JP2013181020A - Ophthalmic composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an ophthalmic composition useful for prevention and amelioration of dry eye symptoms without using any thickening polymer humectant such as hyaluronic acid which may give unsatisfactory usability such as sense of discomfort and unpleasantness when the composition is applied to eyes.SOLUTION: An ophthalmic composition includes: (A) vitamin A; (B) an anti-inflammatory component; (C) cornea protection component; (D) one or more buffers selected from boric acid, borax, and trometamol; and (E) an anti-oxidant. The ophthalmic composition has pH of 5.0-7.5.

Description

  The present invention relates to an ophthalmic composition excellent in the effect of preventing and improving dry eye symptoms.

An increasing number of dry eye patients complain of symptoms such as dry eyes and tired eyes caused by air conditioning indoors, personal computer work, and video games. In addition, with the spread of contact lenses with good wearability, it is possible to wear contacts for a long time, and there are many cases that complain of dryness of the eyes.
Symptoms of dry eye include eye itchiness, itching of the eyes, conjunctival redness, foreign body sensation and discomfort, as well as the main symptoms of dry eyes and tired eyes. There are also many things.
As a method for treating such dry eye, there are methods using artificial tears containing only inorganic components and eye drops containing components having a moisturizing effect such as hyaluronic acid, but none of them is satisfactory. There wasn't. In addition, eye drops containing a thickening polymer such as hyaluronic acid may be unsatisfactory in terms of usability, such as feeling uncomfortable or uncomfortable during eye drops. Therefore, an ophthalmic composition that is excellent in prevention and improvement of dry eye symptoms and has good usability has been desired.

JP-A-60-84225

  The present invention has been made in view of the above circumstances, and an object thereof is to provide an ophthalmic composition useful for prevention and improvement of dry eye symptoms.

As a result of intensive studies to solve the above problems, the present inventors have found that one or more buffering agents selected from vitamin A, anti-inflammatory components, corneal protective components, boric acid, borax, and trometamol. Eye drops containing an anti-oxidant and an ophthalmic composition having a pH of 5.0 to 7.5 are dry eye symptoms without using a thickening polymer moisturizer such as hyaluronic acid. As a result, it was found that an excellent effect was obtained, and the present invention was completed.
Accordingly, the present invention provides the following ophthalmic composition for improving dry eye symptoms.
[1] (A) Vitamin A
(B) an anti-inflammatory component,
(C) corneal protective component,
(D) one or more buffering agents selected from boric acid, borax, and trometamol;
(E) An ophthalmic composition containing an antioxidant and having a pH of 5.0 to 7.5.
[2] The ophthalmic composition according to [1], further comprising (F) an amino acid and / or a salt thereof.
[3] (G) The ophthalmic composition according to [1] [2], further comprising a surfactant.

  According to the present invention, an ophthalmic composition useful for prevention or improvement of dry eye symptoms can be provided.

The present invention is described in detail below.
(A) Vitamin A
Examples of vitamin A used in the present invention include vitamin A derivatives such as vitamin A fatty acid esters in addition to vitamin A itself. Specifically, compounds such as retinol, retinol palmitate, retinol acetate, retinal, retinoid, retinoic acid, and vitamin A-containing mixtures such as vitamin A oil can be used. Of these, retinol palmitate is particularly preferred. Retinol palmitate is usually commercially available in an amount of 1 to 1.8 million international units per gram. Specifically, “Retinol palmitate ester” (1.74 million international units / g) manufactured by DSM Nutrition Japan Co., Ltd., etc. Is mentioned.

  Vitamin A of the present invention is preferably blended in the ophthalmic composition in an amount of 0.001 to 0.3 w / v%, more preferably in the range of 0.005 to 0.1 w / v%. If the blending amount is too small, the effect of blending may not be sufficiently obtained, and if it is too large, the feeling of use may be impaired.

(B) Anti-inflammatory component The anti-inflammatory component of the present invention includes epsilon-aminocaproic acid, glycyrrhizic acid and / or a salt thereof, allantoin, berberine and / or a salt thereof, zinc sulfate, zinc lactate, azulene sulfonic acid and / or a salt thereof. Salt, lysozyme chloride, pranoprofen and the like.

