JP5681472B2 - Ophthalmic composition - Google Patents

Description

  The present invention relates to an ophthalmic composition, and more particularly to an ophthalmic composition effective for alleviating dry eye symptoms.

The lacrimal fluid covering the surface of the eyeball has a three-layer structure of a mucus layer made of mucin, an aqueous layer, and an oil layer from the eyeball side. In addition, it is known that an amphiphilic lecithin layer exists between the water layer and the oil layer, and the tear fluid is stabilized by bridging the water layer and the oil layer (non-patent document). 1).
Since lecithin is a tear component, ophthalmic compositions containing lecithin have been proposed in recent years. For example, Patent Document 1 describes an aqueous eye drop for preventing or treating dry eye containing castor oil and lecithin. Patent Document 2 describes that an O / W emulsion aqueous eye drop containing an oil, a mucopolysaccharide, and lecithin is effective for improving dry evaporation eye.
However, in cases where lipid secretion from the meibomian gland has decreased, such as obstructive meibomian gland dysfunction, dry eye symptoms and keratoconjunctival epithelial disorder have been observed due to the formation of a tear oil layer. This dry eye therapeutic agent is difficult to treat (Non-patent Document 2).

WO2006 / 009112 JP 2007-211007 A

"Japanese ophthalmology" 74, No.6, 2003, 569-572 Monthly Ophthalmology Practice, Vol.1, No.9, December 25, 1998, pages 102-103

  The main object of the present invention is to provide an ophthalmic composition that promotes the production of oil from the meibomian glands.

The present inventors have repeated researches to solve the above problems, and have obtained the following knowledge.
(i) A composition comprising lecithin and vitamin B2 promotes the production of oil from the meibomian glands. Moreover, by including lecithin and vitamin B2s, the action of promoting oil production from the meibomian glands is synergistically stronger than when each component is included alone.
(ii) When a composition containing lecithin and vitamin B2 is instilled in a person who has symptoms in the eyes, the amount in the eyes is suppressed. In addition, by using lecithin and vitamin B2 in combination, the inhibitory action is synergistically stronger than when each component is used alone.
(iii) When a composition containing lecithin and vitamin B2 is instilled into a human who exhibits symptoms of dry eyes, dry eyes are suppressed. Moreover, the combined use of lecithin and vitamin B2 synergistically enhances the effect of suppressing eye dryness compared to the case where each component is used alone.
The present invention has been completed based on the above findings, and provides the following ophthalmic composition.

Item 1. An ophthalmic composition containing lecithin and vitamin B2.
Item 2. Item 2. The ophthalmic composition according to Item 1, wherein the vitamin B2 is at least one selected from the group consisting of flavin adenine dinucleotide and a salt thereof.
Item 3. Item 3. The ophthalmic composition according to Item 1 or 2, wherein the lecithin content is 0.001 to 20 w / v% based on the total amount of the ophthalmic composition.
Item 4. Item 4. The ophthalmic composition according to any one of Items 1 to 3, wherein the content of vitamin B2 is 0.0001 to 1 w / v% based on the total amount of the ophthalmic composition.
Item 5. Item 5. The ophthalmic composition according to any one of Items 1 to 4, further comprising a borate buffer.
Item 6. Item 6. The ophthalmic composition according to Item 5, wherein the content of the borate buffer is 0.01 to 3 w / v% with respect to the total amount of the ophthalmic composition.
Item 7. Item 7. The ophthalmic composition according to any one of Items 1 to 6, for promoting oil production from the meibomian glands.
Item 8. Item 7. The ophthalmic composition according to any one of Items 1 to 6, which is used for treating an evaporation-enhanced dry eye.
Item 9. Item 7. The ophthalmic composition according to any one of Items 1 to 6, which is used for suppressing eyes.

The ophthalmic composition of the present invention effectively promotes the production of oil from the meibomian glands. In addition, it can suppress dryness of the eyes and relieve and treat dry eye symptoms. In addition, it can be expected to have a therapeutic effect on dry eye symptoms (specifically, evaporative dry eye, for example) that are difficult to treat with existing dry eye treatments and whose oil production from the meibomian glands is reduced. Furthermore, it is also useful for tear-reducing dry eyes from the viewpoint of supplementing tear fluid components. Further, the oil production promoting action of the ophthalmic composition of the present invention has a synergistic effect as compared with the case where lecithin and vitamin B2 are each contained alone.
Moreover, the ophthalmic composition of the present invention effectively suppresses the eyes. Thereby, it is possible to improve symptoms such as difficulty in blinking and difficulty in opening eyes. Moreover, the synergistic effect is recognized for the inhibitory action of the ophthalmic composition of this invention compared with the case where each contains lecithin and vitamin B2 individually.

