JP6834434B2 - Ophthalmic composition - Google Patents

Description

The present invention relates to an ophthalmic composition containing a particular phosphatidylcholine.

The lacrimal fluid layer is composed of lipids secreted by the meibomian glands. It is known that saturated lipids increase in the oil layer due to aging and hormonal changes. The increase in saturated lipids causes the tear oil layer to become less stable, which contributes to eye strain and the like. On the other hand, it has been reported that the stability of the tear oil layer is improved by supplying an ophthalmic composition containing lecithin to the tear oil layer (Patent Document 1: Japanese Patent Application Laid-Open No. 2007-211007). However, these stabilizing effects were insufficient when the tear oil layer became unstable due to the increase in saturated lipids.

Japanese Unexamined Patent Publication No. 2007-211007

The present invention has been made in view of the above circumstances, and an ophthalmic composition capable of stabilizing the lacrimal oil layer of a meibomian gland dysfunctional patient in which the lacrimal oil layer is unstable due to an increase in saturated lipids is provided. With the goal. Moreover, since dry eye can be improved by stabilizing the tear oil layer, it is an object of the present invention to provide an ophthalmic composition suitable for dry eye patients.

As a result of diligent studies to achieve the above object, the present inventors have found that a specific phosphatidylcholine having an acyl group having 12, 14, 16 or 18 carbon atoms and an acyl group having 12 or 14 carbon atoms is found in tears. It has been found that it stabilizes the oil layer and exhibits a remarkable effect on dry eye, and has led to the present invention.

Therefore, the present invention provides the following ophthalmic compositions.
[1]. An ophthalmic composition containing a phosphatidylcholine having an acyl group having 12, 14, 16 or 18 carbon atoms and an acyl group having 12 or 14 carbon atoms.
[2]. Phosphatidylcholine has the following formula (1)
(Wherein, R ¹ -C (= O) is an acyl group having 12 or 14 carbon atoms, R ² -C (= O) is an acyl group of the 12, 14, 16 or 18 carbon atoms. )
The ophthalmic composition according to [1], which is a compound represented by.
[3]. The ophthalmic composition according to [1] or [2], wherein the content of phosphatidylcholine is 0.01 to 2.5 W / V%.
[4]. The ophthalmic composition according to any one of [1] to [3], which is an eye drop or an eye wash.
[5]. The ophthalmic composition according to any one of [1] to [4] for soft contact lens wearers.
[6]. The ophthalmic composition according to any one of [1] to [5] for patients with meibomian gland dysfunction.
[7]. The ophthalmic composition according to any one of [1] to [5] for patients with dry eye.
[8]. The ophthalmic composition according to any one of [1] to [5] for asthenopia patients.
[9]. The ophthalmic composition according to any one of [1] to [5], which contains the above-mentioned phosphatidylcholine as an active ingredient and is a tear film oil film stabilizer.
[10]. The ophthalmic composition according to any one of [1] to [5], which contains the above-mentioned phosphatidylcholine as an active ingredient and is a dry eye improving agent.
[11]. The ophthalmic composition according to any one of [1] to [5], which contains the above-mentioned phosphatidylcholine as an active ingredient and is an eye strain improving agent.

According to the present invention, it is possible to provide an ophthalmic composition capable of stabilizing the lacrimal oil layer, particularly in a patient with meibomian gland dysfunction, due to the increase in saturated lipid. Further, since the dry eye can be improved by stabilizing the tear oil layer, it is possible to provide an ophthalmic composition suitable for dry eye patients. Further, since the stabilization of the tear oil layer can improve eye strain, it is possible to provide an ophthalmic composition suitable for patients with eye strain.

It is a photograph which shows the result of the tear oil layer stability test of Example 2. It is a photograph which shows the result of the tear oil layer stability test of Comparative Example 2.

