A composition containing brimonidine for lowering intraocular pressure in patients.

Abstract

To provide a composition for reducing intraocular pressure of a patient.SOLUTION: In one aspect, the present disclosure is a composition (e.g. eye-drops) containing brimonidine for reducing intraocular pressure of a patient, in which a prostaglandin-related agent is administered to the patient, and intraocular pressure before administration of the patient is less than 18 mmHg. In several embodiments, by administering the composition of the present disclosure to a patient with intraocular pressure before administration of less than 18 mmHg, 14 mmHg or more and less than 18 mmHg for example, more preferably 16 mmHg or more and less than 18 mmHg, high therapeutic effect (i.e.intraocular pressure reducing effect) is expected.SELECTED DRAWING: None

Description

Technical Field

[0001] The present disclosure relates to a composition for reducing intraocular pressure in a patient, which contains brimonidine, and related inventions.

Background Art

[0002] In patients for whom the effect of treatment with prostaglandin-related drugs (hereinafter sometimes referred to as "PG-related drugs") used as the first-choice drug for glaucoma treatment is insufficient, brimonidine-containing eye drops or lipasudil-containing eye drops may be administered to reduce intraocular pressure. As brimonidine-containing eye drops, Iopagan eye drops are known.

Summary of the Invention

Means for Solving the Problems

[0003] The inventors of the present invention performed stratified analysis on the initial intraocular pressure values before administration of brimonidine-containing eye drops (the intraocular pressure value measured within 2 hours ± 30 minutes after measurement of the 2-hour value on the administration start date of the target drug (the intraocular pressure value measured at 0 hours on the administration start date of the target drug (the intraocular pressure value measured between 8:30 and 10:30)) and up to 12:30). As a result, it was newly found that brimonidine-containing eye drops exhibit a high intraocular pressure-lowering effect in subjects with an intraocular pressure within a specific range of initial intraocular pressure values. On the other hand, it was found that such a tendency was not observed in a generally used stratified analysis (for example, analysis at the 0-hour value on the administration start date of the target drug). Therefore, the present disclosure relates to a composition for reducing intraocular pressure containing brimonidine, and particularly shows excellent therapeutic effects on specific groups of glaucoma and / or ocular hypertension patients. In addition, the present disclosure can provide an effective drug as a second-choice drug in patients for whom the effect of prostaglandin-related drugs administered as the first-choice drug is insufficient.