The content of epsilon-aminocaproic acid is preferably 0.5 to 5 g / 100 mL, and more preferably 1 to 2 g / 100 mL in the composition of the present invention. As epsilon-aminocaproic acid, ε-amino-n-caproic acid manufactured by Sekisui Medical Co., Ltd. can be obtained as a commercial product.
Examples of glycyrrhizic acid and / or a salt thereof include glycyrrhizic acid, dipotassium glycyrrhizinate, and ammonium glycyrrhizinate. The content of glycyrrhizic acid and / or a salt thereof is preferably 0.01 to 1.0 g / 100 mL, more preferably 0.05 to 0.5 g / 100 mL in the composition of the present invention. .
The allantoin content in the composition of the present invention is preferably 0.01 to 0.5 g / 100 mL, more preferably 0.05 to 0.3 g / 100 mL.
Examples of berberine and / or a salt thereof include berberine, berberine chloride, and berberine sulfate. The content of berberine is preferably 0.001 to 0.05 g / 100 mL, more preferably 0.005 to 0.025 g / 100 mL in the composition of the present invention.

  The content of zinc sulfate and zinc lactate is preferably 0.01 to 0.5 g / 100 mL, more preferably 0.05 to 0.25 g / 100 mL in the composition of the present invention.

Examples of azulene sulfonic acid and / or a salt thereof include sodium azulene sulfonate. The content of azulenesulfonic acid and / or a salt thereof is preferably 0.001 to 0.05 g / 100 mL, more preferably 0.004 to 0.02 g / 100 mL in the composition of the present invention. is there.
The content of lysozyme chloride is preferably 0.05 to 1.0 g / 100 mL, more preferably 0.1 to 0.5 g / 100 mL in the composition of the present invention.

(C) Corneal protective component As a cornea protective component of this invention, chondroitin sulfate and / or its salt are used preferably, and chondroitin sulfate sodium is especially preferable. The content of chondroitin sulfate and / or salt thereof is preferably 0.01 to 1.0 g / 100 mL, more preferably 0.05 to 0.5 g / 100 mL in the composition of the present invention. is there.

(D) One or more buffering agents selected from boric acid, borax, and trometamol The ophthalmic composition of the present invention includes one or more buffering agents selected from boric acid, borax, and trometamol. Is used. These may be used alone, but a buffer system using boric acid and trometamol together is more preferable because the antiseptic power of the composition is improved.

  The content of boric acid and borax is preferably 0.01 to 2.5 g / 100 mL, more preferably 0.1 to 2 g / 100 mL in the composition of the present invention. The boric acid and borax to be used are not particularly limited as long as they can be blended in the ophthalmic composition. Specifically, for example, Japanese Pharmacopoeia manufactured by Kominato Pharmaceutical Co., Ltd., Japanese Pharmacopoeia manufactured by Kominato Pharmaceutical Co., Ltd. Examples include borax.

  The content of trometamol is preferably 0.05 to 5 g / 100 mL in the composition of the present invention, and more preferably 0.1 to 3 g / 100 mL. As trometamol, commercially available products such as 2-amino-2-hydroxymethyl-1, 3-propanediol manufactured by Kanto Chemical Co., Ltd. are available.

(E) Antioxidant Antioxidants used in the present invention include tocopherol and / or derivatives thereof (tocopherol, tocopherol derivatives: tocopherol esters such as tocopherol acetate and tocopherol succinate), fats such as butylhydroxytoluene and butylhydroxyanisole. There are water soluble antioxidants such as soluble antioxidants, vitamin C, hydroquinone, cysteine, glutathione. Preferably, a fat-soluble antioxidant is used. Specifically, for example, Tocopherol can be obtained from RIKEN E-Acetate α manufactured by Riken Vitamin Co., Ltd., and butylhydroxytoluene can be obtained from BWTF manufactured by Wako Pure Chemical Industries, Ltd.

The content of vitamin E in the composition of the present invention is preferably 0.001 to 0.5 g / 100 mL, and more preferably 0.01 to 0.1 g / 100 mL.
The content of butylhydroxytoluene and butylhydroxyanisole is preferably 0.0001 to 0.05 g / 100 mL, more preferably 0.001 to 0.01 g / 100 mL in the composition of the present invention. . Within this range, the stability of vitamin A is particularly good.

