Composition for lowering eye pressure in glaucoma patient, containing brimonidine and timolol

Abstract

To provide a composition for lowering an eye pressure in a glaucoma patient.SOLUTION: In one aspect, the present disclosure provides a composition for lowering an eye pressure in a glaucoma patient, containing brimonidine or its pharmaceutically acceptable salt and timolol or its pharmaceutically acceptable salt. The composition of the present disclosure targets a patient of glaucoma. The composition of the present disclosure may be administered to a patient who has been treated with other glaucoma therapeutics but has not shown sufficient treatment effect.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present disclosure relates to compositions and related inventions for lowering intraocular pressure in patients suffering from glaucoma, comprising brimonidine and timolol. [Background technology]

[0002] Prostaglandin analogues and timolol are used as first-line treatments for glaucoma, but there are cases where these treatments are insufficient. Summary of the Invention [Means for solving the problem]

[0003] The present inventors have newly discovered that an eye drop containing timolol and brimonidine exhibits a high intraocular pressure reducing effect in a specific patient group. They have also newly discovered that the eye drop prevents the progression of glaucoma (e.g., prefield glaucoma). In addition, the present disclosure can provide a drug that is effective as a second-choice drug in patients for whom other glaucoma treatment drugs administered as first-choice drugs are ineffective. Thus, the present disclosure provides, for example, the following items. (Item 1) A composition for lowering intraocular pressure in a patient suffering from glaucoma and having normal intraocular pressure, comprising brimonidine or a pharma- ceutically acceptable salt thereof and timolol or a pharma-ceutically acceptable salt thereof. (Item 2) 2. The composition of claim 1, wherein the normal intraocular pressure is less than 21 mmHg. (Item 3) 3. The composition according to item 1 or 2, characterized in that the composition is administered to a patient for whom treatment with a therapeutic drug for glaucoma other than the composition has been ineffective. (Item 4) The composition according to item 3, wherein the other glaucoma therapeutic agent is a single-ingredient agent of a prostaglandin-related drug or a single-ingredient agent of a beta-blocker. (Item 5) The composition according to item 3, wherein the other glaucoma therapeutic agent is a single-ingredient agent of a beta-blocker. (Item 6) The composition according to any one of items 1 to 5, characterized in that the composition is administered as a second-choice drug when the first-choice drug is a single-component β-blocker drug. (Item 7) 6. The composition according to any one of items 3 to 5, wherein the patient has been administered the other glaucoma therapeutic drug for 4 weeks or more. (Item 8) 6. The composition according to any one of items 3 to 5, wherein the pre-administration intraocular pressure of a patient in whom treatment with the other therapeutic glaucoma agent was ineffective is 15 mmHg or more. (Item 9) 9. The composition of claim 8, wherein the pre-administration intraocular pressure value is a 2-hour value during treatment with the other glaucoma therapeutic agent. (Item 10) 10. The composition according to any one of items 1 to 9, wherein the patient is a patient diagnosed with normal tension glaucoma or a patient diagnosed with preperimetric glaucoma and having normal intraocular pressure. (Item 11) 11. The composition according to item 10, wherein the intraocular pressure of the patient diagnosed with normal tension glaucoma or the patient diagnosed with prefield glaucoma and having normal intraocular pressure is less than 21 mmHg. (Item 12) 12. The composition according to any one of items 1 to 11, wherein the patient is a patient diagnosed with preperitoneal glaucoma and has normal intraocular pressure. (Item 13) 13. The composition according to any one of items 1 to 12, characterized in that the composition is administered for at least 28 weeks. (Item 14) 13. The composition according to any one of items 1 to 12, characterized in that the composition is administered for at least 52 weeks. (Item 15) 15. The composition according to any one of items 1 to 14, wherein the brimonidine or a pharma- ceutically acceptable salt thereof is brimonidine tartrate. (Item 16) 16. The composition according to any one of items 1 to 15, wherein the timolol or a pharma- ceutically acceptable salt thereof is timolol maleate. (Item 17) 17. The composition according to any one of items 1 to 16, wherein the concentration of the brimonidine or a pharma- ceutically acceptable salt thereof in the composition is about 0.1 w / v%. (Item 18) 18. The composition according to any one of items 1 to 17, wherein the concentration of the timolol or a pharma- ceutically acceptable salt thereof in the composition is about 0.5 w / v%. (Item 19) 19. The composition according to any one of items 1 to 18, wherein the brimonidine or a pharma- ceutically acceptable salt thereof is brimonidine tartrate, the timolol or a pharma-ceutically acceptable salt thereof is timolol maleate, the brimonidine tartrate has a concentration of about 0.1 w / v%, the timolol maleate has a concentration of about 0.68 w / v%, and the composition further comprises sodium dihydrogen phosphate hydrate, sodium dihydrogen phosphate hydrate, sodium edetate hydrate, benzalkonium chloride, an isotonicity agent, and a pH adjuster. (Item 20) 20. The composition according to any one of items 1 to 19, wherein the composition is an eye drop. (Item 21) The composition according to any one of items 1 to 20, which is administered to the patient in the form of one drop twice a day. Composition. (Item 22) 22. The composition according to any one of items 1 to 21, wherein the composition reduces intraocular pressure by about 20% or more when evaluated by intraocular pressure reduction rate. (Item 23) 23. The composition according to item 22, wherein the intraocular pressure reduction rate is calculated using the 2-hour value on the day of evaluation of intraocular pressure. (Item 24) A composition for preventing or slowing the progression of visual field defects in glaucoma, comprising brimonidine or a pharma- ceutically acceptable salt thereof and timolol or a pharma-ceutically acceptable salt thereof. (Item 25) A composition for inhibiting the progression of visual field abnormalities or preventing the onset of visual field abnormalities, the composition comprising brimonidine or a pharma- ceutical acceptable salt thereof and timolol or a pharma- ceutical acceptable salt thereof, and being administered to a patient diagnosed with pre-perimetric glaucoma and having normal intraocular pressure. (Item 26) 26. The composition according to item 25, wherein the inhibiting the progression of visual field defects or preventing the onset of visual field defects comprises reducing intraocular pressure. (Item 27) 1. A composition for use in a method for lowering intraocular pressure in a patient with prefield glaucoma having normal intraocular pressure, the composition comprising brimonidine, or a pharma- ceutically acceptable salt thereof, and timolol, or a pharma- ceutically acceptable salt thereof. (Item 28) The composition comprises: 1) administering to the patient another glaucoma medication; 2) measuring the 0 hour and 2 hour values ​​of the patient after administration of 1); 3) administering the composition when the 0-hour and 2-hour values ​​of the patient as a result of the measurement in 2) are 15.0 mmHg or more and 31.0 mmHg or less. 25. The composition according to item 24, comprising: (Item 29) 1. A composition for use in a method for lowering intraocular pressure in a patient with normal tension glaucoma, the composition comprising brimonidine, or a pharma- ceutically acceptable salt thereof, and timolol, or a pharma-ceutically acceptable salt thereof. (Item 30) The method comprises the steps of: 1) administering to the patient another glaucoma medication; 2) measuring the 0 hour and 2 hour values ​​of the patient after administration of 1); 3) administering the composition when the 0-hour and 2-hour values ​​of the patient as a result of the measurement in 2) are 15.0 mmHg or more and 31.0 mmHg or less. 30. The composition according to item 29, comprising: (Item 31) A composition comprising brimonidine or a pharma- ceutical acceptable salt thereof and timolol or a pharma-ceutical acceptable salt thereof, the composition being for use in a method for suppressing the onset or progression of visual field impairment in a patient for whom other glaucoma therapeutic agents than the composition as a first-line drug have an insufficient effect, by lowering intraocular pressure by about 20% or more as assessed by an intraocular pressure reduction rate, the method comprising: a) diagnosing whether the patient has normal tension glaucoma; b) administering another glaucoma medication as a first-line treatment; 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 normal tension glaucoma, selecting a composition containing brimonidine or a pharma- ceutically acceptable salt thereof and timolol or a pharma- ceutically acceptable salt thereof as a second-line drug in place of or in combination with the other glaucoma therapeutic drugs, and administering the composition to the patient; Including, The intraocular pressure reduction rate is calculated using the 2-hour value on the day of evaluation of intraocular pressure, The patient with normal tension glaucoma is (1) The presence of glaucomatous visual field abnormalities as measured by perimeter; (2) the presence of a glaucomatous optic disc on fundus examination; and (3) No history of intraocular pressure of 21.0 mmHg or higher measured using a Goldmann applanation tonometer before administration of other glaucoma medications The composition is a patient who satisfies the above. (Item 32) A composition for use in a method for inhibiting the progression of visual field abnormalities or preventing the onset of visual field abnormalities in a patient for whom other therapeutic glaucoma drugs as first-line drugs are insufficient, comprising brimonidine or a pharma- ceutical acceptable salt thereof and timolol or a pharma-ceutical acceptable salt thereof, by reducing intraocular pressure by about 20% or more as assessed by an intraocular pressure reduction rate, said method comprising: a) diagnosing whether the patient has prefield glaucoma and normal intraocular pressure; b) administering another glaucoma medication as a first-line treatment; 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 prefield glaucoma and normal intraocular pressure, selecting a composition containing brimonidine or a pharma- ceutically acceptable salt thereof and timolol or a pharma- ceutically acceptable salt thereof as a second-choice drug instead of the other glaucoma therapeutic drugs or as a concomitant drug with the other glaucoma therapeutic drugs, and administering the composition to the patient; Including, The intraocular pressure reduction rate is calculated using the 2-hour value on the day of evaluation of intraocular pressure, The patient with normal tension glaucoma is (1) absence of glaucomatous visual field abnormalities as measured by perimeter; (2) the presence of a glaucomatous optic disc on fundus examination; and (3) No history of intraocular pressure of 21.0 mmHg or higher measured using a Goldmann applanation tonometer before administration of other glaucoma medications The composition is a patient who satisfies the above. (Item 33) 33. The composition according to item 31 or 32, wherein the other glaucoma therapeutic agent is a prostaglandin-related drug single component agent or a beta-blocker single component agent. (Item 34) 34. The composition according to any one of items 31 to 33, wherein the other glaucoma therapeutic agent is a β-blocker single component agent. (Item 35) A multiple-component preparation comprising brimonidine or a pharma- ceutical acceptable salt thereof and timolol 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 as a first-line drug have an insufficient effect, by lowering intraocular pressure by about 20% or more as assessed by an intraocular pressure reduction rate, said method comprising: a) diagnosing whether the patient has normal tension glaucoma; b) administering another glaucoma medication as a first-line treatment; 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 normal tension glaucoma, selecting a composition containing brimonidine or a pharma- ceutically acceptable salt thereof and timolol or a pharma- ceutically acceptable salt thereof as a second-line drug in place of or in combination with the other glaucoma therapeutic drugs, and administering the multiple-component preparation to the patient; Including, Multi-ingredient agent. (Item 36) Item 36. The multiple component agent according to item 35, which is a combination drug.

