start of administration is 0.00 to +0.20 diopters (D). (4) The aqueous pharmaceutical composition according to (1) or (2) above, characterized in that it is used in a myopic patient so that the change in spherical equivalent (SE) from before administration to 4 months after the start of administration is 0.00 to +0.15 diopters (D). (5) The aqueous pharmaceutical composition according to (1) or (2) above, characterized in that it is used in a myopic patient so that the change in spherical equivalent (SE) from before administration to 4 months after the start of administration is 0.00 to +0.10 diopters (D). (6) The aqueous pharmaceutical composition according to (1) or (2) above, characterized in that it is used in a myopic patient so that the change in spherical equivalent (SE) from before administration to 4 months after the start of administration is 0.00 to +0.05 diopters (D). (7) The aqueous pharmaceutical composition according to any one of (3) to (6) above, wherein the change in spherical equivalent (SE) from before administration is the change in spherical equivalent (SE) from before administration 8 months after the start of administration. (8) The aqueous pharmaceutical composition according to any one of (3) to (6) above, wherein the change in spherical equivalent (SE) from before administration is the change in spherical equivalent (SE) from before administration 12 months after the start of administration. (9) The aqueous pharmaceutical composition according to (1) above, wherein the treatment, prevention, and / or inhibition of the progression of myopia is inhibition of axial elongation. (10) The aqueous pharmaceutical composition according to any one of (1) to (9) above, characterized in that it is used to achieve a change in axial length of −0.05 to 0.05 mm from before administration to a myopic patient 4 months after the start of administration. (11) The aqueous pharmaceutical composition according to any one of (1) to (9) above, characterized in that it is used to achieve a change in axial length of −0.03 to 0.03 mm from before administration to a myopic patient 4 months after the start of administration. (12) The aqueous pharmaceutical composition according to any one of (1) to (9) above, characterized in that it is used to achieve a change in axial length of −0.01 to 0.01 mm from before administration to a myopic patient 4 months after the start of administration. (13) The aqueous pharmaceutical composition according to any one of (10) to (12) above, wherein the change in axial length from before administration is the change in axial length from before administration 8 months after the start of administration. (14) The aqueous pharmaceutical composition according to any one of (10) to (12) above, wherein the change in axial length from before administration is the change in axial length from before administration 12 months after the start of administration. (15) The aqueous pharmaceutical composition according to any one of (1) to (14) above, which has substantially no mydriatic effect. (16) The aqueous pharmaceutical composition according to any one of (1) to (15) above, wherein the composition is administered by instilling one drop per eye once a day. (17) The aqueous pharmaceutical composition according to (16) above, which is used by being instilled into the eyes before going to bed. (18) The aqueous pharmaceutical composition according to any one of (1) to (17) above, wherein the atropine or a salt thereof is atropine sulfate or a hydrate thereof. (19) The aqueous pharmaceutical composition according to any one of (1) to (18) above, which is an eye drop. (20) An aqueous pharmaceutical composition for the treatment, prevention, and / or inhibition of the progression of myopia, comprising atropine or a salt thereof at a concentration of 0.025% (w / v), wherein the treatment, prevention, and / or inhibition of the progression of myopia is an improvement in refractive error, the aqueous pharmaceutical composition is administered to a myopic patient aged 12 to 15 years, and the amount of change in spherical equivalent (SE) from before administration 4 months after the start of administration is 0.00 to +0.20 diopters (D). (21) An aqueous pharmaceutical composition for the treatment, prevention, and / or inhibition of the progression of myopia, comprising atropine or a salt thereof at a concentration of 0.025% (w / v), wherein the treatment, prevention, and / or inhibition of the progression of myopia is inhibition of axial length elongation, the aqueous pharmaceutical composition being administered to myopic patients aged 12 to 15 years, so that the amount of change in axial length from before administration 4 months after the start of administration is -0.05 to 0.05 mm. (22) The aqueous pharmaceutical composition according to any one of (1) to (21) above, which is contained in a unit-dose container. (23) The aqueous pharmaceutical composition according to any one of (1) to (21) above, which is contained in a multidose container.

