Atropine-containing aqueous pharmaceutical composition

Abstract

To provide a medicine that exhibits effects such as improving myopia and suppressing the progression of myopia in young patients. [Solution] An aqueous pharmaceutical composition for the treatment, prevention and / or inhibition of myopia, comprising a 0.025% (w / v) concentration of atropine or a salt thereof, characterized in that it is used 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 is an aqueous pharmaceutical composition for the treatment, prevention, and / or suppression of the progression of myopia, containing atropine or a salt thereof at a concentration of 0.025% (w / v), and is characterized by being used for administration to myopic patients aged 12 to 15 years.

Background Art

[0002] Myopia is a type of refractive error, referring to a state where light entering the eye from afar forms an image in front of the retina, and objects appear blurred. Myopia occurs when the refractive power of the cornea or lens is too strong, and when looking at a distant object, the focus does not fall on the retina but in front of it (refractive myopia), or when the axial length of the eye (the length from the cornea to the retina) is elongated and too long compared to normal, and even when the lens is made sufficiently thin when looking at a distant object, the focus does not fall on the retina but in front of it (axial myopia).

[0003] For the treatment of myopia, surgery, correction with glasses or contact lenses, or drug therapy is used, but there is no fundamental treatment method. In recent years, research on drug therapy has been actively conducted, and drugs that can suppress or prevent the progression of myopia have been reported. Atropine is one of the drugs therein and is known to have the property of suppressing the elongation of the axial length of the eye. For example, Patent Document 1 discloses that an aqueous composition containing atropine or a salt thereof at a concentration of 0.001 to 0.1% (w / v), a water-soluble polymer, and a first buffering agent and having a pH in the range of 6 or less has an excellent effect of suppressing the elongation of the axial length of the eye and improving refractive error without worsening the mydriatic effect of atropine.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

[0005] Myopia generally develops during childhood and progresses at a rate of approximately 0.50 diopters per year until around age 15-16. Furthermore, early onset and rapid progression of myopia can lead to severe myopia in adulthood, accompanied by pathological myopic lesions that impair vision. Therefore, when developing medicines that improve or inhibit the progression of myopia, it is crucial to consider medications for young myopic patients.

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

[0007] The inventors of the present invention conducted intensive research on atropine-containing aqueous compositions and discovered that when an aqueous composition containing atropine or a salt thereof at a concentration of 0.025% (w / v) was administered to myopic patients aged 5 to 15 years, the change in equivalent spherical power (SE) from before administration was 0.00 diopters (D) or more even 12 months after the start of administration in myopic patients aged 12 to 15 years, demonstrating a higher myopia progression inhibitory effect. This 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 inhibition of myopia, comprising a 0.025% (w / v) concentration of atropine or a salt thereof, characterized in that it is used to be administered to myopic patients aged 12 to 15 years. (2) The aqueous pharmaceutical composition according to (1) above, wherein the treatment, prevention and / or suppression of myopia is an improvement in refractive error. (3) The aqueous pharmaceutical composition according to (1) or (2) above, characterized in that it is used in myopic patients so that the change in equivalent spherical power (SE) from before administration four 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 myopic patients so that the change in equivalent spherical power (SE) from before administration four 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 myopic patients so that the change in equivalent spherical power (SE) from before administration four 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 myopic patients so that the change in equivalent spherical power (SE) from before administration four 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 equivalent spherical frequency (SE) from before administration is the change in equivalent spherical frequency (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 equivalent spherical frequency (SE) from before administration is the change in equivalent spherical frequency (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 myopia progression is inhibition of axial length elongation. (10) The aqueous pharmaceutical composition according to any one of (1) to (9) above, characterized in that it is used in myopic patients so that the change in axial length of the eye from before administration four months after the start of administration is -0.05 to 0.05 mm. (11) The aqueous pharmaceutical composition according to any one of (1) to (9) above, characterized in that it is used in myopic patients so that the change in axial length of the eye from before administration four months after the start of administration is -0.03 to 0.03 mm. (12) The aqueous pharmaceutical composition according to any one of (1) to (9) above, characterized in that it is used in myopic patients so that the change in axial length of the eye from before administration four months after the start of administration is -0.01 to 0.01 mm. (13) The aqueous pharmaceutical composition according to any one of (10) to (12) above, wherein the amount of change in axial length from before administration is the amount of 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 amount of change in axial length from before administration is the amount of change in axial length from before administration 12 months after the start of administration. (15) An aqueous pharmaceutical composition according to any of (1) to (14) above, which has substantially no mydriatic effect. (16) The aqueous pharmaceutical composition according to any one of the above items (1) to (15), characterized in that it is used by instilling one drop per eye once a day. (17) The aqueous pharmaceutical composition described in (16) above, characterized in that it is used as eye drops before going to bed. (18) The aqueous pharmaceutical composition according to any one of (1) to (17) above, wherein atropine or a salt thereof is atropine sulfate or its hydrate. (19) An aqueous pharmaceutical composition according to any of (1) to (18) above, which is an eye drop. (20) An aqueous pharmaceutical composition for the treatment, prevention and / or inhibition of myopia progression, comprising a 0.025% (w / v) concentration of atropine or a salt thereof, wherein the treatment, prevention and / or inhibition of myopia progression is an improvement in refractive error, and is used to administer to myopic patients aged 12 to 15 years, and is used to achieve a change in equivalent spherical power (SE) from pre-administration to +0.20 diopters (D) four months after the start of administration. (21) An aqueous pharmaceutical composition for the treatment, prevention and / or inhibition of myopia progression, comprising a 0.025% (w / v) concentration of atropine or a salt thereof, wherein the treatment, prevention and / or inhibition of myopia progression is the inhibition of axial length elongation, and the composition is used to administer to myopic patients aged 12 to 15 years, and is used to achieve a change in axial length from pre-administration to -0.05 to 0.05 mm four months after the start of administration. (22) An aqueous pharmaceutical composition according to any of (1) to (21) above, contained in a unit dose type container. (23) An aqueous pharmaceutical composition according to any of (1) to (21) above, contained in a multi-dose container.