[0004] It is contemplated that the present disclosure may provide one or more of the above features in combinations other than those specifically described. Further embodiments and advantages of the present disclosure will be recognized by those skilled in the art upon reading and understanding the following detailed description, if necessary. Effect of the Invention

[0005] According to the present disclosure, a composition comprising brimonidine and timolol is provided, which exhibits a high intraocular pressure reducing effect in a specific patient group. Also, according to the present disclosure, a composition comprising brimonidine and timolol is provided, which prevents the progression of glaucoma (e.g., prefield glaucoma). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0006] The present disclosure will be described below. Throughout this specification, the singular expression should be understood to include the concept of the plural form, unless otherwise specified. Thus, the singular article (e.g., in the case of English, "a", "an", "the", etc.) should be understood to include the concept of the plural form, unless otherwise specified. In addition, the terms used in this specification should be understood to be used in the sense commonly used in the art, unless otherwise specified. Therefore, unless otherwise defined, all technical terms and scientific and technical terms used in this specification have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. In the case of conflict, the present specification (including definitions) will take precedence. In this specification, "about" means ±10% of the value that follows. In this specification, the time is displayed in 24-hour format unless otherwise specified.

[0007] (definition) As used herein, "brimonidine" refers to a compound of the formula

[0008] [ka] Brimonidine or its pharma- ceutical acceptable salts are used as pharmaceutical ingredients, and a representative example is brimonidine tartrate (chemical name 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)quinoxalin-6-amine). Brimonidine or its pharma- ceutical acceptable salts are available commercially. Brimonidine and its pharmaceutical acceptable salts are a selective adrenergic α2 receptor agonist, and are marketed as an active ingredient in eye drops. Brimonidine and its pharmaceutical acceptable salts are commercially available. Pharmaceutically acceptable salts of brimonidine include, but are not limited to, tartrate, hydrochloride, or acetate. As eye drops, it is used to treat glaucoma and ocular hypertension, and as a liniment, it is also used to treat skin redness in rosacea. Brimonidine is used to lower intraocular pressure in patients with (open angle) glaucoma or ocular hypertension.

[0009] As used herein, "timolol" refers to a compound represented by the following formula:

[0010] [ka] Timolol or its pharmaceutically acceptable salts are used as pharmaceutical ingredients, and are typically provided as timolol maleate (chemical name (2S)-1-[(1,1-dimethylethyl)amino]-3-(4-morpholin-4-yl-1,2,5-thiadiazol-3-yloxy)propan-2-ol maleate). Timolol or its pharmaceutically acceptable salts are non-selective β-blockers, and are used as eye drops to treat glaucoma by suppressing aqueous humor production and lowering intraocular pressure. Timolol and its pharmaceutically acceptable salts are commercially available. Pharmaceutically acceptable salts of timolol include, but are not limited to, maleate, hydrochloride, and acetate.