[0009] It should be noted that any two or more of the above configurations (1) to (23) can be selected and combined.

[0010] Furthermore, the present invention also provides the following: (24) A method for treating and / or preventing myopia, comprising administering to a myopic patient aged 12 to 15 in need of treatment an aqueous pharmaceutical composition containing a therapeutically effective amount of atropine or a salt thereof at a concentration of 0.025% (w / v). (25) A method for inhibiting the progression of myopia, comprising administering to a myopic patient aged 12 to 15 years in need of treatment an aqueous pharmaceutical composition containing a therapeutically effective amount of atropine or a salt thereof at a concentration of 0.025% (w / v). (26) A method for improving refractive error, comprising administering to a myopic patient aged 12 to 15 years in need of treatment an aqueous pharmaceutical composition containing a therapeutically effective amount of atropine or a salt thereof at a concentration of 0.025% (w / v). (27) A method for inhibiting axial elongation, comprising administering to a 12-15 year old myopic patient in need of treatment an aqueous pharmaceutical composition containing a therapeutically effective amount of atropine or a salt thereof at a concentration of 0.025% (w / v). (28) Use of an aqueous pharmaceutical composition containing atropine or a salt thereof at a concentration of 0.025% (w / v) for producing a myopia treatment agent for myopic patients aged 12 to 15 years. (29) Use of an aqueous pharmaceutical composition containing atropine or a salt thereof at a concentration of 0.025% (w / v) for producing a myopia preventive agent for myopic patients aged 12 to 15 years. (30) Use of an aqueous pharmaceutical composition containing atropine or a salt thereof at a concentration of 0.025% (w / v) for producing a myopia progression inhibitor for myopic patients aged 12 to 15 years. (31) An aqueous pharmaceutical composition for use in the treatment, prevention, and / or suppression of the progression of myopia, comprising atropine or a salt thereof at a concentration of 0.025% (w / v), the aqueous pharmaceutical composition being administered to a myopic patient aged 12 to 15 years. (32) An aqueous pharmaceutical composition for use in improving refractive errors, comprising atropine or a salt thereof at a concentration of 0.025% (w / v), the aqueous pharmaceutical composition being administered to a myopic patient aged 12 to 15 years. (33) An aqueous pharmaceutical composition for use in inhibiting axial elongation, comprising atropine or a salt thereof at a concentration of 0.025% (w / v), the aqueous pharmaceutical composition being administered to a myopic patient aged 12 to 15 years.

[0011] It should be noted that any two or more of the above configurations (1) to (33) can be selected and combined. [Effects of the Invention]

[0012] The present invention provides a myopia treatment, prevention, and / or myopia progression suppression agent for myopic patients aged 12 to 15. More specifically, by administering an aqueous pharmaceutical composition containing atropine or a salt thereof at a concentration of 0.025% (w / v) to a myopic patient aged 12 to 15, the change in spherical equivalent (SE) from before administration is 0.00 diopters (D) or more even 12 months after the start of administration, improving refractive error and providing a higher myopia progression suppression effect. DETAILED DESCRIPTION OF THE INVENTION

[0013] The present invention will be described in detail below.

[0014] The aqueous pharmaceutical composition of the present invention contains "atropine or a salt thereof" as an active ingredient.

[0015] In the present invention, "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.

[0016] The salt of atropine includes, for example, atropine sulfate or a hydrate thereof. The salt of atropine is preferably atropine sulfate hydrate. Atropine sulfate hydrate has the following structure: [ka] It is a compound represented by the formula:

[0017] 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.

[0018] Atropine or a salt thereof may be produced according to a conventional method in the field of organic synthetic chemistry, or a commercially available product may be used. For example, atropine sulfate hydrate is commercially available from Tokyo Chemical Industry Co., Ltd. (product code: A0550).

