JPWO1999026637A1 - Ophthalmic agent and ophthalmic composition - Google Patents

Abstract

(57) [Abstract] A compound represented by the following general formula (1) (wherein R ¹ , R ² and R ³ are the same or different groups and are hydrogen atoms or alkyl groups having 1 to 4 carbon atoms, and m is an integer of 2 to 4), and an ophthalmic composition containing the ophthalmic agent, which essentially consists of a polymer having a phosphorylcholine-like group in a side chain,

Description

[Detailed Description of the Invention] TECHNICAL FIELD The present invention relates to an ophthalmic agent that can be used to relieve symptoms such as dry eyes and discomfort caused by contact lens wear, and an ophthalmic composition containing the ophthalmic agent. BACKGROUND ART In recent years, an increasing number of patients have complained of discomfort such as dryness, heat, and tired eyes, and suffered from corneal damage and disorders, due to dry eyes caused by factors such as decreased tear production. Furthermore, in ophthalmology and otolaryngology, there has been an increase in allergic hypersensitivity diseases such as hay fever and house dust allergy. Therefore, artificial tears containing boric acid, sodium chloride, potassium chloride, calcium chloride, etc. are widely used to relieve symptoms of dry eyes and allergic hypersensitivity.

In addition, to alleviate symptoms such as a gritty feeling and dry eyes when wearing contact lenses,
Ophthalmic drugs or artificial tears containing water-soluble polymers such as polyvinyl alcohol, sodium hyaluronate, and sodium chondroitin sulfate have been disclosed (German Patent Specification DE2714676, JP-A-9-52826, JP-A-4-2004).
18022).

Japanese Patent Application Laid-Open No. 9-52826 discloses sodium hyaluronate as an ophthalmic drug, and Japanese Patent Application Laid-Open No. 4-18022 discloses sodium chondroitin sulfate as an ophthalmic drug.

However, conventional ophthalmic medications and artificial tears using natural or synthetic water-soluble polymers such as polyvinyl alcohol, sodium hyaluronate, and sodium chondroitin sulfate do not provide sufficient moisturizing effect on the cornea.

A polymer obtained by polymerizing 2-methacryloyloxyethyl phosphorylcholine (hereinafter abbreviated as MPC) can be used to coat the surface of an article, thereby making it difficult for proteins to adhere to the surface (see, for example, Kobunshi Ronbunshu, Vol. 46, p. 591, 1999).
1989), and does not induce protein denaturation when in contact with proteins (Biomaterials, Vol. 9, No. 24
3, 1991), and excellent antithrombotic properties (K. Ishihara et al., J. Biomed.
Meter. Res., 26, 1543 (1992)).
[0003] Publication No. 321 discloses that a polymer consisting of 2-methacryloyloxyphosphorylcholine forms a film that protects the stratum corneum when a composition containing the polymer is applied to the skin, and exhibits excellent moisturizing effects. However, the use of this polymer as an ophthalmic drug has not been known until now. Disclosure of the Invention [ 0004] The object of the present invention is to provide an ophthalmic agent and an ophthalmic composition that can provide sufficient water retention to the cornea, etc., and treat or alleviate symptoms such as dry eye, allergies such as hay fever, or dry eyes and gritty sensations caused by wearing contact lenses.

According to the present invention, a compound represented by the following general formula (1) (wherein R ¹ , R ² and R ³ are the same or different groups and are hydrogen atoms or alkyl groups having 1 to 4 carbon atoms, and m is an integer of 2 to 4)

According to the present invention, the polymer is represented by the following general formula (2): (wherein R ¹ , R ² and R ³ are the same or different groups and represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R ⁴ represents a hydrogen atom or a methyl group; R ⁵ represents -(B
O) a group represented by n-B- (wherein B represents an alkylene group having 2 to 12 carbon atoms,
wherein n represents an integer of 0 to 10, and m represents an integer of 2 to 4, or a copolymer of the monomer and another monomer copolymerizable with the monomer.

Furthermore, according to the present invention, the phosphorylcholine-like group-containing monomer is represented by the following formula (3): The ophthalmic agent is 2-methacryloyloxyethyl phosphorylcholine represented by the formula:

Furthermore, according to the present invention, the polymer is represented by the following general formula (4): (wherein R ¹ , R ² and R ³ are the same or different groups and represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R ⁴ represents a hydrogen atom or a methyl group; R ⁵ represents -(B
O) a group represented by n-B- (wherein B represents an alkylene group having 2 to 12 carbon atoms,
wherein n represents an integer of 0 to 10, and m represents an integer of 2 to 4, and the proportion of the structural unit (a) to the total of all structural units is 10 to 100 mol %.

