JP2019199470A - Ophthalmic composition - Google Patents

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

  The present invention relates to an ophthalmic composition comprising brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof, and capable of suppressing the generation of degradation products due to storage.

  Brimonidine and its salts are known as adrenergic α2 receptor agonists, and reduce intraocular pressure by promoting the outflow of aqueous humor through the uveoscleral outflow tract along with suppression of production of aqueous humor. In the past, it has been used to treat glaucoma and ocular hypertension.

  Timolol and its salts are known as β receptor blockers, have the effect of reducing intraocular pressure by suppressing the production of aqueous humor, and are conventionally used for the treatment of glaucoma and ocular hypertension. .

  In recent years, in order to enhance the therapeutic effect of glaucoma and ocular hypertension, a preparation using brimonidine and / or a salt thereof and 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 an excellent effect of reducing intraocular pressure compared to the case where brimonidine or timolol is used alone. ing. 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 of benzalkonium chloride is used to treat glaucoma and ocular hypertension. Is disclosed to be effective. 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 and ocular hypertension, and has side effects. It is disclosed that it can be reduced.

  Conventionally, a formulation technique that focuses on formulation stability has also been studied for a formulation using brimonidine and / or a salt thereof and timolol and / or a salt thereof in combination. For example, in Patent Document 4, a composition containing about 1 to 4.5 mM brimonidine and about 2 to 16 mM timolol and having a pH of about 7 to 8.5 can suppress the generation of decomposition products, It is disclosed that the stability is improved.

JP 2005-523316 A International Publication No. 2008/24846 International Publication No. 2016/149498 Special table 2009-533462

  The present invention provides a novel ophthalmic composition comprising brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof.

  As a result of further studies, 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, phosphoric acid and / or It has been found that the production of decomposition products can be effectively suppressed by reducing the concentration of the salt. Furthermore, in the ophthalmic composition, the concentration of phosphoric acid and / or a salt thereof can be reduced, and the addition of edetic acid and / or a salt thereof can suppress the generation of decomposition products more effectively. I found it. The present invention has been completed by further studies based on these findings.

As an embodiment of the present invention, the following inventions are provided.
Item 1. Brimonidine and / or salt thereof, timolol and / or salt thereof, phosphoric acid and / or salt thereof,
An ophthalmic composition wherein the concentration of phosphoric acid and / or a salt thereof is 32 mM or less.
Item 2. Item 4. The ophthalmic composition according to Item 1, further comprising edetic acid and / or a salt thereof.
Item 3. Item 3. The ophthalmic composition according to Item 1 or 2, wherein the pH is 7.1 to 7.3.
Item 4. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. Item 3. 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. Item 3. 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. Item 3. 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 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%, and the concentration of phosphoric acid and / or its salt is 0.3- Item 3. The ophthalmic composition according to Item 2, wherein the composition is 32 mM and the concentration of edetic acid and / or a salt thereof is 0.01 w / v%.
Item 20. 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. Item 21. The ophthalmic composition according to any one of Items 1 to 20, which is an eye drop.
Item 22. Item 22. The ophthalmic composition according to any one of Items 1 to 21, wherein the amount of decomposition products produced when stored 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 containing edetic acid and / or a salt thereof,
The concentration of phosphoric acid and / or salt thereof is 0.01-32 mM,
The concentration of brimonidine and / or its salt is 0.01-1 w / v%,
The concentration of timolol and / or its salt is 0.1-1.5 w / v%,
The concentration of edetic acid and / or salt thereof optionally contained is 0.0001 to 0.2 w / v%,
Ophthalmic composition.
Item 24. Brimonidine and / or salt thereof, timolol and / or salt thereof, phosphoric acid and / or salt thereof, and optionally edetic acid and / or salt thereof, having a pH of 7.1 to 7.3 An ophthalmic composition comprising:
The concentration of phosphoric acid and / or salt thereof is 0.01-32 mM,
The concentration of brimonidine and / or its salt is 0.01-1 w / v%,
The concentration of timolol and / or its salt is 0.1-1.5 w / v%,
The concentration of edetic acid and / or salt thereof optionally contained is 0.0001 to 0.2 w / v%,
Ophthalmic composition.
Item 25. Brimonidine and / or salt thereof, timolol and / or salt thereof, phosphoric acid and / or salt thereof, preservative, optionally edetic acid and / or salt thereof, pH 7.1 to 7 .3 an ophthalmic composition,
The concentration of phosphoric acid and / or salt thereof is 0.01-32 mM,
The concentration of brimonidine and / or its salt is 0.01-1 w / v%,
The concentration of timolol and / or its salt is 0.1-1.5 w / v%,
The concentration of the preservative is 0.0001 to 0.1 w / v%,
The concentration of edetic acid and / or salt thereof optionally contained is 0.0001 to 0.2 w / v%,
Ophthalmic composition.
Item 26. Item 25. The ophthalmic composition according to any one of Items 23 to 25, wherein the brimonidine salt is brimonidine tartrate and / or the timolol salt 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 containing 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 salt thereof is 6.3 mM,
The concentration of edetic acid and / or its salt 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 containing 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 salt thereof is 6.3 mM,
The concentration of edetic acid and / or its salt optionally contained is 0.01 w / v%,
pH is 7.1,
Ophthalmic composition.
Item 29. An ophthalmic composition containing brimonidine and / or a salt thereof, timolol and / or a salt thereof, phosphoric acid and / or a salt thereof, and benzalkonium chloride, and optionally containing edetic acid and / or a salt thereof. And
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 salt thereof is 6.3 mM,
The concentration of benzalkonium chloride is 0.002 w / v%,
The concentration of edetic acid and / or its salt optionally contained is 0.01 w / v%,
pH is 7.1,
Ophthalmic composition.
Item 30. Item 30. The ophthalmic composition according to any one of Items 27 to 29, wherein the brimonidine salt is brimonidine tartrate and / or the timolol salt is timolol maleate.
Item 31. Ophthalmic composition in which the salt of brimonidine tartrate, timolol includes timolol maleate, disodium hydrogen phosphate and sodium dihydrogen phosphate, benzalkonium chloride and optionally edetic acid and / or its salts A thing,
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 its salt optionally contained is 0.01 w / v%,
pH is 7.1,
Ophthalmic composition.

