JP7218689B2 - eye drops - Google Patents

Description

TECHNICAL FIELD The present invention relates to eye drops containing a copolymer having a specific structure and polyhexamethylene biguanide or a salt thereof.

In recent years, the number of dry eye patients has been increasing with the spread of digital devices and the increase in the number of elderly people and contact lens wearers. One of the causes of dry eye development is lack of moisture associated with increased tear evaporation and the resulting friction between the ocular surface and the upper eyelid. Since dry eye is generally treated with eye drops, eye drops intended for dry eye treatment must have moisturizing properties to prevent the above-mentioned lack of moisture and reduce friction between the palpebral conjunctival margin and the ocular surface. Lubricity is required.

On the other hand, eye drops are sterile until clinical use, but common eye drops, other than single-use ones, are exposed to the risk of microbial contamination from the moment the container is opened. . It is also conceivable that the eye drops themselves may become contaminated through misuse, such as instilling the drops into the eye by contacting the eyelashes or eyelids. Bacterial contamination of these eye drops can lead to serious eye damage, so from the safety perspective of preventing microbial contamination during use, most eye drops contain preservatives, and the use of antiseptic agents is recommended. of preservative efficacy is required.

Eye drops manufacturers usually check the stability of various ingredients, including preservatives, under certain conditions, and set expiration dates within the range that guarantees the effects. However, as mentioned above, eye drops are often indicated for the treatment of many eye diseases, including dry eye, and are relatively easy to obtain at pharmacies. be done. For example, the use of expired eye drops or the use after long-term storage under conditions not intended by the manufacturer. In such cases, the preservative concentration in the eye drops may fall below the standard value, and the preservative efficacy of the eye drops may not be sufficient, which is not preferable from the standpoint of safety. Assuming such a case, an eye drop having sufficient preservative efficacy is required even if the preservative concentration is low to some extent.

In summary, eye drops intended for dry eye treatment should combine moisturizing and lubricating properties while having sufficient preservative efficacy with as few preservatives as possible.
Until now, various ophthalmic compositions that improve the lubricity of the corneal surface or the contact lens surface have been studied with the aim of treating dry eye and improving the wearing comfort of contact lenses (Patent Documents 1 to 3). ).
Patent Document 1 relates to an eye drop for soft contact lenses that enhances the wettability of soft contact lenses and improves wearing comfort.
Patent Document 2 presents a composition that has excellent moisturizing power and greatly improves lubricity, but this relates to contact lens care preparations and contact lens packing liquids, and does not mention eye drops. .
Patent Document 3 relates to an eye drop that provides sufficient lubricity to the corneal surface and soft contact lens surface, but there is no description of the preservative effect of the eye drop described in Patent Document 3.

JP 2011-136923 A JP 2012-88524 A WO2016/140242

On the other hand, for the treatment and alleviation of dry eye symptoms, it is desirable that the above-mentioned moisturizing and lubricating properties are quickly exhibited on the surface of the eye or contact lens. Therefore, after instillation, the eye drops need to quickly spread over the eye or the surface of the contact lens.
In the process of preparing eye drops effective for dry eye treatment as described above, polyhexamethylene biguanide, which is a preservative with less eye irritation, is added in a smaller amount than general eye drops, and further functionality is added. Furthermore, when an eye drop containing both a specific terpolymer that contributes to significant improvement in moisturizing and lubricating properties was prepared, satisfactory preservative efficacy could not be confirmed. In other words, a satisfactory ophthalmic solution having both sufficient preservative efficacy and functionality has not yet been obtained.
Accordingly, an object of the present invention is to impart lubricity and moisturizing properties to the corneal surface and soft contact lenses, to have sufficient preservative efficacy, and to rapidly spread over the surface of the eye or contact lens to provide moisturizing and lubricating effects. To provide an eye drop that exhibits

As a result of intensive research to solve the above problems, the present inventors have found a copolymer having a specific structure having three different structural units at a specific ratio, and a copolymer having two specific structural units at a specific ratio. and a specific antiseptic agent in a specific ratio. Arrived. In addition, the ophthalmic solution of the present invention spreads quickly on the surface of the eye or soft contact lens, and can rapidly exhibit effects such as moisturizing and lubricating properties on the surface of the eye or contact lens.

（式中、Ｒ^１、Ｒ^２、Ｒ^５、Ｒ^７及びＲ^８は、それぞれ独立に、水素原子又はメチル基を示し、Ｒ^３及びＲ^４は、それぞれ独立に、メチル基又はエチル基を示す。Ｒ^６は炭素数１２～２４の一価の炭化水素基を示す。Ｒ^９は炭素数４～１８のアルキル基を示す。）
［２］ポリオキシエチレンポリオキシプロピレングリコールを０．００１～５．０ｗ／ｖ％含む上記［１］記載の点眼剤。
［３］ソフトコンタクトレンズ装用者用である上記［１］または［２］記載の点眼剤。 That is, the present invention is as follows [1] to [3].
[1] It has structural units represented by formulas (1a) to (1c), the molar ratio _na : _nb : _nc of each structural unit is 100:10 to 400:2 to 50, and the weight 0.001 to 1.0 w/v% of the copolymer (P) having an average molecular weight of 5,000 to 2,000,000 and having structural units represented by formulas (1d) to (1e) Then, a copolymer (Q) having a molar ratio n _d : n _e of each structural unit of 10 to 90:10 to 90 and a weight average molecular weight of 10,000 to 5,000,000 is added to 0.01 to 5.0 w/v% and 0.000001-0.001 w/v% polyhexamethylene biguanide or a salt thereof.

