KR20190075956A - Epinastine-containing eye drops - Google Patents

Abstract

The present invention provides an eye drop containing epinastine or a salt thereof at a concentration of more than 0.075% (w / v), substantially free of preservatives and ingredients having preservative action.

Description

Epinastine-containing eye drops

The present invention relates to an eye drop containing epinastine or a salt thereof at a concentration of more than 0.075% (w / v), which is substantially free of an antiseptic and a component having a preservative action Quot; or " an eye drop of an invention ").

In order to prevent the growth of fungi and the like accompanied by repeated use, eye drops are required to be given a predetermined antiseptic measure. Therefore, a preservative is usually incorporated in the eye drops. As an antiseptic, for example, benzalkonium chloride is water-soluble, chemically stable, and has a high preservative effect in comparison with other preservatives, so it is commonly used in eye drops. However, benzalkonium chloride has cytotoxicity, which increases the risk of corneal epithelial damage if exposure is increased. Therefore, it can not be used especially in patients who show an excessive response to benzalkonium chloride or patients with severe corneal epithelial disorders.

Presently, the 0.05% Aesizon ^{(registered trademark)} eye drop currently being marketed in Japan is an eye drop containing epinastine hydrochloride as an active ingredient and, instead of adding preservatives such as benzalkonium chloride, Boric acid, edetic acid (EDTA)) are added (Non-Patent Document 1). That is, in order to repeatedly use an eye drop containing epinastine or a salt thereof, preservatives such as benzalkonium chloride need not necessarily be contained, but it is necessary to secure a preservative effect with a component having another preservative function instead Is recognized. On the other hand, no eye drops containing epinastine or a salt thereof, in which any of preservative and preservative ingredients are not added, is not known at all.

On the other hand, there is known an eye drop in which no preservative or a component having a preservative action is added to the eye drops in the market, but they are in the form of a unit dose type (disposable type) or a preservative free container A container having a specific structure), and an eye drop in which the active ingredient itself exerts a preservative action is not known. That is, it is not known that epinastine or its salt itself has a preservative action.

 Alezion (registered trademark) eye drops 0.05% Attached document

Accordingly, it is an interesting problem to provide an eye drop containing epinastine or a salt thereof that does not substantially contain a preservative and a component having a preservative action.

The inventors of the present invention have made intensive studies to find an eye drop containing epinastine or a salt thereof in which neither preservative nor preservative component is added or the amount thereof is reduced. As a result, epinastine Or a salt thereof in an amount of more than 0.075% (w / v), a sufficient preservative effect can be obtained without containing a preservative or a component having a preservative action, thereby 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 greater than 0.075% (w / v), substantially free of preservatives and ingredients having preservative action.

(2) The eye drop of (1), which contains epinastine 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 the epinastine or its salt is epinastine hydrochloride.

(4) The ophthalmic solution according to (1), wherein the preservative and the preservative component are 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 an active ingredient, and containing only a buffer, an isotonic agent and a pH adjuster as additives.

(6) The eye drop according to (5), which contains epinastine 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 the epinastine or its salt is epinastine hydrochloride.

(8) The eye drop according to any one of (5) to (7), wherein the buffer is phosphoric acid or a salt thereof.

(9) The eye drop described in any one of (5) to (8), wherein the isotonic agent is an ionic isotonic agent.

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

(11) By adding epinastine or a salt thereof at a concentration of more than 0.075% (w / v), it is possible to provide an ophthalmic solution containing epinastine or its salt substantially free from preservatives and preservatives, How to give effect.

(12) A cosmetic composition containing epinastine or a salt thereof, at a concentration of more than 0.075% (w / v), to form an ointment containing epinastine or a salt thereof without containing an ingredient having a substantially preservative and preservative action How to maintain effectiveness.

On the other hand, each of the structures (1) to (12) may be arbitrarily selected from two or more.

The present invention also provides the following.

(13) A method for treating and / or preventing an allergic conjunctivitis, which comprises administering to a patient in need of treatment a therapeutically effective amount of the ophthalmic solution according to any one of (1) to (10).

