Ophthalmic composition

Abstract

To provide a technique for an ophthalmic composition containing brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof, in which the technique makes it possible to suppress the production of a decomposition product due to storage and to improve storage stability.SOLUTION: An ophthalmic composition contains brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof, the concentration of the phosphoric acid and / or a salt thereof being set to 32 mM or less.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an ophthalmic composition which contains brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof, and which can suppress the production of decomposition products due to storage. [Background technology]

[0002] Brimonidine and its salts are known as adrenergic α2 receptor agonists that reduce intraocular pressure by inhibiting aqueous humor production and promoting the outflow of aqueous humor via the uveoscleral outflow pathway, and have traditionally been used to treat glaucoma and ocular hypertension.

[0003] Timolol and its salts are known as β-receptor blockers, which have the effect of reducing intraocular pressure by suppressing the production of aqueous humor, and have been conventionally used in the treatment of glaucoma and ocular hypertension.

[0004] In recent years, in order to enhance the therapeutic effect of glaucoma or ocular hypertension, a preparation using brimonidine and / or a salt thereof in combination with timolol and / or a salt thereof has been proposed. For example, Patent Document 1 discloses that an ophthalmic pharmaceutical composition containing brimonidine and timolol is safe and has a superior effect of lowering intraocular pressure compared to the case where brimonidine or timolol is used alone. In addition, Patent Document 2 discloses that a composition containing about 1 to 4.5 mM brimonidine, about 2 to 15.8 mM timolol, and about 150 to 250 ppm benzalkonium chloride is effective in treating glaucoma or ocular hypertension. Furthermore, Patent Document 3 discloses that a composition containing 0.1 w / v% brimonidine tartrate and 0.68 w / v% timolol maleate is effective in treating glaucoma or ocular hypertension and can reduce side effects.

[0005] In addition, conventionally, formulation techniques focusing on formulation stability have been investigated for preparations in which brimonidine and / or a salt thereof is used in combination with timolol and / or a salt thereof. For example, Patent Document 4 discloses that a composition containing about 1-4.5 mM brimonidine and about 2-16 mM timolol and having a pH of about 7-8.5 can suppress the production of decomposition products and has improved stability. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Special Publication No. 2005-523316 [Patent Document 2] International Publication No. 2008 / 24846 [Patent Document 3] International Publication No. 2016 / 149498 [Patent Document 4] Special Publication No. 2009-533462 Summary of the Invention [Problem to be solved by the invention]

[0007] The present invention provides novel ophthalmic compositions comprising brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof. [Means for solving the problem]

[0008] The present inventors have further studied and found that in an ophthalmic composition comprising brimonidine and / or its salt, timolol and / or its salt, and phosphoric acid and / or its salt, the generation of decomposition products can be effectively suppressed by reducing the concentration of phosphoric acid and / or its salt.Furthermore, the present inventors have found that in the ophthalmic composition, the generation of decomposition products can be more effectively suppressed by reducing the concentration of phosphoric acid and / or its salt and adding edetic acid and / or its salt.The present invention has been completed based on these findings and further studied.

