JP5998918B2 - Ophthalmic composition - Google Patents

Description

  The present invention relates to an ophthalmic composition in which irritation of an ethylenediamineacetic acid derivative or a salt thereof is alleviated.

  The ethylenediamineacetic acid derivative or a salt thereof is blended in the ophthalmic composition as a chelating agent. By mix | blending this component, antiseptic power, especially the antiseptic power to fungi improves. And it was calculated | required that this component should be used effectively.

JP 2004-2364 A

  As described above, (A) the ethylenediamineacetic acid derivative or a salt thereof is blended in an ophthalmic composition as a stabilizer or a chelating agent. Although the antiseptic power, particularly the antiseptic power to fungi, is improved by blending the component (A), when the component (A) is blended more than a certain amount (0.075 W / V% or more), a sensitive panel that feels eye irritation I found out that there was a lot. For this reason, it aims at providing the technique which suppresses the eye irritation | stimulation of the ophthalmic composition which contains a certain amount of (A) ethylenediamine acetic acid derivative or its salt.

  As a result of intensive studies to achieve the above object, the present inventor has (B) calcium salt and (C) trometamol added to an ophthalmic composition containing (A) an ethylenediamineacetic acid derivative or a salt thereof. (A) It has been found that eye irritation when an ethylenediamineacetic acid derivative or a salt thereof is blended at a high concentration in a certain amount is suppressed and reduced.

Accordingly, the present invention provides the following inventions.
[1]. Eye drop, eye wash, contact lens mounting liquid containing (A) ethylenediamineacetic acid derivative or salt thereof 0.075 W / V% or more, (B) calcium salt, and (C) trometamol 0.001-5 W / V% And an ophthalmic composition selected from contact lens removal solutions .
[2]. The ophthalmic composition according to [1], wherein the component (A) is ethylenediaminetetraacetic acid or a salt thereof.
[3]. The ophthalmic composition according to [1] or [2], wherein the content of the component (B) is 0.05 to 10 mmol / L.
[4]. (B) The ophthalmic composition according to any one of [1] to [3], wherein the component is calcium chloride.
[5]. The ophthalmic use according to any one of [1] to [4], wherein the mass ratio of the component (B) and the component (C) represented by (C) / (B) is 0.01 to 700. Composition.
[6]. The ophthalmic composition according to any one of [1] to [5], which has a pH of 3.8 to 8.0.
[7]. (A) ethylenediamineacetic acid derivative or salt thereof 0.075 W / V% or more, (B) calcium salt 0.05 to 10 mmol / L, and (C) trometamol 0.001 to 5 W / V%, (C) / ( Selected from eye drops, eyewashes, contact lens mounting liquids and contact lens removal liquids, which are blended in a range where the mass ratio of the component (B) and the component (C) represented by B) is 0.01 to 700. A method for producing an ophthalmic composition.

  According to the present invention, eye irritation of an ophthalmic composition containing a certain amount or more of an ethylenediamineacetic acid derivative or a salt thereof can be alleviated.

Hereinafter, the present invention will be described in detail.
The ophthalmic composition of the present invention contains (A) an ethylenediamineacetic acid derivative or a salt thereof of 0.075 W / V% or more, (B) a calcium salt, and (C) trometamol.

(A) Ethylenediamineacetic acid derivative or salt thereof Examples of the ethylenediamineacetic acid derivative or salt thereof include edetic acid (ethylenediaminetetraacetic acid, EDTA), ethylenediaminediacetic acid (EDDA), diethylenetriaminepentaacetic acid (DTPA), and N- (2-hydroxy). Ethyl) ethylenediamine triacetic acid (HEDTA) and the like, and may be used as a pharmacologically or physiologically acceptable salt (for example, sodium ethylenediaminetetraacetate). These can be used individually by 1 type or in combination of 2 or more types. Among these, ethylenediaminetetraacetic acid or a salt thereof is preferable, and specific examples include disodium ethylenediaminetetraacetic acid, disodium ethylenediaminetetraacetic acid dihydrate (hereinafter also referred to as sodium edetate), and the like.