Hereinafter, the present invention will be described in detail. Phosphatidylcholine has a structure in which two fatty acids and phosphoric acid are ester-bonded to the hydroxyl group of glycerin, and choline is ester-bonded to phosphoric acid. The phosphatidylcholine of the present invention has one fatty acid having 12, 14, 16 or 18 carbon atoms and the other fatty acid having 12 or 14 carbon atoms. That is, it is phosphatidylcholine having an acyl group having 12, 14, 16 or 18 carbon atoms and an acyl group having 12 or 14 carbon atoms in the molecule. Preferably, one acyl group has 12, 14 or 16 carbon atoms and the other acyl group has 12 or 14 carbon atoms. More preferably, one acyl group has 12 or 14 carbon atoms and the other acyl group has 12 or 14 carbon atoms. The acyl group may be saturated or unsaturated. These can be used alone or in combination of two or more.

In particular, those represented by the following formula (1) are preferable.
(Wherein, R ¹ -C (= O) is an acyl group having 12 or 14 carbon atoms, R ² -C (= O) is an acyl group of the 12, 14, 16 or 18 carbon atoms. )

In the above formula, the acyl group may be saturated or unsaturated. Among them, R ¹ -C (= O) is an acyl group having 12 or 14 carbon atoms, R ² -C (= O) is preferably a combination of an acyl group of the 12, 14 and 16 carbon atoms, R ¹ -C (= O) is an acyl group having 12 or 14 carbon atoms, R ² -C (= O) is more preferably a combination of an acyl group of 12 or 14 carbon atoms.

Specifically, dilauroyl phosphatidylcholine (R ¹ -C (= O) and R ² -C (= O): acyl group of 12 carbon atoms), dimyristoyl phosphatidylcholine (R ¹ -C (= O) and R ² -C (= O): acyl group having a carbon number of 14), Lau b Illuminator Rust yl phosphatidylcholine ^{(R 1 -C (= O)} : acyl group of 12 carbon ^{atoms, R 2 -C (= O)} : C 14 atoms acyl group), lauroyl palmitoyl phosphatidylcholine ^{(R 1 -C (= O)} : acyl group of 12 carbon ^{atoms, R 2 -C (= O)} : acyl group having 16 carbon atoms), lauroyl virus distearoylphosphatidylcholine (R ¹ -C ( = O): 12-carbon acyl group, R ^2- C (= O): 18-carbon acyl group), myristyl palmitoyl phosphatidylcholine (R ^1- C (= O): 14-carbon acyl group, R ² −C (= O): Acyl group having 16 carbon atoms), Myristoyl stearoyl phosphatidylcholine (R ¹ −C (= O): Acyl group having 14 carbon atoms, R ² −C (= O): Acyl group having 18 carbon atoms) ) And a mixture thereof. Among them, dilauroylphosphatidylcholine, dimyristoylationphosphatidylcholine, and lauroylmyristoylation phosphatidylcholine are preferable.

The phosphatidylcholine of the present invention is different from lecithin. Examples of lecithin include egg yolk lecithin and soybean lecithin, all of which are a mixture of phospholipids such as phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), and lysophosphatidylcholine (LPC). Furthermore, the phosphatidylcholine in lecithin contains only an acyl group having 16 or more carbon atoms (The Journal of Nutrition Vol. 111, No 1, January 1981, p166-170, Journal of the Japan Oil Chemists' Society 45 (8) 1996, p63). -66). As shown in the comparative example described later, the effect of the present invention cannot be obtained with lecithin.

The content of phosphatidylcholine is preferably 0.01 to 2.5 W / V% (mass / volume, g / 100 mL), more preferably 0.02 to 2.5 W / V%, and 0.08 in the ophthalmic composition. ~ 1.0 W / V% is particularly preferable. If it is 0.01 W / V% or more, the tear film can be more stabilized, and if it exceeds 2.5 W / V%, the tear film may become unstable.