[0011] In general, "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)"), which includes primary glaucoma, secondary glaucoma, and pediatric glaucoma. Primary glaucoma includes primary open-angle glaucoma (broad sense) and primary angle-closure glaucoma, and primary open-angle glaucoma (broad sense) includes primary open-angle glaucoma and normal tension glaucoma. In this specification, normal tension glaucoma refers to a case where glaucomatous visual field abnormalities are observed and the intraocular pressure is normal (e.g., less than 21 mmHg). In addition, in this specification, preperipheral glaucoma refers to a case where no visual field abnormalities are observed. It is classified into "prefield glaucoma (high intraocular pressure)", in which glaucomatous structural abnormalities and high intraocular pressure (e.g., 21 mmHg or higher) are present, but not in the prefield glaucoma setting, and "prefield glaucoma (normal intraocular pressure)", in which only glaucomatous structural abnormalities are present. In other words, patients with "prefield glaucoma (high intraocular pressure)" are patients who have been diagnosed with prefield glaucoma and who have high intraocular pressure, while patients with "prefield glaucoma (normal intraocular pressure)" are patients who have been diagnosed with prefield glaucoma and who have normal intraocular pressure. Secondary glaucoma includes secondary open-angle glaucoma and secondary angle-closure glaucoma, and is associated with childhood glaucoma. These include primary congenital glaucoma, juvenile open-angle glaucoma, and glaucoma associated with congenital ocular malformations and congenital systemic diseases.

[0012] In this specification, "glaucomatous structural abnormality" refers to structural abnormality of the eye specific to glaucoma, which is mainly caused by increased intraocular pressure. Glaucomatous structural abnormality includes abnormalities suggestive of glaucoma, such as glaucomatous optic disc and retinal nerve fiber layer defects, and such abnormalities can be confirmed by fundus examination. Fundus examination can be performed by fundus photography or optical coherence tomography (OTC). In this specification, "glaucomatous optic disc" refers to, for example, an enlarged optic disc cupping, which can be measured by any method known in the art (Guidelines for the Treatment of Glaucoma (4th Edition)).

[0013] In this specification, the term "visual field abnormality" refers to glaucomatous visual field abnormality, which is a visual field defect observed in a normal automated static visual field test. A normal automated static visual field test can be measured using a perimeter such as a Humphrey perimeter or an Octopus perimeter. (Glaucoma Treatment Guidelines (4th Edition)).

[0014] In the present specification, the term "pre-administration intraocular pressure" refers to intraocular pressure before the start of treatment with the target drug, and refers to intraocular pressure measured on the day when the administration of the target drug is started (administration start date) and before the drug is administered (usually within 12 hours before), and this value is referred to as the "pre-administration intraocular pressure value." In one preferred embodiment, it refers to the morning or daytime intraocular pressure on the day when the administration of the composition of the present disclosure is started. For example, the value at 0 hours or 2 hours in the examples described below can be mentioned, but is not limited thereto, 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 the administration of the drug.

[0015] 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), and the "2 hour value" of the administration start date, evaluation date, etc. refers to the intraocular pressure value measured within 2 hours ± 30 minutes after instillation in the morning of the target day (e.g., administration start date, evaluation date) and by 12:30. In addition, in the morning of the administration start date, another glaucoma therapeutic drug is instilled, and in the morning of the evaluation date, the target drug (the composition of the present disclosure) is instilled instead of the other glaucoma therapeutic 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" and the "2 hour value" are used in the art to indicate a certain value for the intraocular pressure of a patient, and are used as values ​​sufficient to identify the patient.

[0016] In the present specification, the term "evaluation date" refers to the date on which intraocular pressure is evaluated. Any date may be applicable, but for example, the period of about 4 weeks, about 12 weeks, about 3 months, about 6 months, about 28 weeks, about 52 weeks, about 1 year, about 3 years, etc. from the start date of administration may be the target.

[0017] As used herein, the term "intraocular pressure reduction rate" refers to the rate of change in intraocular pressure in the same patient, as compared between the intraocular pressure on the evaluation date, which is the subject of evaluation, and the intraocular pressure on the administration start date, which is the evaluation standard. In the present disclosure, the intraocular pressure reduction rate is typically calculated using the 2-hour value on the evaluation date of intraocular pressure.

[0018] As used herein, the term "single-ingredient preparation" 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 ingredients. Thus, a single-ingredient preparation of a β-blocker refers to a formulation that contains only a β-blocker as an active ingredient and is provided assuming administration of only the β-blocker. On the other hand, as used herein, a "multiple-ingredient preparation" 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-ingredient preparation may be provided in a form in which each active ingredient is present in the same preparation (also referred to as a "combination preparation" in the present specification), and each active ingredient may be administered in combination with an additional active ingredient. The agent may be provided in a form present in another formulation, or in combination. Thus, the agent for duplicated components also includes a dosage form that is formulated as a single-component agent, but is provided with a specific use to be administered in combination with another active ingredient. Thus, the agent for multiple components also includes a formulation that contains a first active ingredient such as a β-blocker as an active ingredient, and further contains an additional active ingredient such as a prostaglandin-related drug, or a formulation that is administered in combination with a separate formulation that contains an additional active ingredient. In this specification, for example, the present disclosure includes an embodiment that is a pharmaceutical agent containing a prostaglandin-related drug and is provided in combination with a pharmaceutical agent containing a β-blocker, and an embodiment that is a pharmaceutical agent containing a β-blocker and is provided in combination with a pharmaceutical agent containing a prostaglandin-related drug.

[0019] As used herein, the term "combination drug" refers to a drug that contains a main active ingredient and an additional active ingredient in the same formulation for the purpose of exerting a medicinal effect, for example, a formulation that contains multiple active ingredients with different or the same mechanism of action in the same formulation for reducing intraocular pressure in glaucoma. As used herein, the combination drug may be used in combination with other glaucoma treatment drugs (whether as a single drug or a combination drug) at the same time or at different times.

[0020] As used herein, the term "prostaglandin-related drug" refers to a prostaglandin or a prostaglandin analogue that exhibits an action equivalent to that of a prostaglandin, or a pharmaceutical containing a pharma- ceutically acceptable salt thereof. Prostaglandin-related drugs are applied to glaucoma as an alternative route (via the uveoscleral flow) by promoting the outflow of aqueous humor. Examples of prostaglandin-related drugs include, but are not limited to, prostaglandin F, such as latanoprost, travoprost, and tafluprost. 2α Derivatives and prostamide derivatives are examples of such compounds.

[0021] In this specification, the terms "eye drops" and "ophthalmic solution" are used interchangeably and have the same meaning as commonly used in the art. These are also commonly known as "eye drops" and are liquid medicines that are administered directly to the eye.

[0022] In this specification, the term "instructions" refers to a description of how to use the present disclosure for the user, and is referred to as a "package insert" in Japan and a label in the United States and other countries. The instructions contain text instructing 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 in Japan, the Food and Drug Administration (FDA) 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, for example, electronic media (e.g., a homepage provided on the Internet, e-mail).

[0023] 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 no improvement is seen after administration of the first-line drug, a second-line drug that prioritizes effectiveness while taking into account other mechanisms of action is administered. For glaucoma, prostaglandin-related drugs and beta-blockers are administered as first-line drugs.

[0024] In this specification, the term "second-line drug" (also called second choice) refers to a drug that is used next when no improvement is seen after administration of the first-line drug, 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 and alpha-adrenergic receptor antagonists. 2 Receptor agonists, ROCK inhibitors, α 1 There are various types of drugs, such as receptor blockers, nonselective sympathomimetics, parasympathomimetics, combinations of first-line and second-line drugs, and combinations of two second-line drugs. Each type has different effects and is suitable for different patients, so Appropriate choice of medication is important in the proper treatment of glaucoma. Second-line medications may be used in combination with other glaucoma medications, including first-line medications.

