WO1999026637A1

WO1999026637A1 - Ophthalmic preparation and ophthalmic composition

Info

Publication number: WO1999026637A1
Application number: PCT/JP1998/005299
Authority: WO
Inventors: Tsuyoshi Miyazaki; Nobuharu Nakada; Ryota Ando; Nobuo Nakabayashi; Kazuhiko Ishihara
Original assignee: Nof Corporation
Priority date: 1997-11-26
Filing date: 1998-11-25
Publication date: 1999-06-03

Abstract

An ophthalmic preparation substantially comprising a polymer having a phosphorylcholine-like group represented by general formula (1) on the side chain, and an ophthalmic composition containing the above preparation. In said formula, R?1, R2 and R3¿ are the same or different and each represents hydrogen or C¿1?-C4 alkyl; and m represents an integer of 2 to 4.

Description

Description Ophthalmic agent and ophthalmic composition

The present invention relates to an ophthalmic agent that can be used for alleviating symptoms such as discomfort when using a dry eye contact lens, and an ophthalmic composition containing the ophthalmic agent.

Background art

In recent years, the number of patients who complain of dryness, heat, tired eyes, and other discomfort due to dry eye due to tear loss and the like, and suffer from corneal damage and corneal disorders are increasing. In addition, allergic hypersensitivity diseases such as hay fever and house dust disease are increasing in ophthalmology and otolaryngology. Therefore, artificial tears composed of boric acid, sodium chloride, potassium chloride, calcium chloride, etc. are widely used to alleviate the symptoms of dry iron allergy. It is used.

It is also intended to alleviate symptoms such as dry eyes when wearing contact lenses, polyvinyl alcohol, sodium hyaluronate and chondroitin sulfate. An ophthalmic drug or artificial tear fluid containing a water-soluble polymer such as sodium has been disclosed (German Patent Specification DE 271 466 76, Japanese Patent Application Laid-Open No. Hei 9-1528). No. 26, Japanese Patent Publication No. Hei 4-181022).

Japanese Patent Application Laid-Open No. Hei 9-152828 describes sodium hyanorenoate. Is disclosed as an ophthalmic drug. Japanese Patent Application Laid-Open No. 4-182022 discloses chondroitin sodium sodium as an ophthalmic drug.

Known natural or synthetic water-soluble substances such as polyvinyl alcohol, sodium hyaluronate and sodium chondroitin sulfate. Ophthalmic drugs and artificial tears using polymers do not have sufficient water retention effect on the cornea.

2 — A polymer obtained by polymerizing methacryloyloxylexylphosphorylcholin (hereinafter abbreviated as MPC) is coated on the surface of an article to form

① It is difficult for proteins to adhere (for example, Journal of Polymers, Vol. 46, Vol. 591, p. 91, 1989),

② Does not induce protein denaturation when contacted with proteins (Biomaterials, Vol. 9, pp. 243, 1991)

③ Excellent antithrombotic properties (K. Ishihara et al., J. Biomed. Meter. Res., 26, 1543 (1992))

It is known that excellent biocompatibility can be imparted. In addition, Japanese Patent Application Laid-Open No. H05-43031 discloses that a polymer comprising 2-methacrylo-leinoleoxy phosphorylcoline is prepared by applying a composition containing the same to the skin. It discloses that a film that protects the stratum corneum is formed to exhibit an excellent moisturizing effect. However, it has not been known to use this polymer as an ophthalmic drug. DISCLOSURE OF THE INVENTION

The purpose of the present invention is to provide the cornea and the like with sufficient water retention and dry eye. Provide ophthalmic preparations and ophthalmic compositions capable of treating or alleviating symptoms such as allergy such as hay fever, or the feeling of feeling at the time of wearing a contact lens or the like, and dry eyes. To do. According to the present invention, the following general formula (1)

OR ¹

-0-P-0- (CH) mN ⁺ -R ² '(1)

O-R ³

(Wherein, R ¹ R ² and R ³ are the same or different groups and are each a hydrogen atom or an alkynole group having 1 to 4 carbon atoms, and m represents an integer of 2 to 4). An ophthalmic agent consisting essentially of a polymer having a styrene-like group in the side chain is provided.

Further, according to the present invention, the polymer has the following general formula (2):

R ⁴ OR ¹

I II to ₂

CH, = CC-0-R ⁵ -0-P-0- (CH ₂ ) mN ⁺ -R ² (2)

II I L

OO—R ³

(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 is a group represented by 1 (BO) n—B— (where B is an alkylene group having 2 to 12 carbon atoms, and n is 0 to 10) Indicates an integer. ) And m represents an integer of 2 to 4. The above ophthalmology, which is a homopolymer of a phosphorylcholine-like group-containing monomer represented by the formula: or a copolymer of the monomer and another monomer copolymerizable with the monomer. An agent is provided.