Furthermore, according to the present invention, the structural unit (a) is represented by the following formula (5): and the weight average molecular weight of the polymer is 1,000 to 1
0,000,000.

Furthermore, according to the present invention, there is provided the ophthalmic preparation, which further comprises a structural unit (b) obtained by polymerizing a monomer selected from the group consisting of methyl (meth)acrylate, butyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, 2-hydroxyethyl (meth)acrylate, and mixtures thereof.

Furthermore, the present invention provides an ophthalmic composition containing the ophthalmic agent.

Furthermore, the present invention provides the ophthalmic composition, wherein the content of the ophthalmic agent is 0.0001 to 40% by weight.

Furthermore, the present invention provides the above ophthalmic composition, which has a pH of 3.0 to 9.0 and an osmotic pressure ratio to physiological saline of 0.5 to 2.3.

Furthermore, according to the present invention, there is provided an ophthalmic composition comprising, in addition to the ophthalmic agent, a substance having other pharmacological effects.Best Mode for Carrying Out the InventionThe ophthalmic agent of the present invention essentially consists of a polymer having a phosphorylcholine-like group in its side chain, represented by the general formula (1) (hereinafter referred to as PC-1 polymer).

In the general formula (1), R ¹ , R ² and R ³ are the same or different groups and represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and m represents an integer of ² to 4.
It is difficult to obtain raw materials that give compounds having 5 or more carbon atoms in ^{R 2} and R ³ , and m is 1.
Those having 5 or more are difficult to synthesize.

The PC-1 polymer may be a monomer having a phosphorylcholine-like group represented by the general formula (2) (hereinafter referred to as PC-1 monomer) or a monomer having a phosphorylcholine-like group represented by the general formula (1).
Examples of the monomer include a homopolymer of a monomer containing a phosphorylcholine-like group, such as maleic acid, fumaric acid, or itaconic acid, which has a phosphorylcholine-like group in its side chain, represented by the formula (I), or a copolymer of these monomers and other monomers copolymerizable therewith.

Specific examples of the PC-1 monomer include 2-(meth)acryloyloxyethyl-2'-(trimethylammonio)ethyl phosphate, 3-(meth)acryloyloxypropyl-2'-(trimethylammonio)ethyl phosphate, 4-(meth)acryloyloxybutyl-2'-(trimethylammonio)ethyl phosphate, 5-(meth)acryloyloxypentyl-2'-
(trimethylammonio)ethyl phosphate, 2-(meth)acryloyloxyethyl-2'-(triethylammonio)ethyl phosphate, 3-(meth)
Acryloyloxypropyl-2'-(triethylammonio)ethyl phosphate, 4-(meth)acryloyloxybutyl-2'-(triethylammonio)ethyl phosphate, 5-(meth)acryloyloxypentyl-2'-(triethylammonio)ethyl phosphate, 2-(meth)acryloyloxyethyl-2'-(tripropylammonio)ethyl phosphate, 3-(meth)acryloyloxypropyl-2'-(tripropylammonio)ethyl phosphate, 4-(meth)acryloyloxybutyl-2'-(tripropylammonio)ethyl phosphate, 5-(meth)acryloyloxypentyl-2'-(
(tripropylammonio)ethyl phosphate, 2-(meth)acryloyloxyethyl-2'-(tributylammonio)ethyl phosphate, 3-(meth)
acryloyloxypropyl-2'-(tributylammonio)ethyl phosphate, 4-(meth)acryloyloxybutyl-2'-(tributylammonio)ethyl phosphate, 5-(meth)acryloyloxypentyl-2'-(tributylammonio)ethyl phosphate, 2-(meth)acryloyloxyethyl-3'-(trimethylammonio)propyl phosphate, 2-(meth)acryloyloxyethyl-4'-(trimethylammonio)butyl phosphate, 2-(meth)acryloyloxyethyl-3'-(triethylammonio)propyl phosphate, 2-(meth)acryloyloxyethyl-4'-(triethylammonio)butyl phosphate, 2-(meth)acryloyloxyethyl-3'-(tripropylammonio)propyl phosphate, 2-(meth)acryloyloxyethyl-4'-(tripropylammonio)butyl phosphate, 2-(meth)acryloyloxyethyl-3'-(tributylammonio)propyl phosphate, 2-(meth)acryloyloxyethyl-4'-(tributylammonio)butyl phosphate, 3-(meth)acryloyloxypropyl-3'-(trimethylammonio)propyl phosphate, 3-(meth)acryloyloxypropyl-4'-(trimethylammonio)butyl phosphate, 3-(meth)acryloyloxypropyl-3'-(triethylammonio)
propyl phosphate, 3-(meth)acryloyloxypropyl-4'-triethylammonio)butyl phosphate, 3-(meth)acryloyloxypropyl-3'-(tripropylammonio)propyl phosphate, 3-(meth)
Acryloyloxypropyl-4'-(tripropylammonio)butyl phosphate, 3-(meth)acryloyloxypropyl-3'-(tributylammonio)propyl phosphate, 3-(meth)acryloyloxypropyl-4'
-(tributylammonio)butyl phosphate, 4-(meth)acryloyloxybutyl-3'-(trimethylammonio)propyl phosphate, 4-(meth)acryloyloxybutyl-4'-(trimethylammonio)butyl phosphate, 4-(meth)acryloyloxybutyl-3'-(triethylammonio)propyl phosphate, 4-(meth)acryloyloxybutyl-4'-(
triethylammonio)butyl phosphate, 4-(meth)acryloyloxybutyl-3'-(tripropylammonio)propyl phosphate, 4-(meth)acryloyloxybutyl-4'-(tripropylammonio)butyl phosphate, 4-(meth)acryloyloxybutyl-3'-(tributylammonio)propyl phosphate, 4-(meth)acryloyloxybutyl-4'-(
In particular, the compound represented by the formula (3) may be mentioned.
2-Methacryloyloxyethyl phosphorylcholine (that is, 2-methacryloyloxyethyl-2'-(triethylammonio)ethyl phosphate), which is a compound represented by the formula: is preferred in terms of availability, etc.

