Composition for lowering intraocular pressure

Abstract

To provide a composition for use in a method of lowering intraocular pressure in a patient.SOLUTION: The composition of the present disclosure includes brimonidine or a pharmaceutically acceptable salt thereof, and brinzolamide or a pharmaceutically acceptable salt thereof. The above method includes: a) a step of confirming whether an effect by other glaucoma remedy is sufficient or insufficient, for a patient; b) a step of measuring an intraocular pressure of the patient before administration of a remedy; c) a step of selecting a patient in which, the effect of other glaucoma remedy is insufficient and the intraocular pressure before administration of the remedy is less than 20 mmHg; and d) a step of administering the composition to the selected patient. The patient is a patient who has glaucoma or ocular hypertension and receives other glaucoma remedy.SELECTED DRAWING: None

Description

Technical Field

[0001] The present disclosure relates to compositions and related inventions for reducing intraocular pressure in patients, comprising brimonidine and brinzolamide.

Background Art

[0002] Alphagan® eye drops containing brimonidine are the only α2 receptor agonist as an intraocular pressure-lowering drug. By combining with existing drugs, a further intraocular pressure-lowering effect can be obtained, with few systemic side effects and a visual field maintenance effect commensurate with the intraocular pressure-lowering effect. Therefore, it is widely combined with existing therapeutic drugs. The number of glaucoma patients is increasing year by year, and there are many patients undergoing combined treatment. There are also many patients combining brimonidine, and formulations containing brimonidine are expected.

[0003] Brinzolamide is a carbonic anhydrase inhibitor with few systemic side effects. Brinzolamide can be prescribed to patients who cannot use β-blockers in combination therapy, patients who show local side effects of prostaglandin (PG)-related drugs, and patients who are insufficiently effective with PG-related drugs. [[ID=IS]]

[0004] In addition, all existing formulations contain β-blockers, and formulations without β-blockers are expected.

Summary of the Invention

Means for Solving the Problems

[0005] The inventors conducted a stratified analysis of pre-administration intraocular pressure (IOP) values ​​before administering an eye drop solution containing brimonidine and brinzolamide, and newly discovered that the eye drop solution exhibits a high IOP-lowering effect in patients whose pre-administration IOP values ​​fall within a specific range. Therefore, this disclosure relates to a composition for lowering IOP containing brimonidine and brinzolamide, and in particular, shows excellent therapeutic effects in a specific group of patients with glaucoma and / or ocular hypertension. Furthermore, this disclosure makes it possible to provide a drug that is effective as an alternative to other glaucoma drugs for administration in place of, or in combination with, some or all of, other glaucoma drugs already administered to patients whose response to other glaucoma drugs is insufficient.