It is a figure which shows the synergistic effect of a lecithin and FAD about the production of oil from a meibomian gland. It is a figure which shows the synergistic effect of a lecithin and FAD regarding the ease of blinking at the time of getting up, the dryness of eyes, the ease of opening of eyes, and the amount of eyes.

Hereinafter, the present invention will be described in detail.
(I) Ophthalmic Composition The ophthalmic composition of the present invention is a composition containing lecithin and vitamin B2.
The ophthalmic composition includes eye drops, eye wash, contact lens mounting liquid, contact lens care liquid (cleaning liquid, preservative liquid, disinfecting liquid, multipurpose solution), eye ointment and the like. The ophthalmic composition of the present invention is particularly suitable as an eye drop and an eye wash because it has an effect of promoting oil production from the meibomian gland, an effect of improving dry eye, and an effect of suppressing eyes.

The origin of lecithin lecithin is not particularly limited. Examples of lecithin include egg yolk lecithin, soybean lecithin, corn lecithin, peanut lecithin, rapeseed lecithin and the like. These lecithins may be unhydrogenated or hydrogenated (including completely hydrogenated and slightly hydrogenated). The iodine value of lecithin is not particularly limited, and may be 10 or less, for example. The range of iodine value is preferably about 20 to 100, more preferably about 30 to 90, and still more preferably about 35 to 85. The acid value of lecithin is preferably 50 or less, more preferably 40 or less, and even more preferably 30 or less.
In addition, lecithin contains phospholipids such as phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), lysophosphatidylcholine (LPC), and the phosphatidylcholine content is 30% by weight or more of the whole. A certain lecithin is preferable, the lecithin which is 50 weight% or more is more preferable, and the lecithin which is 70 weight% or more is still more preferable. Further, lecithin having a phosphatidylethanolamine content of 50% by weight or less is preferable, lecithin having a content of 30% by weight or less is more preferable, and lecithin having a content of 15% by weight or less is even more preferable. In addition, lecithin having a phosphatidylinositol content of 50% by weight or less is preferable, lecithin having a content of 30% by weight or less is more preferable, and lecithin having a content of 15% by weight or less is even more preferable. Moreover, the lecithin whose content of lysophosphatidylcholine is 20 weight% or less is preferable, and the lecithin which is 10 weight% or less is more preferable. As such lecithin, (Resinol S-10, Resinol S-10M, Resinol S-10E, Resinol S-10EX, Resinol S-H50, Resinol WS-50, Resinol LL-20; Nikko Chemicals Co., Ltd.), ( PL-30S, PL-100M, PC-98N, PL-100P; Kewpie Corporation), (SLP-PC90, SLP-PC92H, SLP-white, SLP-white SP, SLP-white H, SLP-PC70, SLP -PC70H, SLP-LPC70; Sakai Oil Co., Ltd., (NC-21, NC-21E, NC-61; Nippon Oil & Fats Co., Ltd.), (Lipoid E-80; Lipoid Co.), (Epicuron 120, Ovothin 160) Lucus Meyer).
Lecithin may be used alone or in combination of two or more.
The content of lecithin in the ophthalmic composition is preferably about 0.001 to 20 w / v%, more preferably about 0.005 to 2 w / v% in terms of the total amount of lecithin with respect to the entire ophthalmic composition. About 0.01 to 0.3 w / v% is even more preferred, and about 0.01 to 0.1 w / v% is particularly preferred. When the lecithin content is in the above range, the effects of the present invention including the oil secretion promoting effect from the meibomian glands are further enhanced.