As another aspect, the present invention provides the following inventions.
Term A1. A method for suppressing degradation products in an ophthalmic composition comprising brimonidine and / or a salt thereof and timolol and / or a salt thereof,
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,
The concentration of the phosphoric acid and / or salt thereof is 32 mM or less.
Method for suppressing decomposition products.
Term A2. Furthermore, the suppression method of the decomposition product of term A1 which makes edetic acid and / or its salt coexist in an ophthalmic composition.

As another aspect, the present invention provides the following inventions.
Term B1. 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,
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;
The concentration of the phosphoric acid and / or salt thereof is 32 mM or less.
How to improve storage stability.
Term B2. Furthermore, the storage stability improvement method according to Item B1, wherein edetic acid and / or a salt thereof is allowed to coexist in the ophthalmic composition.

As another aspect, the present invention provides the following inventions.
Term C1. Production of an ophthalmic composition 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. Use for.
Term C2. The use according to Item C1, wherein the composition further comprises edetic acid and / or a salt thereof.

  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 a predetermined value or less. By setting to, the amount of decomposition products generated by storage can be reduced. As a result, the storage stability of the ophthalmic composition can be improved.

  Further, 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, Although there exists a tendency for another decomposition product to arise, in this invention, the production amount of the said decomposition product can also be suppressed by containing edetic acid and / or its salt further. As a result, the storage stability of the ophthalmic composition can be further improved.

It is the chromatogram obtained by using for the HPLC measurement the test liquid of Example 1 before a preservation | save and after a preservation | save. It is the chromatogram obtained by using the test liquid of Example 1 after a preservation | save, and the comparative example 1 for a HPLC measurement.

  Ophthalmic compositions such as eye drops are administered directly to the ocular mucosa, so it is necessary to ensure high safety, and it is necessary to suppress the generation of degradation products due to storage. In particular, in the development of medicinal products, when the concentration of decomposition products generated by storage under specified conditions exceeds a certain amount, it is mandatory to identify the structure of the decomposition products and report safety. (Regarding revision of guidelines on drug impurities in pharmaceutical products containing new active ingredients No. 0624001), in developing eye drops, the concentration of degradation products usually exceeds 1.0% This obligation arises in some cases. For this reason, in the preparation of eye drops, it is necessary to sufficiently suppress the generation of degradation products caused by storage.

  Patent Documents 1 to 4 include, as a specific example of a preparation containing brimonidine or a salt thereof and timolol or a salt thereof, an embodiment containing 96.1 to 111.4 mM of phosphoric acid and / or a salt thereof in a calculated concentration. It is shown. Therefore, the present inventors have studied to verify the stability of the preparations specifically disclosed in Patent Documents 1 to 4, and in such preparations, the decomposition product (described later) is obtained by storage. It has been found that there is a problem that decomposition products A1, A2, and A3) are generated. Then, the inventors of the present invention use an ophthalmic composition containing brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof at a concentration of 32 mM phosphoric acid and / or a salt thereof. It discovered that the production | generation of decomposition products A1, A2, and A3 can be suppressed effectively by setting to the following.

  On the other hand, in the 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 generation amount of the decomposition products A1, A2, and A3 can be reduced, but another decomposition product ( It was confirmed that the decomposition product B) described later increases. Therefore, the inventors have made further studies, and in the ophthalmic composition, the concentration of phosphoric acid and / or its salt is set to 32 mM or less, and edetic acid and / or its salt is contained. Thus, it was found that the generation of the decomposition products A1, A2, and A3 can be suppressed while the generation of the decomposition product B can be effectively suppressed.

  It is to be understood that the terms used in this specification are used in the meaning normally used in the art unless otherwise specified. Thus, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

1. Definitions As used herein, “ophthalmic composition” means a pharmaceutical composition for ophthalmic use.

  As used herein, “brimonidine” is a compound known as an adrenergic α2 receptor agonist and is 5-bromo-N- (4,5-dihydro-1H-imidazol-2-yl) quinoxaline-6-amine. Point to.

  In the present specification, “thymolol” is a compound known as a β receptor blocker, and is (2S) -1- (tert-butylamino) -3- (4-morpholino-1,2,5-thiadiazole). -3-yloxy) -2-propanol.

In the present specification, “phosphoric acid” is one of phosphorus oxo acids and refers to an inorganic acid having the chemical formula H ₃ PO ₄ .