[0009] Furthermore, two or more of the above configurations (1) to (23) can be arbitrarily selected and combined.

[0010] Furthermore, the present invention also provides the following: (24) A method for treating and / or preventing myopia, characterized by administering an aqueous pharmaceutical composition containing a therapeutically effective amount of atropine or a salt thereof at a concentration of 0.025% (w / v) to a myopic patient aged 12 to 15 years who requires treatment. (25) A method for suppressing the progression of myopia, characterized by administering an aqueous pharmaceutical composition containing a therapeutically effective amount of 0.025% (w / v) atropine or a salt thereof to a myopic patient aged 12 to 15 years who requires treatment. (26) A method for improving refractive errors, characterized by administering an aqueous pharmaceutical composition containing a therapeutically effective amount of 0.025% (w / v) atropine or a salt thereof to a myopic patient aged 12 to 15 years who requires treatment. (27) A method for suppressing axial length elongation, characterized by administering an aqueous pharmaceutical composition containing a therapeutically effective amount of 0.025% (w / v) atropine or a salt thereof to a myopic patient aged 12 to 15 years who requires treatment. (28) Use of an aqueous pharmaceutical composition containing atropine or a salt thereof at a concentration of 0.025% (w / v) for the manufacture of 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 containing atropine or a salt thereof at a concentration of 0.025% (w / v), which is used for treating, preventing and / or inhibiting the progression of myopia, and is characterized in that it is used so as to be administered to myopic patients aged 12 to 15 years. (32) An aqueous pharmaceutical composition containing atropine or a salt thereof at a concentration of 0.025% (w / v), which is used for improving refractive error, and is characterized in that it is used so as to be administered to myopic patients aged 12 to 15 years. (33) An aqueous pharmaceutical composition containing atropine or a salt thereof at a concentration of 0.025% (w / v), which is used for inhibiting the elongation of the axial length of the eye, and is characterized in that it is used so as to be administered to myopic patients aged 12 to 15 years.

[0011] In addition, any two or more of the above-mentioned configurations (1) to (33) can be arbitrarily selected and combined.

Effects of the Invention

[0012] According to the present invention, it is possible to provide a myopia therapeutic agent, a preventive agent and / or a myopia progression inhibitor for myopic patients aged 12 to 15 years. More specifically, by applying an aqueous pharmaceutical composition containing atropine or a salt thereof at a concentration of 0.025% (w / v) to myopic patients aged 12 to 15 years, even 12 months after the start of administration, the change amount of the equivalent spherical power (SE) from before administration shows 0.00 diopter (D) or more, improving refractive error and bringing a higher myopia progression inhibitory effect.

