JP7566670B2 - Composition for reducing intraocular pressure - Google Patents

Description

The present disclosure relates to compositions and related inventions for reducing intraocular pressure in a patient, comprising brimonidine and brinzolamide.

Aiphagan (registered trademark) eye drops containing brimonidine are the only _α2 receptor agonist among intraocular pressure-reducing drugs, and when used in combination with existing drugs, they can further reduce intraocular pressure, have few systemic side effects, and have a visual field-preserving effect that is not commensurate with the intraocular pressure-reducing effect, so they are 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 in combination, so there are high hopes for a combination drug containing brimonidine.

Brinzolamide is a carbonic anhydrase inhibitor with few systemic side effects. It may be prescribed for patients who cannot use beta-blockers in combination therapy, who show local side effects from prostaglandin (PG)-related drugs, or who do not respond well to PG-related drugs.

In addition, all existing combination drugs contain beta-blockers, and there is hope for a combination drug that does not contain beta-blockers.

The present inventors conducted a stratified analysis of pre-administration intraocular pressure values before administration of an eye drop containing brimonidine and brinzolamide, and newly discovered that the eye drop exhibits a high intraocular pressure-reducing effect in patients whose pre-administration intraocular pressure values are in a specific range. Therefore, the present disclosure relates to a composition for reducing intraocular pressure containing brimonidine and brinzolamide, which exhibits excellent therapeutic effects in particular in 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, to be administered in place of part or all of the other glaucoma drugs or in combination with the other glaucoma drugs in patients for whom the effects of other glaucoma drugs already administered are insufficient.

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-dose intraocular pressure;
c) selecting a patient for whom the other glaucoma therapeutic drug is insufficiently effective and whose pre-administration intraocular pressure is less than 20 mmHg;
and d) administering said composition to said selected patient.
(Item 2)
2. The composition of claim 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 of claim 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)
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)
6. The composition according to any one of items 1 to 5, further comprising selecting a patient under 65 years of age in step c).
(Item 7)
The composition according to any one of items 1 to 6, 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 of 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-dose intraocular pressure;
c) selecting a patient for whom the other glaucoma therapeutic drug is insufficiently effective and whose pre-administration intraocular pressure is less than 20 mmHg;
and d) administering said composition to said selected patient.
(Item 12)
Item 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)
The composition according to any one of items 11 to 13, wherein the prevention of the worsening of glaucoma comprises preventing or delaying 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 delaying an increase in intraocular pressure, or preventing or delaying the onset of visual field defects 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 patient's pre-administration intraocular pressure 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)
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)
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 pharma- ceutical acceptable salt thereof and brinzolamide or a pharma-ceutical 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 whose age is less than 65 years.
(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 being administered other glaucoma medications, and is a patient for whom the other glaucoma medications are insufficient.
(Item 2A)
The composition of item 1A, wherein the pre-administration intraocular pressure is greater than or equal to 18 mmHg and less than 20 mmHg.
(Item 3A)
The composition of claim 1A or 2A, wherein the brimonidine or a pharma- ceutically acceptable salt thereof is brimonidine tartrate.
(Item 4A)
The composition of 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 the brinzolamide or a pharma-ceutically acceptable salt thereof is about 1% w/v.
(Item 5A)
The composition according to any one of claims 1A to 3A, wherein 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 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;
and d) administering said composition to said selected patient.
(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 of claim 1 or 2, wherein the brimonidine or a pharma- ceutically acceptable salt thereof is brimonidine tartrate.
(Item 4B)
The composition of 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 the brinzolamide or a pharma-ceutically acceptable salt thereof is about 1% w/v.
(Item 5B)
The composition according to any one of claims 1B to 4B, wherein the composition is administered to the patient in the form of one drop twice a day.
(Item 6B)
The composition of 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 the 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 a period of 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 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;
and d) administering said composition to said selected patient.
(Item 11B)
The composition according to item 10B, wherein the pre-administration intraocular pressure is greater than or equal to 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 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.
(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 insufficiently effective 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 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 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 therapeutic 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 therapeutic drugs but has not been sufficiently effective, 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 therapeutic drugs in a patient who has glaucoma or ocular hypertension and has been administered other glaucoma therapeutic drugs but has not been sufficiently effective, when the patient's pre-administration intraocular pressure is 18 mmHg or more and less than 20 mmHg and is under 65 years of age.
(Item 21B)
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, a composition containing brimonidine or a pharma- ceutically acceptable salt thereof and brinzolamide or a pharma- ceutically acceptable salt thereof is selected as a selective drug different from other glaucoma therapeutic drugs in place of or in combination with the other glaucoma therapeutic drugs, and the multiple-component preparation is administered to the patient.
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 administration start date;
and c) administering said composition to said selected patient.
(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 of claim 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 the brinzolamide or a pharma-ceutically acceptable salt thereof is about 1% w/v.
(Item 27B)
The composition according to any one of claims 23B to 26B, wherein the composition is administered to the patient in one drop twice a day.
(Item 28B)
The composition of 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 a period of at least 7:00 to 18:00, as evaluated by the 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.