[0006] This disclosure provides, for example, the following items: (Item 1) A composition for use in a method for lowering intraocular pressure in a patient, comprising brimonidine or a pharmaceutically acceptable salt thereof and brinzolamide or a pharmaceutically acceptable salt thereof, The patient in question has glaucoma or ocular hypertension and is receiving other glaucoma medications. The method involves the following steps: a) A step to confirm whether the effect of the other glaucoma treatment drug is sufficient or insufficient for the patient, b) A step of measuring the patient's intraocular pressure before administration, c) A step of selecting patients for whom the effect of other glaucoma treatments is insufficient and whose pre-administration intraocular pressure is less than 20 mmHg, d) The step of administering the composition to the selected patient. A composition containing the following: (Item 2) The composition according to item 1, wherein the pre-administration intraocular pressure is 18 mmHg or more and less than 20 mmHg. (Item 3) The composition according to item 1 or 2, wherein the brimonidine or a pharmaceutically acceptable salt thereof is brimonidine tartrate. (Item 4) The composition according to any one of items 1 to 3, wherein the concentration of brimonidine or a pharmaceutically acceptable salt thereof in the composition is about 0.1% w / v, and the concentration of brinzolamide or a pharmaceutically acceptable salt thereof is about 1% w / v. (Item 5) The composition according to any one of items 1 to 3, characterized in that the composition is administered to the patient as eye drops, one drop at a time, twice a day. (Item 6) The composition according to any one of items 1 to 5, further comprising selecting a patient under 65 years of age in step c). (Item 7) The composition according to any one of items 1 to 6, characterized in that the composition reduces the patient's intraocular pressure by 10% or more from the intraocular pressure before administration. (Item 8) The composition according to item 7, characterized in that the composition causes the intraocular pressure to decrease by 10% or more from the pre-administration intraocular pressure for at least 12 hours after administration. (Item 9) The composition according to item 7, characterized in that the composition causes a sustained decrease of 10% or more from the pre-administration intraocular pressure for at least 7:00 to 18:00. (Item 10) The patient has been administered the other glaucoma treatment drug for four weeks or more, the composition according to any one of items 1 to 9. (Item 11) A composition for use in a method for preventing the worsening of glaucoma or ocular hypertension in a patient, comprising brimonidine or a pharmaceutically acceptable salt thereof and brinzolamide or a pharmaceutically acceptable salt thereof, The patient is diagnosed with glaucoma or ocular hypertension and is receiving other glaucoma medications. The method involves the following steps: a) A step to confirm whether the effect of the other glaucoma treatment drug is sufficient or insufficient for the patient, b) A step of measuring the patient's intraocular pressure before administration, c) A step of selecting patients for whom the effect of other glaucoma treatments is insufficient and whose pre-administration intraocular pressure is less than 20 mmHg, d) The step of administering the composition to the selected patient. A composition containing the following: (Item 12) The composition according to item 11, wherein the pre-administration intraocular pressure is 18 mmHg or more and less than 20 mmHg. (Item 13) The composition according to item 11 or 12, further comprising selecting a patient under 65 years of age in step c). (Item 14) The composition according to any one of items 11 to 13, wherein the prevention of worsening glaucoma includes preventing or delaying the progression of visual field defects in the glaucoma patient, and the prevention of worsening ocular hypertension includes lowering intraocular pressure, preventing or delaying an increase in intraocular pressure, or preventing or delaying the onset of visual field defects in the ocular hypertension patient. (Item 15) A method for determining whether treatment with a composition comprising brimonidine or a pharmaceutically acceptable salt thereof and brinzolamide or a pharmaceutically acceptable salt thereof is effective, wherein the composition is effective in the patient if other glaucoma treatments are ineffective and the patient's pre-administration intraocular pressure is less than 20 mmHg. (Item 16) The method according to item 15, which indicates that the composition is effective for the patient if the patient's pre-administration intraocular pressure is 18 mmHg or more and less than 20 mmHg. (Item 17) The method according to item 16, which indicates that the composition is effective for the patient if the patient's pre-administration intraocular pressure is 18 mmHg or more and less than 20 mmHg, and the patient is under 65 years of age. (Item 18) A method for using pre-administration intraocular pressure in a patient as an indicator for selecting a second-line drug to lower intraocular pressure in a patient suffering from glaucoma or ocular hypertension, wherein, in the patient, if the pre-administration intraocular pressure is less than 20 mmHg, a composition comprising brimonidine or a pharmaceutically acceptable salt thereof and brinzolamide or a pharmaceutically acceptable salt thereof is effective as the second-line drug. (Item 19) The method according to item 18, which shows that if the patient's pre-administration intraocular pressure is 18 mmHg or greater and less than 20 mmHg, a composition comprising brimonidine or a pharmaceutically acceptable salt thereof and brinzolamide or a pharmaceutically acceptable salt thereof is effective as the second choice drug. (Item 20) The method according to item 19, which shows that if the patient's pre-administration intraocular pressure is 18 mmHg or greater and less than 20 mmHg, and the patient is under 65 years of age, a composition comprising brimonidine or a pharmaceutically acceptable salt thereof and brinzolamide or a pharmaceutically acceptable salt thereof is effective as the second-choice drug. (Item 21) A method for selecting a second-line drug that reduces intraocular pressure by 10% or more from the pre-administration intraocular pressure for at least 12 hours after administration in patients suffering from glaucoma or ocular hypertension who are receiving other glaucoma medications but whose treatment is insufficient, the method for demonstrating that, in such patients, if the patient's pre-administration intraocular pressure is 18 mmHg or more and less than 20 mmHg, and the patient is under 65 years of age, a composition comprising brimonidine or a pharmaceutically acceptable salt thereof and brinzolamide or a pharmaceutically acceptable salt thereof is effective as the second-line drug. (Item 1A) A composition comprising brimonidine or a pharmaceutically acceptable salt thereof and brinzolamide or a pharmaceutically acceptable salt thereof, for selective treatment of a patient having a pre-administration intraocular pressure of less than 20 mmHg, wherein the patient has glaucoma or ocular hypertension, is receiving other glaucoma medications, and is insufficiently responding to those other glaucoma medications. (Item 2A) The composition according to item 1A, wherein the intraocular pressure before administration is 18 mmHg or more and less than 20 mmHg. (Item 3A) The composition according to item 1A or 2A, wherein the brimonidine or a pharmaceutically acceptable salt thereof is brimonidine tartrate. (Item 4A) The composition according to any one of items 1A to 3A, wherein the concentration of brimonidine or a pharmaceutically acceptable salt thereof in the composition is about 0.1% w / v, and the concentration of brinzolamide or a pharmaceutically acceptable salt thereof is about 1% w / v. (Item 5A) [[ID=​​​​​​​​​​​​​​​​​​​​​​​​​​​​b) A step of measuring the intraocular pressure of the patient, c) A step of selecting patients for whom the effect of other glaucoma treatment drugs is insufficient and whose pre-administration intraocular pressure value on the day of administration is less than 20 mmHg, d) The step of administering the composition to the selected patient. A composition containing the following: (Item 2B) The composition according to item 1B, wherein the pre-administration intraocular pressure value is 18 mmHg or more and less than 20 mmHg. (Item 3B) The composition according to item 1 or 2, wherein the brimonidine or a pharmaceutically acceptable salt thereof is brimonidine tartrate. (Item 4B) The composition according to any one of items 1B to 3B, wherein the concentration of brimonidine or a pharmaceutically acceptable salt thereof in the composition is about 0.1% w / v, and the concentration of brinzolamide or a pharmaceutically acceptable salt thereof is about 1% w / v. (Item 5B) The composition according to any one of items 1B to 4B, characterized in that the composition is administered to the patient as eye drops, one drop at a time, twice a day. (Item 6B) The composition according to any one of items 1B to 5B, further comprising selecting a patient under 65 years of age in step c). (Item 7B) The composition according to any one of items 1B to 6B, characterized in that the composition reduces the intraocular pressure of the patient by 10% or more when evaluated by the rate of reduction in intraocular pressure. (Item 8B) The composition according to item 7B, characterized in that, when evaluated by the rate of reduction in intraocular pressure, it reduces intraocular pressure by 10% or more for at least 12 hours after administration. (Item 9B) The composition according to item 7B, characterized in that, when evaluated by the rate of reduction in intraocular pressure, it continuously reduces intraocular pressure by 10% or more for at least 7:00 to 18:00. (Item 10B) A composition for use in a method for preventing the worsening of glaucoma or ocular hypertension in a patient, comprising brimonidine or a pharmaceutically acceptable salt thereof and brinzolamide or a pharmaceutically acceptable salt thereof, The patient is diagnosed with glaucoma or ocular hypertension and is receiving other glaucoma treatment drugs other than the composition, The method involves the following steps: a) A step to confirm whether the effect of the other glaucoma treatment drug is sufficient or insufficient for the patient, b) A step of measuring the intraocular pressure of the patient, c) A step of selecting patients for whom the effect of other glaucoma treatment drugs is insufficient and whose pre-administration intraocular pressure value on the day of administration is less than 20 mmHg, d) The step of administering the composition to the selected patient. A composition containing the following: (Item 11B) The composition according to item 10B, wherein the pre-administration intraocular pressure is 18 mmHg or more and less than 20 mmHg. (Item 12B) The composition according to item 10B or 11B, further comprising selecting a patient under 65 years of age in step c). (Item 13B) The composition according to any one of items 10B to 12B, wherein the prevention of the worsening of glaucoma includes preventing or delaying the progression of visual field defects in the glaucoma patient, and the prevention of the worsening of ocular hypertension includes lowering intraocular pressure, preventing or delaying an increase in intraocular pressure, or preventing or delaying the occurrence of visual field defects in the ocular hypertension patient. (Item 14B) A method for determining whether treatment with a composition comprising brimonidine or a pharmaceutically acceptable salt thereof and brinzolamide or a pharmaceutically acceptable salt thereof is effective, wherein the composition is effective in the patient if other glaucoma treatments are ineffective and the patient's pre-administration intraocular pressure is less than 20 mmHg. (Item 15B) The method according to item 14B, which indicates that the composition is effective for the patient if the patient's pre-administration intraocular pressure is 18 mmHg or more and less than 20 mmHg. (Item 16B) The method according to item 15B, which indicates that the composition is effective for the patient if the patient's pre-administration intraocular pressure is 18 mmHg or more and less than 20 mmHg, and the patient is under 65 years of age. (Item 17B) A method for using pre-administration intraocular pressure in a patient as an indicator for selecting a different glaucoma treatment drug from other glaucoma treatment drugs for lowering intraocular pressure in a patient suffering from glaucoma or ocular hypertension, wherein, in the patient, if the patient's pre-administration intraocular pressure is less than 20 mmHg, a composition comprising brimonidine or a pharmaceutically acceptable salt thereof and brinzolamide or a pharmaceutically acceptable salt thereof is effective as a different glaucoma treatment drug from other glaucoma treatment drugs. (Item 18B) The method according to item 17B, which shows that, when the patient's pre-administration intraocular pressure is 18 mmHg or greater and less than 20 mmHg, a composition comprising brimonidine or a pharmaceutically acceptable salt thereof and brinzolamide or a pharmaceutically acceptable salt thereof is effective as a different choice from the other glaucoma treatments. (Item 19B) The method according to item 18B, which shows that, if the patient's pre-administration intraocular pressure is 18 mmHg or greater and less than 20 mmHg, and the patient is under 65 years of age, a composition comprising brimonidine or a pharmaceutically acceptable salt thereof and brinzolamide or a pharmaceutically acceptable salt thereof is effective as a different choice from the other glaucoma treatments. (Item 20B) A method for selecting a different drug from other glaucoma treatments when evaluating intraocular pressure reduction rates in patients with glaucoma or ocular hypertension who have been administered other glaucoma treatments but whose response is insufficient, the method for determining whether a composition comprising brimonidine or a pharmaceutically acceptable salt thereof and brinzolamide or a pharmaceutically acceptable salt thereof is effective as a different drug from other glaucoma treatments when evaluating intraocular pressure reduction rates. The method is characterized in that, in such patients, if the patient's pre-administration intraocular pressure is 18 mmHg or higher and less than 20 mmHg, and the patient's age is less than 65 years, then a composition comprising brimonidine or a pharmaceutically acceptable salt thereof and brinzolamide or a pharmaceutically acceptable salt thereof is effective as a different drug from other glaucoma treatments. (Item 21B) A multi-component preparation comprising brimonidine or a pharmaceutically acceptable salt thereof and brinzolamide or a pharmaceutically acceptable salt thereof, for use in a method to suppress the onset or progression of visual field defects in patients in whom the effects of other glaucoma treatments other than the multi-component preparation are insufficient, by reducing intraocular pressure by approximately 10% or more when evaluated by the rate of intraocular pressure reduction, and the method thereof is a) A step of diagnosing whether the patient has glaucoma, b) The step of administering other glaucoma medications, c) A step of diagnosing whether the patient is not adequately treated with other glaucoma medications, d) A step of measuring the intraocular pressure of the patient, e) When the effect of other glaucoma treatments is insufficient and the patient has glaucoma, a step of administering the multi-component preparation to the patient, by selecting a composition comprising brimonidine or a pharmaceutically acceptable salt thereof and brinzolamide or a pharmaceutically acceptable salt thereof as a different alternative to other glaucoma treatments, either in place of or in combination with other glaucoma treatments. including, A multi-component preparation. (Item 22B) A combination preparation, a multi-component preparation as described in item 21B. (Item 23B) A composition for use in a method for lowering intraocular pressure in a patient, comprising brimonidine or a pharmaceutically acceptable salt thereof and brinzolamide or a pharmaceutically acceptable salt thereof, wherein the patient is a patient suffering from glaucoma or ocular hypertension, The method involves the following steps: a) A step of measuring the intraocular pressure of the patient, b) A step of selecting patients whose pre-administration intraocular pressure value on the day of administration is less than 20 mmHg, c) The composition is administered to the selected patient. A composition containing the following: (Item 24B) The composition according to item 23B, wherein the pre-administration intraocular pressure value is 18 mmHg or more and less than 20 mmHg. (Item 25B) The composition according to item 23B or 24B, wherein the brimonidine or a pharmaceutically acceptable salt thereof is brimonidine tartrate. (Item 26B) The composition according to any one of items 23B to 25B, wherein the concentration of brimonidine or a pharmaceutically acceptable salt thereof in the composition is about 0.1% w / v, and the concentration of brinzolamide or a pharmaceutically acceptable salt thereof is about 1% w / v. (Item 27B) The composition according to any one of items 23B to 26B, characterized in that the composition is administered to the patient as eye drops, one drop at a time, twice a day. (Item 28B) The composition according to any one of items 23B to 27B, further comprising selecting a patient under 65 years of age in step b). (Item 29B) The composition according to any one of items 23B to 28B, characterized in that the composition reduces the intraocular pressure of the patient by 10% or more when evaluated by the rate of reduction in intraocular pressure. (Item 30B) The composition according to item 29B, characterized in that, when evaluated by the rate of reduction in intraocular pressure, it reduces intraocular pressure by 10% or more for at least 12 hours after administration. (Item 31B) The composition according to item 29, characterized in that, when evaluated by the rate of reduction in intraocular pressure, it continuously reduces intraocular pressure by 10% or more for at least 7:00 to 18:00. (Item 32B) The composition according to the above item, wherein the pre-administration intraocular pressure value on the day of initiation of administration of a drug of a different choice from other glaucoma treatment drugs is the 2-hour value on the day of initiation of administration of a drug of a different choice from other glaucoma treatment drugs. (Item 33B) The composition described above, wherein the pre-administration intraocular pressure is a value after seasonal variation correction and / or diurnal variation correction.

[0007] In this disclosure, the one or more of the above features are intended to be provided in combinations other than those explicitly stated. Further embodiments and advantages of this disclosure will be apparent to those skilled in the art, by reading and understanding the detailed description below as necessary. [Effects of the Invention]

[0008] According to this disclosure, a composition comprising brimonidine and brinzolamide is provided that exhibits superior intraocular pressure-lowering effects in a specific group of patients for whom other glaucoma treatments are inadequately effective. [Modes for carrying out the invention]

[0009] The following describes this disclosure. Throughout this specification, singular expressions should be understood to include the concept of their plural form unless otherwise specified. Thus, singular articles (e.g., "a," "an," "the" in English) should be understood to include the concept of their plural form unless otherwise specified. Furthermore, terms used herein should be understood to have the meaning commonly used in the art unless otherwise specified. Thus, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure pertains. In case of any conflict, this specification (including definitions) shall prevail. In this specification, "about" means ±10% of the following value. In this specification, times are expressed in 24-hour format unless otherwise specified.

