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 lowering intraocular pressure in a patient, comprising brimonidine and brinzolamide. [Background technology]

[0002] Aiphagan® eye drops containing brimonidine are the only alpha-antihypertensive medication available. 2 It is a receptor agonist, and when used in combination with existing drugs, it can further reduce intraocular pressure, has few systemic side effects, and has a visual field preserving effect that is not commensurate with the intraocular pressure reducing effect, so it is often used in combination with existing treatments. The number of glaucoma patients is increasing year by year, and many patients are treated with combination therapy. Many patients are also using brimonidine, so there are high hopes for a combination drug with brimonidine.

[0003] Brinzolamide is a carbonic anhydrase inhibitor with fewer systemic side effects. It can be prescribed to patients who cannot use β-blockers in combination therapy, who show local side effects of prostaglandin (PG)-related drugs, and who do not respond well to PG-related drugs.

[0004] In addition, all existing combination drugs contain β-blockers, and there is hope for a combination drug that does not contain β-blockers. Summary of the Invention [Means for solving the problem]

[0005] The present inventors conducted a stratified analysis of the intraocular pressure before administration of an eye drop containing brimonidine and brinzolamide, and found that the eye drop exhibits a high intraocular pressure-reducing effect in patients whose intraocular pressure before administration is in a specific range.Therefore, the present disclosure relates to a composition for reducing intraocular pressure containing brimonidine and brinzolamide, and in particular, exhibits excellent therapeutic effects on a specific group of patients with glaucoma and / or ocular hypertension.In addition, the present disclosure can provide an effective drug as a selective drug different from other glaucoma drugs, for use in patients who are already administered other glaucoma drugs in which the effect is insufficient, instead of part or all of the other glaucoma drugs, or in combination with the other glaucoma drugs.

