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 containing brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof, which can suppress the generation of decomposition products due to storage.

Background Art

[0002] Brimonidine and its salts are known as adrenergic α2 receptor agonists, and have the effect of reducing intraocular pressure by suppressing the production of aqueous humor and promoting the outflow of aqueous humor through the uveoscleral outflow pathway. Conventionally, they have been used for the treatment of glaucoma and ocular hypertension.

[0003] In addition, timolol and its salts are known as β-receptor blockers, and have the effect of reducing intraocular pressure by suppressing the production of aqueous humor. Conventionally, they have been used for the treatment of glaucoma and ocular hypertension.

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

[0005] Conventionally, for a preparation containing brimonidine and / or its salt in combination with timolol and / or its salt, formulation technologies focusing on formulation stability have also been studied. For example, Patent Document 4 discloses that a composition containing about 1 to 4.5 mM of brimonidine and about 2 to 16 mM of timolol and having a pH of about 7 to 8.5 can suppress the generation of decomposition products and has improved stability.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Summary of the Invention

Problems to be Solved by the Invention

[0007] The present invention provides a novel ophthalmic composition containing brimonidine and / or its salt, timolol and / or its salt, and phosphoric acid and / or its salt.

Means for Solving the Problems

[0008] As a result of further studies, the present inventors have found that in an ophthalmic composition containing 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, it has been found that in the above ophthalmic composition, by reducing the concentration of phosphoric acid and / or its salt and adding edetic acid and / or its salt, the generation of decomposition products can be more effectively suppressed. The present invention has been completed by further studies based on these findings.

[0009] As one aspect of the present invention, the following inventions are provided. Item 1. An ophthalmic 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. Item 2. The ophthalmic composition according to Item 1, further containing edetic acid and / or a salt thereof. Item 3. The ophthalmic composition according to Item 1 or 2, having a pH of 7.1 to 7.3. Item 4. The ophthalmic composition according to any one of Items 1 to 3, wherein the phosphoric acid and / or a salt thereof contains at least one of disodium hydrogen phosphate and sodium dihydrogen phosphate. Item 5. The ophthalmic composition according to Item 4, wherein the phosphoric acid and / or a salt thereof contains disodium hydrogen phosphate and sodium dihydrogen phosphate. 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. An ophthalmic composition according to any one of Items 1 to 13, wherein the concentration of timolol and / or its salt is 0.5 to 0.9 w / v%. Item 15. An ophthalmic composition according to any one of Items 1 to 14, wherein the concentration of timolol and / or its salt is 0.68 w / v%. Item 16. An ophthalmic composition according to Item 2, wherein the concentration of edetic acid and / or its salt is 0.0001 to 0.2 w / v%. Item 17. An ophthalmic composition according to Item 2, wherein the concentration of edetic acid and / or its salt is 0.001 to 0.03 w / v%. Item 18. An ophthalmic composition according to Item 2, wherein the concentration of edetic acid and / or its salt is 0.01 w / v%. Item 19. An ophthalmic composition according to Item 2, wherein 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 salt is 0.3 to 32 mM, and the concentration of edetic acid and / or its salt is 0.01 w / v%. Item 20. An ophthalmic composition according to Item 19, wherein the concentration of phosphoric acid and / or its salt is 0.3 to 6.3 mM. Item 21. An ophthalmic composition according to any one of Items 1 to 20, which is an eye drop. Item 22. An 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 its salt, timolol and / or its salt, phosphoric acid and / or its salt, and optionally edetic acid and / or its salt, wherein the concentration of phosphoric acid and / or its salt is 0.01 to 32 mM, the concentration of brimonidine and / or its salt is 0.01 to 1 w / v%, the concentration of timolol and / or its salt is 0.1 to 1.5 w / v%, and the concentration of optionally included edetic acid and / or its salt is 0.0001 to 0.2 w / v%. An 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, optionally containing edetic acid and / or a salt thereof, having a pH of 7.1 to 7.3, wherein 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 a salt thereof is 0.1 to 1.5 w / v%, and the concentration of optionally contained edetic acid and / or a salt thereof is 0.0001 to 0.2 w / v%, an 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, optionally containing edetic acid and / or a salt thereof, having a pH of 7.1 to 7.3, wherein 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 a salt thereof is 0.1 to 1.5 w / v%, the concentration of the preservative is 0.0001 to 0.1 w / v%, and the concentration of optionally contained edetic acid and / or a salt thereof is 0.0001 to 0.2 w / v%, an 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, optionally containing edetic acid and / or a salt thereof, 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 6.3 mM, An ophthalmic composition in which the concentration of edetic acid and / or its salt, which is optionally contained, is 0.01 w / v%. Ophthalmic composition. Item 28. An ophthalmic composition comprising brimonidine and / or its salt, timolol and / or its salt, phosphoric acid and / or its salt, and optionally containing edetic acid and / or its salt, wherein 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 salt is 6.3 mM, the concentration of edetic acid and / or its salt, which is optionally contained, is 0.01 w / v%, and the pH is 7.1. Ophthalmic composition. Item 29. An ophthalmic composition comprising brimonidine and / or its salt, timolol and / or its salt, phosphoric acid and / or its salt, benzalkonium chloride, and optionally containing edetic acid and / or its salt, wherein 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 salt is 6.3 mM, the concentration of benzalkonium chloride is 0.002 w / v%, the concentration of edetic acid and / or its salt, which is optionally contained, is 0.01 w / v%, and the 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, the salt of timolol being timolol maleate, disodium hydrogen phosphate and sodium dihydrogen phosphate, benzalkonium chloride, and optionally containing edetic acid and / or its salt, wherein 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 optionally included edetic acid and / or its salt is 0.01 w / v%, the pH is 7.1, an ophthalmic composition.