[0019] In the aqueous pharmaceutical composition of the present invention, the content of atropine or a salt thereof is preferably 0.025% (w / v). In the present invention, "% (w / v)" refers to the mass (g) of the target ingredient contained in 100 mL of the aqueous pharmaceutical composition of the present invention. When a salt of atropine is contained in the present invention, the value refers to the content of the atropine salt. Furthermore, when atropine or a salt thereof is contained in the present invention in the form of a hydrate or organic solvate, the value refers to the content of the hydrate or organic solvate of atropine or a salt thereof. The same applies hereinafter unless otherwise specified.

[0020] In the present invention, "aqueous pharmaceutical composition" and "aqueous composition" refer to a composition containing water as a solvent. The content of water in the aqueous pharmaceutical composition of the present invention is not particularly limited as long as it is an amount usable as an aqueous composition, but is preferably 10% (w / v) or more, more preferably 30% (w / v) or more, and even more preferably 50% (w / v) or more, based on the total weight of the aqueous pharmaceutical composition. In particular, it is preferably 70% (w / v) or more, more preferably 90% (w / v) or more, and even more preferably 95% (w / v) or more.

[0021] In the present invention, " myopia " is defined as the refractive state of eye that the parallel light rays that enter eye under unaccommodated condition form an image in front of retina.In the present invention, " myopia " includes all known classifications and definitions of myopia, for example, can include refractive myopia, axial myopia, pseudomyopia, pathological myopia, simple myopia, extreme myopia, very strong myopia, strong myopia, moderate myopia, weak myopia, myopia that develops glaucoma (particularly juvenile glaucoma), myopia that has the risk of developing glaucoma, myopia that is accompanied by high intraocular pressure etc., preferably can include refractive myopia, axial myopia, extreme myopia, very strong myopia, strong myopia, myopia that develops glaucoma (particularly juvenile glaucoma), more preferably can include refractive myopia and axial myopia, and even more preferably can include axial myopia.

[0022] In the present invention, "treatment" means any treatment of myopia or symptoms associated therewith, such as curing or improving myopia, particularly refractive myopia and / or axial myopia, and alleviating or suppressing symptoms associated with myopia. It also includes preventing the recurrence of myopia. In the present invention, "prevention" means preventing the onset of myopia, delaying the onset of myopia, or reducing the risk of onset of myopia. In the present invention, "suppressing the progression of myopia" means slowing the progression of myopia (retardation of the progression of myopia) or reducing the progression of myopia (attenuation of the progression of myopia). In the present invention, "treating, preventing, and / or inhibiting the progression of myopia" also includes inhibiting axial elongation and / or improving or inhibiting refractive errors.

[0023] The "myopic patient" in the present invention may be a patient who has just developed myopia, a patient who has developed myopia less than one year ago, a patient who has developed myopia one to less than five years ago, or a patient who has developed myopia five years or more ago, and the period during which myopia has developed is not particularly limited. The "myopic patient" in the present invention is preferably a myopic patient aged 12 to 15 years.

[0024] In the present invention, "therapeutically effective amount" means an amount that provides a therapeutic effect on myopia and its associated symptoms, or an amount that delays the onset or progression of myopia, compared to an untreated subject.

[0025] In the present invention, the "amount of change in spherical equivalent power (SE) from before administration" refers to the change in power (D) from the reference spherical equivalent power (D) at each time point after administration of the aqueous pharmaceutical composition of the present invention. Here, "spherical equivalent power (SE)" refers to the power obtained by converting half of the astigmatic power into spherical power so that the position of the circle of least confusion does not change. In the present invention, the change in spherical equivalent power (SE) from before administration is preferably 0.00 diopter (D) or more, and for example, the change in spherical equivalent power (SE) from before administration 4 months after the start of administration may be 0.00 to +0.20 diopter (D), preferably 0.00 to +0.15 diopter (D), more preferably 0.00 to +0.10 diopter (D), and particularly preferably 0.00 to +0.05 diopter (D). The change in spherical equivalent power (SE) from before administration may also be the change in spherical equivalent power (SE) from before administration 8 months after the start of administration and the change in spherical equivalent power (SE) from before administration 12 months after the start of administration.