[0006] The present disclosure provides, for example, the following: (Item 1) 1. A composition for use in a method of reducing intraocular pressure in a patient comprising brimonidine or a pharma- ceutically acceptable salt thereof and brinzolamide or a pharma- ceutically acceptable salt thereof, The patient is suffering from glaucoma or ocular hypertension and is receiving another glaucoma treatment drug, The method comprises the steps of: a) determining whether the effect of the other glaucoma therapeutic drug on the patient is sufficient or insufficient; b) measuring the patient's pre-intraocular pressure; c) selecting a patient for whom the other glaucoma therapeutic agent is insufficiently effective and whose pre-administration intraocular pressure is less than 20 mmHg; d) administering the composition to the selected patient. A composition comprising: (Item 2) 2. The composition according to item 1, wherein the pre-administration intraocular pressure is greater than or equal to 18 mmHg and less than 20 mmHg. (Item 3) 3. The composition according to item 1 or 2, wherein the brimonidine or a pharma- ceutically acceptable salt thereof is brimonidine tartrate. (Item 4) 4. The composition according to any one of items 1 to 3, wherein the concentration of brimonidine or a pharma- ceutically acceptable salt thereof in the composition is about 0.1% w / v and the concentration of brinzolamide or a pharma- ceutically acceptable salt thereof is about 1% w / v. (Item 5) 4. The composition according to any one of items 1 to 3, wherein the composition is administered to the patient by instillation, 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) 7. The composition according to any one of items 1 to 6, wherein the composition reduces the intraocular pressure of the patient by 10% or more from the intraocular pressure before administration. (Item 8) 8. The composition according to item 7, wherein the composition reduces intraocular pressure by 10% or more from the pre-administration intraocular pressure for at least 12 hours after administration. (Item 9) 8. The composition according to item 7, wherein the composition reduces the intraocular pressure by 10% or more from the pre-administration intraocular pressure for a period of at least 7:00 to 18:00. (Item 10) 10. The composition according to any one of items 1 to 9, wherein the patient has been administered the other glaucoma medication for 4 weeks or more. (Item 11) 1. A composition for use in a method for preventing the worsening of glaucoma or ocular hypertension in a patient comprising brimonidine or a pharma- ceutically acceptable salt thereof and brinzolamide or a pharma- ceutically acceptable salt thereof, The patient has been diagnosed with glaucoma or ocular hypertension and is receiving another glaucoma medication, The method comprises the steps of: a) determining whether the effect of the other glaucoma therapeutic drug on the patient is sufficient or insufficient; b) measuring the patient's pre-intraocular pressure; c) selecting a patient for whom the other glaucoma therapeutic agent is insufficiently effective and whose pre-administration intraocular pressure is less than 20 mmHg; d) administering the composition to the selected patient. A composition comprising: (Item 12) 12. The composition according to item 11, wherein the pre-administration intraocular pressure is greater than or equal to 18 mmHg and less than 20 mmHg. (Item 13) 13. The composition according to item 11 or 12, further comprising selecting a patient under 65 years of age in step c). (Item 14) 14. The composition according to any one of items 11 to 13, wherein the prevention of worsening of glaucoma includes prevention or delay of progression of visual field impairment in the glaucoma patient, and the prevention of worsening of ocular hypertension includes reduction of intraocular pressure, prevention or delay of increase in intraocular pressure, or prevention or delay of onset of visual field impairment in a patient with ocular hypertension. (Item 15) A method for using pre-administration intraocular pressure in a patient as an indicator of whether treatment with a composition comprising brimonidine or a pharma- ceutical acceptable salt thereof and brinzolamide or a pharma-ceutical acceptable salt thereof is effective, the method indicating that the composition is effective in the patient if other glaucoma treatment drugs are insufficient in the patient and the pre-administration intraocular pressure of the patient is less than 20 mmHg. (Item 16) 16. The method of claim 15, wherein the composition is effective in a patient when the pre-administration intraocular pressure of the patient is greater than or equal to 18 mmHg and less than 20 mmHg. (Item 17) 17. The method of claim 16, wherein the composition is effective in a patient when the patient's pre-administration intraocular pressure is greater than or equal to 18 mmHg and less than 20 mmHg, and the patient is less than 65 years of age. (Item 18) 1. A method for using a patient's pre-dose intraocular pressure as an indicator for selecting a second-choice drug for lowering intraocular pressure in a patient suffering from glaucoma or ocular hypertension, the method indicating that a composition comprising brimonidine or a pharma- ceutical acceptable salt thereof and brinzolamide or a pharma-ceutical acceptable salt thereof is effective as the second-choice drug in a patient suffering from glaucoma or ocular hypertension when the patient's pre-dose intraocular pressure is less than 20 mmHg. (Item 19) The method according to item 18, which indicates that a composition comprising brimonidine or a pharma- ceutical acceptable salt thereof and brinzolamide or a pharma- ceutical acceptable salt thereof is effective as the second-choice drug when the patient's pre-administration intraocular pressure is 18 mmHg or more and less than 20 mmHg. (Item 20) 20. The method according to item 19, which indicates that a composition comprising brimonidine or a pharma- ceutical acceptable salt thereof and brinzolamide or a pharma- ceutical acceptable salt thereof is effective as the second-line drug when 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 21) A method for using a patient's pre-administration intraocular pressure and age as indicators for selecting a second-choice drug that reduces intraocular pressure by 10% or more from the pre-administration intraocular pressure for at least 12 hours after administration in a patient who suffers from glaucoma or ocular hypertension and has been administered other glaucoma treatment drugs but has not been sufficiently effective, the method showing that a composition comprising brimonidine or a pharmacologic acceptable salt thereof and brinzolamide or a pharmacologic acceptable salt thereof is effective as the second-choice drug in a patient whose pre-administration intraocular pressure is 18 mmHg or more and less than 20 mmHg and who is younger than 65 years of age. (Item 1A) A composition for selectively treating a patient having a pre-administration intraocular pressure of less than 20 mmHg, comprising brimonidine or a pharma- ceutical acceptable salt thereof and brinzolamide or a pharma- ceutical acceptable salt thereof, wherein the patient suffers from glaucoma or ocular hypertension, is receiving other glaucoma medications, and is insufficiently responsive to the other glaucoma medications. (Item 2A) The composition according to item 1A, wherein the pre-administration intraocular pressure is equal to or greater than 18 mmHg and less than 20 mmHg. (Item 3A) The composition according to item 1A or 2A, wherein the brimonidine or a pharma- ceutically 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 pharma- ceutically acceptable salt thereof in the composition is about 0.1% w / v and the concentration of brinzolamide or a pharma-ceutically acceptable salt thereof is about 1% w / v. (Item 5A) The composition according to any one of items 1A to 3A, characterized in that the composition is administered to the patient by instillation, one drop at a time, twice a day. (Item 6A) The composition of any one of paragraphs 1A to 5A, wherein the patient is under 65 years of age. (Item 7A) The composition according to any one of items 1A to 6A, wherein the composition reduces the intraocular pressure of the patient by 10% or more from the intraocular pressure before administration. (Item 8A) The composition according to item 7A, wherein the composition reduces intraocular pressure by 10% or more from the pre-administration intraocular pressure for at least 12 hours after administration. (Item 9A) The composition according to item 7A, wherein the composition reduces the intraocular pressure by 10% or more from the pre-administration intraocular pressure for a period of at least 7:00 to 18:00. (Item 1B) 1. A composition for use in a method of reducing intraocular pressure in a patient comprising brimonidine or a pharma- ceutically acceptable salt thereof and brinzolamide or a pharma- ceutically acceptable salt thereof, The patient is suffering from glaucoma or ocular hypertension and is receiving a therapeutic drug for glaucoma other than the composition, The method comprises the steps of: a) determining whether the effect of the other glaucoma therapeutic drug on the patient is sufficient or insufficient; b) measuring the intraocular pressure of the patient; c) selecting a patient for whom the other glaucoma therapeutic drug is insufficiently effective and whose pre-administration intraocular pressure on the day of administration is less than 20 mmHg; d) administering the composition to the selected patient. A composition comprising: (Item 2B) The composition according to item 1B, wherein the pre-administration intraocular pressure value is equal to or greater than 18 mmHg and less than 20 mmHg. (Item 3B) 3. The composition according to item 1 or 2, wherein the brimonidine or a pharma- ceutically 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 pharma- ceutically acceptable salt thereof in the composition is about 0.1% w / v and the concentration of brinzolamide or a pharma- ceutically acceptable salt thereof is about 1% w / v. (Item 5B) The composition according to any one of items 1B to 4B, wherein the composition is administered to the patient by instillation, 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, wherein the composition reduces the intraocular pressure of the patient by 10% or more when evaluated by an intraocular pressure reduction rate. (Item 8B) The composition according to item 7B, wherein the composition reduces intraocular pressure by 10% or more for at least 12 hours after administration when evaluated by intraocular pressure reduction rate. (Item 9B) The composition according to item 7B, wherein the composition reduces intraocular pressure by 10% or more for at least 7:00 to 18:00, as evaluated by the intraocular pressure reduction rate. (Item 10B) 1. A composition for use in a method for preventing the worsening of glaucoma or ocular hypertension in a patient comprising brimonidine or a pharma- ceutically acceptable salt thereof and brinzolamide or a pharma- ceutically acceptable salt thereof, The patient is a patient who has been diagnosed with glaucoma or ocular hypertension and is receiving a therapeutic drug for glaucoma other than the composition, The method comprises the steps of: a) determining whether the effect of the other glaucoma therapeutic drug on the patient is sufficient or insufficient; b) measuring the intraocular pressure of the patient; c) selecting a patient for whom the other glaucoma therapeutic drug is insufficiently effective and whose pre-administration intraocular pressure on the day of administration is less than 20 mmHg; d) administering the composition to the selected patient. A composition comprising: (Item 11B) The composition according to item 10B, wherein the pre-administration intraocular pressure is equal to or greater than 18 mmHg 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 prevention or delay of progression of visual field defects in the glaucoma patient, and the prevention of the worsening of ocular hypertension includes reduction of intraocular pressure, prevention or delay of increase in intraocular pressure, or prevention or delay of onset of visual field defects in the ocular hypertension patient. (Item 14B) A method for using pre-administration intraocular pressure in a patient as an indicator of whether treatment with a composition comprising brimonidine or a pharma- ceutical acceptable salt thereof and brinzolamide or a pharma-ceutical acceptable salt thereof is effective, the method indicating that the composition is effective in the patient if other glaucoma treatment drugs are insufficient in the patient and the pre-administration intraocular pressure of the patient is less than 20 mmHg. (Item 15B) The method of claim 14B, wherein the composition is effective in a patient when the pre-administration intraocular pressure of the patient is greater than or equal to 18 mmHg and less than 20 mmHg. (Item 16B) The method of claim 15B, wherein the composition is effective in a patient when the pre-administration intraocular pressure of the patient is greater than or equal to 18 mmHg and less than 20 mmHg, and the patient is less than 65 years of age. (Item 17B) A method for using a patient's pre-administration intraocular pressure as an indicator for selecting a drug of choice different from other glaucoma medications for lowering intraocular pressure in a patient suffering from glaucoma or ocular hypertension, the method showing that a composition comprising brimonidine or a pharma- ceutical acceptable salt thereof and brinzolamide or a pharma-ceutical acceptable salt thereof is effective as a drug of choice different from the other glaucoma medications in a patient suffering from glaucoma or ocular hypertension when the patient's pre-administration intraocular pressure is less than 20 mmHg. (Item 18B) The method according to Item 17B, which indicates that a composition comprising brimonidine or a pharma- ceutical acceptable salt thereof and brinzolamide or a pharma- ceutical acceptable salt thereof is effective as a selective drug different from the other glaucoma therapeutic drugs when the patient's pre-administration intraocular pressure is 18 mmHg or more and less than 20 mmHg. (Item 19B) The method according to item 18B, which indicates that a composition comprising brimonidine or a pharma- ceutical acceptable salt thereof and brinzolamide or a pharma- ceutical acceptable salt thereof is effective as an alternative drug different from the other glaucoma therapeutic drugs when 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 20B) A method for using a patient's pre-administration intraocular pressure and age as indicators for selecting a drug of choice different from other glaucoma drugs that reduces intraocular pressure by 10% or more for at least 12 hours after administration when evaluated by the intraocular pressure reduction rate in a patient suffering from glaucoma or ocular hypertension and who has been administered other glaucoma drugs but has not been sufficiently effective, the method showing that a composition comprising brimonidine or a pharmacologic acceptable salt thereof and brinzolamide or a pharmacologic acceptable salt thereof is effective as a drug of choice different from the other glaucoma drugs in a patient whose pre-administration intraocular pressure is 18 mmHg or more and less than 20 mmHg and whose age is less than 65 years old. (Item 21B) A multiple-component preparation comprising brimonidine or a pharma- ceutical acceptable salt thereof and brinzolamide or a pharma-ceutical acceptable salt thereof, the multiple-component preparation being used in a method for suppressing the onset or progression of visual field impairment in a patient for whom other therapeutic glaucoma drugs than the multiple-component preparation are insufficient, by lowering intraocular pressure by about 10% or more as assessed by an intraocular pressure reduction rate, the method comprising: a) diagnosing whether the patient has glaucoma; b) administering another glaucoma medication; c) diagnosing whether the patient is ineffective in treating with other glaucoma medications; d) measuring the intraocular pressure of the patient; e) when the effect of other glaucoma therapeutic drugs is insufficient and the patient has glaucoma, selecting a composition containing brimonidine or a pharma- ceutically acceptable salt thereof and brinzolamide or a pharma- ceutically acceptable salt thereof as a selective drug different from other glaucoma therapeutic drugs in place of or in combination with the other glaucoma therapeutic drugs, and administering the multiple-component preparation to the patient; Including, Multi-ingredient agent. (Item 22B) The multiple-component agent according to item 21B, which is a combination agent. (Item 23B) 1. A composition for use in a method of reducing intraocular pressure in a patient, the method comprising: administering to the patient a medicament for use in a method of reducing intraocular pressure in a patient, the patient suffering from glaucoma or ocular hypertension, the composition comprising brimonidine or a pharma- ceutical acceptable salt thereof and brinzolamide or a pharma-ceutical acceptable salt thereof; The method comprises the steps of: a) measuring the intraocular pressure of the patient; b) selecting a patient whose pre-administration intraocular pressure value is less than 20 mmHg on the day of administration; c) administering the composition to the selected patient. A composition comprising: (Item 24B) The composition according to item 23B, wherein the pre-administration intraocular pressure value is equal to or greater than 18 mmHg and less than 20 mmHg. (Item 25B) The composition according to item 23B or 24B, wherein the brimonidine or a pharma- ceutically 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 pharma- ceutically acceptable salt thereof in the composition is about 0.1% w / v and the concentration of brinzolamide or a pharma- ceutically acceptable salt thereof is about 1% w / v. (Item 27B) The composition according to any one of items 23B to 26B, wherein the composition is administered to the patient by instillation, 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, wherein the composition reduces the intraocular pressure of the patient by 10% or more when evaluated by the intraocular pressure reduction rate. (Item 30B) The composition according to item 29B, wherein the composition reduces intraocular pressure by 10% or more for at least 12 hours after administration, as evaluated by intraocular pressure reduction rate. (Item 31B) 30. The composition according to item 29, wherein the composition reduces intraocular pressure by 10% or more for at least 7:00 to 18:00 when evaluated by intraocular pressure reduction rate. (Item 32B) The composition described in the preceding item, wherein the pre-administration intraocular pressure value on the start date of administration of the selected drug different from the other glaucoma therapeutic drugs is the 2-hour value on the start date of administration of the selected drug different from the other glaucoma therapeutic drugs. (Item 33B) The composition according to the preceding item, wherein the pre-administration intraocular pressure is a value after correction for seasonal variation and / or diurnal variation.

[0007] It is contemplated that the present disclosure may provide one or more of the above features in combinations other than those specifically described. Further embodiments and advantages of the present disclosure will be recognized by those skilled in the art upon reading and understanding the following detailed description, if necessary. Effect of the Invention

[0008] According to the present disclosure, there is provided a composition containing brimonidine and brinzolamide that exhibits excellent intraocular pressure-reducing effects in a specific group of patients for whom other glaucoma treatments are insufficient. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] The present disclosure will be described below. Throughout this specification, the singular expression should be understood to include the concept of the plural form, unless otherwise specified. Thus, the singular article (e.g., in the case of English, "a", "an", "the", etc.) should be understood to include the concept of the plural form, unless otherwise specified. In addition, the terms used in this specification should be understood to be used in the sense commonly used in the art, unless otherwise specified. Therefore, unless otherwise defined, all technical terms and scientific and technical terms used in this specification have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. In the case of conflict, the present specification (including definitions) will take precedence. In this specification, "about" means ±10% of the value that follows. In this specification, the time is displayed in 24-hour format unless otherwise specified.

