Composition

Abstract

To provide means for suppressing the formation of analogs of epinastine or salts thereof.SOLUTION: Provided is a composition containing 0.075% (w / v) or more of epinastine or a salt thereof based on the entire composition, the composition comprising benzalkonium chloride and a preservative other than benzalkonium chloride.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to a composition containing epinastine.

Background Art

[0002] An eye drop containing epinastine or a salt thereof has been approved as a therapeutic agent for allergic conjunctivitis (Non-Patent Document 1). On the other hand, from the viewpoint of preventing the growth of fungi and the like accompanying repeated use of eye drops, a technique for imparting a certain antiseptic function to eye drops has been demanded.

[0003] For example, Patent Document 1 describes an eye drop containing epinastine or a salt thereof at a concentration exceeding 0.075% (w / v) and substantially free of an antiseptic and components having an antiseptic action. On the other hand, Patent Document 2 describes an aqueous composition containing epinastine or a salt thereof and a quaternary ammonium compound, wherein the content ratio of the quaternary ammonium compound to epinastine or a salt thereof is 0.1 part by weight or less with respect to 1 part by weight of the content of epinastine or a salt thereof.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Non-Patent Documents

[0005]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0006] In a composition containing epinastine, a technique for imparting an antiseptic function has not been established, and in order to prevent the deterioration of the composition, a technique in which the composition has higher antibacterial properties has been desired. On the other hand, in epinastine or a salt thereof, it is known that related substances are generated over time.

[0007] An object of the present invention is to provide a means for suppressing the generation of related substances of epinastine or a salt thereof.

Means for Solving the Problems

[0008] As a result of intensive studies to solve the above problems, the present inventors have found that in a composition containing epinastine or a salt thereof at a predetermined concentration or higher and containing a preservative in a predetermined combination, the generation of related substances of epinastine or a salt thereof is significantly suppressed, and have completed the present invention.

[0009] That is, the present invention relates to the following. [1] A composition containing epinastine or a salt thereof at 0.075% (w / v) or more based on the whole composition, A composition containing benzalkonium chloride and a preservative other than benzalkonium chloride. [2] The composition according to [1], wherein the preservative other than benzalkonium chloride is at least one selected from quaternary ammonium salts other than benzalkonium chloride, paraoxybenzoic acid esters, biguanide compounds, chlorobutanol, sorbic acid or a salt thereof, dehydroacetic acid or a salt thereof, benzyl alcohol, parachlorometaxylenol, chlorocresol, phenethyl alcohol, thimerosal, and chlorites. [3] The composition according to [1] or [2], wherein the preservative other than benzalkonium chloride is a biguanide compound. [4] The composition according to [2] or [3], wherein the biguanide compound is selected from polyhexanide and salts thereof. [5] The composition according to any one of [1] to [4], containing phosphoric acid, or a salt thereof, or a solvate thereof. The composition according to any one of [1] to [5], which contains sodium chloride. The composition according to any one of [1] to [6], which contains water. The composition according to any one of [1] to [7], which is for ophthalmic use.

Advantages of the Invention

[0010] According to the present invention, the production of epinastine or an analog of its salt can be suppressed.

Brief Description of the Drawings

[0011]

Figure 1

Figure 2

Figure 3

Modes for Carrying Out the Invention

[0012] (Composition) Hereinafter, embodiments of the invention will be described in detail. However, each embodiment does not limit the invention according to the claims, and not all combinations of the features described in each embodiment are essential for the invention. The features described in each embodiment may be arbitrarily combined.

[0013] The present invention relates to a composition containing epinastine (9,13b-dihydro-1H-dibenz[c,f]imidazo[1,5-a]azepin-3-amine) or a salt thereof (hereinafter referred to as the composition of the present invention).

[0014] The salt of epinastine may be any salt, for example, hydrochloride, sulfate, nitrate, hydrofluoride, hydrobromide, etc.

