Ophthalmic pharmaceutical composition with improved preservative efficacy or photostability

Abstract

To provide an ophthalmic pharmaceutical composition in which the preservative efficacy of carteolol is enhanced and / or photostability is improved.SOLUTION: The ophthalmic pharmaceutical composition comprises carteolol or a pharmaceutically acceptable salt thereof and edetic acid or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an ophthalmic pharmaceutical composition containing the β-blocker carteolol, as well as a method for producing the same and a method for medicinal use thereof. The present invention also relates to a method for enhancing the preservative effectiveness, improving the photostability, and / or inhibiting the decomposition of carteolol. [Background technology]

[0002] Carteolol, a known beta-blocker, has the chemical name 5-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-3,4-dihydroquinolin-2(1H)-one, and is known to be effective in treating glaucoma and ocular hypertension when used as an eye drop. Eye drops generally require the addition of a preservative or antiseptic to prevent contamination by microorganisms during use. Such preservatives or antiseptics typically include benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, parabens, chlorobutanol, and sorbates. However, these preservatives or antiseptics can adversely affect human tissues such as the cornea.

[0003] A method of imparting preservative effect to eye drops by adding boric acid or a salt thereof instead of a preservative or antiseptic is known. However, when boric acid or the like is used, hypersensitivity symptoms such as blepharitis may occur as a side effect (Patent Document 1).

[0004] As eye drops that do not contain preservatives or antiseptics, disposable, single-dose eye drops (unit-dose eye drops) in which a single dose is individually packaged are also used. For example, Patent Document 2 discloses a bacteriostatic-free eye drop containing carteolol hydrochloride, in which a single dose is individually packaged. However, such unit-dose eye drops require a disposable individual container for each administration, and therefore may not be suitable for long-term continuous administration from the standpoint of cost, storage space, etc.

[0005] In the treatment of ocular diseases such as glaucoma and ocular hypertension, which require continuous administration of drugs over a long period of time, stable eye drops with high preservative efficacy are required.

[0006] Some β-blockers, including carteolol, are decomposed by exposure to light, so eye drops containing carteolol usually need to be protected from light during storage and use. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 2011 / 013794 [Patent Document 2] Chinese Patent Publication No. 101461780 Summary of the Invention [Problem to be solved by the invention]

[0008] One of the problems to be solved by the present invention is to provide an ophthalmic pharmaceutical composition having enhanced preservative effectiveness and / or improved photostability of carteolol. Another problem to be solved by the present invention is to provide a method for enhancing the preservative effectiveness, improving the photostability, and / or inhibiting the decomposition of carteolol. [Means for solving the problem]

[0009] As a result of extensive research, the present inventors have discovered that the above-mentioned problems can be solved by combining carteolol or a pharmaceutically acceptable salt thereof with edetic acid or a pharmaceutically acceptable salt thereof, and have thus completed the present invention.

[0010] In one aspect, the present invention provides an ophthalmic pharmaceutical composition comprising carteolol or a pharmaceutically acceptable salt thereof and edetic acid or a pharmaceutically acceptable salt thereof. In another aspect, the present invention provides a method for enhancing the preservative effectiveness of carteolol or a pharmaceutically acceptable salt thereof with edetic acid or a pharmaceutically acceptable salt thereof, which comprises combining carteolol or a pharmaceutically acceptable salt thereof with edetic acid or a pharmaceutically acceptable salt thereof. In yet another aspect, the present invention provides a method for improving the photostability or inhibiting the decomposition of carteolol or a pharmaceutically acceptable salt thereof by using edetic acid or a pharmaceutically acceptable salt thereof and / or a duration-retaining agent, characterized by combining carteolol or a pharmaceutically acceptable salt thereof with edetic acid or a pharmaceutically acceptable salt thereof and / or a duration-retaining agent. In yet another aspect, the present invention provides a method for producing an ophthalmic pharmaceutical composition comprising carteolol or a pharmaceutically acceptable salt thereof and edetic acid or a pharmaceutically acceptable salt thereof, the method comprising combining carteolol or a pharmaceutically acceptable salt thereof with edetic acid or a pharmaceutically acceptable salt thereof. [Effects of the Invention]

[0011] The pharmaceutical composition of the present invention may have preservative or bacteriostatic properties even without containing a preservative or antiseptic. The pharmaceutical composition of the present invention may also have improved photostability. The pharmaceutical composition of the present invention may also have enhanced preservative and / or improved photostability, making it useful for treating ocular diseases such as glaucoma and ocular hypertension that require continuous administration of a drug for a long period of time. According to the present invention, by adding edetic acid or a pharmaceutically acceptable salt thereof to carteolol or a pharmaceutically acceptable salt thereof, which inherently has weak bacteriostatic activity, the preservative effect or bacteriostatic activity of carteolol or a pharmaceutically acceptable salt thereof is enhanced, making it possible to prepare preservative-free eye drops, and further improving the photostability of carteolol, which has poor photostability. Furthermore, the addition of an isotonicity agent (e.g., propylene glycol) and / or a sustaining agent (e.g., alginic acid) can further enhance the preservative effect or bacteriostatic activity of carteolol or a pharmaceutically acceptable salt thereof, or further improve its photostability. DETAILED DESCRIPTION OF THE INVENTION

