JP7341397B2 - Composition for eye drops - Google Patents

Description

The present invention relates to an eye drop composition containing an extract extracted from a plant belonging to the genus Pecan in the family Walnut family and an inorganic salt.

In recent years, the number of dry eye patients has been increasing due to the spread of digital devices and the increase in the number of contact lens wearers, and the potential number of dry eye patients in Japan is said to be as high as 8 million. It is said that dry eye causes increased evaporation, causing a feeling of dryness in the eyes and corneal damage. Conventionally, methods such as instillation of artificial tears have been used to treat dry eyes. However, simply instilling artificial tears into the eyes does not have a sufficient water-retaining effect on the cornea, and the eyes tend to become dry.

In order to reduce the feeling of dryness, approaches have been taken to improve the wettability of eye drops by adding thickeners and the like to eye drops. Artificial tears containing sodium hyaluronate (Patent Document 1) have actually been developed, but their water retention effect on the cornea was not sufficient. In addition, when a large amount of thickener is added to the eye drops, the viscosity of the eye drops becomes high, and when the eye drops are instilled, the eye drops do not spread well to the cornea, resulting in an unfavorable feeling when wearing the eye drops.

Therefore, an ophthalmic preparation containing a polymer containing 2-methacryloyloxyethylphosphorylcholine (MPC) (MPC polymer) has been proposed. Patent Document 2 discloses an eye drop suitable for preventing, alleviating, improving, or treating hyperevaporative dry eye symptoms by stabilizing the tear oil layer and preventing evaporation of the tear aqueous layer on the corneal surface. Proposed. In this case, there is a need for an eye drop that exhibits a sufficient effect of alleviating dryness, spreads more quickly, has a high water retention effect on the cornea, and is comfortable to wear.

As mentioned above, there has been a demand for eye drops to spread more quickly and uniformly over the corneal surface, etc., and to have a high water-retention effect.However, conventional eye drops have been able to improve both dryness and moisture sensation while also making it easier to spread over the corneal surface. I couldn't do it.

WO1989/000044 WO2017/110874

An object of the present invention is to provide an eye drop composition that is easy to spread on the corneal surface and has an excellent moisturizing feeling by using an eye drop composition containing an extract extracted from a plant belonging to the genus Pecan in the family Walnut family and an inorganic salt. It is about providing.

As a result of intensive research to solve the above problems, the present inventors have discovered that an eye drop containing a specific proportion of an extract extracted from a plant belonging to the genus Pecan in the family Walnut family and a specific proportion of an inorganic salt. The present inventors have discovered that the composition can be easily spread over the corneal surface and also provides an excellent moisturizing sensation, leading to the completion of the present invention.

That is, the eye drop composition of the present invention is as follows.
1. 0.00005 to 2.0% by mass of at least one selected from seed extracts and seed shell extracts of plants belonging to the genus Pecan in the family Walnut family, as a solid content, and 0.001 to 1.5% by mass of inorganic salts. An eye drop composition containing.
2. Further, it contains 10 to 90 mol% of a structural unit based on 2-(meth)acryloyloxyethylphosphorylcholine and 90 to 10 mol% of a structural unit based on alkyl (meth)acrylate, and has a weight average molecular weight of 10,000 to 10,000. 5,000,000 of the copolymer (P) in an amount of 0.001 to 5.0% by mass.
3. The eye drop composition according to item 1 above, wherein the inorganic salt is sodium chloride.
4. The eye drop composition according to item 2, wherein the inorganic salt is sodium chloride, the 2-(meth)acryloyloxyethylphosphorylcholine is 2-methacryloyloxyethylphosphorylcholine, and the alkyl(meth)acrylate is butyl methacrylate. thing.

The eye drop composition of the present invention allows the components contained in the eye drop composition to spread uniformly on the corneal surface, and also has an excellent moisturizing feeling.