Specific examples of the copolymerizable other monomers include styrene-based monomers such as styrene, methylstyrene, and chlorostyrene; vinyl ester-based monomers such as vinyl acetate, vinyl propionate, and vinyl pivalate; methyl (meth)acrylate, ethyl (meth)acrylate, n-butyl (meth)acrylate, t-butyl (meth)acrylate, and the like.
(meth)acrylic acid ester monomers such as butyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, dodecyl (meth)acrylate, stearyl (meth)acrylate, 2-hydroxyethyl (meth)acrylate, and benzyl (meth)acrylate; (meth)acrylamide, N,N-dimethyl (meth)acrylamide, N,N-dimethylaminopropyl acrylamide, (meth)
Examples of suitable monomers include (meth)acrylamide monomers such as acryloylmorpholine; vinyl ether monomers such as ethyl vinyl ether and n-butyl vinyl ether; (meth)acrylic acid, sodium (meth)acrylate, itaconic acid, sodium itaconic acid, and N-vinylpyrrolidone. Of these, preferred are methyl(meth)acrylic acid, sodium (meth)acrylate, and N-vinylpyrrolidone.
Acrylate, n-butyl (meth)acrylate, 2-ethylhexyl (meth)acrylate
Examples of the monomers include acrylate, 2-hydroxyethyl (meth)acrylate, etc. These monomers can be used alone or as a mixture. Also, a small amount of a bifunctional monomer such as glycerin di(meth)acrylate or polyoxyethylene di(meth)acrylate may be used in combination so as not to cause gelation during polymerization.

The ophthalmic agent of the present invention preferably contains, as the structural unit (a), a compound represented by the general formula (
Examples of the structural unit include a polymer having a structural unit represented by general formula (4) and a polymer having a structural unit other than the structural unit represented by general formula (4) as the structural unit (b).

Specific examples of the structural unit (a) include structural units obtained by polymerizing the specific examples of the PC-1 monomer, and preferably the structural unit represented by the formula (5).
Specific examples include structural units obtained by polymerizing the various monomers listed above as other monomers copolymerizable with PC-1, and preferred are methyl (meth)acrylate, butyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, and the like.
Examples of the structural units include those obtained by polymerizing a monomer selected from the group consisting of 2-hydroxyethyl (meth)acrylate, 2-hydroxyethyl (meth)acrylate, and mixtures thereof.

The content ratio of the structural unit (a) and the structural unit (b) in the ophthalmic preparation of the present invention is
The proportion of the structural unit (a) relative to the total of the structural units (a) and (b) can be preferably 10 to 100 mol%, more preferably 30 to 95 mol%. By making the content of the structural unit (a) 10 mol% or more, an ophthalmic agent having high water retention properties derived from the phosphorylcholine-like group and high anti-staining properties against proteins and the like can be obtained.

The molecular weight of the polymer constituting the ophthalmic agent of the present invention is preferably 1,000 to 10,000,000, more preferably 5,000 to 2,000,000, in terms of weight average molecular weight.
By making the weight-average molecular weight 1,000 or more, it is possible to achieve the desired functions such as water retention and stain resistance, and by making the weight-average molecular weight 10,000,000 or less, it is possible to keep the viscosity of the product within a range that is easy to manufacture.