[0012] The present invention may include the following exemplary embodiments. Item 1. A pharmaceutical composition for ophthalmic administration comprising carteolol or a pharmaceutically acceptable salt thereof and edetic acid or a pharmaceutically acceptable salt thereof. Item 2. A pharmaceutical ophthalmic composition comprising edetic acid or a pharmaceutically acceptable salt thereof, which enhances the preservative effectiveness and / or improves the photostability of carteolol or a pharmaceutically acceptable salt thereof. Item 3. The pharmaceutical composition according to either Item 1 or 2, further comprising an isotonicity agent, examples of which include propylene glycol, glycerin, polyethylene glycol, trehalose, maltose, sucrose, glucose, sorbitol, mannitol, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and combinations thereof. Item 4. The pharmaceutical composition according to any one of Items 1 to 3, further comprising a sustaining agent. Examples of the sustaining agent include hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, carboxyvinyl polymer, polyvinylpyrrolidone, carboxymethyl cellulose, polyacrylic acid, sodium polyacrylate, alginic acid, sodium alginate, and combinations thereof. Item 5. The pharmaceutical composition according to any one of Items 1 to 4, further comprising a buffer and a pH adjuster. Item 6. The pharmaceutical composition according to any one of Items 1 to 5, further comprising a prostaglandin F2α derivative, examples of which include latanoprost, bimatoprost, travoprost, and tafluprost. Item 7. The pharmaceutical composition according to any one of Items 1 to 6, further comprising a carbonic anhydrase inhibitor. Examples of the carbonic anhydrase inhibitor include dorzolamide, brinzolamide, acetazolamide, and pharmaceutically acceptable salts thereof. Item 8. The pharmaceutical composition according to any one of Items 1 to 7, further comprising another drug having an intraocular pressure-reducing effect, such as an adrenergic α2 agonist or a ROCK (Rho kinase) inhibitor. Examples of the adrenergic α2 agonist include brimonidine tartrate, dipivefrine hydrochloride, and clonidine. Examples of the ROCK inhibitor include ripasudil hydrochloride hydrate and netarsudil mesylate. Item 9. The pharmaceutical composition according to any one of Items 1 to 8, wherein the content of carteolol or a pharmaceutically acceptable salt thereof is 0.1 to 5 w / v % based on the total amount of the composition. Item 10. The pharmaceutical composition according to any one of Items 1 to 9, wherein the content of edetic acid or a pharmaceutically acceptable salt thereof is 0.01 to 0.2 w / v % based on the total amount of the composition. Item 11. The pharmaceutical composition according to any one of Items 1 to 10, wherein the content of edetic acid or a pharmaceutically acceptable salt thereof is 0.002 to 2.0 w / w ratio relative to the content of carteolol or a pharmaceutically acceptable salt thereof. Item 12. The pharmaceutical composition according to any one of Items 1 to 11, which has a pH of 5.0 to 8.0. Item 13. The pharmaceutical composition according to any one of Items 1 to 12, which is an eye drop. Item 14. The pharmaceutical composition according to any one of Items 1 to 13, which is an aqueous eye drop or an eye drop suspension. Item 15. The pharmaceutical composition according to any one of Items 1 to 14, which is used as a multi-dose eye drop. Item 16. The pharmaceutical composition according to any one of Items 1 to 15, which is used to treat glaucoma or ocular hypertension. Item 17. The pharmaceutical composition according to any one of Items 1 to 16, which is used in combination with a prostaglandin preparation. Here, the prostaglandin preparation is a preparation containing a prostaglandin F2α derivative.

[0013] Item 18. A method for enhancing the preservative effectiveness of carteolol or a pharmaceutically acceptable salt thereof with edetic acid or a pharmaceutically acceptable salt thereof, comprising combining carteolol or a pharmaceutically acceptable salt thereof with edetic acid or a pharmaceutically acceptable salt thereof. Item 19. Use of edetic acid or a pharmaceutically acceptable salt thereof to enhance the preservative effectiveness of carteolol or a pharmaceutically acceptable salt thereof. Item 20. A method for enhancing the preservative effectiveness of carteolol or a pharmaceutically acceptable salt thereof with propylene glycol, which comprises combining carteolol or a pharmaceutically acceptable salt thereof with propylene glycol. Item 21. Use of propylene glycol to enhance the preservative effectiveness of carteolol or a pharmaceutically acceptable salt thereof. Item 22. Use of a combination of edetic acid or a pharmaceutically acceptable salt thereof and propylene glycol to enhance the preservative effectiveness of carteolol or a pharmaceutically acceptable salt thereof. Item 23. A method for improving the photostability of carteolol or a pharmaceutically acceptable salt thereof with edetic acid or a pharmaceutically acceptable salt thereof, comprising combining carteolol or a pharmaceutically acceptable salt thereof with edetic acid or a pharmaceutically acceptable salt thereof. Item 24. Use of edetic acid or a pharmaceutically acceptable salt thereof to improve the photostability of carteolol or a pharmaceutically acceptable salt thereof. Item 25. A method for improving the photostability of carteolol or a pharmaceutically acceptable salt thereof with alginic acid, which comprises combining carteolol or a pharmaceutically acceptable salt thereof with alginic acid. Item 26. Use of alginic acid to improve the photostability of carteolol or a pharmaceutically acceptable salt thereof. Item 27. Use of a combination of edetic acid or a pharmaceutically acceptable salt thereof and alginic acid to improve the photostability of carteolol or a pharmaceutically acceptable salt thereof.

[0014] Item 28. A method for producing a pharmaceutical composition for ophthalmic administration, comprising a step of mixing carteolol or a pharmaceutically acceptable salt thereof with edetic acid or a pharmaceutically acceptable salt thereof, optionally with a pH adjuster so that the pH of the resulting pharmaceutical composition is 5.0 to 8.0, and optionally with propylene glycol, alginic acid, or a combination thereof so that the osmotic pressure ratio of the resulting pharmaceutical composition is 0.8 to 1.2.

[0015] The present invention includes the specific embodiments exemplified below, and any combination of the specific embodiments is also included in the present invention. Furthermore, the raw materials of each component used in this specification may be in the form of a solvate such as a hydrate or an anhydrous form, as long as they are pharmaceutically acceptable.

[0016] The pharmaceutical composition of the present invention comprises carteolol or a pharmaceutically acceptable salt thereof and edetic acid or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of the present invention can also exhibit its preservative effect without containing a preservative or antiseptic. Examples of preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, parabens, chlorobutanol, sorbic acid salts, etc. In one embodiment, the pharmaceutical composition of the present invention may be free of a preservative or antiseptic. In another embodiment, the pharmaceutical composition of the present invention may be free of boric acid or a salt thereof. In yet another embodiment, the pharmaceutical composition of the present invention may contain boric acid or a salt thereof.

[0017] In some embodiments, the pharmaceutical composition of the present invention may contain carteolol or a pharmaceutically acceptable salt thereof in an amount of 0.1 to 5 w / v% based on the total amount of the composition. The content (concentration) of carteolol or a pharmaceutically acceptable salt thereof is preferably 0.5 to 2.5 w / v% based on the total amount of the composition, and more preferably 1 to 2 w / v%. Pharmaceutically acceptable salts of carteolol include salts of carteolol with inorganic acids, preferably carteolol hydrochloride.