(F) Amino acid and / or salt thereof As the amino acid and / or salt thereof used in the present invention, aspartic acid, aminoethylsulfonic acid and the like can be mentioned. As the amino acid salt, use of a sodium salt, potassium salt or ammonium salt of an amino acid is preferable in terms of stability. For example, amino acids and / or salts thereof are commercially available, such as aspartate is Kyowa Hakko Kogyo Co., Ltd. L-aspartate potassium, and aminoethyl sulfonic acid is Amino Yaku Kogyo Co., Ltd. Is possible.
The content of the amino acid and / or salt thereof is preferably 0.05 to 2 g / 100 mL, more preferably 0.1 to 1.5 g / 100 mL in the composition of the present invention.

(G) Surfactant A surfactant is preferably added to the ophthalmic composition of the present invention for the purpose of improving the stability of the composition. As the surfactant, a nonionic surfactant is preferably used. Preferred nonionic surfactants are polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan monooleate, polyoxyethylene polyoxypropylene glycol.
Specifically, for example, polyoxyethylene hydrogenated castor oil is Nikko Chemicals HCO-40, HCO-50, HCO-60, etc., and polyoxyethylene sorbitan monooleate is Nikko Chemicals TO-10, TO. As for -10MV, polyoxyethylene polyoxypropylene glycol includes Lutrol F127 manufactured by BASF.

  The surfactant content in the composition of the present invention is preferably 0.01 to 5 g / 100 mL, more preferably 0.02 to 3 g / 100 mL, and still more preferably 0.05 to 3 g / 100 mL. It is a range.

  Specifically, polyoxyethylene hydrogenated castor oil and polyoxyethylene sorbitan monooleate are suitable in terms of stability when blended in the ophthalmic composition of the present invention in an amount of 0.01 to 1 g / 100 mL. From the viewpoint of stability, the lower limit is more preferably 0.02 g / 100 mL or more, and particularly preferably 0.05 g / 100 mL or more. In consideration of eye safety such as eye irritation and stability of vitamin A, the upper limit is preferably 0.2 g / 100 mL or less.

  The polyoxyethylene polyoxypropylene glycol is preferably 0.4 to 5 g / 100 mL, more preferably 0.5 to 3 g / 100 mL in the ophthalmic composition of the present invention.

  In the present invention, the surfactant can be used singly or in combination of two or more, but it is particularly preferable to use two or more in view of stability of vitamin A and appearance stability of the preparation. .

  In the ophthalmic composition of the present invention, in addition to the above components, various components to be blended in the ophthalmic composition can be blended within a range that does not impair the effects of the present invention. Examples of these components include various drugs, stabilizers, cooling agents, retention improvers, dyes, tonicity agents, solubilizers, pH adjusters, preservatives, and the like.

Examples of drugs include
・ Decongestants (such as naphazoline hydrochloride, tetrahydrozoline hydrochloride, phenylephrine hydrochloride, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, dl-methylephedrine hydrochloride, tetrahydrozoline nitrate, naphazoline nitrate)
-Focus regulator (neostigmine methyl sulfate),
・ Antihistamines (such as iproheptin hydrochloride, diphenhydramine hydrochloride, diphenhydramine, isothipentyl hydrochloride, chlorpheniramine maleate)
・ Water-soluble vitamins (flavin adenine dinucleotide sodium, pyridoxine hydrochloride, cyanocobalamin, etc.),
・ Sulfa drugs (sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, sulfisomidine sodium, etc.)
・ Bactericides (sulfur, isopropylmethylphenol, hinokitiol, etc.),
・ Local anesthetics (such as lidocaine, lidocaine hydrochloride, procaine hydrochloride, dibucaine hydrochloride)
・ Antiallergic drugs (sodium cromoglycate, ketotifen fumarate, etc.)
Etc. These can be used individually by 1 type or in combination of 2 or more types.

The content of the drug in the ophthalmic composition of the present invention is set within a range that does not impair the effects of the present invention, in addition to the effective amount of each drug. The content of these drugs is usually blended in the range of 0.001 to 10 g / 100 mL with respect to the total amount of the composition, preferably 0.003 to 5 g / 100 mL, more preferably 0.005 to 4 g / 100 mL. It is.
Examples of the stabilizer include sodium edetate and cyclodextrin. The content of the stabilizer is preferably 0.001 to 5 g / 100 mL in the composition of the present invention, more preferably 0.001 to 2 g / 100 mL, and still more preferably 0.005 to 1 g / 100 mL. It is a range.