[0004] The present disclosure provides, for example, the following items. (Item 1A) A composition for use in a method to suppress the onset or progression of visual field defects in patients who have shown insufficient response to prostaglandin-related drugs as first-line therapy, including brimonidine or a pharmaceutically acceptable salt thereof, by reducing intraocular pressure by approximately 20% or more as evaluated by the rate of intraocular pressure reduction, wherein the method is: a) A step of diagnosing whether the patient is not adequately affected by prostaglandin-related drugs, b) A step of measuring the intraocular pressure of the patient, c) When the effect of prostaglandin-related drugs is insufficient and the patient's pre-administration intraocular pressure value on the day of initiation of the second-line drug is 16 mmHg or more and less than 18 mmHg, the step of selecting brimonidine or a pharmaceutically acceptable salt thereof as a second-line drug to be used in combination with prostaglandin-related drugs, and administering the composition to the patient. Includes, The percentage reduction in intraocular pressure is calculated using the average of the 0-hour value on the day of intraocular pressure evaluation (intraocular pressure measured between 8:30 and 10:30) and the 2-hour value on the day of intraocular pressure evaluation (intraocular pressure measured within 2 hours ± 30 minutes after the measurement of the 0-hour value and by 12:30). The pre-administration intraocular pressure (IOP) value on the day of initiation of the second-line drug is the 2-hour value on the day of initiation of the second-line drug (the IOP value measured within 2 hours ± 30 minutes after the 0-hour value on the day of initiation of the second-line drug (IOP measured between 8:30 and 10:30) and by 12:30). composition. (Item 2A) The composition described in item 1A, wherein the 0-hour value on the first day of administration of the second-line drug for the patient is 18.0 mmHg or higher. (Item 3A) The composition according to item 1A, wherein the intraocular pressure value at 0 hours (measured between 8:30 and 10:30) on at least one day between 1 and 28 days prior to the start of administration of the second-line drug to the patient is 18.0 mmHg or higher. (Item 3A') The composition according to item 3A, wherein the patient has been administered only a prostaglandin-related drug for at least one week at a point in time at least one day between 1 and 28 days prior to the start of administration, and has not been administered any other glaucoma treatment drug. (Item 4A) The composition according to any one of items 1A to 3A, characterized in that the composition is administered together with the prostaglandin-related drug. (Item 4A') A composition according to any one of items 1A to 3A, which is not used in combination with other glaucoma treatments other than the aforementioned prostaglandin-related drugs. (Item 5A) The composition according to any one of items 1A to 4A, wherein the prostaglandin-related drug is a formulation containing an active ingredient selected from the group consisting of latanoprost, travoprost, tafluprost, and isopropylunoprostone. (Item 6A) The composition according to any one of items 1A to 5A, wherein the patient suffers from glaucoma and / or ocular hypertension. (Item 7A) The composition according to any one of items 1A to 6A, characterized in that the composition is administered to the patient for at least four weeks. (Item 7A') The composition according to item 7A, wherein the date of evaluation of the intraocular pressure is at least 4 weeks after the start of administration. (Item 8A) The composition according to any one of items 1A to 7A, wherein the brimonidine or a pharmaceutically acceptable salt thereof is brimonidine tartrate. (Item 9A) The composition described above is an eye drop, according to any one of items 1A to 8A. (Item 10A) The composition according to any one of items 1A to 9A, wherein the concentration of brimonidine in the composition is about 0.1% w / v. (Item 11A) The composition according to item 10A, characterized in that the composition is administered to the patient as eye drops, one drop at a time, twice a day. (Item 11A') The composition according to item 10A, wherein eye drops are administered once between 8:30 and 10:30 and once between 20:00 and 22:00, and the first dose of the composition as a second-line drug is administered between 20:00 and 22:00 on the day administration begins. (Item 12A) A method for determining whether a composition for lowering intraocular pressure in patients whose response to a prostaglandin-related drug as a first-line treatment is insufficient, and which includes brimonidine or a pharmaceutically acceptable salt thereof as a second-line drug, can lower intraocular pressure by approximately 20% or more when evaluated by the rate of intraocular pressure reduction, If the patient's pre-treatment intraocular pressure (IOP) on the day of initiation of the second-line drug is 16 mmHg or higher and less than 18 mmHg, the composition as the second-line drug can reduce the patient's IOP by approximately 20% or more. The percentage reduction in intraocular pressure is calculated using the average of the 0-hour value on the day of intraocular pressure evaluation (intraocular pressure measured between 8:30 and 10:30) and the 2-hour value on the day of intraocular pressure evaluation (intraocular pressure measured within 2 hours ± 30 minutes after the measurement of the 0-hour value and by 12:30). The pre-administration intraocular pressure (IOP) value on the day of initiation of the second-line drug is the 2-hour value on the day of initiation of the second-line drug (the IOP value measured within 2 hours ± 30 minutes after the 0-hour value on the day of initiation of the second-line drug (IOP measured between 8:30 and 10:30) and by 12:30). method. (Item 13A) A method for determining whether a composition for lowering intraocular pressure in patients who have an insufficient response to a prostaglandin-related drug as a first-line treatment, including brimonidine or a pharmaceutically acceptable salt thereof as a second-line treatment, can suppress the onset or progression of visual field defects in said patients, wherein the pre-administration intraocular pressure in a patient is used as an indicator of whether such composition can suppress the onset or progression of visual field defects in said patient. If the patient's pre-treatment intraocular pressure value on the day of initiation of the second-line drug is 16 mmHg or higher and less than 18 mmHg, the composition can suppress the onset or progression of visual field defects in the patient. The pre-administration intraocular pressure (IOP) value on the day of initiation of the second-line drug is the 2-hour value (the IOP value measured within 2 hours ± 30 minutes after the 0-hour value (IOP measured between 8:30 and 10:30) on the day of initiation of the second-line drug, and by 12:30). method. (Item 14A) A method for determining whether treatment with a composition for lowering intraocular pressure in patients for whom the response to prostaglandin-related drugs as a first-line agent is insufficient, using the pre-administration intraocular pressure in a patient as an indicator, If the patient's pre-administration intraocular pressure value on the day of administration initiation is 16 mmHg or higher and less than 18 mmHg, it indicates that the composition may be effective for the patient. The pre-administration intraocular pressure (IOP) value on the day of initiation of the second-line drug is the 2-hour value on the day of initiation of the second-line drug (the IOP value measured within 2 hours ± 30 minutes after the 0-hour value on the day of initiation of the second-line drug (IOP measured between 8:30 and 10:30) and by 12:30). method. (Item 15A) A method for determining whether to select a composition containing brimonidine or a pharmaceutically acceptable salt thereof as a second-line drug, using intraocular pressure in patients who have been administered a prostaglandin-related drug for a predetermined period as a first-line drug, If the patient's pre-administration intraocular pressure value on the day of administration initiation is 16 mmHg or higher and less than 18 mmHg, it indicates that the composition may be effective for the patient. The pre-administration intraocular pressure (IOP) value on the day of initiation of the second-line drug is the 2-hour value on the day of initiation of the second-line drug (the IOP value measured within 2 hours ± 30 minutes after the 0-hour value on the day of initiation of the second-line drug (IOP measured between 8:30 and 10:30) and by 12:30). method. (Item 1B) A method for determining whether a composition for lowering intraocular pressure in patients for whom prostaglandin-related drugs are ineffective can lower the patient's intraocular pressure by approximately 20% or more, using the patient's pre-administration intraocular pressure as an indicator, wherein if the patient's pre-administration intraocular pressure is 16 mmHg or higher and less than 18 mmHg, the reduction in intraocular pressure in the patient after administration of the composition may be approximately 20% or more, provided that the pre-administration intraocular pressure was measured between 10:30 and 12:30, and the reduction in intraocular pressure is expressed by the following formula: Intraocular pressure reduction rate = {(Intraocular pressure value before administration of the composition - Intraocular pressure value after administration of the composition for a predetermined period) / Intraocular pressure value before administration of the composition} × 100 A method used to calculate this. (Item 2B) A method for determining whether a composition for lowering intraocular pressure in patients for whom prostaglandin-related drugs are ineffective can suppress the onset or progression of visual field defects in a patient, wherein the pre-administration intraocular pressure in a patient is 16 mmHg or higher and less than 18 mmHg, and the pre-administration intraocular pressure is measured between 10:30 and 12:30. (Item 3B) A method for determining whether treatment with a composition for lowering intraocular pressure in patients for whom the response to prostaglandin-related drugs is insufficient is effective, wherein the pre-administration intraocular pressure in a patient is an indicator of whether treatment with a composition for lowering intraocular pressure in patients for whom the response to prostaglandin-related drugs is insufficient, the method being characterized by showing that if the patient's pre-administration intraocular pressure is 16 mmHg or higher and less than 18 mmHg, the composition may be effective in the patient, and the pre-administration intraocular pressure was measured between 10:30 and 12:30. (Item 4B) A method for using the intraocular pressure in a patient administered with a prostaglandin-related drug as a first-choice drug for a predetermined period as an indicator for selecting whether or not to select a composition containing brimonidine or a pharmaceutically acceptable salt thereof as a second-choice drug, wherein when the pre-administration intraocular pressure of the patient is 16 mmHg or more and less than 18 mmHg, it indicates that the composition may be effective for the patient, and the pre-administration intraocular pressure is measured in the time period from 10:30 to 12:30. (Item 5B) The method according to Items 3B and 4B, wherein the effectiveness of the composition for the patient includes that the intraocular pressure reduction rate in the patient administered with the composition is about 20% or more. (Item 6B) The intraocular pressure reduction rate is as follows: Intraocular pressure reduction rate = {(intraocular pressure value before administering the composition - intraocular pressure value after administering the composition for a predetermined period) / intraocular pressure value before administering the composition} × 100 The method according to Item 5B, which is calculated by the above formula. (Item 7B) In the above formula, the intraocular pressure value before administering the composition is the average value of the intraocular pressure values measured at a plurality of time points before administering the composition, and the intraocular pressure value after administering the composition for a predetermined period is the average value of the intraocular pressure values measured at a plurality of time points after administering the composition. The method according to Items 1B and 6B. (Item 8B) The method according to Item 7B, wherein the plurality of time points are 0-hour value and 2-hour value. (Item 9B) The method according to Item 8B, wherein the 0-hour value is the value measured in the time period from 8:30 to 10:30, and the 2-hour value is the value measured within 2 hours ± 30 minutes of the 0-hour value and before 12:30. (Item 10B) The method according to Item 8B or 9B, wherein the intraocular pressure value of the 0-hour value (intraocular pressure value measured at 8:30 - 10:30) on the administration start date of the patient is 18.0 mmHg or more, or the intraocular pressure value of the 0-hour value (value measured at 8:30 - 10:30) on at least one day among 1 to 28 days before the administration start date of the patient is 18.0 mmHg or more. (Item 11B) The method according to any one of items 1B to 10B, wherein the patient is a patient who has been administered the prostaglandin-related drug for 90 days or more. (Item 12B) The method according to any one of items 1B to 11B, characterized in that the composition is administered together with the prostaglandin-related drug. (Item 13B) The method according to any one of items 1B to 12B, wherein the prostaglandin-related drug is a formulation comprising an active ingredient selected from the group consisting of latanoprost, travoprost, tafluprost, and isopropylunoprostone. (Item 14B) The method according to any one of items 1B to 13B, wherein the patient has glaucoma and / or ocular hypertension. (Item 15B) The method according to any one of items 1B to 14B, characterized in that the composition is administered to the patient for at least four weeks. (Item 16B) The method according to any one of items 1B to 15B, wherein the brimonidine or a pharmaceutically acceptable salt thereof is brimonidine tartrate. (Item 17B) The method according to any one of items 1B to 16B, wherein the composition is an eye drop. (Item 18B) The method according to any one of items 1B to 17B, wherein the concentration of brimonidine in the composition is about 0.1% w / v. (Item 19B) The method according to item 17B, characterized in that the composition is administered to the patient as eye drops, one drop at a time, twice a day.

