JP2017109995A - Ophthalmic composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an ophthalmic composition which can stabilize a tear fluid oil layer of a meibomian gland dysfunction patient, of which the tear fluid oil layer is unstable, by increase of saturated lipids.SOLUTION: An ophthalmic composition comprises phosphatidyl choline comprising an acyl group having 12, 14, 16 or 18 carbon atoms and an acyl group having 12 or 14 carbon atoms.SELECTED DRAWING: Figure 1

Description

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

  The tear oil layer is composed of lipids secreted from the meibomian glands. It is known that saturated lipids increase in the oil layer due to aging and hormonal changes. As the saturated lipid increases, the tear oil layer becomes less stable and contributes to eye strain and the like. On the other hand, it has been reported that the stability of the tear fluid layer is improved by supplying an ophthalmic composition containing lecithin to the tear fluid layer (Patent Literature 1: JP 2007-211007 A). However, these stabilizing effects were insufficient when the tear oil layer became unstable due to an increase in saturated lipids.

JP 2007-211007 A

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

  As a result of intensive 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 lacrimal fluid. It has been found that the oil layer is stabilized and has a remarkable effect on dry eye, and the present invention has been made.

Accordingly, the present invention provides the following ophthalmic compositions.
[1]. An ophthalmic composition containing 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 is represented by the following formula (1)
(Wherein R ¹ —C (═O) is an acyl group having 12 or 14 carbon atoms, and R ² —C (═O) is an acyl group having 12, 14, 16 or 18 carbon atoms. )
The ophthalmic composition according to [1], which is a compound represented by the formula:
[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], which is for a soft contact lens wearer.
[6]. The ophthalmic composition according to any one of [1] to [5], which is for meibomian gland dysfunction patients.
[7]. The ophthalmic composition according to any one of [1] to [5], which is for dry eye patients.
[8]. The ophthalmic composition according to any one of [1] to [5], which is for eyestrain patients.
[9]. The ophthalmic composition according to any one of [1] to [5], which contains the 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 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 phosphatidylcholine as an active ingredient and is an eye strain improving agent.

  ADVANTAGE OF THE INVENTION According to this invention, the ophthalmic composition which can stabilize the tear oil layer of a patient who is unstable in the meibomian gland dysfunction can be provided by increasing the saturated lipid. In addition, since the dry eye can be improved by stabilizing the tear oil layer, an ophthalmic composition suitable for dry eye patients can be provided. Moreover, since eye fatigue can be improved by stabilizing the tear oil layer, an ophthalmic composition suitable for an eye fatigue patient can be provided.

2 is a photograph showing the results of a tear film stability test of Example 2. FIG. 6 is a photograph showing the results of a tear film 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 a hydroxyl group of glycerin, and choline is ester-bonded to phosphoric acid. In the phosphatidylcholine of the present invention, one fatty acid has 12, 14, 16, or 18 carbon atoms, and the other fatty acid has 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, the carbon number of one acyl group is 12, 14 or 16, and the carbon number of the other acyl group is 12 or 14. 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 individually by 1 type or in combination of 2 or more types.

In particular, what is represented by following formula (1) is preferable.
(Wherein R ¹ —C (═O) is an acyl group having 12 or 14 carbon atoms, and R ² —C (═O) is an acyl group having 12, 14, 16 or 18 carbon atoms. )

In the above formula, the acyl group may be saturated or unsaturated. In particular, R ¹ —C (═O) is an acyl group having 12 or 14 carbon atoms, and R ² —C (═O) is preferably a combination of 12, 14 and 16 acyl groups, ^{A combination in which 1} -C (= O) is an acyl group having 12 or 14 carbon atoms and R ² -C (= O) is an acyl group having 12 or 14 carbon atoms is more preferable.