  Examples of the refreshing agent include menthol, camphor, borneol, geraniol, cineol, linalool, eucalyptus oil, bergamot oil, fennel oil, rose oil, ethanol and the like. The content of the refreshing agent is preferably 0.0001 to 1 g / 100 mL in the composition of the present invention, more preferably 0.001 to 0.1 g / 100 mL, and still more preferably 0.001 to 0.00. The range is 01 g / 100 mL.

  As the retention improver, a water-soluble polymer can be preferably used. Examples thereof include polyvinyl pyrrolidone, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyvinyl alcohol, sodium hyaluronate, sodium chondroitin sulfate, and carboxyvinyl polymer. These contents are preferably 0.001 to 20 g / 100 mL, and more preferably 0.01 to 10 g / 100 mL in the composition of the present invention.

  Examples of the isotonic agent include sodium chloride, potassium chloride, glucose, mannitol and the like.

  Examples of the solubilizer include polyhydric alcohols such as glycerin, propylene glycol, polyethylene glycol and butylene glycol, and preferably glycerin and propylene glycol are used. The preferable content of the polyhydric alcohol is 0.01 to 5 g / 100 mL in the composition.

  Preferred examples of the pH adjuster include hydrochloric acid and citric acid as the acid component, and sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate, sodium citrate and the like as the base component. Among these, it is preferable to use an inorganic acid or an inorganic alkali agent, and hydrochloric acid and sodium hydroxide are particularly preferably used.

  The preservative is more preferably not blended in the present invention, but can be blended within a range not impairing the effects of the present invention. In the case of blending, for example, benzalkonium chloride, benzethonium chloride, sorbic acid or a salt thereof, paraoxybenzoic acid ester, chlorhexidine gluconate, phenylethyl alcohol, alkyldiaminoethylglycine hydrochloride and the like can be mentioned.

The ophthalmic composition of the present invention is preferably adjusted to the following pH, osmotic pressure, and viscosity using the above components.
-PH: 5.0-7.5,
・ Osmotic pressure: 0.1 to 5 pressure ratio ・ Viscosity (20 ° C.): 1 to 200 mPa · s

  The ophthalmic composition of the present invention can be produced by a known method, that is, an oil phase component is added to a water phase and solubilized. A preferred method for producing the ophthalmic composition of the present invention is, for example, mixing a fat-soluble antioxidant such as vitamin A and tocopherol with a surfactant such as polyoxyethylene hydrogenated castor oil 60 and then adding it to water. Solubilize. Then dissolve boric acid and / or trometamol, stabilizers such as sodium EDTA, anti-inflammatory agents, corneal protective agents, amino acids such as potassium aspartate and aminoethylsulfonic acid, and if necessary, various drugs, After adding an agent, a retention improver, a dye, an isotonic agent, and the like, the pH is adjusted to 5.0 to 7.5 with dilute hydrochloric acid or an aqueous sodium hydroxide solution to obtain the ophthalmic composition of the present invention. be able to.

  Hereinafter, although an Example and a comparative example are given to Table 1 and Table 3-Table 5, this invention is demonstrated further in detail, This invention is not limited at all by the following Example.

[Examples 1, 2, 3 and Comparative Example 1]
An eye drop was prepared according to a conventional method according to the composition shown in Table 1, and filled in an eye drop container made of polyethylene terephthalate. For five dry eye subjects with symptoms such as dryness and discomfort to the eyes, instilled 2 to 3 drops of the prescription shown in Table 1 once and 6 times a day. The degree of improvement between feeling and discomfort was examined and evaluated according to the following evaluation criteria. The results are shown in Table 2.

<Evaluation criteria>
5 points: Improved dryness / discomfort 4 points: Slightly improved dryness / discomfort 3 points: No change in dryness / discomfort 2 points: A little worse dryness / discomfort 1 point: Dryness / discomfort Became worse

Claims (3)

(A) Vitamin A
(B) an anti-inflammatory component,
(C) corneal protective component,
(D) one or more buffering agents selected from boric acid, borax, and trometamol;
(E) An ophthalmic composition containing an antioxidant and having a pH of 5.0 to 7.5. The ophthalmic composition according to claim 1, further comprising (F) an amino acid and / or a salt thereof. (G) The ophthalmic composition according to claim 1 or 2, further comprising a surfactant.