[0015] The concentration of epinastine or a salt thereof in the composition of the present invention may be, for example, 0.075% (w / v) (0.75 mg / mL) or more, 0.08% (w / v) (0.8 mg / mL) or more, 0.09% (w / v) (0.9 mg / mL) or more, or 0.1% (w / v) (1.0 mg / mL) or more with respect to the whole composition, or 0.15% (w / v) (1.5 mg / mL) or less, 0.14% (w / v) (1.4 mg / mL) or less, 0.13% (w / v) (1.3 mg / mL) or less, 0.12% (w / v) (1.2 mg / mL) or less, or 0.11% (w / v) (1.1 mg / mL) or less. Any combination of the above-mentioned concentrations may be represented as a predetermined concentration range.

[0016] The composition of the present invention contains benzalkonium chloride. The concentration of benzalkonium chloride in the composition of the present invention is not particularly limited, but may be, for example, 0.00001% (w / v) (0.0001 mg / mL) or more, 0.00005% (w / v) (0.0005 mg / mL) or more, or 0.0001% (w / v) (0.001 mg / mL) or more with respect to the whole composition, or 0.05% (0.5 mg / mL) (w / v) or less, 0.01% (w / v (0.1 mg / mL)) or less, or 0.005% (w / v) (0.05 mg / mL) or less. Any combination of the above-mentioned concentrations may be represented as a predetermined concentration range.

[0017] The composition of the present invention contains a preservative other than benzalkonium chloride. In the present invention, the preservative refers to a component that exhibits a bactericidal or bacteriostatic action against bacteria, fungi, etc. Examples thereof include quaternary ammonium salts other than benzalkonium chloride, paraoxybenzoic acid esters, biguanide compounds, chlorobutanol, sorbic acid or its salts, dehydroacetic acid or its salts, benzyl alcohol, parachlorometaxylenol, chlorocresol, phenethyl alcohol, thimerosal, chlorites, etc. In one aspect, the preservative other than benzalkonium chloride is a biguanide compound.

[0018] Examples of quaternary ammonium salts other than benzalkonium chloride include benzethonium chloride, benzododecinium bromide, poly(dodecylmethylammonium chloride), etc. Examples of biguanide compounds include polyhexanide (polyhexamethylene biguanide), chlorhexidine, and their salts. The salts of polyhexanide (polyhexamethylene biguanide) or chlorhexidine may each be any salt, such as inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrofluoride, hydrobromide, etc., and organic acid salts such as gluconate, acetate, tartrate, lactate, citrate, fumarate, maleate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, naphthalenesulfonate, camphorsulfonate, etc. The salts of sorbic acid or dehydroacetic acid may each be any salt, such as alkali metal salts such as sodium salt, potassium salt, etc., and alkaline earth metal salts such as calcium salt, magnesium salt, etc.

[0019] The concentration of preservatives other than benzalkonium chloride in the composition of the present invention is not particularly limited. As an example, it is preferably a biguanide compound, more preferably polyhexanide or a salt thereof. In that case, for example, it may be 0.000005% (w / v) (0.00005 mg / mL) or more, 0.00001% (w / v) (0.0001 mg / mL) or more, or 0.00005% (w / v) (0.0005 mg / mL) or more with respect to the whole composition, or 0.5% (w / v) (5.0 mg / mL) or less, 0.1% (w / v) or less, 0.05% (w / v) (1.0 mg / mL) or less, 0.01% (w / v) (0.1 mg / mL) or less, 0.005% (w / v) (0.05 mg / mL) or less, 0.002% (w / v) (0.02 mg / mL) or less, or 0.0015% (w / v) (0.015 mg / mL) or less. The above-mentioned concentrations can be arbitrarily combined to represent a predetermined concentration range.

[0020] The composition of the present invention can contain phosphoric acid, or a salt thereof, or a solvate thereof, and these can also be formulated as a buffer or a pH adjuster. The salt of phosphoric acid can be any salt, for example, an alkali metal salt such as a sodium salt or a potassium salt, or an alkaline earth metal salt such as a calcium salt. The solvate of phosphoric acid or a salt thereof can contain any solvent molecule, for example, it can be a hydrate containing water molecules. Also, the number of solvent molecules in the solvate is not particularly limited. For example, the solvate can be a dihydrate containing two water molecules. In addition, the solvate includes an anhydride (anhydrous solvate) obtained by removing water molecules from the hydrate. In one aspect, phosphoric acid, or a salt thereof, or a solvate thereof is one or more selected from sodium hydrogen phosphate hydrate and sodium dihydrogen phosphate hydrate.