The ophthalmic agent of the present invention can be produced by polymerizing monomer components such as the phosphorylcholine-like group-containing monomer, e.g., PC-1 monomer, and other monomers copolymerizable therewith, in the presence of a radical polymerization initiator, under degassing conditions or in an inert gas-substituted or inert gas atmosphere such as nitrogen gas, argon gas, helium gas, or carbon dioxide gas, by heating or irradiating with light in a solvent such as water, methanol, or ethanol.

The polymerization initiator is not particularly limited, and a typical radical polymerization initiator can be used. Specific examples thereof include organic peroxides such as benzoyl peroxide, lauroyl peroxide, diisopropyl peroxydicarbonate, t-butylperoxy-2-ethylhexanoate, t-butylperoxypivalate, and t-butylperoxydiisobutyrate; 2-cyano-2-propylazoformamide; 1,1
-azobis(cyclohexane-1-carbonitrile), 2,2'-azobis(2
-amidinopropane) dihydrochloride, 2,2'-azobis(2-methylbutyronitrile), 2,2'-azobisisobutyronitrile, 2,2'-azobis(2,4-
dimethylvaleronitrile), 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile), 4,4'-azobis(4-cyanovaleric acid), 2,2'-
Dimethyl azobisisobutyrate, 2,2'-azobis(2-(5-methyl-2-imidazolin-2-yl)propane) dihydrochloride, 2,2'-azobis(2-(2-imidazolin-2-yl)propane) dihydrochloride, 2,2'-azobis(2-(2-imidazolin-2-yl)propane) dihydrochloride,
imidazolin-2-yl)propane), 2,2'-azobis(2-methyl-N-
(1,1-bis(hydroxymethyl)ethyl)propionamide), 2,2'-
Azobis(2-methyl-N-(2-hydroxyethyl)propionamide), 2
, 2'-azobisbutyrylamide dihydrate, 2,2'-azobis(2-hydroxymethyl)propionitrile), 2,2'-azobis(2,4,4-trimethylpentane) and other azo compounds; or inorganic peroxides such as ammonium persulfate.

When carrying out the polymerization, the molar ratio of the phosphorylcholine analogous group-containing monomer such as PC-1 monomer to the other monomer copolymerizable therewith is preferably 10:90.
The polymerization initiator may be added in an amount of preferably 0.000001 to 10% by weight, more preferably 0.0001 to 100% by weight, based on the total amount of the monomer components.
The polymerization temperature is -10 to 150°C, preferably 0 to 50°C.
The polymerization temperature can be 100° C. The polymerization time can be 30 minutes to 100 hours, preferably 1 to 24 hours.

The ophthalmic composition of the present invention contains the ophthalmic agent.

The content of the ophthalmic agent in the ophthalmic composition of the present invention is desirably 0.0001 to 40% by weight, preferably 0.001 to 10% by weight, and more preferably 0.01 to 5% by weight. By making it 0.0001% by weight or more, the expected effects such as water retention can be exhibited, and by making it 40% by weight or less,
The viscosity of the product can be low enough to avoid physical irritation to the cornea.

The pH and osmotic pressure of the ophthalmic composition of the present invention are not particularly limited. However, in the case of a liquid preparation as an eye drop, it is particularly preferable that the pH is 3.0 to 9.0 and the osmotic pressure is 0.5 to 2.3 in terms of the osmotic pressure ratio to physiological saline.
By setting the pH and osmotic pressure within these ranges, it is possible to obtain an ophthalmic composition that does not irritate the eyes when applied, which is preferable.

The dosage form of the ophthalmic composition of the present invention is not particularly limited, but may be dissolved in a medium such as water,
Examples of dosage forms include liquid preparations such as suspensions and emulsions, and ointments.

The ophthalmic composition of the present invention may contain, in addition to the ophthalmic agent as an essential component, an osmotic pressure adjuster, a pH adjuster, a viscosity adjuster, a stabilizer, a preservative, or other substances having pharmacological effects, as needed.

Examples of the osmotic pressure adjuster or pH adjuster that can be used include sodium chloride, potassium chloride, calcium chloride, sodium bicarbonate, sodium carbonate, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, boric acid, borax, sodium hydroxide, hydrochloric acid, and glycerin.

Examples of the viscosity adjuster include water-soluble polymers such as polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), methyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol, random or block copolymers of ethylene glycol and propylene glycol, sodium hyaluronate, and sodium chondroitin sulfate.

Examples of the stabilizer include citric acid, EDTA-2-sodium salt, sodium sulfite, and sodium hydrogen sulfite.