  The content of the component (A) is 0.075 W / V% (mass / volume%, g / 100 mL) or more with respect to the total amount of the ophthalmic composition. By setting it to 0.075 W / V% or more, the antiseptic effect is enhanced, but the problem of eye irritation occurs. The upper limit of the content is preferably 0.3 W / V% or less, more preferably 0.2 W / V% or less, and even more preferably 0.1 W / V% or less.

(B) Calcium salt The calcium salt in the present invention is preferably a water-soluble calcium salt, and examples thereof include inorganic salts such as calcium chloride and calcium carbonate, organic salts such as calcium pantothenate, and the like. Or 2 or more types can be used in appropriate combination. Among these, calcium chloride is preferable from the viewpoint of solubility.

  The content of the component (B) can be appropriately set according to other components, but can be 0.05 mmol / L or more with respect to the total amount of the ophthalmic composition, and 0.1 to 10 mmol / L. Is preferably 0.3 to 5 mmol / L, more preferably 0.5 to 3 mmol / L, and particularly preferably 0.8 to 2 mmol / L. If the content is less than 0.05 mmol / L, the effect of reducing the eye irritation of the component (A) may be insufficient, and if it exceeds 10 mmol / L, the eye irritation of the component (B) may be felt. .

(C) Trometamol (Trishydroxymethylaminomethane)
The content of the component (C) is preferably from 0.001 to 5 W / V%, more preferably from 0.01 to 3 W / V%, more preferably from 0.05 to 5% with respect to the total amount of the ophthalmic composition from the viewpoint of reducing irritation. 1 W / V% is more preferable, and 0.1 to 0.5 W / V% is particularly preferable. If it is less than 0.001 W / V%, the eye irritation suppressing effect is not sufficient. In addition, when (C) trometamol is compounded in a large amount, the buffering force becomes strong, and there is a possibility that irritation can be felt more easily.

  The content mass ratio of the component (B) and the component (C) represented by (C) / (B) is preferably 0.01 to 700, more preferably 0.1 to 500, and further preferably 1 to 300. 5-150 is preferred. By setting it as this range, the reduction effect with respect to eye irritation improves more.

  In the ophthalmic composition of the present invention, in addition to the above components, any of buffers, thickeners, solubilizers, tonicity agents, pH adjusters, stabilizers, preservatives, cooling agents, drugs, etc. A component can be used individually by 1 type or in combination of 2 or more types as appropriate.

  Examples of the buffer include boric acid or a salt thereof (such as borax), citric acid or a salt thereof (such as sodium citrate), tartaric acid or a salt thereof (such as sodium tartrate), gluconic acid or a salt thereof (such as sodium gluconate) ), Acetic acid or salts thereof (sodium acetate, etc.), various amino acids, etc. (epsilon-aminocaproic acid, potassium aspartate, aminoethylsulfonic acid, glutamic acid, sodium glutamate, etc.). Especially, antiseptic effect improves by mix | blending boric acid and borax, and also when boric acid and borax are used together, especially antiseptic effect is acquired. The content of the buffer when blended is preferably 0.01 to 10 W / V%, more preferably 0.05 to 5 W / V%, based on the total amount of the ophthalmic composition.

  Examples of the thickener include polyvinyl pyrrolidone, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyvinyl alcohol, sodium hyaluronate, sodium chondroitin sulfate, sodium hyaluronate, polyacrylic acid, carboxyvinyl polymer, and the like. 0.001-10 W / V% is preferable with respect to the ophthalmic composition whole quantity, and, when mix | blending a thickener, 0.01-5 W / V% is more preferable.

  Examples of the solubilizer include polyoxyethylene hydrogenated castor oil such as polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester such as polyoxyethylene (20) sorbitan monooleate (polysorbate 80), polyoxyethylene poly Examples thereof include oxypropylene copolymers.

  Examples of the isotonic agent include sodium chloride and potassium chloride. The content when the isotonic agent is blended is preferably 0.001 to 5 W / V%, more preferably 0.01 to 3 W / V%, more preferably 0.1 to 2 W / V based on the total amount of the ophthalmic composition. V% is more preferable.