[0010] (definition) As used herein, "brimonidine" refers to a compound of the formula

[0011] [ka]

[0012] Brimonidine or a pharmaceutically acceptable salt thereof is used as a pharmaceutical ingredient, and is typically provided as brimonidine tartrate (chemical name 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)quinoxalin-6-amine-mono-(2R,3R)-tartrate). Brimonidine or a pharmaceutically acceptable salt thereof is a selective adrenergic alpha 2Brimonidine is a receptor agonist and is formulated as an active ingredient in general aqueous liquid preparations, especially eye drops, and its tartrate salt is marketed under the trade name AIPHAGAN. Brimonidine and its pharmaceutically acceptable salts are commercially available. Pharmaceutically acceptable salts of brimonidine include, but are not limited to, tartrate, hydrochloride, or acetate. As an eye drop, it is used as a treatment for glaucoma and ocular hypertension. Brimonidine is used to lower intraocular pressure in patients with (open angle) glaucoma or ocular hypertension.

[0013] As used herein, "brinzolamide" refers to a compound represented by the following formula:

[0014] [ka]

[0015] Brinzolamide is a compound with the chemical name (R)-4-(ethylamino)-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno[3,2,e]-1,2-thiazine-6-sulfonamide 1,1-dioxide, which is shown as: Brinzolamide is a carbonic anhydrase inhibitor and can be formulated as an active ingredient in general aqueous solutions, especially eye drops. Brinzolamide and its pharma- ceutical acceptable salts are commercially available. Clinically acceptable salts include, but are not limited to, hydrochloride, acetate, etc. Brinzolamide is used as an eye drop to treat glaucoma and ocular hypertension. Brinzolamide is used to lower intraocular pressure in patients with (open angle) glaucoma or ocular hypertension.

[0016] As used herein, "pharmaceutical acceptable salt" includes salts that can be safely administered to patients.Preferred pharmaceutical 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.Pharmaceutical acceptable salts can 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 characteristic 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 (Japan Glaucoma Society Glaucoma Treatment Guideline Preparation Committee. Glaucoma Treatment Guideline (4th Edition). Journal of the Japanese Ophthalmological Society. Vol. 122, No. 1). p.5-53 (2018.01) (hereinafter referred to as "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 angle-closure glaucoma, while primary open-angle glaucoma (broad sense) includes primary open-angle glaucoma, normal tension glaucoma, and prefield glaucoma. Secondary glaucoma includes secondary open-angle glaucoma and secondary angle-closure glaucoma, while pediatric glaucoma includes primary congenital glaucoma, juvenile open-angle glaucoma, and glaucoma associated with congenital ocular malformations, and glaucoma associated with congenital systemic diseases.

[0018] As used herein, "ocular hypertension" refers to a disease characterized by higher than normal intraocular pressure, although no clear abnormality is observed in the visual field or optic nerve. Ocular hypertension is likely to progress (transition) to glaucoma in the future, and eye drop treatment may be performed to keep intraocular pressure at normal levels.

[0019] As used herein, the term "medicine for treating glaucoma" refers to a drug that suppresses the progression of optic nerve damage and / or visual field impairment due to glaucoma. Since optic nerve damage can be improved or suppressed by lowering intraocular pressure, the drug for treating glaucoma is typically an intraocular pressure-lowering drug. An intraocular pressure-lowering drug can also be used to treat ocular hypertension.

[0020] In this specification, "insufficient effect" refers to a state in which the progression of glaucoma or ocular hypertension is not suppressed from the time of no treatment, taking into consideration the measurement of intraocular pressure, optic disc findings, visual field findings, etc. as a whole. As an indicator of "insufficient effect", the intraocular pressure reduction rate from the time of no treatment may be used, or an intraocular pressure of 18 mmHg or more may be used. As an indicator of "insufficient effect", either one or both of the visual disc findings and visual field findings may be used, and if these findings are confirmed over time and are found to have deteriorated, it may be judged that the effect is insufficient. Whether the effect is sufficient or insufficient is confirmed in patients who have been administered other glaucoma treatment drugs for a certain period of time.

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

[0022] In the present specification, the term "pre-administration intraocular pressure" refers to the intraocular pressure before the start of treatment with the composition of the present disclosure, and refers to the intraocular pressure measured on the day when administration of the composition of the present disclosure is started (administration start date) and before the administration of the pharmaceutical agent (usually within 12 hours before), 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 when administration of the composition of the present disclosure is started. For example, the 2-hour value in the examples described below can be mentioned, but is not limited thereto, and any value such as 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 before administration of the pharmaceutical agent can be assumed.

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

[0024] In this specification, the "administration start date" refers to the date (including the schedule) on which administration of a certain medicine is to be started. Therefore, in the case of companion medicines, the administration start date refers to the date on which it is decided whether or not to start administration. If it is decided not to start administration, the actual administration is not carried out, but in this specification, it is treated as the administration start date.

[0025] In the present specification, the term "evaluation date" refers to the date on which intraocular pressure is evaluated. Any date may be applicable, but for example, the period of about 4 weeks, about 12 weeks, about 3 months, about 6 months, about 28 weeks, about 52 weeks, about 1 year, about 3 years, etc. from the start date of administration may be the target.

[0026] The subject or patient of the present disclosure may be one whose seasonal variation is 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 of the present disclosure may be designed using a "pre-administration intraocular pressure value" after taking into account seasonal variation and adjusting for it.

[0027] The subject or patient to whom the present disclosure is directed may be a patient whose diurnal variation value for 2 to 3 hours is 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, the subject or patient may be a patient whose diurnal variation value for 10:00 to 12:30 is 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 prevention to which the present disclosure is directed may be designed using the "pre-administration intraocular pressure value" after taking into account the diurnal variation and adjusting it.

[0028] As used herein, the term "intraocular pressure reduction rate" refers to the rate of change in the intraocular pressure on the evaluation day, which is the subject of evaluation, compared with the intraocular pressure on the start day of administration, which is the evaluation standard, in the same patient.

[0029] As used herein, the term "single-component preparation" refers to a preparation that contains or uses a single active ingredient (API) for the purpose of exerting a medicinal effect such as lowering intraocular pressure in glaucoma, and does not contain or use any other active ingredient. Thus, a single-component preparation of a carbonic anhydrase inhibitor refers to a preparation that contains only a carbonic anhydrase inhibitor as an active ingredient and is provided assuming administration of only the carbonic anhydrase inhibitor. On the other hand, as used herein, a "multiple-component preparation" refers to a preparation that is administered in combination with an additional active ingredient in addition to the main active ingredient for the purpose of exerting a medicinal effect. A multiple-component preparation may be provided in a form in which each active ingredient exists in the same preparation (also referred to as a "combination preparation" in this specification), or in a form in which each active ingredient exists in a separate preparation, or a combination thereof. Thus, a multiple-component preparation also includes a dosage form that is formulated as a single-component preparation, but is provided with a specific use such that it is administered in combination with another active ingredient. Thus, a multiple-component formulation includes a formulation that contains a first active ingredient, such as a carbonic anhydrase inhibitor, as an active ingredient, and further contains an additional active ingredient, such as a prostaglandin-related drug, or a formulation that is administered in combination with a separate formulation that contains an additional active ingredient. 2 In some embodiments, the invention provides a method for administering the compound in combination with a medicament that includes a receptor agonist. 2 Medicaments including receptor stimulants are provided in embodiments that are intended to be administered in combination with medicaments including carbonic anhydrase inhibitor eye drops.

[0030] As used herein, the term "combination drug" refers to a drug that contains a main active ingredient and an additional active ingredient in the same formulation for the purpose of exerting a medicinal effect, for example, a formulation that contains multiple active ingredients with different or the same mechanism of action in the same formulation for reducing intraocular pressure in glaucoma. As used herein, the combination drug may be used in combination with other glaucoma treatment drugs (whether as a single drug or a combination drug) at the same time or at different times.

[0031] In this specification, the "instructions" are those that explain to the user how to use the present disclosure, and are called "package insert" in Japan and label in the United States and other countries. The instructions contain wording that instructs how to use the present disclosure. If necessary, the instructions are prepared in accordance with a format specified by the supervisory agency of the country in which the present disclosure is implemented (e.g., the Ministry of Health, Labor and Welfare or the Ministry of Agriculture, Forestry and Fisheries in Japan, the Food and Drug Administration (FDA), the Department of Agriculture (USDA), etc. in the United States), and it is clearly stated that the instructions have been approved by the supervisory agency. The instructions may be provided in paper form, but are not limited thereto, and may also be provided in the form of, for example, electronic media (e.g., a homepage provided on the Internet, e-mail).

[0032] In this specification, the term "first-choice drug" (also called first-line or first-choice) refers to a therapeutic drug that should be administered first for a certain disease. Usually, first-choice drugs are selected as drugs with few side effects and a certain degree of effectiveness. If the effect is insufficient or no improvement is seen after administration of the first-choice drug, a second-choice drug that prioritizes effectiveness while taking into account other mechanisms of action is administered. For example, prostaglandin-related drugs and β-blockers are administered as first-choice drugs for glaucoma. Prostaglandin-related drugs also have the advantage of requiring less frequent instillation.