[0025] (Preferred embodiment) Preferred embodiments of the present disclosure are described below. The embodiments provided below are provided for a better understanding of the present disclosure, and it is understood that the scope of the present disclosure should not be limited to the following description. Therefore, it is clear that a person skilled in the art can make appropriate modifications within the scope of the present disclosure in light of the description in this specification. It is also understood that the following embodiments can be used alone or in combination.

[0026] (composition) In one aspect, the present disclosure can be provided as a composition (i.e., a combination drug) for treating or preventing glaucoma, typically for lowering intraocular pressure in patients with glaucoma, comprising brimonidine or its pharmaceutically acceptable salt and timolol or its pharmaceutically acceptable salt.Unexpectedly, the composition of the present disclosure is more effective in patients with glaucoma who have normal intraocular pressure.Therefore, in some embodiments, the composition of the present disclosure can be administered to patients with glaucoma who have normal intraocular pressure.

[0027] Without wishing to be bound by theory, when administered as separate preparations, the active ingredient of the preparation administered earlier may be washed away by the preparation administered later (wash-off effect), and may reduce efficacy.Therefore, when administered as separate preparations, it is usually necessary to administer them at intervals of several minutes, which is a burden for patients.The composition (i.e., combination drug) comprising brimonidine or its pharmaceutically acceptable salt and timolol or its pharmaceutically acceptable salt of the present disclosure is advantageous because it does not cause a decrease in efficacy due to wash-off effect, and does not require the burden of administering them at intervals.

[0028] In some embodiments, normal intraocular pressure may be less than 21 mmHg.

[0029] In one embodiment, the composition of the present disclosure is provided as eye drops, eye ointments, etc., preferably as eye drops. When the two components are provided separately, they may be provided in the same dosage form or in different dosage forms.

[0030] The composition of the present disclosure may contain, for example, an isotonicity agent, a buffer, a viscosity agent, a preservative, a pH adjuster, or a solvent that may be generally used in ophthalmic compositions (particularly aqueous eye drops). More specifically, it may contain one or more additive components such as sodium hydrogen phosphate hydrate, sodium dihydrogen phosphate hydrate, sodium edetate hydrate, benzalkonium chloride, an isotonicity agent, or a pH adjuster. In the composition of the present disclosure, brimonidine or a pharma- ceutically acceptable salt thereof is not particularly limited and may be appropriately set according to the degree of symptoms of the patient to be applied, the amount applied per time, etc., and may be, for example, about 0.05 to about 0.2 w / v%, preferably about 0.1 to about 0.2 w / v%, particularly preferably about 0.1 w / v%. In the composition of the present disclosure, the amount of timolol or its pharma- ceutically acceptable salt is not particularly limited, and may be appropriately set according to the degree of symptoms of the patient to be treated, the amount to be applied per dose, etc., and may be, for example, about 0.25 to about 1.0 w / v%, preferably about 0.5 to about 1.0 w / v%, and particularly preferably about 0.5 w / v%. In this specification, a reference to the content or concentration of brimonidine or a pharma-ceutically acceptable salt thereof means the content or concentration converted into brimonidine tartrate, unless otherwise specified. In this specification, a reference to the content or concentration of timolol or a pharma-ceutically acceptable salt thereof means the content or concentration converted into timolol (without salt), unless otherwise specified. For example, about 0.5 w / v% of timolol is equivalent to 0.68 w / v% of timolol maleate.

[0031] In one embodiment, the following additives may be added to the compositions of the present disclosure: The composition of the present disclosure preferably contains phosphoric acid and / or its salt at a concentration of about 32 mM or less. The phosphoric acid salt is not particularly limited as long as it is pharma- ceutically acceptable, and examples thereof include dialkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; alkali metal dihydrogen phosphates such as sodium dihydrogen phosphate and potassium dihydrogen phosphate; and trialkali metal phosphates such as trisodium phosphate and tripotassium phosphate. The phosphoric acid salt may be in the form of a solvate such as a hydrate, for example, in the case of disodium hydrogen phosphate, it may be in the form of a dodecahydrate, and in the case of sodium dihydrogen phosphate, it may be in the form of a dihydrate. In the present invention, one of phosphoric acid and its salts may be selected and used alone, or two or more of them may be used in combination.

[0032] Among phosphoric acid and its salts, a combination of a dialkali metal hydrogen phosphate and an alkali metal dihydrogen phosphate is preferred, and a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate is more preferred. When a dialkali metal hydrogen phosphate and an alkali metal dihydrogen phosphate are used in combination, the ratio is not particularly limited, but for example, the alkali metal dihydrogen phosphate is about 0.005 to about 1.0 mol per 1 mol of the dialkali metal hydrogen phosphate. From the viewpoint of further stabilizing the pH, the ratio is preferably about 0.01 to about 0.4 mol, more preferably about 0.05 to about 0.5 mol, and particularly preferably about 0.26 mol.

[0033] In the composition of the present disclosure, the concentration of phosphoric acid and / or a salt thereof is set to about 32 mM or less, preferably about 16 mM or less, more preferably about 13 mM or less, and particularly preferably about 6.3 mM or less. The lower limit of the concentration of phosphoric acid and / or a salt thereof is not particularly limited, but may be, for example, about 0.01 mM or more, preferably about 0.3 mM or more, more preferably about 3.2 mM or more, and particularly preferably about 6.3 mM or more. The specific range of the concentration of phosphoric acid and / or a salt thereof is, for example, about 0.01 to 32 mM, preferably about 0.3 to about 32 mM, more preferably about 0.3 to about 16 mM, and particularly preferably about 0.3 to about 6.3 mM.

[0034] The composition of the present disclosure may contain edetic acid and / or its salt in addition to the above-mentioned components. The salt of edetic acid is not particularly limited as long as it is pharma- ceutically acceptable, and may include, for example, sodium salt of edetic acid such as monosodium edetate, disodium edetate (EDTA), and tetrasodium edetate. The salt of edetic acid may also be in the form of a solvate such as a hydrate such as a dihydrate.

[0035] When edetic acid and / or a salt thereof is contained in the composition of the present invention, one kind selected from edetic acid and its salts may be used alone or two or more kinds may be used in combination. Preferred is a salt of edetic acid, and more preferred is disodium edetate (EDTA).

[0036] When edetic acid and / or a salt thereof is contained in the composition of the present disclosure, the concentration thereof is, for example, about 0.0001 to about 0.2 w / v%, preferably about 0.001 to about 0.03 w / v%, more preferably about 0.005 to about 0.015 w / v%, and particularly preferably about 0.01 w / v%. In the present specification, the concentration of edetic acid and / or a salt thereof means the concentration converted into edetate disodium dihydrate.

[0037] In addition to the above-mentioned components, the composition of the present disclosure may contain additives such as an isotonicity agent, a polyhydric alcohol, a surfactant, a viscosity agent, a buffering agent (other than phosphoric acid and its salts), a chelating agent (other than edetic acid and its salts), a cooling agent, a preservative, a stabilizer, and a pH adjuster, as necessary.