In this specification, “edetic acid” refers to a known compound that is also called ethylenediaminetetraacetic acid.

  In the present specification, “degradation product A1” refers to brimonidine and / or a salt thereof, timolol and / or a salt thereof, and an ophthalmic composition containing phosphoric acid and / or a salt thereof, It is a substance corresponding to a peak that is observed at a retention time of about 2.6 minutes when HPLC measurement is performed under the conditions described in the column “HPLC measurement conditions”. “Decomposition product A1” is a decomposition product produced by the interaction of brimonidine and / or its salt with timolol and / or its salt.

  In the present specification, the “decomposition product A2” means that after 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, “( It is a substance corresponding to a peak observed at a time when the retention time is about 7.8 minutes when HPLC measurement is performed under the conditions described in the column “HPLC measurement conditions”. “Decomposition product A2” is a decomposition product caused by brimonidine and / or a salt thereof.

  In the present specification, “degradation product A3” refers to brimonidine and / or a salt thereof, timolol and / or a salt thereof, and an ophthalmic composition containing phosphoric acid and / or a salt thereof, It is a substance corresponding to a peak observed at a time when the retention time is about 14.0 minutes when HPLC measurement is performed under the conditions described in the column “HPLC measurement conditions”. “Decomposition product A3” is a decomposition product caused by brimonidine and / or a salt thereof.

  In this specification, “decomposition product B” includes brimonidine and / or a salt thereof, timolol and / or a salt thereof, phosphoric acid and / or a salt thereof, and includes edetic acid and / or a salt thereof. A substance corresponding to the peak observed at a retention time of about 15.2 minutes when HPLC measurement was performed under the conditions described in the column of “(HPLC measurement conditions)” after storage of a non-ophthalmic composition It is. “Decomposition product B” is a decomposition product resulting from brimonidine and / or a salt thereof.

  In FIG. 1, after 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, they are described in the column of “(HPLC measurement conditions)”. Shows a chromatogram obtained by HPLC measurement under different conditions. In the chromatogram, peaks corresponding to the decomposition products A1, A2, A3, and B are clearly shown.

  The degradation product A1 contains phosphoric acid and / or a salt thereof and is not detected even when an ophthalmic composition containing only brimonidine and / or a salt thereof, or timolol and / or a salt thereof is stored. Is detected by storing an ophthalmic composition comprising brimonidine and / or a salt thereof and timolol and / or a salt thereof together with phosphoric acid and / or a salt thereof. Note that the decomposition product A1 is not detected immediately after the ophthalmic composition is prepared. Therefore, it has been confirmed that the degradation product A1 is a degradation product produced by the involvement of at least brimonidine and / or its salt and timolol and / or its salt by storage of the ophthalmic composition.

  None of the degradation products A2, A3, and B are detected even when an ophthalmic composition containing no brimonidine and / or a salt thereof is stored, and is not detected immediately after the ophthalmic composition is prepared. . Therefore, it has been confirmed that the decomposition products A2, A3, and B are decomposition products produced by the involvement of at least brimonidine and / or a salt thereof upon storage of the ophthalmic composition. As shown in Test Example 2 to be described later, the decomposition products A1, A2, and A3 can suppress the production by setting the concentration of phosphoric acid and / or its salt in the ophthalmic composition to 32 mM or less. It becomes possible. Decomposition product B is a substance whose production amount increases when the concentration of phosphoric acid and / or its salt in the ophthalmic composition is set to 32 mM or less, and its production is suppressed by edetic acid and / or its salt. It becomes possible to do.

  In the present specification, “suppression of decomposition products” includes not only reducing the production amount of decomposition products but also suppressing generation completely. In addition, the “method for suppressing decomposition products” is a method for reducing the generation amount of decomposition products generated by storage of an ophthalmic composition or completely suppressing the generation thereof.

  Further, the degree of the “decomposition product suppression method” can be indicated by the amount of decomposition product produced when stored at 60 ° C. for 4 weeks.

  In the present specification, “storage stability” means that the content of brimonidine and / or a salt thereof, and timolol and / or a salt thereof is reduced by suppressing the generation of degradation products generated by storage of an ophthalmic composition. It means the degree not to let it. The “method for improving storage stability” is to reduce the content of brimonidine and / or a salt thereof, and timolol and / or a salt thereof by suppressing the generation of decomposition products generated by storage of an ophthalmic composition. It is a method of suppressing.

  The degree of “storage stability” can be indicated by the amount of decomposition products generated when stored at 60 ° C. for 4 weeks.

2. DESCRIPTION OF PREFERRED EMBODIMENTS The following is a description of preferred embodiments, but it should be understood that this embodiment is illustrative of the invention and that the scope of the invention is not limited to such preferred embodiments. . It should also be understood that those skilled in the art can easily make modifications, changes and the like within the scope of the present invention with reference to the preferred embodiments described below. Regarding these embodiments, those skilled in the art can appropriately combine arbitrary embodiments.

3. Ophthalmic composition As one embodiment of the present invention, brimonidine and / or a salt thereof, timolol and / or a salt thereof, phosphoric acid and / or a salt thereof are included, and the concentration of phosphoric acid and / or a salt thereof is 32 mM or less. An ophthalmic composition is provided. According to the ophthalmic composition of this aspect, it is possible to solve the problem of suppressing the decomposition products A1, A2, and A3.