[0018] The pharmaceutical composition of the present invention may further contain edetic acid or a pharmaceutically acceptable salt thereof in an amount of 0.01 to 0.2 w / v% based on the total amount of the composition. The content (concentration) of edetic acid or a pharmaceutically acceptable salt thereof is preferably 0.01 to 0.15 w / v% based on the total amount of the composition. It is more preferably 0.02 to 0.1 w / v%, and even more preferably 0.03 to 0.07 w / v%. The content of edetic acid or a pharmaceutically acceptable salt thereof may be 0.002 to 2.0 w / w ratio relative to the content of carteolol or a pharmaceutically acceptable salt thereof, preferably 0.004 to 0.3 w / w ratio, more preferably 0.008 to 0.2 w / w ratio, even more preferably 0.015 to 0.07 w / w ratio, and particularly preferably 0.025 to 0.06 w / w ratio. Pharmaceutically acceptable salts of edetic acid include salts of edetic acid (ethylenediaminetetraacetic acid; EDTA) with inorganic bases, preferably sodium edetate hydrate. Carteolol or a pharmaceutically acceptable salt thereof may be treated with edetic acid or a pharmaceutically acceptable salt thereof to enhance the preservative effectiveness of carteolol itself, improve its photostability, and / or inhibit its decomposition.

[0019] The pharmaceutical composition of the present invention may further contain components such as an isotonicity agent, a sustaining agent, a buffer, a pH adjuster, a solubilizer, a solvent, etc., as needed.

[0020] Examples of isotonicity agents include, but are not limited to, propylene glycol, glycerin, polyethylene glycol, trehalose, maltose, sucrose, glucose, sorbitol, mannitol, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and combinations thereof. Preferred are propylene glycol and sodium chloride. The content (concentration) of the isotonic agent is not particularly limited, but may be an amount that causes the osmotic pressure ratio of the pharmaceutical composition to fall within the range of 0.8 to 1.2, preferably 0.9 to 1.1. Specifically, it is 0.5 to 2.0 w / v%, and preferably 1.0 to 1.6 w / v%. The content of the isotonic agent may be 0.08 to 20 w / w ratio relative to the content of carteolol or a pharmaceutically acceptable salt thereof, preferably 0.16 to 4 w / w ratio, more preferably 0.2 to 2 w / w ratio. The content of the isotonic agent may be 3 to 200 w / w ratio relative to the content of edetic acid or a pharmaceutically acceptable salt thereof, preferably 4 to 100 w / w ratio, more preferably 6 to 70 w / w ratio.

[0021] Examples of the sustaining agent include, but are not limited to, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, carboxyvinyl polymer, polyvinylpyrrolidone, carboxymethyl cellulose, polyacrylic acid, sodium polyacrylate, alginic acid, sodium alginate, and combinations thereof. Alginic acid is preferred. The content (concentration) of the sustaining agent is not particularly limited, but may be 0.1 to 5 w / v%, preferably 0.5 to 2 w / v%, and more preferably 0.8 to 1.2 w / v%. The content of the sustaining agent may be in a ratio of 0.25 to 2 w / w to the content of carteolol or a pharmaceutically acceptable salt thereof, preferably in a ratio of 0.4 to 1.2 w / w. The content of the sustaining agent may be in a ratio of 5 to 100 w / w to the content of edetic acid or a pharmaceutically acceptable salt thereof, preferably in a ratio of 10 to 40 w / w.

[0022] Examples of buffering agents include, but are not limited to, phosphates such as sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate; borates such as boric acid and sodium borate, and potassium borate; citrates such as citric acid and sodium citrate, and disodium citrate; acetates such as acetic acid and sodium acetate, and potassium acetate; carbonates such as sodium carbonate and sodium hydrogen carbonate; and combinations thereof. Phosphates are preferred. Sodium dihydrogen phosphate and disodium hydrogen phosphate are more preferred. The content (concentration) of the buffering agent is not particularly limited, but may be 0.01 to 1 w / v %, and preferably 0.04 to 0.4 w / v %.

[0023] Examples of pH adjusters include, but are not limited to, acids such as hydrochloric acid, lactic acid, citric acid, phosphoric acid, and acetic acid, and alkali bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate. Preferred is hydrochloric acid or sodium hydroxide. The content (concentration) of the pH adjuster is not particularly limited, but may be an amount that adjusts the pH of the pharmaceutical composition to a range of 5.0 to 8.5. Preferably, the pH is adjusted to 5.0 to 8.0. More preferably, the pH is adjusted to 6.0 to 8.0, and even more preferably, 6.2 to 7.2.

[0024] Examples of solubilizers include, but are not limited to, polysorbate 80, polyethylene hydrogenated castor oil 60, macrogol 4000, polyvinyl alcohol, tyloxapol, polyoxyethylene polyoxypropylene glycol, polyoxyl stearate, vegetable oils such as soybean oil, etc. Polysorbate 80 is preferred. The content (concentration) of the solubilizer is not particularly limited, but may be 0.05 to 5 w / v%, preferably 0.1 to 3 w / v%, and more preferably 0.1 to 2 w / v%.

[0025] Examples of the solvent include, but are not limited to, purified water, sterile purified water, water for injection, etc. Sterile purified water or water for injection is preferred.

[0026] The pharmaceutical composition of the present invention may further contain a prostaglandin F2α derivative. The prostaglandin F2α derivative may be contained in an amount of 0.0005 to 0.1 w / v% based on the total amount of the composition. The content (concentration) of the prostaglandin F2α derivative is preferably 0.001 to 0.05 w / v% based on the total amount of the composition, and more preferably 0.0015 to 0.03 w / v%. Prostaglandin F2α derivatives include, but are not limited to, latanoprost, bimatoprost, travoprost, tafluprost, and the like.

[0027] In another aspect, the present invention may be a pharmaceutical composition characterized by being used in combination with a preparation containing a prostaglandin F2α derivative (prostaglandin preparation). The pharmaceutical composition of the present invention may be administered to a subject simultaneously with the administration of the prostaglandin F2α derivative or at a certain interval before or after the administration.

[0028] The pharmaceutical composition of the present invention may further contain a carbonic anhydrase inhibitor. The carbonic anhydrase inhibitor may be contained in an amount of 0.1 to 5 w / v% based on the total amount of the composition. The content (concentration) of the carbonic anhydrase inhibitor is preferably 0.5 to 2.5 w / v% based on the total amount of the composition, and more preferably 1 to 2 w / v%. Carbonic anhydrase inhibitors include, but are not limited to, dorzolamide, brinzolamide, acetazolamide, and pharmaceutically acceptable salts thereof.