[0009] As one aspect of the present invention, the following invention is provided. Item 1. Brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof, An ophthalmic composition having a concentration of phosphoric acid and / or a salt thereof of 32 mM or less. Item 2. The ophthalmic composition according to Item 1, further comprising edetic acid and / or a salt thereof. Item 3. The ophthalmic composition according to item 1 or 2, which has a pH of 7.1 to 7.3. Item 4. The ophthalmic composition according to any one of Items 1 to 3, comprising at least one of disodium hydrogen phosphate and sodium dihydrogen phosphate as phosphoric acid and / or a salt thereof. Item 5. The ophthalmic composition according to Item 4, comprising disodium hydrogen phosphate and sodium dihydrogen phosphate as phosphoric acid and / or a salt thereof. Item 6. The ophthalmic composition according to any one of Items 1 to 5, wherein the concentration of phosphoric acid and / or a salt thereof is 0.01 to 32 mM. Item 7. The ophthalmic composition according to any one of Items 1 to 6, wherein the concentration of phosphoric acid and / or a salt thereof is 0.3 to 32 mM. Item 8. The ophthalmic composition according to any one of Items 1 to 7, wherein the concentration of phosphoric acid and / or a salt thereof is 0.3 to 16 mM. Item 9. The ophthalmic composition according to any one of Items 1 to 8, wherein the concentration of phosphoric acid and / or a salt thereof is 0.3 to 6.3 mM. Item 10. The ophthalmic composition according to any one of Items 1 to 9, wherein the concentration of brimonidine and / or a salt thereof is 0.01 to 1 w / v %. Item 11. The ophthalmic composition according to any one of Items 1 to 10, wherein the concentration of brimonidine and / or a salt thereof is 0.05 to 0.3 w / v %. Item 12. The ophthalmic composition according to any one of Items 1 to 11, wherein the concentration of brimonidine and / or a salt thereof is 0.1 w / v %. Item 13. The ophthalmic composition according to any one of Items 1 to 12, wherein the concentration of timolol and / or a salt thereof is 0.1 to 1.5 w / v %. Item 14. The ophthalmic composition according to any one of Items 1 to 13, wherein the concentration of timolol and / or a salt thereof is 0.5 to 0.9 w / v %. Item 15. The ophthalmic composition according to any one of Items 1 to 14, wherein the concentration of timolol and / or a salt thereof is 0.68 w / v %. Item 16. The ophthalmic composition according to Item 2, wherein the concentration of edetic acid and / or a salt thereof is 0.0001 to 0.2 w / v %. Item 17. The ophthalmic composition according to Item 2, wherein the concentration of edetic acid and / or a salt thereof is 0.001 to 0.03 w / v %. Item 18. The ophthalmic composition according to Item 2, wherein the concentration of edetic acid and / or a salt thereof is 0.01 w / v %. Item 19. The ophthalmic composition according to Item 2, wherein the concentration of brimonidine and / or a salt thereof is 0.1 w / v%, the concentration of timolol and / or a salt thereof is 0.68 w / v%, the concentration of phosphoric acid and / or a salt thereof is 0.3 to 32 mM, and the concentration of edetic acid and / or a salt thereof is 0.01 w / v%. Item 20. The ophthalmic composition according to Item 19, wherein the concentration of phosphoric acid and / or a salt thereof is 0.3 to 6.3 mM. Item 21. The ophthalmic composition according to any one of Items 1 to 20, which is an eye drop. Item 22. The ophthalmic composition according to any one of Items 1 to 21, wherein the amount of decomposition products generated upon storage at 60° C. for 4 weeks does not exceed 1.0%. Item 23. An ophthalmic composition comprising brimonidine and / or a salt thereof, timolol and / or a salt thereof, phosphoric acid and / or a salt thereof, and optionally comprising edetic acid and / or a salt thereof, The concentration of phosphoric acid and / or a salt thereof is 0.01 to 32 mM; The concentration of brimonidine and / or a salt thereof is 0.01 to 1 w / v%, The concentration of timolol and / or its salt is 0.1 to 1.5 w / v%, The concentration of edetic acid and / or a salt thereof optionally contained is 0.0001 to 0.2 w / v%. Ophthalmic composition. Item 24. An ophthalmic composition comprising brimonidine and / or a salt thereof, timolol and / or a salt thereof, phosphoric acid and / or a salt thereof, and optionally containing edetic acid and / or a salt thereof, and having a pH of 7.1 to 7.3, The concentration of phosphoric acid and / or a salt thereof is 0.01 to 32 mM; The concentration of brimonidine and / or a salt thereof is 0.01 to 1 w / v%, The concentration of timolol and / or its salt is 0.1 to 1.5 w / v%, The concentration of edetic acid and / or a salt thereof optionally contained is 0.0001 to 0.2 w / v%. Ophthalmic composition. Item 25. An ophthalmic composition comprising brimonidine and / or a salt thereof, timolol and / or a salt thereof, phosphoric acid and / or a salt thereof, a preservative, and optionally containing edetic acid and / or a salt thereof, and having a pH of 7.1 to 7.3, The concentration of phosphoric acid and / or a salt thereof is 0.01 to 32 mM; The concentration of brimonidine and / or a salt thereof is 0.01 to 1 w / v%, The concentration of timolol and / or its salt is 0.1 to 1.5 w / v%, The concentration of the preservative is 0.0001 to 0.1 w / v%, The concentration of edetic acid and / or a salt thereof optionally contained is 0.0001 to 0.2 w / v%. Ophthalmic composition. Item 26. The ophthalmic composition according to any one of Items 23 to 25, wherein the salt of brimonidine is brimonidine tartrate and / or the salt of timolol is timolol maleate. Item 27. An ophthalmic composition comprising brimonidine and / or a salt thereof, timolol and / or a salt thereof, phosphoric acid and / or a salt thereof, and optionally comprising edetic acid and / or a salt thereof, The concentration of brimonidine and / or its salt is 0.1 w / v%; The concentration of timolol and / or its salt is 0.68 w / v%, The concentration of phosphoric acid and / or its salts is 6.3 mM; The concentration of edetic acid and / or a salt thereof optionally contained is 0.01 w / v%. Ophthalmic composition. Item 28. An ophthalmic composition comprising brimonidine and / or a salt thereof, timolol and / or a salt thereof, phosphoric acid and / or a salt thereof, and optionally comprising edetic acid and / or a salt thereof, The concentration of brimonidine and / or its salt is 0.1 w / v%; The concentration of timolol and / or its salt is 0.68 w / v%, The concentration of phosphoric acid and / or its salts is 6.3 mM; The concentration of edetic acid and / or a salt thereof optionally contained is 0.01 w / v%; pH is 7.1, Ophthalmic composition. Item 29. An ophthalmic composition comprising brimonidine and / or a salt thereof, timolol and / or a salt thereof, phosphoric acid and / or a salt thereof, and benzalkonium chloride, and optionally comprising edetic acid and / or a salt thereof, The concentration of brimonidine and / or its salt is 0.1 w / v%; The concentration of timolol and / or its salt is 0.68 w / v%, The concentration of phosphoric acid and / or its salts is 6.3 mM; The concentration of benzalkonium chloride is 0.002 w / v%. The concentration of edetic acid and / or a salt thereof optionally contained is 0.01 w / v%; pH is 7.1, Ophthalmic composition. Item 30. The ophthalmic composition according to any one of Items 27 to 29, wherein the salt of brimonidine is brimonidine tartrate and / or the salt of timolol is timolol maleate. Item 31. An ophthalmic composition comprising brimonidine tartrate, a salt of timolol including timolol maleate, disodium hydrogen phosphate and sodium dihydrogen phosphate, and benzalkonium chloride, and optionally including edetic acid and / or a salt thereof, The concentration of brimonidine tartrate is 0.1 w / v%; The concentration of timolol maleate is 0.68 w / v%. The total concentration of disodium hydrogen phosphate and sodium dihydrogen phosphate is 6.3 mM. The concentration of benzalkonium chloride is 0.002 w / v%. The concentration of edetic acid and / or a salt thereof optionally contained is 0.01 w / v%; pH is 7.1, Ophthalmic composition.

[0010] In another aspect, the present invention provides the following invention. Item A1. A method for suppressing decomposition products in an ophthalmic composition containing brimonidine and / or a salt thereof and timolol and / or a salt thereof, comprising: The method includes a step of allowing brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof to coexist in an ophthalmic composition, The concentration of the phosphoric acid and / or a salt thereof is 32 mM or less; Methods for suppressing decomposition products. Item A2. The method for inhibiting decomposition products according to Item A1, further comprising allowing edetic acid and / or a salt thereof to coexist in the ophthalmic composition.