  Further, as another embodiment of the present invention, brimonidine and / or a salt thereof, timolol and / or a salt thereof, phosphoric acid and / or a salt thereof of 32 mM or less, and edetic acid and / or a salt thereof are contained. An ophthalmic composition is provided. According to the ophthalmic composition of this aspect, it is possible to solve the problem of suppressing the decomposition product B as well as the decomposition products A1, A2, and A3.

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

[Brimonidine and / or its salt]
The brimonidine salt is not particularly limited as long as it is pharmaceutically acceptable, and specific examples thereof include organic acid salts such as tartrate and acetate; inorganic acid salts such as hydrochloride and the like. Further, brimonidine and / or a salt thereof may be in the form of a solvate such as a hydrate.

  In the present invention, either brimonidine or a salt thereof may be used alone, or a combination thereof may be used. Among brimonidine and its salt, brimonidine tartrate is preferable.

  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 according to the degree of symptom of the patient to be applied, the amount applied per time, and the like. However, 0.01-1 w / v% is mentioned, for example. From the viewpoint of suppressing the concentration of each decomposition product to 1.0% or less, it is preferably 0.05 to 0.3 w / v%, more preferably 0.1 to 0.2 w / v%, particularly preferably 0.8. 1 w / v% is mentioned. In the present specification, the concentration of brimonidine and / or a salt thereof means a concentration converted to brimonidine tartrate.

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

  In the present invention, either timolol or a salt thereof may be used alone or in combination. Among timolol and its salt, timolol maleate is preferable.

  In the ophthalmic composition of the present invention, the concentration of timolol and / or a salt thereof is not particularly limited, and may be set as appropriate according to the degree of symptom of the patient to be applied, the amount applied per time, and the like. Is, for example, 0.1 to 1.5 w / v%. From the viewpoint of further suppressing the generation 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%, particularly preferably 0.68 w / v. %. In the present specification, the concentration of timolol and / or a salt thereof means a concentration converted to timolol maleate.

[Phosphoric acid and / or its salt]
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. Thus, by setting the concentration of phosphoric acid and / or a salt thereof to a predetermined value or less, it is possible to suppress decomposition products A1, A2, and A3 due to storage.

  The salt of phosphoric acid is not particularly limited as long as it is pharmaceutically acceptable. For example, a dialkali metal phosphate such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; sodium dihydrogen phosphate And alkali metal dihydrogen phosphates such as potassium dihydrogen phosphate; trialkali metal phosphates such as trisodium phosphate and tripotassium phosphate. 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, the form of dodecahydrate, sodium dihydrogen phosphate, In some cases, it may be in the form of a dihydrate.

  In the present invention, one kind selected from phosphoric acid and its salt may be used alone, or two or more kinds may be used in combination.

  Among phosphoric acid and its salts, from the viewpoint of providing a buffering action suitable as an ophthalmic composition while effectively suppressing the formation of decomposition products A1, A2 and A3, preferably a dialkali metal hydrogen phosphate A combination of a salt and an alkali metal dihydrogen phosphate, more preferably a combination of disodium hydrogen phosphate and sodium dihydrogen phosphate. When the dihydrogen alkali metal phosphate and the alkali metal dihydrogen phosphate are used in combination, the ratio of these is not particularly limited, but for example, dihydrogen phosphate per mole of hydrogen alkali metal phosphate is used. 0.005-1.0 mol of hydrogen alkali metal salts are mentioned. From the viewpoint of further stabilizing the pH, it is preferably 0.01 to 0.4 mol, more preferably 0.05 to 0.5 mol, and particularly preferably 0.26.

  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. In this way, by making the concentration of phosphoric acid and / or a salt thereof equal to or lower than a predetermined value, it is possible to suppress the formation of decomposition products A1, A2, and A3. From the viewpoint of more effectively suppressing the production 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, particularly preferably 6.3 mM. The following are mentioned. Further, the lower limit value of the concentration of phosphoric acid and / or a salt thereof is not particularly limited, and examples thereof include 0.01 mM or more. In an ophthalmic composition that does not contain edetic acid and / or a salt thereof, from the viewpoint of reducing the amount of decomposition product B produced, it is preferably 0.3 mM or more, more preferably 3.2 mM or more, particularly preferably 6 .3 mM or more. A 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, 0.3 to 32 mM is preferable, 0.3 to 16 mM is more preferable, and 0.3 to 6.3 mM is particularly preferable.

[Edeto acid and / or its salt]
The ophthalmic composition of the present invention may contain edetic acid and / or a salt thereof in addition to the above 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, a decomposition product when the concentration of phosphoric acid and / or a salt thereof is set within the above range Although the production amounts of A1, A2 and A3 are reduced, the production amount of the decomposition product B tends to increase. In contrast, in a preferred embodiment of the ophthalmic composition of the present invention, the amount of decomposition product B can be effectively reduced by further containing edetic acid and / or a salt thereof. Become.

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

  When the ophthalmic composition of the present invention contains edetic acid and / or a salt thereof, one may be selected from edetic acid and a salt thereof and used alone or in combination of two or more. May be. Among the edetic acids and salts thereof, from the viewpoint of more effectively reducing the amount of decomposition product B produced, a salt of edetic acid is preferable, and disodium edetate (EDTA) is more preferable.