[0005] In this disclosure, the one or more of the above features are intended to be provided in combinations other than those explicitly stated. Further embodiments and advantages of this disclosure will be apparent to those skilled in the art, by reading and understanding the detailed description below as necessary. [Effects of the Invention]

[0006] According to this disclosure, a composition comprising brimonidine is provided that exhibits excellent intraocular pressure-lowering effects in a specific group of patients for whom treatment with prostaglandin-related drugs is insufficient. [Modes for carrying out the invention]

[0007] The following describes this disclosure. Throughout this specification, singular expressions should be understood to include the concept of their plural form unless otherwise specified. Thus, singular articles (e.g., "a," "an," "the" in English) should be understood to include the concept of their plural form unless otherwise specified. Furthermore, terms used herein should be understood to have the meaning commonly used in the art unless otherwise specified. Thus, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure pertains. In case of any conflict, this specification (including definitions) shall prevail. In this specification, "about" means ±10% of the following value. In this specification, times are expressed in 24-hour format unless otherwise specified.

[0008] (definition) In this specification, "brimonidine" refers to the following formula

[0009] [ka]

[0010] This compound is represented by the chemical name 5-bromo-N-(4,5-dihydro-1H-imidazole-2-yl)quinoxaline-6-amine. Brimonidine or its pharmaceutically acceptable salts are used as pharmaceutical ingredients, and are typically offered as brimonidine tartrate (chemical name 5-bromo-N-(4,5-dihydro-1H-imidazole-2-yl)quinoxaline-6-amine--(2R,3R)-tartrate). Brimonidine or its pharmaceutically acceptable salts are selective adrenergic α2 receptor agonists and are commonly used as active ingredients in aqueous solutions, especially eye drops, with its tartrate being marketed under the trade name Aiphagan. Brimonidine and its pharmaceutically acceptable salts are commercially available. Pharmacologically acceptable salts of brimonidine include, but are not limited to, tartrate, hydrochloride, or acetate. It is used as eye drops to treat glaucoma and ocular hypertension, and as a topical agent to treat skin redness associated with rosacea. Brimonidine is used to lower intraocular pressure in patients with (open-angle) glaucoma or ocular hypertension.

[0011] In this specification, "glaucoma" refers to a disease characterized by functional and structural abnormalities of the eye that have distinctive changes in the optic nerve and visual field, and in which optic nerve damage can usually be improved or suppressed by sufficiently lowering intraocular pressure (Japanese Glaucoma Society Glaucoma Treatment Guidelines Committee. Glaucoma Treatment Guidelines (4th Edition). Journal of the Japanese Ophthalmological Society. Vol. 122, No. 1). According to pp. 5-53 (2018.01) (hereinafter referred to as the "Glaucoma Treatment Guidelines (4th Edition)"), glaucoma can be classified into primary glaucoma, secondary glaucoma, and pediatric glaucoma. Primary glaucoma includes primary open-angle glaucoma (broad sense) and primary closed-angle glaucoma, and primary open-angle glaucoma (broad sense) includes primary open-angle glaucoma (narrow sense), normal-tension glaucoma, and pre-peripheral field glaucoma. Secondary glaucoma includes secondary open-angle glaucoma and secondary closed-angle glaucoma, and pediatric glaucoma includes primary congenital glaucoma, juvenile open-angle glaucoma, glaucoma associated with congenital ocular malformations, and glaucoma associated with congenital systemic diseases.

[0012] In this specification, "ocular hypertension" refers to a condition characterized by elevated intraocular pressure, although no clear abnormalities are observed in the visual field or optic nerve. Ocular hypertension has a high probability of progressing to glaucoma in the future, and eye drop treatment may be administered to maintain normal intraocular pressure.

[0013] In this specification, "pre-administration intraocular pressure" refers to the intraocular pressure measured on the day the drug of interest is to be administered (administration start date) before the drug is administered, and this value is referred to as the "pre-administration intraocular pressure value." The pre-administration intraocular pressure is the pre-administration intraocular pressure (value) on the administration start date, and the so-called "2-hour value" is adopted (in this case, it may be called the initial intraocular pressure value).

[0014] In this specification, the "0-hour value" on the administration start date, evaluation date, etc., refers to the intraocular pressure (IOP) value measured between 8:30 and 10:30 on the target day (e.g., administration start date, evaluation date), and the "2-hour value" on the administration start date, evaluation date, etc., refers to the IOP value measured within 2 hours ± 30 minutes after the measurement of the 0-hour value on the target day (e.g., administration start date, evaluation date) and by 12:30. On the evaluation date, the "0-hour value" is the IOP measured immediately before the administration of the drug. In this field, the "0-hour value" and "2-hour value" are used to indicate a certain value for a patient's IOP and are used as values ​​sufficient to identify the patient.

[0015] In this specification, "administration start date" refers to the date (including planned dates) on which the administration of a particular drug is to begin. Therefore, in the case of companion drugs, the administration start date refers to the date on which a decision is made as to whether or not to begin administration. If it is decided not to begin administration, no actual administration will take place, but in this specification, this date will be treated as the administration start date.

[0016] In this specification, "evaluation date" refers to the date on which intraocular pressure is evaluated. Any date may be applicable, but for example, periods such as approximately 4 weeks, 12 weeks, 3 months, 6 months, 1 year, and 3 years after the start of administration may be included.