(wherein R ¹ , R ² , R ⁵ , R ⁷ and R ⁸ each independently represent a hydrogen atom or a methyl group, R ³ and R ⁴ each independently represent a methyl group or an ethyl group .R ⁶ represents a monovalent hydrocarbon group having 12 to 24 carbon atoms, and R ⁹ represents an alkyl group having 4 to 18 carbon atoms.)
[2] The ophthalmic solution according to [1] above, containing 0.001 to 5.0 w/v% of polyoxyethylene polyoxypropylene glycol.
[3] The ophthalmic solution according to [1] or [2] above, which is for soft contact lens wearers.

The eye drops of the present invention can impart sufficient lubricity to the corneal surface and soft contact lens surface, and have sufficient preservative efficacy. Furthermore, after instillation, it spreads quickly on the surface of the eye or soft contact lens, and effects such as lubricating properties and moisturizing properties can be rapidly exhibited on the eye surface.

The present invention will be described in detail below.
The copolymer (P) used in the eye drops of the present invention has three structural units represented by the following formulas (1a) to (1c), and the molar ratio _na : _nb : _nc of each structural unit is 100. : 10 to 400: 2 to 50, and the copolymer (Q) used in the eye drops of the present invention has structural units represented by the following formulas (1d) to (1e), and each structural unit The molar ratio n _d : n _e is 10-90:10-90, and the weight average molecular weight is 10,000-5,000,000.

<Copolymer P>
The copolymer (P) used in the eye drops of the present invention has the following three structural units (1) to (3), and the molar ratio _na : _nb : _nc of each structural unit is 100: 10-400:2-50. By including the copolymer (P) in the eye drops, lubricity and spreadability are improved.

<(1) PC constituent unit>
The copolymer (P) used in the eye drops of the present invention has a structural unit represented by the following formula (1a) (hereinafter abbreviated as "PC structural unit"). The PC structural unit is a structural unit derived from a PC monomer represented by formula (2) described later. When the copolymer (P) contains a structural unit derived from a PC monomer, it can impart excellent water retentivity to the ocular surface.

In formula (1a) above, R ¹ represents a hydrogen atom or a methyl group. _na represents the number of structural units represented by the formula (1a) in the copolymer (P).
The PC structural unit in the copolymer (P) is introduced in order to impart hydrophilicity and hydrogel-forming ability to the copolymer (P) and improve lubricity.
The PC structural unit in the copolymer (P) is a phosphorylcholine-like group-containing monomer represented by the following formula (2) used during polymerization of the copolymer (P) (hereinafter abbreviated as PC monomer ).

式（２）中、Ｘは不飽和結合を有する重合性官能基を有する１価の有機基を示す。中でもＸは、（メタ）アクリロイルオキシ基であることが好ましい。
ＰＣ単量体としては、入手性の観点から例えば、２－（（メタ）アクリロイルオキシ）エチル－２’－（トリメチルアンモニオ）エチルホスフェートが好ましく、さらに下記式（３）で表される２－（メタクリロイルオキシ）エチル－２’－（トリメチルアンモニオ）エチルホスフェート（以下、ＭＰＣとする）が好ましい。

In formula (2), X represents a monovalent organic group having a polymerizable functional group having an unsaturated bond. Among them, X is preferably a (meth)acryloyloxy group.
As the PC monomer, from the viewpoint of availability, for example, 2-((meth)acryloyloxy)ethyl-2'-(trimethylammonio)ethyl phosphate is preferable, and further 2- represented by the following formula (3) (Methacryloyloxy)ethyl-2'-(trimethylammonio)ethyl phosphate (hereinafter referred to as MPC) is preferred.

<(2) Amide structural unit>
The copolymer (P) used in the eye drops of the present invention has a structural unit represented by the following formula (1b) (hereinafter abbreviated as "amide structural unit").

In formula (1b) above, R ² represents a hydrogen atom or a methyl group, and R ³ and R ⁴ independently represent a methyl group and an ethyl group. _nb represents the number of structural units represented by the formula (1b) in the copolymer (P).
The amide structural unit in the copolymer (P) is introduced in order to increase the molecular weight of the copolymer (P) and enhance the adhesion to soft contact lenses.
The proportion of amide structural units in the copolymer (P) is n _b /n _a =10 to _400/100 , where the number of moles n _b of the PC structural unit is taken as 100, and It is preferably 30 to 250/100. If _nb is too large, sterile filtration that is necessary in the production of eye drops may become difficult, and if _nb is too small, the effect of improving lubricity cannot be expected.

The amide structural unit in the copolymer (P) is a monomer represented by the following formula (1b′) used during polymerization of the copolymer (P), namely (meth)acrylamide or (meth)acrylamide derivative obtained from In other words, the amide structural unit is a structural unit derived from the monomer represented by formula (1b').

R ² , R ³ and R ⁴ in formula (1b') are respectively the same as R ² , R ³ and R ⁴ in formula (1b).
Examples of the (meth)acrylamide or (meth)acrylamide derivative represented by the formula (1b′) include N,N-dimethyl(meth)acrylamide and N,N-diethyl(meth)acrylamide.

<(3) Hydrophobic structural unit>
The copolymer (P) used in the eye drops of the present invention has a structural unit represented by the following formula (1c) (hereinafter abbreviated as "hydrophobic structural unit").

In formula (1c) above, R ⁵ represents a hydrogen atom or a methyl group, and R ⁶ represents a monovalent hydrocarbon group having 12 to 24 carbon atoms such as a lauryl group, a stearyl group, and a behenyl group. R ⁶ is preferably a monovalent hydrocarbon group having 12 to 20 carbon atoms, more preferably 14 to 20 carbon atoms, still more preferably 17 to 19 carbon atoms. _nc represents the number of structural units represented by the above formula (1c) in the copolymer (P).
The hydrophobic constitutional unit in the copolymer (P) is introduced in order to increase the adsorptivity to the soft contact lens, increase the ability to form a physically crosslinked gel by hydrophobic interaction, and improve the lubricity.