[0011] In another aspect, the present invention provides the following invention. Item B1. A method for improving the storage stability of an ophthalmic composition containing brimonidine and / or a salt thereof and timolol and / or a salt thereof, comprising: The method includes a step of allowing brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof to coexist in an ophthalmic composition, The concentration of the phosphoric acid and / or a salt thereof is 32 mM or less; Methods for improving storage stability. Item B2. The method for improving storage stability according to Item B1, further comprising allowing edetic acid and / or a salt thereof to coexist in the ophthalmic composition.

[0012] In another aspect, the present invention provides the following invention. Item C1. Use of a composition comprising brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof, wherein the concentration of phosphoric acid and / or a salt thereof is 32 mM or less, for the manufacture of an ophthalmic composition. Item C2. The use according to Item C1, wherein the composition further comprises edetic acid and / or a salt thereof. Effect of the Invention

[0013] According to the present invention, in an ophthalmic composition containing brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof, the concentration of phosphoric acid and / or a salt thereof is set to a predetermined value or less, thereby reducing the amount of decomposition products generated during storage, and thus improving the storage stability of the ophthalmic composition.

[0014] In addition, in an ophthalmic composition containing brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof, if the concentration of phosphoric acid and / or a salt thereof is set to a predetermined value or less, other decomposition products tend to be generated, but in the present invention, the amount of the decomposition products generated can be suppressed by further containing edetic acid and / or a salt thereof. As a result, the storage stability of the ophthalmic composition can be further improved. [Brief description of the drawings]

[0015] [Figure 1] 1 shows chromatograms obtained by subjecting the test solution of Example 1 before and after storage to HPLC measurement. [Diagram 2] 1 shows chromatograms obtained by subjecting the test solutions of Example 1 and Comparative Example 1 after storage to HPLC measurement. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] Ophthalmic compositions such as eye drops are administered directly to the ocular mucosa, so it is necessary to ensure high safety and to suppress the generation of decomposition products due to storage. In particular, in the development of medical drugs, if the concentration of a decomposition product generated by storage under specified conditions exceeds a certain amount, it is mandatory to identify the structure of the decomposition product and report on its safety (Notification No. 0624001 of the Pharmaceutical and Medical Devices Agency, "Revision of the Guidelines on Impurities in Preparations of Pharmaceuticals Containing New Active Ingredients"). In the development of eye drops, this obligation usually arises when the concentration of the decomposition product exceeds 1.0%. For this reason, it is necessary to sufficiently suppress the generation of decomposition products caused by storage in the formulation of eye drops.

[0017] In addition, Patent Documents 1-4 show that, as a specific example of a preparation containing brimonidine or a salt thereof and timolol or a salt thereof, the preparation contains phosphoric acid and / or a salt thereof at a calculated concentration of 96.1-111.4 mM. The present inventors have conducted studies to verify the stability of the preparations specifically disclosed in Patent Documents 1-4, and have found that such preparations have a problem in that decomposition products (decomposition products A1, A2, and A3 described below) are generated during storage. The present inventors have found that, in an ophthalmic composition containing brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof, the generation of decomposition products A1, A2, and A3 can be effectively suppressed by setting the concentration of phosphoric acid and / or a salt thereof to 32 mM or less.

[0018] On the other hand, it was confirmed that, in an ophthalmic composition in which the concentration of phosphoric acid and / or a salt thereof is set to 32 mM or less as described above, the amount of the decomposition products A1, A2, and A3 produced can be reduced, but another decomposition product (decomposition product B described below) increases. Therefore, the present inventors conducted further studies and found that, by setting the concentration of phosphoric acid and / or a salt thereof to 32 mM or less in the ophthalmic composition and containing edetic acid and / or a salt thereof, the production of the decomposition products A1, A2, and A3 can be suppressed while also effectively suppressing the production of the decomposition product B.

[0019] It should be understood that the terms used herein are used in the sense commonly used in the art unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this invention belongs.

[0020] 1.Definition As used herein, "ophthalmic composition" refers to a pharmaceutical composition for ophthalmic use.

[0021] As used herein, "brimonidine" refers to a compound known as an adrenergic α2 receptor agonist, and refers to 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)quinoxalin-6-amine.

[0022] As used herein, "timolol" refers to a compound known as a β-receptor blocker, and refers to (2S)-1-(tert-butylamino)-3-(4-morpholino-1,2,5-thiadiazol-3-yloxy)-2-propanol.

[0023] As used herein, "phosphoric acid" refers to a type of phosphorus oxoacid, an inorganic acid with the chemical formula H3PO4.

[0024] As used herein, the term "edetic acid" refers to a known compound also known as ethylenediaminetetraacetic acid.

[0025] In this specification, the term "decomposition product A1" refers to a substance corresponding to a peak observed at a retention time of about 2.6 minutes when an ophthalmic composition containing brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof is stored and then subjected to HPLC measurement under the conditions described in the "HPLC measurement conditions" column. The "decomposition product A1" is a decomposition product generated by the interaction between brimonidine and / or a salt thereof and timolol and / or a salt thereof.

[0026] In this specification, "decomposition product A2" refers to a substance corresponding to a peak observed at a retention time of about 7.8 minutes when an ophthalmic composition containing brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof is stored and then subjected to HPLC measurement under the conditions described in the "HPLC measurement conditions" column. "Decomposition product A2" is a decomposition product caused by brimonidine and / or a salt thereof.

[0027] In this specification, "decomposition product A3" refers to a substance corresponding to a peak observed at a retention time of about 14.0 minutes when an ophthalmic composition containing brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof is stored and then subjected to HPLC measurement under the conditions described in the "HPLC measurement conditions" column. "Decomposition product A3" is a decomposition product caused by brimonidine and / or a salt thereof.