  When edetic acid and / or a salt thereof is contained in the ophthalmic composition of the present invention, the concentration is, for example, 0.0001 to 0.2 w / v%. From the viewpoint of further suppressing the decomposition product B, preferably 0.001 to 0.03 w / v%, more preferably 0.005 to 0.015 w / v%, particularly preferably 0.01 w / v%. Can be mentioned. In this specification, the density | concentration of edetic acid and / or its salt means the density | concentration converted into edetic acid disodium dihydrate.

[Other ingredients]
In the ophthalmic composition of the present invention, in addition to the above components, an isotonic agent, a polyhydric alcohol, a surfactant, a thickener, a buffer (other than phosphoric acid and its salt), a chelate, if necessary. You may contain additives, such as an agent (except edetic acid and its salt), a refreshing agent, antiseptic | preservative, a stabilizer, a pH adjuster.

  The isotonic agent is not particularly limited as long as it is pharmaceutically acceptable. For example, polyhydric alcohols such as glycerin, propylene glycol, butylene glycol, and polyethylene glycol; sodium chloride, potassium chloride, calcium chloride, chloride Examples thereof include metal salts such as magnesium, sodium acetate, potassium acetate, sodium hydrogen sulfite, 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.

  The polyhydric alcohol is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include propylene glycol, butylene glycol, polyethylene glycol, and glycerin. These polyhydric alcohols may be used individually by 1 type, and may be used in combination of 2 or more type.

  The surfactant is not particularly limited as long as it is pharmaceutically acceptable. For example, tyloxapol, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, polyoxyethylene sorbitan fatty acid ester, octoxy Nonionic surfactants such as Nord; amphoteric surfactants such as alkyldiaminoethylglycine and lauryldimethylaminoacetic acid betaine; alkyl sulfates, N-acyl taurine salts, polyoxyethylene alkyl ether phosphates, polyoxyethylene alkyls Anionic surfactants such as ether sulfates; and cationic surfactants such as alkylpyridinium salts and alkylamine salts. These surfactants may be used individually by 1 type, and may be used in combination of 2 or more type.

  The thickening agent is not particularly limited as long as it is pharmaceutically acceptable, but for example, it has a high water solubility such as carboxyvinyl polymer, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, xanthan gum, sodium chondroitin sulfate, sodium hyaluronate, etc. Molecule: Celluloses such as hydroxyethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and the like. These thickeners may be used alone or in combination of two or more.

  The buffer (other than phosphate and its salts) is not particularly limited as long as it is pharmaceutically acceptable. For example, borate buffer, citrate buffer, tartrate buffer, acetate buffer, Tris buffer Agents, amino acids and the like. These buffering agents may be used alone or in combination of two or more. In addition, since the ophthalmic composition of the present invention provides a buffering action by including phosphoric acid and / or a salt thereof, a desired buffering action can be obtained without adding a buffering agent other than phosphoric acid and a salt thereof. Can be provided.

  The chelating agent (other than edetic acid and its salt) is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include citric acid and its salt. These chelating agents may be used individually by 1 type, and may be used in combination of 2 or more type. In addition, in the ophthalmic composition of the present invention, when edetic acid and / or a salt thereof is contained, a chelating action is also imparted. Therefore, a desired chelating agent other than edetic acid and its salt is added. A chelating action can be provided.

  The refreshing agent is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include l-menthol, borneol, camphor, and eucalyptus oil. These refreshing agents may be used alone or in combination of two or more.

The preservative is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include sorbic acid or a salt thereof, benzoic acid or a salt thereof, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, chloro Butanol, Chlorhexidine gluconate, Chlorhexidine hydrochloride, Chlorhexidine acetate, Boric acid or its salt, Dehydroacetic acid or its salt, Benzalkonium chloride, Benzalkonium bromide, Benzethonium chloride, Benzyl alcohol, Zinc chloride, Parachlormeta Examples include xylenol, chlorcresol, phenethyl alcohol, polydronium chloride, thimerosal, and dibutylhydroxytoluene. These preservatives may be used individually by 1 type, and may be used in combination of 2 or more type. Among these, benzalkonium chloride is particularly preferable because it increases the permeability of the preparation together with the antiseptic effect.
Although the density | concentration of antiseptic | preservative can be suitably changed with the kind, 0.0001-0.1 w / v% is mentioned, for example. Preferably it is 0.0005-0.05 w / v%, More preferably, it is 0.001-0.05 w / v%, Most preferably, 0.002 w / v% is mentioned.

  The stabilizer is not particularly limited as long as it is pharmaceutically acceptable. Examples of the stabilizer include polyvinylpyrrolidone, sulfite, monoethanolamine, cyclodextrin, dextran, ascorbic acid, taurine, tocopherol, and dibutylhydroxytoluene. Can be mentioned. These stabilizers may be used individually by 1 type, and may be used in combination of 2 or more type.

  The pH adjuster is not particularly limited as long as it is pharmaceutically acceptable. Examples thereof include acids such as hydrochloric acid, acetic acid, boric acid, aminoethylsulfonic acid, epsilon-aminocaproic acid; sodium hydroxide, potassium hydroxide , Alkali such as borax, triethanolamine, monoethanolamine, sodium hydrogencarbonate, sodium carbonate. These pH adjusters may be used alone or in combination of two or more.