Vitamin B2 As examples of vitamin B2, riboflavin, riboflavin phosphate, riboflavin butyrate, riboflavin acetate, flavin adenine dinucleotide, flavin mononucleotide, or a pharmaceutically acceptable salt thereof can be given. Examples of the salt include sodium salt and potassium salt.
Among them, riboflavin phosphate, riboflavin butyrate, flavin adenine dinucleotide, or a salt thereof is preferable, riboflavin phosphate, sodium riboflavin phosphate, riboflavin butyrate, flavin adenine dinucleotide, sodium flavin adenine dinucleotide is more preferable, flavin adenine dinucleotide Even more preferred is nucleotide sodium.
One type of vitamin B2 may be used alone, or two or more types may be used in combination.
The content of vitamin B2 in the ophthalmic composition is preferably about 0.0001 to 1 w / v%, and preferably about 0.001 to 0.5 w / v in terms of the total amount of vitamin B2 with respect to the entire ophthalmic composition. v% is more preferred, and about 0.005 to 0.05 w / v% is even more preferred. If vitamin B2 content is the said range, the effect of this invention including the oil-secretion promotion effect from a meibomian gland will be improved further.
Moreover, in the ophthalmic composition of the present invention, the ratio of vitamin B2 to lecithin is not particularly limited, but the effect of the present invention including the effect of promoting oil secretion from the meibomian gland is further enhanced. From the viewpoint, the total amount of vitamin B2 per 1 part by weight of lecithin is about 0.001 to 1000 parts by weight, preferably about 0.01 to 100 parts by weight, more preferably about 0.1 to 10 parts by weight, particularly preferably. About 0.5 to 5 parts by weight may be mentioned.

Borate Buffer It is preferable that the ophthalmic composition of the present invention further contains a borate buffer. Since the borate buffer has a bacteriostatic action in addition to the buffering action, the ophthalmic composition containing the borate buffer does not need a separate preservative or the amount of the preservative is small. There is an advantage that it can be stored stably for a long time. Lecithin and vitamin B2 reduce the bacteriostatic power of borate buffer by using in combination with borate buffer, respectively, but boric acid contains boric acid buffer, lecithin, and vitamin B2 A decrease in bacteriostatic power of the buffer is suppressed. In addition, the combined use of lecithin, vitamin B2 and borate buffer improves the effects of the present invention, such as suppression of dry eyes, suppression of the eyes, ease of opening the eyes, ease of blinking, and the like. A further enhanced and stable ophthalmic composition can be obtained.
Examples of the boric acid buffer include boric acid or a salt thereof. Examples of the boric acid salt include sodium borate, potassium tetraborate, potassium metaborate, ammonium borate, and borax. Of these, boric acid or borax is preferred. A boric acid buffer may be used alone or in combination of two or more, and a combination of boric acid and borax is particularly preferred.

As long as the content of the boric acid buffer is within a range where the effects of the present invention can be achieved, the boric acid buffer may be set in a range where the buffering action cannot be exerted alone. It is appropriately set according to the type of other components. For example, the content of borate buffer is preferably about 0.01 to 3 w / v%, more preferably about 0.1 to 2% in terms of the total amount of borate buffer with respect to the total amount of the ophthalmic composition. Examples are 5 w / v%, even more preferably about 0.5 to 2 w / v%.
In addition, the boric acid buffer content is preferably about 0.0001 to 0.05 mol / 100 mL in terms of boron atom concentration with respect to the whole ophthalmic composition, and about 0.0015 to 0.005. It is more preferably 035 mol / 100 mL, and even more preferably about 0.007 to 0.03 mol / 100 mL. If the content of the boric acid buffer is in the above range, the preservability or antiseptic properties are good, and this application includes suppression of dry eyes, suppression of eyes, ease of opening eyes, ease of blinking, etc. The effect of the invention is further enhanced and a stable ophthalmic composition is obtained.

Camphor, Borneol The ophthalmic composition of the present invention preferably further contains one or more selected from the group consisting of camphor and borneol. In addition to suppressing the unpleasant odor of lecithin, camphor or borneol can more reliably exhibit the effects of the present invention described above. For camphor or borneol, either d-form or l-form may be used, more preferably d-camphor, dl-camphor, or d-borneol, and particularly preferably d-camphor. Moreover, the essential oil containing these may be sufficient.
In the case where camphor and / or borneol is blended in the ophthalmic composition of the present invention, the blending ratio of camphor and / or borneol cannot be uniformly defined. However, camphor and / or borneol is generally about a total amount. 0.0001-1 w / v%, preferably about 0.001-0.1 w / v%, more preferably about 0.002-0.03 w / v%, particularly preferably about 0.005-0.02 w / v% The ratio of v% is exemplified.