[0026] In the present invention, the "amount of change in axial length from before administration" refers to the length (mm) elongated or shortened from the axial length (mm) before administration of the aqueous pharmaceutical composition of the present invention at each time point after administration. In the present invention, the change in axial length from before administration is preferably 0 mm or less, and for example, the change in axial length from before administration 4 months after the start of administration may be -0.05 to 0.05 mm, preferably -0.03 to 0.03 mm, more preferably -0.01 to 0.01 mm. The change in axial length from before administration may be the change in axial length from before administration 8 months after the start of administration or the change in axial length from before administration 12 months after the start of administration.

[0027] In the present invention, "having substantially no mydriatic effect" means that the mydriatic effect is not at a level that interferes with daily life. In addition to having no mydriatic effect at all, even if the mydriatic effect is confirmed by some measurement method, if the patient does not experience any visual side effects such as glare or mydriatic dilation that interfere with daily life, the substance is considered to have "substantially no mydriatic effect."

[0028] Unless otherwise specified, the aqueous pharmaceutical composition of the present invention may contain a pharmaceutically acceptable active ingredient other than atropine or a salt thereof.

[0029] The aqueous pharmaceutical composition of the present invention may contain pharmaceutically acceptable additives as needed. Examples of pharmaceutically acceptable additives that can be added include water-soluble polymers, buffers, isotonicity agents, preservatives, stabilizers, surfactants, pH adjusters, etc. These may be used alone or in appropriate combinations of two or more, and may be contained in appropriate amounts.

[0030] The aqueous pharmaceutical composition of the present invention may contain, as appropriate, a water-soluble polymer that can be used as an additive for pharmaceuticals. Examples of water-soluble polymers include celluloses or derivatives thereof (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 or saccharides (e.g., gum arabic, sodium alginate, propylene glycol alginate, agar, gelatin, tragacanth, and xanthan gum).

[0031] When the aqueous pharmaceutical composition of the present invention contains a water-soluble polymer, the content of the water-soluble polymer can be adjusted appropriately depending on the type of water-soluble polymer, but is preferably 0.01 to 5% (w / v), more preferably 0.1 to 2% (w / v). Furthermore, when the aqueous pharmaceutical composition of the present invention contains a water-soluble polymer, one type of water-soluble polymer may be used, or two or more types of water-soluble polymers may be used together.

[0032] The aqueous pharmaceutical composition of the present invention may contain, as appropriate, a buffer that can be used as an additive for pharmaceuticals. Examples of the buffer include phosphate buffer, citrate buffer, borate buffer, carbonate buffer, acetate buffer, tartrate buffer, aminocarboxylic acid buffer, trometamol, etc.

[0033] When the aqueous pharmaceutical composition of the present invention contains a buffer, the content of the buffer can be adjusted appropriately depending on the type of buffer, etc., but is preferably 0.001 to 10% (w / v), more preferably 0.01 to 5% (w / v), even more preferably 0.01 to 3% (w / v), even more preferably 0.01 to 1% (w / v), particularly preferably 0.01 to 0.5% (w / v), and most preferably 0.01 to 0.1% (w / v). Furthermore, when the aqueous pharmaceutical composition of the present invention contains a buffer, one type of buffer may be used, or two or more types of buffers may be used together.

[0034] In the present invention, the phosphate buffer may be made from any pharmaceutically acceptable phosphate buffer. Examples of phosphate buffers include phosphoric acid; phosphate salts such as alkali metal phosphates and alkaline earth metal phosphates; and hydrates thereof. Specific examples thereof include sodium hydrogen phosphate hydrate, sodium dihydrogen phosphate (sometimes referred to as "monosodium phosphate"), sodium dihydrogen phosphate monohydrate, sodium dihydrogen phosphate dihydrate (sometimes simply referred to as "sodium dihydrogen phosphate hydrate"), potassium dihydrogen phosphate (sometimes referred to as "monopotassium phosphate"), sodium hydrogen phosphate heptahydrate, trisodium phosphate, and dipotassium phosphate.