[0028] In this specification, "decomposition product B" refers to a substance corresponding to a peak observed at a retention time of about 15.2 minutes when an ophthalmic composition containing brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof, but not containing edetic acid and / or a salt thereof, is stored and then subjected to HPLC measurement under the conditions described in the "HPLC measurement conditions" column. "Decomposition product B" is a decomposition product caused by brimonidine and / or a salt thereof.

[0029] 1 shows a chromatogram obtained by storing an ophthalmic composition containing brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof, and then subjecting the composition to HPLC measurement under the conditions described in the "HPLC measurement conditions" column. In the chromatogram, peaks corresponding to the decomposition products A1, A2, A3, and B are clearly shown.

[0030] Decomposition product A1 is not detected when an ophthalmic composition containing phosphoric acid and / or its salt and only one of brimonidine and / or its salt or timolol and / or its salt is stored, but is detected when an ophthalmic composition containing phosphoric acid and / or its salt, brimonidine and / or its salt, and timolol and / or its salt is stored. Note that decomposition product A1 is not detected immediately after the preparation of the ophthalmic composition. Therefore, it has been confirmed that decomposition product A1 is a decomposition product generated by the storage of the ophthalmic composition involving at least brimonidine and / or its salt and timolol and / or its salt.

[0031] Decomposition products A2, A3, and B are not detected even when the ophthalmic composition not containing brimonidine and / or its salt is stored, and are not detected immediately after the preparation of the ophthalmic composition. Therefore, it has been confirmed that decomposition products A2, A3, and B are decomposition products generated by the storage of the ophthalmic composition with at least brimonidine and / or its salt. As shown in Test Example 2 described later, the generation of decomposition products A1, A2, and A3 can be suppressed by setting the concentration of phosphoric acid and / or its salt in the ophthalmic composition to 32 mM or less. In addition, decomposition product B is a substance whose generation amount increases by setting the concentration of phosphoric acid and / or its salt in the ophthalmic composition to 32 mM or less, and its generation can be suppressed by edetic acid and / or its salt.

[0032] In this specification, "suppression of decomposition products" includes not only reducing the amount of decomposition products produced but also completely suppressing their generation. Furthermore, "a method for suppressing decomposition products" refers to a method for reducing the amount of decomposition products produced by storage of an ophthalmic composition or completely suppressing their generation.

[0033] Furthermore, the degree of the "method of suppressing decomposition products" can be indicated by the amount of decomposition products produced when stored at 60°C for four weeks.

[0034] In this specification, "storage stability" refers to the degree to which the content of brimonidine and / or a salt thereof, and timolol and / or a salt thereof is not decreased by suppressing the generation of decomposition products caused by storage of the ophthalmic composition. "Method for improving storage stability" refers to a method for suppressing the decrease in the content of brimonidine and / or a salt thereof, and timolol and / or a salt thereof by suppressing the generation of decomposition products caused by storage of the ophthalmic composition.

[0035] The degree of "storage stability" can be indicated by the amount of decomposition products produced when stored at 60°C for 4 weeks.

[0036] 2. Description of the Preferred Embodiments A description of a preferred embodiment will be given below, but it should be understood that this embodiment is an example of the present invention, and the scope of the present invention is not limited to such a preferred embodiment. It should also be understood that those skilled in the art can easily make modifications, changes, etc. within the scope of the present invention by referring to the preferred examples described below. Regarding these embodiments, those skilled in the art can combine any embodiments as appropriate.

[0037] 3. Ophthalmic composition As one aspect of the present invention, there is provided an ophthalmic composition comprising brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof, the concentration of the phosphoric acid and / or a salt thereof being 32 mM or less. The ophthalmic composition of this aspect makes it possible to solve the problem of suppressing the decomposition products A1, A2, and A3.

[0038] In another embodiment of the present invention, there is provided an ophthalmic composition containing brimonidine and / or a salt thereof, timolol and / or a salt thereof, 32 mM or less phosphoric acid and / or a salt thereof, and edetic acid and / or a salt thereof. The ophthalmic composition of this embodiment can solve the problem of suppressing not only the decomposition products A1, A2, and A3 but also the decomposition product B.

[0039] The ophthalmic composition of the present invention will be described in detail below.

[0040] [Brimonidine and / or its salts] Brimonidine salts are not particularly limited as long as they are pharma- ceutically acceptable, and specific examples thereof include organic acid salts such as tartrates and acetates, and inorganic acid salts such as hydrochlorides. Brimonidine and / or its salts may be in the form of a solvate such as a hydrate.

[0041] In the present invention, either brimonidine or a salt thereof may be used alone or in combination. Among brimonidine and its salts, brimonidine tartrate is preferred.

[0042] In the ophthalmic composition of the present invention, the concentration of brimonidine and / or a salt thereof is not particularly limited and may be appropriately set depending on the severity of the symptoms of the patient to be treated, the amount to be applied per time, etc., and may be, for example, 0.01 to 1 w / v%. From the viewpoint of suppressing the concentration of each decomposition product to 1.0% or less, the concentration is preferably 0.05 to 0.3 w / v%, more preferably 0.1 to 0.2 w / v%, and particularly preferably 0.1 w / v%. In the present specification, the concentration of brimonidine and / or a salt thereof means the concentration converted into brimonidine tartrate.

[0043] [Timolol and / or its salts] The salt of timolol is not particularly limited as long as it is pharma- ceutically acceptable, and specific examples thereof include organic acid salts such as maleate, fumarate, acetate, tartrate, citrate, succinate, mesylate, besylate, tosylate, etc.; inorganic acid salts such as hydrochloride, nitrate, sulfate, hydrobromide, hydroiodide, etc. Timolol and / or its salt may be in the form of a solvate such as a hydrate.