[0021] The concentration of phosphoric acid, its salts, or their solvates in the composition of the present invention is not particularly limited. For example, it may be 0.01% (w / v) (0.1 mg / mL) or more, 0.05% (w / v) (0.5 mg / mL) or more, or 0.1% (w / v) (1.0 mg / mL) or more with respect to the whole composition, or may be 5% (w / v) (50 mg / mL) or less, 4% (w / v) (40 mg / mL) or less, 3% (w / v) (30 mg / mL) or less, 2% (w / v) (20 mg / mL) or less, or 1.5% (w / v) (15 mg / mL) or less. The above-mentioned concentrations may be arbitrarily combined to represent a predetermined concentration range.

[0022] The composition of the present invention can contain sodium chloride and can also be formulated as an isotonic agent. The concentration of sodium chloride in the composition of the present invention is not particularly limited. For example, it may be 0.01% (w / v) or more, 0.05% (w / v) or more, or 0.1% (w / v) or more with respect to the whole composition, or may be 2.0 (w / v) or less, 1.5 (w / v) or less, or 1.0% (w / v) or less. The above-mentioned concentrations may be arbitrarily combined to represent a predetermined concentration range.

[0023] The composition of the present invention contains water. The water is not particularly limited, but may be purified water, sterilized purified water, water for injection, etc. The water content in the composition can be, for example, 70% (w / v) or more, 80% (w / v) or more, 90% (w / v) or more, or 95% (w / v) or more.

[0024] The composition of the present invention may contain other components (other components) other than those described above. Examples of other components include buffers, stabilizers, isotonic agents, pH adjusters, thickeners, surfactants, etc. Further, the composition of the present invention may contain one or more active ingredients other than epinastine or its salts.

[0025] The buffer may be any one, and for example, it may be one or more selected from acetic acid, acetate, acetate hydrate, epsilon-aminocaproic acid, citric acid, and citrate hydrate.

[0026] The stabilizer can be any one, for example, it may be one or more selected from ascorbic acid, tocopherol, dibutylhydroxytoluene, povidone, sulfite, monoethanolamine, cyclodextrin, dextran, and taurine.

[0027] The isotonic agent can be any one, for example, it may be one or more selected from potassium chloride, calcium chloride, magnesium chloride, concentrated glycerin, propylene glycol, polyethylene glycol, glucose, sorbitol, mannitol, trehalose, maltose, sucrose, and butylene glycol.

[0028] The pH adjuster can be any one, for example, it may be one or more selected from hydrochloric acid, hydrochloride, hydrochloride hydrate, citric acid, citrate, citrate hydrate, sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate.

[0029] The thickening agent can be any one, for example, it may be one or more selected from carboxyvinyl polymer, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, xanthan gum, sodium chondroitin sulfate, sodium hyaluronate, hydroxyethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and sodium carboxymethyl cellulose.

[0030] The surfactant can be any one, for example, it may be one or more selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene glycol monostearate, polysorbate, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester, and tyloxapol.

[0031] The active ingredient other than epinastine or its salt is not particularly limited, and may be, for example, a compound having an inhibitory effect on the release of chemical mediators such as pemirolast, tranilast, azelastine, ibudilast, or a steroid compound such as dexamethasone, fluormetholone, prednisolone, etc.

[0032] The composition of the present invention can be prepared by any method. For example, the composition of the present invention can be prepared by dissolving each component in water and adjusting the pH.

[0033] In one aspect, the composition of the present invention is an aqueous composition. In the present invention, the term "aqueous composition" means that the water content in the composition is 70% (w / v) or more, 80% (w / v) or more, 90% (w / v) or more, or 95% (w / v) or more. The aqueous composition may have any property such as an aqueous solution, an aqueous suspension, an emulsion, etc.