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

The present invention can obtain an eye drop containing epinastine or a salt thereof having a preservative effect even if none of preservatives and preservative ingredients is added.

Hereinafter, the present invention will be described in detail.

In the present invention, "epinastine" is a compound represented by the chemical name (±) -3-Amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [ In addition,

Lt; / RTI >

In the eye drops of the present invention, the contained epinastine may be a salt, and there is no particular limitation 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 salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like.

Examples of salts with organic acids include salts with organic acids such as acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptonic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, alanine, P-toluenesulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid, -Toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, sulfosalicylic acid and the like.

As a salt of epinastine, monohydrochloride (epinastine hydrochloride) is particularly preferable.

In the present invention, the contained epinastine or its salt may take the form of a hydrate or a solvate.

In the present invention, the content of epinastine or a salt thereof is preferably more than 0.075% (w / v), but may be not less than 0.085% (w / v) or not less than 0.1% (w / v) For example, it is 5% (w / v). The content of epinastine or its salt 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 preferably 0.1 to 0.5% (w / v), 0.1 to 0.3% (w / v), but preferably 0.1 to 0.5% (w / v) 0.4% (w / v), and 0.5% (w / v).

On the other hand, when epinastine salt is contained in the present invention, these values are the epinastine salt content. "% (w / v)" means the mass (g) of the target component (here, epinastine or its salt) contained in 100 mL of the eye drop of the present invention. The same shall apply hereinafter unless otherwise specified.

In the present invention, examples of the preservative include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, chlorhexidine or its salt, sorbic acid or its salt, paraoxybenzoate, propylparaxybenzoate, .

Examples of chlorhexidine or its salt include chlorhexidine gluconate, chlorhexidine hydrochloride, chlorhexidine acetate and the like.

Examples of sorbic acid or its salt include sodium sorbate and potassium sorbate.

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

Examples of the edetic acid or its salt include monosodium edetate, disodium edetate, sodium edetate and the like.

In the present invention, "no preservative and a component having a preservative action" means that the eye drops do not contain any of the "preservative and preservative component ", or the" And is included so as not to comply with the preservation efficacy test described in the Japanese Pharmacopoeia of 17th revision. In the case of EDTA, for example, it may be about 0.01% (w / v) or 0.02% (w / v), as long as it does not conform to the preservation test described in the Japanese Pharmacopoeia Is contained in the eye drops to obtain a stabilizing action rather than a preservative action. Further, for example, if it is boric acid, it may be about 0.01% (w / v) or 0.02% (w / v), which is not included in the preservative action of boric acid but included in the eye drop to obtain buffering action. In the present invention, the term "substantially" does not change its essence. Thus, in the present invention, the term "substantially free from preservatives and ingredients having a preservative action" In the case where the preservative does not contain any preservative or the preservative effect is not intended, the corresponding "preservative and preservative component" alone is included to the extent that it does not comply with the preservation efficacy test described in the Japanese Pharmacopoeia of the 17th Amendment.

In the present invention, the multi-dose type eye drop refers to an eye drop placed in a multi-dose type container. The multi-dose type container is a container which can be opened and closed freely for the purpose of using it plural times, can be used for a certain period after opening, and is portable. In the present invention, the size or shape of the container main body is not particularly limited, and may be a unit dose type container (single use type), but a multi-dose type container is more preferable because the ophthalmic solution has a preservative effect. Containers having a special structure for exerting a preservative effect such as a backflow prevention function, for example, a PFMD (Preservative Free Multi Dose) container are not included. On the other hand, the material of the container is not particularly limited, and containers generally used for general purpose, such as polyethylene (PE), polypropylene (PP), and polyethylene terephthalate (PET) can be used.

In the present invention, the eye drops may be all dissolved or partially suspended, but more preferably the liquid phase in which all of the constituents are dissolved.

In the present invention, as the buffer in the case of mixing the buffer with the eye drops, a buffering agent which can be used as an additive for pharmaceuticals can be suitably compounded. For example, phosphoric acid or its salt, citric acid or its salt, acetic acid or its salt, Or a salt thereof, a tartaric acid or a salt thereof,? -Aminocaproic acid, trometamol and the like, or a hydrate or solvate thereof.