Oil content The ophthalmic composition of the present invention preferably further comprises an oil content. The oil can improve the stability of the ophthalmic composition of the present invention, and more reliably achieve the effects of the present invention described above. Oils include vegetable oils, animal oils such as squalane, mineral oils such as liquid paraffin, petroleum jelly, among others, sesame oil, castor oil, soybean oil, olive oil, wheat germ oil, peppermint oil, sunflower oil, cottonseed oil, corn oil Vegetable oils such as coconut oil, peanut oil, peanut oil, almond oil, safflower oil, jojoba oil, camellia oil, rapeseed oil and orange oil are preferred. More preferred are castor oil and sesame oil, and particularly preferred is sesame oil. An oil component can be used individually by 1 type or in combination of 2 or more types.
The content of oil in the ophthalmic composition is preferably about 0.001 to 10 w / v%, more preferably about 0.005 to 5 w / v%, and more preferably about 0.005 to 5 w / v% in terms of the total amount of oil relative to the entire ophthalmic composition. More preferably, 0.01-1 w / v%.

Alcohol The ophthalmic composition of the present invention preferably further contains alcohol. Alcohol improves the stability of the ophthalmic composition of the present invention, and more reliably exhibits the effects of the present invention described above. As alcohol, either a polyhydric alcohol or a monohydric alcohol may be sufficient. Examples of the polyhydric alcohol include glycerin, propylene glycol, polyethylene glycol, sorbitol, xylitol, mannitol and the like. Examples of the monohydric alcohol include ethanol, propanol, butanol, pentanol and the like. Preferably, glycerin, propylene glycol, and ethanol are used. Alcohol can be used individually by 1 type or in combination of 2 or more types.
The content of the alcohol in the ophthalmic composition is preferably about 0.001 to 20 w / v%, more preferably about 0.01 to 10 w / v% in terms of the total amount of alcohol, with respect to the total ophthalmic composition. 0.05-5 w / v% is even more preferred.

The preferred combinations of preferred combination lecithin and vitamin B2 are illustrated in Table 1 below.

  The ophthalmic composition of the present invention may contain known active ingredients (pharmacologically active ingredients, physiologically active ingredients, etc.) in addition to the above ingredients. The type of such component is not particularly limited, and examples thereof include a decongestant component, an eye muscle modulator component, an anti-inflammatory component or an astringent component, an antihistamine component or an antiallergic component, vitamins, amino acids, antibacterial agents. Examples thereof include a drug component or a bactericidal component, a saccharide, a polymer compound or derivative thereof, cellulose or a derivative thereof, a local anesthetic component, a glaucoma treatment component, a cataract treatment component, and the like. Examples of the pharmacologically active component and physiologically active component suitable in the present invention include the following components.

  Decongestant: For example, α-adrenergic agonists, specifically epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, epinephrine hydrogen tartrate, naphazoline nitrate. These may be d-form, l-form or dl-form.

  Ocular muscle modulator component: For example, cholinesterase inhibitor having an active center similar to acetylcholine, specifically, neostigmine methyl sulfate, tropicamide, helenien, atropine sulfate and the like.

  Anti-inflammatory component or astringent component: for example, zinc sulfate, zinc lactate, allantoin, epsilon-aminocaproic acid, indomethacin, lysozyme chloride, silver nitrate, pranoprofen, sodium azulenesulfonate, dipotassium glycyrrhizinate, diammonium glycyrrhizinate, Diclofenac sodium, bromfenac sodium, berberine chloride, berberine sulfate, etc.

  Antihistamine component or antiallergic agent component: for example, agitazanolast, diphenhydramine or its hydrochloride, chlorpheniramine maleate, ketotifen fumarate, levocabastine or its hydrochloride, etc., amlexanox, ibudilast, tazanolast, tranilast, oxatomide, Suplatast or its tosylate, such as sodium cromoglycate, potassium pemirolast, etc.

  Vitamins: for example, retinol acetate, retinol palmitate, pyridoxine hydrochloride, pyridoxal phosphate, cyanocobalamin, panthenol, calcium pantothenate, sodium pantothenate, ascorbic acid, tocopherol acetate, tocopherol succinate, tocopherol succinate, tocopherol calcium succinate , Ubiquinone derivatives and the like.