The preservative is not particularly limited, but preferred examples thereof include paraoxybenzoic acid esters such as methylparaben and ethylparaben, cationic soaps such as benzalkonium chloride and chlorhexidine gluconate, alcohols such as chlorobutanol and phenylethyl alcohol, sodium dehydroacetate, sorbic acid, and sodium sorbate.

The substance having other pharmacological action is not particularly limited as long as it is an ingredient that exerts an effective effect in the treatment of ophthalmic diseases, and examples thereof include drugs listed in Appendix 1 of 2. Criteria (1) Types of Active Ingredients of the Standards for Approval of Manufacturing (Importing) of General Medicines, or drugs listed in the Ophthalmic Drugs (p. 324) of the Pharmaceutical Directory (Yakugyo Jihosha). Specific examples include anti-inflammatory agents such as dipotassium glycyrrhizinate, epsilon aminocaproic acid, allantoin, berberine chloride, berberine sulfate, sodium azulene sulfonate, zinc sulfate, zinc lactate, and lysozyme chloride; antihistamines such as diphenhydramine hydrochloride and chlorpheniramine maleate; flavin adenine dinucleotide sodium, cyanocobalamin, retinol acetate, retinol palmitate, pyridoxine hydrochloride, panthenol, calcium pantothenate, and panthenol. corneal therapeutic agents such as sodium anthraquinone, sodium chondroitin sulfate, etc.; vasoconstrictors/decongestants such as epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, d,l-methylephedrine hydrochloride, etc.; antibacterial agents such as sulfamethoxazole, sulfamethoxazole sodium, sulfisoxazole, sulfisomidine sodium, etc.; freshening agents such as menthol, borneol, camphor, peppermint oil, etc.;
Miotics such as pilocarpine hydrochloride, pilocarpine, physostigmine salicylate, ethyl paranitrophenylethyl ethylphosphonate, echothiophate iodide, distigmine bromide, carbachol, etc.; glaucoma/ocular hypertension treatment drugs such as timolol maleate, befunolol hydrochloride, carteolol hydrochloride, etc.; mydriatics such as cyclopentolate hydrochloride, homatropine hydrobromide, atropine sulfate, phenylephrine hydrochloride, tropicamide, epinephrine, epinephrine bitartrate, etc.; catalin, phacoridine, glucan Cataract treatment drugs such as glutathione, pirenoxine, sodium pentacecylsulfonate, etc.; enzyme preparations such as urokinase, α-chymotrypsin, etc.; antiseptic astringents such as silver nitrate, etc.; sulfonamides such as sulfisoxazole, etc.; chloramphenicol, erythromycin, erythromycin lactobionate, oxytetracycline hydrochloride, kanamycin sulfate, bekanamycin sulfate, gentamicin sulfate, tobramycin, sisomicin sulfate, micromycin sulfate, dibekacin sulfate, sulbenicillin sodium,
Antibiotics such as pimaricin; corticosteroids such as hydrocortisone acetate, prednisolone acetate, dexamethasone sodium phosphate, dexamethasone, triamcinolone acetonide, fluorometholone; antiviral agents such as idoxuridine and acyclovir; other agents include zinc sulfate, water-soluble azulene, lysozyme chloride, sodium cromoglycate, oxybuprocaine hydrochloride, alkylpolyaminoethylglycine, polyvinyl alcohol/iodine, indomethacin, sodium hyaluronate,
Ofloxacin, tranilast, etrahydrazone hydrochloride, neostigmine methylsulfate, aminoethylsulfonic acid, betamethasone phosphate, and mixtures thereof can be used.

For long-term storage of the ophthalmic composition of the present invention, it is possible to use a disposable type having a volume of 0.5 to 3 ml that is filled under sterile conditions without adding a preservative and sealed, or an ophthalmic composition that has been filled under sterile conditions in a specified container after adding a preservative.

When the ophthalmic composition of the present invention is prepared as an ointment, it may contain an ointment base in addition to the various components described above. The ointment base is not particularly limited, but may be an oily base such as petrolatum, liquid paraffin, polyethylene, or a mixture thereof; an emulsion base in which an oil phase and an aqueous phase are emulsified with a surfactant or the like;
Preferred examples include water-soluble bases such as hydroxypropylmethylcellulose, carboxymethylcellulose, and polyethylene glycol.

The ophthalmic composition of the present invention can be used as eye drops, artificial tears, eyewashes, ointments, etc.

When the ophthalmic composition of the present invention is used as an eye drop or artificial tear, it can be administered by directly instilling it into the eye, preferably into the naked eye, but may also be administered to the eye while wearing a hard contact lens, an oxygen-permeable hard contact lens, a non-water-absorbent soft contact lens, or a water-absorbent soft contact lens.