Further, according to the present invention, the phosphorylcholine-like group-containing monomer is represented by the following formula (3):

CH, O

CH ₂ = CC-OC H ₄ 0-P-0- (CH ₂ ) ₂ — N + — CH ₃ (3)

O O-ichi

The above-mentioned ophthalmic agent, which is 2-methacryloyloxyshetinorephosholcoline, represented by the formula:

Further, according to the present invention, the polymer has the following general formula (4):

HR ⁴

I I

-(C-C-

H C = 0

0 OR ¹

1 II I

R ⁵ — O— P— O— (CH ₂ ) m—N tens— R ²

O-R ³

(Wherein R ¹ R ² and R ³ are the same or different groups and Represents an atom or an alkyl group having 1 to 4 carbon atoms, R ⁴ represents a hydrogen atom or a methyl group, and R ⁵ represents a group represented by one (B B) n—B — In the above, B represents an alkylene group having 2 to 12 carbon atoms, n represents an integer of 0 to 10), and m represents an integer of 2 to 4. The above-mentioned ophthalmic preparation comprising the structural unit (a) represented by the formula (1), wherein the ratio of the structural unit (a) to the total of all the structural units is 10 to 100 mol%.

Further, according to the present invention, the structural unit (a) is represented by the following formula (5):

H

I

"C-one '·' (5)

H CH ₃

And the weight-average molecular weight of the polymer is from 1,000 to 10,0,000,000, and the ophthalmic agent is provided.

Furthermore, according to the present invention, methyl (meta) acrylate, butynole (meta) acrylate, 2-ethylhexyl (meta) acrylate And 2—a hydroxyl group (meta) acrylate and a structural unit (b) obtained by polymerizing a monomer selected from the group consisting of these mixtures. The ophthalmic agent contained in Provided.

Further, according to the present invention, there is provided an ophthalmic composition comprising the ophthalmic agent.

Further, according to the present invention, there is provided the ophthalmic composition, wherein the content of the ophthalmic agent is from 0.000 :! to 40% by weight.

Further, according to the present invention, there is provided the ophthalmic composition having a pH of 3.0 to 9.0 and a physiological saline osmotic pressure ratio of 0.5 to 2.3. .

Further, according to the present invention, there is provided the ophthalmic composition further including a substance having another pharmacological action in addition to the ophthalmic agent. BEST MODE FOR CARRYING OUT THE INVENTION

The ophthalmic agent of the present invention is substantially composed of a polymer having a phosphorylcholine-like group represented by the general formula (1) in the side chain (hereinafter, abbreviated as PC-1 polymer). You.

In the general formula (1), R ′, R ² and R ³ are the same or different 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 a raw material that gives R ¹ R ² and R ³ having 5 or more carbon atoms, and it is difficult to synthesize a material having m of 1 or 5 or more.

As the PC-1 polymer, a monomer having a phosphorylcholine analogous group represented by the general formula (2) (hereinafter, abbreviated as PC-1 monomer) or Or phosphorylcholine such as maleic acid, fumaric acid, or itaconic acid having a phosphorylcholine analogous group represented by the above general formula (1) in the side chain. Homopolymerization of similar group-containing monomer And copolymers of these monomers and other monomers copolymerizable therewith.

Specific examples of the PC-1 monomer include, for example, 2— (meta) ataryloyloxitytil-12,1 (trimethylammonio) ethinolefos, 3— (Meta) acryloyloxy mouth mouth pill 1-2,-(trimethinoleammonio) ethyl phosphate, 41 (meta) atarilo oxybutyl-2 '-(trimethinole butyl) Ammonio) ethylphosphate, 5 — (meta) aryloyloxypentyl 1-2,1 (trimethylammonio) ethylphosphate, 2 — (meta) acryloyl Noreki Shechiru 2, 1 (triethylammonio) ethyl phosphate, 3 — (meta) acryloinorekipropiryl 1, 2 (triethylammonio) etinolejos (Meth) acryloyloxybutyl-2,1 (triethylammonio) ethylphosphate, 5— (meta) acryloyloxypentyl-1,2,1 (Triethylammonio) ethylphosphate, 2 — (meta) acryloyloxyethyl 2 '— (tripropylammonio) ethylinophosphate, 3 — (meta) ak Liloyloxypropyl-1 '(tripropylammonio) ethyl phosphate, 41 (meta) acryloyloxybutyl 1-2,1 (tripropylammonio) ethylpho Space, 5— (meta) acryloyloxypentyl -2 '-(tripropylammonio) ethylphosphate, 21 (meta) acryloyl · The Shechiru 2, one (G Li Buchirua Nmonio) Echiruho scan full E over bets, 3 - (meth) § click Re B A Noreo Xypropinole 2 '— (triptinoleammonio) ethyl phosphate phosphate, 41 (meta) acryloyloxybutyl-2,-(tributylammonio) etinolefos Fate, 5_ (meta) acryloyloxypentyl-2,-(tributylammonio) ethylphosphate, 2— (meta) atalyloyloxetil 1-3 , One (trimethylammonio) propinolephosphate, 2 —

(Meta) acrylonioleki schitinole 4, 1 (trimethinole ammonium) butyl phosphate, 2 _ (meta) acrylonioleki (Methylammonia) propylphosphoate, 2 — (meta) acryloyloxyretinolate 4,-(triethylammonio) butylphosphoate, 2 — (meta) ac Liloyloxy Shechiru 3,-(Tripropylammonio) Propylphosphate, 2 — (Meta) Acryloyloxy Shechiru 4, 1 (Tripropylammonio) Butylphosphate G, 2 —