[0044] In the present invention, either timolol or a salt thereof may be used alone or in combination. Among timolol and its salts, timolol maleate is preferred.

[0045] In the ophthalmic composition of the present invention, the concentration of timolol and / or a salt thereof is not particularly limited and may be appropriately set depending on the severity of the symptoms of the patient to be treated, the amount to be applied per time, etc., and may be, for example, 0.1 to 1.5 w / v%. From the viewpoint of further suppressing the production amount of the decomposition product B, the concentration is preferably 0.3 to 1.1 w / v%, more preferably 0.5 to 0.9 w / v%, and particularly preferably 0.68 w / v%. In the present specification, the concentration of timolol and / or a salt thereof means the concentration converted into timolol maleate.

[0046] [Phosphoric acid and / or its salts] The ophthalmic composition of the present invention contains phosphoric acid and / or a salt thereof, and the concentration of phosphoric acid and / or a salt thereof is set to 32 mM or less. By setting the concentration of phosphoric acid and / or a salt thereof to a predetermined value or less in this manner, it is possible to suppress the decomposition products A1, A2, and A3 due to storage.

[0047] The salt of phosphoric acid 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, trialkali metal phosphates such as trisodium phosphate and tripotassium phosphate, etc. The salt of phosphoric acid 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, etc.

[0048] In the present invention, one kind selected from phosphoric acid and salts thereof may be used alone, or two or more kinds may be used in combination.

[0049] Among phosphoric acid and its salts, from the viewpoint of effectively suppressing the generation of the decomposition products A1, A2 and A3 while providing a suitable buffering effect as an ophthalmic composition, a combination of a dialkali metal hydrogen phosphate and an alkali metal dihydrogen phosphate, and a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate are 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 0.005 to 1.0 mol per 1 mol of the dialkali metal hydrogen phosphate. From the viewpoint of further stabilizing the pH, the ratio is preferably 0.01 to 0.4 mol, more preferably 0.05 to 0.5 mol, and particularly preferably 0.26.

[0050] In the ophthalmic composition of the present invention, the concentration of phosphoric acid and / or a salt thereof is set to 32 mM or less. By setting the concentration of phosphoric acid and / or a salt thereof to a predetermined value or less in this way, it is possible to suppress the generation of the decomposition products A1, A2 and A3. From the viewpoint of more effectively suppressing the generation of the decomposition products A1, A2 and A3, the concentration of phosphoric acid and / or a salt thereof is preferably 16 mM or less, more preferably 13 mM or less, and particularly preferably 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, 0.01 mM or more. In the ophthalmic composition not containing edetic acid and / or a salt thereof, from the viewpoint of reducing the amount of the decomposition product B generated, it is preferably 0.3 mM or more, more preferably 3.2 mM or more, and particularly preferably 6.3 mM or more. The specific range of the concentration of phosphoric acid and / or a salt thereof is, for example, 0.01 to 32 mM. From the viewpoint of further suppressing the total amount of decomposition products, the concentration is preferably 0.3 to 32 mM, more preferably 0.3 to 16 mM, and particularly preferably 0.3 to 6.3 mM.

[0051] [Edetic acid and / or its salts] The ophthalmic composition of the present invention may contain edetic acid and / or a salt thereof in addition to the above-mentioned components. In an ophthalmic composition containing brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof, when the concentration of phosphoric acid and / or a salt thereof is set within the above-mentioned range, the amount of decomposition products A1, A2, and A3 produced tends to decrease, but the amount of decomposition product B produced tends to increase. In contrast, in a preferred embodiment of the ophthalmic composition of the present invention, the amount of decomposition product B produced can be effectively reduced by further containing edetic acid and / or a salt thereof.

[0052] The salt of edetic acid is not particularly limited as long as it is pharma- ceutically acceptable, and examples thereof include sodium salts of edetic acid such as monosodium edetate, disodium edetate (EDTA), tetrasodium edetate, etc. The salt of edetic acid may be in the form of a solvate such as a hydrate such as a dihydrate.

[0053] When edetic acid and / or a salt thereof is contained in the ophthalmic 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. Among edetic acid and its salts, from the viewpoint of more effectively reducing the amount of the decomposition product B produced, preferred are salts of edetic acid, and more preferred are disodium edetate (EDTA).

[0054] When edetic acid and / or a salt thereof is contained in the ophthalmic composition of the present invention, the concentration thereof is, for example, 0.0001 to 0.2 w / v%. From the viewpoint of further suppressing the decomposition product B, the concentration is preferably 0.001 to 0.03 w / v%, more preferably 0.005 to 0.015 w / v%, and particularly preferably 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.

[0055] [Other ingredients] In addition to the above-mentioned components, the ophthalmic composition of the present invention 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.

[0056] 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.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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, and amino acids. 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 containing phosphoric acid and / or a salt thereof, the desired buffering effect can be provided without blending any buffering agent other than phosphoric acid and its salt.

[0061] 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. In the ophthalmic composition of the present invention, when edetic acid and / or its salts are contained, a chelating effect is also imparted, so that the desired chelating effect can be provided without blending a chelating agent other than edetic acid and its salts.

[0062] 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.

[0063] 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. The concentration of the preservative can be appropriately changed depending on the type, and is, for example, 0.0001 to 0.1 w / v%, preferably 0.0005 to 0.05 w / v%, more preferably 0.001 to 0.05 w / v%, and particularly preferably 0.002 w / v%.

[0064] 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.

[0065] The pH adjuster 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 adjusters may be used alone or in combination of two or more.

[0066] 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.

[0067] Furthermore, the ophthalmic composition of the present invention may contain, in addition to brimonidine and / or a salt thereof and timolol and / or a salt thereof, a pharmacological component that exhibits a therapeutic effect against glaucoma or ocular hypertension, if necessary, within a range that does not impair the effects of the present invention.