[0033] In this specification, the term "second-line drug" (also called second choice) refers to a therapeutic drug used when the first-line drug is ineffective or does not improve the condition, or when it is difficult to continue treatment due to side effects. Second-line drugs are used instead of or in addition to first-line drugs. There are many second-line drugs for glaucoma, including carbonic anhydrase inhibitor eye drops and alpha-acetylglucosamine hydrochloride. 2 Receptor agonists, ROCK inhibitors, α 1 There are various types of drugs, such as receptor blockers, non-selective sympathomimetics, and parasympathomimetics, and each has different effects and is suitable for different patients, so the appropriate selection of the second-line drug is important for the appropriate treatment of glaucoma.

[0034] In this specification, the term "drug of choice different from other glaucoma drugs" refers to a drug that is used next when no improvement is seen even after administration of the first-choice or second-choice drug, or when it is difficult to continue treatment due to side effects. "Drug of choice different from other glaucoma drugs" includes various combination drugs containing the first-choice or second-choice drugs for glaucoma. The first-choice and second-choice drugs are as described above, and combination drugs include, for example, a combination drug of a prostaglandin-related drug and a β-blocker, a combination drug of a carbonic anhydrase inhibitor and a β-blocker, etc. Since each drug has different effects and suitable patients, the appropriate selection of "drug of choice different from other glaucoma drugs" is important for the appropriate treatment of glaucoma.

[0035] (Preferred embodiment) Preferred embodiments of the present disclosure are described below. The embodiments provided below are provided for a better understanding of the present disclosure, and it is understood that the scope of the present disclosure should not be limited to the following description. Therefore, it is clear that a person skilled in the art can make appropriate modifications within the scope of the present disclosure in light of the description in this specification. It is also understood that the following embodiments can be used alone or in combination.

[0036] (composition) In one aspect, the present disclosure provides a composition (i.e., a combination drug), e.g., an eye drop, for use in a method for lowering intraocular pressure in a patient, comprising brimonidine or a pharma- ceutically acceptable salt thereof (e.g., brimonidine tartrate) and brinzolamide or a pharma-ceutically acceptable salt thereof. The patient may be a patient suffering from glaucoma or ocular hypertension and receiving other glaucoma treatment drugs (e.g., an intraocular pressure-reducing drug, a neuroprotective drug). The method for lowering intraocular pressure may include: a) determining whether the other glaucoma treatment drugs are sufficiently or insufficiently effective for the patient; b) measuring the intraocular pressure of the patient; c) selecting a patient for whom the other glaucoma treatment drugs are insufficiently effective and whose pre-administration intraocular pressure value on the day of administration is less than 20 mmHg; and d) administering the composition to the selected patient. In this specification, the term "eye drop" is synonymous with "ophthalmic solution." The present inventors have newly discovered that administration of the composition of the present disclosure to a specific patient group shows a more excellent therapeutic effect than other groups. Such a composition is useful for (i) treating patients who have been administered other glaucoma therapeutic drugs and for whom the other glaucoma therapeutic drugs are insufficient. Select (ii) Among these patients, patients whose pre-treatment intraocular pressure was less than 20 mmHg on the day of starting treatment with a selected drug other than other glaucoma drugs were selected. Select (iii) A combination of brimonidine and brinzolamide as a different option from other glaucoma treatments. Select These "three options" provide excellent therapeutic effects, lowering intraocular pressure by approximately 10% or more over a sustained period.

[0037] Without wishing to be bound by theory, when administered as separate preparations, the preparation administered earlier is washed away by the preparation administered later, so it is necessary to administer them at intervals of several minutes, which is a burden to the patient. In addition, the amount of the active ingredient transferred into the eye may change depending on the order of administration, which may reduce efficacy. The composition (i.e., combination preparation) comprising brimonidine or a pharma- ceutically acceptable salt thereof of the present disclosure and brinzolamide or a pharma- ceutically acceptable salt thereof is advantageous in that it is not washed away, does not need to be administered multiple times at intervals, and can prevent unexpected changes in the amount of transfer. In addition, the number of eye drops administered can be reduced, which can reduce the burden on the patient.

[0038] This composition may contain, for example, a suspending agent, an isotonicity agent, a buffer, a viscosity agent, a stabilizer, a preservative, a pH adjuster, or a solvent that may be generally used in ophthalmic compositions (particularly aqueous eye drops, more specifically suspension eye drops). More specifically, it may contain one or more additive components such as tyloxapol, glycerin, boric acid, carboxyvinyl polymer, sodium edetate hydrate, benzalkonium chloride, an isotonicity agent, or a pH adjuster. In the composition of the present disclosure, brimonidine or a pharma- ceutically acceptable salt thereof is not particularly limited and may be appropriately set according to the degree of symptoms of the patient to be applied, the amount applied per time, etc., and may be, for example, about 0.05 to about 0.2 w / v%, preferably about 0.1 to about 0.2 w / v%, particularly preferably about 0.1 w / v%. In this specification, the content or concentration of brimonidine and / or its pharmaceutically acceptable salt refers to the content or concentration converted to brimonidine tartrate unless otherwise specified. In the composition of the present disclosure, brinzolamide and / or its pharmaceutically acceptable salt is not particularly limited and may be appropriately set according to the degree of symptoms of the patient to be applied, the amount applied per time, etc., and may be, for example, about 0.1-3 w / v%, preferably 0.5-2 w / v%, more preferably 1 w / v%. In addition, in this specification, the content or concentration of brinzolamide or its pharmaceutically acceptable salt refers to the content or concentration converted to brinzolamide (without salt) unless otherwise specified.

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

[0040] When a dihydric or trihydric alcohol is incorporated into the composition of the present disclosure, its content may be appropriately set so as to achieve the desired osmotic pressure, and may be, for example, 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] The composition of the present disclosure may also contain a surfactant as necessary. The surfactant is not particularly limited as long as it is acceptable for incorporation into eye drops, and examples thereof include nonionic surfactants such as tyloxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, and octoxynol; amphoteric surfactants such as alkyldiaminoethylglycine and lauryldimethylaminoacetate betaine; anionic surfactants such as alkyl sulfates, N-acyltaurine 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 alone or in combination of two or more. Among these surfactants, nonionic surfactants are preferred, and tyloxapol is more preferred.

[0042] When a surfactant is incorporated into the composition of the present disclosure, the content thereof is not particularly limited, but may be, for example, 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] In addition, the composition of the present disclosure may contain a thickening agent as necessary. The thickening agent is not particularly limited as long as it is acceptable for incorporation into eye drops, and examples thereof include water-soluble polymers such as polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, carboxyvinyl polymer (crosslinked polyacrylic acid polymer, etc.), xanthan gum, sodium chondroitin sulfate, and sodium hyaluronate; celluloses such as hypromellose, hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and sodium carboxymethyl cellulose. These thickening agents may be used alone or in combination of two or more. Among these thickening agents, carboxyvinyl polymer is preferred.

[0044] When a thickening agent is blended into the composition of the present disclosure, the content thereof may be appropriately set depending on the viscosity to be imparted, etc., and may be, 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] In addition, the composition of the present disclosure may contain an alkali metal chloride such as sodium chloride or potassium chloride, if necessary. These alkali metal chlorides may be used alone or in combination of two or more. Among these alkali metal chlorides, sodium chloride is preferred.

[0046] When an alkali metal chloride is blended in the composition of the present disclosure, the content thereof may be appropriately set according to the osmotic pressure to be imparted, taking into consideration the contents of other components, and may be, for example, about 0.01 to 1 w / v%, preferably about 0.05 to about 0.5 w / v%, and more preferably about 0.1 to about 0.3 w / v%.

[0047] Furthermore, the composition of the present disclosure may contain a buffering agent as necessary. The buffering agent is not particularly limited as long as it is acceptable for incorporation into eye drops, and may include, for example, phosphate buffer, borate buffer, citrate buffer, tartrate buffer, acetate buffer, Tris buffer, amino acid, etc. These buffering agents may be used alone or in combination of two or more. Among these buffering agents, borate buffer is preferred.

[0048] When a buffer is incorporated into the composition of the present disclosure, the content thereof may be set appropriately depending on the type of buffer used, etc. For example, when boric acid is used, the content of boric acid is, 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] In addition to the above-mentioned components, the composition of the present disclosure may contain additives such as chelating agents, cooling agents, and preservatives, as necessary. Examples of chelating agents include edetate, citric acid or its salts, etc. These chelating agents may be used alone or in combination of two or more.

[0050] Examples of the cooling agent include 1-menthol, borneol, camphor, eucalyptus oil, etc. These cooling agents may be used alone or in combination of two or more.

[0051] Examples of preservatives include sorbic acid or its salts, benzoic acid or its salts, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, 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, parachlorometaxylenol, chlorcresol, phenethyl alcohol, polidronium chloride, thimerosal, dibutylhydroxytoluene, etc. These preservatives may be used alone or in combination of two or more.

[0052] Examples of the stabilizer include polyvinylpyrrolidone, sulfite, monoethanolamine, glycerin, propylene glycol, cyclodextrin, dextran, ascorbic acid, edetate, taurine, tocopherol, dibutylhydroxytoluene, etc. These stabilizers may be used alone or in combination of two or more.

[0053] The pH adjusting agent is not particularly limited as long as it is pharma- ceutically acceptable. Examples of the pH adjusting agent include hydrochloric acid, acetic acid, boric acid, aminoethylsulfonic acid, and epsilon-aminocaproic acid. Acids: Examples of the acid include alkalis such as sodium hydroxide, potassium hydroxide, borax, triethanolamine, monoethanolamine, sodium hydrogen carbonate, sodium carbonate, etc. These pH adjusters may be used alone or in combination of two or more.

