Epinaschin contains eye drops.

Abstract

To provide eye drops which contain epinastine or a salt thereof and contain substantially no antiseptics or substantially no ingredients having antiseptic activity.SOLUTION: The eye drops contain epinastine or a salt thereof in a concentration exceeding 0.075% (w / v), and contain substantially no antiseptics or substantially no ingredients having antiseptic activity.SELECTED DRAWING: None

Description

TECHNICAL FIELD

[0001] The present invention relates to an ophthalmic solution containing epinastine or a salt thereof at a concentration exceeding 0.075% (w / v), wherein the ophthalmic solution is substantially free of preservatives and components having antiseptic effects (hereinafter also referred to as "the ophthalmic solution of the present invention"). BACKGROUND ART

[0002] Ophthalmic solutions require a certain level or higher antiseptic measures to prevent the proliferation of fungi and the like associated with repeated use. For this reason, ophthalmic solutions usually contain preservatives. As an example of preservatives, benzalkonium chloride is water-soluble, chemically stable, and has higher preservative efficacy compared to other preservatives, so it is widely used in ophthalmic solutions. However, benzalkonium chloride has cytotoxicity, and as the exposure dose increases, the possibility of causing corneal epithelial disorder increases. Therefore, it cannot be used particularly for patients who exhibit hypersensitive reactions to benzalkonium chloride or patients who have severe corneal epithelial disorder.

[0003] Currently, Aleleon marketed in Japan (登録商標) eye drop 0.05% is an ophthalmic solution containing epinastine hydrochloride as an active ingredient, and instead of not adding a preservative such as benzalkonium chloride, other components having antiseptic effects (boric acid, edetic acid (EDTA)) are added (Non-Patent Document 1). That is, for repeated use of an ophthalmic solution containing epinastine or a salt thereof, it is not necessarily required to contain a preservative such as benzalkonium chloride, but it has been recognized that it is necessary to secure preservative efficacy with another component having an alternative antiseptic effect. On the other hand, no ophthalmic solution containing epinastine or a salt thereof, to which neither preservatives nor components having antiseptic effects are added, is known at all.

[0004] While eye drops that do not contain preservatives or preservative-containing ingredients are known to be on the market, these are either unit-dose type (single-use) or stored in preservative-free containers (containers with a special structure to exert preservative effects), and no eye drops in which the active ingredient itself exerts preservative effects are known. In other words, it is not known at all that epinastine or its salts themselves have preservative effects. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Alesion® Ophthalmic Solution 0.05% Package Insert [Overview of the project] [Problems that the invention aims to solve]

[0006] Therefore, it is an interesting challenge to provide an eye drop solution containing epinastine or a salt thereof that is substantially free of preservatives and preservative-containing ingredients. [Means for solving the problem]

[0007] The inventors diligently researched to find an eye drop solution containing epinastine or its salt that contains neither preservatives nor preservative components, or in reduced amounts thereof. They discovered that by setting the concentration of epinastine or its salt in the eye drop solution to over 0.075% (w / v), a sufficient preservative effect can be obtained without substantially containing preservatives or preservative components, leading to the present invention. Specifically, the present invention provides the following: (1) An eye drop containing epinastine or a salt thereof at a concentration of more than 0.075% (w / v), which is substantially free of preservatives and ingredients having preservative properties. (2) The eye drop solution according to (1), containing epinastine or a salt thereof in a concentration of 0.1% to 5.0% (w / v). (3) The eye drop solution according to (1) or (2), wherein epinastine or a salt thereof is epinastine hydrochloride. (4) The eye drop solution according to (1), wherein the preservative and preservative component is at least one component selected from the group consisting of benzalkonium chloride, chlorhexidine or a salt thereof, boric acid, borax, and edetic acid or a salt thereof. (5) An eye drop containing only epinastine or a salt thereof at a concentration of more than 0.075% (w / v) as the active ingredient, and containing only a buffer, an isotonic agent, and a pH adjuster as additives. (6) The eye drop solution according to (5), containing epinastine or a salt thereof in a concentration of 0.1% to 5.0% (w / v). (7) The eye drop solution according to (5) or (6), wherein epinastine or a salt thereof is epinastine hydrochloride. (8) An eye drop solution according to any one of (5) to (7), wherein the buffering agent is phosphoric acid or a salt thereof. (9) An eye drop according to any one of (5) to (8), wherein the isotonic agent is an ionic isotonic agent. (10) A multi-dose eye drop, as described in any one of (1) to (9). (11) A method for imparting preservative efficacy to eye drops containing epinastine or a salt thereof by incorporating epinastine or a salt thereof at a concentration of more than 0.075% (w / v), without substantially containing preservatives or preservative-containing ingredients. (12) A method for maintaining the preservative efficacy of an eye drop containing epinastine or a salt thereof by substantially not containing preservatives or preservative-containing ingredients, and by incorporating epinastine or a salt thereof at a concentration of more than 0.075% (w / v). Furthermore, two or more of the above configurations (1) to (12) can be arbitrarily selected and combined. Furthermore, the present invention also provides the following: (13) A method for treating and / or preventing allergic conjunctivitis, characterized by administering a therapeutically effective amount of any one of (1) to (10) to a patient in need of treatment. (14) Eye drops according to any one of (1) to (10), for use in the treatment and / or prevention of allergic conjunctivitis. [Effects of the Invention]