[0068] Examples of such pharmacological ingredients include prostaglandins such as tafluprost, latanoprost, isopropyl unoprostone, etc.; parasympathomimetics such as pilocarpine hydrochloride, etc.; anticholinesterase drugs such as distigmine bromide, etc.; sympathomimetics such as dipivefrine hydrochloride, etc.; β1 blockers such as betaxolol hydrochloride, etc.; α1 / β blockers such as nipradilol, levobunolol hydrochloride, etc.; α1 blockers such as bunazosin hydrochloride, etc. These pharmacological ingredients may be used alone or in combination of two or more.

[0069] The concentrations of these pharmacological ingredients may be appropriately determined depending on the types of pharmacological ingredients used and the medicinal effects to be imparted.

[0070] [pH] The pH of the ophthalmic composition of the present invention is not particularly limited as long as it is applicable to the ocular mucosa, and may be, for example, pH 6.6 to 7.6. From the viewpoint of reducing the amount of decomposition product B produced, the pH is preferably 6.7 to 7.5, more preferably 6.7 to 7.3, even more preferably 7.1 to 7.3, and particularly preferably 7.1.

[0071] [Osmolality ratio] The osmotic pressure ratio of the ophthalmic composition of the present invention is not particularly limited as long as it is applicable to the ocular mucosa, and may be, for example, 0.5 to 4. From the viewpoint of reducing discomfort such as irritation of the medicinal solution, it is preferably 0.7 to 1.3, and more preferably 0.9 to 1.1. The osmotic pressure ratio is the ratio to the osmotic pressure of a 0.9 w / v% sodium chloride aqueous solution, and the osmotic pressure is measured in accordance with the "osmotic pressure method (osmolarity measurement method)" specified in the 17th revised edition of the Japanese Pharmacopoeia.

[0072] [Formulation and Use] When the ophthalmic composition of the present invention is topically administered to the ocular mucosa, the action of brimonidine and / or a salt thereof and timolol and / or a salt thereof can suppress the production of aqueous humor and reduce intraocular pressure, and therefore the composition is provided as eye drops and is suitably used for the treatment of glaucoma and ocular hypertension.

[0073] [container] The container for containing the ophthalmic composition of the present invention is not particularly limited, and may be any container that has been conventionally used as an eye drop container, and may be made of glass or plastic. When a plastic container is used as a container for containing the ophthalmic composition of the present invention, the constituent material of the plastic container is not particularly limited, and examples thereof include one or a mixture of two or more of polyethylene naphthalate, polyarylate, polyethylene terephthalate, polypropylene, polyethylene, and polyimide. From the viewpoint of more effectively suppressing the decomposition product B due to storage, the material of the container body (the member forming the storage part for containing the ophthalmic composition) is preferably polyethylene or polypropylene, more preferably polyethylene.

[0074] [Characteristics] According to the ophthalmic composition of the present invention, it is possible to suppress the decomposition products A1, A2, and A3. Specifically, the degree of suppression of the decomposition products A1, A2, and A3 in the ophthalmic composition of the present invention is such that the amount of each of the decomposition products A1, A2, and A3 produced after storage in a dark place at 60° C. for 4 weeks is 1.0% or less. From the viewpoint of a more stable ophthalmic composition, the amount is preferably 0.9% or less, and more preferably 0.85% or less.

[0075] Furthermore, when the ophthalmic composition of the present invention contains edetic acid and / or a salt thereof, it is also possible to suppress the decomposition product B. Specifically, the degree of suppression of the decomposition product B in the ophthalmic composition of the present invention is 1.0% or less after storage in a dark place at 60° C. for 4 weeks. From the viewpoint of making the ophthalmic composition more stable, the suppression is preferably 0.1% or less, and more preferably 0%.

[0076] In a preferred embodiment of the ophthalmic composition of the present invention, the total amount of the decomposition products A1, A2, A3, and B is 2.0% or less after storage in a dark place at 60° C. for 4 weeks. From the viewpoint of providing a more stable ophthalmic composition, the total amount is preferably 1.5% or less, and more preferably 1.3% or less.

[0077] In this specification, the concentrations of the decomposition products A1, A2, A3, and B are concentrations in the ophthalmic composition calculated according to the HPLC measurement conditions and calculation formula shown below.

[0078] The decomposition products A1, A2, A3, and B of the ophthalmic composition of the present invention are measured by liquid chromatography (HPLC: Shimadzu Corporation, high performance liquid chromatograph: Prominence) under the following conditions.

[0079] (HPLC measurement conditions) Detector: Ultraviolet spectrophotometer (measurement wavelength: 230 nm) Column: Symmetry C18, 4.6 mm ID x 150 mm, 3.5 μm, Waters Column temperature: 40℃ Mobile phase A: A mixture of 4.3 mM phosphoric acid aqueous solution / methanol / acetonitrile (volume ratio: 84 / 8 / 8) Mobile phase B: A mixture of 4.3 mM phosphoric acid aqueous solution / methanol / acetonitrile (volume ratio: 40 / 30 / 30) Delivery of mobile phase: The mixing ratio of mobile phase A and mobile phase B is changed as shown in Table 1 to perform linear concentration gradient control. Cleaning solution: Acetonitrile / water (volume ratio: 1 / 1) mixture Flow rate: 1.0mL / min Area measurement range: 60 minutes [Table 1]

[0080] (Calculation formula) The amounts of decomposition products A1, A2, A3, and B produced (relative to the indicated percentage) are calculated according to the following formula.

number

[0081] 4. Methods for suppressing decomposition products In one embodiment, the present invention provides a method for suppressing decomposition products of an ophthalmic composition comprising brimonidine and / or a salt thereof and timolol and / or a salt thereof, the method comprising a step of allowing brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof to coexist in the composition, the concentration of the phosphoric acid and / or a salt thereof being 32 mM or less. In the present invention, by making the concentration of the phosphoric acid and / or a salt thereof 32 mM or less, it is possible to suppress the generation of the decomposition products A1, A2 and A3.