In the present disclosure, it is intended that one or more of the above features may be provided in combinations in addition to the combinations explicitly stated. 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.

The present disclosure provides 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 ineffective.

The present disclosure will be described below. Throughout this specification, singular expressions should be understood to include the concept of the plural unless otherwise specified. Thus, singular articles (e.g., in the case of English, "a", "an", "the", etc.) should be understood to include the concept of the plural unless otherwise specified. In addition, it should be understood that the terms used in this specification are used in the sense commonly used in the field 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, time is displayed in 24-hour format unless otherwise specified.

(Definition)
As used herein, "brimonidine" refers to a compound of the formula

Brimonidine or a pharmaceutically acceptable salt thereof is a compound represented by the chemical name 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)quinoxalin-6-amine. Brimonidine or a pharmaceutically acceptable salt thereof is used as an ingredient of medicines, 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 α ₂ receptor agonist, and is incorporated as an active ingredient in general aqueous liquid preparations, particularly eye drops, and its tartrate salt is commercially available 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 to treat glaucoma and ocular hypertension. Brimonidine is used to lower intraocular pressure in patients with (open angle) glaucoma or ocular hypertension.

In this specification, "brinzolamide" refers to the compound of the following formula:

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 liquids, especially eye drops. Brinzolamide and its pharmaceutical acceptable salts are commercially available. Pharmaceutically acceptable salts of Brinzolamide include, but are not limited to, hydrochloride, acetate, and the like. 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.

As used herein, "pharmaceutical acceptable salts" include salts that may be safely administered to a patient. 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 salts. Pharmaceutically acceptable salts may also be prepared from metals such as alkali metals or alkaline earth metals (e.g., sodium, potassium, and calcium, magnesium, and zinc).

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 definition) and primary angle-closure glaucoma, while primary open-angle glaucoma (broad definition) includes primary open-angle glaucoma, normal tension glaucoma, and prefield glaucoma. Secondary glaucoma includes secondary open-angle glaucoma and secondary angle-closure glaucoma, and pediatric glaucoma includes primary congenital glaucoma, juvenile open-angle glaucoma, glaucoma associated with congenital ocular malformations, and glaucoma associated with congenital systemic diseases.

In this specification, "ocular hypertension" refers to a disease characterized by higher than normal intraocular pressure, even though no clear abnormalities are 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 used to keep intraocular pressure at normal levels.

As used herein, the term "antiglaucoma drug" refers to a drug that inhibits the progression of glaucoma optic nerve damage and/or visual field defects. Because optic nerve damage can be improved or inhibited by reducing intraocular pressure, antiglaucoma drugs are typically intraocular pressure-reducing drugs. Intraocular pressure-reducing drugs may also be used to treat ocular hypertension.

In this specification, "insufficient effect" refers to a state in which the progression of glaucoma or ocular hypertension has not been suppressed from the time of no treatment, taking into consideration the intraocular pressure measurement, optic disc findings, visual field findings, etc. as a whole. As an indicator of "insufficient effect", the rate of decrease in intraocular pressure 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 worsen, it may be determined 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.