Regarding the ratio of the hydrophobic constitutional units in the copolymer (P), the number of moles n _c when the number of moles n _a of the PC constitutional units is 100 is n _c /n _a =2 to 50/100. , preferably 5 to 25/100. If _nc is too small, the lubricating effect does not last sufficiently, and if it is too large, the hydrophilicity of the copolymer (P) decreases, resulting in a decrease in the solubility in water, resulting in the production of eye drops. becomes difficult.

The hydrophobic structural unit in the copolymer (P) is obtained from a hydrophobic monomer represented by the following formula (1c') used during polymerization of the copolymer (P). In other words, the hydrophobic structural unit is a structural unit derived from the monomer represented by formula (1c').

R ⁵ and R ⁶ in formula (1c′) are the same as R ⁵ and R ⁶ in formula (1c), respectively.
Examples of the hydrophobic monomer represented by formula (1c′) include linear alkyl (meth)acrylates such as lauryl (meth)acrylate, stearyl (meth)acrylate, and behenyl (meth)acrylate.

<Other structural units>
The copolymer (P) may contain structural units other than the structural units represented by formulas (1a) to (1c) as long as the effects of the present invention are not impaired. _Assuming that na represented by formula (1a) constituting the copolymer (P) is 100, the molar ratio of the other constituent units is preferably 50 or less, more preferably 10 or less, and still more preferably 0.

Other structural units are, for example, structural units derived from other monomers shown below.
Other monomers include, for example, linear or branched alkyl (meth)acrylates, cyclic (meth)acrylates, aromatic group-containing (meth)acrylates, styrene-based monomers, vinyl ether monomers, and vinyl esters. Examples include monomers, hydrophilic hydroxyl group-containing (meth)acrylates, acid group-containing monomers, amino group-containing monomers, cationic group-containing monomers, and the like.
Linear or branched alkyl (meth)acrylates include, for example, methyl (meth)acrylate, ethyl (meth)acrylate, butyl (meth)acrylate, 2-ethylhexyl (meth)acrylate and the like.
Cyclic alkyl (meth)acrylates include, for example, cyclohexyl (meth)acrylate.
Examples of aromatic group-containing (meth)acrylates include benzyl (meth)acrylate and phenoxyethyl (meth)acrylate.
Styrenic monomers include, for example, styrene, methylstyrene, chloromethylstyrene and the like.
Examples of vinyl ether monomers include methyl vinyl ether and butyl vinyl ether.
Vinyl ester monomers include, for example, vinyl acetate and vinyl propionate.

Examples of hydrophilic hydroxyl group-containing (meth)acrylates include polyethylene glycol (meth)acrylate, polypropylene glycol (meth)acrylate, N-vinylpyrrolidone, 2-hydroxyethyl (meth)acrylate, and 2-hydroxybutyl (meth)acrylate. , 4-hydroxybutyl (meth)acrylate and the like.
Examples of acid group-containing monomers include (meth)acrylic acid, styrenesulfonic acid, (meth)acryloyloxyphosphonic acid and the like.
Examples of amino group-containing monomers include aminoethyl methacrylate, dimethylaminoethyl (meth)acrylate, N,N-dimethylaminopropyl (meth)acrylamide and the like.
Cationic group-containing monomers include, for example, 2-hydroxy-3-(meth)acryloyloxypropyltrimethylammonium chloride.

<Molecular Weight of Copolymer (P)>
The copolymer (P) used in the present invention has a weight average molecular weight of 5,000 to 2,000,000, preferably 100,000 to 1,500,000, more preferably 500,000 to 1,500, 000 polymer. If the weight-average molecular weight is less than 5,000, the adhesion of the polymer to the surface of the contact lens is insufficient, and there is a risk that improvement in lubricity cannot be expected. The sterile filtration required during manufacturing can be difficult.

<Method for producing copolymer (P)>
The copolymer (P) includes a monomer represented by the above formula (2), a monomer represented by formula (1b'), and a monomer represented by formula (1c'). It can be obtained by radically polymerizing a monomer composition. In addition, the monomer composition may contain other monomers as described above within a range that does not impair the effects of the present invention.
The copolymer (P) is produced, for example, by radical polymerization of the above monomer composition in the presence of a radical polymerization initiator in an inert gas atmosphere such as nitrogen, carbon dioxide, argon or helium. It can be carried out. Polymerization can be carried out by known methods such as bulk polymerization, suspension polymerization, emulsion polymerization and solution polymerization. The copolymer (P) can be purified by known methods such as reprecipitation, dialysis, and ultrafiltration.
Examples of radical polymerization initiators include azo radical polymerization initiators, organic peroxides, persulfates and the like.

Examples of azo radical polymerization initiators include 2,2-azobis(2-diaminopropyl) dihydrochloride and 2,2-azobis(2-(5-methyl-2-imidazolin-2-yl)propane) dihydrochloride. salt, 4,4-azobis(4-cyanovaleric acid), 2,2-azobisisobutyramide dihydrate, 2,2-azobis(2,4-dimethylvaleronitrile), 2,2-azobisiso butyronitrile (AIBN) and the like.
Examples of organic peroxides include benzoyl peroxide, diisopropylperoxydicarbonate, t-butylperoxy-2-ethylhexanoate, lauroyl peroxide, t-butylperoxyneodecanate, and succinic acid peroxide.
Examples of peroxides include ammonium persulfate, potassium persulfate, sodium persulfate and the like.
These radical polymerization initiators can be used alone, or two or more of them can be used in combination. The amount of polymerization initiator to be used is usually 0.001 to 10 parts by mass, preferably 0.01 to 5.0 parts by mass, per 100 parts by mass of the monomer composition.