[0035] When the aqueous pharmaceutical composition of the present invention contains a phosphate buffer, the content of the phosphate buffer can be adjusted appropriately depending on the type of phosphate buffer, etc., but 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).

[0036] In the present invention, the citrate buffer may be any pharmaceutically acceptable citrate buffer. Examples of citrate buffers include citric acid; citrate salts such as alkali metal citrates and alkaline earth metal citrates; and hydrates thereof. Specific examples include citric acid hydrate, sodium citrate, sodium citrate hydrate, potassium citrate, calcium citrate, sodium dihydrogen citrate, and disodium citrate.

[0037] When the aqueous pharmaceutical composition of the present invention contains a citrate buffer, the content of the citrate buffer can be adjusted appropriately depending on the type of citrate buffer, etc., but 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).

[0038] In the present invention, the borate buffer may be any pharmaceutically acceptable borate buffer. Examples of borate buffers include boric acid or its salts, borax, etc. Specific examples include boric acid, sodium borate, potassium borate, potassium tetraborate, potassium metaborate, ammonium borate, borax, etc.

[0039] In the present invention, the carbonate buffer may be made from any pharmaceutically acceptable carbonate buffer. Examples of carbonate buffers include carbonic acid and salts thereof. Specific examples include carbonic acid, sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, magnesium carbonate, etc.

[0040] In the present invention, the acetate buffer may be made from any pharmaceutically acceptable acetate buffer. Examples of acetate buffers include acetic acid and its salts. Specific examples include acetic acid, ammonium acetate, potassium acetate, calcium acetate, and sodium acetate.

[0041] In the present invention, the tartrate buffer may be any pharmaceutically acceptable tartrate buffer. Examples of tartrate buffers include tartaric acid and its salts. Specific examples include sodium tartrate and potassium tartrate.

[0042] In the present invention, examples of aminocarboxylic acid buffers include aspartic acid buffers, glutamic acid buffers, ε-aminocaproic acid, etc. Examples of aspartic acid buffers include aspartic acid or salts thereof, specific examples of which include sodium aspartate and magnesium aspartate, etc. Examples of glutamic acid buffers include glutamic acid or salts thereof, specific examples of which include sodium glutamate and potassium glutamate, etc.

[0043] The aqueous pharmaceutical composition of the present invention may contain an isotonicity agent that can be used as an additive for pharmaceuticals, such as an ionic isotonicity agent or a non-ionic isotonicity agent.

[0044] Examples of ionic tonicity agents include sodium chloride, potassium chloride, calcium chloride, and magnesium chloride, and examples of nonionic tonicity agents include glycerin (concentrated glycerin), mannitol, propylene glycol, polyethylene glycol, glucose, sorbitol, xylitol, and trehalose.

[0045] When the aqueous pharmaceutical composition of the present invention contains an isotonicity agent, the content of the isotonicity agent can be appropriately adjusted depending on the type of isotonicity agent, but is preferably 0.01 to 10% (w / v), more preferably 0.05 to 5% (w / v), even more preferably 0.1 to 5% (w / v), even more preferably 0.5 to 5% (w / v), and particularly preferably 1 to 5% (w / v). When the aqueous pharmaceutical composition of the present invention contains an isotonicity agent, one or more isotonicity agents may be used together.

[0046] The aqueous pharmaceutical composition of the present invention may contain a preservative that can be used as an additive for pharmaceuticals, as appropriate. Examples of preservatives include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, chlorhexidine gluconate, chlorhexidine hydrochloride, parabens (e.g., methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate), sodium chlorite, phenoxyethanol, sorbic acid, and chlorobutanol.

[0047] When the aqueous pharmaceutical composition of the present invention contains a preservative, the content of the preservative can be appropriately adjusted depending on the type of preservative, and is, for example, 0.001 to 1% (w / v). When the aqueous pharmaceutical composition of the present invention contains a preservative, one type of preservative or two or more types of preservatives may be used together.