[0038] The isotonicity agent is not particularly limited as long as it is pharma- ceutically acceptable, and examples thereof include polyhydric alcohols such as glycerin, propylene glycol, butylene glycol, and polyethylene glycol; and metal salts such as sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium acetate, potassium acetate, sodium hydrogen sulfite, sodium hydrogen carbonate, sodium carbonate, disodium hydrogen phosphate, and sodium dihydrogen phosphate. These isotonicity agents may be used alone or in combination of two or more.

[0039] The polyhydric alcohol is not particularly limited as long as it is pharma- ceutically acceptable, and examples thereof include propylene glycol, butylene glycol, polyethylene glycol, glycerin, etc. These polyhydric alcohols may be used alone or in combination of two or more.

[0040] The surfactant is not particularly limited as long as it is pharma- ceutically acceptable, 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.

[0041] The thickening agent is not particularly limited as long as it is pharma- ceutically acceptable, and examples thereof include water-soluble polymers such as carboxyvinyl polymer, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, xanthan gum, sodium chondroitin sulfate, and sodium hyaluronate; celluloses such as hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, and sodium carboxymethyl cellulose. These thickening agents may be used alone or in combination of two or more.

[0042] The buffering agent (other than phosphoric acid and its salts) is not particularly limited as long as it is pharma- ceutically acceptable, and examples thereof include borate buffering agents, citrate buffering agents, tartrate buffering agents, acetate buffering agents, Tris buffering agents, amino acids, etc. These buffering agents may be used alone or in combination of two or more. In the ophthalmic composition of the present invention, since a buffering effect is imparted by the inclusion of phosphoric acid and / or a salt thereof, it is not necessary to use a buffering agent other than phosphoric acid and its salts. The desired buffering effect can be achieved without the incorporation of any of these ingredients.

[0043] The chelating agent (other than edetic acid and its salts) is not particularly limited as long as it is pharma- ceutically acceptable, and examples thereof include citric acid and its salts. These chelating agents may be used alone or in combination of two or more. When edetic acid and / or its salts are contained in the ophthalmic composition of the present invention, a chelating effect is also imparted, so that the desired chelating effect can be achieved without blending a chelating agent other than edetic acid and its salts. It can be used for various purposes.

[0044] The cooling agent is not particularly limited as long as it is pharma- ceutically acceptable, and examples thereof include 1-menthol, borneol, camphor, eucalyptus oil, and the like. The curing agent may be used alone or in combination of two or more kinds.

[0045] The preservative is not particularly limited as long as it is pharma- ceutically acceptable, and examples thereof include sorbic acid or its salts, benzoic acid or its salts, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, chlorhexidine gluconate, chlorhexidine hydrochloride, chlorhexidine acetate, boric acid or its salts, dehydroacetic acid or its salts, benzalkonium chloride, benzalkonium bromide, benzethonium chloride, benzyl alcohol, zinc chloride, parachlorometaxylenol, chlorcresol, phenethyl alcohol, polidronium chloride, thimerosal, dibutylhydroxytoluene, etc. These preservatives may be used alone or in combination of two or more. Among these, benzalkonium chloride is particularly preferred because it increases the permeability of the preparation as well as its preservative effect.

[0046] The concentration of the preservative can be appropriately varied depending on the type of preservative, and may be, for example, about 0.0001 to about 0.1 w / v%, preferably about 0.0005 to about 0.05 w / v%, more preferably about 0.001 to about 0.05 w / v%, and particularly preferably about 0.002 w / v%.

[0047] The stabilizer is not particularly limited as long as it is pharma- ceutically acceptable, and examples thereof include polyvinylpyrrolidone, sulfite, monoethanolamine, cyclodextrin, dextran, ascorbic acid, taurine, tocopherol, dibutylhydroxytoluene, etc. These stabilizers may be used alone or in combination of two or more.

[0048] The pH regulator is not particularly limited as long as it is pharma- ceutically acceptable, and examples thereof include acids such as hydrochloric acid, acetic acid, boric acid, aminoethylsulfonic acid, epsilon-aminocaproic acid, etc., and alkalis such as sodium hydroxide, potassium hydroxide, borax, triethanolamine, monoethanolamine, sodium bicarbonate, sodium carbonate, etc. These pH regulators may be used alone or in combination of two or more.

[0049] The concentrations of these additives may be appropriately determined depending on the types of additives used and the properties to be imparted to the ophthalmic composition.

[0050] The composition of the present disclosure is typically provided as an aqueous eye drop. The composition of the present disclosure may be clear, light greenish yellow to greenish yellow. The composition of the present disclosure may be provided at a pH of 6.9 to 7.3. The osmolality ratio of the composition of the present disclosure to physiological saline may be about 0.9 to about 1.1. The composition of the present disclosure may be provided as an eye drop, and may be administered, for example, one drop at a time, twice a day, but is not limited thereto. Preferably, the composition of the present disclosure may be administered in the morning and evening (9:00±1 hour and 21:00±1 hour).

[0051] The patient for whom the composition of the present disclosure is intended is a patient suffering from glaucoma. In some embodiments, the patient for whom the composition of the present disclosure is intended may have primary glaucoma, preferably primary open-angle glaucoma (broad definition). The present inventors have found that the therapeutic effect of the composition of the present disclosure is superior to that of a group of patients suffering from primary open-angle glaucoma. In certain embodiments, the patient to be treated with the composition of the present disclosure may be a patient in whom glaucomatous structural abnormalities are observed. Examples of glaucomatous structural abnormalities include, but are not limited to, the presence of a glaucomatous optic disc and defects in the retinal nerve fiber layer. For example, changes such as thinning of the retinal nerve fibers are also findings suggesting defects in the retinal nerve fiber layer. In certain embodiments, the patient to be treated with the composition of the present disclosure may be a patient with normal tension glaucoma or a patient with frontal field glaucoma with normal intraocular pressure. Typically, a patient with normal tension glaucoma or a frontal field glaucoma with normal intraocular pressure may have a glaucomatous structural abnormality. Patients with glaucoma have no history of intraocular pressure of 21 mmHg or higher. Intraocular pressure can be measured using a standard tonometer, such as an applanation tonometer or a rebound tonometer (Glaucoma Clinical Practice Guidelines (4th edition)).

[0052] A normal tension glaucoma patient is a patient who satisfies the following criteria: (1) the presence of glaucomatous visual field abnormality, (2) the presence of glaucomatous optic disc, and (3) no history of past intraocular pressure measurements (e.g., intraocular pressure measured using a Goldmann applanation tonometer) of 21.0 mmHg or higher. See Example 1 for the diagnosis of (1) to (3).

[0053] A patient with normal intraocular pressure and prefield glaucoma is one who meets the following criteria: (1) no glaucomatous visual field abnormality, (2) the presence of a glaucomatous optic disc, and (3) no history of intraocular pressure values ​​(e.g., intraocular pressure values ​​measured using a Goldmann applanation tonometer) of 21.0 mmHg or higher. See Example 1 for the diagnosis of (1) to (3).

