Ophthalmic pharmaceutical composition having improved antiseptic efficacy or light stability

Abstract

The present invention relates to an ophthalmic pharmaceutical composition having improved antiseptic efficacy or light stability. An ophthalmic pharmaceutical composition is disclosed, which comprises carteolol or a pharmaceutically acceptable salt thereof, edetic acid or a pharmaceutically acceptable salt thereof, latanoprost, and alginic acid or a pharmaceutically acceptable salt thereof, wherein edetic acid or a pharmaceutically acceptable salt thereof enhances the antiseptic efficacy of carteolol or a pharmaceutically acceptable salt thereof, and edetic acid or a pharmaceutically acceptable salt thereof and / or alginic acid or a pharmaceutically acceptable salt thereof improves the light stability of carteolol or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of the present invention has enhanced antiseptic efficacy of carteolol and / or improved light stability thereof. A method of using the composition to enhance the antiseptic efficacy of carteolol or a pharmaceutically acceptable salt thereof or to improve the light stability of carteolol or a pharmaceutically acceptable salt thereof is also disclosed.

Description

[0001] This application is a divisional application of International Application PCT / JP2017 / 029934 which entered the Chinese national phase on February 14, 2019, with application number 201780049806.1 and invention title "Ophthalmic pharmaceutical composition having improved antiseptic efficacy or light stability". Technical Field

[0002] The present invention relates to an ophthalmic pharmaceutical composition containing carteolol as a β-blocker, a method for preparing the ophthalmic pharmaceutical composition, and its medical use. The present invention also relates to a method for enhancing the antiseptic efficacy of carteolol, improving its light stability, and / or reducing its decomposition. Background Art

[0003] Carteolol is known as a β-blocker, and its chemical name is 5-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-3,4-dihydroquinolin-2(1H)-one, and it is known to be therapeutically effective for glaucoma and ocular hypertension for ophthalmic use. Eye drops usually need to contain an antiseptic agent or a preservative to avoid contamination by microorganisms during use. Such antiseptic agents or preservatives generally include benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, parabens, chlorobutanol, and sorbate. However, these antiseptic agents and preservatives can have a negative impact on human tissues such as the cornea.

[0004] Instead of using an antiseptic agent or a preservative, a method of imparting antiseptic efficacy to eye drops by adding boric acid or its salts, etc. is known. However, the use of boric acid, etc. may cause allergic symptoms (such as blepharitis) as a side effect (see PTL 1).

[0005] Eye drops without an antiseptic agent or a preservative include single-dose packaged eye drops and single-use disposable eye drops, that is, unit-dose eye drops, in which a single dose is individually packaged. For example, PTL 2 discloses an antibacterial agent-free eye drop containing carteolol hydrochloride, in which a single dose is individually packaged. However, for each administration, such unit-dose eye drops require a disposable individual container, and may not be suitable for long-term continuous administration in terms of cost and stability of storage facilities, etc.

[0006] Eye diseases (such as glaucoma and ocular hypertension) that require long-term continuous administration of drugs require stable eye drops with high antiseptic efficacy.

[0007] Some β-blockers decompose under light, and carteolol is one of such β-blockers. Therefore, it is usually necessary to prevent eye drops containing carteolol from being irradiated with light during storage and use.

[0008] Citation List

[0009] Patent Documents

[0010] [PTL 1] WO 2011 / 013794 brochure

[0011] [PTL 2] CN 101461780A Summary of the Invention

[0012] Technical Problem

[0013] One of the problems to be solved by the present invention is to provide an ophthalmic pharmaceutical composition having enhanced antiseptic efficacy of carteolol and / or improved photostability thereof. Another problem is to provide a method for enhancing the antiseptic efficacy of carteolol, improving its photostability, and / or reducing its decomposition.

[0014] Solution to the Problem

[0015] The inventors have found through extensive research that these problems can be solved by combining carteolol or a pharmaceutically acceptable salt thereof with edetic acid or a pharmaceutically acceptable salt thereof, and thus the present invention has been achieved.

[0016] An embodiment of 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.

[0017] Another embodiment of the present invention further provides a method for enhancing the antiseptic efficacy of carteolol or a pharmaceutically acceptable salt thereof with 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.

[0018] Still another embodiment of the present invention further provides a method for improving the photostability of carteolol or a pharmaceutically acceptable salt thereof or reducing the decomposition of carteolol or a pharmaceutically acceptable salt thereof with edetic acid or a pharmaceutically acceptable salt thereof and / or a stabilizing agent, the method comprising combining carteolol or a pharmaceutically acceptable salt thereof with edetic acid or a pharmaceutically acceptable salt thereof and / or a stabilizing agent.

[0019] Still another embodiment of the present invention further provides a method for preparing an ophthalmic pharmaceutical composition comprising carteolol or a pharmaceutically acceptable salt thereof and edetic acid or a pharmaceutically acceptable salt thereof, the method comprising mixing carteolol or a pharmaceutically acceptable salt thereof with edetic acid or a pharmaceutically acceptable salt thereof.

[0020] Advantages of the Invention

[0021] The pharmaceutical composition of the present invention can have antiseptic efficacy or control microbial growth without antiseptic agents or preservatives. The pharmaceutical composition of the present invention can also improve light stability. The pharmaceutical composition of the present invention can have enhanced antiseptic efficacy and / or improved light stability, and can also be used for treating ocular diseases that require long-term continuous administration of drugs, such as glaucoma and ocular hypertension.

[0022] In the present invention, adding edetic acid or a pharmaceutically acceptable salt thereof to carteolol or a pharmaceutically acceptable salt thereof (which can essentially control microbial growth, although weakly) can enhance the antiseptic efficacy or antibacterial action of carteolol or a pharmaceutically acceptable salt thereof, and allow the provision of eye drops without antiseptic agents or preservatives, thereby improving the light stability of carteolol with poor light stability. In addition, adding a tonicity agent (such as propylene glycol) and / or a thickening agent (such as alginic acid) can enhance the antiseptic efficacy or antibacterial effect of carteolol or a pharmaceutically acceptable salt thereof or improve the light stability of carteolol or a pharmaceutically acceptable salt thereof. Summary of the Invention

[0024] The present invention may include the following examples.

[0025] Item 1. An ophthalmic pharmaceutical composition comprising carteolol or a pharmaceutically acceptable salt thereof and edetic acid or a pharmaceutically acceptable salt thereof.

[0026] Item 2. An ophthalmic pharmaceutical composition for improving the antiseptic efficacy and / or light stability of carteolol or a pharmaceutically acceptable salt thereof, comprising edetic acid or a pharmaceutically acceptable salt thereof.

[0027] Item 3. The composition according to Item 1 or 2, further comprising a tonicity agent. Examples of the tonicity agent include propylene glycol, glycerol, polyethylene glycol, trehalose, maltose, sucrose, glucose, sorbitol, mannitol, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and combinations thereof.

[0028] Item 4. The composition according to any one of Items 1 to 3, further comprising a thickening agent. Examples of the thickening 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.

[0029] Item 5. The composition according to any one of Items 1 to 4, further comprising a buffer and a pH regulator.

[0030] Item 6. The composition according to any one of Items 1 to 5, further comprising a prostaglandin F2α derivative. Examples of the prostaglandin F2α derivative include latanoprost, bimatoprost, travoprost, and tafluprost.

[0031] Item 7. The 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.

[0032] Item 8. The composition according to any one of Items 1 to 7, further comprising another agent having an intraocular pressure-lowering effect, such as an adrenergic α2 agonist and a ROCK (Rho kinase) inhibitor. Examples of the adrenergic α2 agonist include brimonidine tartrate, dipivefrin hydrochloride, and clonidine. Examples of the ROCK inhibitor include ripasudil hydrochloride hydrate and netarsudil mesylate.

[0033] Item 9. The composition according to any one of Items 1 to 8, wherein the content of carteolol or a pharmaceutically acceptable salt thereof in the total amount of the composition ranges from 0.1 to 5 w / v%.

[0034] Item 10. The composition according to any one of Items 1 to 9, wherein the content of edetic acid or a pharmaceutically acceptable salt thereof in the total amount of the composition ranges from 0.01 to 0.2 w / v%.