The copolymer (P) can be produced in the presence of a solvent. Any solvent can be used as long as it dissolves the monomer composition and does not react with it. Examples thereof include alcohol solvents, ketone solvents, ester solvents, linear or cyclic ether solvents, Solvents may be mentioned.
Examples of alcohol solvents include water, methanol, ethanol, n-propanol, isopropanol and the like.
Examples of ketone solvents include acetone, methyl ethyl ketone, diethyl ketone and the like.
Examples of the ester solvent include ethyl acetate.
Linear or cyclic ether solvents include, for example, ethyl cellosolve, tetrahydrofuran, N-methylpyrrolidone and the like.
Examples of nitrogen-containing solvents include acetonitrile and nitromethane. Water, alcohol, or a mixed solvent thereof is preferred.

<Copolymer Q>
The copolymer (Q) used in the eye drops of the present invention has the following two structural units (1) to (2), and the molar ratio n _d : n _e of each structural unit is 10 to 90:10. ˜90 and a weight average molecular weight of 10,000 to 5,000,000.

<(1) PC constituent unit>
The copolymer (Q) used in the present invention contains a PC structural unit represented by the following formula (1d), that is, a structural unit derived from the PC monomer. When the copolymer (Q) contains a structural unit derived from a PC monomer, it can impart excellent water retentivity to the ocular surface, and can exhibit a stabilizing effect on the tear film and the tear oil film.

上記（１ｄ）においてＲ^７は、水素原子又はメチル基を指す。ｎ_ｄは、共重合体（Ｑ）中の上記式（１ｄ）で示される構成単位の数を表す。
共重合体（Ｑ）中のＰＣ構成単位は、前記ＰＣ単量体から得られる。ＰＣ単量体は、前記の通り公知の方法で製造できる。

In (1d) above, R ⁷ represents a hydrogen atom or a methyl group. nd represents the number of structural units represented by the formula ( _1d ) in the copolymer (Q).
The PC structural unit in the copolymer (Q) is obtained from the PC monomer. A PC monomer can be produced by a known method as described above.

The content of the structural unit (1d) in the copolymer (Q) is 10-90 mol%, preferably 20-90 mol%, more preferably 30-90 mol%. If the content is less than 10 mol %, the ocular surface may not be sufficiently moisturized. On the other hand, if the content is more than 90 mol %, there is a possibility that a remarkable effect of improving lubricity cannot be expected.

<(2) Structural unit derived from alkyl group-containing (meth)acrylic monomer>
The copolymer (Q) used in the present invention contains a structural unit represented by the following formula (1e). The structural unit is a structural unit derived from an alkyl group-containing (meth)acrylic monomer.

共重合体（Ｑ）中のアルキル基含有（メタ）アクリル系単量体に由来する構成単位は、下記式（１ｅ’）で表されるアルキル基含有（メタ）アクリル系単量体の重合によって得られる。
式（１ｅ）において、Ｒ^８は水素原子又はメチル基のいずれでもよいが、好ましくはメチル基である。Ｒ^９は炭素数４～１８の直鎖状または分岐状のアルキル基である。ｎ_ｅは、共重合体（Ｑ）中の上記式（１ｅ）で示される構成単位の数を表す。

The structural unit derived from the alkyl group-containing (meth)acrylic monomer in the copolymer (Q) is formed by polymerization of the alkyl group-containing (meth)acrylic monomer represented by the following formula (1e') can get.
In formula (1e), R ⁸ may be either a hydrogen atom or a methyl group, preferably a methyl group. R ⁹ is a linear or branched alkyl group having 4 to 18 carbon atoms. n _e represents the number of structural units represented by the above formula (1e) in the copolymer (Q).

式（１ｅ’）において、Ｒ^８及びＲ^９は式（１ｅ）と同様である。

In formula (1e'), R ⁸ and R ⁹ are the same as in formula (1e).

Examples of the linear alkyl group having 4 to 18 carbon atoms for R ⁹ include n-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group, n -decyl group, n-undecyl group, n-dodecyl group, n-tridecyl group, n-tetradecyl group, n-pentadecyl group, n-hexadecyl group, n-heptadecyl group and n-octadecyl group.
Branched alkyl groups having 4 to 18 carbon atoms include t-butyl, isobutyl, isopentyl, t-pentyl, neopentyl, isohexyl, isoheptyl, isooctyl, isononyl, isodecyl and isoundecyl groups. , isododecyl group, isotridecyl group, isotetradecyl group, isopentadecyl group, isohexadecyl group, isoheptadecyl group, and isooctadecyl group.

From the viewpoint of the hydrophilicity-lipophilicity balance of the copolymer, R ⁹ is preferably a linear alkyl group, more preferably an n-butyl group, an n-dodecyl group or an n-octadecyl group, and an n-butyl group. is most preferred.

As long as it has a structure that satisfies the structural unit (1e), it does not impair the balance between hydrophilicity and lipophilicity of the copolymer (Q), so any of them can be used. Preferred examples of alkyl group-containing (meth)acrylic monomers from the viewpoint of further enhancing the tear oil layer stabilizing effect include butyl (meth)acrylate, lauryl (meth)acrylate, and stearyl (meth)acrylate. Most preferred is butyl (meth)acrylate.

The copolymer (Q) used in the present invention has the structural unit (1e) in the molecular chain, thereby increasing the lipophilicity of the copolymer, without impairing the balance between hydrophilicity and lipophilicity, and tear lipid layer. can be spread over the aqueous tear layer, thus enhancing the effect of stabilizing the tear lipid layer. Further, the copolymer (Q) used in the present invention becomes a tear lipid layer stabilizer by having the structural unit (1d) and the structural unit (1e) in the same polymer chain.

The content of the structural unit (1e) in the copolymer (Q) used in the present invention is 10 to 90 mol%, preferably 10 to 80 mol%, more preferably 10 to 70 mol%. When the content is less than 10 mol%, the lipophilicity of the copolymer (Q) becomes poor, the balance between hydrophilicity and lipophilicity is impaired, the spreading action of the tear lipid layer onto the aqueous tear layer is weakened, and the tear liquid. There is a possibility that the effect of stabilizing the oil layer cannot be expected. On the other hand, if the content is more than 90 mol %, the solubility in water may decrease, making it difficult to prepare eye drops.