[0017] In this specification, "intraocular pressure reduction rate" refers to the rate of change in intraocular pressure (IOP) on the evaluation day compared to the IOP on the administration start day, which is the evaluation criterion, in the same patient. In this disclosure, the IOP reduction rate is typically calculated using the average of the 0-hour value (IOP measured between 8:30 and 10:30) and the 2-hour value (IOP measured within 2 hours ± 30 minutes after the 0-hour value and by 12:30) on the IOP evaluation day. While we do not wish to be bound by theory, the reason for using such an average value as the IOP reduction rate is that by selecting representative time values ​​from the time periods when drug effects are likely to be observed and those when they are unlikely to be observed, and taking the average of these, a more appropriate evaluation of the drug in question can be performed.

[0018] Furthermore, in this specification, "normal intraocular pressure" refers to intraocular pressure measured routinely, other than the pre-administration intraocular pressure measured on the day administration begins. "Normal intraocular pressure" may be intraocular pressure measured on a day prior to the day administration begins (for example, at least one day between 1 and 28 days prior to the day administration begins) or intraocular pressure measured on the day administration begins. It should be noted that intraocular pressure fluctuates throughout the day, and while there are individual differences in the patterns of when intraocular pressure is highest, it is generally thought to fluctuate in a cycle of approximately one day. By using the 0-hour and 2-hour values, it is possible to identify patient groups and enable appropriate evaluation.

[0019] In this specification, "prostaglandin-related drugs" refers to pharmaceuticals containing prostaglandins or prostaglandin analogs that exhibit equivalent effects to prostaglandins, or pharmaceutically acceptable salts thereof. Prostaglandin-related drugs are applied to glaucoma via an alternative route (via uveoscleral flow) by promoting aqueous humor outflow. Examples of prostaglandin-related drugs include, but are not limited to, isopropyl unoprostone, latanoprost, travoprost, tafluprost, and other prostaglandin F 2αExamples include derivatives and prostamide derivatives. Preferably, prostaglandin-related drugs include prostaglandin F such as latanoprost, travoprost, and tafluprost. 2α Examples include derivatives and prostamide derivatives. Prostaglandin-related drugs are often used as first-line treatments.

[0020] In some embodiments, other glaucoma treatments besides prostaglandin-related drugs are intraocular pressure lowering agents, including, but not limited to, β-receptor blockers, ROCK inhibitors, carbonic anhydrase inhibitors, and α1-receptor blockers, selective EP2 receptor agonists, or combinations thereof. Examples of β-receptor blockers include, but are not limited to, formulations containing timolol, levobunolol, betaxolol, nipradilol, or carteolol as active ingredients. Examples of ROCK inhibitors include, but are not limited to, formulations containing ripasudil or netarsudil as active ingredients. Examples of carbonic anhydrase inhibitors include, but are not limited to, formulations containing dorzolamide or brinzolamide as active ingredients. Examples of α1-receptor blockers include, but are not limited to, formulations containing bunazosin as an active ingredient. Examples of selective EP2 receptor agonists include, but are not limited to, formulations containing omidenepag isopropyl as an active ingredient. Other glaucoma treatments besides prostaglandin-related drugs include, but are not limited to, non-selective sympathetic nerve stimulants and parasympathetic nerve stimulants. Examples of non-selective sympathetic nerve stimulants include, but are not limited to, preparations containing dipivefrin as the active ingredient. Examples of parasympathetic nerve stimulants include, but are not limited to, preparations containing pilocarpine as the active ingredient.

[0021] In this specification, “Instructions” are instructions for the user on how to use the Disclosure, and are referred to as “Package Inserts” in Japan and “Labels” in the United States and other countries. These Instructions contain language that instructs the user on how to use the Disclosure. If necessary, these Instructions will be prepared in accordance with the format prescribed by the supervisory authority in the country where the Disclosure is implemented (for example, the Ministry of Health, Labour and Welfare or the Ministry of Agriculture, Forestry and Fisheries in Japan, or the Food and Drug Administration (FDA) or the Department of Agriculture (USDA) in the United States) and will be clearly stated to have been approved by that supervisory authority. Instructions may, but are not limited to, be provided in paper form, and may also be provided in electronic form, for example, on a website or via email.

[0022] In this specification, "first-line drug" (also called first-line treatment or first choice) refers to the medication that should be administered first for a particular disease. Generally, first-line drugs are selected based on their low side effects and relatively high efficacy. If no improvement is seen after administering the first-line drug, a second-line drug, prioritizing efficacy and considering other mechanisms of action, is administered. In glaucoma, prostaglandin-related drugs are administered as first-line treatments.

[0023] In this specification, "second-line drug" (also called second-choice drug) refers to a treatment drug used when the first-line drug does not improve the patient's condition or when it is difficult to continue treatment due to side effects. There are many second-line drugs for glaucoma, including carbonic anhydrase inhibitor eye drops, α2 receptor agonists, ROCK inhibitors, α1 receptor blockers, non-selective sympathetic nerve agonists, and parasympathetic nerve agonists. Since each drug has different effects and is suitable for different patients, the appropriate selection of a second-line drug is important for the proper treatment of glaucoma.

[0024] (Preferred embodiment) Preferred embodiments of the Disclosure are described below. These embodiments are provided for a better understanding of the Disclosure, and it is understood that the scope of the Disclosure should not be limited to the descriptions below. Therefore, it is clear that those skilled in the art can make appropriate modifications within the scope of the Disclosure, taking into consideration the descriptions herein. It is also understood that the embodiments described below can be used individually or in combination.

[0025] (Composition containing brimonidine) In one aspect, this disclosure provides a composition (e.g., eye drops) for lowering intraocular pressure in a patient, comprising brimonidine or a pharmaceutically acceptable salt thereof (e.g., brimonidine tartrate). In this specification, “eye drops” is synonymous with “ophthalmic solution.” The patients targeted by this composition are those receiving prostaglandin-related drugs but with insufficient efficacy, and whose pre-administration intraocular pressure is less than 18 mmHg. The inventors have newly discovered that in certain patient groups with specific characteristics among those receiving prostaglandin-related drugs, administration of the composition of this disclosure shows superior therapeutic effects compared to other groups. Such compositions may be used in the treatment of glaucoma and / or ocular hypertension.