[0010] In another aspect, the present invention provides the inventions listed below. Item A1. A method for suppressing decomposition products in an ophthalmic composition containing brimonidine and / or its salt and timolol and / or its salt, comprising: a step of coexisting brimonidine and / or its salt, timolol and / or its salt, and phosphoric acid and / or its salt in the ophthalmic composition, wherein the concentration of the phosphoric acid and / or its salt is 32 mM or less, a method for suppressing decomposition products. Item A2. The method for suppressing decomposition products according to Item A1, further comprising coexisting edetic acid and / or its salt in the ophthalmic composition.

[0011] In another aspect, the present invention provides the inventions listed below. Item B1. A method for improving the storage stability of an ophthalmic composition containing brimonidine and / or its salt and timolol and / or its salt, comprising: a step of coexisting brimonidine and / or its salt, timolol and / or its salt, and phosphoric acid and / or its salt in the ophthalmic composition, wherein the concentration of the phosphoric acid and / or its salt is 32 mM or less, a method for improving storage stability. Item B2. The method for improving storage stability according to Item B1, further comprising coexisting edetic acid and / or its salt in the ophthalmic composition.

[0012] In another aspect, the present invention provides the inventions listed below. 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.

Advantages 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, by setting the concentration of phosphoric acid and / or a salt thereof to a predetermined value or less, the amount of decomposition products generated by storage can be reduced. As a result, the storage stability of the ophthalmic composition can be improved.

[0014] Also, 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 to a predetermined value or less, another decomposition product tends to be generated. However, in the present invention, by further containing edetic acid and / or a salt thereof, the amount of generation of the decomposition product can also be suppressed. As a result, it becomes possible to further improve the storage stability of the ophthalmic composition.

Brief Description of the Drawings

[0015]

Figure 1

Figure 2

Modes for Carrying Out the Invention

[0016] In ophthalmic compositions such as eye drops, since they are directly administered to the eye mucosa, 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 pharmaceuticals, when the concentration of decomposition products generated by storage under predetermined conditions exceeds a certain amount, it is obligatory to identify the structure of the decomposition products and report on their safety (Pharmaceutical Affairs and Food Sanitation Council Notice No. 0624001 "Regarding the Revision of the Guidelines on Impurities in Preparations among New Active Ingredient-containing Pharmaceuticals"), and in the development of eye drops, this obligation usually arises when the concentration of decomposition products exceeds 1.0%. Therefore, in formulating eye drops, it is necessary to sufficiently suppress the generation of decomposition products due to storage.

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

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

[0019] Unless otherwise noted, the terms used in this specification are to be understood as having the meanings commonly used in the art. Therefore, unless otherwise defined, all technical and scientific terms used herein shall have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0020] 1. Definition As used herein, the term "ophthalmic composition" means 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 one of the oxoacids of phosphorus and refers to an inorganic acid with the chemical formula H3PO4.

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

[0025] As used herein, "decomposition product A1" refers to a substance corresponding to the peak observed at a retention time of about 2.6 minutes when HPLC measurement is performed under the conditions described in the column of "(HPLC measurement conditions)" after storing an ophthalmic composition containing brimonidine and / or its salt, timolol and / or its salt, and phosphoric acid and / or its salt. "Decomposition product A1" is a decomposition product generated by the interaction of brimonidine and / or its salt with timolol and / or its salt.