Modes for Carrying Out the Invention

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

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

[0015] In the present invention, "atropine or its salt" includes (i) hydrates of atropine or its salts, (ii) organic solvent adducts of atropine or its salts, and (iii) mixtures of its hydrates and organic solvent adducts.

[0016] Salts of atropine include, for example, atropine sulfate or its hydrate. The salt of atropine is preferably atropine sulfate hydrate. Atropine sulfate hydrate has the following structure:

Chemical formula

[0017] When crystal polymorphs and crystal polymorph groups (crystal polymorph systems) exist in atropine or its salt, those crystal polymorphs and crystal polymorph groups (crystal polymorph systems) are also included in the scope of the present invention. Here, the crystal polymorph group (crystal polymorph system) means not only the individual crystal forms obtained at each stage when the crystal form changes due to conditions and states such as the production, crystallization, and storage of those crystals, but also mixtures of crystal forms obtained at two or more stages.

[0018] Atropine or its salt may be produced according to the usual methods in the field of organic synthetic chemistry, or commercially available products 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 its salt is preferably 0.025% (w / v). In this invention, "%(w / v)" means the mass (g) of the target component contained in 100 mL of the aqueous pharmaceutical composition of the present invention. In the present invention, if a salt of atropine is contained, the value represents the content of the salt of atropine. Furthermore, in the present invention, if atropine or a salt thereof is contained in the form of a hydrate or organic solvent hydrate, the value represents the content of the hydrate or organic solvent hydrate of atropine or a salt thereof. The same applies hereafter unless otherwise specified.

[0020] In the present invention, "aqueous pharmaceutical composition" and "aqueous composition" mean a composition containing water as a solvent. The water content in the aqueous pharmaceutical composition of the present invention is not particularly limited as long as it is an amount that can be used as an aqueous composition, but it 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 the eye in which parallel light rays entering the eye in an unaccommodated state are imaged in front of the retina. In the present invention, "myopia" includes all known classifications and definitions of myopia, such as refractive myopia, axial myopia, pseudomyopia, pathological myopia, simple myopia, extreme myopia, very severe myopia, high myopia, moderate myopia, mild myopia, myopia with glaucoma (especially juvenile glaucoma), myopia at risk of developing glaucoma, and myopia with high intraocular pressure. Preferably, refractive myopia, axial myopia, extreme myopia, very severe myopia, high myopia, and myopia with glaucoma (especially juvenile glaucoma) are included, more preferably refractive myopia and axial myopia are included, and even more preferably axial myopia is included.

[0022] In the present invention, “treatment” means any treatment of myopia or its associated symptoms, such as curing or improving myopia, particularly refractive myopia and / or axial myopia, or alleviating or suppressing symptoms associated with myopia. It also includes preventing the recurrence of myopia. In this invention, "prevention" means preventing the onset of myopia, delaying the onset of myopia, or reducing the risk of developing myopia. In this invention, "suppression of myopia progression" means slowing down the progression of myopia (delay in myopia progression) or reducing the progression of myopia (reduction in myopia progression). Furthermore, in the present invention, "treatment, prevention, and / or suppression of myopia progression" also includes suppressing elongation of the axial length of the eye and / or improving or suppressing refractive errors.

[0023] In this invention, "myopic patients" may be patients who have just developed myopia, patients who have developed myopia less than one year ago, patients who have developed myopia between one and five years ago, or patients who have developed myopia five years or more ago, and the period of myopia development is not particularly limited. In this invention, "myopic patients" are preferably myopic patients aged 12 to 15 years.

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

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

[0026] In the present invention, "change in axial length from before administration" refers to the length (mm) obtained by elongating or shortening from the axial length (mm) of the aqueous pharmaceutical composition of the present invention at each point in time after administration, based on the axial length (mm) before administration. In the present invention, the change in axial length from before administration is preferably 0 mm or less. 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, and more preferably -0.01 to 0.01 mm. The change in axial length from before administration may also be the change in axial length from before administration 8 months after the start of administration and the change in axial length from before administration 12 months after the start of administration.