[0026] In a further context, the present disclosure provides a composition for use in a method of suppressing the onset or progression of visual field defects in patients who have an insufficient response to prostaglandin-related drugs as first-line therapy, by reducing intraocular pressure by approximately 20% or more as evaluated by the rate of intraocular pressure reduction. This method includes a) diagnosing whether the patient has an insufficient response to prostaglandin-related drugs; b) measuring the patient's intraocular pressure; and c) if the patient has an insufficient response to prostaglandin-related drugs and the patient's pre-administration intraocular pressure on the day of initiation of second-line therapy is 16 mmHg or more and less than 18 mmHg, selecting brimonidine or a pharmaceutically acceptable salt thereof as a second-line drug to be used in combination with a prostaglandin-related drug, and administering the composition to the patient. Here, the intraocular pressure reduction rate used is calculated using the average of the 0-hour value on the intraocular pressure evaluation day (intraocular pressure measured between 8:30 and 10:30) and the 2-hour value on the intraocular pressure evaluation day (intraocular pressure measured within 2 hours ± 30 minutes after the measurement of the 0-hour value and by 12:30). The pre-administration intraocular pressure value on the day the second-line drug is administered is the 2-hour value on the day the second-line drug is administered (intraocular pressure measured within 2 hours ± 30 minutes after the measurement of the 0-hour value on the day the second-line drug is administered (intraocular pressure measured between 8:30 and 10:30) and by 12:30). Such a composition provides an excellent therapeutic effect, lowering intraocular pressure by approximately 20% or more through a "three-step selection" process: (i) selecting patients who have not responded adequately to prostaglandin-related drugs as the first-line treatment; (ii) further selecting patients from that group whose intraocular pressure (IOP) value at 2 hours prior to administration on the day of initiation of the second-line treatment is between 16 mmHg and 18 mmHg; and (iii) selecting brimonidine as the second-line treatment. Since no patient group exhibiting such a special effect was found using stratification based on the 0-hour value, which is commonly used in IOP evaluation, this disclosure can be said to have an unexpectedly remarkable effect in light of conventional techniques for selecting second-line treatments.

[0027] In a preferred embodiment, the present disclosure is also characterized in that the target patients are selected based on whether their 0-hour intraocular pressure (IOP) value on the day of initiation of the second-line drug is 18.0 mmHg or higher, or whether their 0-hour intraocular pressure (IOP measured between 8:30 and 10:30) on at least one day between 1 and 28 days prior to the day of initiation of the second-line drug is 18.0 mmHg or higher. In this embodiment, as shown herein, it has been found that the present disclosure shows remarkable efficacy (an IOP reduction of approximately 20% or more) in a group of patients who show relatively high IOP values ​​at 0 hours but decrease at 2 hours, which can be considered an unexpectedly significant effect from the perspective of this field.

[0028] This composition may contain, for example, isotonic agents, buffers, viscosity modifiers, preservatives, pH adjusters, or solvents that are commonly used in ophthalmic compositions (especially aqueous eye drops). More specifically, it may contain one or more additives such as magnesium chloride, boric acid, borax, carmellose sodium, sodium chlorite, sodium chloride, potassium chloride, calcium chloride hydrate, hydrochloric acid, or sodium hydroxide. In the compositions of this disclosure, the amount of brimonidine or a pharmaceutically acceptable salt thereof is not particularly limited and may be set appropriately according to the severity of the symptoms of the patient to whom it is applied, the amount applied per dose, etc., but examples include about 0.05 to about 0.2 w / v%, preferably about 0.1 to about 0.2 w / v%, and particularly preferably about 0.1 w / v%. In this specification, references to the content or concentration of brimonidine and / or a pharmaceutically acceptable salt thereof mean the content or concentration converted to brimonidine tartrate unless otherwise specified.

[0029] The compositions of this disclosure are typically provided as aqueous eye drops. The compositions of this disclosure may be slightly yellowish-green to yellowish-green and clear. The compositions of this disclosure may be provided at a pH of 6.7 to 7.5. The osmotic pressure ratio of the compositions of this disclosure to physiological saline may be about 1. The compositions of this disclosure may be used in glaucoma and ocular hypertension when other glaucoma treatments are ineffective or unsuitable. The compositions of this disclosure may also be considered when other glaucoma treatments, such as prostaglandin-related drugs and / or beta-blockers, are ineffective or unsuitable due to side effects. The compositions of this disclosure may be provided as eye drops, for example, typically one drop twice daily, but are not limited to this.

[0030] In some embodiments, administering the composition of this disclosure to patients whose pre-administration intraocular pressure is less than 18 mmHg, for example, 14 mmHg or more and less than 18 mmHg, more preferably 16 mmHg or more and less than 18 mmHg, is expected to yield a higher therapeutic effect (i.e., an intraocular pressure-lowering effect). The composition of this disclosure can be administered to patients whose treatment with prostaglandin-related drugs is insufficient. Indicators of insufficient treatment with prostaglandin-related drugs are usually when the deterioration of optic nerve head findings, visual field findings, etc., is not suppressed, or when the rate of intraocular pressure reduction from the untreated intraocular pressure is small. Furthermore, such patients may be those who have been administered prostaglandin-related drugs for 30 days or more, 45 days or more, 60 days or more, 75 days or more, 90 days or more, 105 days or more, or 120 days or more. It takes approximately 90 days to determine whether a prostaglandin-related drug is effective, and these patients are typically those who have been administered for 90 days or more.

[0031] In some embodiments, one indicator of insufficient therapeutic effect of prostaglandin-related drugs may be a 0-hour (8:30-10:30) intraocular pressure value of 18.0 mmHg or higher on the day the patient starts administration of the second-line drug. To determine that the therapeutic effect of prostaglandin-related drugs is insufficient, patients may be selected whose 0-hour value was 18.0 mmHg or higher on at least one day between 1 and 28 days prior to the start of administration of the second-line drug. Alternatively, patients may be those who, at at least one day between 1 and 28 days prior to the start of administration, have been administered only prostaglandin-related drugs for at least one week, at least two weeks, at least three weeks, or at least four weeks, and have not been administered any other glaucoma medications.

[0032] In some embodiments, the pre-administration intraocular pressure may be daytime intraocular pressure (for example, intraocular pressure measured between 10:00 and 13:00, more specifically between 10:30 and 12:30).

[0033] Normal intraocular pressure refers to intraocular pressure measured routinely, in addition to pre-administration intraocular pressure, and is typically measured between 8:00 and 11:00, or more specifically, between 8:30 and 10:30. Normal intraocular pressure may also be measured approximately 1.5 hours, 2 hours, or 2.5 hours before the pre-administration intraocular pressure measurement. In certain embodiments, normal intraocular pressure may be measured approximately 2 hours before the pre-administration intraocular pressure measurement. For example, the 0-hour value in the examples described later is an example.