[0082] In the method, edetic acid and / or a salt thereof may be further present in the ophthalmic composition. By allowing edetic acid and / or a salt thereof to be present, it becomes possible to suppress not only the decomposition products A1, A2, and A3 but also the decomposition product B.

[0083] In the method for inhibiting decomposition products of the present invention, the types, concentrations, etc. of brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof used may be those described in the above section "3. Ophthalmic compositions" used alone or in combination. In addition, in the method for inhibiting decomposition products of the present invention, other components that can be blended in the ophthalmic composition, the pH, osmotic pressure ratio, formulation form, container, etc. of the ophthalmic composition may also be those described in the above section "3. Ophthalmic compositions" used alone or in combination.

[0084] 3. Methods for improving storage stability In one aspect, the present invention provides a method for improving the storage stability of an ophthalmic composition comprising brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof, the method comprising a step of allowing brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof to coexist, the method comprising a step of improving the storage stability of the ophthalmic composition, the concentration of the phosphoric acid and / or a salt thereof being 32 mM or less. In the present invention, by making the concentration of the phosphoric acid and / or a salt thereof 32 mM or less, it is possible to suppress the decomposition products A1, A2, and A3, and improve the storage stability of the ophthalmic composition.

[0085] In the method, edetic acid and / or a salt thereof may be further present in the ophthalmic composition. By allowing edetic acid and / or a salt thereof to be present, not only the decomposition products A1, A2, and A3 but also the decomposition product B are suppressed, and the storage stability of the ophthalmic composition can be further improved.

[0086] In the method for improving the storage stability of the present invention, regarding brimonidine and / or its salt, timolol and / or its salt, and phosphoric acid and / or its salt to be used, their types, concentrations, etc. may be adopted alone or in combination as described in the column of "3. Ophthalmic composition" above. Further, in the method for improving the storage stability of the present invention, regarding other components that can be formulated in the ophthalmic composition, the pH, osmotic pressure ratio, dosage form, container, etc. of the ophthalmic composition may also be adopted alone or in combination as described in the column of "3. Ophthalmic composition" above.

Examples

[0087] Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto.

[0088] Test Example 1 Test solutions (eye drops) having the compositions shown in Table 3 were prepared. 5 mL of each eye drop was filled into a 5 mL polyethylene container, sealed, and stored in the dark at 60 °C for 4 weeks. Each test solution after storage was subjected to HPLC under the following conditions, and the amount of decomposition products was analyzed.

[0089] <HPLC Conditions> · Preparation of Sample Solution 2 mL of each test solution was accurately measured, purified water was added to make it exactly 20 mL, and it was used as a sample solution.

[0090] · Preparation of Standard Solution 10 mg of brimonidine tartrate standard was accurately measured, purified water was added to make it exactly 100 mL, and it was used as a standard solution.

[0091] · Measurement by Liquid Chromatography For 25 μL of the sample solution and the standard solution, measurement was performed by liquid chromatography (high-performance liquid chromatograph: Prominence manufactured by Shimadzu Corporation) under the following conditions, and the peak area of the decomposition product in each sample solution and the peak area of brimonidine tartrate in the standard solution were determined by the automatic integration method.

[0092] (Measurement Conditions) Detector: Ultraviolet spectrophotometer (measurement wavelength: 230 nm) Column: Symmetry C18, 4.6 mm ID x 150 mm, 3.5 μm, Waters Column temperature: 40℃ Mobile phase A: A mixture of 4.3 mM phosphoric acid aqueous solution / methanol / acetonitrile (volume ratio: 84 / 8 / 8) Mobile phase B: A mixture of 4.3 mM phosphoric acid aqueous solution / methanol / acetonitrile (volume ratio: 40 / 30 / 30) Delivery of mobile phase: The mixing ratio of mobile phase A and mobile phase B was changed as shown in Table 2 to control the linear concentration gradient. Cleaning solution: Acetonitrile / water (volume ratio: 1 / 1) mixture Flow rate: 1.0mL / min Area measurement range: 60 minutes [Table 2]

[0093] (Calculation method) The amounts of decomposition products A1, A2, A3, and B produced (relative to the indicated percentage) were calculated according to the following formula.

number

[0094] Chromatograms obtained by subjecting the test solution of Example 1 before and after storage to HPLC are shown in Figure 1. Chromatograms obtained by subjecting the test solutions of Example 1 and Comparative Example 1 after storage to HPLC are shown in Figure 2. As a result, peaks were observed at retention times of about 2.6 minutes, about 7.8 minutes, about 14.0 minutes, and about 15.2 minutes in the test solution of Example 1 after storage. Since no peaks were observed at these retention times in the test solution of Example 1 before storage, it was found that the above peaks were derived from decomposition products generated by storage.

[0095] Table 3 shows the amounts (relative to the indicated percentage) of decomposition products A1 (retention time: about 2.6 minutes), A2 (retention time: about 7.8 minutes), A3 (retention time: about 14.0 minutes), and B (retention time: about 15.2 minutes) produced in each test solution after storage. In Example 1, in which the phosphate concentration is 6.3 mM, the amounts of decomposition products A1, A2, and A3 produced were reduced compared to Comparative Example 1, in which the phosphate concentration was 126 mM. In addition, the total amount of decomposition products A1, A2, A3, and B produced was also reduced in Example 1 compared to Comparative Example 1. From these results, it was confirmed that in an ophthalmic composition containing brimonidine tartrate, timolol maleate, and phosphate, the storage stability of the ophthalmic composition was improved by setting the phosphate concentration low.