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 progression, the cup/disc ratio (C/D ratio) (vertical diameter), etc., through fundus examination (using, for example, an ophthalmoscope, a slit lamp microscope with 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 progression using an automated static perimeter (such as a Humphrey perimeter or an Octopus perimeter).

In this specification, "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 administration of the composition of the present disclosure is started (administration start date) and before the administration of the drug (usually within 12 hours), 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 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 to this, and any value can be assumed, such as within 0 to 11 hours, within 0 to 10 hours, within 0 to 9 hours, within 0 to 8 hours, within 0 to 7 hours, within 0 to 6 hours, within 0 to 5 hours, within 0 to 4 hours, within 0 to 3 hours, within 0 to 2 hours, etc. before administration of the drug.

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 the morning instillation (or the measurement of the 0-hour value) on 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 the morning instillation (or the measurement of the 0-hour value) on the target day (e.g., administration start date, evaluation date). Note that on the morning of the administration start date, another glaucoma treatment drug is instilled, and on the morning of the evaluation date, the target drug (the composition of the present disclosure) is instilled instead of another glaucoma treatment drug. On the evaluation date, the "0-hour value" is the intraocular pressure measured immediately before the administration of the drug. The "0 hour value," "2 hour value," and "7 hour value" are used in the field to indicate certain values for a patient's intraocular pressure and are used as values sufficient to identify the patient.

In this specification, "administration start date" refers to the date (including the planned date) on which administration of a certain medicine is to begin. Therefore, in the case of companion medicines, the administration start date refers to the date on which a decision is made as to whether or not to begin administration. If a decision is made not to begin administration, no actual administration is carried out, but in this specification, it is treated as the administration start date.

In this specification, "evaluation date" refers to the date on which intraocular pressure is evaluated. Any date can apply, but examples of the period of interest include about 4 weeks, about 12 weeks, about 3 months, about 6 months, about 28 weeks, about 52 weeks, about 1 year, and about 3 years after the start of administration.

The subject or patient to whom the present disclosure is directed 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 to which the present disclosure is directed may be designed using the "pre-administration intraocular pressure value" after adjustment, taking into account seasonal variation.

The subject or patient to whom the present disclosure is directed may be a patient whose 2-3 hour diurnal 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. In particular, the subject or patient may be a patient whose 10:00 to 12:30 p.m. diurnal 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 or prevention to which the present disclosure is directed may be designed using the "pre-administration intraocular pressure value" after adjustment, taking into account the diurnal variation.

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

As used herein, the term "single-component agent" refers to a formulation 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 agent of a carbonic anhydrase inhibitor refers to a formulation 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 agent" refers to a formulation 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 agent may be provided in a form in which each active ingredient is present in the same formulation (also referred to as a "combination agent" in this specification), or in a form in which each active ingredient is present in an individual formulation, or a combination thereof. Thus, a multiple-component agent also includes a dosage form that is formulated as a single-component agent, 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 containing an additional active ingredient. For example, in this specification, the present disclosure includes an embodiment that is a pharmaceutical comprising a carbonic anhydrase inhibitor eye drop and is intended to be administered in combination with a pharmaceutical comprising an _α2 receptor agonist, and an embodiment that is a pharmaceutical comprising an _α2 receptor agonist and is intended to be administered in combination with a pharmaceutical comprising a carbonic anhydrase inhibitor eye drop.

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 the same or different mechanisms of action in the same formulation for reducing intraocular pressure in glaucoma. As used herein, a 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.

In this specification, "instructions" refers to instructions for the user on how to use the present disclosure, and is 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) or the Department of Agriculture (USDA) in the United States, etc.), 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 electronic media (e.g., a homepage provided on the Internet, e-mail, etc.).

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

In this specification, the term "second-line drug" (also called second choice drug) 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. The second-line drug is used instead of the first-line drug or in addition to the first-line drug. There are many second-line drugs for glaucoma, including carbonic anhydrase inhibitor eye drops, _α2 receptor stimulants, ROCK inhibitors, _α1 receptor blockers, nonselective sympathetic stimulants, and parasympathetic stimulants. Since each drug has different effects and is suitable for different patients, appropriate selection of the second-line drug is important for appropriate treatment of glaucoma.