The ophthalmic composition of the present invention may contain an appropriate amount of other ingredients as long as the effects of the present invention are not impaired. Examples of other components include surfactants, polyhydric alcohols, thickeners, sugars, buffers, pH adjusters, tonicity agents, stabilizers, cooling agents, drugs and the like.

Examples of the surfactant include polyoxyethylene polyoxypropylene glycol such as Poroxumer, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, and polyoxy such as polysorbate 80 (polyoxyethylene (20) sorbitanoleic acid ester). Nonionic surfactants such as ethylene sorbitan fatty acid ester and polyethylene glycol monostearate, glycine-type amphoteric surfactants such as alkyldiaminoethylglycine, alkyl quaternary ammonium salts such as benzalkonium chloride and benzethonium chloride (cationic surfactants) Agent) and the like. The content of the surfactant is preferably 0.0001 to 10 W / V% in the ophthalmic composition.

Examples of the polyhydric alcohol include glycerin, propylene glycol, butylene glycol, polyethylene glycol and the like. The content of the polyhydric alcohol is preferably 0.001 to 5 W / V% in the ophthalmic composition.

Examples of the thickener include polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, polyvinyl alcohol, sodium hyaluronate, sodium chondroitin sulfate, polyacrylic acid, and carboxyvinyl polymer. The content of the thickening agent is preferably 0.003 to 3 W / V% in the ophthalmic composition.

Examples of saccharides include glucose, cyclodextrin, xylitol, sorbitol, mannitol and the like. These may be d-form, l-form, or dl-form. The content of saccharides is preferably 0.001 to 5 W / V% in the ophthalmic composition.

Examples of the buffer include citric acid, sodium citrate, boric acid, boric acid, phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, glacial acetic acid, tromethamole, sodium hydrogen carbonate and the like. The content of the buffer is preferably 0.003 to 4 W / V% in the ophthalmic composition.

Examples of the pH adjuster include an inorganic acid or an inorganic alkaline agent. For example, examples of the inorganic acid include (dilute) hydrochloric acid. Examples of the inorganic alkaline agent include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate and the like.

Examples of the tonicity agent include sodium chloride, potassium chloride and the like. The content of the tonicity agent is preferably 0.001 to 3 W / V% in the ophthalmic composition.

Examples of the stabilizer include sodium edetate, cyclodextrin, sulfites, dibutylhydroxytoluene and the like. The content of the stabilizer is preferably 0.003 to 2 W / V% in the ophthalmic composition.

Examples of the refreshing agent include menthol, camphor, borneol, geraniol, cineole, linalool and the like. The content of the refreshing agent is preferably 0.0001 to 0.2 W / V% in the ophthalmic composition.

Drugs (pharmaceutically active ingredients) include, for example, decongestant components (eg, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, nafazoline hydrochloride, nafazoline nitrate, phenilefurin hydrochloride, dl-methylephedrine hydrochloride, etc.), Anti-inflammatory and astringent agents (eg, neostigmine methyl sulfate, epsilon-aminocaproic acid, allantin, berberine chloride hydrate, berberine sulfate hydrate, sodium azulene sulfonate, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, lysoteam hydrochloride Salts, etc.), antihistamines (eg, diphenhydramine hydrochloride, chlorpheniramine maleate, etc.), water-soluble vitamins (flavinadenine dinucleotide sodium, cyanocobalamine, pyridoxin hydrochloride, pantenol, calcium pantothenate, sodium pantothenate, etc.) , Fat-soluble vitamins (d-α-tocopherol acetate, retinol palmitate, etc.) Amino acids (eg, potassium L-aspartate, magnesium L-aspartate, potassium-magnesium L-aspartate (equal mixture), aminoethyl (Sulfuric acid, sodium chondroitin sulfate, etc.), sulfa agents, etc. can be mentioned. As for the content of the drug, an effective appropriate amount of each drug can be selected, but from the viewpoint of eye irritation, stability of the composition, etc., 0.001 to 5 W / V% in the ophthalmic composition. Is preferable. The other components may be blended alone or in combination of two or more.