The molar ratio n _d :n _e between the structural unit (1d) and the structural unit (1e) in the copolymer (Q) is 10-90:10-90, more preferably 20-90:10-80. and more preferably 30-90:10-70.

Preferred examples of the combination of the structural unit (1d) and the structural unit (1e) contained in the molecular chain of the copolymer (Q) used in the present invention are the following combinations from the viewpoint of the tear oil layer stabilizing effect. is mentioned.
2-(meth)acryloyloxyethylphosphorylcholine (1d) and butyl (meth)acrylate (1e).
2-(meth)acryloyloxyethylphosphorylcholine (1d) and stearyl (meth)acrylate (1e).
2-(meth)acryloyloxyethylphosphorylcholine (1d) and lauryl (meth)acrylate (1e).
The copolymer (Q) used in the present invention may contain structural units other than the structural unit (1d) and the structural unit (1e), but is composed only of the structural unit (1d) and the structural unit (1e). is preferred.

<Method for producing copolymer (Q)>
As the copolymer (Q) used in the present invention, an MPC polymer polymerized according to the method of JP-A-11-035605 and an MPC polymer polymerized according to the method of JP-A-2004-196868 can be used.
The copolymer (Q) used in the present invention has a weight average molecular weight of 10,000 to 5,000,000, preferably 20,000 to 1,000,000, more preferably 50,000 to 1,000, 000, more preferably 200,000 to 1,000,000. If the weight-average molecular weight is less than 10,000, the lipophilicity decreases, and the effect of stabilizing the lacrimal oil layer cannot be expected. may become difficult.

<Polyhexamethylene biguanide>
The eye drops of the present invention contain 0.000001 to 0.001 w/v % of polyhexamethylene biguanide or its salt as a preservative. Polyhexamethylene biguanide is a compound represented by the following formula (4).

上記式（４）中のｋは繰り返し単位を表す数字で、３～４０の整数である。ｋの値が３未満もしくは４０より大きいと、点眼剤としての保存効力が十分に発揮できなくなるおそれがある。より十分な保存効力を発揮する点において、ｋの値は１０以上であることが好ましく、また、１８以下であることが好ましい。

k in the above formula (4) is a number representing a repeating unit and is an integer of 3-40. If the value of k is less than 3 or greater than 40, there is a possibility that the preservative effect as an eye drop cannot be exhibited sufficiently. The value of k is preferably 10 or more and preferably 18 or less in order to exhibit more sufficient preservative efficacy.

Salts of polyhexamethylene biguanide include, for example, hydrochlorides, borates, acetates, gluconates, sulfonates, tartrates and citrates. Specific examples thereof include Cosmocil CQ and (registered trademark) manufactured by Arch UK Biocides, Vantcil IB (registered trademark), and commercially available products such as BG-1 manufactured by Sanyo Chemical Industries, Ltd. One type of these may be selected and used alone, or two or more types may be used in arbitrary combination.

The blending amount of polyhexamethylene biguanide or its salt is 0.000001 to 0.001 w/v%. If it is less than 0.000001 w/v%, the preservative effect may not be sufficiently exhibited even as an eye drop. . From the viewpoint of improving the preservative effect corresponding to the amount, the amount of polyhexamethylene biguanide or its salt is preferably 0.00007 w/v% or more, and 0.00009 w/v% or less. is more preferred.

The eye drops of the present invention preferably contain polyoxyethylene polyoxypropylene glycol.
Any polyoxyethylene-polyoxypropylene glycol that is commonly used in pharmaceuticals can be used, and for example, products listed in the Japanese Pharmacopoeia can be used. Specific examples thereof include Unilube 70DP-950B manufactured by NOF Corporation, Pronon 188P, a chemical additive manufactured by NOF Corporation, and Newpol PE-68 manufactured by Sanyo Chemical Industries, Ltd. goods are mentioned.

The amount of polyoxyethylene-polyoxypropylene glycol used in the eye drops of the present invention is preferably 0.001 to 5.0 w/v%. When this is 0.001 w/v% or more, the preservative power is improved, and when it is 5.0 w/v% or less, thickening is suppressed and the spreadability of the eye drops of the present invention is improved. The blending amount of polyoxyethylene polyoxypropylene glycol is more preferably 0.01 w/v% to 1.0 w/v%, more preferably 0.1 w/v% to 0.5 w/v%. .

The eye drops of the present invention are prepared by dissolving copolymer (P) in water at a concentration of 0.001 to 1.0 w/v, and adding copolymer (Q) in water at a concentration of 0.01 to 5.0 w/v. It can be obtained by dissolving to 0 w/v %. If the concentration of the copolymer (P) is less than 0.001 w/v%, the effect of improving lubricity is not sufficient, and if it exceeds 1.0 w/v%, it becomes difficult to carry out sterile filtration during the production of eye drops, and furthermore, Preservative efficacy may decrease. If the concentration of the copolymer (Q) is less than 0.01 w/v%, the effect of stabilizing the lacrimal lipid layer is not sufficient, and if it exceeds 5.0 w/v%, sterile filtration during the production of the eye drops is difficult. There is a possibility that it will be. The blending ratio of the copolymer (P) and the copolymer (Q) is preferably copolymer (P):copolymer (Q)=1:5 to 25 in terms of polymer purity ratio, and more preferably. is copolymer (P): copolymer (Q)=1:15-20.