[0035] Item 11. The composition according to any one of Items 1 to 10, wherein the ratio of edetic acid or a pharmaceutically acceptable salt thereof to the amount of carteolol or a pharmaceutically acceptable salt thereof contained in the composition is 0.002 to 2.0 w / w.

[0036] Item 12. The composition according to any one of Items 1 to 11, wherein the pH ranges from 5.0 to 8.0.

[0037] Item 13. The composition according to any one of Items 1 to 12, which is in the form of an eye drop.

[0038] Item 14. The composition according to any one of Items 1 to 13, which is in the form of an aqueous eye drop or a suspension eye drop.

[0039] Item 15. The composition according to any one of Items 1 to 14, which is used as a multi-dose eye drop.

[0040] Item 16. The composition according to any one of Items 1 to 15, which is used for the treatment of glaucoma or ocular hypertension.

[0041] Item 17. The composition according to any one of Items 1 to 16, which is used in combination with a prostaglandin formulation. The prostaglandin formulation refers to a formulation containing a prostaglandin F2α derivative.

[0042] Item 18. A method for enhancing the antiseptic efficacy of carteolol or a pharmaceutically acceptable salt thereof with 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.

[0043] Item 19. Use of edetic acid or a pharmaceutically acceptable salt thereof for enhancing the antiseptic efficacy of carteolol or a pharmaceutically acceptable salt thereof.

[0044] Item 20. A method for enhancing the antiseptic efficacy of carteolol or a pharmaceutically acceptable salt thereof with propylene glycol, the method comprising combining carteolol or a pharmaceutically acceptable salt thereof with propylene glycol.

[0045] Item 21. Use of propylene glycol for enhancing the antiseptic efficacy of carteolol or a pharmaceutically acceptable salt thereof.

[0046] Item 22. Use of a combination of edetic acid or a pharmaceutically acceptable salt thereof and propylene glycol for enhancing the antiseptic efficacy of carteolol or a pharmaceutically acceptable salt thereof.

[0047] 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, the method comprising combining carteolol or a pharmaceutically acceptable salt thereof with edetic acid or a pharmaceutically acceptable salt thereof.

[0048] Item 24. Use of edetic acid or a pharmaceutically acceptable salt thereof for improving the photostability of carteolol or a pharmaceutically acceptable salt thereof.

[0049] Item 25. A method for improving the photostability of carteolol or a pharmaceutically acceptable salt thereof with alginic acid, the method comprising combining carteolol or a pharmaceutically acceptable salt thereof with alginic acid.

[0050] Item 26. Use of alginic acid for improving the photostability of carteolol or a pharmaceutically acceptable salt thereof.

[0051] Item 27. Use of a combination of edetic acid or a pharmaceutically acceptable salt thereof and alginic acid for improving the photostability of carteolol or a pharmaceutically acceptable salt thereof.

[0052] Item 28. A method for preparing an ophthalmic pharmaceutical composition, the method comprising the following steps: mixing carteolol or a pharmaceutically acceptable salt thereof with edetic acid or a pharmaceutically acceptable salt thereof, optionally together with a pH regulator, or propylene glycol, alginic acid, or a combination thereof, wherein the pH regulator is mixed such that the pH of the resulting composition ranges from 5.0 to 8.0, and propylene glycol, alginic acid, or a combination thereof is mixed such that the osmotic pressure ratio of the resulting composition ranges from 0.8 to 1.2.

[0053] The present invention includes the embodiments shown below and any combination thereof. The starting materials of the ingredients used herein may be in the form of solvates (such as hydrates) or anhydrous forms, as long as they are pharmaceutically applicable.

[0054] The pharmaceutical composition of the present invention comprises carteolol or a pharmaceutically acceptable salt thereof and edetic acid or a pharmaceutically acceptable salt thereof.

[0055] The pharmaceutical composition of the present invention can exhibit preservative efficacy without preservatives or antiseptics. Such preservatives or antiseptics generally include, but are not limited to, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, parabens, chlorobutanol, and sorbates. One embodiment of the pharmaceutical composition in the present invention may not contain preservatives or antiseptics. Another embodiment of the pharmaceutical composition in the present invention may not contain boric acid or its salts. Still another embodiment of the pharmaceutical composition in the present invention may contain boric acid or its salts.

[0056] In one embodiment, 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% of the total amount of the composition. The preferred amount (concentration) of carteolol or a pharmaceutically acceptable salt thereof includes a range of 0.5 and 2.5 w / v% relative to the total amount of the composition. A more preferred range is 1 to 2 w / v%.

[0057] The pharmaceutically acceptable salts of carteolol include salts of carteolol with inorganic acids. The preferred salt is carteolol hydrochloride.

[0058] 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% of the total amount of the composition. The preferred amount (concentration) of edetic acid or a pharmaceutically acceptable salt thereof includes a range of 0.01 and 0.15 w / v% relative to the total amount of the composition. A more preferred range is 0.02 to 0.1 w / v%, and further preferably 0.03 to 0.07 w / v%.

[0059] Edetic acid or a pharmaceutically acceptable salt thereof can be included in the composition in a ratio of 0.002 to 2.0 w / w with respect to the amount of carteolol or a pharmaceutically acceptable salt thereof contained in the composition. The preferred ratio range is 0.004 to 0.3 w / w, more preferably 0.008 to 0.2 w / w, further preferably 0.015 to 0.07 w / w, and particularly preferably 0.025 to 0.06 w / w.

[0060] The pharmaceutically acceptable salts of edetic acid include salts of edetic acid (ethylenediaminetetraacetic acid; EDTA) with inorganic bases. The preferred salt is disodium edetate hydrate.

[0061] Edetic acid or a pharmaceutically acceptable salt thereof can enhance the antiseptic efficacy inherent in carteolol or a pharmaceutically acceptable salt thereof, improve the photostability of carteolol, and / or reduce its decomposition.

[0062] The pharmaceutical composition of the present invention may optionally further contain additive components such as tonicity agents, sustaining agents, buffering agents, pH regulators, solubilizing agents, and solvents.

[0063] Such tonicity agents include, but are not limited to, propylene glycol, glycerol, polyethylene glycol, trehalose, maltose, sucrose, glucose, sorbitol, mannitol, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, and combinations thereof. Preferred tonicity agents are propylene glycol or sodium chloride.

[0064] The amount (concentration) of the tonicity agent contained in the composition includes, but is not limited to, an amount such that the osmotic pressure ratio of the composition is in the range of 0.8 to 1.2, preferably in the range of 0.9 to 1.1. The specific range of such an amount is 0.5 to 2.0 w / v%, preferably 1.0 to 1.6 w / v%.

[0065] The tonicity agent can be contained in the composition in a ratio of 0.08 to 20 w / w (preferably 0.16 to 4 w / w, more preferably 0.2 to 2 w / w) to the amount of carteolol or a pharmaceutically acceptable salt thereof contained in the composition.

[0066] The tonicity agent can be contained in the composition in a ratio of 3 to 200 w / w (preferably 4 to 100 w / w, more preferably 6 to 70 w / w) to the amount of edetic acid or a pharmaceutically acceptable salt thereof.

[0067] Such sustaining agents 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. Preferred sustaining agent is alginic acid.

[0068] The amount (concentration) of the sustaining agent contained in the composition includes, but is not limited to, an amount in the range of 0.1 to 5 w / v%. The preferred range is an amount in the range of 0.5 to 2 w / v%, more preferably 0.8 to 1.2 w / v%.

[0069] The sustaining agent can be contained in the composition in a ratio of 0.25 to 2 w / w (preferably 0.4 to 1.2 w / w) to the amount of carteolol or a pharmaceutically acceptable salt thereof contained in the composition.

[0070] The sustaining agent can be contained in the composition in a ratio of 5 to 100 w / w (preferably 10 to 40 w / w) to the amount of edetic acid or a pharmaceutically acceptable salt thereof contained in the composition.

[0071] Such buffers 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, boric acid and borates such as sodium borate and potassium borate, citric acid and citrates such as sodium citrate and disodium citrate, acetic acid and acetates such as sodium acetate and potassium acetate, carbonates such as sodium carbonate and sodium bicarbonate, and combinations thereof. Preferred buffers are phosphates. More preferred buffers are sodium dihydrogen phosphate and disodium hydrogen phosphate.