The pH (20 ° C.) of the ophthalmic composition of the present invention is preferably 3.8 to 8.0, more preferably 5.0 to 7.5, from the viewpoint of eye irritation. The pH is measured at 20 ° C. using a pH osmotic meter (HSMO-1, DKK-TOA CORPORATION). The osmotic pressure of the ophthalmic composition of the present invention is preferably 200 to 800 mOsm, more preferably 200 to 500 mOsm, from the viewpoint of eye irritation.

The method for preparing the ophthalmic composition of the present invention is not particularly limited, and a known production method can be adopted. For example, it can be obtained by mixing the phosphatidylcholine of the present invention, an optional component if necessary, and the balance of water and adjusting the pH. Then fill in a suitable container.

Further, the obtained ophthalmic composition may be filled in a resin container and then sealed with a package to enclose the inert gas concentration in the space formed between the container and the package. The ophthalmic composition may be filled in a resin container and sealed with a packaging material together with an oxygen scavenger.

The ophthalmic composition of the present invention can be suitably used as eye drops (including eye drops for contact lens wearers that can be instilled while wearing contact lenses), eye wash agents, contact lens wearing solutions, etc., but eye drops, eye wash agents, etc. Can be suitably used as. In particular, eye drops are preferable from the viewpoint of stabilizing the tear film oil film. When used as an eye drop, the effect of the present invention can be further exerted by instilling 30 to 60 μL at a time and 3 to 6 times a day. When used as an eye wash, the effects of the present invention can be further exerted by washing the eyes 3 to 6 mL at a time and 3 to 6 times a day.

The ophthalmic composition of the present invention does not merely promote the production of oil components from the meibomian glands, but stabilizes the lacrimal layer oil film. If the production of oil components is simply promoted, saturated lipids increase, which rather causes eye strain and dry eye.

The present invention is particularly effective for patients with meibomian gland dysfunction in which the tear oil layer is unstable, patients with dry eye caused by instability in the tear oil layer, patients with eye strain, and the like.

The increase in saturated lipids in the tear oil layer makes the tear oil layer unstable, but since this is promoted by wearing contact lenses, it is recommended to use it for contact lens wearers, especially for soft contact lens wearers. It is more effective.

<Tear layer oil film stabilizer, dry eye improver, eye strain improver>
The ophthalmic composition of the present invention can be used as the tear film oil film stabilizer and the dry eye improving agent from the viewpoint of the above effects. The effective amount, administration method, formulation, etc. are as described above. For example, the amount of phosphatidylcholine is 0.003 to 1.5 mg per adult, which is administered to the eye in 3 to 6 divided doses a day. ..

Hereinafter, the present invention will be specifically described with reference to Examples and Comparative Examples, but the present invention is not limited to the following Examples. Unless otherwise specified, "%" of the composition is "W / V% mass / volume%".

[Examples 1 to 16, Comparative Examples 1 to 6]
The ophthalmic composition having the composition shown in the table below was produced by mixing each component with water and adjusting the pH to 7.0. The obtained ophthalmic composition was subjected to an in vitro tear oil layer stability test. The results are also shown in the table.

[Examples 17 to 32, Comparative Examples 7 to 12]
The ophthalmic composition having the composition shown in the table below is obtained by pre-dispersing phosphatidylcholine, phosphatidylinositol, phosphatidyl acid or lecithin and polysorbate 80 into an aqueous solution in which other components are dissolved and adjusting the pH to 7.0. It was. The obtained ophthalmic composition was subjected to an in vivo tear oil layer stability test and an eye strain improving effect test. The results are also shown in the table.