[0054] The concentrations of these additives may be appropriately determined depending on the types of additives used and the properties to be imparted to the ophthalmic composition.

[0055] The composition of the present disclosure is typically provided as an aqueous eye drop (preferably a suspension eye drop). The composition of the present disclosure may be a white to slightly yellowish white suspension. The composition of the present disclosure may be provided at a pH of 6.2 to 6.8. The osmotic pressure ratio of the composition of the present disclosure may be 0.9 to 1.2 (e.g., about 1) relative to physiological saline. The composition of the present disclosure may be applied to glaucoma and ocular hypertension when other glaucoma treatment drugs are ineffective or cannot be used. The composition of the present disclosure may be provided as an eye drop, and may be, for example, usually instilled one drop at a time, twice a day, but is not limited thereto.

[0056] In some embodiments, a higher therapeutic effect (i.e., intraocular pressure lowering effect) is expected by administering the composition of the present disclosure to a patient whose pre-administration intraocular pressure value is less than 20 mmHg, preferably 18 mmHg or more and less than 20 mmHg. As long as the pre-administration intraocular pressure value satisfies the pre-administration intraocular pressure value, regardless of diurnal and seasonal variations, a high therapeutic effect by the composition of the present disclosure is achieved. In order to minimize the influence of diurnal and seasonal variations, it is preferable to use a pre-administration intraocular pressure value measured at a specific time (e.g., a 2-hour value). Alternatively, a value corrected in consideration of the influence of diurnal and seasonal variations may be used. The composition of the present disclosure may be administered to a patient whose therapeutic effect of other glaucoma therapeutic drugs is insufficient. An intraocular pressure of 18 mmHg or more is used as an indicator of the insufficient therapeutic effect of other glaucoma therapeutic drugs. Other examples of therapeutic effect include, but are not limited to, optic disc findings, visual field findings, and the like. In addition, when the intraocular pressure reduction rate from untreated intraocular pressure is low, the therapeutic effect of other glaucoma therapeutic drugs may be judged to be insufficient.

[0057] In some embodiments, the pre-administration intraocular pressure can be a daytime intraocular pressure (eg, intraocular pressure measured between 9:30 am and 1 pm, more specifically, between 10 am and 12:30 pm).

[0058] In some embodiments, the other glaucoma therapeutic agent is an intraocular pressure reducing agent other than the composition of the present disclosure, such as a prostaglandin-related agent, a beta-receptor blocker, a ROCK inhibitor, a carbonic anhydrase inhibitor, an alpha 2Receptor agonists, and alpha 1 Prostaglandin-related drugs include, but are not limited to, prostaglandin F receptor blockers, selective EP2 receptor agonists, or combinations thereof. Prostaglandin-related drugs include prostaglandin F receptor blockers, such as latanoprost, travoprost, and tafluprost. 2α Examples of the active ingredients include, but are not limited to, preparations containing, as active ingredients, alpha-adrenergic receptor blockers, alpha-adrenergic receptor blockers, and prostamide derivatives. Examples of the active ingredients of β-receptor blockers include, but are not limited to, preparations containing, as active ingredients, timolol, levobunolol, betaxolol, nipradilol, or carteolol. Examples of the active ingredients of ROCK inhibitors include, but are not limited to, preparations containing, as active ingredients, ripasudil or netarsudil. Examples of the active ingredients of carbonic anhydrase inhibitors include, but are not limited to, preparations containing, as active ingredients, dorzolamide or brinzolamide. 2 Receptor agonists include, but are not limited to, preparations containing brimonidine as an active ingredient. 1 Receptor blockers include, but are not limited to, preparations containing bunazosin as an active ingredient.Selective EP2 receptor agonists include, but are not limited to, preparations containing omidenepag isopropyl as an active ingredient.

[0059] In some embodiments, the other glaucoma therapeutic agent may be administered as a first-line drug. In further embodiments, when the other glaucoma therapeutic agent is administered as a first-line drug, the composition of the present disclosure may be administered as a different drug from the other glaucoma therapeutic agent. In some embodiments, the first-line drug may be a single-component drug, and the composition of the present disclosure may be administered as a different drug from the other glaucoma therapeutic agent, and may be a combination drug.

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

[0061] As an indicator of the insufficient effect of the other glaucoma therapeutic drug, an intraocular pressure of 18 mmHg or more after treatment with the other glaucoma therapeutic drug and before administration of the composition of the present disclosure may be used. Other indicators of the insufficient effect of the other glaucoma therapeutic drug include, but are not limited to, optic disc findings, visual field findings, etc. In addition, if the intraocular pressure reduction rate from untreated intraocular pressure is low (e.g., the intraocular pressure reduction rate is less than 10% or less than 20%), it may be determined that the effect of the other glaucoma therapeutic drug is insufficient. In addition, the patient who can be treated may be a patient who has been administered another glaucoma therapeutic drug for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks or more. For example, the therapeutic effect of Brinzolamide alone can typically be determined in about 4 weeks.

[0062] In some embodiments, when intraocular pressure is used as an index of insufficient effect, it may be intraocular pressure measured on the day administration of other glaucoma therapeutic drugs is terminated, and preferably, intraocular pressure measured at least one or both of the morning (9:00±1 hour) and afternoon (within 2 hours±30 minutes after morning instillation and up to 12:30). On the day administration is terminated, it is preferable that the morning intraocular pressure is measured before administration of other glaucoma therapeutic drugs.

[0063] In some embodiments, a patient who may be treated with the composition of the present disclosure may have a pre-administration intraocular pressure of less than about 20 mmHg. The pre-administration intraocular pressure may be an intraocular pressure measured on the day administration of the composition of the present disclosure is started, and is preferably measured either in the morning (9:00±1 hour) or in the afternoon (within 2 hours±30 minutes after administration in the morning and up to 12:30), preferably in the afternoon (within 2 hours±30 minutes after administration in the morning and up to 12:30). The pre-administration intraocular pressure is preferably greater than or equal to about 18 mmHg and less than about 20 mmHg. The pre-administration intraocular pressure is measured on the day administration is started, before administration of the composition of the present disclosure. The day administration of the composition of the present disclosure is started may be different from or the same as the day administration of other glaucoma therapeutic drugs is ended. In addition, as the pre-administration intraocular pressure, it is also possible to use intraocular pressure measured to be used as an indicator of insufficient effect.

[0064] In some embodiments, the compositions of the present disclosure may be administered to a patient for at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, or at least 8 weeks. In certain embodiments, the compositions of the present disclosure may be administered to a patient for at least 4 weeks.

[0065] In some embodiments, the composition of the present disclosure can reduce the intraocular pressure of a patient by about 5% or more, about 10% or more, about 15% or more, or about 20% or more when evaluated by the intraocular pressure reduction rate. In another embodiment, the composition of the present disclosure can reduce the intraocular pressure of a patient by more than 0% and less than 10%, 10% or more and less than 20%, or 20% or more when evaluated by the intraocular pressure reduction rate. In the treatment of glaucoma, it is known that reducing intraocular pressure leads to a reduction in the risk of progression of visual field defects. It has also been reported that a reduction in intraocular pressure of 1 mmHg reduces the risk of progression of visual field defects. The composition of the present disclosure is intended for patients with intraocular pressure less than 20 mmHg before administration, and for example, the intraocular pressure can be reduced to less than 18 mmHg by reducing the intraocular pressure by 10% or more when evaluated by the intraocular pressure reduction rate. In the treatment of glaucoma, one of the objectives is to lower intraocular pressure to less than 18 mmHg, and in patients who maintained a mean intraocular pressure of less than 18 mmHg over a 6-year observation period, little progression of visual field impairment was observed (Sakamoto Shiro, Suzuki Yasuyuki, Ophthalmology Vol. 60, No. 1, 2018, 27-34; Am J Ophthalmol 130: 429-40, 2000). Therefore, it is extremely important that the present eye drop reduces intraocular pressure by 10% or more in patients whose pre-administration intraocular pressure is less than 20 mmHg. In addition, the present eye drop can be said to be very effective in delaying the progression of visual field impairment by lowering intraocular pressure to less than 18 mmHg. Therefore, in a preferred embodiment, the composition of the present disclosure can reduce the intraocular pressure of a patient by about 10% or more when evaluated by the intraocular pressure reduction rate.