(Meta) acryloyloxy-3,1- (tributylammonio) propyl phosphate, 2— (meta) acryloyloxyxetino 1-4'-1 (tributylammonio) Butyl phosphate, 3— (meta) acryloyloxypropyl-1 '-(trimethylammonio) propyl phosphate, 3— (meta) acryloyloxypro Pills 1, 4 (trimethylammonio) butyl phosphate, 3 — (meta) acryloyloxypropinol 13-1, 1 (trietinoleammonio) propyl phosphate, 3 — (Meta) acryloyloxypropinolee 4, 1, triethylammonio) butyl phosphate, 3 — (meta) acryloyl Oxypropyl-1,3- (tripropylammonio) propyl phosphate, 3— (meta) acryloyloxypropyl-14,-(tripropylammonio) butyl phosphate 3 '-(tributylammonio) propinole phosphate, 3-(meta) acryloyloxypropyl 1' ,-(Tributylammonio) butyl phosphate, 41 (meta) acryloyloxybutyl-3 '-((trimethylammonio) propyl phosphate, 4— (meta) a Cryloyloxybutyl-4,-(trimethylammonio) butyl phosphate, 4_ (meta) acryloyloxybutyl-1,3,-(triethylammonium) Nio) Propyl phosphate, 41 (meta) acryloyloxybutyl-14,1 (triethylammonio) butyl phosphate, 41 (meta) acryloyl Noreoxybutinole 3, 1 (tripropinoleammonio) propinolephosphate, 4 — (meta) acryloyloxybutyl-4,-(trip mouth pyruanmonio) butyl phosphate, 41 (meta) atalyloyloxybutyl-3 '-(tributylammonio) propionolephosphate, 41 (meta) acryloyloxybutyl 4, 1 (tributylammonio) ) Butyl phosphate and the like. In particular, the compound represented by the above formula (3), 2—methacryloyloxyshethylphosphorylcholin (ie, 2—methacryloyloxyshethyl-2 ′ — (tri) (Ethylammonio) is preferable from the viewpoint of availability.

Further, as the other copolymerizable monomer, specifically, Styrene monomers such as styrene, methinorestyrene, and chlorostyrene; bierester monomers such as vinyl acetate, vinyl propionate, and vinyl bivalate Body: Methinole (meta) acrylate, ethyl (meta) acrylate, n-butyl (meta) acrylate, t-butyl (meta) acrylate , 2 —ethylhexyl (meta) atalylate, dodecyl (meta) atalylate, stearyl (meta) atalylate, 2 — hydroxyxethyl (meta) acrylate (Meta) acrylate esters such as acrylates and benzyl (meta) acrylates; (meta) atalynoleamides, N, N — dimethyl (meta) acrylamide, N, N — dimethyl (Meth) acrylamide monomers such as minopropyl acrylamide and (meth) acrylyl morpholine; ethyl vinylinoleether, n-butyl butyl ether Butyl ether monomers such as: (meth) acrylic acid, (meth) acrylic acid sodium salt, itaconic acid, and itaconic acid sodium Um salt, N-bierpyrrolidone, etc., preferably, methyl (meth) acrylate, n-butyl (meta) acrylate, 2 — Ethynolehexyl (meta) acrylate, 2-hydroxyhexyl (meta) acrylate and the like can be mentioned. These monomers can be used alone or as a mixture. In addition, bifunctional monomers such as glycerene (meta) acrylate and polyoxyethylene (meta) acrylate may cause gelation during polymerization. A small amount may be used together.

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

As the structural unit (a), specifically, for example, a structural unit obtained by polymerizing those listed as specific examples of the PC-1 monomer, preferably, a compound represented by the formula (1) The structural unit represented by 5) can be mentioned. The structural unit (b) specifically includes, for example, a polymer obtained by polymerizing various monomers listed above as other monomers copolymerizable with PC-1. Examples of the structural units include, but are preferably, methyl (meth) acrylate, butyl (meth) acrylate, and 2-ethylhexyl (meth) acrylate. Relate and the structural unit obtained by polymerizing a monomer selected from the group consisting of 2-hydroxyl (meth) acrylate and mixtures thereof may be mentioned. it can.

The content of constituent units that put the ophthalmic preparation of the present invention (a) and the structural unit (b) is a proportion of the structural unit against the total of the structural units (a) and the structural unit (b) _(a) Te, and preferred rather than the 1 0-1 0 0 molar%, rather than the preferred Ri good is Ru can and child to 3 0-9 5 mol ^_0/0. By setting the content of the structural unit (a) to at least 10 mol%, an ophthalmic agent having high water retention derived from a phosphorylcholine-like group, high antifouling property against proteins, and the like can be obtained. It can be.

The molecular weight of the polymer constituting the ophthalmic preparation of the present invention is preferably as a weight average molecular weight, more preferably from 1,000 to 10,000, 0000, 0000, and still more preferably. The force S is desirably 5, 000 to 2, 0000, 0000. By setting the weight average molecular weight to 1,000 or more, Expected functions such as water retention and antifouling properties can be exhibited, and the viscosity of the product can be reduced by setting the weight average molecular weight to 100, 000, or less. It can be within the range that is easy to manufacture.

