TW201821060A - Ophthalmic solution comprising epinastine - Google Patents

Abstract

The present invention is to provide an ophthalmic solution comprising epinastine or a salt thereof in a concentration of over 0.075 % w/v wherein the ophthalmic solution is substantially free of preservatives and ingredients with preservative efficacy.

Description

   Eye Drops with Epistine   

The present invention relates to an ophthalmic solution (hereinafter, also referred to as "the ophthalmic solution of the present invention"), which is a point containing epinastine or a salt thereof at a concentration of more than 0.075% (w / v). Eye drops are characterized by being substantially free of preservatives and ingredients with antiseptic properties.

Eye drops are required to have a certain degree of anti-corrosion measures in order to prevent the proliferation of fungi and the like with repeated use. Therefore, preservatives are often incorporated into eye drops. As a preservative, for example, benzyl ammonium chloride is water-soluble, chemically stable, and has a higher preservative effect than other preservatives, so it is widely used in eye drops. However, benzyl ammonium chloride is cytotoxic, and if the amount of exposure is increased, the possibility of causing corneal epithelial disorder will increase. Therefore, it cannot be used in patients who show an allergic reaction specifically to benzyl ammonium chloride or patients with severe corneal epithelial disorder.

At present, Arejion ^{(registered trademark)} eye drops listed in Japan is 0.05%, which is an eye drop containing epitastine hydrochloride as an active ingredient. It does not add preservatives such as benzyl ammonium chloride, and replaces it with Other ingredients (boric acid, edetic acid (EDTA)) having a preservative effect (Non-Patent Document 1). That is, in order to repeatedly use eye drops containing eplestin or a salt thereof, it has been known that it is not necessary to contain a preservative such as benzyl ammonium chloride, but it is necessary to ensure the preservation by replacing other ingredients with a preservative effect Effect. On the other hand, eye drops that do not contain any preservatives or ingredients that have a preservative effect and that contain eplestin or its salt are completely unknown.

In addition, there are known eye drops without any preservatives or ingredients with antiseptic properties at the marketed eye drops, but these are unit dose type (one-time use type) ) Or preserved in a preservative-free container (a container having a special structure to exert a preservative effect), and eye drops that have an antiseptic effect such as an active ingredient have not been known. That is, the fact that Epistine or a salt thereof has a preservative effect is completely unknown.

    [Prior technical literature]         [Non-patent literature]    

[Non-Patent Document 1] Arejion ^{(registered trademark)} eye drops 0.05% drug copy

Therefore, it is an exciting subject to provide an ophthalmic solution that does not substantially contain a preservative and a component having a preservative effect, and also contains eplestin or a salt thereof.

The present inventors conducted intensive research in order to find any preservatives without any preservatives and ingredients with preservative effects, or those eye drops containing eplestin or salt thereof, and found that: The concentration of Epistine or its salt in the eye drops exceeds 0.075% (w / v), which can be substantially free of preservatives or ingredients with preservative effects, and obtain a sufficient preservative effect. this invention. Specifically, the present invention provides the following.

(1) An ophthalmic solution, which is an ophthalmic solution containing ipsitin or a salt thereof in a concentration of more than 0.075% (w / v), which does not substantially contain a preservative and a component having a preservative effect.

(2) The ophthalmic solution according to (1), which contains eplestin or a salt thereof at a concentration of 0.1% to 5.0% (w / v).

(3) The ophthalmic solution according to (1) or (2), wherein eplestin or its salt is eplestin hydrochloride.

(4) The ophthalmic solution according to (1), wherein the preservative and the component having a preservative effect are selected from the group consisting of benzalconium chloride, chlorhexidine or a salt thereof, boric acid, and borax And at least one component of the group of ethylenediaminetetraacetic acid or a salt thereof.

(5) An ophthalmic solution, which contains only eplestin or a salt thereof at a concentration exceeding 0.075% (w / v) as an active ingredient, and contains only a buffering agent, an isotonicity agent, and a pH adjusting agent as additives .

(6) The ophthalmic solution according to (5), which contains eplestin or a salt thereof at a concentration of 0.1% to 5.0% (w / v).

(7) The ophthalmic solution according to (5) or (6), wherein eplestin or its salt is eplestin hydrochloride.

(8) The ophthalmic solution according to any one of (5) to (7), wherein the buffering agent is phosphoric acid or a salt thereof.