[0072] The amount (concentration) of buffer included in the composition includes, but is not limited to, amounts in the range of 0.01 to 1 w / v% (preferably 0.04 to 0.4 w / v%).

[0073] Such pH regulators include, but are not limited to, acids such as hydrochloric acid, lactic acid, citric acid, phosphoric acid, and acetic acid, and basic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate. Preferred pH regulators are hydrochloric acid or sodium hydroxide.

[0074] The amount (concentration) of pH regulator included in the composition includes, but is not limited to, an amount such that the pH value of the composition is adjusted to be in the range of 5.0 and 8.5. Preferably, the pH value is adjusted to be in the range of 5.0 and 8.0. More preferably, the pH value is adjusted to be in the range of 6.0 to 8.0, and further preferably adjusted to be in the range of 6.2 and 7.2.

[0075] Such solubilizers include, but are not limited to, vegetable oils such as polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyethylene glycol (macrogol) 4000, polyvinyl alcohol, tyloxapol, polyoxyethylene polyoxypropylene glycol, polyoxyl stearate, and soybean oil. Preferred solubilizer is polysorbate 80.

[0076] The amount (concentration) of solubilizer included in the composition includes, but is not limited to, amounts in the range of 0.05 to 5 w / v% (preferably 0.1 to 3 w / v%, more preferably 0.1 to 2 w / v%).

[0077] Such solvents include, but are not limited to, pure water, sterile pure water, and water for injection. Preferred solvents are sterile pure water or water for injection.

[0078] The pharmaceutical composition of the present invention may further comprise a prostaglandin F2α derivative. The prostaglandin F2α derivative can be included in the composition in an amount of 0.0005 to 0.1 w / v% relative to the total amount of the composition. The preferred amount (concentration) of the prostaglandin F2α derivative included in the composition includes an amount of 0.001 to 0.05 w / v% (more preferably 0.0015 to 0.03 w / v%) relative to the total amount of the composition.

[0079] Prostaglandin F2α derivatives include, but are not limited to, latanoprost, bimatoprost, travoprost, and tafluprost.

[0080] In another embodiment, the present invention can be a pharmaceutical composition for use in combination with a formulation comprising a prostaglandin F2α derivative (hereinafter also referred to as "prostaglandin formulation"). The pharmaceutical composition of the present invention can be administered to a subject simultaneously or at a time before or after the administration of the prostaglandin F2α derivative.

[0081] The pharmaceutical composition of the present invention can further comprise a carbonic anhydrase inhibitor. The carbonic anhydrase inhibitor can be included in the composition in an amount of 0.1 to 5 w / v% relative to the total amount of the composition. Preferred amounts (concentrations) of the carbonic anhydrase inhibitor included in the composition include amounts of 0.5 to 2.5 w / v% (more preferably 1 to 2 w / v%) relative to the total amount of the composition.

[0082] Carbonic anhydrase inhibitors include, but are not limited to, dorzolamide, brinzolamide, acetazolamide, and pharmaceutically acceptable salts thereof.

[0083] The pharmaceutical composition of the present invention can further comprise another agent having an intraocular pressure-lowering effect. The agent having an intraocular pressure-lowering effect can be included in the composition in an amount of 0.1 to 5 w / v% relative to the total amount of the composition. Preferred amounts (concentrations) of the agent having an intraocular pressure-lowering effect included in the composition include amounts of 0.5 to 2.5 w / v% (more preferably 1 to 2 w / v%) relative to the total amount of the composition.

[0084] The agent having an intraocular pressure-lowering effect includes, but is not limited to, adrenergic α2 agonists and ROCK (Rho kinase) inhibitors. Examples of adrenergic α2 agonists include brimonidine tartrate, dipivefrin hydrochloride, and clonidine. Examples of ROCK inhibitors include ripasudil hydrochloride hydrate and netarsudil mesylate.

[0085] The pharmaceutical composition of the present invention can preferably be in the form of an ophthalmic solution. More preferably, it is an aqueous eye drop or a suspension eye drop containing an aqueous solvent such as purified water, sterile purified water, or water for injection. The pharmaceutical composition of the present invention can also be a unit-dose type eye drop (wherein a single dose is individually packaged), or it can be a reusable multi-dose type eye drop. Preferred is the multi-dose type eye drop.

[0086] The pharmaceutical composition of the present invention can be used for treating glaucoma such as primary open-angle glaucoma, primary angle-closure glaucoma, developmental glaucoma, secondary glaucoma, normal-tension glaucoma, and ocular diseases such as ocular hypertension. Carteolol can reduce intraocular pressure, and the pharmaceutical composition of the present invention can also be used for treating glaucoma such as primary open-angle glaucoma, primary angle-closure glaucoma, developmental glaucoma and secondary glaucoma, and ocular diseases such as ocular hypertension.

[0087] One embodiment of the present invention provides a pharmaceutical composition comprising carteolol or a pharmaceutically acceptable salt thereof and edetic acid or a pharmaceutically acceptable salt thereof, wherein the weak antiseptic potency of carteolol or a pharmaceutically acceptable salt thereof in addition to its main effect is enhanced.

[0088] In another embodiment, edetic acid or a pharmaceutically acceptable salt thereof can enhance the antiseptic potency of carteolol or a pharmaceutically acceptable salt thereof in a mixed solution with carteolol or a pharmaceutically acceptable salt thereof. The antiseptic potency of carteolol or a pharmaceutically acceptable salt thereof can be further enhanced by adding a tonicity agent to the mixed solution.

[0089] One embodiment of the present invention provides a pharmaceutical composition comprising carteolol or a pharmaceutically acceptable salt thereof and edetic acid or a pharmaceutically acceptable salt thereof, wherein the poor light stability of carteolol or a pharmaceutically acceptable salt thereof is improved or its decomposition is reduced.

[0090] In another embodiment, edetic acid or a pharmaceutically acceptable salt thereof can improve the light stability of carteolol or a pharmaceutically acceptable salt thereof or reduce the decomposition of carteolol or a pharmaceutically acceptable salt thereof in a mixed solution with carteolol or a pharmaceutically acceptable salt thereof. Adding a preservative to the mixed solution can further improve the light stability of carteolol or a pharmaceutically acceptable salt thereof or further reduce the decomposition of carteolol or a pharmaceutically acceptable salt thereof.

[0091] Another embodiment of the present invention provides a method for preparing an ophthalmic pharmaceutical composition. The preparation method in the present invention includes the step of mixing carteolol or a pharmaceutically acceptable salt thereof with edetic acid or a pharmaceutically acceptable salt thereof. Carteolol or a pharmaceutically acceptable salt thereof and edetic acid or a pharmaceutically acceptable salt thereof can optionally be mixed with the above pH regulator so that the pH of the resulting pharmaceutical composition is adjusted to be in the range of 5.0 and 8.5, preferably 5.0 and 8.0, more preferably 6.0 and 8.0, and further preferably 6.0 and 7.2. Carteolol or a pharmaceutically acceptable salt thereof and edetic acid or a pharmaceutically acceptable salt thereof can also optionally be mixed with the above tonicity agent, preservative or a combination thereof as needed. Such a tonicity agent can be added so that the osmotic pressure ratio of the resulting pharmaceutical composition is adjusted to be in the range of 0.8 and 1.2, preferably 0.9 and 1.1. Detailed implementation mode

[0092] Example

[0093] The present invention is illustrated in more detail by the following experiments and examples, but is not limited thereto. Unless otherwise specified, the concentrations herein refer to weight % per volume, i.e., "w / v%", which is synonymous with "g / 100 mL".

[0094] <Antiseptic efficacy test>

[0095] According to the test method for antiseptic efficacy described in The Japanese Pharmacopoeia 17th edition, Reference information, the antiseptic efficacy of the test solution was evaluated in the following experiments.