[0008] The present invention provides an eye drop solution containing epinastine or a salt thereof that has a preservative effect without the addition of any preservative or preservative-containing component. [Modes for carrying out the invention]

[0009] The present invention will be described in detail below.

[0010] In the present invention, "epinastine" is a compound represented by the chemical name (±)-3-Amino-9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepine, and also by the following formula: [ka] It is a compound represented by [formula].

[0011] In the eye drops of the present invention, the epinastine contained may be a salt, and there are no particular restrictions as long as it is a pharmaceutically acceptable salt. Examples of salts include salts with inorganic acids and salts with organic acids. Examples of salts with inorganic acids include those with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid. Examples of salts with organic acids include salts with acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, alanine, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, sulfosalicylic acid, and others. As for the salt of epinastine, monohydrochloride (epinastine hydrochloride) is particularly preferred.

[0012] In the present invention, epinastine or a salt thereof contained may be in the form of a hydrate or a solvate.

[0013] In the present invention, the content of epinastine or a salt thereof is sufficient as long as it exceeds 0.075% (w / v), but may also be 0.085% (w / v) or more, or 0.1% (w / v) or more. The upper limit thereof may be any concentration acceptable for an ophthalmic preparation, and is, for example, 5% (w / v). The content of epinastine or a salt thereof is preferably 0.1 to 5.0% (w / v), more preferably 0.1 to 3.0% (w / v), still more preferably 0.1 to 1.0% (w / v). Particularly preferably, it is 0.1 to 0.5% (w / v) or 0.1 to 0.3% (w / v), and 0.1% (w / v), 0.2% (w / v), 0.3% (w / v), 0.4% (w / v), and 0.5% (w / v) are even more preferred. When a salt of epinastine is contained in the present invention, the values described above refer to the content of the salt of epinastine. "%(w / v)" means the mass (g) of the target component (here, epinastine or a salt thereof) contained in 100 mL of the ophthalmic solution of the present invention. Hereinafter, the same definition applies unless otherwise specified.

[0014] In the present invention, examples of preservatives include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, chlorhexidine or a salt thereof, sorbic acid or a salt thereof, methyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, and the like. Examples of chlorhexidine or a salt thereof include chlorhexidine gluconate, chlorhexidine hydrochloride, chlorhexidine acetate, and the like. Examples of sorbic acid or a salt thereof include sodium sorbate, potassium sorbate, and the like.

[0015] In the present invention, examples of components having an antiseptic effect include boric acid, borax, edetic acid or a salt thereof, and the like. Examples of edetic acid or a salt thereof include monosodium edetate, disodium edetate, tetrasodium edetate, and the like.

[0016] In the present invention, "not containing preservatives and preservative components" means that the eye drops do not contain any "preservatives and preservative components" at all, or that the "preservatives and preservative components" are included in an amount that does not meet the preservative efficacy test method described in the 17th edition of the Japanese Pharmacopoeia on their own. The above-mentioned "amount that does not meet the preservative efficacy test method described in the 17th edition of the Japanese Pharmacopoeia on their own" means that, for example, EDTA may be included in an amount of about 0.01% (w / v) or 0.02% (w / v), but this is included in the eye drops not for the preservative effect of EDTA, but for the stabilizing effect. Similarly, for example, boric acid may be included in an amount of about 0.01% (w / v) or 0.02% (w / v), but this is included in the eye drops not for the preservative effect of boric acid, but for the buffering effect. In the present invention, "substantially" means that the essence remains unchanged. Therefore, in the present invention, "substantially free of preservatives and preservative components" means that the "preservatives and preservative components" are not included at all, or that, in cases where a preservative effect is not intended, the "preservatives and preservative components" are included to such an extent that they do not meet the preservative efficacy test method described in the 17th edition of the Japanese Pharmacopoeia on their own.