  As the pH adjuster, it is preferable to use an inorganic acid or an inorganic alkali agent. For example, (diluted) hydrochloric acid is mentioned as an inorganic acid. Examples of the inorganic alkaline agent include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like. Among these, hydrochloric acid, sodium hydroxide, and potassium hydroxide are preferable. The content in the case of blending the pH adjuster is appropriately selected depending on the target pH, but is usually 0.00001 to 10 W / V%, preferably 0.0001 to the total amount of the ophthalmic composition. 5 W / V%, more preferably 0.001 to 3 W / V%.

  Examples of the stabilizer include cyclodextrin, sulfite, dibutylhydroxytoluene and the like. The content when the stabilizer is blended is preferably 0.001 to 5 W / V%, more preferably 0.01 to 3 W / V% with respect to the total amount of the ophthalmic composition.

  Examples of the preservative include cationic surfactants such as benzalkonium chloride and benzethonium chloride, and hydrophobic preservatives such as paraben (methylparaben, ethylparaben, propylparaben, etc.) and chlorobutanol. These contents are preferably 0.001 W / V% or less from the viewpoint of eye irritation, and more preferably no blending.

  Examples of the refreshing agent include menthol, camphor, borneol, geraniol, linalool, cineol, and eucalyptus oil. The content of the refreshing agent with respect to the total amount of the ophthalmic composition is preferably 0.0001 to 5 W / V%, more preferably 0.001 to 2 W / V% as the total amount of the compound from the viewpoint of eye irritation. 005 to 1 W / V% is more preferable, and 0.007 to 0.8 W / V% is particularly preferable. When used by a person with sensitive eyes, camphor, borneol, eucalyptus oil, etc., in which the refreshing feeling of the drug itself is not strong, are suitable. In particular, when a person with sensitive eyes uses, the upper limit of the refreshing agent is preferably 0.1 W / V% or less. In addition, since the eye irritation resulting from the component (A) is masked by the refreshing agent, it is particularly easy to feel irritation in the composition not containing the refreshing agent, and the effects of the present invention are easily exhibited.

Examples of drugs (pharmaceutical active ingredients) include decongestants (for example, naphazoline hydrochloride, tetrahydrozoline hydrochloride, phenylephrine hydrochloride, epinephrine, ephedrine hydrochloride, dl-methylephedrine hydrochloride, tetrahydrozoline nitrate, naphazoline nitrate), anti-inflammatory / astringent agents (For example, neostigmine methyl sulfate, ε-aminocaproic acid, allantoin, berberine chloride, zinc sulfate, zinc lactate, lysozyme chloride, dipotassium glycyrrhizinate, ammonium glycyrrhizinate, glycyrrhetinic acid, methyl salicylate, tranexamic acid, sodium azulene sulfonate, etc.) , Antihistamines (eg, iproheptin hydrochloride, diphenhydramine hydrochloride, diphenhydramine, isothipentyl hydrochloride, chlorpheniramine maleate, etc.), antiallergic agents For example, sodium cromoglycate, etc.), vitamin E such as oily vitamin (acetic d-alpha-tocopherol, vitamin A such as retinol palmitate, etc.), water-soluble vitamins (activated vitamin B _2, vitamin B _6, vitamin B _12, etc.), amino acids (e.g., L- potassium aspartate, L- magnesium aspartate, aminoethylsulfonic acid, sodium chondroitin sulfate, glutathione, etc.), sulfa drugs, fungicides (e.g., sulfur, isopropyl methyl phenol, hinokitiol, etc.) Local anesthetics (eg, lidocaine, lidocaine hydrochloride, procaine hydrochloride, dibucaine hydrochloride, etc.) and mydriatics (eg, tropicamide, etc.) can be appropriately blended. Oily components (for example, vitamin E, which is an oily vitamin, vitamin A, etc., sesame oil, castor oil) are preferably added in order to further reduce irritation.