(9) The ophthalmic solution according to any one of (5) to (8), wherein the isotonicity agent is an ionic isotonicity agent.

(10) The ophthalmic solution according to any one of (1) to (9), which is a multi-dose type ophthalmic solution.

(11) A method for imparting a preservative effect to eye drops by blending eplestin or a salt thereof at a concentration exceeding 0.075% (w / v), which eye drops do not substantially contain Preservatives and ingredients with preservative effect and contain Ibistine or its salt.

(12) A method for maintaining the antiseptic effect of ophthalmic solution by blending eplestin or a salt thereof at a concentration exceeding 0.075% (w / v), which is substantially free of Preservatives and ingredients with preservative effect and contain Ibistine or its salt.

In addition, each of the aforementioned (1) to (12) may be arbitrarily selected and combined.

The present invention further provides the following.

(13) A method for treating and / or preventing allergic conjunctivitis, which is characterized by administering a therapeutically effective amount of the eye drops according to any one of (1) to (10) to a patient in need of treatment.

(14) The ophthalmic solution according to any one of (1) to (10), which is used for the treatment and / or prevention of allergic conjunctivitis.

According to the present invention, an eye drop containing eplestin or a salt thereof can be obtained, which has a preservative effect even without adding any preservative or a component having a preservative effect.

    [Form of Implementing Invention]    

Hereinafter, the present invention will be described in detail.

In the present invention, "Epilastine" refers to the chemical name (±) -3-amino-9,13b-dihydro-1H-diphenyl [c, f] imidazo [1,5-a] aza The compound represented by ((±) -3-Amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine) has the following formula:

The compound shown.

The eyedrops contained in the present invention may contain a salt of eplestin, and there is no particular limitation as long as the salt is acceptable as a medicine. Examples of the salt include a salt with an inorganic acid and a salt with an organic acid.

Examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid.

Examples of salts with organic acids include: with acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, grape heptanoic acid, glucose Uronic acid, terephthalic acid, methanesulfonic acid, alanine, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, 2-isethionic acid, lactoburonic acid, oleic acid, and food Lactic acid, acetic acid, polygalacturonic acid, stearic acid, tannic acid, triflate, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, sulfosalicylate Acid and other salts.

As far as the salt of Ibistine is concerned, monohydrochloride (Ibistine hydrochloride) is particularly preferred.

In the present invention, the eplestatin or a salt thereof may be in the form of a hydrate or a solvate.

In the present invention, the content of eplestin or its salt is sufficient as long as it exceeds 0.075% (w / v), but it may be set to 0.085% (w / v) or more, or 0.1% (w / v) or more. The upper limit may be a concentration that is acceptable as an ophthalmic preparation, and is, for example, 5% (w / v). In terms of the content of eplestatin or its salt, it is preferably 0.1 to 5.0% (w / v), more preferably 0.1 to 3.0% (w / v), and still more preferably 0.1 to 1.0% (w / v). Particularly good is 0.1 ~ 0.5% (w / v), 0.1 ~ 0.3% (w / v), but 0.1% (w / v), 0.2% (w / v), 0.3% (w / v), 0.4% (w / v) and 0.5% (w / v) are further better.

In the case where the salt of eplestin is contained in the present invention, the value is the content of the salt of eplestin. "% (W / v)" means the mass (g) of a target component (here, an epitene or a salt thereof) contained in 100 mL of eye drops of the present invention. Hereinafter, it is the same unless there is particular notice.

In the present invention, as the preservative, for example, benzyl ammonium chloride, benzalconium bromide, benzethonium chloride, lochsetin or a salt thereof, sorbic acid or Its salts, methyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol and the like.

Examples of lochsetin or a salt thereof include lochsetin gluconate, lochsetin hydrochloride, and lochsetin acetic acid.

Examples of the sorbic acid or a salt thereof include sodium sorbate and potassium sorbate.

In the present invention, examples of the component having a preservative effect include boric acid, borax, ethylenediaminetetraacetic acid or a salt thereof.

Examples of ethylenediaminetetraacetic acid or a salt thereof include ethylenediaminetetraacetic acid monosodium, ethylenediaminetetraacetic acid disodium, and ethylenediaminetetraacetic acid tetrasodium.