[0029] The pharmaceutical composition of the present invention may further contain another drug having the effect of lowering intraocular pressure. The other drug having the effect of lowering intraocular pressure may be contained in an amount of 0.1 to 5 w / v% relative to the total amount of the composition. A preferred content (concentration) of the other drug having the effect of lowering intraocular pressure is 0.5 to 2.5 w / v% relative to the total amount of the composition, and more preferably 1 to 2 w / v%. Other drugs that have the effect of lowering intraocular pressure include, but are not limited to, adrenergic α2 agonists, ROCK (Rho kinase) inhibitors, etc. Examples of adrenergic α2 agonists include brimonidine tartrate, dipivefrine hydrochloride, clonidine, etc. Examples of ROCK inhibitors include ripasudil hydrochloride hydrate, netarsudil mesylate, etc.

[0030] The pharmaceutical composition of the present invention may preferably be a liquid preparation for eye drops. More preferably, it is an aqueous eye drop or a suspension eye drop using an aqueous solvent such as purified water, sterile purified water, or water for injection. The pharmaceutical composition of the present invention may also be a unit-dose eye drop in which a single dose is individually packaged, or a multi-dose eye drop that can be used repeatedly. Multi-dose eye drops are preferred.

[0031] The pharmaceutical composition of the present invention may be useful for treating ocular diseases such as glaucoma, including primary open-angle glaucoma, primary angle-closure glaucoma, developmental glaucoma, secondary glaucoma, and normal-tension glaucoma, as well as ocular hypertension. Furthermore, since carteolol has an ocular hypotensive effect, the pharmaceutical composition of the present invention may be useful for treating ocular diseases such as glaucoma, including primary open-angle glaucoma, primary angle-closure glaucoma, developmental glaucoma, and secondary glaucoma, as well as ocular hypertension.

[0032] In one aspect, the present invention provides a pharmaceutical composition comprising carteolol or a pharmaceutically acceptable salt thereof and edetic acid or a pharmaceutically acceptable salt thereof, which is characterized by enhancing the weak preservative effect that carteolol or a pharmaceutically acceptable salt thereof has in addition to its main effect. In another embodiment, edetic acid or a pharmaceutically acceptable salt thereof may be mixed with carteolol or a pharmaceutically acceptable salt thereof to enhance the preservative effectiveness of the carteolol or a pharmaceutically acceptable salt thereof, and the preservative effectiveness of the carteolol or a pharmaceutically acceptable salt thereof may be further enhanced by further mixing an isotonicity agent into the mixture.

[0033] In another aspect, the present invention provides a pharmaceutical composition comprising carteolol or a pharmaceutically acceptable salt thereof and edetic acid or a pharmaceutically acceptable salt thereof, which is characterized by improving the poor photostability of carteolol or a pharmaceutically acceptable salt thereof or inhibiting its decomposition. In another embodiment, edetic acid or a pharmaceutically acceptable salt thereof can improve the photostability or inhibit decomposition of carteolol or a pharmaceutically acceptable salt thereof in a mixed solution with carteolol or a pharmaceutically acceptable salt thereof. By further adding a duration-enhancing agent to the mixed solution, the photostability of carteolol or a pharmaceutically acceptable salt thereof can be further improved or the decomposition thereof can be further inhibited.

[0034] In another aspect, the present invention provides a method for producing an ophthalmic pharmaceutical composition. The method of the present invention comprises the step of mixing carteolol or a pharmaceutically acceptable salt thereof with edetic acid or a pharmaceutically acceptable salt thereof. The carteolol or a pharmaceutically acceptable salt thereof and the edetic acid or a pharmaceutically acceptable salt thereof may be mixed, if necessary, with the pH adjuster described above so that the pH of the resulting pharmaceutical composition is 5.0 to 8.5, preferably 5.0 to 8.0, more preferably 6.0 to 8.0, and even more preferably 6.0 to 7.2. The carteolol or a pharmaceutically acceptable salt thereof and the edetic acid or a pharmaceutically acceptable salt thereof may also be mixed, if necessary, with the tonicity adjuster, sustainer, or a combination thereof described above. The tonicity adjuster may be added so that the osmotic pressure ratio of the resulting pharmaceutical composition is 0.8 to 1.2, preferably 0.9 to 1.1. [Example]

[0035] The present invention will be described in more detail below with reference to test examples and examples, but the present invention is not limited thereto. Furthermore, unless otherwise specified, concentrations are expressed in mass to volume percentage (w / v%), which is equivalent to "g / 100 mL."

[0036] <Preservative effectiveness test> In the following test examples, the preservative effectiveness of the test solution was evaluated in accordance with the preservative effectiveness test method in the reference information of the Japanese Pharmacopoeia, 17th Edition. Specifically, bacterial solutions were prepared using bacteria (Escherichia coli ATCC 8739, Pseudomonas aeruginosa ATCC 9027, Staphylococcus aureus ATCC 6538) and / or fungi (Candida albicans ATCC 10231, Aspergillus brasiliensis ATCC 16404). Each bacterial solution was inoculated into the test solution at a concentration of 10-10 colony-forming units (CFU) / mL and stored at 20-25°C. The viable cell count was measured 7, 14, and 28 days after inoculation. The criterion for judging preservative effectiveness was the change in bacterial count relative to the inoculum count, and for bacteria (Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus), a reduction of 1.0 log or more after 7 days, a reduction of 3.0 log or more after 14 days, and a reduction equal to or less than the 14-day count after 28 days was deemed "compliant." For fungi (Candida albicans and Aspergillus brasiliensis), a "compliant" result was when the bacterial count was equal to or less than the inoculum count after 7 days, and equal to or less than the inoculum count after 14 and 28 days.

[0037] Test Example 1: Preservative effectiveness test of carteolol The preservative effectiveness of carteolol was confirmed according to the following method. Preparation of test solutions for Examples 1 to 10 The compositions of the test solutions for Examples 1 to 10 are shown in Table 1. Carteolol hydrochloride, anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate, and NaCl (amounts such that the osmotic pressure ratio of the solution was 0.9 to 1.1) were weighed out and dissolved in sterile purified water. The pH was adjusted to 5.0, 6.0, 7.0, 8.0, or 8.5 with 5N sodium hydroxide or 1% hydrochloric acid, and sterile purified water was added to make up the specified volume. These solutions were filtered through a 0.22 μm membrane filter and filled into sterilized glass containers in 5 mL portions to prepare the test solutions.