[0096] Specifically, bacteria such as Escherichia coli ATCC 8739, Pseudomonas aeruginosa ATCC 9027, and Staphylococcus aureus ATCC6538, and / or fungi such as Candida albicans ATCC 10231 and Aspergillus brasiliensis ATCC 16404 were used to prepare the corresponding bacterial solutions. Each bacterial solution was inoculated into the test solution to constitute 10 5 to 10 6 CFU (colony forming unit) / mL, and the resulting product was stored at 20 °C to 25 °C. The viable bacteria count was measured on the 7th, 14th, and 28th days after inoculation. The antiseptic efficacy was determined based on the change in the bacterial count relative to the inoculated bacterial count. For bacteria such as Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus, the case where it was determined to be "sufficient" was that the bacterial count decreased by 1.0 log or more 7 days after inoculation and the bacterial count decreased by 3.0 logs or more 14 days after inoculation, and the decrease in the bacterial count 28 days after inoculation was equal to or less than the decrease in the bacterial count 14 days after inoculation. For fungi such as Candida albicans and Aspergillus brasiliensis, the case where it was determined to be "sufficient" was that the bacterial count 7 days after inoculation was equal to or less than the inoculated bacterial count, and the bacterial counts 14 days and 28 days after inoculation were equal to or less than the inoculated bacterial count.

[0097] <Experiment 1>: Antiseptic efficacy test of carteolol

[0098] The antiseptic efficacy of carteolol was evaluated according to the following method.

[0099] <Preparation of test solutions for Examples 1 to 10>

[0100] The components of the test solutions of Examples 1 to 10 are shown in Table 1. Measure carteolol hydrochloride, disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate dihydrate, and NaCl (added in such amounts that the osmotic pressure ratio of the solution is adjusted to 0.9 to 1.1), and add sterile purified water to the mixture to dissolve it. Adjust the pH values of these solutions to 5.0, 6.0, 7.0, 8.0, or 8.5 by adding 5N sodium hydroxide or 1% hydrochloric acid, and add sterile purified water to these solutions to obtain a specified volume. Filter these solutions through a 0.22-μm membrane filter, and load 5 mL of each solution into a sterile glass container to be used as a test solution.

[0101] <Comparative Examples 1 to 4: Preparation of Test Solutions without Carteolol Hydrochloride>

[0102] The components of the test solutions of Comparative Examples 1 to 4 are shown in Table 1. Measure disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate dihydrate, and NaCl (added in such amounts that the osmotic pressure ratio of the solution is adjusted to 0.9 to 1.1), and add sterile purified water to the mixture to dissolve it. Adjust the pH values of these solutions to 5.0, 6.0, 7.0, or 8.0 by adding 5N sodium hydroxide or 1% hydrochloric acid, and add sterile purified water to these solutions to obtain a specified volume. Filter these solutions through a 0.22-μm membrane filter, and load 5 mL of each solution into a sterile glass container to be used as a test solution.

[0103] [Table 1-1]

[0104] Amount (g / 100 mL) Example 1 Example 2 Example 3 Example 4 Example 5 Carteolol Hydrochloride 1.0 1.0 1.0 1.0 1.0 <![CDATA[Na2HPO4]]> 0.04 0.04 0.04 0.04 0.04 <![CDATA[NaH2PO4·2H2O]]> 0.04 0.04 0.04 0.04 0.04 NaOH or HCl Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount NaCl 0.674 0.674 0.674 0.674 0.674 Purified water Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Total volume (mL) 100 100 100 100 100 pH 5.0 6.0 7.0 8.0 8.5 Osmotic pressure ratio 1.0 1.0 1.0 1.0 1.0

[0105] [Table 1-2]

[0106] Amount (g / 100 mL) Example 6 Example 7 Example 8 Example 9 Example 10 Carteolol Hydrochloride 2.0 2.0 2.0 2.0 2.0 <![CDATA[Na2HPO4]]> 0.04 0.04 0.04 0.04 0.04 <![CDATA[NaH2PO4·2H2O]]> 0.04 0.04 0.04 0.04 0.04 NaOH or HCl Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount NaCl 0.564 0.564 0.564 0.564 0.564 Purified water Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Total volume (mL) 100 100 100 100 100 pH 5.0 6.0 7.0 8.0 8.5. Osmotic pressure ratio 1.0 1.0 1.0 1.0 1.1

[0107] [Table 1-3]

[0108] Amount (g / 100 mL) Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Carteolol Hydrochloride - - - - <![CDATA[Na2HPO4]]> 0.04 0.04 0.04 0.04 <![CDATA[NaH2PO4·2H2O]]> 0.04 0.04 0.04 0.04 NaOH or HCl Appropriate amount Appropriate amount Appropriate amount Appropriate amount NaCl 0.843 0.843 0.843 0.843 Purified water Appropriate amount Appropriate amount Appropriate amount Appropriate amount Total volume (mL) 100 100 1.00 100 pH 5.0 6.0 7.0 8.0 Osmotic pressure ratio 1.0 1.0 1.0 1.0

[0109] Measure the antiseptic efficacy of the test solutions of Examples 1 to 10 and Comparative Examples 1 to 4. The test results of the antiseptic efficacy of each example and comparative example are shown in Table 2.

[0110] In view of the test results of the antiseptic efficacy of each bacterium, it is proved that Examples 1 to 10 are sufficient for fungi in the antiseptic efficacy test and basically also show antiseptic efficacy against bacteria. Comparative Examples 1 to 4 without carteolol hydrochloride are all insufficient in the antiseptic efficacy test. The results show that carteolol hydrochloride has antiseptic efficacy.

[0111] [Table 2-1]

[0112] Test strain Escherichia coli Pseudomonas aeruginosa Staphylococcus aureus Example 1 X X O Example 2 X X O Example 3 O X O Example 4 O O O Example 5 O O O Example 6 X X O Example 7 X X O Example 8 O O O Example 9 O O O Example 10 O O O Comparative Example 1 X X O Comparative Example 2 X X X Comparative Example 3 X X X Comparative Example 4 X X X

[0113] [Table 2-2]

[0114]

[0115] O means the test strain is sufficient in the evaluation criteria for each bacterium. X means the test strain is insufficient in the evaluation criteria for each bacterium. <Experiment 2>: Effect of adding disodium edetate hydrate on antiseptic efficacy

[0116] The enhancement of the antiseptic efficacy of disodium edetate hydrate on carteolol hydrochloride was demonstrated according to the following method.

[0117] [Preparation of test solutions for Examples 11 to 15]

[0118] The components of the test solutions for Examples 11 to 15 are shown in Table 3. Measure carteolol hydrochloride, disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate dihydrate, disodium edetate hydrate, and NaCl (added in such amounts that the osmotic pressure ratio of the solution is adjusted to 0.9 to 1.1), and add sterile purified water to the mixture to dissolve it. Adjust the pH values of these solutions to 5.0, 6.0, or 7.0 by adding 5N sodium hydroxide or 1% hydrochloric acid, and add sterile purified water to these solutions to obtain the specified volume. Filter these solutions through a 0.22-μm membrane filter, and load 5 mL of each solution into a sterile glass container to be used as a test solution.

[0119] [Comparative Examples 5 to 8: Preparation of test solutions without carteolol hydrochloride]

[0120] The components of the test solutions for Comparative Examples 5 to 8 are shown in Table 4. Measure disodium edetate hydrate, disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate dihydrate, and NaCl (added in such amounts that the osmotic pressure ratio of the solution is adjusted to 0.9 to 1.1), and add a specified volume of sterile purified water to the mixture. Adjust the pH values of these solutions to 5.0, 6.0, 7.0, or 8.0 by adding 5N sodium hydroxide or 1% hydrochloric acid, and add sterile purified water to these solutions to obtain the specified volume. Filter these solutions through a 0.22-μm membrane filter, and load 5 mL of each solution into a sterile glass container to be used as a test solution.

[0121] [Table 3]

[0122]

[0123] [Table 4]

[0124]

[0125] Measure the antiseptic efficacy of the test solutions of Examples 11 to 15 and Comparative Examples 5 to 8 against bacteria such as Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. The test results of the antiseptic efficacy of each example and comparative example are shown in Table 5.

[0126] Examples 11 to 15 exhibited basic antiseptic efficacy against bacteria, but Comparative Examples 5 to 8 were insufficient in the antiseptic efficacy test. The results indicate that the combination of carteolol hydrochloride and disodium edetate hydrate enhanced the antiseptic efficacy.