In the present invention, the so-called "containing no preservatives and ingredients with a preservative effect" means that the eye drops do not contain the "preservatives and ingredients with a preservative effect" at all, or contain the "preservatives and components with a preservative effect" "It is a degree that does not comply with the preservation efficacy test method described in the 17th edition of the Japanese Pharmacopoeia. The above-mentioned "degree that does not conform to the preservation efficacy test method recorded in the 17th revised edition of the Japanese Pharmacopoeia" means, for example, if it is EDTA, it may be about 0.01% (w / v) or 0.02% (w / v) However, this is not included in the eye drops in order to obtain the antiseptic effect of EDTA, but to obtain the stabilization effect. For example, if it is boric acid, it may be about 0.01% (w / v) or 0.02% (w / v). However, this is not included in order to obtain the antiseptic effect of boric acid but to obtain a buffering effect. Eye drops. In the present invention, "substantially" means that there is no change in nature. Therefore, in the present invention, the "substantially free of preservatives and components having a preservative effect" means the absence of the "preservatives and preservatives at all". "Including the" preservative and ingredients with a preservative effect "without the intention of preservative effect is to the extent that it does not comply with the preservation efficacy test method described in the 17th edition of the Japanese Pharmacopoeia.

In the present invention, a multi-dose type ophthalmic solution refers to an ophthalmic solution that is placed in a multi-dose type container. The multi-dose container is a container that can be opened and closed freely for the purpose of multiple uses. After opening, it can be used for a certain period of time and is easy to carry. In the present invention, the size or shape of the container body is not particularly limited, and may be a unit-dose container (a type used once), but a multi-dose container is more preferable because it imparts an antiseptic effect to eye drops. It does not include a container having a special structure to exert a preservative effect to prevent backflow, etc., such as a PFMD (Preservative Free Multi Dose) container. In addition, the material of the container is not particularly limited, and generally used containers such as containers made of polyethylene (PE), polypropylene (PP), and polyethylene terephthalate (PET) can be used.

In the present invention, the ophthalmic solution may be a solution in which the constituent components are completely dissolved or partially suspended, but more preferably a liquid state in which the constituent components are completely dissolved.

In the present invention, the buffering agent when the buffering agent is blended in the ophthalmic solution can be appropriately blended as a buffering agent that can be used as a pharmaceutical additive. Its salt, carbonic acid or its salt, tartaric acid or its salt, ε-aminohexanoic acid, trometamol, etc. may also be such hydrates or solvates.

Examples of phosphoric acid or a salt thereof include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and the like, and these hydrates may also be mentioned.

Examples of the citric acid or a salt thereof include sodium citrate, disodium citrate, and the like, and these hydrates may also be mentioned.

Examples of the acetic acid or a salt thereof include sodium acetate, potassium acetate, and the like, and such hydrates may also be mentioned.

Examples of the carbonic acid or a salt thereof include sodium carbonate, sodium bicarbonate, and the like, and hydrates thereof may also be mentioned.

Examples of the tartaric acid or a salt thereof include sodium tartarate, potassium tartarate, and the like, and these hydrates may also be mentioned.

In the present invention, the buffering agent when the buffering agent is blended in the ophthalmic solution is more preferably phosphoric acid or a salt thereof, particularly preferably sodium dihydrogen phosphate, disodium hydrogen phosphate, or a hydrate thereof. Moreover, you may use together 2 or more types of buffering agents.

In the present invention, the content of the buffering agent when the buffering agent is blended in the ophthalmic solution can be appropriately adjusted according to the type of the buffering agent, etc., but is preferably 0.001 to 10% (w / v), and more preferably 0.01 to 5 % (w / v), more preferably 0.1 ~ 3% (w / v), and most preferably 0.2 ~ 1.5% (w / v).

In the present invention, the isotonicity agent used when the isotonicity agent is blended in the ophthalmic solution can be appropriately blended into an isotonicity agent that can be used as a pharmaceutical additive, but examples thereof include ionic isotonicity agents, Non-ionic isotonicity agents.

Examples of the ionic isotonicity agent include sodium chloride, potassium chloride, calcium chloride, and magnesium chloride.

Non-ionic isotonicity agents include glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose, and the like.

In the present invention, the isotonicity agent when the isotonicity agent is blended in the ophthalmic solution is more preferably an ionic isotonicity agent, and particularly preferably sodium chloride. In addition, two or more isotonic agents may be used together.