[0066] The intraocular pressure reduction rate is calculated by the following formula: The intraocular pressure reduction rate can be calculated by: intraocular pressure reduction rate = {(intraocular pressure value before administration of the composition of the present disclosure - intraocular pressure value after administration of the composition of the present disclosure for a predetermined period of time) / intraocular pressure value before administration of the composition of the present disclosure} x 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 value, the 2-hour value, or the 7-hour value. For example, the following: Intraocular pressure reduction rate at 0 hour value={(0 hour value on the start date of administration of the composition of the present disclosure (intraocular pressure value measured between 8:00 and 10:00)-0 hour value on the day of evaluation of intraocular pressure after administration of the composition of the present disclosure for a specified period (intraocular pressure value measured between 8:00 and 10:00) / 0 hour value on the start date of administration of the composition of the present disclosure (intraocular pressure value measured between 8:00 and 10:00)}×100 Intraocular pressure reduction rate at 2 hours value={(2-hour value on the start date of administration of the composition of the present disclosure (intraocular pressure value measured within 2 hours ± 30 minutes after the measurement of the zero hour value and by 12:30)-2-hour value on the day of evaluation of intraocular pressure after administration of the composition of the present disclosure for a predetermined period of time (intraocular pressure value measured within 2 hours ± 30 minutes after the measurement of the zero hour value and by 12:30) / 2-hour value on the start date of administration of the composition of the present disclosure (intraocular pressure value measured within 2 hours ± 30 minutes after the measurement of the zero hour value and by 12:30)}×100 The intraocular pressure reduction rate at 7 hours value can be calculated as follows: {(7-hour value on the start date of administration of the composition of the present disclosure (intraocular pressure value measured within 7 hours ± 1 hour after the measurement of the zero hour value and by 18:00) - 7-hour value on the day of evaluation of intraocular pressure after administration of the composition of the present disclosure for a predetermined period of time (intraocular pressure value measured within 7 hours ± 1 hour after the measurement of the zero hour value and by 18:00) / 7-hour value on the start date of administration of the composition of the present disclosure (intraocular pressure value measured within 7 hours ± 1 hour after the measurement of the zero hour value and by 18:00)} × 100.

[0067] The date of assessment of intraocular pressure can be at least 2 weeks (eg, 2 weeks, 4 weeks, 2 months, 3 months, 6 months, 1 year, or later) after the start of dosing.

[0068] In some embodiments, the composition of the present disclosure can reduce the intraocular pressure of a patient 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 intraocular pressure reduction rate, after administration (a certain period of time from the start of administration, for example, 4 weeks after the start of treatment). In certain embodiments, the composition of the present disclosure can reduce the intraocular pressure by 10% or more for at least 7:00 to 18:00, when evaluated by the intraocular pressure reduction rate. It is known that intraocular pressure fluctuates during the day, and the greater the daily average intraocular pressure, maximum intraocular pressure, and intraocular pressure fluctuation range, the more likely visual field impairment is 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 standpoint of preventing the progression of visual field defects.

[0069] Although the patient who can be treated by the composition of the present disclosure is not limited to a specific age, the composition of the present disclosure has a higher therapeutic effect on patients under 65 years old. Thus, in some embodiments, the patient who can be treated by the composition of the present disclosure may be under 65 years old. In a specific embodiment, the patient who can be treated by the composition of the present disclosure may have a pre-administration intraocular pressure of 18 mmHg or more and less than 20 mmHg, and be under 65 years old. Preferably, in a specific embodiment, the patient who can be treated by the composition of the present disclosure may have a pre-administration intraocular pressure of 18 mmHg or more and less than 20 mmHg, and be over 20 years old and under 65 years old.

[0070] In another aspect, the present disclosure provides a composition for reducing intraocular pressure in a patient, comprising brimonidine or a pharma- ceutically acceptable salt thereof and brinzolamide or a pharma- ceutically acceptable salt thereof, wherein the patient is administered another therapeutic drug for glaucoma, and the patient's pre-administration intraocular pressure is 18 mmHg or more and less than 20 mmHg, the composition is administered to the patient by instillation, one drop at a time, twice a day, the composition has a brimonidine concentration of about 0.1% w / v, the brinzolamide concentration of about 1% w / v, and the composition reduces the intraocular pressure of the patient by about 10% or more as evaluated by the intraocular pressure reduction rate.

[0071] In a further aspect, the present 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, the patient being diagnosed with glaucoma or ocular hypertension and being administered another glaucoma treatment drug, the method comprising: a) confirming whether the other glaucoma treatment drug is effective enough or not for the patient; b) measuring the intraocular pressure of the patient; c) selecting a patient who is ineffective with the other glaucoma treatment drug and whose pre-administration intraocular pressure value is less than 20mmHg (e.g., 18mmHg or more and less than 20mmHg) on ​​the day of administration; and d) administering the composition to the selected patient. In the above step c), the method may further comprise selecting a patient who is less than 65 years old. "Preventing the worsening of glaucoma" may include preventing or delaying the progression of visual field impairment in glaucoma patients. "Preventing the worsening of ocular hypertension" can include lowering intraocular pressure in a patient with ocular hypertension, preventing or slowing an increase in intraocular pressure, or preventing or slowing the onset of visual field defects.

[0072] The active ingredients of the present invention, brimonidine or a pharma- ceutically acceptable salt thereof, and brinzolamide or a pharma- ceutically acceptable salt thereof, may be provided as separate preparations (i.e., a combination agent) and administered in combination.

[0073] Thus, in a further aspect, the present disclosure provides a combination for lowering intraocular pressure in a patient suffering from glaucoma or ocular hypertension, comprising brimonidine, or a pharma- ceutically acceptable salt thereof, and brinzolamide, or a pharma- ceutically acceptable salt thereof.

[0074] In a further aspect, the present disclosure provides a composition for lowering intraocular pressure in a patient suffering from glaucoma or ocular hypertension, comprising brimonidine or a pharma- ceutically acceptable salt thereof, wherein the composition is administered in combination with brinzolamide or a pharma- ceutically acceptable salt thereof.

[0075] In a further aspect, the present disclosure provides a composition for lowering intraocular pressure in a patient suffering from glaucoma or ocular hypertension, comprising brinzolamide or a pharma- ceutically acceptable salt thereof, wherein the composition is administered in combination with brimonidine or a pharma- ceutically acceptable salt thereof.

[0076] In a further aspect, the present disclosure provides a multiple-component agent (e.g., a combination agent) of brimonidine or a pharma- ceutical acceptable salt thereof and brinzolamide or a pharma-ceutical acceptable salt thereof for use in a method for suppressing the onset or progression of visual field impairment in a patient in whom other glaucoma therapeutic agents other than the multiple-component agent have had insufficient effects by lowering intraocular pressure by about 10% or more as assessed by an intraocular pressure reduction rate, the method comprising: a) diagnosing whether the patient has glaucoma; b) administering another glaucoma medication; c) diagnosing whether the patient is ineffective in treating with other glaucoma medications; d) measuring the intraocular pressure of the patient; e) when the effect of other glaucoma therapeutic drugs is insufficient and the patient has glaucoma, selecting a composition containing brimonidine or a pharma- ceutically acceptable salt thereof and brinzolamide or a pharma- ceutically acceptable salt thereof as a selective drug different from other glaucoma therapeutic drugs in place of or in combination with the other glaucoma therapeutic drugs, and administering the multiple-component preparation to the patient; Including, A multiple component formulation is provided.

[0077] In a further aspect, the disclosure provides a composition for use in a method of reducing intraocular pressure in a patient comprising brimonidine or a pharma- ceutically acceptable salt thereof and brinzolamide or a pharma-ceutically acceptable salt thereof, wherein the patient is suffering from glaucoma or ocular hypertension; The method comprises the steps of: a) measuring the intraocular pressure of the patient; b) selecting a patient whose pre-administration intraocular pressure value is less than 20 mmHg on the day of administration; c) administering the composition to the selected patient. The present invention provides a composition comprising:

[0078] (Efficacy evaluation method) In a further aspect, there is provided a method for using pre-administration intraocular pressure in a patient as an indicator of whether treatment with, for example, a composition comprising brimonidine or a pharma- ceutically acceptable salt thereof and brinzolamide or a pharma-ceutically acceptable salt thereof is effective, the method indicating that the composition is effective in a patient when other glaucoma therapeutic agents are insufficiently effective in the patient and the pre-administration intraocular pressure of the patient is less than 20 mmHg.

[0079] In some embodiments, a patient's pre-administration intraocular pressure of 18 mmHg or more and less than 20 mmHg may indicate that the composition is effective in the patient. In certain embodiments, a patient's pre-administration intraocular pressure of 18 mmHg or more and less than 20 mmHg and the patient is less than 65 years old may indicate that the composition is effective in the patient.

[0080] (Different drug selection method than other glaucoma medications) In a further aspect, there is provided a method for using a patient's pre-administration intraocular pressure as an indicator for selecting a drug of choice different from other glaucoma therapeutic agents for lowering intraocular pressure in a patient suffering from glaucoma or ocular hypertension, the method showing that a composition comprising brimonidine or a pharmaceutical acceptable salt thereof and brinzolamide or a pharmaceutical acceptable salt thereof is effective as a drug of choice different from the other glaucoma therapeutic agents in a patient having glaucoma or ocular hypertension when the patient's pre-administration intraocular pressure is less than 20 mmHg.

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

[0082] The present disclosure has been described above by showing preferred embodiments for ease of understanding. The present disclosure will be described below based on examples, but the above description and the following examples are provided for illustrative purposes only and are not provided for the purpose of limiting the present disclosure. Therefore, the scope of the present disclosure is not limited to the embodiments or examples specifically described in this specification, but is limited only by the scope of the claims. EXAMPLES

[0083] The present disclosure will now be described more specifically with reference to examples.

[0084] Example 1: Stratified Analysis In this example, patients were stratified according to pre-administration intraocular pressure, and an investigation was conducted into which stratum the eye drops of the present disclosure (eye drops containing brimonidine and brinzolamide) would have the greatest therapeutic effect.