Examples of the phosphoric acid or its salt include sodium phosphate, sodium dihydrogenphosphate, disodium hydrogenphosphate, potassium phosphate, potassium dihydrogenphosphate, potassium dihydrogenphosphate, and the like, or a hydrate thereof.

Examples of the citric acid or its salt include sodium citrate and disodium citrate, and hydrates thereof.

Examples of the acetic acid or its salt include sodium acetate and potassium acetate, and hydrates thereof.

Examples of the carbonic acid or its salt include sodium carbonate, sodium hydrogencarbonate and the like, and hydrates thereof.

Examples of the tartaric acid or its salt include sodium tartrate and potassium tartrate, and they may be hydrates thereof.

In the present invention, as the buffer in the case of adding a buffer to the eye drops, phosphoric acid or a salt thereof is more preferable, and sodium dihydrogenphosphate, sodium dihydrogenphosphate or a hydrate thereof is particularly preferable. Two or more buffering agents may be used together.

In the present invention, the content of the buffering agent in the case of adding the buffering agent to the eye drops can be suitably adjusted according to the type of the buffering agent and is preferably 0.001 to 10% (w / v), more preferably 0.01 to 5% , More preferably 0.1 to 3% (w / v), and most preferably 0.2 to 1.5% (w / v).

In the present invention, the isotonic agent when the isotonic agent is formulated into the eye drops can be appropriately blended with the isotonic agent that can be used as an additive for pharmaceuticals, and examples thereof include ionic isotonic agents and nonionic isotonic agents have.

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

Examples of the nonionic isotonizing agent include glycerin, propylene glycol, polyethylene glycol, sorbitol, mannitol, trehalose, maltose, sucrose and the like.

In the present invention, as the isotonic agent when an isotonic agent is formulated in an eye drop, an ionic isotonic agent is more preferable, and sodium chloride is particularly preferable. In addition, two or more isotonic agents may be used together.

In the present invention, the content of the isotonic agent in the case of adding the isotonic agent to the eye drops can be suitably adjusted according to the kind of the isotonic agent and is preferably 0.001 to 10% (w / v), more preferably 0.01 to 5% / v) is more preferable, 0.1 to 1% (w / v) is more preferable, and 0.2 to 0.5% (w / v) is most preferable.

In the present invention, the osmotic pressure ratio of the ophthalmic solution should be within a range acceptable to ophthalmic preparations, 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 .

In the present invention, the pH adjusting agent when the pH adjusting agent is added to the eye drops can be appropriately mixed with a pH adjusting agent which can be used as an additive for pharmaceuticals. For example, the pH adjusting agent may be an acid or a base, Phosphoric acid, citric acid, and acetic acid. Examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like.

In the present invention, the pH of the eye drops should be within the range acceptable for ophthalmic preparations, 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 is 6.7 to 7.3, but more preferably 6.7, 6.8, 6.9, 7.0, 7.1, 7.2 and 7.3 degrees.

In the present invention, in addition to the above-mentioned buffering agents, isotonizing agents and pH adjusting agents, at least one additive (excluding a preservative and a preservative-acting component) acceptable for ophthalmic preparations may be added if necessary, A stabilizer, an antioxidant, a tackifier, etc. may be added. In addition, unless otherwise specified, the active ingredient may be contained in an eye drop other than epinastine or a salt thereof.

Examples of the solubilizing agent include polyoxyethylene hydrogenated castor oil, povidone, and polysorbate 80; examples of the stabilizer include povidone and polysorbate 80; examples of the antioxidant include dibutylhydroxytoluene, sodium sulfite and the like Examples of the viscosifying agent include carboxyvinyl polymer, hydroxyethyl cellulose, and the like. These additives can be added within a range permissible for the ophthalmic preparation, and for example, they can be added to 2% or less, or 0.2% or less, 0.02% or less, and 0.002% or less.

The eye drops of the present invention are useful as therapeutic agents for allergic conjunctivitis.