[0127] [Table 5]

[0128]

[0129] O means that the test strain is sufficient in the evaluation criteria for each bacterium

[0130] X means that the test strain is insufficient in the evaluation criteria for each bacterium

[0131] <Experiment 3>: Effect of adding propylene glycol on antiseptic efficacy

[0132] According to the following method, the effect of adding propylene glycol on the antiseptic efficacy of carteolol hydrochloride was demonstrated at pH 5.0 and 6.0.

[0133] <Test solutions of Examples 16 to 19>

[0134] The components of the test solutions of Examples 16 to 19 are shown in Table 6. Measure carteolol hydrochloride, disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate dihydrate, disodium edetate hydrate, and propylene glycol to prepare the compositions shown in Table 6. Add sterile purified water to the mixture to dissolve it. Adjust the pH value of these solutions to 5.0 or 6.0 by adding 1% hydrochloric acid, and add sterile purified water to these solutions to obtain a specified volume. Filter these solutions through a 0.22-μm membrane filter, and load 5 mL of each solution into a sterile glass container to be used as a test solution.

[0135] <Preparation of test solutions of Comparative Examples 9 to 16>

[0136] The components of the test solutions of Comparative Examples 9 to 16 are shown in Table 7. Mix carteolol hydrochloride, disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate dihydrate, and propylene glycol (for Comparative Examples 9 to 12) to dissolve them; mix disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate dihydrate, propylene glycol, and NaCl (added in such amounts that the osmotic pressure ratio of the solution is adjusted to 0.9 to 1.1, for Comparative Examples 13 and 14) to dissolve them; or mix disodium edetate hydrate, disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate dihydrate, propylene glycol, and NaCl (added in such amounts that the osmotic pressure ratio of the solution is adjusted to 0.9 to 1.1, for Comparative Examples 15 and 16) to dissolve them. Adjust the pH value of these solutions to 5.0 or 6.0 by adding 1% hydrochloric acid, and add sterile purified water to these solutions to obtain a specified volume. Filter these solutions through a 0.22-μm membrane filter, and load 5 mL of each solution into a sterile glass container to be used as a test solution.

[0137] [Table 6]

[0138]

[0139] [Table 7-1]

[0140]

[0141] [Table 7-2]

[0142]

[0143] Measure the antiseptic efficacy of the test solutions of Measurement Examples 16 to 19 and Comparative Examples 9 to 16 against bacteria such as Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. The test results of the antiseptic efficacy of each example and comparative example are shown in Table 8.

[0144] Examples 16 to 19, in which propylene glycol is added to a composition containing carteolol hydrochloride and disodium edetate hydrate, meet the standards against all three bacteria, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus, and are sufficient in the antiseptic efficacy test. Comparative Examples 9 to 12 containing carteolol hydrochloride but not containing disodium edetate hydrate do not meet the standards against Escherichia coli or Pseudomonas aeruginosa and are insufficient. Comparative Examples 13 and 14 not containing carteolol hydrochloride or disodium edetate hydrate but containing propylene glycol are insufficient in the antiseptic efficacy test. Comparative Examples 15 and 16 not containing carteolol hydrochloride but containing propylene glycol and disodium edetate hydrate do not meet the standards and are insufficient in the antiseptic efficacy test. The results show that the combination of carteolol hydrochloride, disodium edetate hydrate, and propylene glycol shows good antiseptic efficacy.

[0145] [Table 8]

[0146]

[0147] O means that the test strain is sufficient in the evaluation criteria for each bacterium.

[0148] X means that the test strain is insufficient in the evaluation criteria for each bacterium.

[0149] <Experiment 4>: Effect of adding alginic acid on antiseptic efficacy

[0150] The enhancement of the antiseptic efficacy of alginic acid on carteolol hydrochloride was demonstrated according to the following method.

[0151] <Preparation of test solutions for Examples 20 and 21>

[0152] The components of the test solutions for Examples 20 and 21 are shown in Table 9. Carteolol hydrochloride, disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate dihydrate, disodium edetate hydrate, propylene glycol, and alginic acid were measured to prepare the compositions shown in Table 9, and sterile purified water and 5N sodium hydroxide were added to the mixture to dissolve it. The pH values of these solutions were adjusted to 6.7 by adding 5N sodium hydroxide, and sterile purified water was added to these solutions to obtain the specified volume. These solutions were filtered through a 0.22-μm membrane filter, and 5 mL of each solution was loaded into a sterile glass container to be used as a test solution.

[0153] <Test solutions for Comparative Examples 17 and 18: Preparation of test solutions without alginic acid>

[0154] The components of the test solutions for Comparative Examples 17 and 18 are shown in Table 9. Carteolol hydrochloride, disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate dihydrate, disodium edetate hydrate, and propylene glycol were measured to prepare the compositions shown in Table 9. Sterile purified water was added to the mixture to dissolve it. The pH values of these solutions were adjusted to 6.7 by adding 5N sodium hydroxide, and sterile purified water was added to these solutions to obtain the specified volume. These solutions were filtered through a 0.22-μm membrane filter, and 5 mL of each solution was loaded into a sterile glass container to be used as a test solution.

[0155] [Table 9]

[0156]

[0157] The antiseptic efficacies of the test solutions for Examples 20 and 21 and Comparative Examples 17 and 18 against bacteria such as Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus were measured. The test results of the antiseptic efficacies of each example and comparative example are shown in Table 10.

[0158] [Table 10]

[0159]

[0160] O means the test strain is sufficient in the evaluation criteria for each bacterium. X means the test strain is insufficient in the evaluation criteria for each bacterium. <Experiment 5>: Effect of adding disodium edetate hydrate on photostability

[0161] The improvement of the photostability of carteolol hydrochloride by disodium edetate hydrate was demonstrated by the following method.

[0162] <Test solutions of Examples 22 to 25>

[0163] The components of the test solutions of Examples 22 to 25 are shown in Table 11. Carteolol hydrochloride, disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate dihydrate and disodium edetate hydrate were mixed to prepare the compositions shown in Table 11. Sterile purified water was added to the mixture to dissolve it. The pH values of these solutions were adjusted to 6.7 by adding 5N sodium hydroxide, and sterile purified water was added to these solutions to obtain a specified volume. These solutions were filtered through a 0.22-μm membrane filter, and 5 mL of each solution was loaded into a sterile glass container to be used as a test solution.

[0164] <Test solutions of Comparative Examples 19 and 20: Preparation of test solutions without disodium edetate hydrate>

[0165] The components of the test solutions of Comparative Examples 19 and 20 are shown in Table 12. Carteolol hydrochloride, disodium hydrogen phosphate anhydrous and sodium dihydrogen phosphate dihydrate were mixed to prepare the compositions shown in Table 12. Sterile purified water was added to the mixture to dissolve it. The pH values of these solutions were adjusted to 6.7 by adding 5N sodium hydroxide, and sterile purified water was added to these solutions to obtain a specified volume. These solutions were filtered through a 0.22-μm membrane filter, and 5 mL of each solution was loaded into a sterile glass container to be used as a test solution.

[0166] [Table 11]

[0167]

[0168] [Table 12]

[0169] Amount (g / 100 mL) Comparative Example 19 Comparative Example 20 Carteolol Hydrochloride 1.0 2.0 Disodium Edetate Hydrate - - <![CDATA[Na2HPO4]]> 0.04 0.04 <![CDATA[NaH2PO4·2H2O]]> 0.04 0.04 NaOH Appropriate amount Appropriate amount Purified water Appropriate amount Appropriate amount Total volume (mL) 100 100 pH 6.7 6.7

[0170] Measure the photostability of the test solutions of Examples 22 to 25 and Comparative Examples 19 and 20. The illuminance of white light from a white lamp was 3000 Lx, and the light intensity from a chemical lamp was 50 μW / cm 2Irradiate with ultraviolet light for 400 hours. Compare the irradiated sample solutions with the sample solutions stored in the dark without light at 4 °C, and measure the amount of 3,4-dehydro carteolol and the total amount of decomposition products produced by the photolysis of carteolol hydrochloride in each sample solution. The results are shown in Table 13. Analyze the decomposition products of carteolol hydrochloride by high performance liquid chromatography (HPLC).