[0054] The composition of the present disclosure can unexpectedly reduce intraocular pressure in glaucoma patients with normal intraocular pressure.In addition, the composition of the present disclosure is effective in prefield glaucoma, which is glaucoma without glaucomatous visual field abnormality, and can prevent the onset of glaucomatous visual field abnormality, which is excellent.In particular, it was a surprising discovery that the composition of the present disclosure shows a high intraocular pressure reduction rate in prefield glaucoma patients with normal intraocular pressure.

[0055] In some embodiments, the composition of the present disclosure can be administered to patients who have not been sufficiently treated with other glaucoma therapeutic drugs other than the composition of the present disclosure.Other glaucoma therapeutic drugs refer to glaucoma therapeutic drugs other than the composition of the present disclosure, and include, but are not limited to, β-blockers, α-receptor agonists, prostaglandin-related drugs, carbonic anhydrase inhibitors, ROCK inhibitors, selective EP2 receptor agonists, or combinations thereof.Beta-blockers include, but are not limited to, timolol, levobunolol, betaxolol, nipradilol, or pharma- ceutically acceptable salts thereof.Prostaglandin-related drugs include prostaglandin F such as latanoprost, travoprost, and tafluprost. 2α Derivatives, prostamide derivatives, etc. are included, but are not limited to these. Carbonic anhydrase inhibitors include, but are not limited to, dorzolamide, brinzolamide, and ROCK inhibitors include, but are not limited to, ripasudil. Selective EP2 receptor agonists include, but are not limited to, omidenepag isopropyl.

[0056] 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 second-line medication. In some embodiments, the first-line medication may be a single-component agent, and the composition of the present disclosure may be a combination agent and administered as a second-line medication.

[0057] In some embodiments, the other glaucoma therapeutic agent may be a prostaglandin-related drug single component agent or a beta-blocker single component agent. In some embodiments, the other glaucoma therapeutic agent may be a beta-blocker single component agent. In certain embodiments, the other glaucoma therapeutic agent may be timolol or a pharma- ceutically acceptable salt thereof.

[0058] As an indicator of insufficient therapeutic effect of other glaucoma therapeutic drugs, an intraocular pressure of 15 mmHg or more after treatment with other glaucoma therapeutic drugs and before administration of the composition of the present disclosure may be used. Other examples of therapeutic effect include, but are not limited to, optic disc findings, visual field findings, etc. In addition, insufficient effect may be determined when the intraocular pressure reduction rate from untreated intraocular pressure is low (e.g., intraocular pressure reduction rate is less than 10%, or 20%, etc.). In addition, patients who can be treated may be those who have been treated with other glaucoma therapeutic drugs, and those who have been treated with other glaucoma therapeutic drugs .... The patient may have been receiving the drug for 1, 2, 3, 4, 5, 6, 7, or 8 weeks or more. For example, the therapeutic effect of a beta-blocker (e.g., timolol) can typically be determined in about 4 weeks.

[0059] A patient who is treated with the composition of the present disclosure and for whom the therapeutic effect of other glaucoma treatment drugs is insufficient may have a pre-administration intraocular pressure of about 15 mmHg to about 31 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 an intraocular pressure of about 15 mmHg to about 31 mmHg both in the morning (9:00±1 hour) and in the afternoon (within 2 hours±30 minutes after morning instillation and up to 12:30). The intraocular pressure is measured before administration of the composition of the present disclosure. On the day administration is started, administration of the composition of the present disclosure is started after the pre-administration intraocular pressure is measured, that is, later than the afternoon (preferably at night, more specifically at 21:00±1 hour). In a preferred embodiment, a patient who can be treated with the composition of the present disclosure may have an intraocular pressure of about 15 mmHg to about 21 mmHg.

[0060] 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, at least 12 weeks, at least 16 weeks, at least 28 weeks, at least 36 weeks, at least 44 weeks, at least 52 weeks.

[0061] In some embodiments, the composition of the present disclosure can reduce the intraocular pressure of a patient by about 5% or more, about 10% or more, about 15% or more, or about 20% or more when evaluated by the intraocular pressure reduction rate. In another embodiment, the composition of the present disclosure can reduce the intraocular pressure of a patient by more than 0% and less than 10%, 10% or more and less than 20%, or 20% or more when evaluated by the intraocular pressure reduction rate. It is known that reducing intraocular pressure in the treatment of glaucoma leads to a reduction in the risk of visual field abnormality progression. It has also been reported that a reduction of intraocular pressure by 1 mmHg reduces the risk of visual field abnormality progression by 10%. In addition, in the treatment of glaucoma, it is recommended to set a target of intraocular pressure reduction rate from untreated intraocular pressure, with 20% or more being one target (Guidelines for the Treatment of Glaucoma (4th Edition), Kazuhide Kawase, Ophthalmology, Vol. 48, No. 6, p. 871-881 (2006); Akira Aoyama et al., Japanese Journal of Ophthalmology, Vol. 54, No. 2, p. 117-23 (2010) (DOI: 10.1007 / s10384-009-0779-z)). Thus, in a preferred embodiment, the composition of the present disclosure can reduce a patient's intraocular pressure by about 20% or more when evaluated by the intraocular pressure reduction rate.

[0062] The intraocular pressure reduction rate is calculated by the following formula: The intraocular pressure reduction rate can be calculated by: intraocular pressure reduction rate = {(intraocular pressure value before administration of the composition of the present disclosure - intraocular pressure value after administration of the composition of the present disclosure for a predetermined period) / intraocular pressure value before administration of the composition of the present disclosure} x 100. The intraocular pressure value in the formula may be the average value of intraocular pressure measured at multiple time points. In some embodiments, the intraocular pressure value may be a 2-hour value. Therefore, in this case, the intraocular pressure reduction rate can be calculated by: intraocular pressure value (2-hour value) on the start date of administration of the composition of the present disclosure - intraocular pressure value (2-hour value) on the day of evaluation of intraocular pressure after administration of the composition of the present disclosure for a predetermined period} / intraocular pressure value (2-hour value) on the start date of administration of the composition of the present disclosure x 100.

[0063] In a further aspect, the present disclosure provides a composition for preventing or slowing the progression of visual field defects in glaucoma, comprising brimonidine or a pharma- ceutically acceptable salt thereof and timolol or a pharma-ceutically acceptable salt thereof. In some embodiments, a patient with glaucoma may have normal intraocular pressure.

[0064] In a further aspect, the disclosure provides a composition for lowering intraocular pressure in a patient with normal tension glaucoma, the composition comprising brimonidine, or a pharma- ceutically acceptable salt thereof, and timolol, or a pharma-ceutically acceptable salt thereof.

[0065] In some embodiments, a composition of the present disclosure may include the steps of 1) administering to the patient another glaucoma medication; 2) measuring the patient's 0-hour and 2-hour values ​​after administration of 1); and 3) if the patient's 0-hour and 2-hour values ​​as a result of measurement 2) are 15.0 mmHg or greater and 31.0 mmHg or less, administering a composition of the present disclosure.

[0066] In a further aspect, the present disclosure provides a composition for administration to a patient diagnosed with preperitoneal glaucoma to inhibit progression of visual field abnormalities or prevent the onset of visual field abnormalities, the composition comprising brimonidine or a pharma- ceutically acceptable salt thereof and timolol or a pharma-ceutically acceptable salt thereof. In some embodiments, the patient diagnosed with preperitoneal glaucoma may have normal intraocular pressure.