[0026] As used herein, the "degradation product A2" refers to a substance corresponding to the peak observed at a retention time of about 7.8 minutes when HPLC measurement is performed under the conditions described in the column of "(HPLC measurement conditions)" after storing an ophthalmic composition containing brimonidine and / or its salt, timolol and / or its salt, and phosphoric acid and / or its salt. The "degradation product A2" is a degradation product resulting from brimonidine and / or its salt.

[0027] As used herein, the "degradation product A3" refers to a substance corresponding to the peak observed at a retention time of about 14.0 minutes when HPLC measurement is performed under the conditions described in the column of "(HPLC measurement conditions)" after storing an ophthalmic composition containing brimonidine and / or its salt, timolol and / or its salt, and phosphoric acid and / or its salt. The "degradation product A3" is a degradation product resulting from brimonidine and / or its salt.

[0028] As used herein, the "degradation product B" refers to a substance corresponding to the peak observed at a retention time of about 15.2 minutes when HPLC measurement is performed under the conditions described in the column of "(HPLC measurement conditions)" after storing an ophthalmic composition containing brimonidine and / or its salt, timolol and / or its salt, phosphoric acid and / or its salt, and not containing edetic acid and / or its salt. The "degradation product B" is a degradation product resulting from brimonidine and / or its salt.

[0029] Figure 1 shows a chromatogram obtained by performing HPLC measurement under the conditions described in the column of "(HPLC measurement conditions)" after storing an ophthalmic composition containing brimonidine and / or its salt, timolol and / or its salt, and phosphoric acid and / or its salt. The peaks corresponding to the degradation products A1, A2, A3, and B are clearly indicated in the chromatogram.

[0030] The decomposition product A1 contains phosphoric acid and / or its salts, and is not detected even when storing an ophthalmic composition containing only one of brimonidine and / or its salts, or timolol and / or its salts. However, it is detected by storing an ophthalmic composition containing phosphoric acid and / or its salts, brimonidine and / or its salts, and timolol and / or its salts. Note that the decomposition product A1 is not detected immediately after preparing the ophthalmic composition. Therefore, it has been confirmed that the decomposition product A1 is a decomposition product generated by the involvement of at least brimonidine and / or its salts and timolol and / or its salts during the storage of the ophthalmic composition.

[0031] The decomposition products A2, A3, and B are not detected even when storing an ophthalmic composition that does not contain brimonidine and / or its salts, nor are they detected immediately after preparing the ophthalmic composition. Therefore, it has been confirmed that the decomposition products A2, A3, and B are decomposition products generated by the involvement of at least brimonidine and / or its salts during the storage of the ophthalmic composition. As shown in Test Example 2 described later, the generation of the decomposition products A1, A2, and A3 can be suppressed by setting the concentration of phosphoric acid and / or its salts in the ophthalmic composition to 32 mM or less. Also, the decomposition product B is a substance whose production amount increases by setting the concentration of phosphoric acid and / or its salts in the ophthalmic composition to 32 mM or less, and its generation can be suppressed by edetic acid and / or its salts.

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

[0033] Also, the degree of the "method for suppressing decomposition products" can be indicated by the amount of decomposition products generated when storing at 60°C for 4 weeks.

[0034] As used herein, "storage stability" means the degree of not reducing the contents of brimonidine and / or its salts, and timolol and / or its salts by suppressing the generation of decomposition products caused by the storage of the ophthalmic composition. The "method for improving storage stability" is a method of suppressing the reduction in the contents of brimonidine and / or its salts, and timolol and / or its salts by suppressing the generation of decomposition products caused by the storage of the ophthalmic composition.

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

[0036] 2. Description of Preferred Embodiments The following describes preferred embodiments. It should be understood that these embodiments are illustrative of the present invention and that the scope of the present invention is not limited to such preferred embodiments. Those skilled in the art should also understand that modifications, changes, etc. within the scope of the present invention can be easily made with reference to the preferred examples described below. Regarding these embodiments, those skilled in the art can appropriately combine any embodiments.

[0037] 3. Ophthalmic Composition As one aspect of the present invention, there is provided an ophthalmic composition comprising brimonidine and / or its salts, timolol and / or its salts, and phosphoric acid and / or its salts, wherein the concentration of phosphoric acid and / or its salts is 32 mM or less. According to the ophthalmic composition of this aspect, it becomes possible to solve the problem of suppressing decomposition products A1, A2, and A3.