In this specification, "a drug of choice different from other glaucoma treatments" 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. "A drug of choice different from other glaucoma treatments" 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, or a combination drug of a carbonic anhydrase inhibitor and a β-blocker. Since the effects and appropriate patients of each drug are different, the appropriate selection of a "drug of choice different from other glaucoma treatments" is important for the appropriate treatment of glaucoma.

Preferred Embodiments
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.

(Composition)
In one aspect, the present disclosure provides a composition (i.e., a combination drug), e.g., eye drops, 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., intraocular pressure-reducing drugs, neuroprotective drugs). 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, "eye drops" 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 superior therapeutic effect compared to other groups. Such a composition provides an excellent therapeutic effect of sustainedly lowering intraocular pressure by about 10% or more through "three selections": (i) selecting patients who are not sufficiently responsive to other glaucoma drugs from among patients who have been administered other glaucoma drugs, (ii) selecting from among the patients, patients whose pre-administration intraocular pressure value is less than 20 mmHg on the start date of administration of a selected drug different from the other glaucoma drugs, and (iii) selecting a combination drug of brimonidine and brinzolamide as the selected drug different from the other glaucoma drugs.

Without wishing to be bound by theory, when administered as separate formulations, the formulation administered earlier is washed away by the formulation administered later, so it is necessary to administer them at intervals of several minutes, which is a burden for the patient. In addition, the amount of the active ingredient that migrates into the eye may change depending on the order of administration, which may reduce efficacy. The composition (i.e., combination preparation) containing brimonidine or a pharma- ceutically acceptable salt thereof and brinzolamide or a pharma-ceutically acceptable salt thereof disclosed herein 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 migration. In addition, the number of eye drops administered can be reduced, which can reduce the burden on the patient.

The 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, the composition 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, the amount of brimonidine or a pharma- ceutically acceptable salt thereof is not particularly limited and may be appropriately determined depending on the degree of symptoms of the patient to be treated, the amount to be applied per dose, 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%, and particularly preferably about 0.1 w/v%. In this specification, a reference to the content or concentration of brimonidine and/or a pharma- ceutically acceptable salt thereof means the content or concentration converted into brimonidine tartrate unless otherwise specified. In the composition of the present disclosure, the amount of brinzolamide and/or a pharma- ceutically acceptable salt thereof is not particularly limited and may be appropriately set depending on the severity of the symptoms of the patient to whom the composition is to be applied, the amount to be applied per dose, etc., and may be, for example, about 0.1 to 3 w/v%, preferably 0.5 to 2 w/v%, and more preferably 1 w/v%. In addition, in this specification, a reference to the content or concentration of brinzolamide or a pharma- ceutically acceptable salt thereof means the content or concentration converted into brinzolamide (without salt), unless otherwise specified.

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.

When a dihydric or trihydric alcohol is added to 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%.

The composition of the present disclosure may also contain a surfactant, if necessary. The surfactant is not particularly limited as long as it is acceptable for incorporation into an eye drop, 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.

When a surfactant is added to the composition of the present disclosure, the content 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%.

The composition of the present disclosure may also contain a thickening agent, if necessary. The thickening agent is not particularly limited as long as it is acceptable for incorporation into an eye drop, 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; and 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.

When a thickening agent is added to the composition of the present disclosure, the content may be appropriately set depending on the viscosity to be imparted, 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%.

The composition of the present disclosure may also contain alkali metal chlorides such as sodium chloride and potassium chloride, if necessary. These alkali metal chlorides may be used alone or in combination of two or more. Of these alkali metal chlorides, sodium chloride is preferred.

When an alkali metal chloride is incorporated into the composition of the present disclosure, its content may be appropriately set according to the osmotic pressure to be imparted, taking into account the content 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%.