  Amino acids: for example, aminoethylsulfonic acid (taurine), glutamic acid, creatinine, sodium aspartate, potassium aspartate, magnesium aspartate, magnesium aspartate / potassium mixture, glutamic acid, sodium glutamate, magnesium glutamate, epsilon-aminocaproic acid, glycine , Alanine, arginine, lysine, γ-aminobutyric acid, γ-aminovaleric acid, sodium chondroitin sulfate and the like. These may be d-form, l-form or dl-form.

  Antibacterial component or bactericidal component: for example, alkylpolyaminoethylglycine, chloramphenicol, sulfamethoxazole, sulfisoxazole, sulfamethoxazole sodium, sulfisoxazole diethanolamine, sulfisoxa Zole monoethanolamine, sodium sulfisomezole, sodium sulfisomidine, ofloxacin, norfloxacin, levofloxacin, lomefloxacin hydrochloride, acyclovir and the like.

  Sugars: For example, monosaccharides, disaccharides, specifically glucose, maltose, trehalose, sucrose, cyclodextrin, xylitol, sorbitol, mannitol and the like.

  High molecular compound or derivative thereof: for example, alginic acid, sodium alginate, dextrin, dextran, pectin, hyaluronic acid, chondroitin sulfate, polyvinyl alcohol (completely or partially saponified product), polyvinylpyrrolidone, carboxyvinyl polymer, macrogol and its pharmaceutical Acceptable salts.

  Cellulose or derivatives thereof: for example, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose sodium, carboxyethyl cellulose, nitrocellulose and the like.

  Local anesthetic components: for example, chlorobutanol, procaine hydrochloride, lidocaine hydrochloride, etc.

The blending ratio of various components is known in the field of ophthalmic compositions, and the blending ratio of the above components in the ophthalmic composition of the present invention is the type of the composition, the pharmacologically active component, or the physiologically active component. It sets suitably according to etc. For example, the blending ratio of the pharmacologically active ingredient or the physiologically active ingredient is selected from the range of about 0.0001 to 30 w / v%, preferably about 0.001 to 10 w / v% with respect to the total amount of the ophthalmic composition. it can.
A known active ingredient can be used individually by 1 type or in combination of 2 or more types.

In the ophthalmic composition of the present invention, various carriers and additives can be appropriately selected according to conventional methods according to the use and form as long as the effects of the invention are not impaired. It can be included. As such carriers or additives, for example, carriers (aqueous solvent, aqueous or oily base, etc.) generally used for the preparation of semi-solid agents and liquid agents, surfactants, preservatives, bactericides or antibacterial agents And various additives such as pH adjusters, tonicity agents, chelating agents, buffering agents, and stabilizers.

  Although the typical component used for the ophthalmic composition of this invention is illustrated below, it is not limited to these.

  Carrier: aqueous solvent such as water or water-containing ethanol.

  Surfactant: For example, polyoxyethylene (hereinafter abbreviated as POE) -polyoxypropylene (hereinafter abbreviated as POP) block copolymer (specifically, poloxamer 407, etc.), ethylenediamine POE-POP block copolymer adduct ( Specifically, such as poloxamine), POE sorbitan fatty acid ester (specifically, polysorbate 80), POE hydrogenated castor oil (specifically, POE (60) hydrogenated castor oil), non-oxygen such as polyoxyl stearate Ionic surfactants; glycine type amphoteric surfactants such as alkyldiaminoethylglycine; cationic surfactants of alkyl quaternary ammonium salts (specifically, benzalkonium chloride, benzethonium chloride, etc.). The numbers in parentheses indicate the number of added moles.

  Perfume or refreshing agent: for example, terpenes (specifically, anethole, eugenol, geraniol, menthol, limonene, etc. These may be d-form, l-form or dl-form), essential oils (eucalyptus oil, bergamot) Mint water, mint oil, peppermint oil, rose oil, etc.).