In the case of administration of the eye drop of the present invention, there is no particular limitation on the dose of the eye drop as long as it is sufficient to show the desired drug efficacy. However, one drop per dose, 1 to 10 times per day, preferably 2 to 6 times per day, It may be divided into 2 to 4 times per day, more preferably 2 times per day and 4 times per day. Further, the eye drops of the present invention can be used also when wearing a contact lens.

Example

Hereinafter, the formulation examples and the results of the preservative effect test are shown, but they are for the purpose of better understanding of the present invention and do not limit the scope of the present invention.

[Formulation Example]

Representative formulation examples of the present invention are shown below. On the other hand, in the following formulation examples, the blending amount of each component is the content in 1 mL of the preparation.

Formulation example  One

In multi-dose containers (1 mL)

 Epinastine hydrochloride 1 mg

 Sodium dihydrogenphosphate 3 mg

 Sodium chloride 5 mg

 Dilute acid quantity

 Sodium hydroxide qs

 Purified water quantity

Formulation example  2

In multi-dose containers (1 mL)

 Epinastine hydrochloride 3 mg

 Sodium dihydrogenphosphate 3 mg

 Sodium dihydrogenphosphate 12 mg

 Sodium chloride 4 mg

 Dilute acid quantity

 Sodium hydroxide qs

 Purified water quantity

Conserveability test (1)

This test was conducted in accordance with the preservation efficacy test method described in the 17th Japanese Pharmacopoeia.

1. Preparation of preparation for treatment

(50 mg), sodium dihydrogenphosphate (25 mg), disodium hydrogen disodium hydrogenphosphate (122 mg) and sodium chloride (40 mg) were dissolved in water and subjected to filtration sterilization, and the total amount was adjusted to 10 mL by adding a pH adjusting agent and water , The preparation of Example 1 was prepared.

Example  One

In 1 mL

 Epinastine hydrochloride 5 mg

 Sodium dihydrogenphosphate 2.5 mg

 12.2 mg of disodium hydrogen phosphate hydrate

 Sodium chloride 4 mg

 Dilute acid quantity

 Sodium hydroxide qs

 Purified water quantity

 pH 6.7

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

Example  2

In 1 mL

 Epinastine hydrochloride 50 mg

 Sodium dihydrogenphosphate 2.5 mg

 12.2 mg of disodium hydrogen phosphate hydrate

 Dilute acid quantity

 Sodium hydroxide qs

 Purified water quantity

 pH 6.7

Example  3

In 1 mL

 Epinastine hydrochloride 1 mg

 Sodium dihydrogenphosphate 2.5 mg

 12.2 mg of disodium hydrogen phosphate hydrate

 Sodium chloride 4.7 mg

 Dilute acid quantity

 Sodium hydroxide qs

 Purified water quantity

 pH 6.7

Example 4

In 1 mL

 Epinastine hydrochloride 2 mg

 Sodium dihydrogenphosphate 2.5 mg

 12.2 mg of disodium hydrogen phosphate hydrate

 Sodium Chloride 4.5 mg

 Dilute acid quantity

 Sodium hydroxide qs

 Purified water quantity

 pH 6.7

Comparative Example  One

In 1 mL

 Epinastine hydrochloride 0.5 mg

 Sodium dihydrogenphosphate 2.5 mg

 12.2 mg of disodium hydrogen phosphate hydrate

 Sodium chloride 5 mg

 Dilute acid quantity

 Sodium hydroxide qs

 Purified water quantity

 pH 6.7

Comparative Example  2

In 1 mL

 0.75 mg epinastine hydrochloride

 Sodium dihydrogenphosphate 2.5 mg

 12.2 mg of disodium hydrogen phosphate hydrate

 Sodium chloride 4.7 mg

 Dilute acid quantity

 Sodium hydroxide qs

 Purified water quantity

 pH 6.7

2. Test method

 The following strains were used as the inoculum.