[0171] (HPLC conditions for measuring the amount of 3,4-dehydro carteolol)

[0172] Column: Load 5 μm octadecylsilylated silica gel for liquid chromatography into a stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm.

[0173] Mobile phase: Add acetic acid (100%; 3 mL) and water (1000 mL) to sodium 1-hexanesulfonate (1.51 g), and dissolve the mixture. Add acetonitrile (170 mL) to this solution (830 mL).

[0174] Detector: Ultraviolet absorptiometer

[0175] [Table 13]

[0176] Decomposition product (%) Total amount of decomposition product (%) Example 22 1.369 3.31 Example 23 0.939 2.48 Example 24 1.605 3.62 Example 25 1.451 3.28 Comparative Example 19 1.720 3.97 Comparative Example 20 1.841 4.34

[0177] By adding disodium edetate hydrate to the carteolol solution, the amount of 3,4-dehydro carteolol as a photolysis product of carteolol hydrochloride and the total amount of decomposition products were decreased in a concentration-dependent manner. The results indicate that disodium edetate hydrate improves the photostability of carteolol hydrochloride.

[0178] <Experiment 6>: Effect of adding alginic acid on photostability

[0179] The improvement of the photostability of carteolol hydrochloride by alginic acid was demonstrated according to the following method.

[0180] <Test solutions of Examples 26 to 29, 60 and 61>

[0181] The components of the test solutions of Examples 26 to 29, 60 and 61 are shown in Table 14. Measure carteolol hydrochloride, disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate dihydrate, disodium edetate hydrate, propylene glycol and alginic acid to prepare the compositions shown in Table 14. Add sterile purified water to the mixture. Add 5N sodium hydroxide to the mixture and stir until dissolved. Adjust the pH value of these solutions to 6.7 by adding 5N sodium hydroxide, and add sterile purified water to these solutions to obtain a specified volume. Filter these solutions through a 0.22-μm membrane filter, and load 5 mL of each solution into a sterile glass container for use as a test solution.

[0182] <Preparation of test solutions for Comparative Examples 21 to 28: Test solutions without disodium edetate hydrate and / or alginic acid>

[0183] The components of the test solutions for Comparative Examples 21 to 28 are shown in Table 15. Carteolol hydrochloride, disodium hydrogen phosphate anhydrous, sodium dihydrogen phosphate dihydrate, disodium edetate hydrate, propylene glycol, and NaCl were measured (added in such amounts that the osmotic pressure ratio of the solution was adjusted to 0.9 to 1.1) in order to prepare the compositions shown in Table 15, and sterile purified water was added to the mixture to dissolve it. Then, for Comparative Examples 21 and 25, alginic acid was added to these solutions with stirring, and 5N sodium hydroxide was added to the mixture to dissolve the alginic acid. The pH values of these solutions were adjusted to 6.7 by adding 5N sodium hydroxide, and sterile purified water was added to these solutions to obtain a specified volume. These solutions were filtered through a 0.22-μm membrane filter, and 5 mL of each solution was loaded into a sterile glass container to be used as a test solution.

[0184] [Table 14]

[0185]

[0186] [Table 15-1]

[0187] Amount (g / 100 mL) Comparative Example 21 Comparative Example 22 Comparative Example 23 Comparative Example 24 Carteolol Hydrochloride 1.0 1.0 1.0 1.0 Alginic acid 1.0 - - - Disodium Edetate Hydrate - - 0.05 0.1 Propylene glycol 1.3 1.3 1.3 1.3 <![CDATA[Na2HPO4]]> 0.04 0.04 0.04 0.04 <![CDATA[NaH2PO4·2H2O]]> 0.04 0.04 0.04 0.04 NaOH Appropriate amount Appropriate amount Appropriate amount Appropriate amount Purified water Appropriate amount Appropriate amount Appropriate amount Appropriate amount Total volume (mL) 100 100 100 100 pH 6.7 6.7 6.7 6.7 Osmotic pressure ratio 1.0 1.0 1.0 1.0

[0188] [Table 15-2]

[0189] Amount (g / 100 mL) Comparative Example 25 Comparative Example 26 Comparative Example 27 Comparative Example 28 Carteolol Hydrochloride 2.0 2.0 2.0 2.0 Alginic acid 1.0 - - - Disodium Edetate Hydrate - - 0.05 0.1 Propylene glycol 1.3 1.3 1.3 1.3 <![CDATA[Na2HPO4]]> 0.04 0.04 0.04 0.04 <![CDATA[NaH2PO4·2H2O]]> 0.04 0.04 0.04 0.04 NaOH Appropriate amount Appropriate amount Appropriate amount Appropriate amount Purified water Appropriate amount Appropriate amount Appropriate amount Appropriate amount Total volume (mL) 100 100 100 100 pH 6.7 6.7 6.7 6.7 Osmotic pressure ratio 1.0 1.0 1.0 1.0

[0190] The photostability of the test solutions of Measurement Examples 26 to 29, 60, and 61 and Comparative Examples 21 to 28 was measured. White light with an illuminance of 3000 Lx from a white lamp and ultraviolet light with a light intensity of 50 μW / cm 2 was irradiated for 400 hours. In each sample solution after light irradiation, the amount of 3,4-dehydrocarteolol and the total amount of decomposition products in the decomposition products generated under photolysis of carteolol hydrochloride were measured. The results are shown in Table 16. The decomposition products of carteolol hydrochloride under photolysis were analyzed by high performance liquid chromatography (HPLC).

[0191] (HPLC conditions for measuring the amount of 3,4-dehydrocarteolol)

[0192] Column: 5 μm octadecylsilylated silica gel for liquid chromatography was loaded into a stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm.

[0193] Mobile phase: Sodium 1-hexanesulfonate (1.51 g) was added with acetic acid (100%; 3 mL) and water (1000 mL), and the mixture was dissolved. Acetonitrile (170 mL) was added to this solution (830 mL).

[0194] Detector: Ultraviolet absorptiometer

[0195] [Table 16]

[0196] Decomposition product (%) Total amount of decomposition product (%) Example 26 0.038 0.53 Example 27 0.043 0.57 Example 28 0.050 0.52 Example 29 0.055 0.65 Example 60 0.009 0.61 Example 61 0.018 0.50 Comparative Example 21 0.836 2.57 Comparative Example 22 1.838 4.01 Comparative Example 23 1.554 3.48 Comparative Example 24 1.129 2.57 Comparative Example 25 1.233 2.28 Comparative Example 26 1.989 4.54 Comparative Example 27 1.813 3.95 Comparative Example 28 1.501 3.24

[0197] Adding alginic acid to a sample solution containing carteolol hydrochloride and disodium edetate hydrate significantly reduced the photolysis of carteolol hydrochloride, and when neither alginic acid nor disodium edetate hydrate or both were added, the amount of 3,4-dehydrocarteolol, a decomposition product under the photolysis of carteolol hydrochloride, increased. The amount of 3,4-dehydrocarteolol and the total amount of decomposition products were significantly increased in Comparative Examples 22 and 26 without alginic acid or disodium edetate hydrate compared to the samples adding only alginic acid (Comparative Examples 21 and 25) or disodium edetate hydrate (Comparative Examples 23, 24, 27, and 28). The results showed that alginic acid and disodium edetate hydrate reduced the photolysis of carteolol hydrochloride and improved its photostability. It was also shown that the combination of alginic acid and disodium edetate hydrate improved the photostability of carteolol hydrochloride.

[0198] <Evaluation of test results>

[0199] The results showed that the pharmaceutical composition in the present invention was sufficient in the preservative efficacy test described in the 17th Edition of the Japanese Pharmacopoeia - Reference Information and reduced the photolysis of carteolol hydrochloride, thus being stable under light.

[0200] In the present invention, it was revealed that adding disodium edetate hydrate, an optional tonicity agent (such as propylene glycol), and / or a sustaining agent (such as alginic acid) to a β-blocker allowed maintaining the preservative efficacy of the β-blocker without using preservatives (such as benzalkonium chloride and boric acid), which would cause concerns about side effects even when using a conventional eye drop bottle allowing multi-dose. It was also revealed that the pharmaceutical composition in the present invention had good photostability, such that the active ingredient would not decompose under light even when storing the composition under light irradiation.