  Preservatives, bactericides or antibacterials: for example, polydronium chloride, alkyldiaminoethylglycine hydrochloride, sodium benzoate, ethanol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, sorbic acid, potassium sorbate, dehydroacetic acid Sodium, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, oxyquinoline sulfate, phenethyl alcohol, benzyl alcohol, biguanide compounds (specifically, polyhexamethylene biguanide or its hydrochloride) , Glow Kill (trade name, manufactured by Rhodia).

  pH adjuster: For example, hydrochloric acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, triethanolamine, monoethanolamine, diisopropanolamine, sulfuric acid, phosphoric acid and the like.

  Isotonizing agents: for example, sodium bisulfite, sodium sulfite, potassium chloride, calcium chloride, sodium chloride, magnesium chloride, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium thiosulfate, magnesium sulfate, dihydrogen phosphate Sodium, sodium dihydrogen phosphate, potassium dihydrogen phosphate, glycerin, propylene glycol and the like.

  Chelating agent: for example, ascorbic acid, tetrasodium edetate, sodium edetate, citric acid and the like.

  Buffer: citrate buffer, acetate buffer, carbonate buffer, phosphate buffer, etc. Specifically, citric acid, sodium citrate, acetic acid, potassium acetate, sodium acetate, sodium bicarbonate, sodium carbonate, boric acid, borax, phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, phosphoric acid Such as potassium dihydrogen.

Stabilizers: dibutylhydroxytoluene, trometamol, sodium formaldehyde sulfoxylate (Longalite), tocopherol, sodium pyrosulfite, monoethanolamine, aluminum monostearate, glyceryl monostearate, etc.
A carrier and an additive can be used individually by 1 type or in combination of 2 or more types.

Property, pH
The ophthalmic composition of the present invention may be usually a liquid except when it is an eye ointment. In that case, the content of water is usually 90 w / v% or more, preferably 95 w / v% or more.
In the case of an eye ointment, a known eye ointment base such as white petrolatum, liquid paraffin, plastibase, or purified lanolin can be used.
The pH of the ophthalmic composition of the present invention may be about 3 to 9, preferably about 4.5 to 7.5, and more preferably about 4.8 to 6.5. If pH is the said range, while being able to acquire the effect of this invention including the oil secretion promotion effect from a meibomian gland more reliably, these effects can be acquired stably also after a preservation | save.

Container The container filled with the ophthalmic composition of the present invention is not particularly limited, and examples thereof include containers containing materials such as polyethylene terephthalate, polyarylate, polycarbonate, polyethylene, and polypropylene. Preferably, the light-shielded container is filled. By putting it in a light-shielding container, the ophthalmic composition of the present invention can be kept stable for a long period of time. The container may be shielded from light by, for example, mixing a colorant or the like with the above materials, or may be shielded from light by covering with a shrink film or an outer box.

Production Method The ophthalmic composition of the present invention can be prepared by a conventional method. For example, after each component is dispersed in one or more mixtures selected from the group consisting of water, oil, alcohol and surfactant, the pH is adjusted by homogenizing, dissolving or emulsifying using a homogenizer. What is necessary is just to adjust by adjusting pH with an agent.

Method of Use When the ophthalmic composition of the present invention is a liquid or eye ointment, the dosage and dosage vary depending on the patient's symptoms, age, etc., but usually about 1 to 6 times a day, about 1 to 1 times a day. Two drops may be instilled or an appropriate amount may be applied.
When the ophthalmic composition of the present invention is an eye drop, the subject of use is reduced oil secretion from meibomian glands such as obstructive meibomian gland dysfunction, dry eye (especially hyperevaporative dry eye), eye inflammation, Patients who show symptoms such as eyes and nibs are preferred. In particular, patients who exhibit symptoms of decreased oil secretion from meibomian glands, dry eye, and particularly hyperevaporative dry eye are suitable subjects.
Therefore, the ophthalmic composition of the present invention is used for promoting oil production from meibomian glands, for treating dry eye (especially hyperevaporation type dry eye), for suppressing eye irritation, for improving eye inflammation, for improving dryness of eyes, etc. It can use suitably for the use of.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these.