[0017] In this invention, a multi-dose eye drop solution refers to an eye drop solution contained in a multi-dose container. A multi-dose container is a container with a cap that can be freely opened and closed for the purpose of multiple uses, and can be used for a certain period after opening and is easy to carry. In this invention, there are no particular restrictions on the size or shape of the container body, and a unit-dose container (single-use type) may be used, but a multi-dose container is more preferred because the eye drop solution has a preservative effect. Containers with special structures to exhibit preservative effects such as backflow prevention functions, such as PFMD (Preservative Free Multi Dose) containers, are not included. There are no particular restrictions on the material of the container, and commonly used containers, such as those made of polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET), etc., can be used.

[0018] In the present invention, the eye drops may be in a state where all of the constituent components are dissolved or partially suspended, but a liquid state in which all of the constituent components are dissolved is more preferable.

[0019] In the present invention, when a buffering agent is incorporated into the eye drop solution, any buffering agent that can be used as a pharmaceutical additive may be appropriately incorporated. Examples include phosphoric acid or its salt, citric acid or its salt, acetic acid or its salt, carbonate or its salt, tartaric acid or its salt, ε-aminocaproic acid, trometamol, etc., and these may also be hydrates or solvates thereof. Examples of phosphoric acid or its salts include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, and dipotassium hydrogen phosphate, and their hydrates may also be used. Examples of citric acid or its salts include sodium citrate and disodium citrate, and hydrates thereof may also be used. Examples of acetic acid or its salts include sodium acetate and potassium acetate, and hydrates thereof may also be used. Examples of carbonic acid or its salts include sodium carbonate and sodium bicarbonate, and hydrates thereof may also be used. Examples of tartaric acid or its salts include sodium tartrate and potassium tartrate, and hydrates thereof may also be used. In the present invention, when a buffering agent is incorporated into the eye drop solution, phosphoric acid or a salt thereof is more preferably used as the buffering agent, and sodium dihydrogen phosphate, disodium hydrogen phosphate, or hydrates thereof are particularly preferred. Two or more buffering agents may also be used together. In the present invention, when a buffering agent is incorporated into the eye drop solution, the amount of buffering agent can be appropriately adjusted depending on the type of buffering agent, but 0.001 to 10% (w / v) is preferred, 0.01 to 5% (w / v) is more preferred, 0.1 to 3% (w / v) is even more preferred, and 0.2 to 1.5% (w / v) is most preferred.

[0020] In the present invention, when an isotonic agent is incorporated into the eye drop solution, any isotonic agent that can be used as a pharmaceutical additive can be appropriately incorporated, such as ionic isotonic agents and nonionic isotonic agents. Examples of ionic isotonic agents include sodium chloride, potassium chloride, calcium chloride, and magnesium chloride. Examples of nonionic isotonic agents include glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, and sucrose. In the present invention, when an isotonic agent is incorporated into the eye drop solution, an ionic isotonic agent is more preferred, and sodium chloride is particularly preferred. Two or more isotonic agents may also be used together. In the present invention, when an isotonic agent is incorporated into the eye drop solution, the content of the isotonic agent can be appropriately adjusted depending on the type of isotonic agent, but 0.001 to 10% (w / v) is preferred, 0.01 to 5% (w / v) is more preferred, 0.1 to 1% (w / v) is even more preferred, and 0.2 to 0.5% (w / v) is most preferred. In the present invention, the osmotic pressure ratio of the eye drops should be within the range acceptable for ophthalmic formulations, for example, 0.5 to 2.0, preferably 0.7 to 1.6, more preferably 0.8 to 1.4, and even more preferably 0.9 to 1.2.

[0021] In the present invention, when a pH adjusting agent is incorporated into the eye drop solution, any pH adjusting agent that can be used as a pharmaceutical additive may be appropriately incorporated. Examples include acids or bases. Examples of acids include hydrochloric acid, phosphoric acid, citric acid, acetic acid, etc., and examples of bases include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, etc. In the present invention, the pH of the eye drops should be within the range acceptable for ophthalmic formulations, preferably in the range of 4.0 to 8.0, more preferably 6.0 to 8.0, and even more preferably 6.5 to 7.5. Particularly preferred pH ranges are 6.7 to 7.3, but 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, and 7.3 are also even more preferred.