[0048] The aqueous pharmaceutical composition of the present invention may contain a stabilizer that can be used as an additive for pharmaceuticals. Examples of stabilizers include edetic acid or its salts, cyclodextrin, etc., which may be in the form of a hydrate or solvate. Examples of salts of edetic acid include disodium edetate (hereinafter sometimes referred to as "sodium edetate") and tetrasodium edetate. When the pharmaceutical composition of the present invention contains a stabilizer, the content of the stabilizer can be appropriately adjusted depending on the type of stabilizer, for example, 0.01 to 1% (w / v), although this is not limited thereto when the stabilizer has an effect other than as a stabilizing agent. Furthermore, when the aqueous pharmaceutical composition of the present invention contains a stabilizer, one type of stabilizer may be used, or two or more types of stabilizers may be used together.

[0049] In the present invention, the aqueous pharmaceutical composition may contain a surfactant that can be used as an additive for pharmaceuticals, such as polyoxyethylene sorbitan monooleate, polyoxyl 40 stearate, and polyoxyethylene hydrogenated castor oil. When the pharmaceutical composition of the present invention contains a surfactant, the content of the surfactant can be appropriately adjusted depending on the type of surfactant, and is, for example, 0.01 to 1% (w / v). When the aqueous pharmaceutical composition of the present invention contains a surfactant, one type of surfactant may be used, or two or more types of surfactants may be used together.

[0050] In the present invention, the aqueous pharmaceutical composition may contain a pH adjuster that can be used as an additive for pharmaceuticals. The pH adjuster may be, for example, an acid or a base. Examples of acids include hydrochloric acid, phosphoric acid, acetic acid, and citric acid, and examples of bases include sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate.

[0051] The pH of the aqueous pharmaceutical composition of the present invention may be within a pharmaceutically acceptable range, preferably 6 or less, more preferably 4 to 6, even more preferably 4 to 5, and particularly preferably around 4 or 5. The pH of the aqueous pharmaceutical composition of the present invention may be, for example, 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, or 6.0. When the aqueous pharmaceutical composition of the present invention contains a pH adjuster, one or more pH adjusters may be used in combination.

[0052] The aqueous pharmaceutical composition of the present invention is preferably used as an eye drop, particularly an aqueous eye drop.

[0053] The dosage of the aqueous pharmaceutical composition of the present invention is not particularly limited as long as it is sufficient to achieve the desired medicinal effect. The aqueous pharmaceutical composition of the present invention may be instilled into the eyes, preferably 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.

[0054] In the present invention, the term "unit-dose container" refers to an eye drop container having a cap fused to the mouth of the bottle, which is intended to be opened by breaking the fused portion between the cap and the bottle-shaped body at the time of use. The unit-dose container may contain an amount of aqueous pharmaceutical composition for single use, or may contain an amount of aqueous pharmaceutical composition for use in one day that is sufficient for several uses.

[0055] In the present invention, the term "multi-dose container" refers to an eye drop container comprising a container body and a cap that can be attached to the container body, and the cap can be freely opened and resealed. The multi-dose container usually contains multiple doses of an aqueous pharmaceutical composition for use over a certain period of time.

[0056] The aqueous pharmaceutical composition of the present invention can be contained in a unit-dose container or a multi-dose container. When the aqueous pharmaceutical composition of the present invention is substantially free of preservatives such as benzalkonium chloride, it is preferably contained in a unit-dose container.

[0057] Furthermore, the osmotic pressure of the aqueous pharmaceutical 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 pharmaceutical 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 pharmaceutical composition is affected to some extent by the amount of drug and additives in the aqueous pharmaceutical 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 pharmaceutical composition of the present invention can be measured by conventional methods. For example, the osmotic pressure of the aqueous pharmaceutical composition of the present invention can be measured according to the method described in the "Osmolality Measurement Method" in the 18th Edition of the Japanese Pharmacopoeia. [Example]

[0058] Representative formulation examples using the aqueous pharmaceutical composition of the present invention are shown below, but the present invention is not limited to these formulation examples. In the formulation examples below, the content (% (w / v)) of each component is the content (g) in 100 mL of the aqueous pharmaceutical composition.