<In vitro tear oil layer stability test>
The tear oil layer mainly contains wax ester (oleyl oleate, etc.), cholesterol ester (cholesterol oleate, etc.), and phosphatidylcholine, and among these, _{those consisting of C 16} F ₁ and C ₁₈ F ₁ fatty acids are mainly contained. (Journal of Lipid Research 2014; 55: 289-298). _{However, it is known that the proportion of saturated lipids (C 16} F ₀ , C ₁₈ F ₀ ) increases due to aging and changes in hormonal balance, which causes destabilization of the tear oil layer (Cornea 2000, 19, p72-74). Therefore, as a tear oil layer model with increased saturated lipids, oleyl oleate 3.8 μg, cholesterol oleate 5.8 μg, phosphatidylcholine (C ₁₈ F ₀ / C ₁₈ F ₀ ) 0.4 μg, and perylene 0.1 μg were added to 1,000 μL chloroform. An oil layer prepared by the procedure of dissolving 10 μL of the solution in a 35 mm plastic dish and developing it on an aqueous layer prepared with 1 mL of water was used. After allowing the oil layer to stand at room temperature for 10 minutes, 50 μL of the prepared eye drop was added, and the mixture was placed on a hot plate at 37 ° C. and allowed to stand for 30 minutes. Then, the oil layer was irradiated with ultraviolet light of 254 nm, the fluorescence of the oil layer was photographed with a digital camera, and the stability of the oil layer was evaluated from the image. It was assumed that the oil layer was stable when the water layer was not exposed. The results are shown by the following evaluation criteria. The photographs of Example 2 and Comparative Example 2 are shown in FIGS. 1 and 2. In Example 2 of the present application, a uniform oil layer is formed, but in Comparative Example 2, the oil layer is broken and white streaks are formed, and the aqueous phase is exposed (in the photograph, the exposed portion is dark in color).

[In vitro tear oil layer stability evaluation criteria]
⊚: Uniform oil layer ○: There is a part where the oil layer is not uniform (uneven), but the water layer is not exposed ×: The water layer is exposed

<In vivo tear oil layer stability test>
The stability of the tear oil layer was evaluated by measuring BUT (break up time) using a dry eye observation device DR-1 (manufactured by Kowa Company, Ltd.). DR-1 is a device capable of measuring an interference image of light reflected at the interface between the tear oil layer surface and the tear water layer. In a healthy eye, a uniform gray or white interference image is observed, and the interference image disappears when the tear oil layer collapses. 30 μL of each eye drop was instilled in the subject, and after 10 minutes had passed, several blinks were made, and the time (BUT) from the blink to the collapse of the tear oil layer was measured. Three subjects were selected who had a BUT of 10 seconds or less and who met the diagnostic criteria for meibomian gland dysfunction (new ophthalmology 27 (5): 627-631 2010). The results before and after instillation are shown by the average value of three people, and the results of the average value after instillation are shown by the following evaluation criteria.
[In vivo tear oil layer stability evaluation criteria]
⊚: Oil layer BUT is 15 seconds or more ○: Oil layer BUT is 10 seconds or more and less than 15 seconds ×: Oil layer BUT is less than 10 seconds

<Eye strain improvement effect>
Regarding the ophthalmic composition, the effect of improving eye strain was confirmed by the following method.
50 μL of ophthalmic composition was instilled (3 times at 2 hour intervals) for 3 persons with eye strain symptoms (see ACTA OHTHALMOLOGICA 71 (1993), p347-352), and eyes 30 minutes after the 3rd instillation. The improvement effect of asthenopia was evaluated based on the following scores. The results are shown by the following evaluation criteria from the average value of the scores of the three people.
[Eye strain improvement effect score]
2: Symptoms disappeared 1: Symptoms alleviated 0: No change [Eye strain improvement effect evaluation criteria]
⊚: 1.5 or more ○: 1.0 or more and less than 1.5 ×: less than 1.0