[0034] In some embodiments, the compositions of the present disclosure may be administered together with a prostaglandin-related drug. In some embodiments, the compositions of the present disclosure are not used in combination with other glaucoma treatments other than prostaglandin-related drugs. Examples of prostaglandin-related drugs include, but are not limited to, formulations containing latanoprost as the active ingredient, formulations containing travoprost as the active ingredient, formulations containing tafluprost as the active ingredient, and formulations containing isopropylunoprostone as the active ingredient. In some embodiments, the prostaglandin-related drug is preferably a formulation containing latanoprost as the active ingredient, a formulation containing travoprost as the active ingredient, or a formulation containing tafluprost as the active ingredient.

[0035] In some embodiments, the compositions of the Disclosure may be administered to a patient for at least two weeks, at least three weeks, at least four weeks, at least five weeks, at least six hours, at least seven weeks, or at least eight weeks. In certain embodiments, the compositions of the Disclosure may be administered to a patient for at least four weeks. Typically, the effects of an α2 receptor agonist may be evaluable after about four weeks.

[0036] In some embodiments, the compositions of the Disclosure may reduce a patient's intraocular pressure by approximately 5% or more, approximately 10% or more, approximately 15% or more, or approximately 20% or more, as evaluated by the rate of reduction in intraocular pressure. In other embodiments, the compositions of the Disclosure may reduce a patient's intraocular pressure by more than 0% but less than 10%, 10% or more but less than 20%, or 20% or more, as evaluated by the rate of reduction in intraocular pressure. In glaucoma treatment, 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 1 mmHg reduction in intraocular pressure reduces the risk of progression of visual field defects by 10%. Furthermore, in glaucoma treatment, it is recommended to set a target for the percentage reduction in intraocular pressure from the untreated intraocular pressure, with 20% or more being considered a target (Glaucoma Treatment Guidelines (4th edition), Kawase, Kazuhide. Ophthalmology. Vol. 48, No. 6. pp. 871-881 (2006), Akira Aoyama et al., Japanese Journal of Ophthalmology Vol. 54, No. 2. pp. 117-23 (2010) (DOI: 10.1007 / s10384-009-0779-z)). Therefore, in a preferred embodiment, the composition of this disclosure can reduce the patient's intraocular pressure by approximately 20% or more when evaluated by the percentage reduction in intraocular pressure. The percentage reduction in intraocular pressure is given by the following formula: The intraocular pressure reduction rate can be calculated by the formula: Intraocular pressure reduction rate = {(Intraocular pressure value before administration of the composition disclosed - Intraocular pressure value after administration of the composition disclosed for a predetermined period) / Intraocular pressure value before administration of the composition disclosed} × 100. The intraocular pressure value in the formula may be the average of intraocular pressure measured at multiple time points, and is typically the average of the 0-hour and 2-hour values. Therefore, in this case, the intraocular pressure reduction rate can be calculated by: {(average of the 0-hour value on the day administration of the composition of this disclosure is started (intraocular pressure measured between 8:30 and 10:30) and the 2-hour value on the day administration is started (intraocular pressure measured within 2 hours ± 30 minutes after the measurement of the 0-hour value and by 12:30) - average of the 0-hour value on the day of intraocular pressure evaluation after administration of the composition of this disclosure for a predetermined period (intraocular pressure measured between 8:30 and 10:30) and the 2-hour value on the day of intraocular pressure evaluation (intraocular pressure measured within 2 hours ± 30 minutes after the measurement of the 0-hour value and by 12:30)) / average of the 0-hour value on the day administration of the composition of this disclosure is started (intraocular pressure measured between 8:30 and 10:30) and the 2-hour value on the day of intraocular pressure evaluation (intraocular pressure measured within 2 hours ± 30 minutes after the measurement of the 0-hour value and by 12:30)} × 100.

[0037] The date for evaluating intraocular pressure may be at least four weeks after the start of administration (for example, four weeks, two months, three months, six months, one year, or later).

[0038] In another aspect, the present disclosure provides a composition for lowering intraocular pressure in a patient, comprising brimonidine or a pharmaceutically acceptable salt thereof, wherein the patient is receiving a prostaglandin-related drug, the patient's pre-administration intraocular pressure is 16 mmHg or greater and less than 18 mmHg, the composition is administered to the patient as one drop twice daily, the concentration of brimonidine in the composition is about 0.1% w / v, and the composition lowers the patient's intraocular pressure by about 20% or more, as evaluated by the rate of reduction in intraocular pressure.

[0039] In certain embodiments, eye drop administration may be twice a day, in the morning and evening, typically once between 8:30 and 10:30 and once between 20:00 and 22:00, with the initial dose of the composition of this disclosure as a second-line drug being between 20:00 and 22:00 on the day administration begins.

[0040] In a further context, the present disclosure provides a composition for lowering intraocular pressure in a patient, comprising brimonidine or a pharmaceutically acceptable salt thereof, wherein the patient has been administered a prostaglandin-related drug for 90 days or more, the patient's normal intraocular pressure is 18 mmHg or higher, and the normal intraocular pressure is measured between 8:30 and 10:30, the patient's pre-administration intraocular pressure is 16 mmHg or higher and less than 18 mmHg, and the pre-administration intraocular pressure is measured between 10:30 and 12:30, the composition is administered to the patient as eye drops, one drop at a time, twice daily for at least four weeks, the concentration of brimonidine in the composition is approximately 0.1% w / v, and the composition lowers the patient's intraocular pressure by approximately 20% or more, as evaluated by the rate of reduction in intraocular pressure.

[0041] (Methods for predicting treatment effectiveness) In one aspect, the present disclosure provides a method for using pre-administration intraocular pressure in a patient as an indicator of whether treatment with a composition for lowering intraocular pressure containing brimonidine is effective, wherein if the patient's pre-administration intraocular pressure is less than 18 mmHg, the composition is effective in the patient, and the patient is a patient receiving a prostaglandin-related drug.

[0042] In a further context, the present invention provides a method for determining whether a composition for lowering intraocular pressure in patients for whom prostaglandin-related drugs are ineffective can lower the patient's intraocular pressure by approximately 20% or more, using the patient's pre-administration intraocular pressure as an indicator, wherein if the patient's pre-administration intraocular pressure is 16 mmHg or higher and less than 18 mmHg, the intraocular pressure reduction rate in the patient after administration of the composition may be approximately 20% or more.

[0043] In a further context, the present invention provides a method for using the pre-administration intraocular pressure of a patient as an indicator of whether a composition for lowering intraocular pressure in patients for whom prostaglandin-related drugs are insufficiently effective can suppress the onset or progression of visual field defects in the patient, wherein the pre-administration intraocular pressure of the patient is 16 mmHg or higher and less than 18 mmHg, indicating that the composition can suppress the onset or progression of visual field defects in the patient.