  What is necessary is just to set the density | concentration of these additives suitably according to the characteristic etc. which should be provided to the kind of additive to be used, or an ophthalmic composition.

  Furthermore, in the ophthalmic composition of the present invention, in addition to brimonidine and / or a salt thereof and timolol and / or a salt thereof, as long as it does not interfere with the effects of the present invention, glaucoma and ocular hypertension can be prevented. And a pharmacological component showing a therapeutic effect.

Examples of such pharmacological components include prostaglandins such as tafluprost, latanoprost, and isopropyl unoprostone; parasympathomimetic drugs such as pilocarpine hydrochloride; anticholinesterase drugs such as distigmine bromide; and sympathetic nerves such as dipivefrin hydrochloride. Stimulants; β ₁ blockers such as betaxolol hydrochloride; α ₁ / β blockers such as nipradilol and levobanolol hydrochloride; α ₁ blockers such as bunazosin hydrochloride and the like. These pharmacological components may be used alone or in combination of two or more.

  What is necessary is just to set the density | concentration of these pharmacological components suitably according to the kind of pharmacological component to be used, the medicinal effect to be provided, etc.

[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 examples thereof include pH 6.6 to 7.6. From the viewpoint of reducing the production amount of the decomposition product B, the pH is preferably 6.7 to 7.5, more preferably 6.7 to 7.3, still more preferably 7.1 to 7.3, and particularly preferably. pH 7.1 is mentioned.

[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 chemical solution irritation, 0.7 to 1.3 is preferable, and 0.9 to 1.1 is more preferable. The osmotic pressure ratio is a ratio to the osmotic pressure of a 0.9 w / v% sodium chloride aqueous solution, and the osmotic pressure is in accordance with the “osmotic pressure method (osmolarity measurement method)” defined in the 17th revision Japanese Pharmacopoeia Measured.

[Formulation and use]
When the ophthalmic composition of the present invention is locally administered to the ocular mucosa, the action of brimonidine and / or its salt and timolol and / or its salt suppresses the production of aqueous humor and reduces intraocular pressure. Therefore, it is provided as an eye drop and is suitably used for the treatment of glaucoma and ocular hypertension.

[container]
The container for storing the ophthalmic composition of the present invention is not particularly limited as long as it is conventionally used as an eye drop container, and may be made of glass or plastic. When the plastic container is used as the container for storing the ophthalmic composition of the present invention, the constituent material of the plastic container is not particularly limited. For example, polyethylene naphthalate, polyarylate, polyethylene terephthalate, polypropylene, polyethylene, Any one type of polyimide or a mixture of two or more types may be mentioned. From the viewpoint of more effectively exerting the effect of suppressing the decomposition product B due to storage, the material of the container main body (the member forming the accommodating portion for accommodating the ophthalmic composition) is preferably polyethylene or polypropylene, More preferred is polyethylene.

[Characteristic]
According to the ophthalmic composition of the present invention, the decomposition products A1, A2 and A3 can be suppressed. Specifically, as the degree of suppression of the decomposition products A1, A2 and A3 in the ophthalmic composition of the present invention, specifically, each of the decomposition products A1, A2 and A3 after being stored in the dark at 60 ° C. for 4 weeks. A production amount is 1.0% or less. From the viewpoint that the ophthalmic composition is more stable, it is preferably 0.9% or less, more preferably 0.85% or less.

  Further, when the ophthalmic composition of the present invention contains edetic acid and / or a salt thereof, the decomposition product B can be suppressed. Specifically, the degree of inhibition of the decomposition product B in the ophthalmic composition of the present invention is 1.0% or less of the decomposition product B after being stored in a dark place at 60 ° C. for 4 weeks. From the viewpoint that the ophthalmic composition is more stable, it is preferably 0.1% or less, more preferably 0%.

  Moreover, as a suitable aspect of the ophthalmic composition of the present invention, the total amount of decomposition products A1, A2, A3, and B after being stored in a dark place at 60 ° C. for 4 weeks is 2.0% or less. From the viewpoint that the ophthalmic composition is more stable, it is preferably 1.5% or less, more preferably 1.3% or less.

  In the present specification, the concentrations of the decomposition products A1, A2, A3, and B are concentrations in the ophthalmic composition determined according to the HPLC measurement conditions and calculation formulas shown below.

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

(HPLC measurement conditions)
Detector: UV absorptiometer (measurement wavelength: 230 nm)
Column: Symmetry C18, 4.6 mm I.D. D. × 150 mm, 3.5 μm, Waters column temperature: 40 ° C.
Mobile phase A: Mixed solution of 4.3 mM phosphoric acid aqueous solution / methanol / acetonitrile (volume ratio: 84/8/8) Mobile phase B: 4.3 mM phosphoric acid aqueous solution / methanol / acetonitrile (volume ratio: 40/30/30) Liquid mixture mobile phase feeding: The mixing ratio of the mobile phase A and the mobile phase B is changed as shown in Table 1 to control the linear concentration gradient.
Washing liquid: acetonitrile / water (volume ratio: 1/1) mixed liquid flow rate: 1.0 mL / min
Area measurement range: 60 minutes

(Calculation formula)
In accordance with the following equation, the amount of decomposition products A1, A2, A3, and B generated (vs. display rate%) is calculated.