[0059] [Table 1]

[0060] [Table 2]

[0061] [Table 3]

[0062] [Table 4]

[0063] [Table 5]

[0064] [Table 6]

[0065] [Table 7]

[0066] [Table 8]

[0067] The following 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.

[0068] Example 1: Effect of an aqueous composition containing atropine on myopic patients aged 5 to 15 (spherical equivalent (SE)) According to the following method, the change in spherical equivalent (SE) from before administration to after administration of the placebo and the atropine-containing aqueous composition was calculated, and the effect of the atropine-containing aqueous composition on myopic patients aged 5 to 15 years was evaluated.

[0069] (Sample preparation) Atropine sulfate hydrate (0.1 mg), sodium dihydrogen phosphate dihydrate, sodium citrate hydrate, concentrated glycerin, and hydroxyethyl cellulose were dissolved in purified water, and a pH adjuster (dilute hydrochloric acid and / or sodium hydroxide) and purified water were added to make a total volume of 1 mL to prepare a 0.01% atropine-containing aqueous composition. Atropine sulfate hydrate (0.25 mg), sodium dihydrogen phosphate dihydrate, sodium citrate hydrate, concentrated glycerin, and hydroxyethyl cellulose were dissolved in purified water, and a pH adjuster (dilute hydrochloric acid and / or sodium hydroxide) and purified water were added to make a total volume of 1 mL to prepare a 0.025% atropine-containing aqueous composition. Furthermore, as a placebo (control), an aqueous composition not containing atropine sulfate hydrate was prepared by dissolving sodium dihydrogen phosphate dihydrate, sodium citrate hydrate, concentrated glycerin, and hydroxyethyl cellulose in purified water, and adding a pH adjuster (dilute hydrochloric acid and / or sodium hydroxide) and purified water to make the total volume 1 mL.

[0070] (Test Method) Patients aged 5 to 15 years who had been diagnosed with myopia in both eyes were enrolled. Placebo, an aqueous composition containing 0.01% atropine, or an aqueous composition containing 0.025% atropine were administered as one drop once daily (before bedtime) to both eyes for 24 months.

[0071] (Evaluation method) The patient was administered 1% Cypressin (registered trademark) eye drops twice at 5-minute intervals to induce cycloplegia. The patient was checked 45 minutes after the last instillation to determine whether cycloplegia had occurred. If the patient was determined to have insufficient cycloplegia, another 1% Cypressin (registered trademark) eye drops was administered. Next, under cycloplegia, the spherical power, cylindrical power, and cylindrical axis angle of both eyes of the patient were measured five times using an autorefractor. The values for spherical power and cylindrical power of both eyes were adopted when the minimum and maximum values of the five measurements were within 0.50 D. From the five measurements of spherical power and cylindrical power of both eyes, the spherical equivalent power for each was calculated using the following formula, and the average spherical equivalent power was calculated. Measurements of the spherical equivalent power were performed every four months from the start of treatment. Calculation formula: Equivalent spherical power (D) = spherical power + cylindrical power x 1 / 2

[0072] (Test results) Table 9 shows the mean values (D) of spherical equivalent power (SE) in each age group for the placebo group, the 0.01% atropine-containing aqueous composition group, and the 0.025% atropine-containing aqueous composition group. [Table 9]

[0073] As shown in Table 9, in patients aged 10 to 15 years who received an aqueous composition containing 0.025% atropine, the change in spherical equivalent (SE) from pre-administration to 4 months after the start of administration was 0.00 diopters (D) or more, confirming improvement in refractive error. In particular, in patients aged 12 to 15 years who received an aqueous composition containing 0.025% atropine, improvement in refractive error was confirmed even 12 months after administration. This suggests that the aqueous composition containing 0.025% atropine has a significant effect in inhibiting the progression of myopia, particularly in myopic patients aged 12 to 15 years.

[0074] Example 2: Effect of an aqueous composition containing atropine on myopic patients aged 5 to 15 (axial length) According to the following method, the change in axial length from before administration to after administration of the placebo and the atropine-containing aqueous composition was calculated, and the effect of the atropine-containing aqueous composition on myopic patients aged 5 to 15 years was evaluated.