The raw materials used in the above example are shown below. Unless otherwise specified, the amount of each component in the table is a net conversion amount.
・ Dilauroylphosphatidylcholine: (manufactured by NOF CORPORATION, COATSOME, MC-2020)
Zimiristoylation phosphatidylcholine: (Larodan Fine Chemicals AB, 37-1400)
-Myristoylation palmitoylphosphatidylcholine: (Avanti Polar Lipids, Inc., 850445P)
Myristoyl stearoyl phosphatidylcholine: (Avanti Polar Lipids, Inc., 850446P)
Palmitoyl stearoyl phosphatidylcholine: Avanti Polar Lipids, Inc. Made, 850456P
Distearoyl phosphatidylcholine: (Larodan Fine Chemicals AB, 37-1800)
-Phosphatidylinositol: (Cayman Chemical Company, Inc., 64924)
-Phosphatidic acid: Larodan Fine Chemicals AB, 38-1660)
-Lecithin: (Coatsome nc-50, manufactured by NOF CORPORATION)
・ Sodium edetate (Clewat N, manufactured by Nagase ChemteX Corporation)
・ Trometa Mall (manufactured by Kanto Chemical Co., Inc.)
・ Boric acid (manufactured by Kosakai Pharmaceutical Co., Ltd.)
・ Borax (manufactured by Kosakai Pharmaceutical Co., Ltd.)
・ Sodium chloride (manufactured by Wako Pure Chemical Industries, Ltd.)
・ Potassium chloride (manufactured by Wako Pure Chemical Industries, Ltd.)
・ Sodium hydroxide (manufactured by Wako Pure Chemical Industries, Ltd.)
・ Dilute hydrochloric acid (manufactured by Wako Pure Chemical Industries, Ltd.)

Claims (13)

An ophthalmic composition containing a phosphatidylcholine having an acyl group having 12, 14, 16 or 18 carbon atoms and an acyl group having 12 or 14 carbon atoms (provided that an expression plasmid vector for the β-galactosidase gene and dilauroyl phosphatidylcholine are used. Excludes liposome eye drops containing.) . Phosphatidylcholine has the following formula (1)
(Wherein, R ¹ -C (= O) is an acyl group having 12 or 14 carbon atoms, R ² -C (= O) is an acyl group of the 12, 14, 16 or 18 carbon atoms. )
The ophthalmic composition according to claim 1, which is a compound represented by. The ophthalmic composition according to claim 2, wherein the phosphatidylcholine is one or more selected from dipalmitoylphosphatidylcholine, lauroylmilstoylphosphatidylcholine, lauroylpalmitoylphosphatidylcholine, lauroylstearoylphosphatidylcholine, myristoylpalmitoylphosphatidylcholine and myristoylstearoylphosphatidylcholine. The ophthalmic composition according to claim 2, wherein the phosphatidylcholine is dilauroylphosphatidylcholine. The ophthalmic composition according to any one of claims 1 to 4, wherein the content of phosphatidylcholine is 0.01 to 2.5 W / V%. The ophthalmic composition according to any one of claims 1 to 5 , which is an eye drop or an eye wash. The ophthalmic composition according to any one of claims 1 to 6 , which is intended for wearers of soft contact lenses. The ophthalmic composition according to any one of claims 1 to 7 , which is for patients with meibomian gland dysfunction. The ophthalmic composition according to any one of claims 1 to 7 , which is for patients with dry eye. The ophthalmic composition according to any one of claims 1 to 7 , which is for an eye strain patient. The ophthalmic composition according to any one of claims 1 to 7 , which contains the above-mentioned phosphatidylcholine as an active ingredient and is a tear film oil film stabilizer. The ophthalmic composition according to any one of claims 1 to 7 , which contains the above-mentioned phosphatidylcholine as an active ingredient and is a dry eye improving agent. The ophthalmic composition according to any one of claims 1 to 7 , which contains the above-mentioned phosphatidylcholine as an active ingredient and is an eye strain improving agent.