[0034] In one aspect, the composition of the present invention is an ophthalmic composition. The ophthalmic composition refers to a composition that can be used for the treatment (including treatment, examination, etc.) in the ophthalmic field. In another aspect, the composition of the present invention is an eye drop composition.

[0035] (Inhibition of the production of related substances) In the present invention, the production of analogs of epinastine or a salt thereof can be suppressed. Examples of the analogs of epinastine or a salt thereof include 3-Amino-1,13b-dihydro-9H-dibenz [c,f] imidazo [1,5-a] azepin-9-one hydrochloride (which may also be referred to as Degradant A in this specification), 3-Amino-9H-dibenz [c,f] imidazo [1,5-a] azepine hydrochloride (which may also be referred to as Degradant B in this specification), 6-Aminomethyl-6,11-dihydro-5H-dibenz [b,e] azepine fumarate, 3-Amino-7-chloro-9,13b-dihydro-1H-dibenz [c,f] imidazo [1,5-a] azepine hydrochloride, 3-Amino-7-bromo-9,13b-dihydro-1H-dibenz [c,f] imidazo [1,5-a] azepine hydrobromide, and the like.

[0036] The analogs of epinastine or a salt thereof can be measured by methods known to those skilled in the art. The method may be, for example, to evaluate by analyzing the amount of the analogs by high performance liquid chromatography (HPLC) method after storage for a predetermined period under predetermined conditions (any temperature and humidity, open, light-shielded, airtight, etc.). The suppression of the production of the analogs may mean that the amount of one or more of the analogs after storage for a predetermined period is less compared to any control.

[0037] In one aspect, in the composition of the present invention, when stored at 50 °C for 60 days, the production of analogs of epinastine or a salt thereof is suppressed such that one or more of the following (i) and (ii) are satisfied: (i) The amount of 3-Amino-9H-dibenz [c,f] imidazo [1,5-a] azepine hydrochloride, which is an analog of epinastine or a salt thereof, is 90% or less, 85% or less, 80% or less, 75% or less, 70% or less, 65% or less, or 60% or less compared to the case without a preservative or compared to the case containing only benzalkonium chloride as a preservative; (ii) The total amount of the analogs of epinastine or a salt thereof (total analog amount) is 90% or less, 85% or less, 80% or less, 75% or less, 70% or less, 65% or less, or 60% or less compared to the case without a preservative or compared to the case containing only benzalkonium chloride as a preservative.

[0038] In another aspect, in the composition of the present invention containing 0.1% (w / v) (1.0 mg / mL) of epinastine or a salt thereof, when stored at 50 °C for 60 days, the formation of analogs of epinastine or a salt thereof is suppressed so that one or more of the following (iii) and (iv) are satisfied: (iii) The amount of 3-Amino-9H-dibenz [c,f] imidazo [1,5-a] azepine hydrochloride, which is an analog of epinastine or a salt thereof, is 1000 ppm or less, 950 ppm or less, or 900 ppm or less; (iv) The total amount of the analogs of epinastine or a salt thereof (total analog amount) is 3200 ppm or less, 3100 ppm or less, 3000 ppm or less, or 2900 ppm or less.

[0039] (Container) From the viewpoints of storage stability and portability, etc., the composition of the present invention can be contained in a container. The container is a package that directly contains the composition. The container is any one of "sealed container", "airtight container", and "hermetically sealed container" defined in the General Rules of the Japanese Pharmacopoeia (18th Revision).

[0040] Alternatively, the composition may be contained in a container sterilized with a gas such as ethylene oxide gas or hydrogen peroxide. The type of gas used for the gas sterilization treatment is not particularly limited, and examples thereof include ethylene oxide gas, hydrogen peroxide gas, and a mixed gas of these and carbon dioxide, etc. The composition may be contained in a container sterilized with radiation such as gamma-ray irradiation and electron beam irradiation.

[0041] The form of the container may be any form that can contain the composition, and may be appropriately selected according to the dosage form, etc. The form of the container includes, for example, containers for injections, containers for inhalants, containers for sprays, bottle-shaped containers, tube-shaped containers, containers for eye drops, containers for nasal drops, containers for ear drops, and bag containers, etc. Further, the container containing the composition may be further packaged with a box, a bag, etc.