[0201] <Formulation Example 1>: Formulation examples of formulations containing prostaglandin F2α derivatives were prepared for Examples 30 to 39 and Comparative Example 29 according to the following method.

[0202] <Example 30>

[0203] Measure latanoprost (0.005 g), polysorbate 80 (0.1 g) and purified water (80 g) and mix them. Warm the mixture to 60 °C to dissolve it. Then, cool the mixture to room temperature. Add carteolol hydrochloride (2.0 g), alginic acid (1.0 g), boric acid (1.0 g) and disodium edetate hydrate (0.1 g) to the solution. Dissolve the mixture by adding sodium hydroxide and adjust the pH value of the mixture to 6.5. Then, add purified water to the mixture to make the total amount 100 g. Filter the solution through a membrane filter with a pore size of 0.2 μm to prepare Example 30.

[0204] <Example 31>

[0205] Measure latanoprost (0.005 g), polysorbate 80 (0.1 g) and purified water (80 g) and mix them. Warm the mixture to 60 °C to dissolve it. Then, cool the mixture to room temperature. Add carteolol hydrochloride (2.0 g), alginic acid (1.0 g), sodium chloride (0.4 g), sodium dihydrogen phosphate dihydrate (0.04 g), disodium hydrogen phosphate anhydrous (0.04 g) and disodium edetate hydrate (0.1 g) to the solution. Dissolve the mixture by adding sodium hydroxide and adjust the pH value of the mixture to 6.5. Then, add purified water to the mixture to make the total amount 100 g. Filter the solution through a membrane filter with a pore size of 0.2 μm to prepare Example 31.

[0206] <Example 32>

[0207] Measure latanoprost (0.005 g) and purified water (80 g) and mix them. Warm the mixture to 60 °C to dissolve it. Then, cool the mixture to room temperature. Add carteolol hydrochloride (2.0 g), alginic acid (1.0 g), sodium chloride (0.4 g), sodium dihydrogen phosphate dihydrate (0.04 g), disodium hydrogen phosphate anhydrous (0.04 g) and disodium edetate hydrate (0.1 g) to the solution. Dissolve the mixture by adding sodium hydroxide and adjust the pH value of the mixture to 6.5. Then, add purified water to the mixture to make the total amount 100 g. Filter the solution through a membrane filter with a pore size of 0.2 μm to prepare Example 32.

[0208] <Examples 33, 36 and 39>

[0209] Prepare Examples 33, 36 and 39 according to the method described in Example 30.

[0210] <Examples 34, 35, 37 and 38>

[0211] Prepare Examples 34, 35, 37 and 38 according to the method described in Example 31.

[0212] <Comparative Example 29>

[0213] Measure latanoprost (0.005 g), polysorbate 80 (0.2 g) and purified water (80 g) and mix them. Warm the mixture to 60 °C to dissolve it. Then, cool the mixture to room temperature. Add alginic acid (1.0 g), boric acid (1.5 g) and disodium edetate hydrate (0.2 g) to this solution. Dissolve the mixture by adding sodium hydroxide and adjust the pH value of the mixture to 6.5. Then, add purified water to the mixture to make the total amount 100 g. Filter the solution through a membrane filter with a pore size of 0.2 μm for Comparative Example 29.

[0214] [Table 17-1]

[0215] Amount (g / 100 mL) Example 30 Example 31 Example 32 Example 33 Example 34 Carteolol Hydrochloride 2.0 2.0 2.0 2.0 2.0 Latanoprost 0.005 0.005 0.005 0.005 0.005 Alginic acid 1.0 1.0 1.0 1.0 1.0 Boric acid 1.0 - - 1.0 - NaCl - 0.4 0.4 - 0.4 <![CDATA[NaH2PO4·2H2O]]> - 0.04 0.04 - 0.04 <![CDATA[Na2HPO4]]> - 0.04 0.04 - 0.04 Disodium Edetate Hydrate 0.1 0.1 0.1 0.05 0.03 Polysorbate 80 0.1 0.1 - 0.1 0.2 NaOH Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Purified water Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount pH 6.5 6.5 6.5 6.5 6.5

[0216] [Table 17-2]

[0217] Amount (g / 100 mL) Example 35 Example 36 Example 37 Example 38 Example 39 Carteolol Hydrochloride 2.0 2.0 2.0 2.0 2.0 Latanoprost 0.005 0.005 0.005 0.005 0.005 Alginic acid 1.0 1.0 1.0 1.0 1.0 Boric acid - - 1.0 - 1.0 NaCl 0.4 0.4 - 0.4 - <![CDATA[NaH2PO4·2H2O]]> 0.04 0.04 - 0.04 - <![CDATA[Na2HPO4]]> 0.04 0.04 - 0.04 - Disodium Edetate Hydrate 0.02 0.07 0.1 0.15 0.2 Polysorbate 80 0.2 0.2 0.2 0.1 0.1 NaOH Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Purified water Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount pH 6.5 6.5 6.5 6.5 6.5

[0218] [Table 17-3]

[0219] Amount (g / 100 mL) Comparative Example 29 Carteolol Hydrochloride - Latanoprost 0.005 Alginic acid 1.0 Boric acid 1.5 NaCl - <![CDATA[NaH2PO 4· 2H2O]]> - <![CDATA[Na2HPO4]]> - Disodium Edetate Hydrate 0.2 Polysorbate 80 0.2 NaOH Appropriate amount Purified water Appropriate amount pH 6.5

[0220] <Formulation Example 2>

[0221] Examples 40 to 47 without benzalkonium chloride were prepared according to the following method.

[0222] <Example 40>

[0223] Measure purified water (80 g), carteolol hydrochloride (1.0 g), alginic acid (1.0 g), propylene glycol (1.3 g), sodium dihydrogen phosphate dihydrate (0.04 g), disodium hydrogen phosphate anhydrous (0.04 g) and disodium edetate hydrate (0.01 g) and mix them. Dissolve the mixture by adding sodium hydroxide with stirring and adjust the pH value of the mixture to 6.7. Then, add purified water to the mixture to make the total amount 100 g. Stir the solution and filter it through a membrane filter with a pore size of 0.2 μm to prepare Example 40.

[0224] <Examples 41 to 47>

[0225] Examples 41 to 47 were prepared according to the method described in Example 40.

[0226] [Table 18-1]

[0227] Amount (g / 100 mL) Example 40 Example 41 Example 42 Example 43 Carteolol Hydrochloride 1.0 1.0 1.0 2.0 Alginic acid 1.0 1.0 1.0 1.0 Disodium Edetate Hydrate 0.01 0.03 0.2 0.01 Propylene glycol 1.3 1.3 1.3 1.0 <![CDATA[Na2HPO4]]> 0.04 0.04 0.04 0.04 <![CDATA[NaH2PO4·2H2O]]> 0.04 0.04 0.04 0.04 NaOH Appropriate amount Appropriate amount Appropriate amount Appropriate amount Purified water Appropriate amount Appropriate amount Appropriate amount Appropriate amount Total volume (mL) 100 100 100 100 pH 6.7 6.7 6.7 6.7

[0228] [Table 18-2]

[0229] Amount (g / 100 mL) Example 44 Example 45 Example 46 Example 47 Carteolol Hydrochloride 2.0 2.0 2.0 2.0 Alginic acid 1.0 1.0 1.0 1.0 Disodium Edetate Hydrate 0.03 0.05 0.1 0.2 Propylene glycol 1.0 1.0 1.0 1.0 <![CDATA[Na2HPO4]]> 0.04 0.04 0.04 0.04 <![CDATA[NaH2PO4·2H2O]]> 0.04 0.04 0.04 0.04 NaOH Appropriate amount Appropriate amount Appropriate amount Appropriate amount Purified water Appropriate amount Appropriate amount Appropriate amount Appropriate amount Total volume (mL) 100 100 100 100 pH 6.7 6.7 6.7 6.7

[0230] <Formulation Example 3>: Formulation example of a formulation containing a carbonic anhydrase inhibitor

[0231] Examples 48 to 59 were prepared according to the following method.