Specifically, dilauroyl phosphatidylcholine (R ¹ —C (═O) and R ² —C (═O): an acyl group having 12 carbon atoms), dimyristoyl phosphatidylcholine (R ¹ —C (═O) and R ² ) -C (= O): acyl group having a carbon number of 14), dipalmitoylphosphatidylcholine (R ¹ -C (= O) and R ² -C (= O): acyl group having 16 carbon atoms), lauroyl Illuminator Rust yl phosphatidylcholine ( R ¹ —C (═O): C12 acyl group, R ² —C (═O): C14 acyl group), lauroyl palmitoylphosphatidylcholine (R ¹ —C (═O): C12 Acyl group, R ² —C (═O): C16 acyl group), lauroyl stearoylphosphatidylcholine (R ¹ —C (═O): C12 acyl group, R ² —C (═O): carbon Number 1 Acyl group) of myristoyl palmitoyl phosphatidylcholine ^{(R 1 -C (= O)} : acyl group having a carbon number of ^{14, R 2 -C (= O} ): acyl group having a carbon number of 16), myristoyl virus distearoylphosphatidylcholine (R ¹ -C (= O): an acyl group having 14 carbon atoms, R ² —C (═O): an acyl group having 18 carbon atoms) and a mixture thereof. Among these, dilauroyl phosphatidylcholine, dimyristoyl phosphatidylcholine, and lauroylmyristoyl phosphatidylcholine are preferable.

  The phosphatidylcholine of the present invention is different from lecithin. Examples of lecithin include egg yolk lecithin, soybean lecithin and the like, and any of them is a mixture of phospholipids such as phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), lysophosphatidylcholine (LPC) and the like. Furthermore, 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). In addition, as shown by the comparative example mentioned later, the effect of this invention is not acquired with a lecithin.

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

  The ophthalmic composition of the present invention can be blended with other components in appropriate amounts within a range not impairing the effects of the present invention. Examples of other components include surfactants, polyhydric alcohols, thickeners, sugars, buffers, pH adjusters, isotonic agents, stabilizers, cooling agents, drugs, and the like.

  Examples of the surfactant include polyoxyethylene polyoxypropylene glycol such as poloxamer, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, and polysorbate 80 (polyoxyethylene (20) sorbitan oleate). 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 surface activity) 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, and polyethylene glycol. The content of the polyhydric alcohol is preferably 0.001 to 5 W / V% in the ophthalmic composition.

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

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

  Examples of the buffer include citric acid, sodium citrate, boric acid, borax, phosphoric acid, sodium hydrogen phosphate, sodium dihydrogen phosphate, glacial acetic acid, trometamol, 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 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.

  Examples of the isotonic agent include sodium chloride and potassium chloride. 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, sulfite, 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, cineol, linalool and the like. The content of the refreshing agent is preferably 0.0001 to 0.2 W / V% in the ophthalmic composition.

  Examples of drugs (pharmaceutical active ingredients) include decongestants (eg, epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, dl-methylephedrine hydrochloride, etc.) Anti-inflammatory / astringent (eg, neostigmine methyl sulfate, epsilon-aminocaproic acid, allantoin, berberine chloride hydrate, berberine sulfate hydrate, azulene sulfonate, dipotassium glycyrrhizinate, zinc sulfate, zinc lactate, lysozyme hydrochloride Salt), antihistamines (eg, diphenhydramine hydrochloride, chlorpheniramine maleate, etc.), water-soluble vitamins (flavin adenine dinucleotide sodium, cyanocobalamin, pyridoxine hydrochloride, bread Ol, calcium pantothenate, sodium pantothenate, etc.), fat-soluble vitamins (eg, d-α-tocopherol acetate, retinol palmitate, etc.) amino acids (eg, potassium L-aspartate, magnesium L-aspartate, L-aspartate) Potassium / magnesium (a mixture of equal amounts), aminoethylsulfonic acid, sodium chondroitin sulfate, etc.), sulfa drugs, and the like. The effective content of each drug can be selected as the content of the drug. From the viewpoint of irritation to the eye, stability of the composition, etc., 0.001 to 5 W / V% in the ophthalmic composition Is preferred. The said other component can be mix | blended individually by 1 type or in combination of 2 or more types as appropriate.