[0042] The material of the container may be a material that can be appropriately selected according to the form of the container. The material of the container includes, for example, glass, plastic, cellulose, pulp, rubber, and metal, etc. From the viewpoints of processability, squeezability, and durability, the material of the container may be plastic.

[0043] The resin used for the plastic container is a thermoplastic resin. The thermoplastic resin includes, for example, polyolefin resins, polyester resins, polyphenylene ether resins, polycarbonate resins, polysulfone resins, polyamide resins, polyvinyl chloride resins, and styrene resins.

[0044] The polyolefin resin is a resin including, for example, low-density polyethylene (including linear low-density polyethylene), high-density polyethylene, medium-density polyethylene, polypropylene, cyclic polyolefin, etc.

[0045] The polyester resin is a resin including, for example, polyethylene terephthalate, polybutylene terephthalate, polyethylene naphthalate, polybutylene naphthalate, poly(1,4-cyclohexylene dimethylene terephthalate), etc.

[0046] In addition, the resin used for the plastic container may be a mixture (polymer alloy) obtained by combining two or more of the above resins.

[0047] In one aspect, the composition of the present invention is contained in a container made of a polyolefin resin from the viewpoint of suppressing discoloration. The "container made of a polyolefin resin" means a container in which at least a portion in contact with the composition is "made of a polyolefin resin". Therefore, for example, a container in which a polyolefin layer is provided on the inner layer in contact with the composition and other resin materials are laminated on the outside also falls under the category of "container made of a polyolefin resin". The polyolefin resin is not particularly limited and may be a polymer (homopolymer) of a single type of monomer or a copolymer (copolymer) of a plurality of types of monomers. Further, in the case of a copolymer, the polymerization mode is not particularly limited and may be random polymerization or block polymerization, and furthermore, its stereoregularity (tacticity) is not particularly limited.

[0048] The polyolefin resin may be polypropylene. The container made of a polyolefin resin may have substances that prevent the transmission of ultraviolet rays, such as an ultraviolet absorber and an ultraviolet scattering agent.

[0049] The ultraviolet absorber may be, for example, 2-(2H-benzotriazol-2-yl)-p-cresol (for example, Tinuvin P: BASF) or 2-(2H-benzotriazol-2-yl)-4,6-bis(1-methyl-1-phenylethyl)phenol (for example, Tinuvin 234: BASF).

[0050] The ultraviolet scattering agent may be, for example, titanium oxide and zinc oxide.

[0051] In one aspect, the composition of the present invention is contained in a multi-dose type container. The multi-dose type container refers to a container that holds a composition for a plurality of usage amounts and can be used repeatedly. For example, the multi-dose type container includes a multi-dose type preservative-free container and a normal multi-dose type container.

[0052] The multi-dose preservative-free container has a mechanism for preventing the composition leached outside the multi-dose container from flowing back into the multi-dose container and a mechanism for preventing foreign matter from entering the multi-dose container. The multi-dose preservative-free container has structures such as a backflow prevention valve, a microfilter, and a special double-structured container.

[0053] A normal multi-dose container is a multi-dose container that does not have the above mechanisms. When a composition is contained in a normal multi-dose container, it is necessary to pass the composition through a filter in the filtration sterilization step during the production of the composition.

[0054] In addition, the composition of the present invention may be contained in a unit-dose container. A unit-dose container refers to a container that holds a single-use amount of the composition and is used up after one eye drop.

[0055] The composition of the present invention is provided to the affected area through a step of passing through a filter. Here, the "filter" refers to a porous membrane that allows the composition to pass through but does not allow bacteria and fungi to pass through. The pore diameter of the filter is usually preferably 5 μm or less, more preferably 0.1 to 2.5 μm, and still more preferably 0.1 to 1 μm. The composition of the present invention may be contained in a container with a filter and poured out of the container through the filter of the container during use. Further, the composition of the present invention may be one that has passed through a filter in the filtration sterilization step during production. The material of the filter is not particularly limited, and examples thereof include polyethersulfone, polyvinylidene fluoride, polycarbonate, polytetrafluoroethylene, cellulose mixed ester, nylon, polyamide, and the like.