[0010] (definition) In this specification, "brimonidine" refers to the following formula

[0011] [ka]

[0012] This compound is represented by the chemical name 5-bromo-N-(4,5-dihydro-1H-imidazole-2-yl)quinoxaline-6-amine. Brimonidine or its pharmaceutically acceptable salts are used as pharmaceutical ingredients, and are typically offered as brimonidine tartrate (chemical name 5-bromo-N-(4,5-dihydro-1H-imidazole-2-yl)quinoxaline-6-amine--(2R,3R)-tartrate). Brimonidine or its pharmaceutically acceptable salts are selective adrenergic α2 receptor agonists and are commonly used as active ingredients in aqueous solutions, especially eye drops, with its tartrate being marketed under the trade name AIPHAGAN. Brimonidine and its pharmaceutically acceptable salts are commercially available. Pharmacochemically acceptable salts of brimonidine include, but are not limited to, tartrate, hydrochloride, or acetate. It is used as eye drops to treat glaucoma and ocular hypertension. Brimonidine is used to lower intraocular pressure in patients with (open-angle) glaucoma or ocular hypertension.

[0013] In this specification, "brinzolamide" refers to the following formula

[0014] [ka]

[0015] Brinzolamide is a compound represented by the chemical name (R)-4-(ethylamino)-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2,e]-1,2-thiazin-6-sulfonamide 1,1-dioxide. Brinzolamide is a carbonic anhydrase inhibitor and can be incorporated as an active ingredient in common aqueous solutions, particularly eye drops. Brinzolamide and its pharmaceutically acceptable salts are commercially available. Scientifically acceptable salts include, but are not limited to, hydrochloride and acetate. Brinzolamide is used as eye drops to treat glaucoma and ocular hypertension. Brinzolamide is used to lower intraocular pressure in patients with (open-angle) glaucoma or ocular hypertension.

[0016] In this specification, “pharmaceutically acceptable salt” includes salts that can be safely administered to patients. Preferred pharmaceutically acceptable salts of brimonidine and brinzolamide include, but are not limited to, those prepared from hydrochloride, hydrobromide, sulfate, nitrate, phosphate, maleate, salicylate, p-toluenesulfonate, tartrate, citrate, methanesulfonate, formate, malonate, succinate, naphthalene-2-sulfonate, and benzenesulfonate. Pharmaceutically acceptable salts may also be prepared from metals such as alkali metals or alkaline earth metals (e.g., sodium, potassium and calcium, magnesium and zinc).

[0017] In this specification, "glaucoma" refers to a disease characterized by functional and structural abnormalities of the eye that have distinctive changes in the optic nerve and visual field, and in which optic nerve damage can usually be improved or suppressed by sufficiently lowering intraocular pressure (Japanese Glaucoma Society Glaucoma Treatment Guidelines Committee. Glaucoma Treatment Guidelines (4th Edition). Journal of the Japanese Ophthalmological Society. Vol. 122, No. 1). According to pp. 5-53 (2018.01) (hereinafter referred to as the "Glaucoma Treatment Guidelines (4th Edition)"), glaucoma can be classified into primary glaucoma, secondary glaucoma, and pediatric glaucoma. Primary glaucoma includes primary open-angle glaucoma (broad sense) and primary closed-angle glaucoma, and primary open-angle glaucoma (broad sense) includes primary open-angle glaucoma, normal-tension glaucoma, and pre-peripheral field glaucoma. Secondary glaucoma includes secondary open-angle glaucoma and secondary closed-angle glaucoma, and pediatric glaucoma includes primary congenital glaucoma, juvenile open-angle glaucoma, glaucoma associated with congenital ocular malformations, and glaucoma associated with congenital systemic diseases.

[0018] In this specification, "ocular hypertension" refers to a disease characterized by elevated intraocular pressure, although no clear abnormalities are observed in the visual field or optic nerve. Ocular hypertension has a high probability of progressing to glaucoma in the future, and eye drop treatment may be administered to maintain normal intraocular pressure.

[0019] In this specification, “glaucoma medication” refers to medications that suppress the progression of optic nerve damage and / or visual field defects in glaucoma. Since optic nerve damage can be improved or suppressed by lowering intraocular pressure, glaucoma medications are typically intraocular pressure lowering agents. Intraocular pressure lowering agents may also be used to treat ocular hypertension.

[0020] In this specification, "insufficient efficacy" refers to a state in which the progression of glaucoma or ocular hypertension from the untreated state is not suppressed, based on a comprehensive consideration of intraocular pressure measurements, optic nerve head findings, visual field findings, etc. An indicator of "insufficient efficacy" may be the percentage reduction in intraocular pressure from the untreated state, or an intraocular pressure of 18 mmHg or higher. An indicator of "insufficient efficacy" may be either or both of visual field nerve head findings and / or visual field findings; if these findings worsen over time, the efficacy may be judged as insufficient. Whether the efficacy is sufficient or insufficient is confirmed in patients who have received other glaucoma medications for a certain period.

[0021] Intraocular pressure, optic nerve head findings, and visual field findings can be examined by referring to the Glaucoma Treatment Guidelines (4th Edition). For example, intraocular pressure can be measured using a Goldmann applanation tonometer, optic nerve head findings can be confirmed by fundus examination (e.g., using an ophthalmoscope, slit-lamp microscope with auxiliary lenses, fundus photography, red-free fundus observation, three-dimensional fundus image analysis, etc.) to detect the presence or absence of glaucomatous abnormalities or their progression, the cup / disc ratio (C / D ratio) (vertical diameter), etc., and visual field findings can be confirmed by using an automated static perimeter (Humphrey perimeter or Octopus perimeter, etc.) to detect the presence or absence of glaucomatous visual field abnormalities or their progression.

[0022] In this specification, “pre-administration intraocular pressure” refers to the intraocular pressure before the start of treatment with the composition of this disclosure, and means the intraocular pressure measured on the day the administration of the composition of this disclosure is started (administration start date) before the administration of the drug (usually within 12 hours prior), and this value is referred to as the “pre-administration intraocular pressure value.” In one preferred embodiment, it refers to the daytime intraocular pressure on the day the administration of the composition of this disclosure is started. For example, the 2-hour value in the example described later can be cited, but is not limited to this, and any value such as within 0 to 11 hours, 0 to 10 hours, 0 to 9 hours, 0 to 8 hours, 0 to 7 hours, 0 to 6 hours, 0 to 5 hours, 0 to 4 hours, 0 to 3 hours, or 0 to 2 hours prior to the administration of the drug can be assumed.

[0023] In this specification, the "0-hour value" on the administration start date, evaluation date, etc., refers to the intraocular pressure (IOP) value measured between 8:00 and 10:00 on the target day (e.g., administration start date, evaluation date). The "2-hour value" on the administration start date, evaluation date, etc., refers to the IOP value measured within 2 hours ± 30 minutes after morning eye instillation (or measurement of the 0-hour value) and by 12:30 on the target day (e.g., administration start date, evaluation date). The "7-hour value" on the administration start date, evaluation date, etc., refers to the IOP value measured within 7 hours ± 1 hour after morning eye instillation (or measurement of the 0-hour value) and by 18:00 on the target day (e.g., administration start date, evaluation date). Note that on the morning of the administration start date, another glaucoma treatment drug is instilled, and on the morning of the evaluation date, the target drug (the composition of this disclosure) is instilled instead of another glaucoma treatment drug. On the evaluation date, the "0-hour value" is the IOP value measured immediately before the administration of the drug. In this field, "0-hour value," "2-hour value," and "7-hour value" are used to indicate a certain value for a patient's intraocular pressure and are considered sufficient values ​​to identify a patient.

[0024] In this specification, "administration start date" refers to the date (including planned dates) on which the administration of a particular drug is to begin. Therefore, in the case of companion drugs, the administration start date refers to the date on which a decision is made as to whether or not to begin administration. If it is decided not to begin administration, no actual administration will take place, but in this specification, this date will be treated as the administration start date.

[0025] In this specification, "evaluation date" refers to the date on which intraocular pressure is evaluated. Any date may be applicable, but for example, periods such as approximately 4 weeks, 12 weeks, 3 months, 6 months, 28 weeks, 52 weeks, 1 year, and 3 years after the start of administration may be included.

[0026] The subjects or patients covered by this disclosure may be those with a seasonal variation of 1.0 mmHg or less, preferably 0.5 mmHg or less, more preferably 0.3 mmHg or less, and even more preferably 0.2 mmHg or less. Alternatively, the treatment covered by this disclosure may be designed using a “pre-administration intraocular pressure value” adjusted for seasonal variation.

[0027] The subjects or patients covered by this disclosure may be those with a 2-3 hour diurnal variation of 1.0 mmHg or less, preferably 0.5 mmHg or less, more preferably 0.3 mmHg or less, and even more preferably 0.2 mmHg or less. In particular, they may be patients with a 10:00-12:30 diurnal variation of 1.0 mmHg or less, preferably 0.5 mmHg or less, more preferably 0.3 mmHg or less, and even more preferably 0.2 mmHg or less. Alternatively, the treatment or prophylaxis covered by this disclosure may be designed using a “pre-administration intraocular pressure value” adjusted for diurnal variation.