The configuration of the present invention will be explained below.
In this specification, "(meth)acrylate" means "acrylate or methacrylate", and the same applies to other similar terms.
Further, in this specification, when preferred numerical ranges (for example, ranges of concentration and weight average molecular weight) are described in stages, each lower limit value and upper limit value can be independently combined. For example, in the statement "preferably 10 or more, more preferably 20 or more, and preferably 100 or less, more preferably 90 or less", "preferable lower limit: 10" and "more preferable upper limit: 90" are combined. It can be set to "10 or more and 90 or less". For example, the statement "preferably 10 to 100, more preferably 20 to 90" can similarly be set to "10 to 90".

[Seed extract and seed husk extract of plants belonging to the genus Pecan in the family Walnut family]
The eye drop composition of the present invention contains at least one selected from seed extracts and seed shell extracts of plants belonging to the genus Pecan in the family Walnut family. There are no particular restrictions on the method for producing these extracts, and for example, plants belonging to the Juglandaceae family, pecan genus (Carya), specifically hickory (Carya tomentosa (Poir.) Nutt.) and pecan (Carya Seeds and/or seed shells of C. illinoensis (Wang) K. Koch), etc., as they are/or after drying, are treated with hydrocarbon compounds, esters, ketones, ethers, halogenated hydrocarbon compounds, alcohols and/or water. The desired extract can be obtained mainly by heating under reflux or immersion in one or more solvents selected from the following. A preferred extract is one obtained by extracting the seed shell of pecan, belonging to the genus Pecan in the family Walnut family, with water or one or more kinds of lower alcohols, and more preferably with water.

Specific examples of extraction methods include the following methods.
First, the seeds and/or seed husks to be treated are pulverized as they are or after drying, and extracted with an extraction solvent in an amount of about 5 to 100 times its weight. The extraction temperature is appropriately selected depending on the type of extraction solvent used. For example, when the extraction solvent is water, the extraction temperature is usually about 20 to 120 degrees, and when the extraction solvent is a lower alcohol, the extraction is usually carried out at about 20 to 50 degrees, preferably at room temperature. Further, the extraction time may be about 5 to 60 minutes when the extraction solvent is water, and about 24 to 96 hours when the extraction solvent is a lower alcohol.
After the extraction process, the extract is taken out by solid-liquid separation by means such as filtration, the extraction solvent is distilled off according to a conventional method, and the desired extract is obtained by drying if necessary.

The content of the extract of the present invention is in the range of 0.00005 to 2.0% by mass as solid content (solid content) based on the total amount of the eye drop composition. When this amount is less than 0.00005% by mass, sufficient effects may not be obtained. On the other hand, if it exceeds 2.0% by mass, not only will the stability over time deteriorate, but there is also the possibility that it will be disadvantageous in terms of cost. The preferred content of the extract component is 0.0001 to 1.5% by mass, more preferably 0.0005 to 1.0% by mass, in terms of solid content (solid content amount).

In the present invention, the extract can be contained as the extract itself, or as a concentrate or dry product thereof. Therefore, when the extract contains an extraction solvent, the amount of the solvent is analyzed and quantified by gas chromatography, high performance liquid chromatography, etc., the solid content is calculated, and the content is corrected.

[Inorganic salt]
The eye drop composition of the present invention contains an inorganic salt. More specifically, neutral salts such as sodium chloride, potassium chloride, and calcium chloride may be mentioned, with sodium chloride being preferred. Preferably, it is Japanese Pharmacopoeia grade, and commercially available products include sodium chloride “Otsuka” manufactured by Otsuka Pharmaceutical Co., Ltd., potassium chloride “Nichi-Iko” manufactured by Nichi-Iko Co., Ltd., and potassium chloride “Nichi-Iko” manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. Calcium chloride hydrate "for manufacturing only" is mentioned.

The content of the inorganic salt of the present invention is in the range of 0.001 to 1.5% by mass based on the total amount of the eye drop composition as a solid content. When this amount is less than 0.001% by mass, sufficient effects may not be obtained. On the other hand, if it exceeds 1.5% by mass, there is a possibility that a feeling of irritation may be felt in some cases. The preferred content of the inorganic salt is 0.005 to 1.2% by mass, more preferably 0.01 to 1% by mass.