[0038] Also, as another aspect of the present invention, there is provided an ophthalmic composition comprising brimonidine and / or its salts, timolol and / or its salts, phosphoric acid and / or its salts at 32 mM or less, and edetic acid and / or its salts. According to the ophthalmic composition of this aspect, it becomes possible to solve the problem of suppressing not only decomposition products A1, A2, and A3 but also decomposition product B.

[0039] Hereinafter, the ophthalmic composition of the present invention will be described in detail.

[0040] [Brimonidine and / or its salt] The salts of brimonidine are not particularly limited as long as they are pharmaceutically acceptable. Specifically, organic acid salts such as tartrate and acetate; inorganic acid salts such as hydrochloride can be mentioned. Further, brimonidine and / or its salt may be in the form of a solvate such as a hydrate.

[0041] In the present invention, either brimonidine or its salt may be used alone, or they may be used in combination. Among brimonidine and its salts, preferably brimonidine tartrate can be mentioned.

[0042] In the ophthalmic composition of the present invention, the concentration of brimonidine and / or its salt is not particularly limited and may be appropriately set according to the degree of symptoms of the patient to be applied, the dosage per application, etc. For example, 0.01 to 1 w / v% can be mentioned. From the viewpoint of suppressing the concentration of each decomposition product to 1.0% or less, preferably 0.05 to 0.3 w / v%, more preferably 0.1 to 0.2 w / v%, and particularly preferably 0.1 w / v% can be mentioned. In this specification, the concentration of brimonidine and / or its salt means the concentration converted to brimonidine tartrate.

[0043] [Timolol and / or its salt] The salts of timolol are not particularly limited as long as they are pharmaceutically acceptable. Specifically, organic acid salts such as maleate, fumarate, acetate, tartrate, citrate, succinate, mesylate, besylate, tosylate; inorganic acid salts such as hydrochloride, nitrate, sulfate, hydrobromide, hydroiodide can be mentioned. Further, 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 its salt may be used alone, or they may be used in combination. Among timolol and its salts, preferably timolol maleate can be mentioned.

[0045] In the ophthalmic composition of the present invention, the concentration of timolol and / or its salt is not particularly limited and may be appropriately set according to the degree of symptoms of the patient to be treated, the dosage per application, etc. For example, it may be 0.1 to 1.5 w / v%. From the viewpoint of further suppressing the production amount of the decomposition product B, it 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 its salt means the concentration converted to timolol maleate.

[0046] [Phosphoric acid and / or its salt] The ophthalmic composition of the present invention contains phosphoric acid and / or its salt, and the concentration of phosphoric acid and / or its salt is set to 32 mM or less. By setting the concentration of phosphoric acid and / or its salt to a predetermined value or less in this way, it becomes 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 pharmaceutically acceptable. For example, dipotassium hydrogen phosphate, dipotassium hydrogen phosphate and other dipotassium hydrogen phosphate salts; sodium dihydrogen phosphate, potassium dihydrogen phosphate and other sodium dihydrogen phosphate salts; trisodium phosphate, tripotassium phosphate and other trisodium phosphate salts. Further, the salt of phosphoric acid may be in the form of a solvate such as a hydrate. For example, in the case of dipotassium 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.

[0048] In the present invention, one kind may be selected from phosphoric acid and its salts and 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 decomposition products A1, A2, and A3 and having a suitable buffering action as an ophthalmic composition, preferably a combination of an alkali metal hydrogen phosphate and an alkali metal dihydrogen phosphate, more preferably a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate can be mentioned. When using a combination of an alkali metal hydrogen phosphate and an alkali metal dihydrogen phosphate, the ratio thereof is not particularly limited. For example, per 1 mol of the alkali metal hydrogen phosphate, the alkali metal dihydrogen phosphate is 0.005 to 1.0 mol. From the viewpoint of further stabilizing the pH, preferably 0.01 to 0.4 mol, more preferably 0.05 to 0.5 mol, and particularly preferably 0.26 can be mentioned.