Furthermore, the composition of the present disclosure may contain a buffering agent, if necessary. The buffering agent is not particularly limited as long as it is acceptable for incorporation into eye drops, and examples thereof include 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.

When a buffer is added to the composition of the present disclosure, the content may be appropriately set depending on the type of buffer used, but 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%.

In addition to the above-mentioned components, the composition of the present disclosure may contain additives such as a chelating agent, a cooling agent, and a preservative, as necessary. Examples of chelating agents include edetate, citric acid or a salt thereof, and the like. These chelating agents may be used alone or in combination of two or more.

Examples of cooling agents include l-menthol, borneol, camphor, eucalyptus oil, etc. These cooling agents may be used alone or in combination of two or more.

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

Examples of stabilizers 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.

There are no particular limitations on the pH regulator, so long as it is pharma- ceutically acceptable. Examples of the pH regulator include acids such as hydrochloric acid, acetic acid, boric acid, aminoethylsulfonic acid, and epsilon-aminocaproic acid; and alkalis such as sodium hydroxide, potassium hydroxide, borax, triethanolamine, monoethanolamine, sodium bicarbonate, and sodium carbonate. These pH regulators may be used alone or in combination of two or more.

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

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, typically instilled one drop at a time, twice a day, but is not limited thereto.

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 of 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 in whom the 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.

In some embodiments, the pre-dose intraocular pressure can be a daytime intraocular pressure (e.g., intraocular pressure measured between 9:30am and 1pm, more specifically between 10am and 12:30pm).

In some embodiments, the other glaucoma therapeutic agent is an intraocular pressure reducing agent other than the composition of the present disclosure, for example, but not limited to, prostaglandin-related drugs, beta-receptor blockers, ROCK inhibitors, carbonic anhydrase inhibitors, alpha ₂ receptor agonists, and alpha ₁ receptor blockers, selective EP2 receptor agonists, or combinations thereof. Prostaglandin-related drugs include, but are not limited to, preparations containing prostaglandin _F2α derivatives, such as latanoprost, travoprost, and tafluprost, and prostamide derivatives as active ingredients. Beta-receptor blockers include, but are not limited to, preparations containing timolol, levobunolol, betaxolol, nipradilol, or carteolol as active ingredients. ROCK inhibitors include, but are not limited to, preparations containing ripasudil or netarsudil as active ingredients. Carbonic anhydrase inhibitors include, but are not limited to, preparations containing dorzolamide or brinzolamide as active ingredients. Examples of α2 receptor agonists include, but are not limited to, preparations containing brimonidine as an active ingredient. Examples of _α1 receptor blockers include, but are not limited to, preparations containing bunazosin as an active ingredient. Examples of selective _EP2 receptor agonists include, but are not limited to, preparations containing omidenepag isopropyl as an active ingredient.

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

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

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 and visual field findings. In addition, if the rate of decrease in intraocular pressure from untreated intraocular pressure is low (e.g., the rate of decrease in intraocular pressure 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, patients who can be treated may be patients who have 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.

In some embodiments, when intraocular pressure is used as an indicator of insufficient efficacy, it may be intraocular pressure measured on the day administration of the other glaucoma medication is terminated, and preferably, it may be intraocular pressure measured in 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 the other glaucoma medication.

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 morning administration and up to 12:30), preferably in the afternoon (within 2 hours±30 minutes after morning administration 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 the other glaucoma therapeutic drug is stopped. In addition, the pre-administration intraocular pressure may be an intraocular pressure measured to be used as an indicator of insufficient effect.

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.

In some embodiments, the composition of the present disclosure may 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 may reduce the intraocular pressure of a patient by more than 0% and less than 10%, 10% or more but 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 an intraocular pressure of 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 whose average intraocular pressure was maintained at 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 slowing 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.