[0027] In this invention, "substantially without pupillary dilation" means that the pupillary dilation is not at a level that interferes with daily life. In addition to having no pupillary dilation at all, even if pupillary dilation is confirmed by some measurement method, if the patient does not experience glare or other visual side effects of pupil dilation that interfere with daily life, it is understood that the product "substantially has no pupillary dilation."

[0028] Unless otherwise specified, the aqueous pharmaceutical composition of the present invention may contain pharmaceutically acceptable active ingredients other than atropine or its salts.

[0029] The aqueous pharmaceutical composition of the present invention may optionally contain pharmaceutically acceptable additives. Examples of pharmaceutically acceptable additives include water-soluble polymers, buffers, isotonic agents, preservatives, stabilizers, surfactants, pH adjusters, and the like. These may be used individually or in combination of two or more as appropriate, and may be included in appropriate amounts.

[0030] The aqueous pharmaceutical composition of the present invention may optionally contain a water-soluble polymer that can be used as an additive for pharmaceuticals. Examples of water-soluble polymers include celluloses or their derivatives (e.g., methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, cellulose acetate phthalate, ethylcellulose, hydroxymethylcellulose, hydroxyethyl methylcellulose, hypromellose acetate succinate, and hypromellose phthalate), synthetic polymers (e.g., polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, and carboxyvinyl polymer), and polymers or saccharides derived from natural products (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 appropriately adjusted depending on the type of water-soluble polymer, but 0.01 to 5% (w / v) is preferred, and 0.1 to 2% (w / v) is more preferred. Furthermore, when the aqueous pharmaceutical composition of the present invention contains a water-soluble polymer, one or more types of water-soluble polymers may be used together.

[0032] The aqueous pharmaceutical composition of the present invention may appropriately contain buffering agents that can be used as additives to pharmaceuticals. Examples of buffering agents include phosphate buffering agents, citrate buffering agents, borate buffering agents, carbonate buffering agents, acetate buffering agents, tartaric acid buffering agents, aminocarboxylic acid buffering agents, trometamol, and the like.

[0033] When the aqueous pharmaceutical composition of the present invention contains a buffer, the buffer content can be appropriately adjusted depending on the type of buffer, 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 or more types of buffers may be used together.

[0034] In the present invention, the phosphate buffer can be any pharmaceutically acceptable phosphate buffer as a raw material. Examples of phosphate buffers include phosphoric acid; phosphates such as alkali metal phosphates and alkaline earth metal phosphates; and their hydrates. Specific examples 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 "monosodium 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 appropriately adjusted depending on the type of phosphate buffer, but 0.01 to 1.0% (w / v) is preferred, 0.05 to 1.0% (w / v) is more preferred, and 0.05 to 0.5% (w / v) is even more preferred.

[0036] In the present invention, the citrate buffer can be any pharmaceutically acceptable citrate buffer as a raw material. Examples of citrate buffers include citric acid; citrates such as alkali metal citrate and alkaline earth metal citrate; and their hydrates. 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 citrate buffer content can be appropriately adjusted depending on the type of citrate buffer, but 0.001 to 1.0% (w / v) is preferred, 0.005 to 0.5% (w / v) is more preferred, 0.01 to 0.1% (w / v) is even more preferred, 0.01 to 0.05% (w / v) is even more preferred, and 0.02 to 0.04% (w / v) is particularly preferred.

[0038] In the present invention, the borate buffer can be any pharmaceutically acceptable borate buffer as a raw material. 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 can be any pharmaceutically acceptable carbonate buffer as a raw material. Examples of carbonate buffers include carbonic acid or its salts. Specific examples include carbonic acid, sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, magnesium carbonate, and the like.

[0040] In the present invention, the acetic acid buffer can be any pharmaceutically acceptable acetic acid buffer as a raw material. Examples of acetic acid buffers include acetic acid or its salts. Specific examples include acetic acid, ammonium acetate, potassium acetate, calcium acetate, sodium acetate, etc.

[0041] In the present invention, the tartrate buffer can be any pharmaceutically acceptable tartrate buffer as a raw material. Examples of tartrate buffers include tartaric acid or 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, and ε-aminocaproic acid. Examples of aspartic acid buffers include aspartic acid or its salts, with specific examples including sodium aspartate and magnesium aspartate. Examples of glutamic acid buffers include glutamic acid or its salts, with specific examples including sodium glutamate and potassium glutamate.