[0038] Preparation of Comparative Examples 1 to 4: Test Solutions Not Containing Carteolol Hydrochloride The compositions of the test solutions for Comparative Examples 1 to 4 are shown in Table 1. Anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate, and NaCl (in amounts such that the osmotic pressure ratio of the solution was 0.9 to 1.1) were weighed out and dissolved in sterile purified water. The pH was adjusted to 5.0, 6.0, 7.0, or 8.0 with 5N sodium hydroxide or 1% hydrochloric acid, and sterile purified water was added to make up the specified volume. These solutions were filtered through a 0.22 μm membrane filter and filled into sterilized glass containers in 5 mL portions to prepare the test solutions.

[0039] [Table 1] TIFF2026021353000002.tif72153 TIFF2026021353000003.tif72153

[0040] A preservative effectiveness test was carried out on the test solutions of Examples 1 to 10 and Comparative Examples 1 to 4. The results of the preservative effectiveness test for each Example and Comparative Example are shown in Table 2. Considering the overall results of the preservative effectiveness tests against individual bacteria, it was confirmed that Examples 1 to 10 passed the preservative effectiveness test against fungi and also had general preservative effectiveness against bacteria. Comparative Examples 1 to 4, which did not contain carteolol hydrochloride, all failed the preservative effectiveness test. These results confirmed that carteolol hydrochloride has preservative effectiveness.

[0041] [Table 2] ○: Meets the criteria for each individual bacterium ×: Does not meet the criteria for individual bacteria

[0042] Test Example 2: Evaluation of preservative effectiveness by adding sodium edetate hydrate The enhancing effect of sodium edetate hydrate on the preservative efficacy of carteolol hydrochloride was confirmed according to the following method. Preparation of test solutions for Examples 11 to 15 The compositions of the test solutions for Examples 11 to 15 are shown in Table 3. Carteolol hydrochloride, anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate, sodium edetate hydrate, and NaCl (amounts such that the osmotic pressure ratio of the solution was 0.9 to 1.1) were weighed out and dissolved in sterile purified water. The pH was adjusted to 5.0, 6.0, or 7.0 with 5N sodium hydroxide or 1% hydrochloric acid, and sterile purified water was added to make up the specified volume. These solutions were filtered through a 0.22 μm membrane filter and filled into sterilized glass containers in 5 mL aliquots to prepare the test solutions.

[0043] <Test Solutions of Comparative Examples 5 to 8: Preparation of Test Solutions Not Containing Carteolol Hydrochloride> The compositions of the test solutions for Comparative Examples 5 to 8 are shown in Table 4. Sodium edetate hydrate, anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate, and NaCl (amounts such that the osmotic pressure ratio of the solution was 0.9 to 1.1) were measured, and a predetermined amount of sterile purified water was added. 5N sodium hydroxide or 1% hydrochloric acid was added to adjust the pH to 5.0, 6.0, 7.0, or 8.0, and sterile purified water was added to make the predetermined volume. These solutions were filtered through a 0.22 μm membrane filter. 5 mL of this solution was filled into sterilized glass containers to prepare the test solutions.

[0044] [Table 3] [Table 4]

[0045] The preservative effectiveness tests were carried out against bacteria (Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus) for the test solutions of Examples 11 to 15 and Comparative Examples 5 to 8. The results of the preservative effectiveness tests for each Example and Comparative Example are shown in Table 5. Examples 11 to 15 generally had preservative effectiveness against bacteria, but Comparative Examples 5 to 8 failed the preservative effectiveness test. These results confirmed that the preservative effectiveness was enhanced by combining carteolol hydrochloride and sodium edetate hydrate.

[0046] [Table 5] ○: Meets the criteria for each individual bacterium ×: Does not meet the criteria for individual bacteria

[0047] Test Example 3: Evaluation of preservative effect by adding propylene glycol The effect of adding propylene glycol on the preservative efficacy of carteolol hydrochloride at pH 5.0 and 6.0 was confirmed according to the following method. Test Solutions of Examples 16 to 19 The compositions of the test solutions for Examples 16 to 19 are shown in Table 6. Carteolol hydrochloride, anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate, sodium edetate hydrate, and propylene glycol were weighed out to the compositions shown in Table 6, dissolved in sterile purified water, and then 1% hydrochloric acid was added to adjust the pH to 5.0 or 6.0, followed by addition of sterile purified water to the specified volume. These solutions were filtered through a 0.22 μm membrane filter and filled into sterilized glass containers in 5 mL portions to prepare the test solutions.

[0048] Preparation of test solutions for Comparative Examples 9 to 16 The compositions of the test solutions for Comparative Examples 9 to 16 are shown in Table 7. Carteolol hydrochloride, anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate, and propylene glycol (Comparative Examples 9 to 12), anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate, propylene glycol, and NaCl (in an amount that would result in an osmotic pressure ratio of the solution of 0.9 to 1.1) (Comparative Examples 13 and 14), or sodium edetate hydrate, anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate, propylene glycol, and NaCl (in an amount that would result in an osmotic pressure ratio of the solution of 0.9 to 1.1) (Comparative Examples 15 and 16) were dissolved, and the pH was adjusted to 5.0 or 6.0 with 1% hydrochloric acid. Sterile purified water was added to the desired volume. These solutions were filtered through a 0.22 μm membrane filter and filled into sterilized glass containers in 5 mL aliquots to prepare the test solutions.

[0049] [Table 6]

[0050] [Table 7] TIFF2026021353000010.tif89153

[0051] The preservative effectiveness tests were carried out against bacteria (Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus) for the test solutions of Examples 16 to 19 and Comparative Examples 9 to 16. The results of the preservative effectiveness tests for each Example and Comparative Example are shown in Table 8. Examples 16 to 19, in which propylene glycol was added to compositions containing carteolol hydrochloride and sodium edetate hydrate, all met the standards for three bacterial species (Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus) and passed the preservative effectiveness test. Comparative Examples 9 to 12, which contained carteolol hydrochloride but not sodium edetate hydrate, did not meet the standards for E. coli or Pseudomonas aeruginosa and failed to pass the test. Comparative Examples 13 and 14, which did not contain carteolol hydrochloride or sodium edetate hydrate, failed to pass the preservative effectiveness test because they contained only propylene glycol. Comparative Examples 15 and 16, which did not contain carteolol hydrochloride, did not meet the standards for the preservative effectiveness test despite the addition of propylene glycol and sodium edetate hydrate. These results demonstrate that the combination of carteolol hydrochloride, sodium edetate hydrate, and propylene glycol provides excellent preservative effectiveness.