  Water such as sterilized purified water may be blended with the remainder to make 100 W / V%, but the content is usually about 0.0001 to 30 W / V% with respect to the total amount of the ophthalmic composition.

  The pH of the ophthalmic composition of the present invention is preferably 3.8 to 8.0, more preferably 5.0 to 7.5. If the pH is too low, eye irritation may be felt. In the present invention, the pH is measured at 20 ° C. using a pH osmometer (for example, HOSM-1, manufactured by Toa DKK Co., Ltd.).

  The viscosity of the ophthalmic composition of the present invention is preferably 1 to 50 mPa · s, more preferably 1 to 30 mPa · s, further preferably 1 to 20 mPa · s, and further preferably 1 to 5 mPa · s. The viscosity is measured at 20 ° C. using an E-type viscometer (VISCONIC ELD-R, Tokyo Keiki Co., Ltd.).

  The ophthalmic composition of the present invention includes eye drops (for example, general eye drops, eye drops for contact lenses, etc.), eye wash (general eye wash, eye wash used after removing contact lenses, etc.), contact A lens mounting liquid, a contact lens removing liquid, and the like can be given.

  The contact lens is not particularly limited, and examples thereof include a hard contact lens, an oxygen permeable hard contact lens, a soft contact lens, a disposable contact lens, and a silicon hydrogel contact lens.

  The ophthalmic composition of the present invention can be obtained by a known method, for example, by blending each component with purified water in an adjustment kettle, filling the container after aseptic filtration.

  EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example.

[Examples 1 to 13, Reference Example 1, Comparative Examples 1 to 3]
Ophthalmic compositions (eye drops) having the compositions shown in Tables 1 to 3 were prepared and evaluated as follows. The results are also shown in the table.

[Eye irritation test]
Five sensitive panelists who feel irritation were selected by instilling a solution containing 0.075 W / V% of ethylenediaminetetraacetic acid disodium in physiological saline. In the five panelists, one drop of the ophthalmic composition was instilled into both eyes 6 times a day (every 1.5-2 hours), and the irritation feeling was evaluated.
(Judgment criteria for stimulus evaluation)
1: Unsatisfactory to resist 2: Feels a lot of stimulation 3: Feels a stimulus 4: Feels a slight stimulus 5: Does not feel a stimulus The average value of five people in the above five-level evaluation shows the result of eye irritation 4 or more was indicated by “◎”, 3 or more and less than 4 were indicated by “◯”, 2 or more and less than 3 were indicated by “Δ”, and those less than 2 were indicated by “x”.

  In addition, as a result of conducting the antiseptic efficacy test according to the preservation efficacy test of the 16th revised Japanese Pharmacopoeia / Reference Information, the judgment criteria were cleared and good results were obtained.

Claims (7)

Eye drop, eye wash, contact lens mounting liquid containing (A) ethylenediamineacetic acid derivative or salt thereof 0.075 W / V% or more, (B) calcium salt, and (C) trometamol 0.001-5 W / V% And an ophthalmic composition selected from contact lens removal solutions .   The ophthalmic composition according to claim 1, wherein the component (A) is ethylenediaminetetraacetic acid or a salt thereof.   The ophthalmic composition according to claim 1 or 2, wherein the content of the component (B) is 0.05 to 10 mmol / L.   (B) A component is calcium chloride, The ophthalmic composition of any one of Claims 1-3.   The ophthalmic composition according to any one of claims 1 to 4, wherein the mass ratio of the component (B) and the component (C) represented by (C) / (B) is 0.01 to 700. . The ophthalmic composition according to any one of claims 1 to 5, which has a pH of 3.8 to 8.0. (A) ethylenediamineacetic acid derivative or salt thereof 0.075 W / V% or more, (B) calcium salt 0.05 to 10 mmol / L, and (C) trometamol 0.001 to 5 W / V%, (C) / ( Selected from eye drops, eyewashes, contact lens mounting liquids and contact lens removal liquids, which are blended in a range where the mass ratio of the component (B) and the component (C) represented by B) is 0.01 to 700. A method for producing an ophthalmic composition.