The intraocular pressure reduction rate was calculated using 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 an average value of intraocular pressures measured at multiple time points. In some embodiments, the intraocular pressure value may be a value at 0 hours, 2 hours, or 7 hours. For example, the following:
Intraocular pressure reduction rate at time 0={(time 0 value on the start date of administration of the composition of the present disclosure (intraocular pressure value measured between 8:00 and 10:00)−time 0 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 between 8:00 and 10:00)/time 0 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
Intraocular pressure reduction rate at 7 hours value={(7 hours 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 hours 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 hours 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
It can be calculated by:

The date of intraocular pressure assessment may be at least 2 weeks (e.g., 2 weeks, 4 weeks, 2 months, 3 months, 6 months, 1 year, or later) after the start of treatment.

In some embodiments, the composition of the present disclosure may 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 rate of reduction in intraocular pressure, 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 may reduce the intraocular pressure by 10% or more for at least 7:00 to 18:00, when evaluated by the rate of reduction in intraocular pressure. 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 (Takano Yasuko et al., Ophthalmology 60(1), 9-13, 2018-01; Noro Takahiko et al., Journal of the Japanese Ophthalmological Society 118(10): 831-837, 2014). Therefore, maintaining low intraocular pressure throughout the day is important in terms of preventing the progression of visual field defects.

Although patients who may be treated with the composition of the present disclosure are not limited to patients of a particular age, the composition of the present disclosure has a higher therapeutic effect on patients under 65 years of age. Thus, in some embodiments, patients who may be treated with the composition of the present disclosure may be under 65 years of age. In certain embodiments, patients who may be treated with the composition of the present disclosure may have a pre-administration intraocular pressure of 18 mmHg or more and less than 20 mmHg, and may be under 65 years of age. Preferably, in certain embodiments, patients who may be treated with the composition of the present disclosure may have a pre-administration intraocular pressure of 18 mmHg or more and less than 20 mmHg, and may be over 20 years of age and under 65 years of age.

In another aspect, the present disclosure provides a composition for reducing intraocular pressure in a patient, the composition comprising brimonidine or a pharma- ceutically acceptable salt thereof and brinzolamide or a pharma-ceutically acceptable salt thereof, the patient being administered another glaucoma treatment drug, the patient's pre-administration intraocular pressure being 18 mmHg or more and less than 20 mmHg, the composition being administered to the patient twice daily as an instillation, the composition having a brimonidine concentration of about 0.1% w/v, the brinzolamide concentration of about 1% w/v, and the composition reducing the intraocular pressure of the patient by about 10% or more as evaluated by the intraocular pressure reduction rate.

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 pharma- ceutically acceptable salt thereof and brinzolamide or a pharma- ceutically acceptable salt thereof, the method comprising: a) determining whether the other glaucoma therapeutic drug is sufficiently or insufficiently effective for the patient; b) measuring the intraocular pressure of the patient; c) selecting a patient for whom the other glaucoma therapeutic drug is not sufficiently effective and whose pre-administration intraocular pressure value is less than 20 mmHg (e.g., 18 mmHg or more and less than 20 mmHg) on the day of administration; and d) administering the composition to the selected patient. Step c) may further comprise selecting a patient under the age of 65. "Preventing the worsening of glaucoma" may include preventing or delaying the progression of visual field impairment in a glaucoma patient. "Preventing the worsening of ocular hypertension" can include lowering intraocular pressure in a patient with ocular hypertension, preventing or delaying an increase in intraocular pressure, or preventing or delaying the onset of visual field defects.

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., combination drugs) and administered in combination.

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

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

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

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 therapeutic glaucoma drugs other than the multiple-component agent have an insufficient effect, 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, a composition containing brimonidine or a pharma- ceutically acceptable salt thereof and brinzolamide or a pharma- ceutically acceptable salt thereof is selected as a selective drug different from other glaucoma therapeutic drugs in place of or in combination with the other glaucoma therapeutic drugs, and the multiple-component preparation is administered to the patient.
A multiple component formulation is provided.

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 administration start date;
and c) administering said composition to said selected patient.

(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 the patient if other glaucoma therapeutic agents are insufficiently effective in the patient and the pre-administration intraocular pressure of the patient is less than 20 mmHg.

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

(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 pharmacologic salt thereof and brinzolamide or a pharmacologic 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.