[0075] (Sample preparation) According to the same method as in Example 1 (Sample Preparation), an aqueous composition containing 0.01% atropine, an aqueous composition containing 0.025% atropine, and a placebo were prepared.

[0076] (Test Method) This test was carried out in the same manner as in Example 1 (Test Method).

[0077] (Evaluation method) The patient was administered 1% Cypressin (registered trademark) eye drops twice at 5-minute intervals to induce cycloplegia. The patient was checked 45 minutes after the last instillation to determine whether cycloplegia had occurred. If the patient was determined to have insufficient cycloplegia, another 1% Cypressin (registered trademark) eye drops was administered. Next, under cycloplegic conditions, the axial length of both eyes of the patients was measured using an optical axial length measuring device. Measurements of axial length were performed every four months from the start of treatment.

[0078] (Test results) Table 10 shows the mean axial length (mm) in each age group for the placebo group, the 0.01% atropine-containing aqueous composition group, and the 0.025% atropine-containing aqueous composition group. [Table 10]

[0079] As shown in Table 10, inhibition of axial length elongation was confirmed in the patient group administered the aqueous atropine-containing composition. In particular, it was confirmed that axial length did not elongate in 12-15 year old patients administered the 0.025% aqueous atropine composition 4 months after administration. This suggests that the 0.025% aqueous atropine composition is particularly effective in inhibiting the progression of myopia in 12-15 year old myopic patients. [Industrial Applicability]

[0080] The present invention provides a myopia treatment, prevention, and / or myopia progression inhibitor for myopic patients aged 12 to 15. More specifically, by administering an aqueous composition containing atropine or a salt thereof at a concentration of 0.025% (w / v) to a myopic patient aged 12 to 15, the change in spherical equivalent (SE) from before administration is 0.00 diopters (D) or more even 12 months after the start of administration, improving refractive error and providing a higher myopia progression inhibition effect.

Claims

1. 1. An aqueous pharmaceutical composition for inhibiting the progression of myopia, comprising atropine or a salt thereof at a concentration of 0.025% (w / v), the aqueous pharmaceutical composition being administered to a myopic patient aged 12 to 15 years, wherein the inhibition of the progression of myopia is characterized by an improvement in refractive error 4 to 12 months after the start of administration, and the improvement in refractive error is characterized by a change in spherical equivalent (SE) from before administration of more than 0.00 diopters (D).

2. The aqueous pharmaceutical composition according to claim 1, wherein the improvement in refractive error is achieved by changing the spherical equivalent (SE) from before administration to more than 0.00 to +0.20 diopters (D).

3. The aqueous pharmaceutical composition according to claim 1, wherein the improvement in refractive error is achieved by changing the spherical equivalent (SE) from before administration to more than 0.00 to +0.15 diopters (D).

4. The aqueous pharmaceutical composition according to claim 1, wherein the improvement in refractive error is achieved by changing the spherical equivalent (SE) from before administration to more than 0.00 to +0.10 diopters (D).

5. The aqueous pharmaceutical composition according to claim 1, wherein the improvement in refractive error is achieved by changing the spherical equivalent (SE) from before administration to more than 0.00 to +0.05 diopters (D).

6. An aqueous pharmaceutical composition for inhibiting the progression of myopia, comprising atropine or a salt thereof at a concentration of 0.025% (w / v), which is to be administered to a myopic patient aged 12 to 15 by instilling one drop per eye once daily for a 12-month administration period, and which is characterized in that the inhibition of myopia progression is such that the change in spherical equivalent (SE) from before administration exceeds 0.00 diopters (D).

7. 7. The aqueous pharmaceutical composition according to claim 1, wherein the composition is administered by instillation into the eyes before going to bed.

8. 7. The aqueous pharmaceutical composition according to claim 1, wherein the atropine or a salt thereof is atropine sulfate or a hydrate thereof.

9. The aqueous pharmaceutical composition according to any one of claims 1 to 6, which is an eye drop.

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