Examples

[0056] The present invention will be specifically described below with reference to examples, but the present invention is not construed as being limited thereto.

[0057] Three samples of each composition were prepared to have the compositions shown in Table 1 or 2. Specifically, components (1) to (6) shown in Table 1 or 2 were dissolved in purified water, and sodium hydroxide or hydrochloric acid was added as necessary to adjust the pH to 7.0. The total volume was made 100 mL, and each composition was prepared by filtering through a filter.

[0058]

Table 1

[0059]

Table 2

[0060] The amount of related substances of epinastine hydrochloride was measured by high performance liquid chromatography (HPLC). (HPLC conditions for measuring decomposition products of epinastine hydrochloride) Detector: Ultraviolet absorptiometer Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 25 cm is filled with 5 μm octadecylsilylated silica gel for liquid chromatography.

[0061] The results of measuring related substances at the time of storage at 50 °C for 60 days are shown in Figs. 1 to 3. Degradation product A (not shown) is a related substance with a relative retention time (RRT) of 0.51 to 0.52 with respect to epinastine hydrochloride, degradation product B is a related substance with an RRT of 1.16 to 1.17, degradation product C is a related substance with an RRT of 0.49 to 0.50, degradation product D (not shown) is a related substance with an RRT of 1.78 to 1.80, and the total related substances are the total amount of related substances including degradation products other than degradation products A to D (however, values below the quantification limit are not included). In addition, in order to confirm that they are related substances derived from epinastine hydrochloride, components (2) to (6) shown in Table 1 or 2 were dissolved in purified water, and sodium hydroxide or hydrochloric acid was added as necessary to adjust the pH to 7.0. The total volume was made 100 mL, and each composition was prepared by filtering through a filter. The values detected in each measurement result were excluded.

[0062] In the case of degradation products A and D, when no preservative was included, or when BAC or PHMB was included alone (Comparative Examples 1 to 3), compared with the case where preservatives were combined (Examples 1 to 10), all the compositions (BAC + PHMB) were below the quantification limit. In the case of degradation product B, degradation product C, and total related substances, when no preservative was included, or when BAC or PHMB was included alone (Comparative Examples 1 to 3), compared with the case where preservatives were combined (Examples 1 to 10), it was confirmed that the generation of related substances was suppressed in all the compositions (BAC + PHMB) (Figure 1 (degradation product B), Figure 2 (degradation product C), and Figure 3 (total related substances)). Moreover, surprisingly, compared with the case where BAC or PHMB was included alone (Comparative Examples 2 and 3), in all the compositions (BAC + PHMB) in the case where preservatives were combined (Examples 1 to 10), the variation in the amount of generated related substances was small, and the effect of suppressing the generation of related substances was stable. Note that no related substances were observed immediately after preparation.

Claims

1. A composition comprising epinastine or a salt thereof in an amount of 0.075% (w / v) or more based on the total composition, the composition comprising benzalkonium chloride and a preservative other than benzalkonium chloride.

2. The composition according to claim 1, wherein the preservative other than benzalkonium chloride is at least one selected from quaternary ammonium salts other than benzalkonium chloride, paraoxybenzoic acid esters, biguanide compounds, chlorobutanol, sorbic acid or a salt thereof, dehydroacetic acid or a salt thereof, benzyl alcohol, parachlorometaxylenol, chlorocresol, phenethyl alcohol, thimerosal, and chlorites.

3. The composition according to claim 2, wherein the preservative other than benzalkonium chloride is a biguanide compound.

4. The composition according to claim 3, wherein the biguanide compound is selected from polyhexanide and a salt thereof.

5. The composition according to any one of claims 1 to 4, comprising phosphoric acid, or a salt thereof, or a solvate thereof.

6. The composition according to any one of claims 1 to 4, comprising sodium chloride.

7. The composition according to any one of claims 1 to 4, comprising water.

8. The composition according to any one of claims 1 to 4, for ophthalmic use.

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