[0043] The aqueous pharmaceutical composition of the present invention may appropriately contain an isotonic agent that can be used as an additive to pharmaceuticals. Examples of isotonic agents include ionic isotonic agents and nonionic isotonic agents.

[0044] Examples of ionic isotonic agents include sodium chloride, potassium chloride, calcium chloride, and magnesium chloride, while examples of nonionic isotonic 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 isotonic agent, the content of the isotonic agent can be appropriately adjusted depending on the type of isotonic agent, but 0.01 to 10% (w / v) is preferred, 0.05 to 5% (w / v) is more preferred, 0.1 to 5% (w / v) is even more preferred, 0.5 to 5% (w / v) is even more preferred, and 1 to 5% (w / v) is particularly preferred. Furthermore, when the aqueous pharmaceutical composition of the present invention contains an isotonic agent, one or more isotonic agents may be used together.

[0046] The aqueous pharmaceutical composition of the present invention may appropriately contain preservatives that can be used as additives to pharmaceuticals. 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, chlorobutanol, and the like.

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

[0048] The aqueous pharmaceutical composition of the present invention may optionally contain stabilizers that can be used as pharmaceutical additives. Examples of stabilizers include EDTA or its salts, cyclodextrin, etc. These may take the form of hydrates or solvates. Examples of EDTA salts include disodium EDTA (hereinafter sometimes referred to as "sodium EDTA"), tetrasodium EDTA, etc. When the pharmaceutical composition of the present invention contains a stabilizer, the amount of the stabilizer can be appropriately adjusted depending on the type of stabilizer, for example, 0.01 to 1% (w / v), however, this is not limited to cases where the stabilizer also has effects other than stabilization. Furthermore, when the aqueous pharmaceutical composition of the present invention contains a stabilizer, one or more types of stabilizers may be used together.

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

[0050] In the present invention, the aqueous pharmaceutical composition may appropriately contain a pH adjusting agent that can be used as an additive to a pharmaceutical. The pH adjusting agent is, 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 an acceptable range for a pharmaceutical product, but is preferably in the range of 6 or less, more preferably 4 to 6, even more preferably 4 to 5, and particularly preferably near 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. Furthermore, if the aqueous pharmaceutical composition of the present invention contains a pH adjusting agent, one or more pH adjusting agents may be used together.

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

[0053] The dosage and administration of the aqueous pharmaceutical composition of the present invention are not particularly limited as long as they are sufficient to produce the desired therapeutic effect. The aqueous pharmaceutical composition of the present invention may preferably be administered as 1 to 3 drops 1 to 5 times a day, more preferably as 1 to 2 drops 2 to 4 times a day, and most preferably as 1 drop once a day before bedtime.

[0054] In the present invention, "unit dose type container" refers to an eye drop container in which a cap is fused and sealed to the neck of the bottle, and which is intended to be opened by breaking the fused portion between the cap and the bottle-shaped body when in use. The unit dose type container may contain an aqueous pharmaceutical composition for single use, or it may contain an aqueous pharmaceutical composition for several uses, intended for daily use.

[0055] In the present invention, "multi-dose container" refers to an eye drop container comprising a container body and a cap that can be attached to the container body, wherein the cap can be freely opened and resealed. The multi-dose container typically contains multiple doses of 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 unit-dose containers or multi-dose containers. When substantially free of preservatives such as benzalkonium chloride, the aqueous pharmaceutical composition of the present invention is preferably contained in unit-dose containers.

[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 living organisms. 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 drugs 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 "Osmotic Pressure Measurement Method (Osmolar Concentration Measurement Method)" of the 18th edition of the Japanese Pharmacopoeia. [Examples]

[0058] Representative formulations using the aqueous pharmaceutical composition of the present invention are shown below, but the present invention is not limited to these formulations. In the formulations 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 embodiments are provided for a better understanding of the present invention, but the scope of the invention should not be limited thereto.