  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 osmometer (HSMO-1, Toa DKK). 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 preparation method of the ophthalmic composition of this invention is not specifically limited, A well-known manufacturing method is employable. For example, it can be obtained by mixing the phosphatidylcholine of the present invention, an optional component, if necessary, and the remaining water and adjusting the pH. Thereafter, it is filled into a suitable container.

  Further, after filling the obtained ophthalmic composition in a resin container, it is further sealed with a package, and the inert gas concentration in the space formed between the container and the package may be enclosed, The ophthalmic composition may be filled in a resin container and sealed with a package 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 applied while wearing contact lenses), eye washes, contact lens mounting liquids, etc. Can be suitably used. 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 exhibited by instilling 30 to 60 μL per time and 3 to 6 times per day. When using as an eye wash, the effect of this invention can be exhibited more by washing eyes 3-6mL per time and 3-6 times per day.

  The ophthalmic composition of the present invention does not merely promote the production of oil components from the meibomian glands, but stabilizes the tear film oil film. If the production of the oil component is simply promoted, the saturated lipid increases, and rather causes eye strain, dry eye, and the like.

  The present invention is particularly effective for a meibomian gland dysfunction patient in which the tear fluid layer is unstable, a dry eye patient, an eye strain patient, and the like caused by an unstable tear fluid layer.

  Although the tear oil layer becomes unstable due to the increase in saturated lipid in the tear oil layer, this is facilitated by wearing a contact lens, so it can be used for contact lens wearers, especially for soft contact lens wearers. More effective.

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

  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. Unless otherwise specified, “%” of the composition is “W / V% mass / volume%”.

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

[Examples 17 to 32, Comparative Examples 7 to 12]
An ophthalmic composition having the composition shown in the following table is obtained by adding phosphatidylcholine, phosphatidylinositol, phosphatidic acid, or lecithin and polysorbate 80 to 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 film stability test and an eye strain improvement test. The results are also shown in the table.

<In vitro tear film stability test>
The tear oil layer mainly contains wax ester (oleyl oleate, etc.), cholesterol ester (cholesterol oleate, etc.), and phosphatidylcholine, and among these, those composed mainly 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 ratio of saturated lipids (C ₁₆ F ₀ , C ₁₈ F ₀ ) increases due to aging and changes in hormone balance, which causes the tear oil layer to become unstable (Cornea 2000, 19, p72-74). Therefore, oleyl oleate 3.8 μg, cholesterol oleate 5.8 μg, phosphatidylcholine (C ₁₈ F ₀ / C ₁₈ F ₀ ) 0.4 μg, perylene 0.1 μg in 1,000 μL chloroform was used as a tear oil layer model with increased saturated lipids. An oil layer prepared by a procedure of dissolving 10 μL of the solution on a water layer prepared with 1 mL of water in a 35 mm plastic dish was used. After the oil layer was allowed to stand at room temperature for 10 minutes, 50 μL of the prepared eye drop was added, placed on a 37 ° C. hot plate, and allowed to stand for 30 minutes. Thereafter, 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 oil layer stability was evaluated based on the image. The oil layer was considered stable when the water layer was not exposed. A result is shown by the following evaluation criteria. The photographs of Example 2 and Comparative Example 2 are shown in FIGS. In Example 2 of the present application, a uniform oil layer was formed, but in Comparative Example 2, the oil layer was broken and white streaks were formed, and the aqueous phase was exposed (in the photograph, the exposed portion is dark in color).