[0044] In a further context, the present disclosure provides a method for using a patient's pre-administration intraocular pressure as an indicator of whether treatment with a composition for lowering intraocular pressure in patients for whom prostaglandin-related drugs are insufficiently effective, the method for showing that if the patient's pre-administration intraocular pressure is 16 mmHg or greater and less than 18 mmHg, the composition may be effective in the patient.

[0045] In a further context, the present invention provides a method for using the intraocular pressure of a patient who has been administered a prostaglandin-related drug as a first-line drug for a predetermined period as an indicator of whether or not to select a composition containing brimonidine or a pharmaceutically acceptable salt thereof as a second-line drug, wherein the method shows that if the patient's pre-administration intraocular pressure is 16 mmHg or higher and less than 18 mmHg, the composition may be effective for the patient. Embodiments of this method may appropriately adopt one or more embodiments described in the "Compositions Containing Brimonidine" above.

[0046] The present disclosure has been described above with reference to preferred embodiments for ease of understanding. The present disclosure will now be described based on examples, but the above description and the following examples are provided for illustrative purposes only and not to limit the present disclosure. Accordingly, the scope of the present disclosure is not limited to the embodiments or examples specifically described herein, but is limited only by the claims. [Examples]

[0047] The present disclosure will be described in more detail below based on examples.

[0048] (Example 1: Stratified Analysis) In this example, patients were stratified according to their pre-administration intraocular pressure, and the effectiveness of the eye drop solution disclosed herein (brimonidine-containing eye drop solution) was investigated for each patient group.

[0049] A multicenter, randomized, double-blind, parallel-group comparative study was conducted targeting primary open-angle glaucoma (broad sense) or ocular hypertension. In this study, the intraocular pressure-lowering effect of administering one drop twice daily for four weeks of continuous eye drop administration of brimonidine-containing eye drops (Alphagan eye drops (active ingredient: 0.1% brimonidine, excipients: magnesium chloride, boric acid, borax, carmellose sodium, sodium chlorite, sodium chloride, potassium chloride, calcium chloride hydrate, hydrochloric acid, sodium hydroxide)) in combination with prostaglandin-containing drugs was compared to the base of the eye drops (placebo) as a control. The prostaglandin-containing drugs used were eye drops commercially available in Japan, excluding isopropyl unoprostone, administered once daily.

[0050] The main selection criteria for the subjects were as follows: • Items to confirm when obtaining consent: 1) Patients with primary open-angle glaucoma (broad sense) or ocular hypertension 2) Individuals whose intraocular pressure is 25.0 mmHg or less in both eyes. 3) Persons with corrected visual acuity of 0.5 or higher in both eyes • Things to check on the day of intraocular pressure check: 4) The prescribed washout has been completed. The pre-treatment medication history was reviewed, and if other glaucoma medications other than the PG-related drug being used concomitantly were being used, it was required that the use of those other glaucoma medications be discontinued and that a prescribed period (washout period, at least one week) had elapsed by the time of intraocular pressure check. 5) Individuals who have received treatment with prostaglandin-related drugs for 90 days or more in both eyes. • Items to confirm on the day of intraocular pressure check and on the day of administration initiation: 6) Individuals whose intraocular pressure (IOP) value at 0:00 (8:30-10:30) is 25.0 mmHg or less in both eyes. 7) The intraocular pressure (IOP) value at 0 hours (8:30-10:30) of the eye being evaluated for efficacy must be 18.0 mmHg or higher. Furthermore, the exclusion criteria were as follows: 1) Patients who have an active ophthalmic disease other than glaucoma or ocular hypertension in either eye on the day of administration (e.g., inflammation or infection of the external or internal eye, severe xerophthalmos) 2) Individuals who, at the time of obtaining consent, have a retinal disease in either eye that may progress during the study period (e.g., diabetic retinopathy, retinal detachment, macular disease, retinitis pigmentosa). 3) Individuals who, at the time of obtaining consent, have circulatory problems such as liver impairment, kidney impairment, depression, Raynaud's disease, thromboangiitis obliterans, orthostatic hypotension, cerebrovascular insufficiency, coronary artery insufficiency, or severe cardiovascular disease, and who have been deemed by a physician to be unsuitable for participation in this study. 4) Individuals who have a history of serious side effects from α2 agonists at the time of obtaining consent. The intraocular pressure (IOP) of each subject was measured twice by a physician using a Goldmann applanation tonometer at the measurement points shown in Table 1 below: at the time of screening, on the day of IOP confirmation, on the day of administration initiation, and 2 and 4 weeks after administration. The average of the two measured values ​​was used as the IOP value.

[0051] The control drug used was the base of the eye drop in question (hereinafter referred to as "placebo").

[0052] The subjects received either brimonidine-containing eye drops or a placebo, one drop in each eye twice daily (morning and evening (8:30-10:30 and 20:00-22:00)) for four weeks. On the first day of administration, the drops were administered only at night, and from four weeks onward, only in the morning. Additionally, the morning drops at two and four weeks after administration were administered after measuring intraocular pressure at 0 hours (8:30-10:30) and between 8:30 and 10:30.

[0053] For subjects receiving glaucoma medications other than the PG-related drugs used in combination, a washout period of at least one week was set between the discontinuation date of medication and the date of intraocular pressure check.

[0054] The prostaglandin-related drugs used in combination were latanoprost eye drops, travoprost eye drops, or tafluprost eye drops, administered once daily.

[0055] Concomitant use of glaucoma and ocular hypertension treatments other than PG-related drugs is prohibited from the date of intraocular pressure confirmation throughout the period of administration of this eye drop.

[0056] Furthermore, when using topical eye medications in combination and administering them at the same time as this eye drop, this eye drop should be administered last. The interval between administrations should be at least 5 minutes.

[0057] Furthermore, from the day of intraocular pressure confirmation throughout the trial period, procedures that could affect the evaluation of this eye drop, such as corneal refractive surgery, glaucoma surgery, other intraocular surgery, and contact lens wear, were prohibited. Contact lens wear was prohibited starting one week prior to the day of intraocular pressure confirmation.

[0058] The timing of the tests and observations, which are the measurement points for this test, are summarized in the table below. Notes are provided at the bottom of the table.

[0059] [Table 1]

[0060] *1: Written consent was obtained before the screening was conducted. *2: This was performed between 1 and 28 days after the intraocular pressure was checked. *3: The points for measuring intraocular pressure were as follows. (Day of intraocular pressure check) 0-hour value (8:30-10:30) (Day of administration start) 0-hour value (8:30-10:30), 2-hour value (within 2 hours ± 30 minutes after the measurement of the 0-hour value and up to 12:30) (4 weeks after administration) 0-hour value (before morning instillation of this eye drop and between 8:30 and 10:30), 2-hour value (within 2 hours ± 30 minutes after instillation and up to 12:30) (During screening) Measurements were taken at any time. *4: The fundus examination four weeks after administration was performed after administering the eye drops in the morning.