[0050] In the ophthalmic composition of the present invention, the concentration of phosphoric acid and / or its salt is set to 32 mM or less. By setting the concentration of phosphoric acid and / or its salt to a predetermined value or less in this way, it becomes possible to suppress the generation of decomposition products A1, A2, and A3. From the viewpoint of more effectively suppressing the generation of decomposition products A1, A2, and A3, the concentration of phosphoric acid and / or its salt is preferably 16 mM or less, more preferably 13 mM or less, and particularly preferably 6.3 mM or less. Also, the lower limit of the concentration of phosphoric acid and / or its salt is not particularly limited. For example, 0.01 mM or more can be mentioned. In an ophthalmic composition containing no edetic acid and / or its salt, from the viewpoint of reducing the amount of decomposition product B generated, preferably 0.3 mM or more, more preferably 3.2 mM or more, and particularly preferably 6.3 mM or more can be mentioned. As a specific range of the concentration of phosphoric acid and / or its salt, for example, 0.01 to 32 mM can be mentioned. From the viewpoint of further suppressing the total amount of decomposition products, preferably 0.3 to 32 mM, more preferably 0.3 to 16 mM, and particularly preferably 0.3 to 6.3 mM can be mentioned.

[0051] [Edetic acid and / or its salt] In addition to the above components, the ophthalmic composition of the present invention may contain edetic acid and / or its salts. In an ophthalmic composition containing brimonidine and / or its salts, timolol and / or its salts, and phosphoric acid and / or its salts, when the concentration of phosphoric acid and / or its salts is set within the above range, the amounts of decomposition products A1, A2, and A3 produced are reduced, but the amount of decomposition product B produced tends to increase. On the other hand, in a preferred embodiment of the ophthalmic composition of the present invention, by further containing edetic acid and / or its salts, it becomes possible to effectively reduce the amount of decomposition product B produced.

[0052] The salts of edetic acid are not particularly limited as long as they are pharmaceutically acceptable. Examples include sodium edetate salts such as sodium edetate monohydrate, disodium edetate (EDTA), and tetrasodium edetate. The salts of edetic acid may also be in the form of solvates such as hydrates like dihydrate.

[0053] When the ophthalmic composition of the present invention contains edetic acid and / or its salts, one kind may be selected from edetic acid and its salts and 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 decomposition product B produced, preferably a salt of edetic acid, more preferably disodium edetate (EDTA).

[0054] When the ophthalmic composition of the present invention contains edetic acid and / or its salts, the concentration thereof is, for example, 0.0001 to 0.2 w / v%. From the viewpoint of further suppressing decomposition product B, 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 this specification, the concentration of edetic acid and / or its salts means the concentration converted to disodium edetate dihydrate.

[0055] [Other Components] In addition to the above components, the ophthalmic composition of the present invention may contain, if necessary, additives such as isotonic agents, polyhydric alcohols, surfactants, thickeners, buffers (other than phosphoric acid and its salts), chelating agents (other than edetic acid and its salts), cooling agents, preservatives, stabilizers, pH adjusters, etc.

[0056] The isotonic agent is not particularly limited as long as it is pharmaceutically acceptable. Examples include polyhydric alcohols such as glycerin, propylene glycol, butylene glycol, and polyethylene glycol; metal salts such as sodium chloride, potassium chloride, calcium chloride, magnesium chloride, sodium acetate, potassium acetate, sodium bisulfite, sodium hydrogen carbonate, sodium carbonate, disodium hydrogen phosphate, and sodium dihydrogen phosphate. These isotonic 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 pharmaceutically acceptable. Examples include propylene glycol, butylene glycol, polyethylene glycol, and glycerin. 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 pharmaceutically acceptable. Examples 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 alkyldiaminoethyl glycine and lauryldimethylaminoacetic acid betaine; anionic surfactants such as alkyl sulfates, N-acyl taurine salts, polyoxyethylene alkyl ether phosphates, and polyoxyethylene alkyl ether sulfates; cationic surfactants such as alkyl pyridinium 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 pharmaceutically acceptable. Examples thereof include water-soluble polymers such as carboxyvinyl polymer, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, xanthan gum, sodium chondroitin sulfate, and sodium hyaluronate; and celluloses such as hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and sodium carboxymethyl cellulose. These thickening agents may be used alone or in combination of two or more.

[0060] The buffering agent (other than phosphoric acid and its salts) is not particularly limited as long as it is pharmaceutically acceptable. Examples thereof include boric acid buffer, citric acid buffer, tartaric acid buffer, acetic acid buffer, Tris buffer, 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 action is imparted by containing phosphoric acid and / or its salts, a desired buffering action can be provided without blending a buffering agent other than phosphoric acid and its salts.