[0232] <Example 48>

[0233] Measure carteolol hydrochloride (2.0 g), dorzolamide hydrochloride (1.113 g), disodium edetate hydrate (0.01 g), D-mannitol (2.0 g) and sodium citrate hydrate (0.3 g) and dissolve in water. Sterilize the resulting solution by filtering through a membrane filter with a pore size of 0.2 μm. Combine this solution with the solution obtained by the following steps: dissolve hydroxyethyl cellulose (0.5 g) in water and sterilize by steam under high pressure. Adjust the pH value of the combined solution to 5.7 by adding sodium hydroxide. Then, add pure water to the solution to prepare Example 48, with a total solution volume of 100 g.

[0234] <Examples 49 to 51>

[0235] Examples 49 to 51 were prepared according to the method described in Example 48.

[0236] <Example 52>

[0237] Measure pure water (80 g), carteolol hydrochloride (2.0 g), dorzolamide hydrochloride (1.113 g), disodium edetate hydrate (0.01 g), propylene glycol (0.7 g) and sodium citrate hydrate (0.3 g) and dissolve them. Adjust the pH value of the solution to 5.7 by adding sodium hydroxide. Then, add pure water to the solution to make the total amount 100 g. Stir the solution and filter it through a membrane filter with a pore size of 0.2 μm to prepare Example 52.

[0238] <Examples 53 to 55>

[0239] Examples 53 to 55 were prepared according to the method described in Example 52.

[0240] <Example 56>

[0241] Measure tyloxapol (0.025 g) and load it into a cylindrical glass container, and dissolve it by adding purified water (6 g) heated to 60 °C. Add brinzolamide (1.0 g) and yttria-stabilized zirconia beads (12 g) to this solution, and seal the container and heat it at 121 °C for 20 minutes. Cool the mixture, and then rotate it at 50 rpm for 20 hours to make a brinzolamide suspension. Measure carteolol hydrochloride (2.0 g), disodium edetate hydrate (0.01 g), and propylene glycol (1.0 g) separately, and dissolve them in purified water (50 g). Add to this solution a solution in which carbomer (0.4 g) is uniformly dispersed in purified water (25 g) at 60 °C. Heat the resulting solution at 121 °C for 20 minutes, and then adjust the pH value of the solution to 7.2 by adding sodium hydroxide to use it as a solvent. Filter the brinzolamide suspension to remove the yttria-stabilized zirconia beads and combine it with this solvent, and add purified water to the mixture to make it 100 g to prepare Example 56.

[0242] <Examples 57 to 59>

[0243] Prepare Examples 57 to 59 according to the method described in Example 56.

[0244] [Table 19-1]

[0245] Amount (g / 100 mL) Example 48 Example 49 Example 50 Example 51 Carteolol Hydrochloride 2.0 2.0 2.0 2.0 Dorzolamide Hydrochloride 1.113 1.113 1.113 1.113 Hydroxyethylcellulose 0.5 0.5 0.5 0.5 Disodium Edetate Hydrate 0.01 0.03 0.05 0.1 D-Mannitol 2.0 2.0 2.0 2.0 Propylene glycol - - - - Sodium Citrate Hydrate 0.3 0.3 0.3 0.3 NaOH Appropriate amount Appropriate amount Appropriate amount Appropriate amount Purified water Appropriate amount Appropriate amount Appropriate amount Appropriate amount Total volume (mL) 100 100 100 100 pH 5.7 5.7 5.7 5.7

[0246] [Table 19-2]

[0247] Amount (g / 100 mL) Example 52 Example 53 Example 54 Example 55 Carteolol Hydrochloride 2.0 2.0 2.0 2.0 Dorzolamide Hydrochloride 1.113 1.113 1.113 1.113 Hydroxyethylcellulose - - - - Disodium Edetate Hydrate 0.01 0.03 0.05 0.1 D-Mannitol - - - - Propylene glycol 0.7 0.7 0.7 0.7 Sodium Citrate Hydrate 0.3 0.3 0.3 0.3 NaOH Appropriate amount Appropriate amount Appropriate amount Appropriate amount Purified water Appropriate amount Appropriate amount Appropriate amount Appropriate amount Total volume (mL) 100 100 100 100 pH 5.7 5.7 5.7 5.7

[0248] [Table 19-3]

[0249] Amount (g / 100 mL) Example 56 Example 57 Example 58 Example 59 Carteolol Hydrochloride 2.0 2.0 2.0 2.0 Brinzolamide 1.0 1.0 1.0 1.0 Carbomer 0.4 0.4 0.4 0.4 Disodium Edetate Hydrate 0.01 0.03 0.05 0.1 Tyloxapol 0.025 0.025 0.025 0.025 Propylene glycol 1.0 1.0 1.0 1.0 NaOH Appropriate amount Appropriate amount Appropriate amount Appropriate amount Purified water Appropriate amount Appropriate amount Appropriate amount Appropriate amount Total volume (mL) 100 100 100 100 pH 7.2 7.2 7.2 7.2

[0250] <Experiment 7>: Antiseptic efficacy test of the formulations of Examples 30 to 39 and Comparative Example 29

[0251] According to the antiseptic efficacy test, evaluate the antiseptic efficacy of the formulations of Examples 30 to 39 and Comparative Example 29. The results are shown below.

[0252] [Table 20]

[0253] Overall evaluation of preservative efficacy Example 30 Sufficient Example 31 Sufficient Example 32 Sufficient Example 33 Sufficient Example 34 Sufficient Example 35 Sufficient Example 36 Sufficient Example 37 Sufficient Example 38 Sufficient Example 39 Sufficient Comparative Example 29 Insufficient

[0254] [Industrial Applicability]

[0255] The pharmaceutical composition in the present invention can have enhanced antiseptic efficacy and / or improved photo-stability, and can also be used for treating eye diseases such as glaucoma and ocular hypertension.

Claims

1. An ophthalmic pharmaceutical composition comprising carteolol or a pharmaceutically acceptable salt thereof, edetic acid or a pharmaceutically acceptable salt thereof, latanoprost, and alginic acid or a pharmaceutically acceptable salt thereof, wherein edetic acid or a pharmaceutically acceptable salt thereof enhances the antiseptic efficacy of carteolol or a pharmaceutically acceptable salt thereof, edetic acid or a pharmaceutically acceptable salt thereof and / or alginic acid or a pharmaceutically acceptable salt thereof improves the photostability of carteolol or a pharmaceutically acceptable salt thereof, wherein the ratio of the amount of edetic acid or a pharmaceutically acceptable salt thereof to the amount of carteolol or a pharmaceutically acceptable salt thereof is from 0.002 w / w to 2.0 w / w, wherein the content of carteolol or a pharmaceutically acceptable salt thereof ranges from 0.1 w / v% to 5 w / v% based on the total amount of the composition, wherein the content of edetic acid or a pharmaceutically acceptable salt thereof ranges from 0.01 w / v% to 0.2 w / v% based on the total amount of the composition, wherein the ratio of the amount of alginic acid or a pharmaceutically acceptable salt thereof to the amount of carteolol or a pharmaceutically acceptable salt thereof is from 0.25 w / w to 2 w / w, and wherein the pH range of the composition is from 5.0 to 8.

0.

2. The composition according to claim 1, further comprising a tonicity agent.

3. The composition according to claim 1, further comprising a buffer and a pH regulator.

4. The composition according to claim 1, further comprising a carbonic anhydrase inhibitor.

5. The composition according to claim 1, further comprising another medicament having an intraocular pressure-lowering effect.

6. The composition according to claim 1, in the form of an eye drop.

7. The composition according to claim 1, in the form of an aqueous eye drop or a suspension eye drop.

8. The composition according to claim 1, used as a multi-dose eye drop.

9. The composition according to any one of claims 1 to 8, for the treatment of glaucoma or ocular hypertension.

10. Use of the composition according to claim 1 for enhancing the antiseptic efficacy of carteolol or a pharmaceutically acceptable salt thereof.

11. Use of the composition according to claim 1 for improving the photostability of carteolol or a pharmaceutically acceptable salt thereof.

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