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

[0069] (Sample preparation) A 0.01% atropine-containing aqueous composition was prepared by dissolving atropine sulfate hydrate (0.1 mg), sodium dihydrogen phosphate dihydrate, sodium citrate hydrate, concentrated glycerin, and hydroxyethylcellulose in purified water, and adding a pH adjuster (dilute hydrochloric acid and / or sodium hydroxide) and purified water to a total volume of 1 mL. Additionally, a 0.025% atropine-containing aqueous composition was prepared by dissolving atropine sulfate hydrate (0.25 mg), sodium dihydrogen phosphate dihydrate, sodium citrate hydrate, concentrated glycerin, and hydroxyethylcellulose in purified water, and adding a pH adjuster (dilute hydrochloric acid and / or sodium hydroxide) and purified water to a total volume of 1 mL. Furthermore, as a placebo (control), sodium dihydrogen phosphate dihydrate, sodium citrate hydrate, concentrated glycerin, and hydroxyethylcellulose 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 an aqueous composition that did not contain atropine sulfate hydrate.

[0070] (Test method) This study included patients aged 5 to 15 years diagnosed with bilateral myopia. Each patient received one drop of either a placebo, a 0.01% atropine aqueous composition, or a 0.025% atropine aqueous composition daily (before bedtime) for 24 months.

[0071] (Evaluation method) Patients were given cycloplegic 1% eye drops twice at 5-minute intervals to induce cycloplegic state. The presence or absence of cycloplegic state was checked 45 minutes after the last eye drop, and if it was determined that the cycloplegic state was insufficient, an additional cycloplegic 1% eye drops were 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 / keratometer. The values ​​adopted were those in which the minimum and maximum values ​​of the five measurements of spherical power and cylindrical power of both eyes were within 0.50 D. From the five measurements of spherical power and cylindrical power of both eyes, the equivalent spherical power was calculated using the following formula, and the average value of these equivalent spherical powers was calculated. The equivalent spherical power was measured every four months from the start of administration. Calculation formula: Equivalent spherical frequency (D) = Spherical frequency + Cylindrical frequency x 1 / 2

[0072] (Test results) Table 9 shows the mean values ​​(D) of the equivalent spherical frequency (SE) for each age group in 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 10-15 years who were administered the 0.025% atropine aqueous composition, the change in equivalent spherical power (SE) from pre-administration to pre-administration was 0.00 diopters (D) or greater four months after the start of administration, confirming improvement in refractive errors. In particular, in patients aged 12-15 years who were administered the 0.025% atropine aqueous composition, improvement in refractive errors was confirmed even 12 months after administration. Therefore, it was suggested that the 0.025% atropine aqueous composition provides a higher myopia progression inhibitory effect, especially in myopic patients aged 12-15 years.

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

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

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

[0077] (Evaluation method) Patients were given cycloplegic 1% eye drops twice at 5-minute intervals to induce cycloplegic state. The presence or absence of cycloplegic state was checked 45 minutes after the last eye drop, and if it was determined that the cycloplegic state was insufficient, an additional cycloplegic 1% eye drops were administered. Next, under cycloplegia, the axial length of both of the patient's eyes was measured using an optical axial length measuring device. Axial length measurements were performed every four months from the start of administration.

[0078] (Test results) Table 10 shows the average axial length (mm) for each age group in 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, suppression of axial length elongation was observed in the patient group administered the atropine-containing aqueous composition. In particular, in patients aged 12-15 years who were administered the 0.025% atropine-containing aqueous composition, no elongation of axial length was observed 4 months after administration. Therefore, it was suggested that the 0.025% atropine-containing aqueous composition provides a higher myopia progression inhibitory effect, especially in myopic patients aged 12-15 years. [Industrial applicability]

[0080] According to the present invention, a myopia treatment, preventive agent, and / or myopia progression inhibitor can be provided for myopic patients aged 12 to 15 years. More specifically, by applying an aqueous composition containing atropine or a salt thereof at a concentration of 0.025% (w / v) to myopic patients aged 12 to 15 years, even 12 months after the start of administration, the change in equivalent spherical power (SE) from before administration is 0.00 diopters (D) or more, improving refractive errors and providing a higher myopia progression inhibitory effect.

Claims

1. An aqueous pharmaceutical composition for the treatment, prevention, and / or inhibition of myopia progression, comprising a 0.025% (w / v) concentration of atropine or a salt thereof, characterized in that it is used to be administered to myopic patients aged 12 to 15 years.