[0061] The chelating agent (other than edetic acid and its salts) is not particularly limited as long as it is pharmaceutically acceptable. 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 action is also imparted. Therefore, a desired chelating action 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 pharmaceutically acceptable. Examples thereof include l-menthol, borneol, camphor, and eucalyptus oil. These cooling agents may be used alone or in combination of two or more.

[0063] As the preservative, there is no particular limitation as long as it is pharmaceutically acceptable. For example, 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, chlorocresol, phenethyl alcohol, polidronium chloride, thimerosal, dibutylhydroxytoluene, etc. may be mentioned. These preservatives may be used alone or in combination of two or more. Among these, benzalkonium chloride is particularly preferable because it enhances the permeability of the preparation as well as the preservative effect. The concentration of the preservative can be appropriately changed depending on its type, and for example, 0.0001 to 0.1 w / v% may be mentioned. Preferably, 0.0005 to 0.05 w / v%, more preferably 0.001 to 0.05 w / v%, and particularly preferably 0.002 w / v% may be mentioned.

[0064] As the stabilizer, there is no particular limitation as long as it is pharmaceutically acceptable. For example, polyvinylpyrrolidone, sulfite, monoethanolamine, cyclodextrin, dextran, ascorbic acid, taurine, tocopherol, dibutylhydroxytoluene, etc. may be mentioned. These stabilizers may be used alone or in combination of two or more.

[0065] As the pH adjuster, there is no particular limitation as long as it is pharmaceutically acceptable. For example, acids such as hydrochloric acid, acetic acid, boric acid, aminoethylsulfonic acid, epsilon-aminocaproic acid; alkalis such as sodium hydroxide, potassium hydroxide, borax, triethanolamine, monoethanolamine, sodium hydrogen carbonate, sodium carbonate may be mentioned. These pH adjusters may be used alone or in combination of two or more.

[0066] The concentrations of these additives may be appropriately set according to the type of additive used, the properties to be imparted to the ophthalmic composition, and the like.

[0067] Furthermore, in addition to brimonidine and / or its salt and timolol and / or its salt, the ophthalmic composition of the present invention may contain, if necessary, a pharmacological component that exhibits a therapeutic effect on glaucoma or ocular hypertension, as long as the effects of the present invention are not impaired.

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

[0069] The concentrations of these pharmacological components may be appropriately set according to the type of pharmacological component used, the medicinal effects to be imparted, and the like.

[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. For example, pH 6.6 to 7.6 can be mentioned. From the viewpoint of reducing the production amount of degradation product B, preferably pH 6.7 to 7.5, more preferably pH 6.7 to 7.3, still more preferably pH 7.1 to 7.3, and particularly preferably pH 7.1 can be mentioned.

[0071] [Osmotic pressure 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 examples thereof include 0.5 to 4. From the viewpoint of reducing discomfort such as a stinging sensation of the drug solution, it is preferably 0.7 to 1.3, more preferably 0.9 to 1.1. The osmotic pressure ratio is the ratio to the osmotic pressure of a 0.9 w / v% aqueous sodium chloride solution, and the osmotic pressure is measured in accordance with the "Osmotic Pressure Method (Osmolality Measurement Method)" defined in the 17th Revised Japanese Pharmacopoeia.

[0072] [Formulation form and use] When the ophthalmic composition of the present invention is topically administered to the ocular mucosa, it can suppress the production of aqueous humor and reduce intraocular pressure by the action of brimonidine and / or its salt and timolol and / or its salt, and thus is provided as an eye drop and is suitably used for the treatment of glaucoma and ocular hypertension.

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

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

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

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

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

[0078] Regarding the decomposition products A1, A2, A3, and B of the ophthalmic composition of the present invention, they are measured by liquid chromatography (HPLC: High Performance Liquid Chromatograph Prominence manufactured by Shimadzu Corporation) under the following conditions.

[0079] (Measurement conditions for HPLC) Detector: Ultraviolet absorption photometer (measurement wavelength: 230 nm) Column: Symmetry C18, 4.6 mm I.D.×150 mm, 3.5 μm, manufactured by Waters Column temperature: 40 °C Mobile phase A: A mixture of 4.3 mM aqueous phosphoric acid / methanol / acetonitrile (volume ratio: 84 / 8 / 8) Mobile phase B: A mixture of 4.3 mM aqueous phosphoric acid / methanol / acetonitrile (volume ratio: 40 / 30 / 30) Liquid delivery of the mobile phase: The mixing ratio of mobile phase A and mobile phase B is changed as shown in Table 1, and linear concentration gradient control is performed. Washing solution: A mixture of acetonitrile / water (volume ratio: 1 / 1) Flow rate: 1.0 mL / min Area measurement range: 60 minutes

Table 1

[0080] (Calculation formula) The production amounts (display ratio %) of decomposition products A1, A2, A3, and B are calculated according to the following formula.