[0022] In the present invention, in addition to the buffering agent, isotonic agent, and pH adjuster mentioned above, one or more additives acceptable for ophthalmic formulations (excluding preservatives and components having preservative properties) may be added as needed. Examples of such additives include solubilizers, stabilizers, antioxidants, viscosity modifiers, etc. Furthermore, unless otherwise specified, the present invention may also contain active ingredients used in eye drops other than epinastine or its salts. Examples of solubilizers include polyoxyethylene hydrogenated castor oil, povidone, and polysorbate 80; examples of stabilizers include povidone and polysorbate 80; examples of antioxidants include dibutylhydroxytoluene and sodium sulfite; and examples of viscosity enhancers include carboxyvinyl polymer and hydroxyethylcellulose. These additives can be added within limits acceptable for ophthalmic preparations, for example, at concentrations of 2% or less, or even in the range of 0.2%, 0.02%, or 0.002% or less.

[0023] The eye drops of the present invention are useful as a therapeutic agent for allergic conjunctivitis.

[0024] When administering the eye drops of the present invention, there are no particular restrictions on the dosage or administration as long as it is sufficient to achieve the desired pharmacological effect. However, it can be administered as one drop at a time, 1 to 10 times a day, preferably 2 to 6 times a day, more preferably 2 to 4 times a day, and even more preferably 2 or 4 times a day. Furthermore, the eye drops of the present invention can also be used when wearing contact lenses. [Examples]

[0025] The following are examples of formulations and the results of preservative efficacy tests, which are provided to better understand the present invention and do not limit its scope.

[0026] [Examples of formulations] Representative formulations of the present invention are shown below. Note that the amounts of each component in the formulations below represent the content per 1 mL of the formulation.

[0027] Formulation Example 1 In a multi-dose container (1 mL) Epinastine hydrochloride 1 mg Sodium dihydrogen phosphate 3 mg Sodium chloride 5mg Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount)

[0028] Formulation Example 2 In a multi-dose container (1 mL) Epinastine hydrochloride 3mg Sodium dihydrogen phosphate 3 mg Disodium hydrogen phosphate 12 mg Sodium chloride 4mg Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount)

[0029] Preservative efficacy test (1) This test was conducted in accordance with the preservative efficacy test method described in the 17th edition of the Japanese Pharmacopoeia. 1. Preparation of the test product The formulation of Example 1 was prepared by dissolving epinastine (50 mg), sodium dihydrogen phosphate (25 mg), disodium hydrogen phosphate hydrate (122 mg), and sodium chloride (40 mg) in water, sterilizing by filtration, and adding a pH adjuster and water to make a total volume of 10 mL.

[0030] Example 1 in 1mL Epinastine hydrochloride 5mg Sodium dihydrogen phosphate 2.5 mg Disodium hydrogen phosphate hydrate 12.2 mg Sodium chloride 4mg Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) pH 6.7

[0031] The formulations for Examples 2-4 and Comparative Examples 1-2 were prepared using the same method as in Example 1.

[0032] Example 2 in 1mL Epinastine hydrochloride 50mg Sodium dihydrogen phosphate 2.5 mg Disodium hydrogen phosphate hydrate 12.2 mg Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) pH 6.7

[0033] Example 3 in 1mL Epinastine hydrochloride 1 mg Sodium dihydrogen phosphate 2.5 mg Disodium hydrogen phosphate hydrate 12.2 mg Sodium chloride 4.7 mg Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) pH 6.7

[0034] Example 4 in 1mL Epinastine hydrochloride 2mg Sodium dihydrogen phosphate 2.5 mg Disodium hydrogen phosphate hydrate 12.2 mg Sodium chloride 4.5 mg Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) pH 6.7

[0035] Comparative Example 1 in 1mL Epinastine hydrochloride 0.5 mg Sodium dihydrogen phosphate 2.5 mg Disodium hydrogen phosphate hydrate 12.2 mg Sodium chloride 5mg Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) pH 6.7

[0036] Comparative Example 2 in 1mL Epinastine hydrochloride 0.75 mg Sodium dihydrogen phosphate 2.5 mg Disodium hydrogen phosphate hydrate 12.2 mg Sodium chloride 4.7 mg Dilute hydrochloric acid (appropriate amount) Sodium hydroxide (appropriate amount) Purified water (appropriate amount) pH 6.7