The ophthalmic preparation of the present invention comprises a monomer component such as the above-mentioned monomer having a phosphorylcholine analogous group and another monomer copolymerizable therewith, such as a PC_1 monomer. In the presence of a radical polymerization initiator, under degassing conditions, or in the presence of an inert gas such as nitrogen gas, argon gas, helium gas, or carbon dioxide gas or in an atmosphere. The compound can be produced by polymerization in a solvent such as methanol or ethanol by heating or irradiation with light.

The polymerization initiator is not particularly limited, and a usual radical polymerization initiator and the like can be used. Specifically, for example, benzoic peroxide ^^, Diisopropinole noreoxy sizzle carbonate, t-butyl hexolenoxie 2 — ethynol hexanoate, t butyl phenol phenol phenolate, t — butyl phenol Organic peroxides such as norexigisobutyrate; 2-cyano 2-propylazoformamide, 1,1-azobis (cyclohexane 11 ), 2,2, -azobis (2-amidinopropane) dihydrochloride, 2,2, -azobis (2-methylbutyronitrile), 2, 2,-azo Bisisobutyronitrile, 2, 2'-azobis (2,4-dimethylsilyl relonitrile), 2,2,1 azobis (4—methoxy 1, 2,4-dimethylsilyl rilonitrile), 4,4,4 -Azobis (4-cyanovaleric acid), 2,2, -azobis dimethyl isobutyrate, 2,2, -azobis (2-(5-methino 1-2-imidazo) 1,2'-yl) propane) dihydrochloride, 2,2'-azobis (21- (2-imidazoline_2-yl) propane) dihydrochloride, 2, 2,1 azobis (2— (2—imidazoline 1 2—yl) propane), 2,2,2 azobis (2—methinolay N— (1,1—bis 2,3,2, -azobis (2—methyl N— (2—hydroxymethyl) propion amide) , 2,2, -azobis butyrilamidoni hydrate, 2,2'-azobis (2 -hydroxymethyl) propionitol, 2,2,1azo Examples include azo compounds such as bis (2,4,4-trimethylpentan); and inorganic peroxides such as ammonium persulfate.

In carrying out the above-mentioned polymerization, the charge ratio of the monomer having a similar group to a phosphorinolecholine such as a PC-1 monomer and the other monomer copolymerizable therewith are preferably in the form of a monomer ratio. It can be 10:90 to: 100: 0, more preferably 30:70 to 95: 5. Further, the charge ratio of the polymerization initiator at the time of performing the polymerization is preferably 0.00000 to 10% by weight, more preferably 0.001 to 10% by weight, based on the total amount of the monomer components. Preferably, it can be 0.0001 to 5% by weight. The polymerization temperature is from _10 to 150 ° (preferably from 0 to 100 ° C. The polymerization time is from 30 minutes to 100 hours, preferably from 10 minutes to 100 hours. It can be 1 to 24 hours.

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

The content ratio of the ophthalmic agent in the ophthalmic composition of the present invention is 0.0001 to 40% by weight, preferably 0.001 to 10% by weight, More preferably, it is 0.01 to 5% by weight. By setting the content to 0.0001 or more, expected effects such as water retention can be exhibited, and by setting the content to 40% by weight or less, the viscosity of the product can be reduced. However, it can be set to a low value that does not give a physical stimulus to the cornea.

The pH and the osmotic pressure of the ophthalmic composition of the present invention are not particularly limited, but in the case of a liquid preparation as an ophthalmic solution, the pH is from 3.0 to 9.0. It is particularly preferable that the osmotic pressure is 0.5 to 2.3 as an osmotic pressure ratio to physiological saline. By setting the pH and the osmotic pressure within these ranges, an ophthalmic composition that does not irritate the eyes when applied can be preferably obtained.

The dosage form of the ophthalmic composition of the present invention is not particularly limited, and examples thereof include liquid dosage forms dissolved, suspended, and emulsified in a medium such as water, and ointment dosage forms.

The ophthalmic composition of the present invention may further comprise, as necessary, an osmotic pressure adjusting agent, a pH adjusting agent, a viscosity adjusting agent, a stabilizing agent, a preservative, or other components in addition to the ophthalmic agent, which is an essential component. It can contain substances that have pharmacological effects.

Examples of the osmotic pressure adjusting agent or pH adjusting agent include sodium chloride, potassium chloride, calcium chloride, sodium hydrogencarbonate, sodium carbonate, magnesium sulfate, and the like. Sodium hydrogen phosphate, sodium dihydrogen phosphate, dicalcium hydrogen phosphate, boric acid, borax, sodium hydroxide, hydrochloric acid, grease Can be used. Examples of the viscosity modifier include polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), methylcellulose, canoleboxyl, phenolic alcohol, and hydrazine. Loki sip mouth Pinore methinoresorenose, polyethylene glycol, ethyl alcohol and random alcohol or propylene glycol Water-soluble polymers such as rock copolymers, sodium hyanolenoate, sodium chondroitin sulfate, and the like. Examples of the stabilizer include citric acid, EDTA-2-sodium salt, sodium sulfite, and sodium hydrogen sulfite.