In addition to the copolymer (P) and the copolymer (Q), the components of the eyedrops of the present invention may include other components within a range that does not impair the effects of the present invention and in anticipation of other effects. Alternatively, ingredients that are usually used in eye drops can be blended in appropriate amounts depending on the purpose and the like.
Other ingredients include, for example, decongestants, antiphlogistic and astringent ingredients, vitamins, amino acids, sulfa drugs, sugars, thickening agents, cooling agents, inorganic salts, salts of organic acids, acids, bases, antioxidants. agents, stabilizers, preservatives, mucopolysaccharides, mucin secretagogues.

Decongestant components include, for example, epinephrine or its salts, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline or its salts, phenylephrine, methylephedrine hydrochloride.
Antiphlogistic/astringent components include, for example, epsilon-aminocaproic acid, allantoin, berberine or its salts, azulene sodium sulfonate, glycyrrhizic acid or its salts, zinc lactate, zinc sulfate, and lysozyme chloride.

Examples of vitamins include flavin adenine nucleoside sodium, cyanocobalamin, retinol acetate, pyridoxine hydrochloride, panthenol, sodium pantothenate, and calcium pantothenate.
Amino acids include, for example, aspartic acid or salts thereof, sulfisoxazole, and sodium sulfisomidine.
Sugars include, for example, glucose, mannitol, sorbitol, xylitol, trehalose and the like.
Thickening agents include, for example, hydroxypropylmethylcellulose.

Cooling agents include, for example, menthol and camphor.
Examples of inorganic salts include potassium chloride, borax, potassium hydrogen carbonate, potassium hydrogen phosphate, anhydrous potassium dihydrogen phosphate and the like.
Salts of organic acids include, for example, sodium citrate.
Acids include, for example, boric acid, phosphoric acid, citric acid, sulfuric acid, acetic acid, and hydrochloric acid.
Bases include, for example, sodium hydroxide, potassium hydroxide, trishydroxymethylaminomethane, and monoethanolamine.
Examples of antioxidants include tocopherol acetate and dibutylhydroxytoluene.
Examples of stabilizers include sodium edetate and glycine.
Preservatives include, for example, benzalkonium chloride, chlorhexidine gluconate, potassium sorbate, polyhexanide hydrochloride.
Examples of mucopolysaccharides include sodium hyaluronate and sodium chondroitin sulfate.
Mucin secretagogues include, for example, diquafosol sodium and rebamipide.

The eyedrops of the present invention are in the form of an aqueous solution in which the copolymer (P), copolymer (Q), polyhexamethylenebiguanide and, if desired, the above other components are dissolved in water. From the viewpoint of safety, pure water, ion-exchanged water, and the like are preferable as water.
Specific product forms of the eye drops of the present invention include general eye drops, antibacterial eye drops, eye washes, contact lens solution, artificial tears, and the like. Among them, it is preferably used as a contact lens wetting solution, and more preferably used for soft contact lens wearers.

Soft contact lenses to which the eye drops of the present invention are instilled are categorized as Group I (nonionic soft contact lenses with a water content of less than 50%), Group II (water content of 50% group III (soft contact lenses with a water content of less than 50% and ionic), Group IV (soft contact lenses with a water content of 50% or more and ionic), There are five categories of silicone hydrogel contact lenses.

The ophthalmic solution of the present invention can be used for any of these soft contact lenses, but is preferably used for Group IV soft contact lenses from the viewpoint of the effect of improving the lubricity of the soft contact lens surface.

A method for producing the eye drops of the present invention will be described.
The eye drops of the present invention can be produced by adding the copolymer (P) and, if desired, the above-mentioned other ingredients to water at room temperature to about 50° C. and stirring to dissolve them. As for the order of addition of the copolymer (P) and the other components, any component may be added first.
Heating, cooling and agitation in the production can be performed by any known instruments and devices as long as the entire solution can be uniformly heated, cooled and agitated.

EXAMPLES The present invention will be specifically described below with reference to examples and comparative examples.

1. Molecular Weight Measurement of Polymer 5 mg of each obtained polymer (P) was dissolved in a methanol/chloroform mixed solution (80:20) to prepare a sample solution. The following analysis conditions were used.
Column: PLgel-mixed-C
Standard substance: Polyethylene glycol Detector: Differential refractometer RI-8020 (manufactured by Tosoh Corporation)
Weight average molecular weight calculation method: molecular weight calculation program (GPC program for SC-8020)
Flow rate: 1mL/min
Injection volume: 100 μL
Column oven: Constant temperature around 40°C

The weight average molecular weight of the polymer is the weight average molecular weight value measured by gel permeation chromatography (GPC) using polyethylene glycol as a standard sample, as described above.
The obtained polymer solution was diluted with a methanol/chloroform mixed solution (80:20) so that the polymer concentration was 0.5% by mass, and this solution was filtered through a 0.45 μm membrane filter and measured.

2. pH of eye drops
The pH of the eye drops of each Example and Comparative Example was measured according to "The Japanese Pharmacopoeia 17th Edition General Test Method 2.54 pH measurement method".

3. Osmotic Pressure of Eye Drops The osmotic pressure of the eye drops of each Example and Comparative Example was measured according to "The Japanese Pharmacopoeia 17th Edition, General Test Methods, 2.47 Osmolarity measurement method (osmolality measurement method)". Specifically, it was measured using an osmometer (Fiske Model 210 microsample osmometer) based on the freezing point measurement method.

[Synthesis Example 1] (Synthesis of copolymer (P))
31.8 g of MPC (manufactured by NOF Corporation), 3.6 g of stearyl methacrylate (SMA, manufactured by NOF Corporation) and N,N-dimethylacrylamide (DMAA, manufactured by KOHJIN Film & Chemicals Co., Ltd.)9. 6 g was placed in a four-necked flask, dissolved in 55.0 g of ethanol, and nitrogen gas was blown for 30 minutes. After that, 0.10 g of a polymerization initiator (Perbutyl ND (PB-ND), manufactured by NOF Corporation) was added, and the polymerization reaction was carried out for 8 hours. After the polymerization reaction, the polymerization liquid was added dropwise to 3 liters of diethyl ether while stirring, and the deposited precipitate was filtered and vacuum-dried at room temperature for 48 hours to obtain a powder. Yield was 40.2 g. The molecular weight of the polymer was measured by GPC, and its weight average molecular weight was 1,000,000. This was designated as Polymer 1. The chemical structure of polymer 1 obtained from IR, NMR, and elemental analysis is shown in Table 1 below.