[0028] In this specification, "intraocular pressure reduction rate" refers to the rate of change in intraocular pressure on the evaluation day (the subject of evaluation) compared to the intraocular pressure on the administration start day (the evaluation criterion) in the same patient.

[0029] In this specification, "single-component preparation" refers to a formulation that contains or uses a single active ingredient (API) for the purpose of exerting a therapeutic effect, such as lowering intraocular pressure in glaucoma, and does not contain or use any other active ingredients. Therefore, a single-component preparation of a carbonic anhydrase inhibitor refers to a formulation that contains only a carbonic anhydrase inhibitor as the active ingredient and is provided for administration of the carbonic anhydrase inhibitor alone. On the other hand, in this specification, "multiple-component preparation" refers to a formulation that, in terms of the purpose of exerting a therapeutic effect, is administered in combination with additional active ingredients in addition to the main active ingredient. A multiple-component preparation may be provided in the form in which each active ingredient is present in the same formulation (also referred to as a "combination preparation" in this specification), in the form in which each active ingredient is present in separate formulations, or in combination thereof. Therefore, a multiple-component preparation also includes a dosage form that has been formulated as a single-component preparation but is provided for a specific purpose, such as administration in combination with other active ingredients. Therefore, multi-component preparations include preparations that contain a first active ingredient such as a carbonic anhydrase inhibitor as an active ingredient, and further contain additional active ingredients such as prostaglandin-related drugs, or preparations that are administered in combination with a separate preparation containing additional active ingredients. In this specification, for example, this disclosure includes embodiments of a pharmaceutical product containing a carbonic anhydrase inhibitor eye drop, intended to be administered in combination with a pharmaceutical product containing an α2 receptor agonist, and embodiments of a pharmaceutical product containing an α2 receptor agonist, intended to be administered in combination with a pharmaceutical product containing a carbonic anhydrase inhibitor eye drop.

[0030] In this specification, "combination drug" refers to a drug that contains a primary active ingredient and additional active ingredients in the same formulation for the purpose of exerting its therapeutic effect. For example, it refers to a drug that contains multiple active ingredients with different or the same mechanism of action in the same formulation for lowering intraocular pressure in glaucoma. In this specification, combination drugs may also be used in combination with other glaucoma treatment drugs (whether monotherapy drugs or combination drugs), either simultaneously or at different times.

[0031] In this specification, “Instructions” are instructions for the user on how to use the Disclosure, and are referred to as “Package Inserts” in Japan and “Labels” in the United States and other countries. These Instructions contain language that instructs the user on how to use the Disclosure. If necessary, these Instructions will be prepared in accordance with the format prescribed by the supervisory authority in the country where the Disclosure is implemented (for example, the Ministry of Health, Labour and Welfare or the Ministry of Agriculture, Forestry and Fisheries in Japan, or the Food and Drug Administration (FDA) or the Department of Agriculture (USDA) in the United States) and will be clearly stated to have been approved by that supervisory authority. Instructions may, but are not limited to, be provided in paper form, and may also be provided in electronic form, for example, on a website or via email.

[0032] In this specification, "first-line drug" (also called first-line treatment or first choice) refers to the medication that should be administered first for a particular disease. Generally, first-line drugs are selected based on their low side effects and relatively high efficacy. If the effect is insufficient or no improvement is seen after administering the first-line drug, a second-line drug, prioritizing efficacy and considering other mechanisms of action, is administered. In glaucoma, for example, prostaglandin-related drugs and beta-blockers are administered as first-line drugs. Prostaglandin-related drugs also have the advantage of requiring fewer eye drops.

[0033] In this specification, "second-line therapy" (also called second-choice or second-line treatment) refers to a therapeutic agent used when the first-line therapy is ineffective, does not improve the condition, or is difficult to continue due to side effects. Second-line therapy is used in place of or in addition to the first-line therapy. There are many second-line therapy options for glaucoma, including carbonic anhydrase inhibitor eye drops, α2 receptor agonists, ROCK inhibitors, α1 receptor blockers, non-selective sympathetic nerve stimulants, and parasympathetic nerve stimulants. Each has different effects and is suitable for different patients, so the appropriate selection of a second-line therapy is crucial for the proper treatment of glaucoma.

[0034] In this specification, "alternative drugs for treating glaucoma" refers to drugs used as a next step when there is no improvement after administering first-line or second-line drugs, or when it is difficult to continue treatment due to side effects. "Alternative drugs for treating glaucoma" include various combination drugs, including first-line and second-line drugs for glaucoma. First-line and second-line drugs are as described above, and combination drugs include, for example, combination drugs of prostaglandin-related drugs and beta-blockers, and combination drugs of carbonic anhydrase inhibitors and beta-blockers. Since each drug has different effects and is suitable for different patients, the appropriate selection of "alternative drugs for treating glaucoma" is important for the appropriate treatment of glaucoma.

[0035] (Preferred embodiment) Preferred embodiments of the Disclosure are described below. These embodiments are provided for a better understanding of the Disclosure, and it is understood that the scope of the Disclosure should not be limited to the descriptions below. Therefore, it is clear that those skilled in the art can make appropriate modifications within the scope of the Disclosure, taking into consideration the descriptions herein. It is also understood that the embodiments described below can be used individually or in combination.

[0036] (composition) In one aspect, the present disclosure provides a composition (i.e., a combination), e.g., eye drops, for use in a method of lowering intraocular pressure in a patient, comprising brimonidine or a pharmaceutically acceptable salt thereof (e.g., brimonidine tartrate) and brinzolamide or a pharmaceutically acceptable salt thereof. The patient may be a patient suffering from glaucoma or ocular hypertension and who is receiving other glaucoma treatments (e.g., intraocular pressure lowering agents, neuroprotective agents). The method of lowering intraocular pressure may include a) a step of determining whether the other glaucoma treatments are sufficient or insufficient for the patient; b) a step of measuring the patient's intraocular pressure; c) a step of selecting a patient whose other glaucoma treatments are insufficient and whose pre-administration intraocular pressure value on the initiation date is less than 20 mmHg; and d) a step of administering the composition to the selected patient. In this specification, “eye drops” is synonymous with “ophthalmic solution.” The inventors have newly discovered that in a specific patient group, administration of the composition of this disclosure shows a superior therapeutic effect compared to other groups. Such a composition is effective in patients who have been administered other glaucoma medications, specifically in patients whose response to other glaucoma medications is insufficient. Select (ii) Among those patients, further, patients whose pre-administration intraocular pressure value on the day of initiation of a different glaucoma treatment drug is less than 20 mmHg. Select (iii) As an alternative to other glaucoma medications, a combination drug of brimonidine and brinzolamide Select These "three options" provide excellent therapeutic effects, such as continuously lowering intraocular pressure by more than 10%.

[0037] While we do not wish to be bound by theory, when administered as separate formulations, the formulation administered first is washed away by the formulation administered later, requiring administration at intervals of several minutes, which is burdensome for the patient. Furthermore, the amount of active ingredient delivered into the eye may change depending on the order of administration, potentially reducing efficacy. The composition comprising brimonidine or a pharmaceutically acceptable salt thereof and brinzolamide or a pharmaceutically acceptable salt thereof (i.e., a combination formulation) of this disclosure is advantageous because it does not wash away, does not require administration at multiple time intervals, and prevents unexpected changes in the amount delivered. It can also reduce the number of eye drops administered, thereby reducing the burden on the patient.

[0038] This composition may contain, for example, suspending agents, isotonic agents, buffering agents, viscosity modifiers, stabilizers, preservatives, pH adjusters, or solvents that are commonly used in ophthalmic compositions (especially aqueous eye drops, more specifically suspension eye drops). More specifically, it may contain one or more additives such as tyroxapol, glycerin, boric acid, carboxyvinyl polymer, sodium edetate hydrate, benzalkonium chloride, isotonic agents, and pH adjusters. In the compositions of this disclosure, the amount of brimonidine or a pharmaceutically acceptable salt thereof is not particularly limited and may be set appropriately according to the severity of the symptoms of the target patient, the amount applied per dose, etc., but examples include about 0.05 to about 0.2 w / v%, preferably about 0.1 to about 0.2 w / v%, and particularly preferably about 0.1 w / v%. In this specification, any reference to the content or concentration of brimonidine and / or its pharmaceutically acceptable salt means the content or concentration converted to brimonidine tartrate unless otherwise specified. In the compositions of this disclosure, brinzolamide and / or its pharmaceutically acceptable salt is not particularly limited and may be set appropriately according to the severity of the symptoms of the target patient, the amount applied per dose, etc., but examples include about 0.1 to 3 w / v%, preferably 0.5 to 2 w / v%, and more preferably 1 w / v%. Also in this specification, any reference to the content or concentration of brinzolamide or its pharmaceutically acceptable salt means the content or concentration converted to brinzolamide (without salt) unless otherwise specified.

[0039] In one embodiment, the composition of the present disclosure may include the following additives: The compositions of this disclosure preferably contain a dihydric or trihydric alcohol. The dihydric or trihydric alcohol is not particularly limited as long as it is permissible for incorporation into eye drops, but examples include glycerin, propylene glycol, butylene glycol, polyethylene glycol, and the like. These dihydric or trihydric alcohols may be used individually or in combination of two or more. Among these dihydric or trihydric alcohols, glycerin is particularly preferred.