  Germ:

   E. coli, Escherichia coli ATCC 8739 (also referred to as E. coli)

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

   Staphylococcus aureus ATCC 6538 (also known as S. aureus)

   Yeast and fungi:

   Candida, Candida albicans ATCC 10231 (also known as C. albicans)

   Aspergillus brasiliensis ATCC 16404 (also known as A. brasiliensis)

The inoculum of the inoculum was inoculated into the test sample so that the concentration of the bacterial solution in the test sample consisting of each preparation was 10 ⁵ to 10 ⁶ cells / mL (all five species). Specifically, an inoculum of the inoculum was prepared so as to have a concentration of 10 ⁷ to 10 ⁸ cfu / mL, and the resulting inoculum was adjusted to have a concentration of 10 ⁵ to 10 ⁶ cfu / mL. Each inoculum was inoculated into the test sample and uniformly mixed to prepare a sample. These samples were stored at 20 to 25 캜 under shading, and 1 mL of each sample was sampled at each sampling point (after 7 days, 14 days, or 28 days) by micropipette, and the viable cell count was measured. At each sampling point, the lid of the sample solution was opened and sampled, and the lid was closed.

3. Test Results and Considerations

The test results are shown in Tables 1 and 2. The test results shown in Table 1 and Table 2 are expressed by the logarithm of the ratio (B / A) of the number of bacteria (B) at the time of inoculation to the number of live bacteria (A) Is "1 ", it indicates that the viable cell count at the time of the test has decreased to 10% of the number of inoculated bacteria.

As for bacterial species (E. coli, P. aeruginosa, and S. aureus), the number of fungal species (C. parasiticis) was 1.0 or more after 7 days of inoculation, 3.0 or more after 14 days or 28 days after inoculation. albicans, and A. brasiliensis) were suitable when all of the values after 14 days or 28 days after the inoculation were not decreased compared with those after 7 days of inoculation.

As shown in Tables 1 and 2, the preparations of Examples 1 to 4 containing epinastine or a salt thereof did not contain a preservative and a component having a preservative action, Respectively. On the contrary, it was found that the preparations of Comparative Example 1 and Comparative Example 2 did not have sufficient preservative effect. Thus, the eye drops of the present invention containing epinastine or a salt thereof at a concentration of more than 0.075% (w / v) can be used as a multi-dose type eye drops repeatedly, without containing any preservative and a component having a preservative action, It can be used by opening and closing.

The present invention provides an eye drop containing epinastine or a salt thereof at a concentration of more than 0.075% (w / v), substantially free of preservatives and ingredients having preservative action.

Claims (12)

An eye drop comprising epinastine or a salt thereof at a concentration of more than 0.075% (w / v), the composition being substantially free of preservatives and ingredients having an antiseptic action. The method according to claim 1,
Wherein the composition contains epinastine or a salt thereof at a concentration of 0.1% to 5.0% (w / v). 3. The method according to claim 1 or 2,
Wherein the epinastine or its salt is epinastine hydrochloride. The method according to claim 1,
Wherein the component having an antiseptic and antiseptic action 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. An eye drop containing only epinastine or a salt thereof at a concentration of more than 0.075% (w / v) as an active ingredient, and containing only a buffer, an isotonic agent and a pH adjuster as additives. 6. The method of claim 5,
Wherein the composition contains epinastine or a salt thereof at a concentration of 0.1% to 5.0% (w / v). The method according to claim 5 or 6,
Wherein the epinastine or its salt is epinastine hydrochloride. 8. The method according to any one of claims 5 to 7,
Wherein the buffer is phosphoric acid or a salt thereof. 9. The method according to any one of claims 5 to 8,
Wherein the isotonic agent is an ionic isotonic agent. 10. The method according to any one of claims 1 to 9,
Multidose type eye drops, eye drops. By adding epinastine or a salt thereof at a concentration of more than 0.075% (w / v), the ophthalmic solution containing epinastine or a salt thereof, which does not substantially contain a preservative and a preservative ingredient, is given a preservative effect How to. By combining epinastine or a salt thereof at a concentration of more than 0.075% (w / v), it is possible to maintain the preservative effect of an eye drop containing epinastine or a salt thereof, substantially free from preservatives and ingredients having a preservative action How to.