1. Effects on production of oil from meibomian glands
Method Meibomian glands were removed from the eyelids of white rats (Japan SLC) under a stereomicroscope. This was subdivided into about 1 mm and treated with 0.25 w / v% dispase (Roche) and 0.25 w / v% collagenase (Nitta gelatin) at 37 ° C. for 2.5 hours.
The meibomian glands were collected from the obtained treatment solution, and tissue-cultured at 37 ° C. for 3 days at 37 ° C. with 5% CO ₂ in a petri dish for cell culture (IWAKI) coated with collagen I. Phenolphthalein (−) in DMEM / F12 (GIBCO), 10 ng / mL mEGF (Kurabo), 0.4 μg / mL hydrocortisone (Kurabo), 5 mg / L insulin (Kurabo), 10 mg / L transferrin (Kurabo) and antibiotics (Antibiotic-Antimycotic; GIBCO) added (Medium 1).
Three days after the start of culture, cells obtained from meibomian glands were treated with trypsin (GIBCO), subcultured to a collagen I-coated 96-well cell culture plate (Sumitomo Bakelite), and cultured at 37 ° C. with 5% CO ₂ . Continued. After subculture, phenolphthalein (−) DMEM / F12 (GIBCO), 10 ng / mL mEGF (Kurabo), 0.4 μg / mL hydrocortisone (Kurabo), antibiotics (Antibiotic-Antimycotic; GIBCO), The test was performed using a medium supplemented with 10 v / v% fetal bovine serum.
When the cells became confluent, the passage medium was removed by aspiration, and each well was washed three times with DMEM / F12.
Then, the test substance was prepared by dissolving in the above-mentioned medium 1 so as to have a concentration shown in Table 2 below, and 200 μL was added to the well. As a control, instead of the medium 1 in which the test substance was dissolved, 200 μL of the medium 1 in which the test substance was not dissolved was added to another well. Thereafter, the cells were cultured for 48 hours under conditions of 5% CO ₂ and 37 ° C. Soy lecithin in Table 2 uses S-10M (PC content 60%, acid value 40 or less) manufactured by Nikko Chemicals, and flavin adenine dinucleotide sodium (hereinafter sometimes referred to as FAD) is manufactured by Kyowa Hakko Kirin Co., Ltd. The thing of was used.

Results The medium was removed by suction from the 96-well plate, and the cells were fixed with 4% paraformaldehyde for 1 hour. After the fixing solution was removed by suction, each well was washed with PBS (−) (Kohjin Bio), and intracellular oil droplets were stained using BODIPY (invitrogen). Using IN CELL Analyzer (GE Healthcare Japan), stained images were taken and analyzed.
In addition, based on the fluorescence value of the stained image (fluorescence intensity multiplied by the area value, ie, fluorescence intensity × area value), the rate of increase in the amount of oil droplets compared to the control with no test substance added (in accordance with the following formula) %) Was calculated.

Increase rate of oil droplet amount (%) = [(fluorescence value in each case / fluorescence value of control) -1]
× 100

  The rate of increase in the amount of oil droplets in each example is shown in FIG. As apparent from FIG. 1, when only FAD was added, the amount of oil droplets was almost the same as that of the control, but the amount of oil droplets increased synergistically by combining with lecithin.

2. Sensory test Eye drops having the formulations shown in Table 3 below were prepared, and aseptically filled into PET eye drop bottles to prepare test samples. Soy lecithin was S-10M (PC content 60%, acid value 40 or less) manufactured by Nikko Chemicals, and FAD manufactured by Kyowa Hakko Kirin Co., Ltd. was used. Sodium hydroxide was used as the pH adjuster.
Eleven subjects who had subjective symptoms in the eyes when waking up, each test sample was instilled once or twice in 1 to 2 drops at 1 to 30 minutes before going to bed.
Each subject evaluated ease of blinking when waking up, dryness of eyes when waking up, ease of opening eyes when waking up, and amount of eyes and eyes when waking up. The state where no eye drops were used was set to 0 point, and the degree of improvement compared with this was evaluated according to the following criteria.
When it deteriorated: The case where it deteriorated slightly was set to -1 point, the case where it deteriorated very much was set to -5 point, and it evaluated in five steps.
In the case of improvement: The case of slight improvement was set to 1 point, and the case of very improvement was set to 5 points.
The results are shown in FIG. As is clear from FIG. 2, synergistic improvement was observed by the combined use of lecithin and FAD in all items of ease of blinking, dryness of eyes, ease of opening of eyes, and amount of eyes and eyes.