Examples of the preservative include, but are not particularly limited to, parahydroxybenzoic acid esters such as methylparaben and ethylparaben, and invertible stones such as benzalkonium chloride and chlorhexidine dalconate. Specimens, chlorobutanol, phenol, ethyl alcohol, etc., sodium hydroxide, sodium dehydroacetate, sorbic acid, sorbic acid A preferable example is a nursery. The other pharmacologically active substance is not particularly limited as long as it is a component that exhibits an effective action in the treatment of ophthalmic diseases, for example, 2. Standards for approval of manufacturing (import) of general drugs 2. Criteria (1) Types of active ingredients, drugs listed in Annex 1 or Pharmaceuticals Handbook (Pharmaceutical Timeline) Ophthalmology Drugs listed in Drugs (p. 324) can be listed. To be specific, for example, there are, for example, glucuritic acid dicarbamate, epsilon aminocapranate inlantoin, and berberine chloride. , Berberine sulfate, sodium azulene sulfonate, zinc sulfate, zinc lactate, lysochloride Anti-inflammatory agents such as teams; anti-histamines such as diphenhydramine hydrochloride and chlorpheniramine maleate; flavinade N, N-nucleotide natrimodium, cyanocovalamine, retinol acetate, retinol panolemitinitate, pyridoxine hydrochloride Cornea such as ^non -pentanol, calcium pantothenate, sodium nontothenate, sodium chondroitin sulfate Therapeutic agents: epinephrine, epinephrine hydrochloride, ephedrine hydrochloride, tetrahydrozolin hydrochloride, naphazolin hydrochloride, nafa nitrate Vasoconstrictors such as zoline, phenylephrine hydrochloride, d, l-methyl hydrochloride monohydrochloride ♦ Decongestant; Sulfame Anti-smoke protection, such as x-ray, x-ray, x-ray, x-ray, x-ray, x-ray, x-ray, x-ray, x-ray, etc. Bacterial agents; refreshing agents such as menthol, bonore neo-ole, camphor, and coconut oil; pilocarpine hydrochloride, pilocarinolepine, sari Physiotinamine, tinolenate, etinolefoline benzoate, benzoyl benzoate, phenol benzoate, iodicothiophyte, dimethyl bromide. Miotic agents, such as gumin and quinolone, and green tea, such as timolol maleate, fenolol hydrochloride, and carteol hydrochloride. Disorders: Ocular hypertension treatment drugs; pentorate for hydrochloride, pin for hydrobromide, and atropine sulfate , Mydriatics such as phenylephrine hydrochloride, tropicamide, epipinephrine, hydrogen tartrate and epinefin, etc.; Cataract remedies such as gin, gnoretathione, pyrenoxine, sodium pentacecilsulfonate; perokinase, _α -ki Enzyme preparations such as motripsin; antiseptic astringents such as silver nitrate; sulfa agents such as sulfisoxazonole; kufenramenikonore, Eris Romanisin, lactobionic acid Mycin, Hydroxoxytratracycline, Canamycin Sulfate, Becanamicin Sulfate, Gentamycin Sulfate, Genbramycin Sulfate Such as mysin, shiso-mycin sulfate, micro-mycin sulfate, dibekacin sulfate, snorvenicillin natrime, pimaricin, etc. Antibiotics: Hydrochlorizon acetate, prednisolone acetate, dexamethasone phosphinate phosphate, dexamethasone sodium, toxin Adrenal cortical hormones such as riamsinolone acetonide, phenolic methrone, etc .; idoxperidine, aciclovinole etc. Antiviral agent; Others Zinc sulfate, water-soluble azulene, lysozyme chloride chromoglyme sodium, hydrochloride Shibu-pro-force, polyolefin polymethyl glycine, polyvinyl alcohol, iodine, indonemethine, heat Sodium sodium luonate, ofloxacin, tranilast, etorahydrazon hydrochloride, neostigmine methyl sulfate, a Mineoethylsnolephonic acid, betamethasone phosphinate, and mixtures thereof can be used.

For long-term storage of the ophthalmic composition of the present invention, a disposable type having a capacity of 0.5 to 3 ml, which is filled in an aseptic condition and sealed in a sealed state without adding a preservative. It is conceivable that a preservative is added to the ophthalmic composition, and a predetermined container is filled under aseptic conditions.

In addition, when the ophthalmic composition of the present invention is prepared as an ointment, it may contain an ointment base in addition to the above-mentioned various components. Examples of the ointment base include, but are not particularly limited to, petrolatum, liquid paraffin, polyethylene, or a mixture thereof. Oil-based base; Emulsified base obtained by emulsifying an oil phase and an aqueous phase with a surfactant or the like; Hydroxypropyl propylmethyl cellulose, Canoleboxime cellulose Cellulose, Polyethylene Water-soluble bases such as lenglycol are preferred.

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

When the ophthalmic composition of the present invention is used as eye drops or artificial tears, it can be used by instilling it directly into the eye. In this case, it is preferable to use the naked eye, but it is hard contact lenses, oxygen permeable hard contact lenses, and non-hydrous soft contacts. The eye may be instilled while wearing a lens or a hydrated soft contact lens.