[0037] 2. Test Method The following strains were used as inoculation. Bacteria: Escherichia coli ATCC 8739 (also known as E. coli) Pseudomonas aeruginosa ATCC 9027 (also known as P. aeruginosa) Staphylococcus aureus ATCC 6538 (also known as S. aureus) Yeasts and fungi: Candida, Candida albicans ATCC 10231 (also known as C. albicans) Aspergillus brasiliensis ATCC16404 (also known as A. brasiliensis)

[0038] The bacterial concentration in the test sample consisting of each preparation is 10 5 ~10 6 The inoculum was inoculated into the test sample so that the concentration was 10 cells / mL (for all 5 bacterial species). Specifically, 10 7 ~10 8 Prepare an inoculum to a concentration of cfu / mL, and then 10 5 ~10 6Each inoculum was inoculated into test samples consisting of formulations from Examples 1-4 and Comparative Examples 1-2 to achieve a cfu / mL ratio, and then uniformly mixed to prepare the samples. These samples were stored in the dark at 20-25°C, and at each sampling point (after 7, 14, or 28 days), 1 mL was taken from each sample using a micropipette, and the number of viable bacteria was measured. At each sampling point, the lid of the sample solution was opened to perform sampling, and then the lid was closed.

[0039] 3. Test Results and Discussion The test results are shown in Tables 1 and 2. The test results in Tables 1 and 2 are shown as the common logarithm of the ratio (B / A) of the number of bacteria at inoculation (B) to the number of bacteria at the time of measurement (A). For example, a value of "1" indicates that the number of bacteria at the time of testing decreased to 10% of the number of bacteria in the inoculation. For the pass / fail criteria of the test, for bacterial species (E. coli, P. aeruginosa, S. aureus), the sample was deemed to pass if it met both of the following conditions: the value was 1.0 or higher 7 days after sowing and 3.0 or higher 14 or 28 days after sowing; and for fungal species (C. albicans, A. brasiliensis), the value at 14 or 28 days after sowing did not decrease compared to the value at 7 days after sowing.

[0040] [Table 1]

[0041] [Table 2]

[0042] As shown in Tables 1 and 2, the formulations of Examples 1 to 4 containing epinastine or its salts showed sufficient preservative effect against all types of bacteria, even though they did not contain preservatives or preservative components. In contrast, the formulations of Comparative Examples 1 and 2 were shown not to have sufficient preservative effect. This suggests that the eye drops of the present invention containing epinastine or its salts at a concentration of more than 0.075% (w / v) can be used repeatedly as a multi-dose eye drop by opening and closing the container, even without containing preservatives or preservative components. [Industrial applicability]

[0043] The present invention provides an eye drop solution containing epinastine or a salt thereof at a concentration of more than 0.075% (w / v), which substantially does not contain preservatives or components having preservative properties.

Claims

1. An eye drop containing only epinastine or a salt thereof at a concentration of more than 0.075% (w / v) as the active ingredient, and containing sodium dihydrogen phosphate or its hydrate, disodium hydrogen phosphate or its hydrate, sodium chloride, and a pH adjuster as additives, and not containing preservatives or preservative components, or containing only benzalkonium chloride as a preservative and preservative component, wherein the amount of benzalkonium chloride alone does not conform to the preservative efficacy test method described in the 17th edition of the Japanese Pharmacopoeia.

2. The eye drop solution according to claim 1, wherein the concentration of sodium dihydrogen phosphate or its hydrate is 0.25% (w / v) and the concentration of disodium hydrogen phosphate or its hydrate is 1.22% (w / v).

3. The eye drop solution according to claim 1, wherein the concentration of sodium chloride is 0.1 to 1% (w / v).

4. The eye drop solution according to claim 1, wherein the pH is 6.5 to 7.

5.

5. The eye drop solution according to any one of claims 1 to 4, wherein epinastine or a salt thereof is epinastine hydrochloride.

6. The eye drop solution according to any one of claims 1 to 4, wherein the concentration of epinastine or a salt thereof is 0.1% (w / v).

7. The eye drop according to any one of claims 1 to 6, which is a multi-dose eye drop.

8. An eye drop containing only 0.1% (w / v) epinastine hydrochloride as the active ingredient, and containing 0.25% (w / v) sodium dihydrogen phosphate or its hydrate, 1.22% (w / v) disodium hydrogen phosphate or its hydrate, 0.1-1% (w / v) sodium chloride, and a pH adjuster as additives, and not containing preservatives or preservative components, or containing only benzalkonium chloride as a preservative and preservative component, characterized in that the amount of benzalkonium chloride alone does not conform to the preservative efficacy test method described in the 17th edition of the Japanese Pharmacopoeia, and having a pH of 6.5-7.5.

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