[0067] In a further aspect, the present disclosure may provide a composition for lowering intraocular pressure in a patient with prefield glaucoma having normal intraocular pressure, the composition comprising brimonidine, or a pharma- ceutically acceptable salt thereof, and timolol, or a pharma-ceutically acceptable salt thereof.

[0068] In some embodiments, a composition of the present disclosure may include the steps of 1) administering to the patient another glaucoma medication; 2) measuring the patient's 0-hour and 2-hour values ​​after administration of 1); and 3) if the patient's 0-hour and 2-hour values ​​as a result of measurement 2) are 15.0 mmHg or greater and 31.0 mmHg or less, administering a composition of the present disclosure.

[0069] The active ingredients of the present invention, brimonidine or a pharma- ceutically acceptable salt thereof, and timolol or a pharma- ceutically acceptable salt thereof, may be provided as separate preparations (i.e., a combination agent) and administered in combination.

[0070] Thus, in a further aspect, the present disclosure provides a combination for lowering intraocular pressure in a patient suffering from glaucoma and having normal intraocular pressure, the combination comprising brimonidine, or a pharma- ceutically acceptable salt thereof, and timolol, or a pharma- ceutically acceptable salt thereof.

[0071] In a further aspect, the present disclosure provides a pharmaceutical, such as an eye drop, for lowering intraocular pressure in a patient suffering from glaucoma and having normal intraocular pressure, the pharmaceutical comprising brimonidine or a pharma- ceutical acceptable salt thereof, and administered in combination with timolol or a pharma- ceutical acceptable salt thereof.

[0072] In a further aspect, the present disclosure provides a pharmaceutical, such as an eye drop, for lowering intraocular pressure in a patient suffering from glaucoma and having normal intraocular pressure, the pharmaceutical comprising timolol or a pharma- ceutical acceptable salt thereof, administered in combination with brimonidine or a pharma- ceutical acceptable salt thereof.

[0073] In a further aspect, the present disclosure provides a composition comprising brimonidine or a pharma- ceutically acceptable salt thereof and timolol or a pharma-ceutically acceptable salt thereof, for use in a method for suppressing the onset or progression of visual field impairment in a patient for whom other glaucoma therapeutic agents than the composition as a first-line drug have an insufficient effect, by lowering intraocular pressure by about 20% or more as assessed by an intraocular pressure reduction rate, the method comprising: a) diagnosing whether the patient has normal tension glaucoma; b) administering another glaucoma medication as a first-line treatment; c) diagnosing whether the patient is ineffective in treating with other glaucoma medications; d) measuring the intraocular pressure of the patient; e) Brimo is used in place of or in combination with other glaucoma medications when other glaucoma medications have been ineffective and the patient has normal tension glaucoma. selecting a composition comprising nidin or a pharma- ceutical acceptable salt thereof and timolol or a pharma-ceutical acceptable salt thereof as a second-line drug, and administering the composition to the patient; Including, The intraocular pressure reduction rate is calculated using the 2-hour value on the day of evaluation of intraocular pressure, The patient with normal tension glaucoma is (1) The presence of glaucomatous visual field abnormalities as measured by perimeter; (2) the presence of a glaucomatous optic disc on fundus examination; and (3) No history of intraocular pressure of 21.0 mmHg or higher measured using a Goldmann applanation tonometer before administration of other glaucoma medications The composition is provided for patients who meet the above criteria.

[0074] In a further aspect, the present disclosure provides a composition for use in a method for inhibiting progression of visual field abnormalities or preventing the onset of visual field abnormalities in a patient in whom other antiglaucoma drugs as first-line drugs have an insufficient effect, comprising: brimonidine or a pharma- ceutical acceptable salt thereof; and timolol or a pharma-ceutical acceptable salt thereof, thereby reducing intraocular pressure by about 20% or more as assessed by an intraocular pressure reduction rate, the method comprising: a) diagnosing whether the patient has prefield glaucoma and normal intraocular pressure; b) administering another glaucoma medication as a first-line treatment; 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 prefield glaucoma and normal intraocular pressure, selecting a composition containing brimonidine or a pharma- ceutically acceptable salt thereof and timolol or a pharma- ceutically acceptable salt thereof as a second-choice drug instead of the other glaucoma therapeutic drugs or as a concomitant drug with the other glaucoma therapeutic drugs, and administering the composition to the patient; Including, The intraocular pressure reduction rate is calculated using the 2-hour value on the day of evaluation of intraocular pressure, The patient with normal tension glaucoma is (1) absence of glaucomatous visual field abnormalities as measured by perimeter; (2) the presence of a glaucomatous optic disc on fundus examination; and (3) No history of intraocular pressure of 21.0 mmHg or higher measured using a Goldmann applanation tonometer before administration of other glaucoma medications The composition is provided for patients who meet the above criteria. a) The step of diagnosing whether the patient has prefield glaucoma and normal intraocular pressure is preferably performed before the start of administration of the composition of the present disclosure, more specifically, before the start of administration of another glaucoma treatment drug as a first-choice drug. After that, if the effect of the other glaucoma treatment drug is insufficient in the patient, the use of a second-choice drug is considered. When considering the use of the second-choice drug, it is confirmed whether the patient has prefield glaucoma and normal intraocular pressure, and if the patient has prefield glaucoma and normal intraocular pressure, the composition of the present disclosure is selected as the second-choice drug for the treatment of the patient.

[0075] The present disclosure relates to a multiple-component preparation of brimonidine or a pharma- ceutical acceptable salt thereof, and timolol 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 glaucoma therapeutic drugs than the multiple-component preparation as a first-line drug have an insufficient effect, by lowering intraocular pressure by about 20% or more as assessed by an intraocular pressure reduction rate, the method comprising: a) diagnosing whether the patient has normal tension glaucoma; b) administering another glaucoma medication as a first-line treatment; 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 normal tension glaucoma, selecting a composition containing brimonidine or a pharma- ceutically acceptable salt thereof and timolol or a pharma- ceutically acceptable salt thereof as a second-line drug in place of or in combination with the other glaucoma therapeutic drugs, and administering the multiple-component preparation to the patient; Including, Provided is the multi-component agent. Here, in one embodiment, the multi-component agent can be advantageously a combination drug.It is understood by those skilled in the art that one or more of the various embodiments of this multi-component agent can be applied to any embodiment that can be adopted in other embodiments of the present disclosure, as long as they are appropriate.

[0076] Embodiments of these aspects may employ one or more of the embodiments described above as appropriate.

[0077] In some embodiments, inhibiting the progression of visual field defects or the onset of visual field defects may also be considered as preventing the progression of pre-peritoneal glaucoma, and may include reducing intraocular pressure.

[0078] (method) In another aspect, the present disclosure provides a method for treating or preventing glaucoma in a subject in need thereof, typically for lowering intraocular pressure in a patient suffering from glaucoma, or for preventing or slowing the progression of visual field abnormalities, and / or for preventing the progression of pre-peripheral glaucoma. This method includes administering to a subject in need thereof an effective amount of brimonidine or a pharmaceutically acceptable salt thereof and timolol or a pharmaceutically acceptable salt thereof. In the administration step, the timolol or a pharmaceutically acceptable salt thereof and brimonidine or a pharmaceutically acceptable salt thereof of the present disclosure can be administered together, and administration can be such that the two components are administered simultaneously, or can be administered as a combined drug. Such a method can be provided, for example, as a package insert or label. It is understood that any element provided as a method can appropriately adopt any embodiment described in (composition and combination, etc.).