When the ophthalmic composition of the present invention is administered by instillation, the number of administrations and the amount of administration are not particularly limited, but, for example, as in the case of ordinary eye drops, 1 to 12 times a day and 1 to 1 time a day. 6 drops can be applied.

When the ophthalmic composition of the present invention is used as an eyewash, the ophthalmic composition of the present invention is transferred to an appropriately sized force, and the eyelids are repeatedly opened and closed. It can be used by returning it. In addition, eyes can be washed by directly pouring the ophthalmic composition of the present invention from a container into the eyes.

The ophthalmic composition of the present invention improves the water retentivity of the surface of the cornea, conjunctiva, etc., so that it can be used for allergic diseases such as dry eye, hay fever, and contact lenses. It can be used to treat or alleviate symptoms such as dry eyes. In addition, It can also be used for the purpose of preventing protein stains and the like from adhering to the contact lens when using a contact lens.

Since the ophthalmic agent of the present invention is made of a polymer having a specific side chain, it provides sufficient water retention to the cornea, and is suitable for dry eye, pollen allergy, etc., or contact lens. It is useful as an ophthalmological agent that can treat or alleviate symptoms such as a feeling of sensation of the eyes, dry eyes, etc. when wearing eyewear.

Further, since the ophthalmic composition of the present invention contains the above-mentioned specific ophthalmic agent, it imparts sufficient water retention to the cornea, and is used for allergic diseases such as dry eye and hay fever, or when wearing a contact lens. It is useful as an ophthalmic composition capable of treating or alleviating symptoms such as dry feeling and dry feeling in the eyes.

Example

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

Synthesis example 1

5 MPC as a monomer. 0 g (1 6. 9 mmol), ethanoate Lumpur ₅ 0 m 1 as a solvent, and a polymerization initiator § zone bi sweep rate Su Wu Ciro two preparative Li Le ( Using 25 mg (0.5 parts by weight with respect to 100 parts by weight of all monomers), a polymerization reaction was carried out at 55 ° C for 6 hours under a nitrogen stream using 25 mg (hereinafter abbreviated as AIBN). After completion of the reaction, the precipitate was precipitated in 200 ml of acetone, dissolved in ethanol, and reprecipitated with 200 ml of acetone. After drying under reduced pressure for 24 hours, a solid white polymer was obtained. The obtained polymer was water-soluble. Table 1 shows the measurement results of the yield and the molecular weight by GPC (developing solvent; water, standard sample; polyethylene glycol).

Synthesis Example 2 7

Same as in Synthesis Example 1 except that the monomers and AIBN were used as the monomer and polymerization initiator in the types and amounts shown in Table 1, and the reaction was carried out for the reaction time and temperature shown in Table 1. The polymer was obtained and the molecular weight was measured. Table 1 shows the results. In addition, the proportion of structural units based on MPC in the obtained polymer was determined by quantifying the amount of phosphorus contained in the polymer. Table 1 shows the results.

The abbreviations used in the table are as follows

E H M A; 2 — ethyl methacrylate

B H A; n-butyl methacrylate

MMA; methyl methacrylate HEMA; 2—Hydroxy Shechilmeta Crylate

Example 1

1. Og of the MPC polymer synthesized and purified in Synthesis Example 1 was dissolved in 99 g of purified water to form an aqueous solution. This was sterilized with a 0.2 // m membrane filter to obtain an ophthalmic solution.

Examples 2 to 7

Example 1 was repeated except that 1.0 g of the MPC polymer synthesized and purified in Synthesis Example 1 and 99 g of purified water were replaced with the types and amounts of the polymer and purified water shown in Table 2. The same procedure as described above was performed to obtain eye drops.

Table 2

In the table, Synthesis 1 to Synthesis 7 indicate that the polymers synthesized and purified in Synthesis Examples 1 to 7, respectively, were used.

Examples 8 to 12

Example 8 used the polymer obtained in Synthesis Example 2, Example 9 used the polymer obtained in Synthesis Example 7, Example 10 used the polymer obtained in Synthesis Examples 1 and 3, and Example 11 used the polymer obtained in Synthesis Examples 1 and 3. The polymers obtained in Synthetic Examples 2 and 4 and the polymers obtained in Synthetic Examples 2 and 5 in Example 12 were used in the amounts shown in Table 3, respectively, and further, sodium chloride and potassium chloride were used. And calcium chloride were used in the amounts shown in Table 3 and dissolved in purified water to prepare eye drops whose pH and osmotic pressure ratio were adjusted. Table 3 shows the results. Note that p The measurement of H is performed in accordance with JISZ8802 (19894), and the osmotic pressure ratio is determined by an ozmometer (Fiske Mode 1 — 110 The measurement was carried out using a nomometer (Ozmometer). Table 3

Example 13

200 μg of the ophthalmic solution prepared in Example 5 was applied to a commercially available acrylic plate (size: 40 mm long × 10 mm wide × lmm thick) by spraying, and immediately physiological saline was applied. Washed with water 10 Om1. Using a dynamic contact angle meter (Oriental Industrial Co., Ltd .; DCA-10), this was repeatedly immersed in 20 Om1 distilled water 50 times and pulled up. Returned. As a result of measuring the advancing contact angle during this immersion, the average value of 50 measurements was 23.5 ± 1.8 degrees.