When the ophthalmic composition of the present invention is administered by instillation, the number of administrations and the dosage are not particularly limited. For example, the composition may be administered 1 to 12 times a day, 1 to 6 times a day, in the same manner as in conventional eye drops.
Drops can be instilled into the eyes.

When the ophthalmic composition of the present invention is used as an eyewash, it can be used by transferring the ophthalmic composition of the present invention to a cup or the like of an appropriate size and repeatedly opening and closing the eyelids in the cup. Alternatively, the ophthalmic composition of the present invention can be directly poured from a container into the eyes for eyewashing.

The ophthalmic composition of the present invention can be used for the purpose of treating or alleviating symptoms such as dry eye, allergies such as hay fever, and dry eyes and a feeling of grittiness in the eyes when wearing contact lenses, by improving the water retention of the surfaces of the cornea, conjunctiva, etc. It can also be used with the intention of preventing the adhesion of proteinaceous soiling and the like to contact lenses when they are used.

The ophthalmic preparation of the present invention is made of a polymer having specific side chains, and is therefore useful as an ophthalmic preparation that can provide sufficient water retention to the cornea and treat or alleviate symptoms such as dry eye, allergies such as hay fever, or dry eyes and a feeling of grittiness in the eyes when wearing contact lenses.

Furthermore, since the ophthalmic composition of the present invention contains the specific ophthalmic agent, it is useful as an ophthalmic composition that can provide sufficient moisture retention to the cornea and treat or alleviate symptoms such as dry eye, allergies such as hay fever, or eye irritation and dry eyes caused by wearing contact lenses. Examples : The present invention will be explained in more detail below with reference to examples, but is not limited to these. Synthesis Example 1: Using 5.0 g (16.9 mmol) of MPC as the monomer, 50 ml of ethanol as the solvent, and 25 mg (0.5 parts by weight per 100 parts by weight of the total monomers) of azobisisobutyronitrile (hereinafter referred to as AIBN) as the polymerization initiator, a polymerization reaction was carried out at 55°C for 6 hours under a nitrogen stream. After completion of the reaction, the product was precipitated in 2000 ml of acetone, dissolved in ethanol, and reprecipitated in 2000 ml of acetone.
The polymer was dried under reduced pressure at 60° C. for 24 hours to obtain a solid white polymer, which was water-soluble.

The yield and the results of measuring the molecular weight by GPC (developing solvent: water, standard sample: polyethylene glycol) are shown in Table 1. Synthesis Examples 2 to 7 Monomers and polymerization initiators were the monomers and AIBN of the types and amounts shown in Table 1.
The same procedures as in Synthesis Example 1 were carried out except that the reaction was carried out for the reaction time and temperature shown in Table 1, to obtain a polymer and measure its molecular weight. The results are shown in Table 1. The proportion of structural units based on MPC in the obtained polymer was also determined by quantifying the phosphorus contained in the polymer. The results are shown in Table 1.

The abbreviations used in the table are as follows:

EHMA: 2-ethylhexyl methacrylate BHA: n-butyl methacrylate MMA: methyl methacrylate HEMA: 2-hydroxyethyl methacrylate Example 1 1.0 g of the MPC polymer synthesized and purified in Synthesis Example 1 was dissolved in 99 g of purified water to prepare an aqueous solution. This was sterilized using a 0.2 μm membrane filter to obtain an ophthalmic solution. Examples 2 to 7 Eye drops were obtained in the same manner as in Example 1, except that the types and amounts of polymers and purified water shown in Table 2 were used instead of 1.0 g of the MPC polymer synthesized and purified in Synthesis Example 1 and 99 g of purified water.

In the table, Synthesis 1 to Synthesis 7 indicate that the polymers synthesized and purified in Synthesis Examples 1 to 7 were used. In Examples 8 to 12, the polymer obtained in Synthesis Example 2 was used in Example 8, the polymer obtained in Synthesis Example 7 in Example 9, the polymer obtained in Synthesis Examples 1 and 3 in Example 10, the polymers obtained in Synthesis Examples 2 and 4 in Example 11, and the polymers obtained in Synthesis Examples 2 and 5 in Example 12 were used in the amounts shown in Table 3. Sodium chloride, potassium chloride, and calcium chloride were also used in the amounts shown in Table 3 and dissolved in purified water to prepare eye drops with adjusted pH and osmotic pressure ratio. The results are shown in Table 3. pH was measured according to JIS Z8802 (1984
The osmotic pressure ratio was measured by cryoscopic osmometer (Fiske
Measurements were made using a Model-110 Microsample Osmometer.