4). In one embodiment, the present invention relates to a method for inhibiting degradation products of an ophthalmic composition comprising brimonidine and / or a salt thereof and timolol and / or a salt thereof, the composition comprising: Including a step of coexisting brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof, and the concentration of the phosphoric acid and / or the salt thereof is 32 mM or less. A method of inhibiting degradation products of ophthalmic compositions is provided. In this invention, it becomes possible to suppress the production | generation of decomposition products A1, A2, and A3 by making the density | concentration of phosphoric acid and / or its salt into 32 mM or less.

  In the method, edetic acid and / or a salt thereof may be allowed to coexist in the ophthalmic composition. By allowing edetic acid and / or a salt thereof to coexist, it is possible to suppress not only the decomposition products A1, A2 and A3 but also the decomposition product B.

  In the method for inhibiting degradation products of the present invention, regarding brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof, the type, concentration and the like thereof are described in “3. Those described in the column of “Ophthalmic composition” may be used alone or in combination. In addition, in the method for inhibiting degradation products of the present invention, other components that can be blended in the ophthalmic composition, pH, osmotic pressure ratio, formulation form, container, etc. of the ophthalmic composition are also described in “3. You may employ | adopt the thing as described in the column of a thing individually or in combination.

3. Method for Improving Storage Stability In one embodiment, the present invention improves 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 comprises the step of coexisting brimonidine and / or a salt thereof, timolol and / or a salt thereof, and phosphoric acid and / or a salt thereof, and the concentration of the phosphoric acid and / or the salt thereof is 32 mM or less. A method for improving the storage stability 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 is possible to suppress degradation products A1, A2, and A3 and improve the storage stability of the ophthalmic composition. .

  In the method, edetic acid and / or a salt thereof may be allowed to coexist in the ophthalmic composition. By allowing edetic acid and / or a salt thereof to coexist, 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.

  Regarding the brimonidine and / or salt thereof, timolol and / or salt thereof, and phosphoric acid and / or salt thereof used in the method for improving storage stability of the present invention, the type, concentration and the like thereof are described in “3. Those described in the column of “Ophthalmic composition” may be used alone or in combination. In the method for improving the storage stability of the present invention, other components that can be blended in the ophthalmic composition, pH, osmotic pressure ratio, formulation form, container, etc. of the ophthalmic composition are also described in “3. You may employ | adopt the thing as described in the column of a thing individually or in combination.

  EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

Test example 1
Test solutions (eye drops) having the compositions shown in Table 3 were prepared. 5 mL of each eye drop was filled in 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.

<HPLC conditions>
-Preparation of sample solution Each test solution was accurately weighed in 2 mL, and purified water was added to make exactly 20 mL to obtain a sample solution.

-Preparation of standard solution 10 mg of a brimonidine tartrate standard product was accurately weighed and purified water was added to make exactly 100 mL to obtain a standard solution.

・ Measurement by liquid chromatography About 25 μL of the sample solution and the standard solution, measurement is performed by liquid chromatography under the following conditions (high-speed liquid chromatograph: Prominence, manufactured by Shimadzu Corporation), and the peak area of the decomposition product in each sample solution, and The peak area of brimonidine tartrate in the standard solution was determined by the automatic integration method.

(Measurement condition)
Detector: UV absorptiometer (measurement wavelength: 230 nm)
Column: Symmetry C18, 4.6 mm I.D. D. × 150 mm, 3.5 μm, Waters column temperature: 40 ° C.
Mobile phase A: Mixed solution of 4.3 mM phosphoric acid aqueous solution / methanol / acetonitrile (volume ratio: 84/8/8) Mobile phase B: 4.3 mM phosphoric acid aqueous solution / methanol / acetonitrile (volume ratio: 40/30/30) Liquid mixture mobile phase feeding: The mixing ratio of mobile phase A and mobile phase B was changed as shown in Table 2 to control the linear concentration gradient.
Washing liquid: acetonitrile / water (volume ratio: 1/1) mixed liquid flow rate: 1.0 mL / min
Area measurement range: 60 minutes

(Method of calculation)
According to the following formula | equation, the production amount (vs. display rate%) of decomposition products A1, A2, A3, and B was calculated.

  FIG. 1 shows a chromatogram obtained by subjecting the test solution of Example 1 before and after storage to HPLC. Further, FIG. 2 shows a chromatogram obtained by subjecting the test solutions of Example 1 and Comparative Example 1 after storage to HPLC. As a result, in the test solution of Example 1 after storage, 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 before storage, no peak was observed in these retention times, and thus it was found that each peak was derived from a decomposition product generated by storage.

  Degradation products A1 (retention time of about 2.6 minutes), A2 (retention time of about 7.8 minutes), A3 (retention time of about 14.0 minutes), and B (retention time of about 15 minutes) in each test solution after storage .2 minutes) is shown in Table 3. In Example 1 where the phosphate concentration was 6.3 mM, the amount of decomposition products A1, A2 and A3 produced was reduced compared to Comparative Example 1 where the phosphate concentration was 126 mM. In addition, the total amount of decomposition products A1, A2, A3, and B was also reduced in Example 1 compared to Comparative Example 1. From these results, in the ophthalmic composition containing brimonidine tartrate, timolol maleate, and phosphate, the storage stability of the ophthalmic composition is improved by setting the phosphate concentration low. It was confirmed.