2. The aqueous pharmaceutical composition according to claim 1, wherein the treatment, prevention, and / or inhibition of the progression of myopia is the improvement of a refractive error.

3. The aqueous pharmaceutical composition according to claim 1 or 2, characterized in that it is used in myopic patients so that the change in equivalent spherical power (SE) from before administration four months after the start of administration is 0.00 to +0.20 diopters (D).

4. The aqueous pharmaceutical composition according to claim 1 or 2, characterized in that it is used in myopic patients so that the change in equivalent spherical power (SE) from before administration four months after the start of administration is 0.00 to +0.15 diopters (D).

5. The aqueous pharmaceutical composition according to claim 1 or 2, characterized in that it is used in myopic patients so that the change in equivalent spherical power (SE) from before administration four months after the start of administration is 0.00 to +0.10 diopters (D).

6. The aqueous pharmaceutical composition according to claim 1 or 2, characterized in that it is used in myopic patients so that the change in equivalent spherical power (SE) from before administration four months after the start of administration is 0.00 to +0.05 diopters (D).

7. The aqueous pharmaceutical composition according to any one of claims 3 to 6, wherein the amount of change in equivalent spherical frequency (SE) from before administration is the amount of change in equivalent spherical frequency (SE) from before administration 8 months after the start of administration.

8. The aqueous pharmaceutical composition according to any one of claims 3 to 6, wherein the change in equivalent spherical frequency (SE) from before administration is the change in equivalent spherical frequency (SE) from before administration 12 months after the start of administration.

9. The aqueous pharmaceutical composition according to claim 1, wherein the treatment, prevention, and / or inhibition of myopia progression is the inhibition of axial length elongation.

10. The aqueous pharmaceutical composition according to any one of claims 1 to 9, characterized in that it is used in myopic patients so that the change in axial length of the eye from before administration four months after the start of administration is -0.05 to 0.05 mm.

11. The aqueous pharmaceutical composition according to any one of claims 1 to 9, characterized in that it is used in myopic patients so that the change in axial length of the eye from before administration four months after the start of administration is -0.03 to 0.03 mm.

12. The aqueous pharmaceutical composition according to any one of claims 1 to 9, characterized in that it is used in myopic patients so that the change in axial length of the eye from before administration four months after the start of administration is -0.01 to 0.01 mm.

13. The aqueous pharmaceutical composition according to any one of claims 10 to 12, wherein the amount of change in axial length from before administration is the amount of change in axial length from before administration 8 months after the start of administration.

14. The aqueous pharmaceutical composition according to any one of claims 10 to 12, wherein the amount of change in axial length from before administration is the amount of change in axial length from before administration 12 months after the start of administration.

15. An aqueous pharmaceutical composition according to any one of claims 1 to 14, which has substantially no mydriatic effect.

16. The aqueous pharmaceutical composition according to any one of claims 1 to 15, characterized in that it is used by instilling one drop per eye once a day.

17. The aqueous pharmaceutical composition according to claim 16, characterized in that it is used as eye drops before going to bed.

18. The aqueous pharmaceutical composition according to any one of claims 1 to 17, wherein atropine or a salt thereof is atropine sulfate or its hydrate.

19. An aqueous pharmaceutical composition according to any one of claims 1 to 18, which is an eye drop.

20. An aqueous pharmaceutical composition for the treatment, prevention, and / or inhibition of myopia progression, comprising a 0.025% (w / v) concentration of atropine or a salt thereof, wherein the treatment, prevention, and / or inhibition of myopia progression is an improvement in refractive error, and the composition is used to administer to myopic patients aged 12 to 15 years, and is used to achieve a change in equivalent spherical power (SE) from pre-administration to +0.20 diopters (D) four months after the start of administration.

21. An aqueous pharmaceutical composition for the treatment, prevention, and / or inhibition of myopia progression, comprising a 0.025% (w / v) concentration of atropine or a salt thereof, wherein the treatment, prevention, and / or inhibition of myopia progression is the inhibition of axial length elongation, and the composition is used to administer to myopic patients aged 12 to 15 years, and is used to achieve a change in axial length from pre-administration to -0.05 to 0.05 mm four months after the start of administration.

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