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- tically acceptable salt thereof and brinzolamide or a pharma- tically acceptable salt thereof may be effective as a drug of choice different from other glaucoma treatment 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, a composition comprising brimonidine or a pharma- tically acceptable salt thereof and brinzolamide or a pharma- tically acceptable salt thereof may be effective as a drug of choice different from other glaucoma treatment drugs.

The present disclosure has been described above by showing preferred embodiments for ease of understanding. Below, the present disclosure will be described 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.

The following describes this disclosure in more detail with reference to examples.

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.

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 (eye drop 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 patients (163 patients) with primary open-angle glaucoma (broad definition) or ocular hypertension, compared with a 1% brinzolamide suspension eye drop.

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 presence of glaucomatous optic neuropathy (signs of damage to the optic disc or retinal nerve fiber layer).
When visual field is measured using a Humphrey perimeter, the Anderson-Patella criteria (Anderson DR, Patella VM. Automated Static Perimetry. 2nd edition. St. Louis: Mosby; 1999: 152-3.) are followed.
(2) The presence of a glaucomatous optic disc.
Diagnosis is made by 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 start of the observation period to the morning of the end of the observation period (start of the treatment period)]. If the intraocular pressure values at 0 and 2 hours in the eye to be evaluated for efficacy on the end of the observation period (start 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 eye to be evaluated for efficacy on the end of the observation period (start of the treatment period) was within 3.0 mmHg, the patient was to proceed to the treatment period.

During the treatment period, the eye drops were administered once in each eye, twice a day (morning and evening (9:00 ± 1 hour) in both eyes, once a day (morning and evening (9:00 ± 1 hour and 21:00 ± 1 hour) in the evening of the last day of the observation period (starting day of the treatment period)) for 4 weeks (morning instillation 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 hour.

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 and up to 12:30 after instillation in the morning are referred to as 2-hour values, and intraocular pressure values measured within 7 hours ± 1 hour and up to 18:00 after instillation in the morning are referred to as 7-hour values.

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 day 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 day 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-hour value) - intraocular pressure value on each observation day (2-hour value)} / intraocular pressure value on the start of the treatment period (2-hour value)] * 100
Intraocular pressure reduction rate at 7 hours (%) = [{intraocular pressure value on the start of the treatment period (7-hour value) - intraocular pressure value on each observation day (7-hour value)} / intraocular pressure value on the start of the treatment period (7-hour value)] * 100
Regarding the calculated intraocular pressure reduction rate, patients who achieved a reduction rate of 10% or less at any of the time points 0, 2, and 7 hours were classified as (+) from patients who did not (±). For each group divided by pre-administration intraocular pressure and age, the ratio of the number of (+) and (±) patients 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.

Table 1 shows the results stratified by pre-treatment intraocular pressure.

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, this eye drop is considered to be 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 reduces the risk of progression of visual field defects. It has also been reported that a 1 mmHg reduction in intraocular pressure reduces the risk of progression of visual field defects (Glaucoma Treatment Guidelines (4th Edition), Kawase Kazuhide. Ophthalmology. Vol. 48, No. 6, p. 871-881 (2006)).

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.

It is generally known that a greater intraocular pressure-reducing 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 groups administered the intraocular pressure-reducing drug Ripasudil eye drops, a greater intraocular pressure-reducing 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-reducing effect was observed in patients with a relatively low pre-administration intraocular pressure of 18 mmHg or more and less than 20 mmHg.

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

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. In the group with a pre-administration intraocular pressure of less than 20 mmHg and age of less than 65 years, it was found that 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 (Takano Yasuko et al., Ophthalmology 60(1), 9-13, 2018-01; Noro Takahiko et al., Journal of the Japanese Ophthalmological Society 118(10): 831-837, 2014). Therefore, it is important to maintain low intraocular pressure throughout the day in order to prevent the progression of visual field defects.

(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 (twice a day) of 0.1 w/v% brimonidine tartrate/1 w/v% brinzolamide suspension eye drops (eye drops 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). 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 administration begins. If the pre-administration intraocular pressure is 18 mmHg or more and 20 mmHg or more, administration of the eye drops is started. Every month, the 0 hour, 2 hour, and 7 hour values will be measured to confirm the effect of lowering intraocular pressure. In addition, the fundus and visual field abnormalities will be measured and the progress will be monitored.