[0085] A multicenter, randomized, single-masked (evaluator-masked), parallel-group comparative study was conducted to evaluate the efficacy (intraocular pressure-reducing effect) of a 0.1 w / v% brimonidine tartrate / 1 w / v% brinzolamide suspension eye drop (ophthalmic solution containing 1 mg brimonidine tartrate, 10 mg brimonidine tartrate, tyloxapol, concentrated glycerin, boric acid, carboxyvinyl polymer, sodium edetate hydrate, benzalkonium chloride, isotonicity agent, and pH adjuster per mL) (hereinafter referred to as "this eye drop"), when instilled twice daily for four weeks in 163 patients with primary open-angle glaucoma (broad definition) or ocular hypertension.

[0086] In this example, primary open angle glaucoma (broad definition) included primary open angle glaucoma (POAG) and preperimetric glaucoma (PPG). Among the criteria for primary open angle glaucoma (broad definition), the POAG group was defined as those who met the following (1) and (2), and the PPG group was defined as those who met only the following (2) and were judged to require treatment. (1) The patient has glaucomatous optic neuropathy (danger of the optic disc or retinal nerve fiber layer). If visual field is measured using a Humphrey perimeter, the Anderson-Patella criteria should be followed (Anderson DR, Patella VM. Automated Static Perimetry. 2nd edition. St. Louis: Mosby; 1999: 152-3.). (2) The presence of a glaucomatous optic disc. The diagnosis is made through fundus examination (Glaucoma Treatment Guidelines (3rd edition), etc.) One drop of 1% brinzolamide eye suspension (investigational drug for the observation period) was instilled into both eyes twice a day [morning and night (9:00 ± 1 hour and 21:00 ± 1 hour)] for 4 weeks [from the evening of the first day of the observation period to the morning of the last day of the observation period (start day of the treatment period)]. If the intraocular pressure values ​​at 0 and 2 hours in the efficacy evaluation eye on the last day of the observation period (start day of the treatment period) were 18.0 mmHg or more and 31.0 mmHg or less, and the difference between the intraocular pressure values ​​at 0 and 2 hours in the efficacy evaluation eye on the last day of the observation period (start day of the treatment period) was within 3.0 mmHg, the patient was to proceed to the treatment period.

[0087] During the treatment period, one drop was administered to each eye twice a day [morning and night (9:00 ± 1 hour)]. The eye drops were administered starting from the evening of the last day of the observation period (the first day of the treatment period) for 4 weeks (morning only on the last day of the treatment period). Morning instillation during weeks 2 and 4 of the treatment period was performed after the intraocular pressure measurement at 0 hours and between 9:00 ± 1 hours.

[0088] Intraocular pressure values ​​measured before instillation in the morning and at 9:00±1 hour are referred to as 0-hour values, intraocular pressure values ​​measured within 2 hours±30 minutes after instillation in the morning and up to 12:30 are referred to as 2-hour values, and intraocular pressure values ​​measured within 7 hours±1 hour after instillation in the morning and up to 18:00 are referred to as 7-hour values.

[0089] Using the measured intraocular pressure values, the intraocular pressure reduction rate was calculated according to the following formula. Intraocular pressure reduction rate at time 0 (%) = [{intraocular pressure value on the start of the treatment period (value at time 0) - intraocular pressure value on each observation day (value at time 0)} / intraocular pressure value on the start of the treatment period (value at time 0)] * 100 -Intraocular pressure reduction rate at 2 hours (%) = [{Intraocular pressure value on the start of the treatment period (2 hours value) - Intraocular pressure value on each observation day (2 hours value)} / Intraocular pressure value on the start of the treatment period (2 hours value)] * 100 -Intraocular pressure reduction rate at 7 hours (%) = [{Intraocular pressure value on the start of the treatment period (7 hours value) - Intraocular pressure value on each observation day (7 hours value)} / Intraocular pressure value on the start of the treatment period (7 hours value)] * 100 For the calculated intraocular pressure reduction rate, patients were classified as (+) who achieved a reduction rate of 10% or less at all time points of 0, 2, and 7 hours, and those who did not (±). For each group divided by pre-administration intraocular pressure and age, the percentage of patients with (+) or (±) to the total number of patients was calculated, and the results are shown in the table below. Pre-administration intraocular pressure is the value at 2 hours on the start day of the treatment period.

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

[0091] [Table 1]

[0092] As shown in Table 1, only about 30% of patients with a pre-administration intraocular pressure of 20 mmHg or more achieved a 10% or more reduction in intraocular pressure from the pre-administration intraocular pressure, whereas more than 50% of patients with a pre-administration intraocular pressure of 18 mmHg or more and less than 20 mmHg achieved a 10% or more reduction in intraocular pressure from the pre-administration intraocular pressure. Thus, it is considered that the present eye drops are more effective in patients with a pre-administration intraocular pressure of 18 mmHg or more and less than 20 mmHg. In the treatment of glaucoma, it is known that lowering intraocular pressure leads to a reduction in the risk of progression of visual field disorders. It has also been reported that a 1 mmHg reduction in intraocular pressure reduces the risk of progression of visual field disorders (Glaucoma Treatment Guidelines (4th Edition), Kazuhide Kawase. Ophthalmology. Vol. 48, No. 6, p. 871-881 (2006)).

[0093] In patients with a pre-administration intraocular pressure of 18 mmHg or more and less than 20 mmHg, lowering intraocular pressure by 10% or more means lowering intraocular pressure to less than 18 mmHg. In the treatment of glaucoma, lowering intraocular pressure to less than 18 mmHg is one of the objectives, and patients who maintained a mean intraocular pressure of less than 18 mmHg over a 6-year observation period showed little progression of visual field impairment (Sakamoto Shiro, Suzuki Yasuyuki, Ophthalmology Vol. 60, No. 1, 2018, 27-34; Am J Ophthalmol 130: 429-40, 2000). Therefore, it is extremely important that this eye drop lowers intraocular pressure by 10% or more in patients with a pre-administration intraocular pressure of 18 mmHg or more and less than 20 mmHg. In addition, this eye drop can be said to be very effective in slowing the progression of visual field impairment by lowering intraocular pressure to less than 18 mmHg.

[0094] It is generally known that a greater intraocular pressure-lowering effect is observed in groups with higher intraocular pressure (Aihara Hajime, Atarashii Ophthalmology 32(6):767-773; Nakauchi Masashi et al., Atarashii Ophthalmology 28(8):1161-1165). For example, in a group administered with the intraocular pressure-lowering drug Ripasudil eye drops, a greater intraocular pressure-lowering effect was observed in groups with higher intraocular pressure (Suzuki Kanako et al., Atarashii Ophthalmology 35(8):1114-1116). Given this, it was highly unexpected that a greater intraocular pressure-lowering effect was observed in patients with a relatively low pre-administration intraocular pressure of 18mmHg or more and less than 20mmHg.

[0095] The results of further stratification by age are shown in Table 2.

[0096] [Table 2]

[0097] In the group with a pre-administration intraocular pressure of less than 20 mmHg and age of less than 65 years, the proportion of patients (+) with a 10% or less decrease rate at 0, 2, and 7 hours was 60% or more, which was higher than the other groups. It was found that in the group with a pre-administration intraocular pressure of less than 20 mmHg and age of less than 65 years, this eye drop can more effectively lower intraocular pressure continuously during the day. It is known that the greater the daily average intraocular pressure, maximum 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, it is important to maintain a low intraocular pressure throughout the day in order to prevent the progression of visual field defects.

[0098] (Reference example: Treatment example) Case 1: For patients who have been diagnosed with primary open-angle glaucoma and are being treated with PG-related drugs, but the effect is insufficient, in addition to the PG-related drugs, start administration of 0.1 w / v% brimonidine tartrate / 1 w / v% brinzolamide suspension eye drop (eye drop containing 1 mg brimonidine tartrate, 10 mg brimonidine tartrate, tyloxapol, concentrated glycerin, boric acid, carboxyvinyl polymer, sodium edetate hydrate, benzalkonium chloride, isotonic agent, and pH adjuster, twice a day). The patient's intraocular pressure is measured with a Goldmann applanation tonometer, and intraocular pressure (pre-administration intraocular pressure) is measured between 10:00 a.m. and 12:30 p.m. on the day of administration start. If the pre-administration intraocular pressure is 18 mmHg or more and 20 mmHg or more, administration of this eye drop is started. The 0-hour, 2-hour, and 7-hour values ​​are measured every other month to confirm the effect of lowering intraocular pressure. In addition, measurements will be taken of the fundus and visual field abnormalities, and the patient will be monitored over time.

[0099] Case 2: For patients who have been diagnosed with primary open-angle glaucoma and are being treated with timolol ophthalmic solution or a combination of a PG-related drug and timolol, but are not seeing results, switch to a 0.1 w / v% brimonidine tartrate / 1 w / v% brinzolamide suspension ophthalmic solution (ophthalmic solution containing 1 mg brimonidine tartrate, 10 mg brimonidine tartrate, tyloxapol, concentrated glycerin, boric acid, carboxyvinyl polymer, sodium edetate hydrate, benzalkonium chloride, isotonicity agent, and pH adjuster in 1 mL) and begin administration (twice daily). The patient's intraocular pressure is measured using a Goldmann applanation tonometer between 10:00 and 12:30 on the day administration begins (pre-administration intraocular pressure). If pre-administration intraocular pressure is between 18mmHg and 20mmHg, administration of the eye drops is initiated. Every other month, the 0-hour, 2-hour, and 7-hour values ​​are measured to confirm the effect of lowering intraocular pressure. Additionally, measurements are taken of the fundus and visual field abnormalities, and follow-up observations are conducted.