[Synthesis Example 2] (Synthesis of copolymer (P))
A polymer was produced according to the same procedure as in Synthesis Example 1, except that the types and amounts of components shown in Table 1 below were used. Its weight average molecular weight was 1,200,000 and the yield was 42.4 g. The chemical structure of Polymer 2 obtained from IR, NMR, and elemental analysis is shown in Table 1 below.

[Synthesis Example 3] (Synthesis of copolymer (P))
A polymer was produced according to the same procedure as in Synthesis Example 1, except that the types and amounts of components shown in Table 1 below were used. Its weight average molecular weight was 700,000 and the yield was 36.1 g. The chemical structure of polymer 3 obtained from IR, NMR, and elemental analysis is shown in Table 1 below.

[Synthesis Example 4] (Synthesis of copolymer (P))
A polymer was produced according to the same procedure as in Synthesis Example 1, except that the types and amounts of components shown in Table 1 below were used. Its weight average molecular weight was 1,000,000 and the yield was 39.9 g. The chemical structure of polymer 4 obtained from IR, NMR, and elemental analysis is shown in Table 1 below.

Copolymer Q is a copolymer composed of structural units derived from MPC and structural units derived from butyl methacrylate, having a molar ratio nd:ne of 80:20 and a weight average molecular weight of 600,000. was used (polymer 5).

The preparation procedures for the examples are given below. In Table 2, "common ingredients" are those that are common in both the ingredients and the blending amounts in the examples and the comparative examples.

[Example 1]
About 50 g of purified water was heated to 80° C., and 0.1 g of hypromellose 60SH-50 was added and stirred. After visually confirming uniform dispersion, the mixture was cooled to 47.5°C and further stirred. 0.4 g of boric acid, 0.1 g of potassium chloride, 1.05 g of glycerin, 1.05 g of trometamol, 0.00008 g of Cosmocil CQ (registered trademark) while maintaining the temperature at 47.5 ° C. (containing 0.000016 g of polyhexamethylenepiguanide hydrochloride), polymer 1 (0.005 g), polymer 5 (0.095 g) and hydrochloric acid 0.48 g were sequentially added and stirred. After that, purified water was added so that the total volume was 100 mL. After that, filtration sterilization was performed to obtain a sterile eye drop. This eye drop had an osmotic pressure of 296 mOsm/kg, an osmotic pressure ratio of 1.03, a pH of 7.46, and a colorless and transparent appearance. The details are shown in Table 3 below.

[Examples 2 to 8]
A sterile eye drop was prepared according to the same procedure as in Example 1, except that the ingredients of the types and amounts shown in Table 3 were used. The appearance, pH and osmotic pressure ratio of each example are shown in Table 3 below.

[Comparative Examples 1 to 5]
Except for using the types and amounts of ingredients shown in Table 4 below, a sterile eye drop was prepared according to the same procedure as in Example. The appearance, pH and osmotic pressure ratio of each comparative example are shown in Table 4 below.

<Confirmation of lubricity improvement effect>
The lubricity-enhancing effect of the eye drops produced in each example and comparative example was confirmed by the following procedure. In the test, a 2-hydroxyethyl methacrylate (HEMA)-methacrylic acid (MAA) gel plate was prepared and used assuming a soft contact lens (hereinafter also referred to as SCL).

(procedure)
<Production of gel plate>
1) 2-HEMA (manufactured by NOF Corporation) 99.0075 g, MAA (manufactured by Tokyo Kasei Co., Ltd.) 1.0075 g, ethylene glycol dimethacrylate (manufactured by Tokyo Kasei Co., Ltd.) 0.7224 g, 0.5017 g of 2,2-azobis(isobutyronitrile) (Fujifilm Wako Pure Chemical Industries, Ltd.) was added and mixed by stirring with a wave rotor for 15 minutes.
2) After filtration through a filter, it was dispensed into a cell for plate material production with a pipettor.
3) Cured at 100°C for 1 hour.
4) The cured gel slab was immersed overnight in ISO physiological saline prepared according to ISO18369-3:2017 to obtain a HEMA-MAA gel slab.

<Measurement of friction coefficient>
1) The prepared gel plate was cut into 2 cm x 10 cm.
2) The gel plate was immersed in the eye drops produced in Examples 1 to 8 and Comparative Examples 1 to 5, and the distance between the gel plate and the probe was measured using a KES-SE friction tester (manufactured by Kato Tech Co., Ltd.). The coefficient of friction was measured.

Based on the obtained friction coefficient, the lubricity was evaluated according to the following criteria.
◎: 0 or more and 0.20 or less friction coefficient ◯: more than 0.20 and 1.0 or less friction coefficient △: more than 1.0 friction coefficient

Table 5 below shows the measurement results of the coefficient of friction.
Compared to Comparative Example 1 in which the copolymer (P) was not blended, it was smaller in Examples 1 to 8 and Comparative Examples 2 to 5 in which the copolymer (P) was blended. As described above, the eye drops of the present invention exhibit excellent lubricity.