Example 13 200 μg of the eye drops prepared in Example 5 was sprayed onto a commercially available acrylic plate (size: length 40 mm × width 10 mm × thickness 1 mm) using a spray bottle, and immediately 100 ml of physiological saline was added.
The sample was washed with a dynamic contact angle meter (manufactured by Oriental Kogyo Co., Ltd.; DCA
The advancing contact angle was measured during this immersion, and the average value of the 50 measurements was 23.
It was 5±1.8 degrees.

This confirms that the ophthalmic composition of the present invention can impart water retention to the surface of an acrylic plate, and that the water retention imparted to the surface of the acrylic plate is stable even after repeated immersion and withdrawal as many as 50 times.

From these experimental results, it can be seen that the ophthalmic composition of the present invention can provide water retention to each tissue of the eye when administered by eye drops, etc. Comparative Example 1 : The same procedure as in Example 13 was carried out except that no eye drops were applied, and the advancing contact angle of the acrylic plate not treated with eye drops was measured, resulting in a value of 89.0±2.2 degrees. Comparative Example 2: The same procedure as in Examples 5 and 13 was carried out except that 0.1 g of sodium hyaluronate (manufactured by Wako Pure Chemical Industries, Ltd., derived from Streptococcus) was used instead of the polymer obtained in Synthesis Example 5, to obtain an eye drop. The advancing contact angle was measured using this eye drop, resulting in a value of 88.2±
Comparative Example 3: An eye drop was obtained in the same manner as in Examples 5 and 13, except that 0.1 g of sodium chondroitin sulfate (manufactured by Wako Pure Chemical Industries, Ltd.) was used instead of the polymer obtained in Synthesis Example 5.
The advancing contact angle of this eye drop was measured to be 88.6±3.4 degrees, indicating that the water retention was low. Comparative Example 4 Instead of the polymer obtained in Synthesis Example 5, polyvinylpyrrolidone (manufactured by Wako Pure Chemical Industries, Ltd.) was used.
An eye drop was obtained in the same manner as in Examples 5 and 13, except that 0.1 g of K25 (trade name) was used. The advancing contact angle of this eye drop was measured to be 88.1±1.2 degrees, indicating that the water retention capacity was low.

The results of Example 13 and Comparative Examples 1 to 4 demonstrate that the ophthalmic composition of the present invention can provide higher water retention when applied compared to conventional ophthalmic preparations containing sodium hyaluronate, sodium chondroitin sulfate, or polyvinylpyrrolidone. Example 14: Five naked-sighted human subjects received 1 to 2 drops of the eye drops prepared in Example 8 or 9 in the right eye and 1 to 2 drops of artificial tears (trade name: "Santen Soft Santear," manufactured by Santen Pharmaceutical Co., Ltd.) in the left eye. After 1 minute, the tears in the right eye were stained with 1% sodium fluorescein. After blinking several times, the tear breakup time (BUT) was measured using a slit lamp and a cobalt filter with the eyelids open, the time until a dark area appeared on the stained tear film. After each measurement, the right eye was washed with artificial tears for the next measurement. Measurements were performed three times and averaged. The results are shown in Table 4. Comparative Example 5 : The same procedure as in Example 14 was repeated to measure BUT for the same subject, except that artificial tears (trade name, "Santen Soft Santear," manufactured by Santen Pharmaceutical Co., Ltd.) were used as the eye drops instead of the eye drops prepared in Example 8 or 9. The results are shown in Table 4. Comparative Example 6 : The same procedure as in Example 14 was repeated to measure BUT for the same subject, except that "Santen Hyalein 0.1" (trade name, containing 0.1% by weight of sodium hyaluronate) was used as the eye drops instead of the eye drops prepared in Example 8 or 9. The results are shown in Table 4.

In Example 14, subjects A, B, and C were given the eye drops prepared in Example 8, and subjects D and E were given the eye drops prepared in Example 9.

In Example 14 and Comparative Examples 5 and 6, no reactions thought to be side effects such as congestion were observed in any of the subjects. In Example 15 and Comparative Examples 7 and 8 , the subjects were humans wearing hard contact lenses (product name "Seiko Hard EX", manufactured by Seiko Contact Lenses), but the procedures for Example 15 were the same as those for Example 14, for Comparative Example 7 as those for Comparative Example 5, and for Comparative Example 8 as those for Comparative Example 6, and BUT was measured. The results are shown in Table 5. In any of the subjects, no reactions thought to be side effects were observed compared to when wearing contact lenses before instillation.

In Example 15, subjects A, B, and C were given the eye drops prepared in Example 8, and subjects D and E were given the eye drops prepared in Example 9.