From this, it was confirmed that the ophthalmic composition of the present invention can impart water retention to the surface of an acryl plate. In addition, the water retention provided on the acrylic plate surface was soaked 50 times. It was confirmed that it was stable even after repeated lifting operations. These experimental results indicate that the ophthalmic composition of the present invention can impart water retention to each tissue of the eye when administered by eye drops or the like.

Comparative Example 1

The same operation as in Example 13 was carried out except that the eye drops were not applied, and the advancing contact angle of the acrylic plate not treated with the eye drops was measured. As a result, 89.0 ± 2.2 was obtained. It was a degree.

Comparative Example 2

The procedure was performed 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. An ophthalmic solution was obtained in the same manner as in Examples 5 and 13, and the advancing contact angle was measured using this ophthalmic solution. As a result, it was 88.2 ± 3.1 degrees, indicating that the water retention was low. I understood.

Comparative Example 3

Same as in Examples 5 and 13 except that 0.1 g of chondroitin sulfate (manufactured by Wako Pure Chemical Industries, Ltd.) was used instead of the polymer obtained in Synthesis Example 5. As a result of measuring the advancing contact angle with this eye drop, it was found to be 88.6 ± 3.4 degrees, indicating low water retention.

Comparative Example 4

In the same manner as in Examples 5 and 13, except that 0.1 g of polypyrrolopyridone (manufactured by Wako Pure Chemical Industries, Ltd., trade name: K25) was used instead of the polymer obtained in Synthesis Example 5. Operate to obtain an eye drop, and use this eye drop As a result of measuring the advancing contact angle, it was found to be 88.1 ± 1.2 degrees, indicating low water retention.

From the results of Example 13 and Comparative Examples 1 to 4, the ophthalmic composition of the present invention was found to contain sodium hyaluronate, sodium chondroitin sulfate or polyvinylpyrrolidone. It can be seen that higher water retention can be imparted when these are applied as compared to conventional ophthalmic drugs containing don.

Example 14

In five naked human subjects, one or two drops of the eye drops prepared in Example 8 or 9 were instilled into the right eye, and artificial tears (trade name, “Santen Soft Santana”) were instilled into the left eye. A), one or two drops of Santen Pharmaceutical Co., Ltd.). After 1 minute, stain the tears in the right eye with 1% Fluorescein Trium, blink several times, and keep the eyelids open, slit lamps and cobalt filters. Using a microscope, the time to liquid layer disruption (BUT) until the dark portion appeared in the stained tear film was measured. After each measurement, the right eye was washed with artificial tears for the next measurement. The measurement was performed three times and the average was calculated. Table 4 shows the results. Comparative Example 5

As the eye drops, artificial tears (trade name, “Santen Soft Santania”, manufactured by Santen Pharmaceutical Co., Ltd.) were used instead of the eye drops prepared in Examples 8 or 9. By operating in the same manner as in Example 14, BUT was measured for the same subject. Table 4 shows the results.

Comparative Example 6

As an eye drop, instead of the eye drop prepared in Example 8 or 9, The same operation was performed as in Example 14 except that "Santen Hia Lein 0.1" (trade name, containing 0.1% by weight of sodium hyaluronate) was used. The BUT was measured for. Table 4 shows the results. Table 4

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

In addition, in Example 14 and Comparative Examples 5 and 6, none of the subjects showed any reaction that was considered to be a side effect such as hyperemia.

Example 15 and Comparative Examples 7 and 8

Except for using a human wearing a hard contact lens (trade name “Seiko Hard EX”, manufactured by Seiko Contact Lenses) as a subject, BUT was measured in Example 15 in the same manner as in Example 14, in Comparative Example 7 in the same manner as in Comparative Example 5, and in Comparative Example 8 in the same manner as in Comparative Example 6. The results are shown in Table 5. Note that none of the subjects showed any reaction that was considered to be a side effect as compared to when wearing contact lenses before instillation. Table 5

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

From the results of Examples 14 to 15 and Comparative Examples 5 to 8, the ophthalmic composition of the present invention showed that both the naked eye and the contact lens wearing eye had artificial tears and hyaluronan. It can be seen that the effect of extending BUT is higher than that of sodium phosphate. Therefore, the ophthalmic composition of the present invention has a higher effect of stabilizing the tear film as compared with artificial tears and sodium hyaluronate, and thus keeps water in the cornea and the like. The results show that it is highly effective and is effective in alleviating and treating symptoms such as dry eyes and dry eyes.

Example 16

The MPC polymer synthesized and purified in Synthesis Example 1 2.0 g, etolahydrazoline hydrochloride 0.02 g, chloronoferene maleate 0.01 g, 0.05 g of neostigmine thiosulfate, 1.0 g of ipsilon (ε-) aminocaproic acid, 0.05 g of benzalkonium chloride, chloronodalonic acid Take 0.05 g of hexidine and 0.5 g of boric acid, add purified water to make a total of 100 g, and divide this with a 0.2 μπι membrane finolator. Bacterial treatment and eye drops It was prepared.

Example 17 to 4 8

An eye drop was obtained in the same manner as in Example 16 except that the kinds and amounts of the polymers, drug components and other components shown in Tables 6 to 10 were used.