[In vitro tear oil layer stability evaluation criteria]
◎: Uniform oil layer ○: Oil layer is not uniform (there is unevenness), but water layer is not exposed ×: Water layer is exposed

<In vivo tear film stability test>
The tear fluid layer stability was evaluated by measuring BUT (break up time) using a dry eye observation device DR-1 (manufactured by Kowa Co., Ltd.). DR-1 is an apparatus capable of measuring an interference image of light reflected at the boundary surface between the tear fluid layer surface and the tear fluid layer. In healthy eyes, a uniform gray or white interference image is observed, and the interference image disappears when the tear oil layer collapses. Each subject was instilled with 30 μL of each eye drop, and after 10 minutes, blinked several times, and the time from the blink to the collapse of the tear fluid layer (BUT) was measured. The subjects selected 3 persons who had a BUT of 10 seconds or less and met the criteria for diagnosis of meibomian gland dysfunction (new ophthalmology 27 (5): 627-631 2010). The results before and after the instillation are shown as the average value of the three people, and the following evaluation criteria are shown from the results of the average value after the instillation.
[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>
About the ophthalmic composition, the eyestrain improvement effect was confirmed by the following method.
Three persons with eyestrain symptoms (ACTA OPTHALMOLOGICA 71 (1993), p347-352) were instilled with 50 μL of an ophthalmic composition (3 times at 2 hour intervals) and the eye 30 minutes after the third instillation The effect of improving fine fatigue symptoms was evaluated based on the following scores. A result is shown on the following evaluation criteria from the average value of the score of three persons.
[Evaluation of eye strain improvement effect]
2: Symptoms disappeared: Symptoms relieved 0: No change [Evaluation criteria for eye strain improvement effect]
◎: 1.5 or more ○: 1.0 or more and less than 1.5 ×: less than 1.0

The raw materials used in the above examples are shown below. Unless otherwise specified, the amount of each component in the table is a pure conversion amount.
Dilauroyl phosphatidylcholine: (NOF Corporation, COATSOME, MC-2020)
Dimyristoylphosphatidylcholine: (Larodane Fine Chemicals AB, 37-1400)
Myristoyl palmitoyl phosphatidylcholine: (Avanti Polar Lipids, Inc., 850445P)
Myristoyl stearoyl phosphatidylcholine: (Avanti Polar Lipids, Inc., 850446P)
Palmitoyl stearoyl phosphatidylcholine: Avanti Polar Lipids, Inc. Made by 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 (Kanto Chemical Co., Ltd.)
・ Boric acid (manufactured by Obuchi Pharmaceutical Co., Ltd.)
・ Bosand (manufactured by Kosuge Pharmaceutical Co., Ltd.)
・ Sodium chloride (Wako Pure Chemical Industries, Ltd.)
・ Potassium chloride (manufactured by Wako Pure Chemical Industries, Ltd.)
・ Sodium hydroxide (Wako Pure Chemical Industries, Ltd.)
・ Diluted hydrochloric acid (Wako Pure Chemical Industries, Ltd.)

Claims (11)

  An ophthalmic composition containing phosphatidylcholine having an acyl group having 12, 14, 16 or 18 carbon atoms and an acyl group having 12 or 14 carbon atoms. Phosphatidylcholine is represented by the following formula (1)
(Wherein R ¹ —C (═O) is an acyl group having 12 or 14 carbon atoms, and R ² —C (═O) is an acyl group having 12, 14, 16 or 18 carbon atoms. )
The ophthalmic composition according to claim 1, which is a compound represented by the formula:   The ophthalmic composition according to claim 1 or 2, wherein the content of phosphatidylcholine is 0.01 to 2.5 W / V%.   The ophthalmic composition according to any one of claims 1 to 3, which is an eye drop or an eye wash.   It is for soft contact lens wearers, The ophthalmic composition of any one of Claims 1-4.   The ophthalmic composition according to any one of claims 1 to 5, which is used for patients with meibomian gland dysfunction.   The ophthalmic composition according to any one of claims 1 to 5, which is for dry eye patients.   The ophthalmic composition according to any one of claims 1 to 5, which is used for patients with eye strain.   The ophthalmic composition according to any one of claims 1 to 5, which contains the phosphatidylcholine as an active ingredient and is a tear film oil film stabilizer.   The ophthalmic composition according to any one of claims 1 to 5, which contains the phosphatidylcholine as an active ingredient and is a dry eye improving agent.   The ophthalmic composition according to any one of claims 1 to 5, which contains the phosphatidylcholine as an active ingredient and is an eye strain improving agent.