[0052] [Table 8] ○: Meets the criteria for each individual bacterium ×: Does not meet the criteria for individual bacteria

[0053] Test Example 4: Evaluation of preservative effect by adding alginic acid The enhancing effect of alginic acid on the preservative efficacy of carteolol hydrochloride was confirmed according to the following method. Preparation of test solutions for Examples 20 and 21 The compositions of the test solutions for Examples 20 and 21 are shown in Table 9. Carteolol hydrochloride, anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate, sodium edetate hydrate, propylene glycol, and alginic acid were weighed out to the compositions shown in Table 9, and sterilized purified water and 5N sodium hydroxide were added to dissolve. 5N sodium hydroxide was then added to adjust the pH to 6.7, and sterilized purified water was added to make up the specified volume. These solutions were filtered through a 0.22 μm membrane filter and filled into sterilized glass containers in 5 mL portions to prepare the test solutions.

[0054] Preparation of Test Solutions for Comparative Examples 17 and 18: Test Solutions Containing Alginic Acid The compositions of the test solutions for Comparative Examples 17 and 18 are shown in Table 9. Carteolol hydrochloride, anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate, sodium edetate hydrate, and propylene glycol were weighed out to the compositions shown in Table 9, dissolved in sterile purified water, and then the pH was adjusted to 6.7 with 5N sodium hydroxide, followed by addition of sterile purified water to the specified volume. These solutions were filtered through a 0.22 μm membrane filter and filled into sterilized glass containers in 5 mL portions to prepare the test solutions.

[0055] [Table 9]

[0056] The preservative effectiveness tests were carried out against bacteria (Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus) for the test solutions of Examples 20 and 21 and Comparative Examples 17 and 18. The results of the preservative effectiveness tests for each Example and Comparative Example are shown in Table 10.

[0057] [Table 10] ○: Meets the criteria for each individual bacterium ×: Does not meet the criteria for individual bacteria

[0058] Test Example 5: Evaluation of photostability by adding sodium edetate hydrate The effect of sodium edetate hydrate on improving the photostability of carteolol hydrochloride was confirmed according to the following method. Test Solutions of Examples 22 to 25 The compositions of the test solutions for Examples 22 to 25 are shown in Table 11. Carteolol hydrochloride, anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate, and sodium edetate hydrate were mixed to the compositions shown in Table 11, and then sterilized purified water was added to dissolve the mixture. 5N sodium hydroxide was added to the mixture to adjust the pH to 6.7, and sterilized purified water was added to make the required volume. These solutions were filtered through a 0.22 μm membrane filter and filled into sterilized glass containers in 5 mL portions to prepare the test solutions.

[0059] Preparation of Test Solutions for Comparative Examples 19 and 20: Test Solutions Containing Sodium Edetate Hydrate The compositions of the test solutions for Comparative Examples 19 and 20 are shown in Table 12. Carteolol hydrochloride, anhydrous disodium hydrogen phosphate, and sodium dihydrogen phosphate dihydrate were mixed to the compositions shown in Table 12, and then sterile purified water was added to dissolve the mixture. 5N sodium hydroxide was added to the mixture to adjust the pH to 6.7, and sterile purified water was added to make the required volume. These solutions were filtered through a 0.22 μm membrane filter and filled into sterilized glass containers in 5 mL portions to prepare the test solutions.

[0060] [Table 11]

[0061] [Table 12]

[0062] A photostability test was conducted on the test solutions of Examples 22 to 25 and Comparative Examples 19 and 20. The test solutions were irradiated for 400 hours with white light from a white lamp at an illuminance of 3,000 Lx and ultraviolet light from a chemical lamp at an intensity of 50 μW / cm2. Each sample solution after irradiation was compared with a sample solution stored in a dark place at 4°C and not irradiated with light. Among the decomposition products produced by photodecomposition of carteolol hydrochloride in each sample solution, the amount of 3,4-dehydrocarteolol produced and the total amount of decomposition products were measured, and the results are shown in Table 13. The decomposition products of carteolol hydrochloride were analyzed by high-performance liquid chromatography (HPLC).

[0063] (HPLC conditions for measuring the amount of 3,4-dehydrocarteolol produced) Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 15 cm was packed with 5 μm octadecylsilanized silica gel for liquid chromatography. Mobile phase: 1.51 g of sodium 1-hexanesulfonate was dissolved in 3 mL of acetic acid (100) and 1,000 mL of water. 170 mL of acetonitrile was added to 830 mL of this solution. Detector: UV absorption photometer

[0064] [Table 13]

[0065] The addition of sodium edetate hydrate to carteolol solution reduced the amount of 3,4-dehydrocarteolol, a photodegradation product of carteolol hydrochloride, and the total amount of decomposition products in a concentration-dependent manner. These results confirmed that sodium edetate hydrate improves the photostability of carteolol hydrochloride.

[0066] Test Example 6: Evaluation of photostability by adding alginic acid The effect of alginic acid on improving the photostability of carteolol hydrochloride was confirmed according to the following method. Test Solutions of Examples 26 to 29, 60, and 61 The compositions of the test solutions for Examples 26 to 29, 60, and 61 are shown in Table 14. Carteolol hydrochloride, anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate, sodium edetate hydrate, propylene glycol, and alginic acid were weighed out to the compositions shown in Table 14, and sterilized purified water was added. 5N sodium hydroxide was added while stirring to dissolve the solution. 5N sodium hydroxide was further added to adjust the pH to 6.7, and sterilized purified water was added to make the required volume. These solutions were filtered through a 0.22 μm membrane filter and filled into sterilized glass containers in 5 mL portions to prepare the test solutions.