[0061] (result) The subjects of this stratified analysis were 133 patients in the brimonidine-containing eye drop group and 130 patients in the placebo group. The rate of reduction in intraocular pressure was calculated using the change in intraocular pressure (average of the 0-hour and 2-hour values) after 4 weeks of administration, and the 2-hour value on the start of administration (pre-administration intraocular pressure value) was used as the initial intraocular pressure value for the stratified analysis. The method for calculating the rate of reduction in intraocular pressure is as follows. Intraocular pressure reduction rate = (Average of 0-hour and 2-hour values ​​on the first day of administration - Average of 0-hour and 2-hour values ​​4 weeks after administration) / Average of 0-hour and 2-hour values ​​on the first day of administration * 100 The obtained results were evaluated as follows: (++): intraocular pressure reduction rate ≥ 20%, (+): 20% > intraocular pressure reduction rate ≥ 10%, (±): intraocular pressure reduction rate < 10%. For each initial intraocular pressure value group, the proportion of cases rated (++), (+), and (±) to the total number of cases was calculated, and the results are shown in the table below.

[0062] [Table 2]

[0063] The results showed that brimonidine-containing eye drops had a higher proportion of subjects with an initial intraocular pressure (IOP) of less than 18 mmHg compared to other groups with different IOP values, resulting in a (++) reduction in IOP (≥20%). Brimonidine-containing eye drops were considered particularly effective in the group with an initial IOP of 16 ≤ x < 18 (mmHg). In glaucoma treatment, lowering IOP is known to reduce the risk of visual field defect progression. It has also been reported that a 1 mmHg reduction in IOP reduces the risk of visual field defect progression by 10%. In glaucoma treatment, it is recommended to set the target as the percentage reduction in intraocular pressure from the untreated intraocular pressure, with a target of 20% or more (Glaucoma Treatment Guidelines (4th edition), Kawase, Kazuhide. Ophthalmology. Vol. 48, No. 6. pp. 871-881 (2006), Akira Aoyama et al., Japanese Journal of Ophthalmology Vol. 54, No. 2. pp. 117-23 (2010) (DOI: 10.1007 / s10384-009-0779-z)). In this example, since the percentage reduction in intraocular pressure from the start of administration is shown, the percentage reduction in intraocular pressure from the untreated intraocular pressure is considered to be even greater, and is thought to contribute to reducing the risk of progression of visual field defects.

[0064] Furthermore, when stratified by 0-hour values, no group with a high proportion of patients showing a significant reduction in intraocular pressure was observed.

[0065] In this clinical trial, subjects were selected based on their intraocular pressure (IOP) of 18 mmHg or higher, using the 0-hour value. Stratification of subjects was performed using the 2-hour value on the first day of administration. The reason for subjects showing an IOP of less than 18 mmHg at 2 hours on the first day of administration may be due to diurnal fluctuations in IOP.

[0066] As described above, while the present disclosure has been illustrated using preferred embodiments thereof, it is understood that the scope of this disclosure should be interpreted solely by the claims. Patents, patent applications, and documents cited herein should be incorporated herein by reference as if their contents were specifically described herein. [Industrial applicability]

[0067] A composition for treating glaucoma and / or ocular hypertension is provided. This technology can be used in fields such as pharmaceuticals.

Claims

1. A composition for use in a method to suppress the onset or progression of visual field defects in patients who have shown insufficient response to prostaglandin-related drugs as first-line therapy, including brimonidine or a pharmaceutically acceptable salt thereof, by reducing intraocular pressure by approximately 20% or more as evaluated by the rate of intraocular pressure reduction, wherein the method is: a) A step of diagnosing whether the patient is not adequately affected by prostaglandin-related drugs, b) The step of measuring the patient's intraocular pressure using a Goldmann applanation tonometer, c) When the effect of the prostaglandin-related drug is insufficient and the patient's pre-administration intraocular pressure value on the day of initiation of the second-line drug is 16 mmHg or more and less than 18 mmHg, the step of selecting brimonidine or a pharmaceutically acceptable salt thereof as a second-line drug to be used in combination with the prostaglandin-related drug, and administering the composition to the patient. Includes, The intraocular pressure reduction rate is calculated using the average of the 0-hour value on the day of intraocular pressure evaluation (intraocular pressure measured between 8:30 and 10:30) and the 2-hour value on the day of intraocular pressure evaluation (intraocular pressure measured within 2 hours ± 30 minutes after the measurement of the 0-hour value and by 12:30). The pre-administration intraocular pressure (IOP) value on the day of initiation of the second-line drug is the 2-hour value on the day of initiation of the second-line drug (the IOP value measured within 2 hours ± 30 minutes after the measurement of the 0-hour value on the day of initiation of the second-line drug (IOP measured between 8:30 and 10:30) and by 12:30). The patient's 0-hour blood pressure on the first day of administration of the second-line drug was 18.0 mmHg or higher. The patient's 0-hour value (intraocular pressure measured between 8:30 and 10:30) on at least one day between 1 and 28 days prior to the start of administration of the second-line drug was 18.0 mmHg or higher, and the patient had received only prostaglandin-related drugs for at least one week on at least one day between 1 and 28 days prior to the start of administration, and had not received any other glaucoma medications. The 0-hour value and the 2-hour value were measured using a Goldmann applanation tonometer. The composition is an aqueous eye drop containing an isotonic agent, a buffering agent, a preservative, a pH adjuster, and a solvent. composition.

2. The composition according to claim 1, wherein the prostaglandin-related drug is a formulation comprising an active ingredient selected from the group consisting of latanoprost, travoprost, tafluprost, and isopropylunoprostone.

3. The composition according to claim 1, wherein the patient suffers from glaucoma and / or ocular hypertension.

4. The composition according to any one of claims 1 to 3, characterized in that the composition is administered to the patient for at least four weeks, and the date of evaluation of the intraocular pressure is at least four weeks after the start of administration.

5. The composition according to any one of claims 1 to 4, wherein the brimonidine or a pharmaceutically acceptable salt thereof is brimonidine tartrate.

6. The composition according to any one of claims 1 to 5, wherein the brimonidine or a pharmaceutically acceptable salt thereof is used in combination with brinzolamide or timolol.

7. The composition according to any one of claims 1 to 6, wherein the buffering agent comprises boric acid.

8. The composition according to any one of claims 1 to 7, wherein the concentration of brimonidine in the composition is about 0.1% w / v.

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