[0040] When a divalent or trivalent alcohol is incorporated into the composition of this disclosure, its content can be appropriately set to achieve the desired osmotic pressure, but examples include about 0.1 to about 5 w / v%, preferably about 0.5 to about 3 w / v%, and more preferably about 1 to about 2 w / v%.

[0041] Furthermore, the compositions of this disclosure may optionally contain surfactants. The surfactants are not particularly limited as long as they are permissible for incorporation into eye drops, but examples include nonionic surfactants such as tyroxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, and octoxynol; amphoteric surfactants such as alkyldiaminoethylglycine and lauryldimethylaminoacetic acid betaine; anionic surfactants such as alkyl sulfates, N-acyl taurine salts, polyoxyethylene alkyl ether phosphates, and polyoxyethylene alkyl ether sulfates; and cationic surfactants such as alkylpyridinium salts and alkylamine salts. These surfactants may be used individually or in combination of two or more. Among these surfactants, nonionic surfactants are preferred, and tyroxapol is more preferred.

[0042] When a surfactant is incorporated into the composition of this disclosure, its content is not particularly limited, but for example, it may be about 0.005 to about 0.1 w / v%, preferably about 0.01 to about 0.05 w / v%, and more preferably about 0.02 to about 0.03 w / v%.

[0043] Furthermore, the compositions of this disclosure may optionally contain a viscosity agent. The viscosity agent is not particularly limited as long as it is permissible to incorporate it into eye drops, but examples include water-soluble polymers such as polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, carboxyvinyl polymer (cross-linked polyacrylic acid polymer, etc.), xanthan gum, sodium chondroitin sulfate, and sodium hyaluronate; and celluloses such as hypromellose, hydroxyethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose. These viscosity agents may be used individually or in combination of two or more. Among these viscosity agents, carboxyvinyl polymers are preferred.

[0044] When a viscosity-enhancing agent is incorporated into the composition of this disclosure, its content can be appropriately set according to the viscosity to be imparted, for example, about 0.1 to about 1 w / v%, preferably about 0.1 to about 0.5 w / v%, and more preferably about 0.3 to about 0.5 w / v%.

[0045] Furthermore, the compositions of this disclosure may optionally contain alkali metal chlorides such as sodium chloride and potassium chloride. These alkali metal chlorides may be used individually or in combination of two or more. Among these alkali metal chlorides, sodium chloride is preferred.

[0046] When alkali metal chlorides are incorporated into the compositions of this disclosure, their content can be appropriately set according to the osmotic pressure to be imparted, taking into account the content of other components. For example, approximately 0.01 to 1 w / v%, preferably approximately 0.05 to approximately 0.5 w / v%, and more preferably approximately 0.1 to approximately 0.3 w / v%.

[0047] Furthermore, the compositions of this disclosure may optionally contain buffering agents. The buffering agents are not particularly limited as long as they are permissible for incorporation into eye drops, but examples include phosphate buffering agents, borate buffering agents, citrate buffering agents, tartaric acid buffering agents, acetate buffering agents, Tris buffering agents, amino acids, and the like. These buffering agents may be used individually or in combination of two or more. Among these buffering agents, borate buffering agents are preferred.

[0048] When a buffering agent is incorporated into the composition of this disclosure, its content can be appropriately set according to the type of buffering agent used, etc. For example, when boric acid is used, the boric acid content can be, for example, about 0.01 to about 5 w / v%, preferably about 0.05 to about 1 w / v%, and more preferably about 0.1 to about 0.5 w / v%.

[0049] Furthermore, in addition to the components mentioned above, the compositions of this disclosure may optionally contain additives such as chelating agents, cooling agents, and preservatives. Examples of chelating agents include EDTA salts, citric acid, or salts thereof. These chelating agents may be used individually or in combination of two or more.

[0050] Examples of cooling agents include l-menthol, borneol, camphor, and eucalyptus oil. These cooling agents may be used individually or in combination of two or more.

[0051] Examples of preservatives include sorbic acid or its salts, benzoic acid or its salts, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, chlorhexidine gluconate, chlorhexidine hydrochloride, chlorhexidine acetate, boric acid or its salts, dehydroacetic acid or its salts, benzalkonium chloride, benzalkonium bromide, benzethonium chloride, benzyl alcohol, zinc chloride, parachlormetaxylenol, chlorcresol, phenethyl alcohol, polydronium chloride, thimerosal, and dibutylhydroxytoluene. These preservatives may be used individually or in combination of two or more.

[0052] Examples of stabilizers include polyvinylpyrrolidone, sulfites, monoethanolamine, glycerin, propylene glycol, cyclodextrin, dextran, ascorbic acid, EDTA, taurine, tocopherol, and dibutylhydroxytoluene. These stabilizers may be used individually or in combination of two or more.

[0053] pH adjusting agents are not particularly limited as long as they are pharmaceutically acceptable, but examples include hydrochloric acid, acetic acid, boric acid, aminoethylsulfonic acid, epsilon-aminocaproic acid, etc. Acids; examples include sodium hydroxide, potassium hydroxide, borax, triethanolamine, monoethanolamine, sodium bicarbonate, sodium carbonate, and other alkalis. These pH adjusting agents may be used individually or in combination of two or more.

[0054] The concentrations of these additives should be set appropriately depending on the type of additive used and the properties to be imparted to the ophthalmic composition.

[0055] The compositions of this disclosure are typically provided as aqueous eye drops (preferably as suspension eye drops). The compositions of this disclosure may be white to slightly yellowish-white suspensions. The compositions of this disclosure may be provided at a pH of 6.2 to 6.8. The osmotic pressure ratio of the compositions of this disclosure may be 0.9 to 1.2 (e.g., about 1) relative to physiological saline. The compositions of this disclosure may be used for glaucoma and ocular hypertension when other glaucoma treatments are ineffective or unsuitable. The compositions of this disclosure may be provided as eye drops, for example, typically one drop twice daily, but are not limited thereto.

[0056] In some embodiments, administering the composition of this disclosure to patients with a pre-administration intraocular pressure (IOP) value of less than 20 mmHg, preferably 18 mmHg or more and less than 20 mmHg, is expected to yield a higher therapeutic effect (i.e., IOP-lowering effect). The high therapeutic effect of the composition of this disclosure is achieved as long as the pre-administration IOP value is met, regardless of diurnal and seasonal variations. To minimize the effects of diurnal and seasonal variations, it is preferable to use a pre-administration IOP value measured at a specific time (e.g., a 2-hour value). Alternatively, a value corrected to account for the effects of diurnal and seasonal variations may be used. The composition of this disclosure may be administered to patients for whom other glaucoma medications have shown insufficient therapeutic effects. An IOP of 18 mmHg or higher is used as an indicator of insufficient therapeutic effects from other glaucoma medications. Other indicators of therapeutic effect include, but are not limited to, optic nerve head findings and visual field findings. Furthermore, insufficient efficacy may also be judged if the IOP reduction rate from the untreated IOP is low.

[0057] In some embodiments, the pre-administration intraocular pressure may be daytime intraocular pressure (for example, intraocular pressure measured between 9:30 and 13:00, more specifically between 10:00 and 12:30).

[0058] In some embodiments, other glaucoma treatments are intraocular pressure lowering agents other than the compositions of this disclosure, and include, but are not limited to, prostaglandin-related agents, β-receptor blockers, ROCK inhibitors, carbonic anhydrase inhibitors, α2-receptor agonists, and α1-receptor blockers, selective EP2-receptor agonists, or combinations thereof. Examples of prostaglandin-related agents include prostaglandin F such as latanoprost, travoprost, and tafluprost. 2α Examples of active ingredients include, but are not limited to, formulations containing derivatives, prostamide derivatives, etc. Examples of β-receptor blockers include, but are not limited to, formulations containing timolol, levobunolol, betaxolol, nipradilol, or carteolol as active ingredients. Examples of ROCK inhibitors include, but are not limited to, formulations containing ripasudil or netarsudil as active ingredients. Examples of carbonic anhydrase inhibitors include, but are not limited to, formulations containing dorzolamide or brinzolamide as active ingredients. Examples of α2 receptor agonists include, but are not limited to, formulations containing brimonidine as an active ingredient. Examples of α1 receptor blockers include, but are not limited to, formulations containing bunazosin as an active ingredient. Examples of selective EP2 receptor agonists include, but are not limited to, formulations containing omidenepag isopropyl as an active ingredient.

[0059] In some embodiments, other glaucoma treatments may be administered as first-line agents. In further embodiments, when other glaucoma treatments are administered as first-line agents, the compositions of the present disclosure may be administered as alternative agents to the other glaucoma treatments. In some embodiments, the first-line agent may be a single-component preparation, and the compositions of the present disclosure may be administered as alternative agents to the other glaucoma treatments and may be combination preparations.

[0060] In some embodiments, the other glaucoma treatment may be a single-component prostaglandin-related drug, a single-component beta-blocker drug, or a single-component carbonic anhydrase inhibitor drug. In some embodiments, the other glaucoma treatment may be a single-component carbonic anhydrase inhibitor drug. In certain embodiments, the other glaucoma treatment may be brinzolamide or a pharmaceutically acceptable salt thereof.

[0061] As an indicator of insufficient efficacy of other glaucoma medications, a patient's intraocular pressure (IOP) of 18 mmHg or higher prior to administration of the composition of this disclosure, after treatment with other glaucoma medications, may be used. Other indicators of insufficient efficacy of other glaucoma medications include, but are not limited to, optic nerve head findings and visual field findings. In addition, if the rate of reduction in IOP from the untreated IOP is low (for example, a reduction of less than 10% or less than 20%), it may be judged that the efficacy of other glaucoma medications is insufficient. Patients who can be treated may be those who have been administered other glaucoma medications for 1, 2, 3, 4, 5, 6, 7, or 8 weeks or more. For example, the therapeutic effect of brinzolamide monotherapy can typically be judged in about 4 weeks.