[0096] On the other hand, in Example 1, the amounts of decomposition products A1, A2, and A3 produced were reduced compared to Comparative Example 1, but the amount of decomposition product B produced was increased. In contrast, in Example 2, in which EDTA dihydrate was further added, the amount of decomposition product B produced was so small that it could not be detected. In other words, it was confirmed that the decomposition product B produced by reducing the concentration of phosphate can be reduced by further adding EDTA dihydrate, and storage stability can be further improved.

[0097] [Table 3]

[0098] Test Example 2 In an ophthalmic composition containing brimonidine tartrate, timolol maleate, and phosphate, the effect of the concentration of phosphate on the amount of decomposition products was examined. Specifically, test solutions (eye drops) having the compositions shown in Tables 4 and 5 were prepared, and stored under the same conditions as in Test Example 1, and the amount of decomposition products was measured.

[0099] The results are shown in Tables 4 and 5. Compared with Comparative Example 1 in which the phosphate concentration was 126 mM, Examples 1 and 3 to 7 in which the phosphate concentration was 32 mM or less were able to reduce the amount of decomposition products A1 to A3 produced. That is, it was confirmed that in an ophthalmic composition containing brimonidine tartrate, timolol maleate, and phosphate, the production of decomposition products A1 to A3 can be suppressed by setting the phosphate concentration to 32 mM or less.

[0100] Furthermore, when brimonidine tartrate and timolol maleate were included and the phosphate concentration was 32 mM or less, an increase in decomposition product B was observed when EDTA dihydrate was not included (Examples 1 and 3 to 7), but the production of decomposition product B was completely suppressed when EDTA dihydrate was included (Examples 2 and 8 to 12).

[0101] From the results of this test, in an ophthalmic composition containing brimonidine tartrate, timolol maleate, and phosphate, a phosphate concentration of 32 mM or less specifically reduced the amount of decomposition products A1 to A3 produced, but a new problem was confirmed that the amount of decomposition product B produced increased. However, in the ophthalmic composition, it was confirmed that further incorporation of EDTA dihydrate specifically inhibited the production of decomposition product B (EDTA dihydrate does not reduce the amount of decomposition products A1 to A3 produced). Therefore, it was revealed that the most effective way to reduce decomposition products is to further incorporate EDTA dihydrate in addition to a phosphate concentration of 32 mM or less.

[0102] [Table 4]

[0103] [Table 5]

[0104] Test Example 3 The effect of pH on the amount of decomposition products produced in an ophthalmic composition containing brimonidine tartrate, timolol maleate, and phosphate was examined. Specifically, a test solution (eye drop) having the composition shown in Table 6 was prepared and stored under the same conditions as in Test Example 1, except that a 5 mL polypropylene container was used as the container for filling the test solution, and the amount of decomposition products produced was measured.

[0105] The results are shown in Table 6. As a result, in Examples 16 and 17, in which the pH was within the range of 7.1 to 7.3, the amount of decomposition product B produced was reduced compared to Examples 13 to 15 and 18, in which the pH was outside the range of 7.1 to 7.3. Therefore, it was revealed that in an ophthalmic composition containing brimonidine tartrate and timolol maleate and having a phosphate concentration set to a low concentration of 32 mM or less, by setting the pH to 7.1 to 7.3, the amount of decomposition product B produced can be more effectively suppressed and storage stability can be further improved.

[0106] [Table 6]

[0107] Formulation examples Specific embodiments of the ophthalmic composition of the present invention include ophthalmic compositions containing the components shown in Tables 7 to 10. In Tables 7 to 10, the unit of the content of each component is "w / v%." In the tables, Formulation Examples 1 to 18 are contained in polyethylene (hereinafter, PE) containers, Formulation Examples 19 to 28 are contained in polypropylene (PP) containers, and Formulation Examples 29 to 36 are contained in glass containers.

[0108] [Table 7]

[0109] [Table 8]

[0110] [Table 9]

[0111]

Table 10

Claims

1. Brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof, An ophthalmic composition having a concentration of phosphoric acid and / or a salt thereof of 6.3 mM or more and 32 mM or less.

2. The ophthalmic composition of claim 1, having a pH of 7.1 to 7.

3.

3. 3. The ophthalmic composition according to claim 1, comprising at least one of disodium hydrogen phosphate and sodium dihydrogen phosphate as phosphoric acid and / or a salt thereof.

4. The ophthalmic composition according to claim 3 , comprising disodium hydrogen phosphate and sodium dihydrogen phosphate as phosphoric acid and / or salts thereof.

5. 5. The ophthalmic composition according to claim 1, wherein the concentration of brimonidine and / or a salt thereof is 0.01 to 1 w / v %.

6. 6. The ophthalmic composition according to claim 1, wherein the concentration of timolol and / or a salt thereof is 0.1 to 1.5 w / v %.

7. The concentration of brimonidine and / or its salt is 0.1 w / v%; The concentration of timolol and / or its salt is 0.68 w / v%; The concentration of phosphoric acid and / or a salt thereof is 6.3 to 32 mM; The ophthalmic composition according to any one of claims 1 to 4.

8. The ophthalmic composition according to any one of claims 1 to 7, which is an eye drop.

9. A method for inhibiting decomposition products in an ophthalmic composition comprising brimonidine and / or a salt thereof and timolol and / or a salt thereof, comprising the steps of: The method includes a step of allowing brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof to coexist in an ophthalmic composition, The concentration of the phosphoric acid and / or a salt thereof is 6.3 mM or more and 32 mM or less; Methods for suppressing decomposition products.

10. A method for improving the storage stability of an ophthalmic composition containing brimonidine and / or a salt thereof, and timolol and / or a salt thereof, comprising the steps of: The method includes a step of allowing brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof to coexist in an ophthalmic composition, The concentration of the phosphoric acid and / or a salt thereof is 6.3 mM or more and 32 mM or less; Methods for improving storage stability.

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