[0100] Although the present disclosure has been illustrated using the preferred embodiments thereof, it is understood that the present disclosure should be interpreted in scope only by the claims. It is understood that the patents, patent applications and literature cited in this specification should be incorporated by reference in their entirety as if the contents themselves were specifically set forth in this specification. [Industrial Applicability]

[0101] The present invention provides a composition for treating glaucoma and / or ocular hypertension. This technology can be used in fields such as pharmaceuticals.

Claims

1. 1. A composition for use in a method of reducing intraocular pressure in a patient comprising brimonidine or a pharma- ceutically acceptable salt thereof and brinzolamide or a pharma- ceutically acceptable salt thereof, The patient is suffering from glaucoma or ocular hypertension and is receiving a therapeutic drug for glaucoma other than the composition, The method comprises the steps of: a) determining whether the effect of the other glaucoma therapeutic drug on the patient is sufficient or insufficient; b) measuring the intraocular pressure of the patient; c) selecting a patient for whom the effect of the other glaucoma therapeutic drug is insufficient and whose pre-administration intraocular pressure on the day of administration is started is less than 20 mmHg; d) administering the composition to the selected patient. A composition comprising:

2. The composition of claim 1 , wherein the pre-administration intraocular pressure value is greater than or equal to 18 mmHg and less than 20 mmHg.

3. 3. The composition of claim 1 or 2, wherein the brimonidine or a pharma- ceutically acceptable salt thereof is brimonidine tartrate.

4. 4. The composition of claim 1, wherein the concentration of brimonidine or a pharma- ceutically acceptable salt thereof in the composition is about 0.1% w / v and the concentration of brinzolamide or a pharma- ceutically acceptable salt thereof is about 1% w / v.

5. The composition according to any one of claims 1 to 4, wherein the composition is administered to the patient by eye drop, one drop at a time, twice a day.

6. The composition according to any one of claims 1 to 5, further comprising selecting a patient under 65 years of age in step c).

7. The composition according to any one of claims 1 to 6, wherein the composition reduces intraocular pressure of the patient by 10% or more when evaluated by an intraocular pressure reduction rate.

8. The composition according to claim 7, wherein the composition reduces intraocular pressure by 10% or more for at least 12 hours after administration, as evaluated by the intraocular pressure reduction rate.

9. The composition according to claim 7, wherein the composition reduces intraocular pressure by 10% or more for a period of at least 7:00 to 18:00, as evaluated by the rate of reduction in intraocular pressure.

10. 1. A composition for use in a method for preventing the worsening of glaucoma or ocular hypertension in a patient comprising brimonidine or a pharma- ceutically acceptable salt thereof and brinzolamide or a pharma- ceutically acceptable salt thereof, The patient is a patient who has been diagnosed with glaucoma or ocular hypertension and is receiving a therapeutic drug for glaucoma other than the composition, The method comprises the steps of: a) determining whether the effect of the other glaucoma therapeutic drug on the patient is sufficient or insufficient; b) measuring the intraocular pressure of the patient; c) selecting a patient for whom the effect of the other glaucoma therapeutic drug is insufficient and whose pre-administration intraocular pressure on the day of administration is started is less than 20 mmHg; d) administering the composition to the selected patient. A composition comprising:

11. The composition of claim 10, wherein the pre-administration intraocular pressure is greater than or equal to 18 mmHg and less than 20 mmHg.

12. The composition of claim 10 or 11, further comprising selecting a patient under 65 years of age in step c).

13. The composition according to any one of claims 10 to 12, wherein the prevention of the worsening of glaucoma comprises preventing or slowing the progression of visual field defects in the glaucoma patient, and the prevention of the worsening of ocular hypertension comprises reducing intraocular pressure, preventing or slowing an increase in intraocular pressure, or preventing or slowing the onset of visual field defects in a patient with ocular hypertension.

14. A method for using pre-administration intraocular pressure in a patient as an indicator of whether treatment with a composition comprising brimonidine or a pharma- ceutical acceptable salt thereof and brinzolamide or a pharma-ceutical acceptable salt thereof is effective, the method indicating that the composition is effective in the patient if other glaucoma treatment drugs are insufficiently effective in the patient and the pre-administration intraocular pressure of the patient is less than 20 mmHg.

15. 15. The method of claim 14, wherein the pre-administration intraocular pressure of the patient is greater than or equal to 18 mmHg and less than 20 mmHg, indicating that the composition is effective in the patient.

16. 16. The method of claim 15, wherein the patient's pre-administration intraocular pressure is greater than or equal to 18 mmHg and less than 20 mmHg, and the patient is less than 65 years of age, indicates that the composition is effective in the patient.

17. A method for using a patient's pre-administration intraocular pressure as an indicator for selecting a drug of choice different from other glaucoma medications for lowering intraocular pressure in a patient suffering from glaucoma or ocular hypertension, the method showing that a composition comprising brimonidine or a pharma- ceutical acceptable salt thereof and brinzolamide or a pharma-ceutical acceptable salt thereof is effective as a drug of choice different from the other glaucoma medications in a patient suffering from glaucoma or ocular hypertension when the patient's pre-administration intraocular pressure is less than 20 mmHg.

18. The method according to claim 17, which indicates that a composition comprising brimonidine or a pharma- ceutical acceptable salt thereof and brinzolamide or a pharma- ceutical acceptable salt thereof is effective as an alternative drug different from the other glaucoma therapeutic drugs when the patient's pre-administration intraocular pressure is 18 mmHg or more and less than 20 mmHg.

19. The method of claim 18, which indicates that a composition comprising brimonidine or a pharma- ceutical acceptable salt thereof and brinzolamide or a pharma- ceutical acceptable salt thereof is effective as an alternative drug different from the other glaucoma therapeutic drugs when the patient's pre-administration intraocular pressure is greater than or equal to 18 mmHg and less than 20 mmHg and the patient is under 65 years of age.

20. A method for selecting a drug different from other glaucoma therapeutic drugs that reduces intraocular pressure by 10% or more for at least 12 hours after administration in a patient who is suffering from glaucoma or ocular hypertension and has been administered other glaucoma therapeutic drugs but has not shown an adequate effect, the method comprising: A method showing that when the pre-administration intraocular pressure is 18 mmHg or more and less than 20 mmHg and the age is less than 65 years old, a composition comprising brimonidine or a pharma- ceutical acceptable salt thereof and brinzolamide or a pharma-ceutical acceptable salt thereof is effective as an alternative drug different from the other glaucoma treatment drugs.

21. A multiple-component preparation comprising brimonidine or a pharma- ceutical acceptable salt thereof and brinzolamide or a pharma-ceutical acceptable salt thereof, for use in a method for suppressing the onset or progression of visual field impairment in a patient for whom other therapeutic glaucoma drugs than the multiple-component preparation are insufficient, by lowering intraocular pressure by about 10% or more as assessed by an intraocular pressure reduction rate, the method comprising: a) diagnosing whether the patient has glaucoma; b) administering another glaucoma medication; c) diagnosing whether the patient is ineffective in treating with other glaucoma medications; d) measuring the intraocular pressure of the patient; e) when the effect of other glaucoma therapeutic drugs is insufficient and the patient has glaucoma, selecting a composition containing brimonidine or a pharma- ceutically acceptable salt thereof and brinzolamide or a pharma- ceutically acceptable salt thereof as a selective drug different from other glaucoma therapeutic drugs in place of or in combination with the other glaucoma therapeutic drugs, and administering the multiple-component preparation to the patient; Including, Multi-ingredient agent.

22. 22. The multiple component agent of claim 21 which is a combination agent.

23. 1. A composition for use in a method of reducing intraocular pressure in a patient, the method comprising: administering to the patient a medicament for use in a method of reducing intraocular pressure in a patient, the patient suffering from glaucoma or ocular hypertension, the composition comprising brimonidine or a pharma- ceutical acceptable salt thereof and brinzolamide or a pharma-ceutical acceptable salt thereof; The method comprises the steps of: a) measuring the intraocular pressure of the patient; b) selecting a patient whose pre-administration intraocular pressure value is less than 20 mmHg on the administration start date; c) administering the composition to the selected patient. A composition comprising:

24. The composition of claim 23, wherein the pre-administration intraocular pressure value is greater than or equal to 18 mmHg and less than 20 mmHg.

25. 25. The composition of claim 23 or 24, wherein the brimonidine or a pharma- ceutically acceptable salt thereof is brimonidine tartrate.

26. 26. The composition of any one of claims 23 to 25, wherein the concentration of brimonidine or a pharma- ceutically acceptable salt thereof in the composition is about 0.1% w / v and the concentration of brinzolamide or a pharma- ceutically acceptable salt thereof is about 1% w / v.

27. The composition according to any one of claims 23 to 26, wherein the composition is administered to the patient by eye drop, one drop at a time, twice a day.

28. The composition according to any one of claims 23 to 27, further comprising selecting a patient under 65 years of age in step b).

29. The composition reduces intraocular pressure of the patient by 10% or more when evaluated by the intraocular pressure reduction rate. The composition according to any one of claims 23 to 28,

30. The composition according to claim 29, wherein the composition reduces intraocular pressure by 10% or more for at least 12 hours after administration, as evaluated by the intraocular pressure reduction rate.

31. The composition according to claim 29, wherein the composition reduces intraocular pressure by 10% or more for a period of at least 7:00 to 18:00, as evaluated by the rate of reduction in intraocular pressure.

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