[0062] In some embodiments, when intraocular pressure is used as an indicator of insufficient efficacy, it may be the intraocular pressure measured on the day the administration of the other glaucoma medication is discontinued, and preferably the intraocular pressure measured in the morning (9:00 ± 1 hour) and midday (within 2 hours ± 30 minutes after morning eye drops and up to 12:30), or both. On the day the administration is discontinued, it is preferable that the morning intraocular pressure be measured before the administration of the other glaucoma medication.

[0063] In some embodiments, patients who can be treated with the compositions of the present disclosure may have a pre-administration intraocular pressure (IOP) of less than approximately 20 mmHg. The pre-administration IOP may be the IOP measured on the day administration of the compositions of the present disclosure is initiated, preferably in the morning (9:00 ± 1 hour) or at noon (within 2 hours ± 30 minutes after morning instillation and up to 12:30), preferably at noon (within 2 hours ± 30 minutes after morning instillation and up to 12:30). The pre-administration IOP is preferably between approximately 18 mmHg and less than approximately 20 mmHg. The pre-administration IOP is measured on the day administration is initiated, before administration of the compositions of the present disclosure. The day administration of the compositions of the present disclosure may be different from or the same as the day administration of other glaucoma treatments is initiated. It is also possible to use the IOP measured to indicate insufficient efficacy as the pre-administration IOP.

[0064] In some embodiments, the compositions of the Disclosure may be administered to a patient for at least two weeks, at least three weeks, at least four weeks, at least five weeks, at least six weeks, at least seven weeks, or at least eight weeks. In certain embodiments, the compositions of the Disclosure may be administered to a patient for at least four weeks.

[0065] In some embodiments, the compositions of the Disclosure may reduce a patient's intraocular pressure (IOP) by approximately 5% or more, approximately 10% or more, approximately 15% or more, or approximately 20% or more, as evaluated by the percentage reduction in IOP. In other embodiments, the compositions of the Disclosure may reduce a patient's IOP by more than 0% but less than 10%, 10% or more but less than 20%, or 20% or more, as evaluated by the percentage reduction in IOP. In glaucoma treatment, it is known that reducing IOP leads to a reduction in the risk of progression of visual field defects. It has also been reported that a 1 mmHg reduction in IOP reduces the risk of progression of visual field defects. The compositions of the Disclosure are intended for patients with a pre-administration IOP of less than 20 mmHg, and for example, by reducing IOP by 10% or more as evaluated by the percentage reduction in IOP, it is possible to reduce IOP to less than 18 mmHg. In the treatment of glaucoma, one objective is to lower intraocular pressure (IOP) to below 18 mmHg. Patients who maintained an average IOP of below 18 mmHg over a 6-year observation period showed little progression of visual field defects (Shiro Sakamoto, Yasuyuki Suzuki, Ophthalmology Vol.60, No.1, 2018, 27-34; Am J Ophthalmol 130:429-40, 2000). Therefore, it is extremely important that this eye drop reduces IOP by 10% or more in patients with a pre-administration IOP of less than 20 mmHg. Furthermore, by lowering IOP to below 18 mmHg, this eye drop can be said to be very effective in slowing the progression of visual field defects. Accordingly, in a preferred embodiment, the composition of this disclosure can reduce a patient's IOP by approximately 10% or more when evaluated by the rate of IOP reduction.

[0066] The rate of reduction in intraocular pressure is calculated using the following formula: The intraocular pressure reduction rate can be calculated by the following formula: Intraocular pressure reduction rate = {(Intraocular pressure value before administration of the composition of this disclosure - Intraocular pressure value after administration of the composition of this disclosure for a predetermined period) / Intraocular pressure value before administration of the composition of this disclosure} × 100. The intraocular pressure value in the formula may be the average value of intraocular pressure measured at multiple time points. In some embodiments, the intraocular pressure value may be the 0-hour, 2-hour, or 7-hour value. For example: • Percentage reduction in intraocular pressure at 0 hours = {(0-hour value on the day administration of the composition disclosed herein begins (intraocular pressure measured between 8:00 and 10:00) - 0-hour value on the day of evaluation of intraocular pressure after administration of the composition disclosed herein for a predetermined period (intraocular pressure measured between 8:00 and 10:00) / 0-hour value on the day administration of the composition disclosed herein begins (intraocular pressure measured between 8:00 and 10:00)} × 100 • Percentage reduction in intraocular pressure at 2 hours = {(2-hour value on the day administration of the composition disclosed (intraocular pressure measured within 2 hours ± 30 minutes after the measurement of the 0-hour value and by 12:30) - 2-hour value on the day of evaluation of intraocular pressure after administration of the composition disclosed for a predetermined period (intraocular pressure measured within 2 hours ± 30 minutes after the measurement of the 0-hour value and by 12:30) / 2-hour value on the day administration of the composition disclosed (intraocular pressure measured within 2 hours ± 30 minutes after the measurement of the 0-hour value and by 12:30)} × 100 The rate of reduction in intraocular pressure at 7 hours can be calculated by the following formula: {(7-hour value on the day administration of the composition of this disclosure is initiated (intraocular pressure measured within 7 hours ± 1 hour after the measurement of the 0-hour value and by 18:00) - 7-hour value on the day of evaluation of intraocular pressure after administration of the composition of this disclosure for a predetermined period (intraocular pressure measured within 7 hours ± 1 hour after the measurement of the 0-hour value and by 18:00) / 7-hour value on the day administration of the composition of this disclosure is initiated (intraocular pressure measured within 7 hours ± 1 hour after the measurement of the 0-hour value and by 18:00)} × 100.

[0067] The date for evaluating intraocular pressure may be at least two weeks after the start of administration (for example, two weeks, four weeks, two months, three months, six months, one year, or later).

[0068] In some embodiments, the compositions of the present disclosure can reduce a patient's intraocular pressure by 10% or more for at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours, or longer, when evaluated by the rate of reduction in intraocular pressure after administration (a certain period after the start of administration, for example, 4 weeks after the start of treatment). In certain embodiments, the compositions of the present disclosure can reduce intraocular pressure by 10% or more for at least 7:00 to 18:00, when evaluated by the rate of reduction in intraocular pressure. Intraocular pressure fluctuates throughout the day, but it is known that the greater the average daily intraocular pressure, peak intraocular pressure, and the greater the range of intraocular pressure fluctuation, the more likely visual field defects are to progress (Yasuko Takano et al., Ophthalmology 60(1), 9-13, 2018-01; Takahiko Noro et al., Journal of the Japanese Ophthalmological Society 118(10): 831-837, 2014). Therefore, maintaining low intraocular pressure throughout the day is important from the perspective of suppressing the progression of visual field defects.

[0069] While the patients who can be treated with the compositions of this disclosure are not limited to patients of a specific age, the compositions of this disclosure have shown greater therapeutic efficacy in patients under 65 years of age. Therefore, in some embodiments, the patients who can be treated with the compositions of this disclosure may be under 65 years of age. In certain embodiments, the patients who can be treated with the compositions of this disclosure may have a pre-administration intraocular pressure of 18 mmHg or more and less than 20 mmHg, and may be under 65 years of age. Preferably, in certain embodiments, the patients who can be treated with the compositions of this disclosure may have a pre-administration intraocular pressure of 18 mmHg or more and less than 20 mmHg, and may be between 20 and 65 years of age.

[0070] In another aspect, the present disclosure provides a composition for lowering intraocular pressure in a patient, comprising brimonidine or a pharmaceutically acceptable salt thereof and brinzolamide or a pharmaceutically acceptable salt thereof, wherein the patient is receiving other glaucoma medications, the patient's pre-administration intraocular pressure is 18 mmHg or greater and less than 20 mmHg, the composition is administered to the patient as one drop twice daily, the concentration of brimonidine in the composition is about 0.1% w / v, the concentration of brinzolamide is about 1% w / v, and the composition lowers the patient's intraocular pressure by about 10% or more, as evaluated by the rate of intraocular pressure reduction.

[0071] In a further context, the Disclosure provides a composition for use in a method for preventing the worsening of glaucoma or ocular hypertension in a patient, comprising brimonidine or a pharmaceutically acceptable salt thereof and brinzolamide or a pharmaceutically acceptable salt thereof, wherein the patient is diagnosed with glaucoma or ocular hypertension and is receiving other glaucoma treatments, and the method comprises: a) determining whether the other glaucoma treatments are sufficient or insufficient for the patient; b) measuring the patient's intraocular pressure; c) selecting a patient in whom the other glaucoma treatments are insufficient and whose pre-administration intraocular pressure on the initiation date is less than 20 mmHg (e.g., 18 mmHg or more and less than 20 mmHg); and d) administering the composition to the selected patient. Step c) may further include selecting a patient under 65 years of age. "Prevention of worsening of glaucoma" may include preventing or delaying the progression of visual field defects in patients with glaucoma. "Prevention of worsening of ocular hypertension" may include lowering intraocular pressure, preventing or delaying an increase in intraocular pressure, or preventing or delaying the onset of visual field defects in patients with ocular hypertension.

[0072] The active ingredients of the present invention, brimonidine or a pharmaceutically acceptable salt thereof, and brinzolamide or a pharmaceutically acceptable salt thereof, are provided as separate formulations (i.e., combination agents) and may be administered in combination.