Equation

[0081] 4. Method for Suppressing Degradation Products In one aspect, the present invention is a method for suppressing decomposition products of an ophthalmic composition containing brimonidine and / or a salt thereof and timolol and / or a salt thereof, the method comprising the step of co-existing brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof in the composition, wherein the concentration of the phosphoric acid and / or a salt thereof is 32 mM or less, and a method for suppressing decomposition products of an ophthalmic composition is provided. In the present invention, by setting the concentration of phosphoric acid and / or a salt thereof to 32 mM or less, it becomes possible to suppress the production of decomposition products A1, A2, and A3.

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

[0083] In the method for suppressing decomposition products of the present invention, regarding brimonidine and / or its salt, timolol and / or its salt, and phosphoric acid and / or its salt, their types, concentrations, etc. may be employed alone or in combination as described in the column of "3. Ophthalmic composition" above. Further, in the method for suppressing decomposition products of the present invention, regarding other components that can be incorporated into the ophthalmic composition, the pH, osmotic pressure ratio, dosage form, container, etc. of the ophthalmic composition may also be employed alone or in combination as described in the column of "3. Ophthalmic composition" above.

[0084] 3. Method 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 its salt, timolol and / or its salt, and phosphoric acid and / or its salt, the method comprising a step of co-existing brimonidine and / or its salt, timolol and / or its salt, and phosphoric acid and / or its salt, wherein the concentration of the phosphoric acid and / or its salt is 32 mM or less. In the present invention, by setting the concentration of the phosphoric acid and / or its salt to 32 mM or less, it becomes possible to suppress decomposition products A1, A2, and A3 and improve the storage stability of the ophthalmic composition.

[0085] Further, in this method, edetic acid and / or its salt may further co-exist in the ophthalmic composition. By co-existing edetic acid and / or its salt, not only decomposition products A1, A2, and A3 but also decomposition product B can be 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, formulation 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.

Example

[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 Exactly 2 mL of each test solution was measured, purified water was added to make exactly 20 mL, and it was used as the sample solution.

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

[0091] · Measurement by Liquid Chromatography For 25 μL of the sample solution and the standard solution, measurement was carried out 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 absorption photometer (measurement wavelength: 230 nm) Column: Symmetry C18, 4.6 mm I.D.×150 mm, 3.5 μm, manufactured by Waters Column temperature: 40 °C Mobile phase A: Mixed solution of 4.3 mM aqueous phosphoric acid solution / methanol / acetonitrile (volume ratio: 84 / 8 / 8) Mobile phase B: Mixed solution of 4.3 mM aqueous phosphoric acid solution / methanol / acetonitrile (volume ratio: 40 / 30 / 30) Liquid feeding of the mobile phase: Linear concentration gradient control was performed by changing the mixing ratio of mobile phase A and mobile phase B as shown in Table 2. Washing solution: Mixed solution of acetonitrile / water (volume ratio: 1 / 1) Flow rate: 1.0 mL / min Area measurement range: 60 minutes

Table 2

[0093] (Calculation method) The production amounts (relative display rates %) of decomposition products A1, A2, A3, and B were calculated according to the following formula.

Equation

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

[0095] The production amounts (display ratio %) of decomposition products A1 (retention time: approximately 2.6 minutes), A2 (retention time: approximately 7.8 minutes), A3 (retention time: approximately 14.0 minutes), and B (retention time: approximately 15.2 minutes) in each test solution after storage are shown in Table 3. In Example 1 where the phosphate concentration was 6.3 mM, the production amounts of decomposition products A1, A2, and A3 were reduced compared to Comparative Example 1 where the phosphate concentration was 126 mM. Also, the total production amount of decomposition products A1, A2, A3, and B was 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, by setting the phosphate concentration low, the storage stability of the ophthalmic composition is improved.

[0096] On the other hand, in Example 1, although the production amounts of decomposition products A1, A2, and A3 were reduced compared to Comparative Example 1, the production amount of decomposition product B was increased. In contrast, in Example 2 where EDTA dihydrate was further formulated, the production amount of decomposition product B was so trace that it could not be detected. That is, it was confirmed that decomposition product B generated by reducing the phosphate concentration can be reduced by further adding EDTA dihydrate, and the 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 influence of the phosphate concentration on the production amount of decomposition products was verified. Specifically, test solutions (eye drops) having the compositions shown in Tables 4 and 5 were prepared, and storage and measurement of the production amount of decomposition products were carried out under the same conditions as in Test Example 1.