[0067] Preparation of Test Solutions of Comparative Examples 21 to 28: Test Solutions Free of Sodium Edetate Hydrate and / or Alginic Acid The compositions of the test solutions for Comparative Examples 21 to 28 are shown in Table 15. Carteolol hydrochloride, anhydrous disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate, sodium edetate hydrate, propylene glycol, and NaCl (in amounts such that the osmotic pressure ratio of the solution was 0.9 to 1.1) were weighed out to the compositions shown in Table 15, and sterile purified water was added to dissolve. Next, for Comparative Examples 21 and 25, alginic acid was added while stirring the solution, and 5N sodium hydroxide was added to dissolve the alginic acid. Further, 5N sodium hydroxide was added to adjust the pH to 6.7, and sterile purified water was added to make up the specified volume. These solutions were filtered through a 0.22 μm membrane filter and filled into sterilized glass containers in 5 mL amounts to prepare the test solutions.

[0068] [Table 14]

[0069] [Table 15]

[0070] A photostability test was conducted on the test solutions of Examples 26 to 29, 60, and 61 and Comparative Examples 21 to 28. Each sample solution was irradiated for 400 hours with white light from a white lamp at an illuminance of 3,000 Lx and ultraviolet light from a chemical lamp at an intensity of 50 μW / cm2. Among the decomposition products produced by photodecomposition of carteolol hydrochloride, the amount of 3,4-dehydrocarteolol produced and the total amount of the decomposition products were measured, and the results are shown in Table 16. The photodecomposition products of carteolol hydrochloride were analyzed by high-performance liquid chromatography (HPLC).

[0071] (HPLC conditions for measuring the amount of 3,4-dehydrocarteolol produced) Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 15 cm was packed with 5 μm octadecylsilanized silica gel for liquid chromatography. Mobile phase: 1.51 g of sodium 1-hexanesulfonate was dissolved in 3 mL of acetic acid (100) and 1,000 mL of water. 170 mL of acetonitrile was added to 830 mL of this solution. Detector: UV absorption photometer

[0072] [Table 16]

[0073] When alginic acid was added to a sample solution containing carteolol hydrochloride and sodium edetate hydrate, photodecomposition of carteolol hydrochloride was significantly inhibited. The absence of either alginic acid or sodium edetate hydrate, or both, increased the amount of 3,4-dehydrocarteolol, a photodecomposition product of carteolol hydrochloride. Furthermore, in Comparative Examples 22 and 26, which did not contain either alginic acid or sodium edetate hydrate, the amount of 3,4-dehydrocarteolol produced and the total amount of decomposition products were significantly greater than in samples containing only alginic acid (Comparative Examples 21 and 25) or sodium edetate hydrate (Comparative Examples 23, 24, 27, and 28). These results suggest that alginic acid and sodium edetate hydrate inhibit the photodecomposition of carteolol hydrochloride and improve its photostability. Furthermore, the combination of alginic acid and sodium edetate hydrate further improved the photostability of carteolol hydrochloride.

[0074] <Test result determination> It was revealed that the pharmaceutical composition of the present invention complies with the preservative effectiveness test described in the Reference Information of the 17th Edition of the Japanese Pharmacopoeia, and also inhibits photodecomposition of carteolol hydrochloride, thereby stabilizing it against light. That is, in the present invention, it has been revealed that the preservative effectiveness of a β-blocker can be maintained even when filled into a general-purpose eye dropper container that allows multiple administrations by adding sodium edetate hydrate, and optionally an isotonicity agent (e.g., propylene glycol) and / or a duration-retaining agent (e.g., alginic acid) to a β-blocker, without incorporating a preservative such as benzalkonium chloride or boric acid, which may cause side effects. Furthermore, it has been revealed that the pharmaceutical composition of the present invention is so photostable that the active ingredient can be stored without being photodegraded even without being stored in a light-shielded environment.

[0075] <Formulation Example 1>: Manufacturing example of a formulation containing prostaglandin F2α derivative Examples 30 to 39 and Comparative Example 29 were produced according to the following methods. Example 30 0.005 g of latanoprost, 0.1 g of polysorbate 80, and 80 g of purified water were weighed out, heated to 60°C, dissolved, and then returned to room temperature. To this solution, 2.0 g of carteolol hydrochloride, 1.0 g of alginic acid, 1.0 g of boric acid, and 0.1 g of sodium edetate hydrate were added, and sodium hydroxide was added to dissolve the solution and adjust the pH to 6.5. Purified water was then added to make a total of 100 g. This solution was filtered using a membrane filter with a pore size of 0.2 μm to give Example 30.

[0076] Example 31 0.005 g of latanoprost, 0.1 g of polysorbate 80, and 80 g of purified water were weighed out, heated to 60°C, dissolved, and then returned to room temperature. To this solution, 2.0 g of carteolol hydrochloride, 1.0 g of alginic acid, 0.4 g of sodium chloride, 0.04 g of sodium dihydrogen phosphate dihydrate, 0.04 g of anhydrous disodium hydrogen phosphate, and 0.1 g of sodium edetate hydrate were added, and sodium hydroxide was added to dissolve the solution, adjusting the pH to 6.5, followed by adding purified water to bring the total volume to 100 g. This solution was filtered using a 0.2 μm pore size membrane filter to prepare Example 31.

[0077] Example 32 0.005 g of latanoprost and 80 g of purified water were weighed out, heated to 60°C, dissolved, and then returned to room temperature. To this solution, 2.0 g of carteolol hydrochloride, 1.0 g of alginic acid, 0.4 g of sodium chloride, 0.04 g of sodium dihydrogen phosphate dihydrate, 0.04 g of anhydrous disodium hydrogen phosphate, and 0.1 g of sodium edetate hydrate were added, and sodium hydroxide was added to dissolve the solution, adjusting the pH to 6.5, followed by adding purified water to bring the total volume to 100 g. This solution was filtered using a 0.2 μm pore membrane filter to prepare Example 32.

[0078] Examples 33, 36, and 39 Following the method described in Example 30, Examples 33, 36 and 39 were prepared.

[0079] Examples 34, 35, 37, and 38 Following the method described in Example 31, Examples 34, 35, 37 and 38 were prepared.

[0080] Comparative Example 29 0.005 g of latanoprost, 0.2 g of polysorbate 80, and 80 g of purified water were weighed out, heated to 60°C, dissolved, and then returned to room temperature. To this solution, 1.0 g of alginic acid, 1.5 g of boric acid, and 0.2 g of sodium edetate hydrate were added, and sodium hydroxide was further added to dissolve and adjust the pH to 6.5, followed by adding purified water to make the total amount 100 g. This solution was filtered using a membrane filter with a pore size of 0.2 μm, and designated Comparative Example 29.