[Copolymer (P)]
The eye drop composition of the present invention can preferably contain a copolymer (P) described below.
The copolymer (P) that can be contained in the ophthalmic composition of the present invention includes a structural unit based on a monomer having a phosphorylcholine structure (hereinafter referred to as "hydrophilic monomer") and a hydrophobic monomer. Examples include copolymers containing structural units based on polymers.

[Structural unit based on hydrophilic monomer]
The structural unit based on a hydrophilic monomer is a structural unit based on 2-(meth)acryloyloxyethylphosphorylcholine represented by the following formula (1). In addition, in this specification, "(meth)acryloyl" means "acryloyl or methacryloyl." As the hydrophilic monomer, 2-methacryloyloxyethylphosphorylcholine is preferred.

In formula (1), R ¹ represents a hydrogen atom or a methyl group.

[Constitution unit based on hydrophobic monomer]
The structural unit based on a hydrophobic monomer is a structural unit based on an alkyl (meth)acrylate ester.
The structural unit based on (meth)acrylic acid alkyl ester is represented by the following formula (2). Here, "(meth)acrylic acid" means "acrylic acid or methacrylic acid".

In formula (2), R ² is a hydrogen atom or a methyl group, preferably a methyl group.
In formula (2), R ³ is a hydrocarbon group having 1 to 24 carbon atoms, preferably a straight chain saturated hydrocarbon group having 1 to 24 carbon atoms, and the straight chain saturated hydrocarbon group having 1 to 24 carbon atoms is , for example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, decyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group, octadecyl group, Examples include docosyl group.

Examples of structural units based on the alkyl (meth)acrylate represented by formula (2) include methyl (meth)acrylate, ethyl (meth)acrylate, propyl (meth)acrylate, butyl (meth)acrylate, Structural units based on 2-ethylhexyl (meth)acrylate, dodecyl (lauryl) (meth)acrylate, tridecyl (meth)acrylate, octadecyl (stearyl) (meth)acrylate, docosyl (behenyl) (meth)acrylate, etc. can be mentioned.
Among the hydrophobic monomers, butyl (meth)acrylate or octadecyl (stearyl) (meth)acrylate is preferred, butyl (meth)acrylate is more preferred, and butyl methacrylate is particularly preferred.

The content of the structural unit based on the hydrophilic monomer in the copolymer (P) is 10 to 90 mol%, preferably 50 to 90 mol%, and particularly preferably 75 to 85 mol%. Within this range, the balance between hydrophilicity and lipophilicity is good, and the effects of the present invention can be sufficiently obtained.

The content of the structural unit based on the hydrophobic monomer in the copolymer (P) is 10 to 90 mol%, preferably 10 to 50 mol%, and particularly preferably 15 to 25 mol%.

Preferred examples of the copolymer (P) of the present invention are as follows.
R ¹ : methyl group, R ² : methyl group, R ³ : butyl group, content of structural units based on hydrophilic monomer: 80 mol%, content of structural units based on hydrophobic monomer: 20 mol %

[Other constituent units]
The copolymer (P) may contain other structural units other than the structural units based on the hydrophilic monomer and the hydrophobic monomer as long as the effects of the present invention are not impaired. However, it is preferable to consist only of structural units based on hydrophilic monomers and structural units based on hydrophobic monomers.

Other structural units include, for example, hydroxyl group-containing monomers such as glyceryl mono(meth)acrylate, nitrogen-containing monomers such as aminoethyl (meth)acrylate, and 2-hydroxy-3-(meth)acryloyl Examples include structural units based on polymerizable monomers such as cationic group-containing monomers such as oxypropyltrimethylammonium chloride.

[Weight average molecular weight of copolymer (P)]
The weight average molecular weight of the copolymer (P) is 10,000 to 1,000,000, preferably 20,000 to 900,000, more preferably 30,000 to 800,000, and even more preferably 50,000. 700,000, more preferably 80,000 to 600,000. Within this range, the effects of the present invention can be easily obtained and the handleability is also excellent.

The weight average molecular weight of the copolymer (P) refers to a value determined by gel permeation chromatography (GPC). Specifically, it refers to the molecular weight in terms of polyethylene glycol measured using any one of chloroform, dimethylformamide, tetrahydrofuran, methanol, and a combination of these solvents as an eluent.