In the present invention, the content of the isotonicity agent when the isotonicity agent is blended in the ophthalmic solution can be appropriately adjusted according to the type of the isotonicity agent, etc., but is preferably 0.001 to 10% (w / v), It is more preferably 0.01 to 5% (w / v), still more preferably 0.1 to 1% (w / v), and most preferably 0.2 to 0.5% (w / v).

In the present invention, the osmotic pressure ratio of the ophthalmic solution may be within the range allowed by the ophthalmic preparation, for example, 0.5 to 2.0, preferably 0.7 to 1.6, more preferably 0.8 to 1.4, and still more preferably 0.9 to 1.2. .

In the present invention, the pH adjusting agent when the pH adjusting agent is blended in the ophthalmic solution may be appropriately blended. The pH adjusting agent that can be used as a pharmaceutical additive is, for example, an acid or a base. Examples of the acid include hydrochloric acid , Phosphoric acid, citric acid, acetic acid, and the like; examples of the alkali include sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate.

In the present invention, the pH of the ophthalmic solution may be within the range allowed by the ophthalmic preparation, preferably within 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 good pH is 6.7 ~ 7.3, but 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3 are also better.

In the present invention, in addition to the aforementioned buffering agents, isotonicity agents, and pH adjusting agents, if necessary, one or more ophthalmic preparations may be added (other than preservatives and ingredients having a preservative effect), For this additive, for example, a solubilizer, a stabilizer, an antioxidant, a thickener, and the like can be added. In addition, unless otherwise specified, it may contain active ingredients for eye drops other than eplestin or a salt thereof.

Examples of the solubilizer include polyoxyethylene hardened ramie oil, povidone, polysorbate 80, and the like; and examples of the stabilizer include povidone, polysorbate 80, and the like; Examples of the antioxidant include dibutyl hydroxytoluene, sodium sulfite, and the like; and examples of the thickener include carboxyvinyl polymer, hydroxyethyl cellulose, and the like. These additives may be added within the range allowed by the ophthalmic preparation, for example, each may be added at 2% or less, or may be added at a range of 0.2% or less, 0.02% or less, and 0.002% or less.

The ophthalmic solution of the present invention is useful as a therapeutic agent for allergic conjunctivitis.

When the ophthalmic solution of the present invention is administered, the dosage is not particularly limited as long as it is sufficient to exhibit the desired medicinal effect, but it can be divided into 1 drop 1 time, 1 to 10 times a day, preferably 1 day 2 -6 times, more preferably 2 to 4 times a day, even more preferably 2 times a day and 4 times a day. The eye drops of the present invention can also be used when wearing contact lenses.

    [Example]    

The formulation examples and the results of the preservative efficacy test are shown below, but these are for easier understanding of the present inventors and do not limit the scope of the present invention.

[Formulation example]

Representative formulation examples of the present invention are shown below. In addition, the blending amount of each component in the following formulation examples is the content in 1 mL of the formulation.

Preparation Example 1

Multi-dose container (1mL)

Preparation Example 2

Multi-dose container (1mL)

Anticorrosive efficacy test (1)

This test was carried out in accordance with the preservation efficacy test method described in the 17th revised edition of the Japanese Pharmacopoeia.

1. Preparation of test preparation

Dissolve eplestin (50 mg), sodium dihydrogen phosphate (25 mg), disodium hydrogen phosphate hydrate (122 mg), sodium chloride (40 mg) in water and filter sterilize, and add a pH adjuster and water and A total of 10 mL was prepared to prepare the preparation of Example 1.

Example 1

1mL

pH 6.7

In the same manner as the preparation method of Example 1, the preparations of Examples 2 to 4 and Comparative Examples 1 to 2 were prepared.

Example 2

1mL

Example 3

1mL

Example 4

1mL

Ibistine hydrochloride 2mg

Comparative Example 1

1mL

Comparative Example 2

1mL

2. Test method

The following strains were used as inoculating bacteria.