  On the other hand, in Example 1, compared with the comparative example 1, although the production amount of decomposition products A1, A2, and A3 was able to be reduced, the production amount of decomposition product B was increasing. In contrast, in Example 2 in which EDTA dihydrate was further blended, the amount of decomposition product B produced was so small that it could not be detected. That is, it was confirmed that the decomposition product B generated by lowering the phosphate concentration can be reduced by further adding EDTA dihydrate, and the storage stability can be further improved.

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

  The obtained 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, in the ophthalmic composition containing brimonidine tartrate, timolol maleate, and phosphate, it was confirmed that the production of decomposition products A1 to A3 can be suppressed by setting the phosphate concentration to 32 mM or less. It was.

  In addition, when brimonidine tartrate and timolol maleate are included and the phosphate concentration is 32 mM or less, in the case where EDTA dihydrate is not included (Examples 1 and 3 to 7), the increase of decomposition product B is increased. Although it was recognized, when EDTA dihydrate was contained (Examples 2 and 8 to 12), the formation of the decomposition product B could be completely suppressed.

  From the results of this test, in the ophthalmic composition containing brimonidine tartrate, timolol maleate, and phosphate, reducing the phosphate concentration to 32 mM or less reduces the amount of decomposition products A1 to A3 produced. Although reduced specifically, the new subject that the production amount of the decomposition product B increases was confirmed. However, in the ophthalmic composition, it was confirmed that further blending of EDTA dihydrate specifically suppresses the formation of degradation product B (EDTA dihydrate is degradation product A1 to 1). (The amount of A3 produced is not reduced). Therefore, it became clear that the addition of EDTA dihydrate in addition to the phosphate concentration of 32 mM or less would most effectively reduce degradation products.

Test example 3
In an ophthalmic composition containing brimonidine tartrate, timolol maleate, and phosphate, the effect of pH on the amount of decomposition products was examined. Specifically, a test solution (eye drops) 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 a container for filling the test solution. Then, the production amount of the decomposition product was measured.

  The results obtained are shown in Table 6. As a result, in Examples 16 and 17 in which the pH is in the range of 7.1 to 7.3, compared with Examples 13 to 15 and 18 in which the pH is out of the range of 7.1 to 7.3, decomposition occurs. The amount of product B produced was reduced. Therefore, 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, decomposition is performed by setting the pH to 7.1 to 7.3. It became clear that the production amount of the product B can be suppressed more effectively and the storage stability can be further improved.

Formulation Example Specific embodiments of the ophthalmic composition of the present invention include ophthalmic compositions having the components shown in Tables 7 to 10. In Tables 7 to 10, the unit of content of each component is “w / v%”. Formulation examples 1 to 18 in the table are accommodated in polyethylene (hereinafter referred to as PE) containers, formulation examples 19 to 28 are accommodated in polypropylene (PP) containers, and formulation examples 29 to 36 are accommodated in glass containers.

Claims (16)

Brimonidine and / or salt thereof, timolol and / or salt thereof, phosphoric acid and / or salt thereof,
An ophthalmic composition wherein the concentration of phosphoric acid and / or a salt thereof is 32 mM or less.   The ophthalmic composition according to claim 1, further comprising edetic acid and / or a salt thereof.   The ophthalmic composition according to claim 1 or 2, wherein the pH is 7.1 to 7.3.   The ophthalmic composition according to any one of claims 1 to 3, comprising at least one of disodium hydrogen phosphate and sodium dihydrogen phosphate as phosphoric acid and / or a salt thereof.   The ophthalmic composition according to claim 4, which contains disodium hydrogen phosphate and sodium dihydrogen phosphate as phosphoric acid and / or a salt thereof.   The ophthalmic composition according to any one of claims 1 to 5, wherein the concentration of phosphoric acid and / or a salt thereof is 0.01 to 32 mM.   The ophthalmic composition according to any one of claims 1 to 6, wherein the concentration of brimonidine and / or a salt thereof is 0.01 to 1 w / v%.   The ophthalmic composition according to any one of claims 1 to 7, wherein the concentration of timolol and / or a salt thereof is 0.1 to 1.5 w / v%.   The ophthalmic composition according to claim 2, wherein the concentration of edetic acid and / or a salt thereof is 0.0001 to 0.2 w / v%. 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 0.3-32 mM,
The concentration of edetic acid and / or its salt is 0.01 w / v%,
The ophthalmic composition according to claim 2.   The ophthalmic composition according to claim 10, wherein the concentration of phosphoric acid and / or a salt thereof is 0.3 to 6.3 mM.   The ophthalmic composition according to any one of claims 1 to 11, which is an eye drop. A method for suppressing degradation products in an ophthalmic composition comprising brimonidine and / or a salt thereof and timolol and / or a salt thereof,
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,
The concentration of the phosphoric acid and / or salt thereof is 32 mM or less.
Method for suppressing decomposition products.   Furthermore, the suppression method of the decomposition product of Claim 13 which makes edetic acid and / or its salt coexist in an ophthalmic composition. 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,
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;
The concentration of the phosphoric acid and / or salt thereof is 32 mM or less.
How to improve storage stability.   Furthermore, the storage stability improvement method of Claim 15 which coexists edetic acid and / or its salt in an ophthalmic composition.