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

[0100] Further, when containing brimonidine tartrate and timolol maleate and setting the phosphate concentration to 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 could be completely suppressed when EDTA dihydrate was included (Examples 2 and 8 to 12).

[0101] From the results of this test, in the ophthalmic composition containing brimonidine tartrate, timolol maleate, and phosphate, setting the phosphate concentration to 32 mM or less specifically reduced the production amounts of decomposition products A1 to A3, but a new problem was confirmed that the production amount of decomposition product B increased. However, in the ophthalmic composition, it was confirmed that further blending of EDTA dihydrate specifically suppressed the production of decomposition product B (EDTA dihydrate does not reduce the production amounts of decomposition products A1 to A3). Therefore, it became clear that in addition to setting the phosphate concentration to 32 mM or less, further blending of EDTA dihydrate was most effective in reducing the decomposition products.

[0102] [Table 4]

[0103] [Table 5]

[0104] Test Example 3 In an ophthalmic composition containing brimonidine tartrate, timolol maleate, and phosphate, the effect of pH on the production amount of decomposition products was verified. Specifically, test solutions (eye drops) having the compositions shown in Table 6 were prepared, and were stored under the same conditions as in Test Example 1 except that 5-mL polypropylene containers were used as the containers for filling the test solutions, and the production amount of decomposition products was measured.

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

[0106]

Table 6

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

[0108]

Table 7

[0109]

Table 8

[0110]

Table 9

[0111]

Table 10

Claims

1. An ophthalmic 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.

2. The ophthalmic composition according to claim 1, wherein the pH is 7.1 to 7.

3.

3. The ophthalmic composition according to claim 1 or 2, wherein the phosphoric acid and / or a salt thereof contains at least one of disodium hydrogen phosphate and sodium dihydrogen phosphate.

4. The ophthalmic composition according to claim 3, wherein the phosphoric acid and / or a salt thereof contains disodium hydrogen phosphate and sodium dihydrogen phosphate.

5. The ophthalmic composition according to any one of claims 1 to 4, wherein the concentration of phosphoric acid and / or a salt thereof is 0.01 to 32 mM.

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

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

8. The ophthalmic composition according to any one of claims 1 to 4, 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%, and the concentration of phosphoric acid and / or a salt thereof is 0.3 to 32 mM.

9. The ophthalmic composition according to claim 8, wherein the concentration of phosphoric acid and / or a salt thereof is 0.3 to 6.3 mM.

10. The ophthalmic composition according to any one of claims 1 to 9, which is an eye drop.

11. A method for suppressing decomposition products in an ophthalmic composition comprising brimonidine and / or a salt thereof and timolol and / or a salt thereof, the method comprising a step of coexisting brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof in the ophthalmic composition, wherein the concentration of the phosphoric acid and / or a salt thereof is 32 mM or less.

12. A method for improving the storage stability of an ophthalmic composition comprising brimonidine and / or a salt thereof and timolol and / or a salt thereof, the method comprising a step of coexisting brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof in the ophthalmic composition, wherein the concentration of the phosphoric acid and / or a salt thereof is 32 mM or less.

13. A method for improving the storage stability of an ophthalmic composition comprising brimonidine and / or a salt thereof and timolol and / or a salt thereof, the method comprising a step of coexisting brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof in the ophthalmic composition, wherein the concentration of the phosphoric acid and / or a salt thereof is 32 mM or less.

14. A method for improving the storage stability of an ophthalmic composition comprising brimonidine and / or a salt thereof and timolol and / or a salt thereof, the method comprising a step of coexisting brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof in the ophthalmic composition, wherein the concentration of the phosphoric acid and / or a salt thereof is 32 mM or less.

15. A method for improving the storage stability of an ophthalmic composition comprising brimonidine and / or a salt thereof and timolol and / or a salt thereof, the method comprising a step of coexisting brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof in the ophthalmic composition, wherein the concentration of the phosphoric acid and / or a salt thereof is 32 mM or less.

16. A method for improving the storage stability of an ophthalmic composition comprising brimonidine and / or a salt thereof and timolol and / or a salt thereof, the method comprising a step of coexisting brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof in the ophthalmic composition, wherein the concentration of the phosphoric acid and / or a salt thereof is 32 mM or less.

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