Bacteria: Escherichia coli, Escherichia Coli ATCC 8739 (also known as E.coli)

Pseudomonas aeruginosa ATCC 9027 (also known as P. aeruginosa)

Staphylococcus aureus, Staphylococcus aureus ATCC6538 (also known as S. aureus)

Yeasts and molds: Candida, Candida albicans ATCC 10231 (also known as C. albicans)

Black fungus, Aspergillus brasiliensis ATCC16404 (also known as A. brasiliensis)

The inoculum was inoculated into a test sample, comprising the test that the bacterial concentration in a sample of each formulation becomes 10 ⁵ to 10 ⁶ / mL (a total of 5 strains). Specifically, the inoculating bacterial solution was prepared so as to be 10 ⁷ to 10 ⁸ cfu / mL, and each inoculating bacterial solution was inoculated into a test sample containing the preparations of Examples 1 to 4 and Comparative Examples 1 to 2, and the inoculating bacteria The solution was 10 ⁵ to 10 ⁶ cfu / mL, and the mixture was uniformly mixed to prepare a sample. These samples were stored under light-shielding at 20 to 25 ° C. At each sample point (after 7 days, 14 days, or 28 days), 1 mL was taken from each sample using a micropipette to measure the number of bacteria. At each sample point, the lid of the sample solution is opened to perform sampling and close the lid.

3. Test results and investigations

The test results are shown in Tables 1 and 2. The test results in Tables 1 and 2 are expressed by a commonly used logarithmic value of the ratio of the number of bacteria (B) at the time of inoculation to the number of bacteria (A) when measuring the number of bacteria (B / A). For example, when the value is " In the case of "1", it was shown that the number of bacterial strains at the time of inspection was reduced to 10% of the number of inoculated bacteria.

The determination of the eligibility of the test is considered to be acceptable when any of the following is satisfied: For the bacterial species (E.coli, P.aeruginosa, S. aureus), it is 1.0 or more after 7 days of sowing and 14 days after Or 3.0 after 28 days; and for fungal species (C. albicans, A. brasiliensis), compared with 7 days after sowing, the value after 14 days or 28 days after sowing did not decrease.

As shown in Tables 1 and 2, the preparations of Examples 1 to 4 containing eplestin or a salt thereof did not contain a preservative or a component having a preservative effect, but showed a sufficient preservative effect on any bacteria. In contrast, the preparations of Comparative Examples 1 and 2 did not have sufficient antiseptic effect. It is suggested that the eye drops of the present invention containing ipsitin or a salt thereof at a concentration of more than 0.075% (w / v) can be used as a multi-component solution even if it does not contain a preservative or a component having a preservative effect. Dosage eye drops and repeatedly open and close the container for use.

    [Industrial availability]    

The present invention provides an ophthalmic solution, which is an ophthalmic solution containing ipsitin or a salt thereof at a concentration of more than 0.075% (w / v), which does not substantially contain a preservative and a component having a preservative effect.

Claims (12)

    An ophthalmic solution is an ophthalmic solution containing epinastine or a salt thereof in a concentration of more than 0.075% (w / v), which does not substantially contain a preservative and a component having a preservative effect.         For example, the ophthalmic solution of claim 1 contains eplestin or a salt thereof at a concentration of 0.1% to 5.0% (w / v).         The ophthalmic solution of claim 1 or 2, wherein eplestin or its salt is eplestin hydrochloride.         The ophthalmic solution of claim 1, wherein the preservative and the preservative-containing component are selected from the group consisting of benzalconium chloride, chlorhexidine or a salt thereof, boric acid, borax, and ethylenediamine. At least one component of the group of edetic acid or a salt thereof.         An ophthalmic solution containing only eplestin or a salt thereof at a concentration exceeding 0.075% (w / v) as an active ingredient, and containing only a buffering agent, an isotonicity agent, and a pH adjusting agent as additives.         The ophthalmic solution of claim 5 contains eplestin or a salt thereof at a concentration of 0.1% to 5.0% (w / v).         The ophthalmic solution of claim 5 or 6, wherein eplestin or its salt is eplestin hydrochloride.         The ophthalmic solution of any one of claims 5 to 7, wherein the buffering agent is phosphoric acid or a salt thereof.         The ophthalmic solution of any one of claims 5 to 8, wherein the isotonicity agent is an ionic isotonicity agent.         The eye drops of any one of claims 1 to 9 are multi-dose eye drops.         A method for imparting a preservative effect to an eye drop by blending eplestin or a salt thereof at a concentration exceeding 0.075% (w / v), the eye drop being substantially free of a preservative And has antiseptic ingredients and contains eplestin or a salt thereof.         A method for maintaining the antiseptic effect of eye drops by blending eplestin or a salt thereof at a concentration exceeding 0.075% (w / v), which is substantially free of preservatives And has antiseptic ingredients and contains eplestin or a salt thereof.