<Confirmation of preservative efficacy of eye drops>
The preservative efficacy of the eye drops produced in each example and comparative example was confirmed by the following procedure.
The preservative efficacy of the eye drops was evaluated according to the section "Japanese Pharmacopoeia 17th Edition Reference Information Preservative efficacy test method". As bacteria, Escherichia coli (Escherichia coli, hereinafter abbreviated as Ec) (NBRC3972), Pseudomonas aeruginosa (Pseudomonas aeruginosa, hereinafter abbreviated as Pa) (NBRC13275), Staphylococcus aureus (Staphylococcus aureus, hereinafter S.a.) (abbreviated as ) (NBRC 13276), and as fungi, Candida albicans (abbreviated as Ca) (NBRC 13276), Aspergillus brasiliensis (aspergillus black mold, abbreviated as Ab) (NBRC 9455 ) were used.
The above Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Candida, and Aspergillus niger are cultured in advance so that 10 ⁸ cfu (Colony Forming Unit, the number of units capable of forming colonies) per 1 mL, and the test bacterial solution bottom. This test bacterial solution was added to the eye drops prepared in Examples 1 to 8 and Comparative Examples 1 to 5 so as to have a concentration of 1% (v/v), and the number of inoculated bacteria was 10 ⁶ cfu per 1 mL. and stored at 25°C.
7 days, 14 days, and 28 days after the inoculation, samples were taken, cultured, and viable counts were measured. Judgment was made in accordance with the judgment criteria (formulation classification: Category IA) described in "17th Edition Japanese Pharmacopoeia Reference Information Preservative Effectiveness Test Method". Judgment criteria are shown in Table 6 below.

The results of the preservative efficacy test are shown in Table 7 below. The evaluation criteria are as follows.
When sampling after 14 days has passed, Δ is indicated when the above judgment criteria are not met, and ◯ is indicated when the above judgment criteria are met.

In addition, the overall evaluation of preservative efficacy was based on the following criteria: 〇: If all bacteria and fungi meet the above criteria △: At least some bacteria and fungi do not meet the above criteria case

As a result, in Examples 1 to 8, all bacteria and fungi satisfied the criteria. Moreover, Comparative Example 1 also met the criteria. On the other hand, Comparative Examples 2 to 5 did not satisfy the criteria.
As described above, the eye drops of the present invention have sufficient preservative efficacy.

<Confirmation of extensibility improvement effect on SCL>
Assuming actual use of the eye drops produced in each of Examples and Comparative Examples, confirmation of the extensibility-improving effect using a soft contact lens was examined by the following procedure.
In addition, 1DAY ACUVUE (registered trademark) (manufactured by Johnson & Johnson Co., Ltd., FDA classification: Group IV) was used as the test SCL for the examination of the extensibility-improving effect.

(procedure)
1) One piece of test SCL was taken out from the blister pack and placed on a test table. 2) 1 μL of the eye drop of Example 1 was dropped onto the surface of the test SCL using a syringe.
3) After dropping, the contact angle from 1.5 seconds to 5.5 seconds was measured with a contact angle meter Drop Master 500 (manufactured by Kyowa Interface Science Co., Ltd.) to confirm wettability and extensibility.

The eye drops of Examples 2 to 8 and Comparative Examples 1 to 5 were also evaluated according to the above tests.
Based on the obtained contact angle values, hydrophilicity and extensibility were evaluated according to the following criteria.
◎ All contact angles from 1.5 to 5.5 seconds after instillation are 2° or less 〇 All contact angles from 3.5 to 5.5 seconds after instillation are 2° or less except for)
△ All contact angles from 1.5 seconds to 5.5 seconds after instillation of the eye drops are greater than 2°

The hydrophilicity/extensibility evaluation results are shown in Table 8 below.
With regard to 1-day Acuvue True Eye, in Examples 1 to 8 and Comparative Examples 1 to 5 in which the copolymer (P) was blended, the contact angle was so small that it could not be measured, and had high hydrophilicity. Further, in Examples 1 to 5 and Comparative Examples 2 to 5, the contact angle could not be measured at 1.5 seconds after instillation, and it spread rapidly on the SCL surface.
As described above, the eye drops of the present invention exhibit excellent hydrophilicity and spreadability.

<Summary>
A summary of the above test results is shown in Table 9 below.

As described above, the ophthalmic solution of the present invention achieves both excellent lubricity and preservative efficacy, and can exhibit effects of improving moisturizing properties and lubricity by quickly spreading on the ocular surface and contact lenses.

Next, eye drops of Examples 9 to 16 were prepared according to the formulations shown in Table 10 instead of the eye drops described in Examples 1 to 8 above. It was found that eye drops can also be prepared with the formulations shown in Examples 9-16.

INDUSTRIAL APPLICABILITY The present invention can provide a novel eye drop that imparts sufficient lubricity to the corneal surface and soft contact lens surface and has sufficient preservative efficacy.

Claims (3)

It has structural units represented by formulas (1a) to (1c), the molar ratio n _a : n _b : n _c of each structural unit is 100:10 to 400:2 to 50, and the weight average molecular weight is 0.001 to 1.0 w/v% of the copolymer (P) of 5,000 to 2,000,000, and having structural units represented by formulas (1d) to (1e), each 0.01 to 5.0 w of a copolymer (Q) having a structural unit molar ratio n _d : n _e of 10 to 90:10 to 90 and a weight average molecular weight of 10,000 to 5,000,000 /v% and 0.000001 to 0.001 w/v% of polyhexamethylene biguanide or a salt thereof.

(wherein R ¹ , R ² , R ⁵ , R ⁷ and R ⁸ each independently represent a hydrogen atom or a methyl group, R ³ and R ⁴ each independently represent a methyl group or an ethyl group .R ⁶ represents a monovalent hydrocarbon group having 12 to 24 carbon atoms, and R ⁹ represents an alkyl group having 4 to 18 carbon atoms.) The ophthalmic solution according to claim 1, containing 0.001 to 5.0 w/v% of polyoxyethylene polyoxypropylene glycol. 3. The ophthalmic solution according to claim 1 or 2, which is for soft contact lens wearers.