[Method for producing copolymer (P)]
The copolymer (P) can be prepared by copolymerizing the above monomers according to a known method.

<Concentration of copolymer (P)>
When the ophthalmic composition of the present invention contains the copolymer (P), the content is preferably 0.001 to 5.0% by mass, more preferably 0.002 to 4.0% by mass, even more preferably is 0.003 to 3.5% by weight, even more preferably 0.005 to 2.0% by weight, particularly preferably 0.01 to 1.0% by weight.

In the present invention, "mass%" refers to the mass of a certain component in 100 g of a solution in grams (g). For example, "the solution of the present invention contains 1.0% by mass of copolymer (P)" means that 100 g of the solution contains 1.0 g of copolymer (P). .

<Solvent>
The eye drop composition of the present invention preferably uses water as a solvent, and in addition to water, alcohols such as ethanol, n-propanol, and isopropanol can be used.

The water used in the eye drop composition of the present invention can be water that is normally used in the production of pharmaceuticals, medical devices, and the like. Specifically, ion exchange water, purified water, sterile purified water, distilled water, water for injection, etc. can be used.

<Other ingredients>
The ophthalmic composition of the present invention contains, in addition to a seed extract and a seed shell extract belonging to the genus Pecan of the family Walnut family, an inorganic salt, a copolymer (P), and water, if necessary, additives. It's okay.
Examples of additives include those used in conventional eye drop compositions, such as vitamins, amino acids, sugars, cooling agents, antioxidants, stabilizers, preservatives, and chelating agents. , buffering agents, etc.
When the ophthalmic composition of the present invention contains additives, the content thereof is preferably 0.001 to 5% by mass, more preferably 0.01 to 1% by mass, based on the total amount of the ophthalmic composition. .

<Method for producing eye drop composition>
The ophthalmic composition of the present invention comprises a seed extract and a seed shell extract belonging to the genus Pecan in the family Walnut family, an inorganic salt, a copolymer (P) if necessary, water if necessary, and others if necessary. It can be produced by a general method for producing eye drop compositions, which involves mixing and stirring the following ingredients. Note that the obtained eye drop composition may be subjected to operations such as sterile filtration, if necessary.

<pH of eye drop composition>
The pH of the eye drop composition of the present invention is preferably 3.0 to 9.0, more preferably 3.0 to 8.0, even more preferably 4. 0 to 8.0, more preferably 4.0 to 7.4.
In addition, the pH of the eye drop composition in this specification refers to the value measured according to the 17th edition Japanese Pharmacopoeia General Test Method 2.54 pH measurement method.

<Osmotic pressure and osmotic pressure ratio of eye drop composition>
The osmotic pressure of the eye drop composition of the present invention is preferably 200 to 400 mOsm, more preferably 210 to 350 mOsm, even more preferably 220 to 340 mOsm, and the osmotic pressure ratio is preferably is from 0.7 to 1.4, more preferably from 0.8 to 1.3, even more preferably from 0.8 to 1.2.
The osmotic pressure of the eye drop composition in this specification is a value measured according to the 17th edition Japanese Pharmacopoeia General Test Method 2.47 Osmolality measurement method (osmolarity measurement method).

<How to use the eye drop composition>
Specific product forms of the eye drop composition of the present invention include, for example, general eye drops, antibacterial eye drops, artificial lachrymal fluid, eye wash solution, and contact lens mounting solution.

EXAMPLES Hereinafter, the ophthalmic composition of the present invention will be specifically explained with reference to Examples and Comparative Examples, but the present invention is not limited thereto. The extracts and copolymers used in the Examples and Comparative Examples are as follows.

An extract was produced with reference to the method described in JP-A No. 2004-196745.

Production Example Pecan seeds (pecan nuts) of the genus Pecan in the family Walnut family were crushed with the seed shell attached, and 500 mL of distilled water was added to 100 g of the crushed product, and the mixture was heated under reflux at 110 degrees for 10 minutes to obtain an extract. The solvent (water) was distilled off from this extract under reduced pressure to produce a pecan seed husk extract (6.5 g of light brown powder).