[0081] [Table 17] TIFF2026021353000021.tif132168

[0082] Formulation Example 2 According to the following method, preparations of Examples 40 to 47 that do not contain benzalkonium chloride were produced. Example 40 80 g of purified water, 1.0 g of carteolol hydrochloride, 1.0 g of alginic acid, 1.0 g of propylene glycol, 0.04 g of sodium dihydrogen phosphate dihydrate, 0.04 g of anhydrous disodium hydrogen phosphate, and 0.01 g of sodium edetate hydrate were weighed out, and sodium hydroxide was added while stirring to dissolve the mixture. The pH was adjusted to 6.7. Further purified water was added to bring the total volume to 100 g and the mixture was stirred. The resulting solution was filtered through a 0.2 μm membrane filter to prepare Example 40.

[0083] Examples 41 to 47 Examples 41-47 were prepared according to the method described in Example 40.

[0084] [Table 18] TIFF2026021353000023.tif101153

[0085] Formulation Example 3: Manufacturing example of a formulation containing a carbonic anhydrase inhibitor Examples 48 to 59 were prepared according to the following methods. Example 48 Example 48 was prepared by dissolving 2.0 g of carteolol hydrochloride, 1.113 g of dorzolamide hydrochloride, 0.01 g of sodium edetate hydrate, 2.0 g of D-mannitol, and 0.3 g of sodium citrate hydrate in water and sterilizing the solution by filtration using a 0.2 μm membrane filter. This solution was then mixed with a solution of 0.5 g of hydroxyethyl cellulose dissolved in water and sterilized by autoclaving. Sodium hydroxide was added to adjust the pH to 5.7. Purified water was then added to bring the total volume to 100 g to prepare Example 48.

[0086] Examples 49 to 51 Following the method described in Example 48, Examples 49-51 were prepared.

[0087] Example 52 80 g of purified water, 2.0 g of carteolol hydrochloride, 1.113 g of dorzolamide hydrochloride, 0.01 g of sodium edetate hydrate, 0.7 g of propylene glycol, and 0.3 g of sodium citrate hydrate were weighed and dissolved, and sodium hydroxide was added to adjust the pH to 5.7. Purified water was added to bring the total volume to 100 g and the mixture was stirred. The solution was filtered using a 0.2 μm pore size membrane filter to prepare Example 52.

[0088] Examples 53 to 55 Following the method described in Example 52, Examples 53-55 were prepared.

[0089] Example 56 0.025 g of tyloxapol was weighed into a cylindrical glass container, dissolved in 6 g of purified water heated to 60°C, and then 1.0 g of brinzolamide and 12 g of zirconia-yttria beads were added. The container was sealed and heated at 121°C for 20 minutes, cooled, and then rotated at 50 rpm for 20 hours to produce a brinzolamide suspension. Separately, 2.0 g of carteolol hydrochloride, 0.01 g of sodium edetate hydrate, and 1.0 g of propylene glycol were weighed and dissolved in 50 g of purified water. 0.4 g of Carbopol was weighed and added to 25 g of purified water heated to 60°C to form a uniform dispersion. The mixture was heated at 121°C for 20 minutes, and then sodium hydroxide was added to adjust the pH to 7.2 to produce a solvent. The brinzolamide suspension from which the zirconia-yttria beads had been removed by filtration was mixed with the solvent and purified water was added to make a final volume of 100 g, designated Example 56.

[0090] Examples 57 to 59 Following the method described in Example 56, Examples 57-59 were prepared.

[0091] [Table 19] TIFF2026021353000025.tif81153 TIFF2026021353000026.tif70153

[0092] Test Example 7: Preservative effectiveness test of the preparations of Examples 30 to 39 and Comparative Example 29 According to the above preservative effectiveness test method, the preservative effectiveness of the preparations of Examples 30 to 39 and Comparative Example 29 was confirmed. The results are shown below. [Table 20] [Industrial Applicability]

[0093] The pharmaceutical compositions of the present invention may have enhanced preservative efficacy and / or improved photostability and may therefore be useful in treating ocular diseases such as glaucoma and ocular hypertension.

Claims

1. A pharmaceutical composition for ophthalmic administration comprising carteolol or a pharmaceutically acceptable salt thereof and edetic acid or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition of claim 1, further comprising an isotonicity agent.

3. The pharmaceutical composition according to claim 1 or 2, further comprising a sustaining agent.

4. The pharmaceutical composition according to any one of claims 1 to 3, further comprising a buffer and a pH adjusting agent.

5. The pharmaceutical composition according to any one of claims 1 to 4, further comprising a prostaglandin F2α derivative.

6. The pharmaceutical composition according to any one of claims 1 to 5, further comprising a carbonic anhydrase inhibitor.

7. The pharmaceutical composition according to any one of claims 1 to 6, further comprising another drug having an effect of lowering intraocular pressure.

8. 8. The pharmaceutical composition according to claim 1, wherein the content of carteolol or a pharmaceutically acceptable salt thereof is 0.1 to 5 w / v % based on the total amount of the composition.

9. 9. The pharmaceutical composition according to claim 1, wherein the content of edetic acid or a pharmaceutically acceptable salt thereof is 0.01 to 0.2 w / v % based on the total amount of the composition.

10. The pharmaceutical composition according to any one of claims 1 to 9, having a pH of 5.0 to 8.

0.

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

12. The pharmaceutical composition according to any one of claims 1 to 11, which is an aqueous eye drop or an eye drop suspension.

13. The pharmaceutical composition according to any one of claims 1 to 12, which is used as a multi-dose eye drop.

14. The pharmaceutical composition according to any one of claims 1 to 13, which is for treating glaucoma or ocular hypertension.

15. A method for enhancing the preservative effectiveness of carteolol or a pharmaceutically acceptable salt thereof with edetic acid or a pharmaceutically acceptable salt thereof, comprising combining carteolol or a pharmaceutically acceptable salt thereof with edetic acid or a pharmaceutically acceptable salt thereof.

16. A method for improving the photostability of carteolol or a pharmaceutically acceptable salt thereof with edetic acid, alginic acid, or a pharmaceutically acceptable salt thereof, characterized by combining carteolol or a pharmaceutically acceptable salt thereof with edetic acid or a pharmaceutically acceptable salt thereof.

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