Table 6

Example of failure

16 17 18 19 20 21 22 Polymer Synthesis example Synthesis example Synthesis example Synthesis example Synthesis example Synthesis example Synthesis example

1 1 1 1 2 2 S

9. ΠU υ.ο υ. U.U υ.ο

Etrahydrazone 0.02 0.05

Drug Naphazoline 0.002 0.003

Chlorpheniramine maleate 0.01 0.03 0.03 0.01 0.2 agent Allantoin 0.1 0.1 Potassium glycyrrhizinate 0.1 0.25 0.1 0.05 Neostigmine methylate 0.005 0.002 0.02 ε-Aminocapro ^ 1.0 1.0

Min ^ pyridoxine 0.1 0.1 0.1 Cyancolamin 0.01 etc.Aminoethyl sulfo ^ 0.5 0.1 0.5 Benzalkonium chloride 0.005 0.005 0.005 0.05

(g) Chlorobutane mono 0.2 0.2

0.03 0.03

Kunoreconic acid mouth mouth hexidine 0.005

Sodium chloride 0.84 0.9 Salt (b * Luc 0.02

Salt jb¾rium 0.02

Boric acid 0.5 0.5 0.5 0.3 0.3

EDTA .2Na 0.1

Table 7

Table 8

Table 9

Example

37 38 39 40 41 42 43 Polymer X Synthesis Example 1 Synthesis Example 1 Synthesis Example 2 Synthesis Example 2 Synthesis Example 2 Synthesis Example 2 Quantity (g) X 0.5 X0.5 X0.5 X0.5 X 0.5 X 0.5 X0.5 Synthesis example 4

X 0.2

Inverted component y acid salt Indomethazulene lysochloride chromog chromog pirenoki tamethazometron tasin team liquid needle sodium

4 (g) 0.01 0.1 0.5 0.02 0.5 2 0.05 0

Example

44 45 46 47 48 Polymer X Synthetic Example 2 Synthetic Example 2 Synthetic Example 2 Synthetic Example 2 Synthetic Example 2 Amount (g) X0.5 X 0.5 X0.5 X0.5 X 0.5 Difficult component Epinev カルマレインコリママTheolo Moro On

Nore

Amount (g) 0.25 2 0.25 0.015 2

Claims

The scope of the claims

The following general formula (1)

OR ¹

-0-P-0- (CH ₂ ) mN ⁺ -R ² (1)

CD "R ³

(Wherein, R ¹ R and are the same or different groups and are each a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and m represents an integer of 2 to 4). An ophthalmic agent substantially consisting of a polymer having a similar side chain of a lycline.

2. The polymer has 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; ⁵ represents a group represented by 1 (BO) n—B— (where B represents an alkylene group having 2 to 12 carbon atoms, and n represents an integer of 0 to 10). , M represents an integer of 2 to 4.) The ophthalmology according to claim 1, wherein the polymer is a homopolymer of a phosphorylcholine-like group-containing monomer, or a copolymer of the monomer and another monomer copolymerizable with the monomer. Agent.

3. The monomer having a phosphorylcholine-like group is represented by the following formula (3):

CH ₃ 〇 CH

I II I

CH ₂ = C— C-OC ₂ H ₄ 0— P— O— (CH ₂ ) ₂ -N ⁺ -CH ₃ (3)

II I I

o o— CH,

3. The ophthalmic preparation according to claim 2, which is 2-metacryloyloxy-shethylphosphorylcholine represented by:

4. The polymer has the following general formula (4)

HR ⁴

I I

~ fc—cto ... (4)

H C = 0

OOR ¹

R ⁵ -0-P-0- (CH ₂ ) mN ⁺ -R ²

O- R ³

(Wherein, R ¹ R ² and R ³ are the same or different and represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R ⁴ represents a hydrogen atom or a methyl group. , R ⁵ is a group represented by one (BO) n—B— Here, B represents an alkylene group having 2 to 12 carbon atoms, and n represents an integer of 0 to 10. ) And m represents an integer of 2 to 4. The ophthalmic preparation according to claim 1, comprising a structural unit (a) represented by the formula: wherein the ratio of the structural unit (a) to the total of all the structural units is 10 to 100 mol%.

5. The structural unit (a) is represented by the following formula (5)

H CH ₃

One C to '(5)

H C = 0

OO CH ₃

C ₂ H ₄ — O— P— O— (CH ₂ ) ₂ -N ⁺ -CH ₃

Cr CH ₃

The ophthalmic preparation according to claim 4, which is a constitutional unit represented by the formula: and a weight average molecular weight of the polymer is from 1,000 to 10,000,000,000.

6. Methyl (meta) acrylate, butyl (meta) acrylate, 2-ethylhexyl (meta) acrylate and 2—hydroxyxethyl (meta) The ophthalmic preparation according to claim 4, further comprising a structural unit () obtained by polymerizing a monomer selected from the group consisting of acrylates and mixtures 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. The ophthalmic composition according to claim 7, wherein the pH is 3.0 to 9.0 and the ratio of physiological saline to osmotic pressure is 0.5 to 2.3.

10. The ophthalmic composition according to claim 7, further comprising a substance having another pharmacological action in addition to the ophthalmic agent.