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 who 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 a day). The intraocular pressure of the patient is measured using a Goldmann applanation tonometer between 10:00 a.m. and 12:30 p.m. on the day administration begins (pre-administration intraocular pressure). If the pre-administration intraocular pressure is between 18 mmHg and 20 mmHg, 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, visual field abnormalities, etc., and follow-up observations are conducted.

Although the present disclosure has been illustrated using preferred embodiments thereof, it is understood that the scope of the present disclosure should be interpreted only by the claims. It is understood that the patents, patent applications, and literature cited in this specification are incorporated by reference into this specification in the same manner as if the contents themselves were specifically set forth in this specification.

A composition for treating glaucoma and/or ocular hypertension is provided. This technology can be used in the fields of pharmaceuticals, etc.

Claims (16)

A composition comprising brimonidine or a pharma- ceutically acceptable salt thereof and brinzolamide or a pharma- ceutically acceptable salt thereof, 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 brimonidine or a pharma- ceutically acceptable salt thereof is about 1% w/v, said composition being used to reduce intraocular pressure in a patient suffering from glaucoma or ocular hypertension who is being administered a glaucoma therapeutic drug other than said composition, in which the other glaucoma therapeutic drug is not effective enough and whose pre-administration intraocular pressure on the day administration of the composition is started is 18 mmHg or more and less than 20 mmHg. 2. The composition of claim 1 , wherein the brimonidine or a pharma- ceutically acceptable salt thereof is brimonidine tartrate. 3. The composition according to claim 1 or 2 , wherein the composition is administered to the patient by eye drop, one drop at a time, twice a day. The composition according to any one of claims 1 to 3 , wherein the patient is under 65 years of age. The composition according to any one of claims 1 to 4 , wherein the composition reduces intraocular pressure of the patient by 10% or more when evaluated by an intraocular pressure reduction rate. The composition according to claim 5 , wherein the composition reduces intraocular pressure of the patient by 10% or more for at least 12 hours after administration, as evaluated by the intraocular pressure reduction rate. The composition according to claim 5 or 6 , wherein the intraocular pressure reduction rate is evaluated 4 weeks after the start of administration. A composition comprising brimonidine or a pharma- ceutically acceptable salt thereof and brinzolamide or a pharma- ceutically acceptable salt thereof, 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 brimonidine or a pharma- ceutically acceptable salt thereof is about 1% w/v, said composition being for treating glaucoma or ocular hypertension in a patient who is being administered a glaucoma therapeutic drug other than said composition, in whom the effect of the other glaucoma therapeutic drug is insufficient, and whose pre-administration intraocular pressure on the day administration of the composition is started is 18 mmHg or more and less than 20 mmHg. The brimonidine or a pharma- ceutically acceptable salt thereof is brimonidine tartrate.
The composition of claim 8 . 10. The composition according to claim 8 or 9 , wherein the composition is administered to the patient by eye drop, one drop at a time, twice a day. The composition according to any one of claims 8 to 10 , wherein the patient is under 65 years of age. The composition according to any one of claims 8 to 11 , wherein the composition is for treating glaucoma or ocular hypertension by lowering intraocular pressure in the patient. The composition according to any one of claims 8 to 12 , characterized in that the composition reduces the intraocular pressure of the patient by 10% or more when evaluated by the intraocular pressure reduction rate. The composition according to claim 13 , characterized in that the composition reduces the intraocular pressure of the patient by 10% or more for at least 12 hours after administration, as evaluated by the intraocular pressure reduction rate. The composition according to claim 13 or 14 , wherein the intraocular pressure reduction rate is evaluated 4 weeks after the start of administration. The composition of any one of claims 8 to 15 , wherein the treatment of glaucoma comprises preventing or slowing the progression of visual field defects in the glaucoma patient, and the treatment of ocular hypertension comprises preventing or slowing the onset of visual field defects.