[0073] Accordingly, in a further context, the present disclosure provides a combination for lowering intraocular pressure in patients with glaucoma or ocular hypertension, comprising brimonidine or a pharmaceutically acceptable salt thereof and brinzolamide or a pharmaceutically acceptable salt thereof.

[0074] In a further context, the present disclosure provides a composition for lowering intraocular pressure in patients with glaucoma or ocular hypertension, comprising brimonidine or a pharmaceutically acceptable salt thereof, characterized in that the composition is administered in combination with brinzolamide or a pharmaceutically acceptable salt thereof.

[0075] In a further aspect, the present disclosure provides a composition for lowering intraocular pressure in patients with glaucoma or ocular hypertension, comprising brinzolamide or a pharmaceutically acceptable salt thereof, characterized in that the composition is administered in combination with brimonidine or a pharmaceutically acceptable salt thereof.

[0076] In a further context, the present disclosure relates to a multi-component preparation (e.g., a combination preparation) comprising brimonidine or a pharmaceutically acceptable salt thereof and brinzolamide or a pharmaceutically acceptable salt thereof, for use in a method of suppressing the onset or progression of visual field defects in patients in whom the effects of other glaucoma treatments other than the multi-component preparation are insufficient, by reducing intraocular pressure by approximately 10% or more as evaluated by the rate of intraocular pressure reduction, and the method is as follows: a) A step of diagnosing whether the patient has glaucoma, b) The step of administering other glaucoma medications, c) A step of diagnosing whether the patient is not adequately treated with other glaucoma medications, d) A step of measuring the intraocular pressure of the patient, e) When the effect of other glaucoma treatments is insufficient and the patient has glaucoma, a step of administering the multi-component preparation to the patient, by selecting a composition comprising brimonidine or a pharmaceutically acceptable salt thereof and brinzolamide or a pharmaceutically acceptable salt thereof as a different alternative to other glaucoma treatments, either in place of or in combination with other glaucoma treatments. including, We provide a multi-component preparation.

[0077] In a further context, the present disclosure relates to a composition for use in a method for lowering intraocular pressure in a patient, comprising brimonidine or a pharmaceutically acceptable salt thereof and brinzolamide or a pharmaceutically acceptable salt thereof, wherein the patient is a patient suffering from glaucoma or ocular hypertension. The method involves the following steps: a) A step of measuring the intraocular pressure of the patient, b) A step of selecting patients whose pre-administration intraocular pressure value on the day of administration is less than 20 mmHg, c) The composition is administered to the selected patient. The present invention provides a composition containing [a certain substance].

[0078] (Method for evaluating effectiveness) In a further context, the present invention provides a method for using the pre-administration intraocular pressure in a patient as an indicator of whether treatment with a composition comprising, for example, brimonidine or a pharmaceutically acceptable salt thereof and brinzolamide or a pharmaceutically acceptable salt thereof is effective, wherein the method indicates that the composition is effective in the patient if other glaucoma treatments are ineffective and the patient's pre-administration intraocular pressure is less than 20 mmHg.

[0079] In some embodiments, the composition may be effective in a patient when the patient's pre-administration intraocular pressure is 18 mmHg or higher and less than 20 mmHg. In certain embodiments, the composition may be effective in a patient when the patient's pre-administration intraocular pressure is 18 mmHg or higher and less than 20 mmHg, and the patient is under 65 years of age.

[0080] (A different approach to selecting medications compared to other glaucoma treatments) In a further context, the present invention provides a method for using a patient's pre-administration intraocular pressure as an indicator for selecting a different glaucoma treatment drug from other glaucoma treatment drugs for lowering intraocular pressure in a patient suffering from glaucoma or ocular hypertension, wherein, in the patient, if the patient's pre-administration intraocular pressure is less than 20 mmHg, a composition comprising brimonidine or a pharmaceutically acceptable salt thereof and brinzolamide or a pharmaceutically acceptable salt thereof is effective as a different glaucoma treatment drug from other glaucoma treatment drugs.

[0081] In some embodiments, when a patient's pre-administration intraocular pressure is between 18 mmHg and less than 20 mmHg, a composition comprising brimonidine or a pharmaceutically acceptable salt thereof and brinzolamide or a pharmaceutically acceptable salt thereof may be shown to be effective as a different choice from other glaucoma treatments. When a patient's pre-administration intraocular pressure is between 18 mmHg and less than 20 mmHg and the patient is under 65 years of age, a composition comprising brimonidine or a pharmaceutically acceptable salt thereof and brinzolamide or a pharmaceutically acceptable salt thereof may be shown to be effective as a different choice from other glaucoma treatments.

[0082] The present disclosure has been described above with reference to preferred embodiments for ease of understanding. The present disclosure will now be described based on examples, but the above description and the following examples are provided for illustrative purposes only and not to limit the present disclosure. Accordingly, the scope of the present disclosure is not limited to the embodiments or examples specifically described herein, but is limited only by the claims. [Examples]

[0083] The present disclosure will be described in more detail below based on examples.

[0084] (Example 1: Stratified Analysis) In this example, patients were stratified by pre-administration intraocular pressure, and the effectiveness of the eye drops disclosed herein (brimonidine and brinzolamide-containing eye drops) was investigated for each patient strata.

[0085] In a multicenter, randomized, single-blind (evaluator-blinded), parallel-group comparative study, the efficacy (intraocular pressure-lowering effect) of a 0.1 w / v brimonidine tartrate / 1 w / v brinzolamide combination eye drop suspension (containing 1 mg of brimonidine tartrate, 10 mg of brinzolamide, tyroxapol, concentrated glycerin, boric acid, carboxyvinyl polymer, sodium edetate hydrate, benzalkonium chloride, isotonic agent, and pH adjuster per 1 mL) (hereinafter referred to as "this eye drop") when administered twice daily for 4 weeks was compared with a 1% brinzolamide eye drop suspension as a control in 163 patients with primary open-angle glaucoma (broad sense) or ocular hypertension.

[0086] In this embodiment, primary open-angle glaucoma (broad definition) included primary open-angle glaucoma (POAG) and preperimetric glaucoma (PPG). Of the criteria for primary open-angle glaucoma (broad definition), the POAG group consisted of individuals who met both (1) and (2) below, while the PPG group consisted of individuals who met only (2) below and were judged to require treatment. (1) Glaucomatous optic neuropathy (disorders of the optic nerve head or retinal nerve fiber layer) are present. If visual field measurements are performed using a Humphrey perimeter, follow the Anderson-Patella criteria (Anderson DR, Patella VM. Automated Static Perimetry. 2nd edition. St. Louis: Mosby; 1999: 152-3.). (2) A glaucomatous optic disc is present. Diagnosis is made through fundus examination (Glaucoma Treatment Guidelines (3rd Edition), etc.). 1% brinzolamide suspension eye drops (investigational drug for the observation period) were administered to each eye, one drop twice daily [morning and evening (9:00 ± 1 hour and 21:00 ± 1 hour)] for 4 weeks [from the evening of the start of the observation period to the morning of the end of the observation period (start of the treatment period)]. On the end of the observation period (start of the treatment period), if the intraocular pressure (IOP) values ​​at 0 and 2 hours for the eye being evaluated for efficacy were between 18.0 mmHg and 31.0 mmHg, and the difference between the IOP values ​​at 0 and 2 hours for the eye being evaluated for efficacy on the end of the observation period (start of the treatment period) was within 3.0 mmHg, the patient would proceed to the treatment period.

[0087] During the treatment period, one drop was administered to each eye twice a day [morning and evening (9:00 ± 1 hour and 21:00 ± 1 hour)]. The eye drops were started on the evening of the last day of the observation period (the start of the treatment period) and administered for 4 weeks (only in the morning on the last day of the treatment period). For the morning instillation during weeks 2 and 4 of the treatment period, the instillation was performed after measuring the intraocular pressure at 0 hours and within 9:00 ± 1 hour.

[0088] The intraocular pressure (IOP) value measured before morning eye drops and at 9:00 ± 1 hour is referred to as the 0-hour value, the IOP value measured within 2 hours ± 30 minutes after morning eye drops and by 12:30 is referred to as the 2-hour value, and the IOP value measured within 7 hours ± 1 hour after morning eye drops and by 18:00 is referred to as the 7-hour value.

[0089] The intraocular pressure reduction rate was calculated using the following formula based on the measured intraocular pressure values. • Percentage decrease in intraocular pressure at 0 hours (%) = [{Intraocular pressure value on the start of treatment (0-hour value) - Intraocular pressure value on each observation day (0-hour value)} / Intraocular pressure value on the start of treatment (0-hour value)] * 100 • Percentage decrease in intraocular pressure (IOP) at 2 hours = [{IOP value at 2 hours on the start of treatment - IOP value at 2 hours on each observation day} / IOP value at 2 hours on the start of treatment] * 100 • Percentage decrease in intraocular pressure (IOP) at 7 hours = [{IOP value on the start of treatment (7-hour value) - IOP value on each observation day (7-hour value)} / IOP value on the start of treatment (7-hour value)] * 100 Regarding the calculated intraocular pressure reduction rate, patients were distinguished into those whose reduction rate was 10% or less (+) and those whose reduction rate was not 10% or less (±) at each of the 0, 2, and 7-hour time points. In each group, which was divided by pre-treatment intraocular pressure and age, the proportion of (+) and (±) patients relative to the total number of patients was calculated, and the results are shown in the table below. Pre-treatment intraocular pressure is the value at 2 hours on the start of the treatment period.