Copolymer (P)
A 2-methacryloyloxyethylphosphorylcholine/butyl methacrylate copolymer (2-methacryloyloxyethylphosphorylcholine/butyl methacrylate = 80/20 (mole ratio), weight average molecular weight 600,000) was used.

Example 1
Weigh out about 80 g of purified water, add 0.4 g of boric acid, 0.0072 g of sodium hydroxide, 0.65 g of sodium chloride, and 0.0004 g of 20% hydrochloric acid polyhexanide solution (trade name: Cosmocil CQ) (since it is a 20% solution, (containing 0.00008 g of polyhexanide hydrochloride) and 0.001 g of the pecan seed husk extract of Production Example were added and stirred. The components shown in Table 1 below were used as common additive components (additives). After that, purified water was added so that the total amount was 100 g. Furthermore, filtration was performed to remove seed shells and to sterilize the mixture to produce an eye drop composition. The resulting eye drop composition was evaluated for its moisturizing feel and spreadability. The results are shown in Table 2.

[Example 2, 3]
A sterile eye drop composition was prepared in the same manner as in Example 1, except that the ingredients and amounts shown in Table 2 were used. The resulting eye drop composition was evaluated for its moisturizing feel and spreadability. The results are shown in Table 2. In addition, the components shown in Table 1 were used as common additive components (additives).

[Comparative Examples 1 and 2]
A sterile eye drop composition was prepared according to the same procedure as in the example except that the ingredients and amounts shown in Table 3 below were used. The resulting eye drop composition was evaluated for its moisturizing feel and spreadability. The results are shown in Table 3. In addition, the components shown in Table 1 were used as common additive components (additives).

<Evaluation of moisture feeling after eye drops>
One drop of the ophthalmic compositions of Examples and Comparative Examples was instilled into the eyes, and the feeling of moisture after instillation was evaluated using the following three-level criteria. The evaluation was carried out by 10 people, and a cumulative total of 20 or more points was evaluated as an eye drop composition with a good moisturizing feeling.
3: Feels moisturized.
2: Feels slightly moist.
1: I don't feel any moisture.

<Evaluation of ease of spreading during eye drops>
One drop of the ophthalmic compositions of Examples and Comparative Examples was instilled into the eyes, and after blinking twice, the ease with which the ingredients contained in the ophthalmic compositions spread was evaluated using the following three-level criteria. The evaluation was carried out by 10 people, and a cumulative total of 20 or more points was evaluated as an eye drop composition with good spreadability.
3: It felt that the eye drop composition was sufficiently spread uniformly on the ocular surface.
2: It felt that the eye drop composition was spread uniformly on the ocular surface.
1: I felt that the eye drop composition did not spread uniformly on the ocular surface.

Since Comparative Example 2 does not contain pecan seed husk extract, and the eye drop composition of Comparative Example 1 does not contain inorganic salts, the eye drop composition satisfies all of the evaluations of moisturizing sensation and spreadability after instillation. I couldn't turn it into a thing.
On the other hand, the eye drop compositions of Examples 1 to 3 met the criteria in both the moisture feeling evaluation and the spreadability evaluation, indicating that the eye drop compositions had excellent spreadability and suppressed dryness. there were. Furthermore, the eye drop composition of Example 3 containing the copolymer (P) at a predetermined concentration had particularly excellent evaluation results in both the moisture feeling evaluation and the spreadability evaluation, showing that it suppressed the dry feeling and spread easily. It was an extremely excellent eye drop composition.

Use of the eye drop composition of the present invention suppresses the feeling of dryness and is effective in improving the feeling of use and the therapeutic effect on dry eye.

Claims (2)

An eye drop composition containing 0.00005 to 2.0% by mass of at least one selected from pecan seed husk hot water extract as a solid content and 0.001 to 1.5% by mass of an inorganic salt.
Further, it contains 10 to 90 mol% of a structural unit based on 2-(meth)acryloyloxyethylphosphorylcholine and 90 to 10 mol% of a structural unit based on alkyl (meth)acrylate, and has a weight average molecular weight of 10,000 to 10,000. The eye drop composition according to claim 1, containing 0.001 to 5.0% by mass of the copolymer (P) having a molecular weight of 5,000,000%.