3. Evaluation of antiseptic properties
Staphylococcus aureus (ATCC6538) was inoculated on the surface of soybean / casein / digest agar plate and cultured at 33 ° C. for 24 hours. The cultured cells were aseptically collected with a platinum loop and suspended in an appropriate amount of sterile physiological saline to prepare a bacterial suspension containing about 1 × 10 ⁸ CFU / mL viable bacteria.
The number of viable bacteria (final concentration) in the test solution is about 1.6 × 10 ⁴ CFU / mL, and the concentration of each component in the test solution is the composition of Example 4 and Comparative Examples 6 and 7 shown in Table 4 below. A test solution was prepared as follows.
Using this test solution, a preservative efficacy test (preservative strength test) was performed according to the method defined in the Japanese Pharmacopoeia (15th revision), and the antiseptic properties of the compositions of the respective examples were evaluated. Specifically, each test solution was allowed to stand at 25 ° C. for 75 hours, and the number of viable bacteria was measured at the time of inoculation, after 46 hours, and after 75 hours. The bacteria were counted by a membrane filter filtration method. The results are shown in Table 4 below.

  As is apparent from Table 4, when lecithin and FAD were each used in combination with boric acid alone, the bacteriostatic power of boric acid was greatly reduced. However, when lecithin and FAD were used in combination with boric acid, bacteriostatic bacteriostasis was achieved. The decrease in force was suppressed. That is, even when there is little preservative or no preservative is contained, an appropriate preservative power can be imparted to the preparation.

Formulation Examples The characteristics of lecithin used in the following formulation examples are as follows.
Purified egg yolk lecithin PL-100M (manufactured by Kewpie): The same test example was used.
Purified egg yolk lecithin PC-98N (manufactured by Kewpie Corporation): an iodine value of 64, a PC content of 98.3%, and an acid value of 0.1 was used.
Refined soybean lecithin SLP-PC92H (manufactured by Sakai Oil Co., Ltd.): An iodine value of 41, a PC content of 90% or more, and an acid value of 3 or less was used.
Purified soybean lecithin S-10M (manufactured by Nikko Chemicals): The same test example was used.
Purified soybean lecithin S-10EX (manufactured by Nikko Chemicals): a PC content of 95% or more and an acid value of 40 or less was used.

(Continued from Table 5)

  The ophthalmic composition of the present invention can promote the production of oil from the meibomian glands, suppress dryness of the eyes, and relieve and treat dry eye symptoms (particularly, hyperevaporation type dry eye). It also effectively improves eye irritation and eye irritation.

Claims (6)

(a) lecithin, and (b) at least one selected from the group consisting of riboflavin, riboflavin phosphate, riboflavin butyrate, riboflavin acetate, flavin adenine dinucleotide, and flavin mononucleotide, and pharmaceutically acceptable salts thereof. by weight of vitamin B2 such, the content of lecithin, based on the total amount of the ophthalmic composition is a 0.005~2w / v%, the content of vitamin B2 such that, the total amount of the ophthalmic composition On the other hand, the ophthalmic composition is 0.0001 to 0.5 w / v% and is an eye drop, an eye wash, a contact lens care solution, a contact lens mounting solution, or an eye ointment .   The ophthalmic composition according to claim 1, wherein the vitamin B2 is at least one selected from the group consisting of flavin adenine dinucleotide and a salt thereof. The ophthalmic composition according to claim 1, comprising 0.1 to 10 parts by weight of vitamin B2 with respect to 1 part by weight of lecithin. (a) lecithin, (b) at least one selected from the group consisting of riboflavin, riboflavin phosphate, riboflavin butyrate, riboflavin acetate, flavin adenine dinucleotide, and flavin mononucleotide, and pharmaceutically acceptable salts thereof vitamin B2 compounds, and (c) boric acid buffer agent including ophthalmology composition.   The ophthalmic composition according to claim 4, wherein the content of the borate buffer is 0.01 to 3 w / v% with respect to the total amount of the ophthalmic composition. (a) lecithin, and (b) at least one selected from the group consisting of riboflavin, phosphate riboflavin, riboflavin butyrate, riboflavin acetate, flavin adenine dinucleotide, and flavin mononucleotide, and pharmaceutically acceptable salts thereof An ophthalmic composition for promoting oil production from meibomian glands, for alleviating or treating dry eyes, for improving dryness of the eyes, or for suppressing the eyes.