[0079] The present disclosure has been described above by showing preferred embodiments for ease of understanding. The present disclosure will be described below based on examples, but the above description and the following examples are provided for illustrative purposes only and are not provided for the purpose of limiting the present disclosure. Therefore, the scope of the present disclosure is not limited to the embodiments or examples specifically described in this specification, but is limited only by the scope of the claims. EXAMPLES

[0080] Examples are described below. Where necessary, the following examples were conducted in accordance with the Declaration of Helsinki, in compliance with the matters to be observed in ICH or equivalent clinical trials, and with the standards approved for conducting clinical trials. The reagents used were specifically the products described in the examples, but equivalent products from other manufacturers can also be used.

[0081] Example 1 A multicenter, uncontrolled, unobstructed study was carried out to confirm the efficacy (intraocular pressure-reducing effect) of a 0.1% brimonidine tartrate / 0.5% timolol combination eye drop (an eye drop solution containing 1 mg brimonidine tartrate, 6.8 mg timolol maleate (5 mg as timolol), sodium hydrogen phosphate hydrate, sodium dihydrogen phosphate hydrate, sodium edetate hydrate, benzalkonium chloride, an isotonicity agent, and a pH adjuster per mL) (hereinafter referred to as the "eye drop"), when instilled twice daily for 52 weeks in patients (107 patients) with primary open-angle glaucoma (broad definition). Note that in this example, the intraocular pressure measured before instillation in the morning and at 9:00 ± 1 hour was defined as the 0-hour value, The intraocular pressure value measured within 2 hours ± 30 minutes after instillation in the morning and up to 12:30 is referred to as the 2-hour value.

[0082] The efficacy was evaluated in the eye with the higher intraocular pressure at 0 hours measured on the end of the observation period (the start of the treatment period) (the eye to be evaluated for efficacy), and the same eye was evaluated up to week 52 of the treatment period. Note that in this example, the subjects were those who had been given a sufficient explanation regarding participation at the time of patient screening and had given their own voluntary written consent.

[0083] In this embodiment, primary open angle glaucoma (broad definition) included primary open angle glaucoma (hereinafter referred to as POAG), normal tension glaucoma (hereinafter referred to as NTG), preperimetric glaucoma (high intraocular pressure group) (hereinafter referred to as PPG (high intraocular pressure)), and preperimetric glaucoma (normal intraocular pressure group) (hereinafter referred to as PPG (normal intraocular pressure)). Of the criteria for primary open angle glaucoma (broad definition), the POAG group was defined as those who met the following (1) and (2), the PPG (high intraocular pressure) group was defined as those who met only the following (2) and were judged to need treatment, the NTG group was defined as those who met all of the following (1), (2), and (3), and the PPG (normal intraocular pressure) group was defined as those who met the following (2) and (3) and were judged to need treatment.

[0084] (1) The patient has glaucomatous visual field abnormalities.

[0085] If visual field is measured using a Humphrey perimeter, the Anderson-Patella criteria should be followed (Anderson DR, Patella VM. Automated Static Perimetry. 2nd edition. St. Louis: Mosby; 1999: 152-3.). If visual field is measured using other automated static perimeters, the physician should determine the presence of glaucomatous visual field abnormalities (Glaucoma Management Guidelines (3rd edition), etc.).

[0086] (2) The presence of a glaucomatous optic disc.

[0087] The diagnosis is made through fundus examination (Glaucoma Treatment Guidelines (3rd edition), etc.) (3) There has been no history of intraocular pressure of 21.0 mmHg or higher measured using a Goldmann applanation tonometer.

[0088] First, in the observation period, timolol maleate ophthalmic solution was instilled into both eyes, one drop at a time, twice a day [morning and night (9:00±1 hour and 21:00±1 hour)] for 4 weeks [from the evening of the first day of the observation period to the morning of the last day of the observation period (first day of the treatment period)]. On the last day of the observation period (first day of the treatment period), the 0-hour and 2-hour values ​​of the eye to be evaluated for efficacy were confirmed, and if the 0-hour and 2-hour values ​​were 15.0mmHg or more and 31.0mmHg or less, the patient was to move on to the treatment period.

[0089] During the treatment period, the eye drops were administered in both eyes, one drop at a time, twice a day [morning and evening (9:00±1 hour and 21:00±1 hour)], starting on the evening of the end of the observation period (start of the treatment period) and continued for 52 weeks (morning only on the end of the treatment period). Intraocular pressure (2-hour value) was measured on each observation day of the 4th, 12th, 28th, and 52nd weeks from the start of the treatment period, and the change in intraocular pressure (2-hour value) from the start of the treatment period was confirmed.

[0090] Timolol maleate eye drops were administered in the morning of the final day of the observation period (the first day of the treatment period), and on each observation day of the treatment period, this eye drop was administered at 9:00 ± 1 hour after the measurement of intraocular pressure at 0 hour.

[0091] In addition, fundus findings and visual field defects were checked at screening, 28 weeks, and 52 weeks after the start of the treatment period.

[0092] Using the measured intraocular pressure values, the intraocular pressure reduction rate was calculated according to the following formula.

[0093] Intraocular pressure reduction rate (%) = {(intraocular pressure value (2-hour value) on the start of the treatment period - intraocular pressure value (2-hour value) on each observation day (each intraocular pressure evaluation day)) / intraocular pressure value (2-hour value) on the start of the treatment period} * 100 The calculated rate of change in intraocular pressure was evaluated as follows: (++): 20%≦rate of decrease, (+): 10%≦rate of decrease<20%, (±): rate of decrease<10%.

[0094] (result) For each of the POAG, NTG, PPG (high intraocular pressure), and PPG (normal intraocular pressure) groups, the percentage of cases with (++), (+), and (±) to the total number of cases on each observation day was calculated, and the results are shown in the table below.

[0095] As a result, it was confirmed that in the NTG group, the proportion of cases showing (++) was continuously greater than or equal to 40% from 12 weeks to 52 weeks after administration, and in the PPG (normal intraocular pressure) group, it was continuously greater than or equal to 40% from 4 weeks to 52 weeks after administration.

[0096] In the NTG group (39 cases), no cases showed worsening of fundus findings, and visual field defects did not progress in almost all cases.In the PPG (normal intraocular pressure) group (14 cases), no cases showed worsening of fundus findings, and visual field defects were not observed in almost all cases.

[0097] [Table 1]

[0098] (Note) Although the present disclosure has been illustrated using the preferred embodiments thereof, it is understood that the present disclosure should be interpreted in scope only by the claims. It is understood that the patents, patent applications and literature cited in this specification should be incorporated by reference in their entirety as if the contents themselves were specifically set forth in this specification. [Industrial Applicability]

[0099] The present invention provides a composition for treating glaucoma. This technology can be used in fields such as pharmaceuticals.

Claims

[Claim 1] The invention described in the specification.

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