From the results of Examples 14-15 and Comparative Examples 5-8, it can be seen that the ophthalmic composition of the present invention is more effective in prolonging BUT than artificial tears and sodium hyaluronate in both the naked eye and eyes wearing contact lenses. Therefore, it can be seen that the ophthalmic composition of the present invention is more effective in stabilizing the tear film than artificial tears and sodium hyaluronate, and therefore is more effective in maintaining moisture in the cornea, etc., and is effective in alleviating and treating symptoms such as a feeling of grittiness in the eyes and dry eyes caused by dry eye, etc. Example 16 2.0 g of the MPC polymer synthesized and purified in Synthesis Example 1, 0.0 g of tetrahydrazone hydrochloride, and 0.0 g of hydroxybenzoates were mixed together.
Eye drops were prepared by adding purified water to a total of 100 g of 0.02 g of benzoyl perfluorooctanoate, 0.01 g of chlorpheniramine maleate, 0.005 g of neostigmine methylsulfate, 1.0 g of epsilon (ε-) aminocaproic acid, 0.005 g of benzalkonium chloride, 0.005 g of chlorhexidine gluconate, and 0.5 g of boric acid. This was then sterilized using a 0.2 μm membrane filter to prepare eye drops. Examples 17 to 48: Eye drops were obtained by the same procedure as in Example 16, except that the types and amounts of polymers, drug components, and other ingredients shown in Tables 6 to 10 were used.

───────────────────────────────────────────────────── Continued from the front page (72) Inventor: Shinji Nakata 2-26-2 Kasuga, Tsukuba, Ibaraki Prefecture (72) Inventor: Ryota Ando 2-26-2 Kasuga, Tsukuba, Ibaraki Prefecture (Note) This publication is based on the publication published internationally by the International Bureau of Patents (WIPO). The effect of the international publication of the Japanese patent application (Japanese utility model registration application) related to this publication arises pursuant to Article 184-10, Paragraph 1 of the Patent Act (Article 48-13, Paragraph 2 of the Utility Model Act) and is unrelated to this publication.

Claims (10)

[Claims] Claim 1: A compound represented by the following general formula (1): An ophthalmic preparation essentially consisting of a polymer having a phosphorylcholine-like group in its side chain, represented by the formula: (wherein R ¹ , R ² and R ³ are the same or different groups and are hydrogen atoms or alkyl groups having 1 to 4 carbon atoms, and m is an integer of 2 to 4). 2. The polymer represented by the following general formula (2): (wherein R ¹ , R ² and R ³ are the same or different groups and represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R ⁴ represents a hydrogen atom or a methyl group; R ⁵ represents -(B
O) a group represented by n-B- (wherein B represents an alkylene group having 2 to 12 carbon atoms,
2. The ophthalmic preparation according to claim 1, which is a homopolymer of a phosphorylcholine-like group-containing monomer represented by the formula (I), wherein n is an integer of 0 to 10, and m is an integer of 2 to 4, or a copolymer of said monomer and another monomer copolymerizable with said monomer. 3. The phosphorylcholine-like group-containing monomer represented by the following formula (3): 3. The ophthalmic preparation according to claim 2, which is 2-methacryloyloxyethyl phosphorylcholine represented by the formula: 4. The polymer represented by the following general formula (4): (wherein R ¹ , R ² and R ³ are the same or different groups and represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; R ⁴ represents a hydrogen atom or a methyl group; R ⁵ represents -(B
O) a group represented by n-B- (wherein B represents an alkylene group having 2 to 12 carbon atoms,
2. The ophthalmic preparation according to claim 1, which comprises a structural unit (a) represented by the formula (I), wherein n represents an integer of 0 to 10, and m represents an integer of 2 to 4, and the proportion of the structural unit (a) to the total of all structural units is 10 to 100 mol %. 5. The structural unit (a) is represented by the following formula (5): and the weight average molecular weight of the polymer is 1,000 to 1
5. The ophthalmic preparation according to claim 4, wherein the viscosity is 0,000,000. 6. Methyl (meth)acrylate, butyl (meth)acrylate, 2-
5. The ophthalmic composition according to claim 4, further comprising a structural unit (b) obtained by polymerizing a monomer selected from the group consisting of ethylhexyl (meth)acrylate, 2-hydroxyethyl (meth)acrylate, and a mixture thereof. 7. An ophthalmic composition comprising the ophthalmic agent according to claim 1. 8. The ophthalmic composition according to claim 7, wherein the content of the ophthalmic agent is 0.0001 to 40% by weight. 9. A solution having a pH of 3.0 to 9.0 and an osmotic pressure ratio to physiological saline of 0.5 to 1.0.
8. The ophthalmic composition according to claim 7, wherein the viscosity is 2.3. 10. The ophthalmic composition according to claim 7, further comprising, in addition to the ophthalmic agent, a substance having other pharmacological activity.