[0090] Table 1 shows the results stratified by pre-administration intraocular pressure.

[0091] [Table 1]

[0092] As shown in Table 1, only about 30% of patients with a pre-administration intraocular pressure (IOP) of 20 mmHg or higher achieved an IOP reduction of 10% or more from their pre-administration IOP. In contrast, more than 50% of patients with a pre-administration IOP between 18 mmHg and 20 mmHg achieved an IOP reduction of 10% or more from their pre-administration IOP. Thus, this eye drop is considered to be more effective in patients with a pre-administration IOP between 18 mmHg and 20 mmHg. In glaucoma treatment, it is known that lowering IOP leads to a reduction in the risk of visual field defect progression. It has also been reported that a 1 mmHg reduction in IOP reduces the risk of visual field defect progression (Glaucoma Treatment Guidelines (4th edition), Kawase, Kazuhide. Ophthalmology. Vol. 48, No. 6. pp. 871-881 (2006)).

[0093] In patients with a pre-administration intraocular pressure (IOP) of 18 mmHg or higher but less than 20 mmHg, a reduction of 10% or more in IOP means bringing the IOP to below 18 mmHg. In the treatment of glaucoma, lowering IOP to below 18 mmHg is one of the objectives, and in patients who maintained an average IOP of less than 18 mmHg over a 6-year observation period, almost no progression of visual field defects was observed (Shiro Sakamoto, Yasuyuki Suzuki, Ophthalmology Vol.60, No.1, 2018, 27-34; Am J Ophthalmol 130:429-40, 2000). Therefore, it is extremely important that this eye drop reduces IOP by 10% or more in patients with an IOP of 18 mmHg or higher but less than 20 mmHg. Furthermore, by lowering IOP to below 18 mmHg, this eye drop can be said to be very effective in slowing the progression of visual field defects.

[0094] It is generally known that a greater intraocular pressure-lowering effect is observed in groups with high intraocular pressure (Aihara, Hajime; Atarashii Ganka 32(6):767~773; Nakauchi, Masashi et al.; Atarashii Ganka 28(8):1161~1165). For example, in the group administered ripasudil eye drops, a greater intraocular pressure-lowering effect was observed in the group with high intraocular pressure (Suzuki, Kanako et al.; Atarashii Ganka 35(8):1114~1116). Therefore, it was extremely unexpected that a greater intraocular pressure-lowering effect was observed in patients with relatively low pre-administration intraocular pressure of 18 mmHg to less than 20 mmHg.

[0095] Table 2 shows the results after further stratification by age.

[0096] [Table 2]

[0097] In the group with a pre-administration intraocular pressure of less than 20 mmHg and an age of less than 65 years, the proportion of patients (+) with a reduction rate of 10% or less was over 60% at all three time points (0, 2, and 7 hours), which was higher than in other groups. It was found that in the group with a pre-administration intraocular pressure of less than 20 mmHg and an age of less than 65 years, this eye drop was more effectively able to continuously lower intraocular pressure throughout the day. It is known that the greater the mean daily intraocular pressure, peak intraocular pressure, and intraocular pressure fluctuation range, the more likely visual field defects are to progress (Yasuko Takano et al., Ophthalmology 60(1), 9-13, 2018-01; Takahiko Noro et al., Journal of the Japanese Ophthalmological Society 118(10): 831-837, 2014). Therefore, maintaining low intraocular pressure throughout the day is important from the perspective of suppressing the progression of visual field defects.

[0098] (Example: Treatment example) Case 1: For patients diagnosed with primary open-angle glaucoma who are being treated with prostaglandin-related drugs but are experiencing insufficient response, administration of a 0.1 w / v% brimonidine tartrate / 1 w / v% brinzolamide combination suspension eye drop (containing 1 mg of brimonidine tartrate, 10 mg of brinzolamide, tyroxapol, concentrated glycerin, boric acid, carboxyvinyl polymer, sodium edetate hydrate, benzalkonium chloride, isotonic agent, and pH adjuster per 1 mL) twice daily will be initiated in addition to the prostaglandin-related drug. The patient's intraocular pressure (IOP) will be measured using a Goldmann applanation tonometer. The IOP (pre-administration IOP) will be measured between 10:00 AM and 12:30 PM on the day administration begins, and administration of this eye drop will be started if the pre-administration IOP is 18 mmHg or higher and 20 mmHg or higher. The IOP will be measured every month at 0, 2, and 7 hours to confirm the IOP-lowering effect. In addition, measurements of the fundus, visual field abnormalities, etc., will be taken and monitored.

[0099] Case 2: For patients diagnosed with primary open-angle glaucoma who are being treated with timolol eye drops or a combination of a prostaglandin-related drug and timolol but whose treatment is insufficient, the treatment should be switched to a 0.1 w / v% brimonidine tartrate / 1 w / v% brinzolamide combination eye drop suspension (containing 1 mg of brimonidine tartrate, 10 mg of brinzolamide, tyroxapol, concentrated glycerin, boric acid, carboxyvinyl polymer, sodium edetate hydrate, benzalkonium chloride, isotonic agent, and pH adjuster per 1 mL) and administration (twice daily) should be initiated. The patient's intraocular pressure (IOP) will be measured using a Goldmann applanation tonometer. The IOP (pre-administration IOP) will be measured between 10:00 AM and 12:30 PM on the day of administration. If the pre-administration IOP is between 18 mmHg and 20 mmHg, administration of this eye drop will be started. Every month, the 0-hour, 2-hour, and 7-hour IOP values ​​will be measured to confirm the IOP-lowering effect. In addition, fundus and visual field abnormalities will be measured and monitored.

[0100] As described above, while the present disclosure has been illustrated using preferred embodiments thereof, it is understood that the scope of this disclosure should be interpreted solely by the claims. Patents, patent applications, and documents cited herein should be incorporated herein by reference as if their contents were specifically described herein. [Industrial applicability]

[0101] A composition for treating glaucoma and / or ocular hypertension is provided. This technology can be used in fields such as pharmaceuticals.

Claims

1. A composition comprising brimonidine or a pharmaceutically acceptable salt thereof and brinzolamide or a pharmaceutically acceptable salt thereof, wherein the concentration of brimonidine or a pharmaceutically acceptable salt thereof is about 0.1% w / v and the concentration of brinzolamide or a pharmaceutically acceptable salt thereof is about 1% w / v, The composition further comprises tyroxapol, glycerin, boric acid, carboxyvinyl polymer, sodium edetate hydrate, benzalkonium chloride, isotonic agent, and pH adjuster. A composition for lowering intraocular pressure in patients suffering from glaucoma or ocular hypertension who are being administered other glaucoma treatment drugs besides the composition, and whose intraocular pressure value after treatment with other glaucoma treatment drugs is 18 mmHg or more and less than 20 mmHg.

2. The composition according to claim 1, wherein the brimonidine or a pharmaceutically acceptable salt thereof is brimonidine tartrate.

3. The composition according to claim 1 or 2, characterized in that the composition is administered to the patient as eye drops, one drop at a time, twice a day.

4. The composition according to any one of claims 1 to 3, wherein the patient is a patient under 65 years of age.

5. The composition according to any one of claims 1 to 4, characterized in that the composition reduces the intraocular pressure of the patient by 10% or more when evaluated by the rate of reduction in intraocular pressure.

6. The composition according to claim 5, characterized in that, when evaluated by the rate of reduction in intraocular pressure, the composition continues to reduce the intraocular pressure of the patient by 10% or more for at least 12 hours after administration.

7. The composition according to claim 5 or 6, wherein the rate of reduction in intraocular pressure is evaluated four weeks after the start of administration.

8. A composition comprising brimonidine or a pharmaceutically acceptable salt thereof and brinzolamide or a pharmaceutically acceptable salt thereof, wherein the concentration of brimonidine or a pharmaceutically acceptable salt thereof is about 0.1% w / v and the concentration of brinzolamide or a pharmaceutically acceptable salt thereof is about 1% w / v, The composition further comprises tyroxapol, glycerin, boric acid, carboxyvinyl polymer, sodium edetate hydrate, benzalkonium chloride, isotonic agent, and pH adjuster. A composition for treating glaucoma or ocular hypertension in patients who are receiving other glaucoma treatment drugs besides the composition, and whose intraocular pressure value after treatment with the other glaucoma treatment drug is 18 mmHg or more and less than 20 mmHg.

9. The composition according to claim 8, wherein the brimonidine or a pharmaceutically acceptable salt thereof is brimonidine tartrate.

10. The composition according to claim 8 or 9, characterized in that the composition is administered to the patient as eye drops, one drop at a time, twice a day.

11. The composition according to any one of claims 8 to 10, wherein the patient is a patient under 65 years of age.

12. The composition according to any one of claims 8 to 11, wherein the composition is for treating glaucoma or ocular hypertension by lowering the intraocular pressure of the patient.

13. The composition according to any one of claims 8 to 12, characterized in that the composition reduces the intraocular pressure of the patient by 10% or more when evaluated by the rate of reduction in intraocular pressure.

14. The composition according to claim 13, characterized in that, when evaluated by the rate of reduction in intraocular pressure, the composition continues to reduce the intraocular pressure of the patient by 10% or more for at least 12 hours after administration.

15. The composition according to claim 13 or 14, wherein the rate of reduction in intraocular pressure is evaluated four weeks after the start of administration.

16. The composition according to any one of claims 8 to 15, wherein the treatment of glaucoma includes preventing or delaying the progression of visual field defects in the glaucoma patient, and the treatment of ocular hypertension includes preventing or delaying the onset of visual field defects.

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